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Dispensing With Equipoise
SYMPOSIUM ARTICLE
Dispensing With Equipoise Franklin G. Miller, PhD
Abstract: Equipoise is widely endorsed as a necessary requirement for ethical design and conduct of randomized controlled trials. Nevertheless, I argue in this article that the equipoise principle suffers from fundamental defects. In particular, equipoise provides flawed ethical guidance for placebo-controlled trials and for decisions to terminate trials early based on interim data relating to benefit. The problems with equipoise are traced to a “therapeutic orientation to clinical trials,” which conflates the ethics of clinical research with the ethics of medical care. Because of this mistaken therapeutic orientation, equipoise fails to adequately account for the central purpose of randomized trials in providing evidence sufficient to guide health policy decisions relating to licensing new treatments and insurance coverage. I conclude that it is time to dispense with equipoise. The principles of research ethics are sufficient to provide adequate guidance to protect subjects and to promote socially valuable research without any appeal to equipoise. Key Indexing Terms: Clinical equipoise; Informed consent; Clinical research; Research ethics. [Am J Med Sci 2011;342(4):276–281.]
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quipoise has long been regarded as a fundamental norm of research ethics, governing the design and conduct of randomized clinical trials (RCTs). Viewed from the perspective of medical ethics, it has strong intuitive appeal. RCTs evaluate treatments for patients with various medical conditions and accordingly enroll only patients who are diagnosed by physicians as in need of treatment. Because they recruit patients in need of treatment and they are conducted by physicians, it seems natural to assume that RCTs can be ethical only if the medical care of enrolled patients is not knowingly compromised by trial participation. Some commentators hold that RCTs necessarily compromise medical care.1 The very fact of randomization violates the duty of physicians to select medical treatment based on their professional judgment of what is best for particular patients. On this view, randomization fundamentally conflicts with individualized care that physicians owe to their patients. Most ethicists, however, have rejected this blanket dismissal of RCTs as contrary to medical ethics. Instead, they believe that there is a solution to the “RCT dilemma” posed by the potential conflict between medical care and enrollment in RCTs.2 Patient-centered care and clinical trial participation are ethically compatible as long as physicians find themselves in a state of equipoise regarding the treatments under investigation in an RCT.3 More precisely, ethical trial participation requires equipoise between the treatment arms (including a placebo From the Department of Bioethics, National Institutes of Health, Bethesda, Maryland. The opinions expressed are those of the author and do not reflect the position or policy of the National Institutes of Health, the Public Health Service, or the Department of Health and Human Services. This paper was part of the 17th Annual Thomas A. Pitts Memorial Lectureship held at the Medical University of South Carolina, October 29 –30, 2010. Correspondence: Franklin G. Miller, PhD, Department of Bioethics, Clinical Center, National Institutes of Health, Building 10, Room 1C118, Bethesda, MD 20892-1156 (E-mail: [email protected]).
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intervention) and between these treatments and the established medical standard of care. Various formulations of equipoise have been propounded. All of them incorporate the idea of uncertainty about the relative therapeutic value of treatment (and comparator) interventions under investigation in a clinical trial. When equipoise obtains, no patient is knowingly randomized to treatment that is inferior to the standard of care. In other words, RCTs can be conducted without compromising medical care of trial participants as long as physicians remain in a state of equipoise. Despite its intuitive appeal, equipoise is fundamentally flawed. It rests on a mistaken “therapeutic orientation to clinical trials,” which distorts the ethics of clinical research.4 Strictly applied, equipoise rules out socially valuable placebo-controlled trials for a wide range of symptomatic treatments. These trials often do not pose undue risks of harm to patient-subjects who consent to time-limited withholding of standard (proven effective) treatment.5 By virtue of characterizing these trials as unethical, the equipoise doctrine encourages methodologically deficient active-controlled equivalence (or noninferiority) trials for symptomatic treatments. In addition, adherence to equipoise promotes premature stopping of RCTs based on interim evidence of benefit, thus compromising the rigorous evaluation of experimental or inadequately tested treatments and the comparative effectiveness of beneficial treatments. More broadly, the clinically oriented focus of the equipoise doctrine makes it deficient in evaluating clinical research for the sake of guiding health policy. Documenting these normative and practical problems with the equipoise doctrine leads, I shall argue, to an inescapable conclusion: it is time to dispense with equipoise. Dispensing with equipoise does not leave us in an ethical vacuum. The resources of research ethics are fully adequate to guide the design and conduct of clinical trials without appeal to equipoise. Moreover, dispensing with equipoise eliminates normative incoherence within research ethics relating to risk-benefit assessment of potentially therapeutic and nontherapeutic interventions and between the equipoise-dominated understanding of research ethics and the practice of research ethics committees in commonly approving RCTs that are inconsistent with equipoise.
CLINICAL EQUIPOISE Within bioethics, the canonical conception of equipoise is known as “clinical equipoise.” This conception was initially developed by Benjamin Freedman3 in a 1987 article in the New England Journal of Medicine, which is one of the most frequently cited articles in the bioethics literature. At the beginning of the article, Freedman asserts that “Equipoise is an ethically necessary condition in all cases of clinical research.” A charitable interpretation of Freedman’s intent will not take this pronouncement literally. Clearly, there are many areas of clinical research for which equipoise has no possible normative bearing. These include phase 1 studies of drugs in healthy volunteers and studies of the pathophysiology of diverse medical conditions that expose patient-subjects to experimental
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interventions without evaluating treatments. Anderson and Kimmelman6 have recently argued persuasively that ethically justifiable phase 1 trials enrolling patient-subjects cannot be understood as compatible with equipoise. For the sake of this critical analysis, I will focus primarily on randomized trials, where equipoise most naturally pertains. Freedman’s distinctive contribution to the articulation and justification of equipoise was to lodge equipoise in the community of physicians. RCTs would be too difficult to commence and too readily aborted if there were an ethical requirement of individual equipoise among physicians associated with clinical trials. Because medicine is a professional activity, which operates in accordance with a communally endorsed standard of care, the equipoise required for ethical trial design and conduct should be defined in light of the views characterizing the expert medical community. According to Freedman, equipoise exists when “there is no consensus within the expert clinical community about the comparative merits of the alternatives to be tested” (including the standard of care).3 In a later article, written with 2 colleagues, Freedman further elaborated the concept of clinical equipoise. Clinical equipoise is presented as both a normative and a scientific principle. “As a normative matter, it defines ethical trial design as prohibiting any compromise of a patient’s right to medical treatment by enrolling in a study. The same concern is often stated scientifically when we assert that a study must start with an honest null hypothesis, genuine medical uncertainty concerning the relative merits of the various treatment arms included in the trial’s design.”7 An important implication of clinical equipoise is that it prohibits placebo-controlled trials in the face of proven effective treatments: it “foreclose[s] the use of placebos in the face of established treatment, because enrolling in a trial would imply that a proportion of enrollees will receive medical attention considered inferior by the expert community.”7 In addition to guiding the design of RCTs, equipoise governs decisions to terminate trials early when interim data indicate that equipoise has been disturbed.
CONCEPTUAL PROBLEMS WITH EQUIPOISE Although equipoise is widely endorsed and frequently invoked, there is a notable lack of clarity in the application of the principle. What is the expert community in terms of which equipoise should be assessed? How do we know whether the relevant community or communities are in equipoise? More specifically, what proportion of expert clinicians must believe that a treatment has therapeutic merit to justify conducting a clinical trial on the basis of equipoise? How should it be determined that equipoise has been disturbed on the basis of interim RCT results? It is remarkable that proponents of equipoise have devoted so little attention to answering these questions. An additional conceptual problem with equipoise derives from the stated position of Freedman and colleagues, quoted above, that the scientific formulation of the “honest null hypothesis” is equivalent to the normative principle that patients should not be randomized to treatment known to be inferior. The honest null hypothesis reflects the need for uncertainty about the answer to a clinically relevant scientific question as a precondition for conducting an RCT. Without the requisite uncertainty, there is no scientific or social value in conducting the study, and any net risks to subjects cannot be justified. It does not follow that when an honest null hypothesis obtains, no patient-subject will be randomized to treatment known to be inferior to the established (proven effective) standard of care. For example, an RCT that compares an © 2011 Lippincott Williams & Wilkins
experimental treatment for migraine headaches against a placebo control will have an honest null hypothesis when there is no rigorous experimental evidence that this treatment is superior to placebo. However, given standard, proven effective treatments for migraine, patients receiving placebo will receive treatment likely in the aggregate to be inferior to the medical standard of care. The normative formulation of clinical equipoise prohibits placebo controls in this situation, even though they may be consistent with an honest null hypothesis. Apart from this conceptual confusion, equating the normative and scientific formulations is problematic because it makes clinical equipoise appear unassailable, as no one will reject the need for uncertainty about the answer to a research question as a scientific and ethical prerequisite to conducting a clinical trial. I shall argue, however, that the normative formulation, although intuitively appealing, is erroneous. In sum, it is a conceptual mistake to conflate the no-inferior-treatment principle with the honest null hypothesis.
CONFLATING THE ETHICS OF CLINICAL TRIALS WITH THE ETHICS OF MEDICAL CARE The underlying normative thrust of all forms of equipoise is to harmonize the ethics of RCTs with the traditional ethics of medical care. Physicians have a therapeutic obligation to offer competent medical care to patients diagnosed as in need of treatment, and medical care should not be compromised by trial participation. The existence and maintenance of equipoise makes it possible to conduct RCTs while preserving the basic normative commitment underlying the physician-patient relationship. Although it would be desirable if all socially valuable clinical research involving patient-subjects could be undertaken within the ethical orbit of medical care, this is impossible. In particular, RCTs differ fundamentally from medical care in normatively salient respects.8 RCTs are scientific experiments designed to produce rigorous generalizable knowledge about treatment effectiveness and safety by means of studying groups of patients under controlled protocols. This scientific orientation of RCTs contrasts fundamentally with the activity of medical therapy aimed at providing personal care for particular patients. To be sure, medical therapy should be evidence based, and thus physicians need to apply general knowledge to the situation of individual patients. But it is an activity devoted to patient-centered care. The fundamentally different purposes of medical care and RCTs call for different ethical standards of risk-benefit assessment. In medical care, with the notable exception of live organ and tissue donation, risks of diagnostic and therapeutic interventions are justified by compensating medical benefits to the patients who are exposed to those risks. In other words, the proportionality of risks and benefits is patient centered. In contrast, most clinical research involves 1 or more nontherapeutic procedures, which carry some risks of discomfort or harm to research subjects. These are used to test study hypotheses. In RCTs, such nontherapeutic procedures include, for example, extra blood draws, lumbar punctures, biopsies, or imaging procedures involving radiation, which are administered to confirm diagnoses and/or measure study outcomes. Risks of these procedures cannot be justified by medical benefits to patient-subjects. They are justified by the anticipated social value of the knowledge to be gained from the research. Of course, proponents of equipoise recognize that clinical research in general, and RCTs in particular, use nontherapeutic procedures. However, they have failed to provide any
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rationale for why these research procedures are permitted, but it is not permissible to expose patient-subjects knowingly to any net risks from therapeutic interventions or from the omission of therapeutic interventions associated with the use of placebo controls.9 (Net risks consist of risks to subjects which are not compensated by medical benefits to them.) If, within limits, the value of the knowledge to be gained from the research can justify net risks from nontherapeutic procedures, it should also be able to justify net risks associated with therapeutic procedures and placebo controls. Indeed, it is particularly incoherent to argue that placebo controls should not expose subjects to any net risks of harm by withholding proven effective treatment. Placebos in the context of clinical trials are research procedures, not intended as therapeutic interventions, which are administered for the purpose of rigorous assessment of treatment efficacy. It follows that riskbenefit assessment under the doctrine of equipoise is normatively incoherent. It conflates the ethics of RCTs with the ethics of medical care and offers no credible account for why net risks are permissible for nontherapeutic research procedures but not for either treatment interventions or placebo controls.
PLACEBO-CONTROLLED TRIALS Placebo-controlled trials have been seen as ethically problematic whenever they withhold proven effective treatment or the established standard of care. As the passage quoted from Freedman and colleagues above indicates, such trials are contrary to clinical equipoise and thus considered unethical because they randomize patients to treatment known or believed to be inferior. Nevertheless, placebo-controlled trials, despite proven treatment, are common to evaluate novel or previously untested symptomatic treatments for a wide range of medical conditions, including mood and anxiety disorders, migraine headaches, irritable bowel syndrome and a host of chronic pain conditions. These conditions typically are associated with high rates of placebo response in RCTs, and treatment efficacy is typically assessed in terms of subjective, patient-reported outcomes. Accordingly, double-blind trials comparing new treatments to placebo controls for such conditions are believed to be methodologically indicated to achieve valid results. Consider the following RCT designed to evaluate the efficacy of the popular herbal treatment St. John’s wort in major depression, sponsored by the U.S. National Center for Complementary and Alternative Medicine and the National Institute of Mental Health.10 St. John’s wort had previously been shown to be superior to placebo for mild depression in some placebo-controlled trials. It was unknown whether it was effective for major depression, despite widespread use. The trial enrolled 340 patients randomized to 3 arms: St. John’s wort, placebo or sertraline, a Food and Drug Administration (FDA)-approved agent for major depression. Examining this trial from the perspective of equipoise, it would be reasonable to judge that there was equipoise between St. John’s wort and placebo, given the lack of previous evaluation of the herbal treatment in major depression. Was there equipoise between St. John’s wort and sertraline? It is not clear whether psychiatrists and primary care physicians who treat patients with major depression would be in clinical equipoise between an oftenprescribed FDA-approved agent for major depression and an herbal remedy available over-the-counter. In any case, it is clear that this trial violated equipoise by virtue of randomizing patients with major depression to a placebo control, despite proven effective treatment for this condition. Freedman et al7 have recommended active-controlled equivalence trials (ACTs) instead of placebo-controlled trials
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when proven effective treatment exists for the disorder under study. They are alleged to be ethically superior not only because the placebo-controlled trials withhold effective treatments. When proven effective treatments exist, the clinically relevant question for RCTs is how a new treatment compares with standard treatment, not whether it is better than nothing. If this were true, then Freedman et al would be correct that the no-inferior-treatment principle is equivalent to the honest null hypothesis. This stance, however, fails to withstand critical scrutiny. There were good reasons for evaluating whether St. John’s wort is superior to a placebo control because many depressed individuals use this treatment, and it was unknown whether it is effective in ameliorating the symptoms of depression. Moreover, ACTs suffer from serious methodological problems in evaluating symptomatic treatments with high rates of placebo response, such as major depression.11 Suppose that the St. John’s wort trial was designed as an ACT evaluating the equivalence or noninferiority of this herbal treatment and sertraline. If no statistically significant difference was observed between these 2 treatments in reducing symptoms of major depression, does it follow that St. John’s wort is just as effective or not inferior in efficacy (by an acceptable margin) to sertraline? Although this conclusion seems intuitively plausible, the ACT design is not able to rule out the hypothesis that neither St. John’s wort nor sertraline was effective (ie, better than placebo) in this sample of depressed patients. Indeed, proven effective agents for major depression frequently fail to beat placebo in particular trials.11 Without a placebo control, such a trial lacks internal validity because it is not able to demonstrate rigorously the efficacy of St. John’s wort in treating major depression. In fact, the results of the actual St. John’s wort trial bear this out. Neither St. John’s wort nor sertraline was superior to placebo in reducing symptoms of depression. If this study had been designed instead as an ACT evaluating equivalence, the study results might have led to the erroneous inference that St. John’s wort had been shown to be effective and equivalent to sertraline. Proponents of equipoise might object that this alleged methodological defect in ACTs is merely a function of underpowered trials. Although this National Institutes of Health– sponsored trial was not a small study relative to other antidepressant RCTs, it could be argued that in a sufficiently large trial, it would be highly unlikely for sertraline to fail to be effective. Accordingly, if there were no significant difference in observed effectiveness between St. John’s wort and sertraline in a sufficiently large trial, equivalence could be validly inferred. The problem with this objection is that it is unclear how large trials would need to be to ensure valid results in evaluating symptomatic treatments. Examining trial results for another natural product in a different medical condition is instructive. Saw palmetto is a widely used treatment for male urinary symptoms associated with benign prostatic hyperplasia. A recent Cochrane systematic review of saw palmetto concluded that it is no better than placebo, based on a meta-analysis of placebo-controlled trials encompassing a large number of patients.12 Nevertheless, 2 European ACTs comparing saw palmetto to 2 different FDA-approved agents for benign prostatic hyperplasia found no difference between either of these drugs and saw palmetto in reducing urinary symptoms. The first trial compared saw palmetto with finasteride in 1098 patients13; the second compared it with tamsulosin in 704 patients.14 The upshot is that the methodological problems with ACTs are not limited to small-scale RCTs. Volume 342, Number 4, October 2011
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Suppose, however, that we could be confident that large ACTs would not pose this problem of internal validity. Avoiding placebo-controlled trials of symptomatic treatments in the face of proven effective treatments by implementing large ACTs would add great expense to clinical trial evaluation and expose large numbers of patient-subjects to potentially ineffective treatments. Given the lack of efficiency in large trials, and the lack of clarity regarding the sample size necessary to avoid the methodological defects of ACTs, rigorous trials to evaluate the equivalence or noninferiority of symptomatic treatments, other things being equal, should also include a placebo control to ensure the efficacy of the investigational treatment. Furthermore, small-scale early phase efficacy trials of symptomatic treatments, designed to detect signals of benefit, should test novel treatments solely against placebo before undertaking larger head-to-head comparisons with standard treatments. In sum, placebo-controlled trials are both methodologically indicated and clinically relevant in the evaluation of novel or untested symptomatic treatments, despite the existence of proven effective treatments. The equipoise doctrine, animated by a misplaced therapeutic orientation to clinical trials, poses the wrong ethical question regarding placebo-controlled trials. Instead of asking whether particular trials compromise medical care of enrolled patients by randomizing them to treatments known to be inferior, we should ask whether these trials expose consenting patient-subjects to unreasonable net risks of harm from placebo assignment. In other words, examination of the merits of placebo-controlled trials of symptomatic treatments reinforces the normative deficiency of equipoise with respect to riskbenefit assessment that is appropriate to the research context. What are the risks to which patient-subjects are exposed in placebo-controlled trials of major depression? Although this is a serious medical condition, it does not follow that short-term RCTs that withhold proven effective treatment in the context of careful monitoring of subjects pose unreasonable risks of harm. A meta-analysis of the antidepressant trials in the FDA database, encompassing thousands of patients, showed that, compared with patients receiving active drugs, those randomized to placebo are at no greater risk of suicide or attempted suicide.15 Moreover, mean symptom reduction for subjects on placebo was 31% versus 41% on active drugs. Although this difference is highly significant statistically, it is not large. Antidepressants are only partially effective in reducing symptoms. Those receiving placebo in RCTs also show mean symptom reduction, which amount to 75% of that in patients who receive active drugs. From an ethical perspective, it is significant that depressed patients are not made worse off (than their baseline condition) in the aggregate by being exposed to placebo in short-term trials. Placebo-controlled trials of symptomatic treatments that withhold proven effective treatment are not risk free. Compared with receiving standard treatment, those randomized to placebo may be more likely to experience symptomatic worsening, and (as in the case of major depression) they may be less likely to experience the same degree of symptomatic improvement as those randomized to novel or untested active treatments. Riskbenefit assessment involves determining whether these risks in the light of careful monitoring of the condition of subjects are acceptable for the purpose of obtaining scientifically valid and clinically relevant knowledge from placebo-controlled trials. Such judgments are necessarily contextual and should be guided by available evidence. (There is scant systematic data across diverse medical conditions about the risks of harm from © 2011 Lippincott Williams & Wilkins
placebo assignment in RCTs that withhold proven effective treatment.) However, the mere fact that proven effective treatment is withheld is not ethically dispositive. Recognition of the methodological limitations of placebo-controlled trials has led to a revision of the Declaration of Helsinki. In 2000, the declaration precluded the use of placebo controls when proven effective treatments exist. As of 2008, the revised declaration permits placebo-controlled trials in the face of proven effective treatments under the following conditions: “Where for compelling and scientifically sound methodological reasons the use of placebo is necessary to determine the efficacy or safety of an intervention and the patients who receive placebo or no treatment will not be subject to any risk of serious or irreversible harm.”16 Whereas the adequacy of this particular guidance is open to question, it is clear that this leading international set of principles for clinical research now departs from equipoise as a necessary condition for the design of RCTs.
PREMATURE STOPPING OF RCTS Equipoise is understood not only as governing the design of RCTs but also as guiding decisions to stop trials earlier than planned based on interim data. When these data indicate that equipoise has been disturbed, such that continuing the trial will randomize patients to treatment now known to be inferior, it becomes ethically imperative to stop the trial. Proponents of equipoise, however, have not provided clear guidance on how to determine when equipoise is disturbed. More significantly, Gifford17 has argued that it is likely that equipoise, no matter how it is understood, will be judged to be disturbed before adequate data have been obtained to inform policy decisions regarding the net benefit of treatments under investigation for the purpose of licensing new drugs or health coverage. Data Monitoring Committees are charged with interim monitoring of the results of RCTs, especially multicentered trials. One of the purposes of interim monitoring is to decide whether the study must be terminated early owing to evidence that one of the treatment interventions is superior to the other. Generally, these decisions are made in accordance with stringent guidelines of statistical significance. If interim efficacy data cross the stipulated boundary for statistical significance, the decision typically is made to stop the trial early. The equipoise doctrine provides the normative foundation for early stopping for reasons of benefit. However, equipoise-driven early stopping is problematic from the perspective of health policy. A 2005 systematic review noted that “RCTs stopped early for benefit are becoming more common and show implausibly large treatment effects, particularly those with few events.”18 As an explanation for this trend, the authors suggested that “A commitment to promptly offer participants in the less favorable group the better treatment choice may motivate investigators, patients and their advocates and the DSMB.”18 When interim data indicate statistically significant superiority of one treatment over the other, equipoise appears disturbed because continuing trial enrollment or follow-up would involve a proportion of patient-subjects receiving what would seem to be inferior treatment. The following example is instructive regarding the problems with early stopping. In 2004, a placebo-controlled trial of letrozole, an aromatase inhibitor evaluated as an adjuvant therapy for postmenopausal women with breast cancer, was stopped early (after an average of 2.4 years of a planned 4-year follow-up).19 The trial was powered to detect a 2.5% difference in the primary endpoint of disease-free survival. In the letrozole
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group, an estimated 92.8% of the subjects experienced diseasefree survival after 4 years versus 86.8% in the placebo group. The 95% confidence intervals for this 6% difference were 2.0 to 10.1. Although there was no significant difference in overall survival, the trial was stopped early by the Data Monitoring Committee, as the interim results had crossed the preset boundary of statistical significance with respect to the primary outcome. This early stopping decision proved controversial. An editorial in the New York Times described the decision as “ethical overkill.”20 The National Breast Cancer Coalition, a patient advocacy group, complained that the trial was stopped before sufficient data had been obtained regarding the toxicity of letrozole.20 The principal investigators of the letrozole study defended the decision to stop the trial early in a Times letter to the editor: “The only ethical option was to unblind the study medication and offer treatment to all participants.”21 The only ethical option? Those who subscribe to equipoise as an ethically necessary condition for trial conduct and judge that equipoise was disturbed on the basis of these interim data will view early stopping as the only acceptable option in this case. Nevertheless, when interim data indicate that treatment A is more beneficial than treatment B, or a placebo control, there still may be insufficient data to assess the risk-benefit ratio of treatment A. In the letrozole trial, there was an observed trend for a higher incidence of new diagnoses of osteoporosis in the letrozole group, which may have become statistically significant if the trial had been continued to its planned completion.19 Stopping trials early for benefit may result in widespread use of a treatment ultimately found on the basis of future research to have an unfavorable risk-benefit ratio. In sum, the application of the equipoise doctrine to interim monitoring of RCTs arguably encourages premature stopping of trials with potentially deleterious consequences for health policy.22 The ethical imperative to terminate the letrozole trial early is open to question. Because benefit is only one component of a treatment’s risk-benefit ratio, it is not clear that continuing this trial in the face of the observed superior disease-free survival associated with letrozole would have exposed patient-subjects to unreasonable risks of harm. Relatively small apparent benefit in terms of disease-free survival should be balanced against the potential for adverse effects. It is noteworthy that the lower bound of the 95% confidence interval for the primary outcome was less than the 2.5% absolute difference in disease-free survival that the trial was designed to detect. This suggests that the investigators and trial sponsors saw this difference as representing a minimal clinically significant benefit. However, the results at the time of stopping did not rule out a potentially smaller magnitude of benefit with 95% confidence. Setting equipoise aside, it is difficult to see that it was ethically necessary to stop this trial early. In sum, it would have been reasonable to continue the trial until the planned follow-up had been reached or until substantially more pronounced evidence of therapeutic benefit emerged. To be sure, equipoise proponents might argue that equipoise should be understood as a function of the overall therapeutic merits of a treatment, not just effectiveness in terms of a clinically relevant outcome. Accordingly, some might judge that the interim results of the letrozole trial did not disturb equipoise, all things considered, despite crossing the stopping guidelines for benefit. But, then, how do we determine operational stopping guidelines in light of equipoise? Adherents of
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equipoise who intend this principle to offer practical guidance cannot escape this question.
EQUIPOISE AND HEALTH POLICY The problem of premature stopping underscores the generic defect in the equipoise doctrine. As argued above, equipoise reflects a misguided therapeutic orientation to clinical trials, such that they are considered ethical only when consistent with the ethics of the physician-patient relationship. But this fails to give due attention to the central role of clinical trials in guiding health policy. As Gifford noted, “The reason the RCT dilemma exists in the first place is that there is a difference between the amount of evidence needed to justify decisions to act at the present patient and policy levels.”17 The equipoise doctrine fails to provide a satisfactory solution to the RCT dilemma, biasing ethical judgments about trial design and conduct on individual, patient-centered therapeutic grounds at the expense of the knowledge needed for health policy in the areas of licensing approval of novel drugs and health coverage decisions. In addition to the misguided implications of equipoise for placebo-controlled trials and for interim monitoring of trial results, this normative stance arguably impedes the conduct of socially valuable RCTs for promising, but unproven, new potential therapies for life-threatening conditions without good treatment options. Clinicians are unlikely to be in a state of equipoise between a biologically plausible novel treatment that provides impressive signals of benefit with respect to a surrogate outcome such as tumor shrinkage in early phase uncontrolled studies and an existing standard treatment that offers a small prospect of survival benefit with substantial toxicity. A recent New York Times article featuring an RCT underway for an experimental targeted treatment for metastatic melanoma exemplifies this issue.23 Although these situations are ethically challenging, equipoise provides one-sided guidance that fails to do justice to the societal interest in rigorous evaluation of new treatments before they are introduced into clinical practice. The problem is only compounded when the high costs of novel treatments are considered. In health systems undergoing rapid and ultimately unsustainable cost increases, rigorous evaluation of net benefit is all the more crucial from a societal perspective. On the other hand, equipoise also provides dubious guidance for clinical trials of alternative treatments that lack support within the established medical community. Although controversial, the case of Laetrile for treatment of advanced cancer is an example. Noting the implications of clinical equipoise, Freedman3 argued that clinical trials of Laetrile would be unethical owing to a lack of support for this treatment within the expert clinical community. In fact, some expert physicians supported the use of Laetrile.24 But even if no established experts endorsed the therapeutic potential of Laetrile, or a comparable untested alternative treatment, it arguably still would be desirable from the perspective of public health to evaluate its efficacy and safety, despite lacking any solid scientific rationale. With support from the FDA, Laetrile was tested by the National Cancer Institute and found ineffective in a phase II clinical trial.25 Another example is secretin for autism. After media attention to a report of a child with autism who experienced dramatic improvements in behavior and language after intravenous administration of secretin, many children received this treatment.26 Despite the lack of support for this treatment in the expert medical community, a randomized, placebo-controlled trial was conducted that found no significant improvement in any of the outcome measures compared with Volume 342, Number 4, October 2011
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placebo.25 Notwithstanding the absence of equipoise, such trials have social value in promoting public health by demonstrating the lack of efficacy and potential harm in widely used treatments.
CONCLUSION It is time to dispense with equipoise. Not only does equipoise provide fundamentally flawed normative guidance for the design and conduct of clinical trials, the principles of research ethics have adequate resources to guide ethical judgment without invoking equipoise. RCTs should address valuable questions, the answers to which have the potential to contribute to improving medical care or promoting public health. They must be designed in accordance with statistically valid methods, which will require placebo controls to test symptomatic treatments for many conditions despite the existence of proven effective treatment. The design and conduct of RCTs must protect subjects from unreasonable risks of harm, but this does not mean that it is unethical to expose them to any net risks from withholding proven effective treatment. And patient-subjects must be given a fair opportunity to provide informed consent to research participation, without coercion, undue influence or deception. Regardless of equipoise, when these principles are satisfied, clinical research is ethical. REFERENCES 1. Hellman S, Hellman DS. Of mice but not men: problems of the randomized controlled trial. N Engl J Med 1991;324:1585–9. 2. Gifford F. The conflict between randomized clinical trials and the therapeutic obligation. J Med Philos 1986;11:347– 66. 3. Freedman B. Equipoise and the ethics of clinical research. N Engl J Med 1987;317:141–5. 4. Miller FG, Rosenstein DL. The therapeutic orientation to clinical trials. N Engl J Med 2003;348:1383– 6. 5. Emanuel EJ, Miller FG. The ethics of placebo-controlled trials—a middle ground. N Engl J Med 2001;345:915–9. 6. Anderson JA, Kimmelman J. Extending clinical equipoise to phase 1 trials involving patients: unresolved problems. Kennedy Inst Ethics J 2010;20:75–98. 7. Freedman B, Glass KC, Weijer C. Placebo orthodoxy in clinical research. II. Ethical, legal, and regulatory myths. J Law Med Ethics 1996;24:252–9. 8. Miller FG, Brody H. A critique of clinical equipoise: therapeutic misconception in the ethics of clinical trials. Hastings Cent Rep 2003; 33:19 –28.
11. Temple R, Ellenberg SE. Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 1. Ethical and scientific issues. Ann Intern Med 2000;133:455– 63. 12. Tacklind J, MacDonald R, Rutks I, et al. Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev 2009, April 15: CD001423. 13. Carraro J-C, Raynaud J-P, Kock G, et al. Comparison of phytotherapy (Permixon) with finasteride in the treatment of benign prostate hyperplasia: a randomized international study of 1,098 patients. Prostate 1996;29:231– 40. 14. Debruyne F, Koch G, Boyle P, et al. Comparison of a phytotherapeutic agent (Permixon) with an alpha-blocker (Tamsulosin) in the treatment of benign prostatic hyperplasia: a 1-year randomized international study. Eur Urol 2002;41:497–507. 15. Khan A, Warner HA, Brown WA. Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials: an analysis of the Food and Drug Administration database. Arch Gen Psychiatry 2000;57:311–7. 16. World Medical Association. Declaration of Helsinki. Ethical principles for medical research involving human subjects. Available at: http://www.wma.net/en/30publications/10policies/63/index.html. Accessed March 23, 2011. 17. Gifford F. Community equipoise and the ethics of randomized clinical trials. Bioethics 1995;9:127– 48. 18. Montori VM, Devereaux PJ, Adhikari NK, et al. Randomized trials stopped early for benefit: a systematic review. JAMA 2005;294: 2203–9. 19. Goss PE, Ingle J, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349:1793– 802. 20. Halting a breast cancer trial (editorial). New York Times, October 12, 2003. 21. Goss PE, Ingle J. Letter to the editor. New York Times, October 17, 2003. 22. Buchanan D, Miller FG. Principles of early stopping of randomized trials for efficacy: a critique of equipoise and an alternative ethical framework. Kennedy Inst Ethics J 2005;15:161–78. 23. Harmon A. New drugs stir debate on rules of clinical trials. New York Times, September 18, 2010:A1. 24. Carpenter D. Reputation and power: organizational image and pharmaceutical regulation at the FDA. Princeton (NJ): Princeton University Press; 2010. p. 410 –28.
9. Miller FG, Brody H. Clinical equipoise and the incoherence of research ethics. J Med Philos 2007;32:151– 65.
25. Moertel CG, Fleming TR, Rubin J, et al. A clinical trial of amygdalin (laetrile) in the treatment of human cancer. N Engl J Med 1982;306: 201– 6.
10. Hypericum Depression Trial Study Group. Effect of Hypericum Perforatum (St John’s Wort) in major depressive disorder: a randomized controlled trial. JAMA 2002;287:1807–14.
26. Sandler AD, Suttton KA, DeWeese J, et al. Lack of benefit of a single dose of synthetic human secretin in the treatment of autism and pervasive developmental disorder. New Engl J Med 1999;341:1801– 6.
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Dispensing With Equipoise Franklin G. Miller, PhD
Abstract: Equipoise is widely endorsed as a necessary requirement for ethical design and conduct of randomized controlled trials. Nevertheless, I argue in this article that the equipoise principle suffers from fundamental defects. In particular, equipoise provides flawed ethical guidance for placebo-controlled trials and for decisions to terminate trials early based on interim data relating to benefit. The problems with equipoise are traced to a “therapeutic orientation to clinical trials,” which conflates the ethics of clinical research with the ethics of medical care. Because of this mistaken therapeutic orientation, equipoise fails to adequately account for the central purpose of randomized trials in providing evidence sufficient to guide health policy decisions relating to licensing new treatments and insurance coverage. I conclude that it is time to dispense with equipoise. The principles of research ethics are sufficient to provide adequate guidance to protect subjects and to promote socially valuable research without any appeal to equipoise. Key Indexing Terms: Clinical equipoise; Informed consent; Clinical research; Research ethics. [Am J Med Sci 2011;342(4):276–281.]
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quipoise has long been regarded as a fundamental norm of research ethics, governing the design and conduct of randomized clinical trials (RCTs). Viewed from the perspective of medical ethics, it has strong intuitive appeal. RCTs evaluate treatments for patients with various medical conditions and accordingly enroll only patients who are diagnosed by physicians as in need of treatment. Because they recruit patients in need of treatment and they are conducted by physicians, it seems natural to assume that RCTs can be ethical only if the medical care of enrolled patients is not knowingly compromised by trial participation. Some commentators hold that RCTs necessarily compromise medical care.1 The very fact of randomization violates the duty of physicians to select medical treatment based on their professional judgment of what is best for particular patients. On this view, randomization fundamentally conflicts with individualized care that physicians owe to their patients. Most ethicists, however, have rejected this blanket dismissal of RCTs as contrary to medical ethics. Instead, they believe that there is a solution to the “RCT dilemma” posed by the potential conflict between medical care and enrollment in RCTs.2 Patient-centered care and clinical trial participation are ethically compatible as long as physicians find themselves in a state of equipoise regarding the treatments under investigation in an RCT.3 More precisely, ethical trial participation requires equipoise between the treatment arms (including a placebo From the Department of Bioethics, National Institutes of Health, Bethesda, Maryland. The opinions expressed are those of the author and do not reflect the position or policy of the National Institutes of Health, the Public Health Service, or the Department of Health and Human Services. This paper was part of the 17th Annual Thomas A. Pitts Memorial Lectureship held at the Medical University of South Carolina, October 29 –30, 2010. Correspondence: Franklin G. Miller, PhD, Department of Bioethics, Clinical Center, National Institutes of Health, Building 10, Room 1C118, Bethesda, MD 20892-1156 (E-mail: [email protected]).
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intervention) and between these treatments and the established medical standard of care. Various formulations of equipoise have been propounded. All of them incorporate the idea of uncertainty about the relative therapeutic value of treatment (and comparator) interventions under investigation in a clinical trial. When equipoise obtains, no patient is knowingly randomized to treatment that is inferior to the standard of care. In other words, RCTs can be conducted without compromising medical care of trial participants as long as physicians remain in a state of equipoise. Despite its intuitive appeal, equipoise is fundamentally flawed. It rests on a mistaken “therapeutic orientation to clinical trials,” which distorts the ethics of clinical research.4 Strictly applied, equipoise rules out socially valuable placebo-controlled trials for a wide range of symptomatic treatments. These trials often do not pose undue risks of harm to patient-subjects who consent to time-limited withholding of standard (proven effective) treatment.5 By virtue of characterizing these trials as unethical, the equipoise doctrine encourages methodologically deficient active-controlled equivalence (or noninferiority) trials for symptomatic treatments. In addition, adherence to equipoise promotes premature stopping of RCTs based on interim evidence of benefit, thus compromising the rigorous evaluation of experimental or inadequately tested treatments and the comparative effectiveness of beneficial treatments. More broadly, the clinically oriented focus of the equipoise doctrine makes it deficient in evaluating clinical research for the sake of guiding health policy. Documenting these normative and practical problems with the equipoise doctrine leads, I shall argue, to an inescapable conclusion: it is time to dispense with equipoise. Dispensing with equipoise does not leave us in an ethical vacuum. The resources of research ethics are fully adequate to guide the design and conduct of clinical trials without appeal to equipoise. Moreover, dispensing with equipoise eliminates normative incoherence within research ethics relating to risk-benefit assessment of potentially therapeutic and nontherapeutic interventions and between the equipoise-dominated understanding of research ethics and the practice of research ethics committees in commonly approving RCTs that are inconsistent with equipoise.
CLINICAL EQUIPOISE Within bioethics, the canonical conception of equipoise is known as “clinical equipoise.” This conception was initially developed by Benjamin Freedman3 in a 1987 article in the New England Journal of Medicine, which is one of the most frequently cited articles in the bioethics literature. At the beginning of the article, Freedman asserts that “Equipoise is an ethically necessary condition in all cases of clinical research.” A charitable interpretation of Freedman’s intent will not take this pronouncement literally. Clearly, there are many areas of clinical research for which equipoise has no possible normative bearing. These include phase 1 studies of drugs in healthy volunteers and studies of the pathophysiology of diverse medical conditions that expose patient-subjects to experimental
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interventions without evaluating treatments. Anderson and Kimmelman6 have recently argued persuasively that ethically justifiable phase 1 trials enrolling patient-subjects cannot be understood as compatible with equipoise. For the sake of this critical analysis, I will focus primarily on randomized trials, where equipoise most naturally pertains. Freedman’s distinctive contribution to the articulation and justification of equipoise was to lodge equipoise in the community of physicians. RCTs would be too difficult to commence and too readily aborted if there were an ethical requirement of individual equipoise among physicians associated with clinical trials. Because medicine is a professional activity, which operates in accordance with a communally endorsed standard of care, the equipoise required for ethical trial design and conduct should be defined in light of the views characterizing the expert medical community. According to Freedman, equipoise exists when “there is no consensus within the expert clinical community about the comparative merits of the alternatives to be tested” (including the standard of care).3 In a later article, written with 2 colleagues, Freedman further elaborated the concept of clinical equipoise. Clinical equipoise is presented as both a normative and a scientific principle. “As a normative matter, it defines ethical trial design as prohibiting any compromise of a patient’s right to medical treatment by enrolling in a study. The same concern is often stated scientifically when we assert that a study must start with an honest null hypothesis, genuine medical uncertainty concerning the relative merits of the various treatment arms included in the trial’s design.”7 An important implication of clinical equipoise is that it prohibits placebo-controlled trials in the face of proven effective treatments: it “foreclose[s] the use of placebos in the face of established treatment, because enrolling in a trial would imply that a proportion of enrollees will receive medical attention considered inferior by the expert community.”7 In addition to guiding the design of RCTs, equipoise governs decisions to terminate trials early when interim data indicate that equipoise has been disturbed.
CONCEPTUAL PROBLEMS WITH EQUIPOISE Although equipoise is widely endorsed and frequently invoked, there is a notable lack of clarity in the application of the principle. What is the expert community in terms of which equipoise should be assessed? How do we know whether the relevant community or communities are in equipoise? More specifically, what proportion of expert clinicians must believe that a treatment has therapeutic merit to justify conducting a clinical trial on the basis of equipoise? How should it be determined that equipoise has been disturbed on the basis of interim RCT results? It is remarkable that proponents of equipoise have devoted so little attention to answering these questions. An additional conceptual problem with equipoise derives from the stated position of Freedman and colleagues, quoted above, that the scientific formulation of the “honest null hypothesis” is equivalent to the normative principle that patients should not be randomized to treatment known to be inferior. The honest null hypothesis reflects the need for uncertainty about the answer to a clinically relevant scientific question as a precondition for conducting an RCT. Without the requisite uncertainty, there is no scientific or social value in conducting the study, and any net risks to subjects cannot be justified. It does not follow that when an honest null hypothesis obtains, no patient-subject will be randomized to treatment known to be inferior to the established (proven effective) standard of care. For example, an RCT that compares an © 2011 Lippincott Williams & Wilkins
experimental treatment for migraine headaches against a placebo control will have an honest null hypothesis when there is no rigorous experimental evidence that this treatment is superior to placebo. However, given standard, proven effective treatments for migraine, patients receiving placebo will receive treatment likely in the aggregate to be inferior to the medical standard of care. The normative formulation of clinical equipoise prohibits placebo controls in this situation, even though they may be consistent with an honest null hypothesis. Apart from this conceptual confusion, equating the normative and scientific formulations is problematic because it makes clinical equipoise appear unassailable, as no one will reject the need for uncertainty about the answer to a research question as a scientific and ethical prerequisite to conducting a clinical trial. I shall argue, however, that the normative formulation, although intuitively appealing, is erroneous. In sum, it is a conceptual mistake to conflate the no-inferior-treatment principle with the honest null hypothesis.
CONFLATING THE ETHICS OF CLINICAL TRIALS WITH THE ETHICS OF MEDICAL CARE The underlying normative thrust of all forms of equipoise is to harmonize the ethics of RCTs with the traditional ethics of medical care. Physicians have a therapeutic obligation to offer competent medical care to patients diagnosed as in need of treatment, and medical care should not be compromised by trial participation. The existence and maintenance of equipoise makes it possible to conduct RCTs while preserving the basic normative commitment underlying the physician-patient relationship. Although it would be desirable if all socially valuable clinical research involving patient-subjects could be undertaken within the ethical orbit of medical care, this is impossible. In particular, RCTs differ fundamentally from medical care in normatively salient respects.8 RCTs are scientific experiments designed to produce rigorous generalizable knowledge about treatment effectiveness and safety by means of studying groups of patients under controlled protocols. This scientific orientation of RCTs contrasts fundamentally with the activity of medical therapy aimed at providing personal care for particular patients. To be sure, medical therapy should be evidence based, and thus physicians need to apply general knowledge to the situation of individual patients. But it is an activity devoted to patient-centered care. The fundamentally different purposes of medical care and RCTs call for different ethical standards of risk-benefit assessment. In medical care, with the notable exception of live organ and tissue donation, risks of diagnostic and therapeutic interventions are justified by compensating medical benefits to the patients who are exposed to those risks. In other words, the proportionality of risks and benefits is patient centered. In contrast, most clinical research involves 1 or more nontherapeutic procedures, which carry some risks of discomfort or harm to research subjects. These are used to test study hypotheses. In RCTs, such nontherapeutic procedures include, for example, extra blood draws, lumbar punctures, biopsies, or imaging procedures involving radiation, which are administered to confirm diagnoses and/or measure study outcomes. Risks of these procedures cannot be justified by medical benefits to patient-subjects. They are justified by the anticipated social value of the knowledge to be gained from the research. Of course, proponents of equipoise recognize that clinical research in general, and RCTs in particular, use nontherapeutic procedures. However, they have failed to provide any
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rationale for why these research procedures are permitted, but it is not permissible to expose patient-subjects knowingly to any net risks from therapeutic interventions or from the omission of therapeutic interventions associated with the use of placebo controls.9 (Net risks consist of risks to subjects which are not compensated by medical benefits to them.) If, within limits, the value of the knowledge to be gained from the research can justify net risks from nontherapeutic procedures, it should also be able to justify net risks associated with therapeutic procedures and placebo controls. Indeed, it is particularly incoherent to argue that placebo controls should not expose subjects to any net risks of harm by withholding proven effective treatment. Placebos in the context of clinical trials are research procedures, not intended as therapeutic interventions, which are administered for the purpose of rigorous assessment of treatment efficacy. It follows that riskbenefit assessment under the doctrine of equipoise is normatively incoherent. It conflates the ethics of RCTs with the ethics of medical care and offers no credible account for why net risks are permissible for nontherapeutic research procedures but not for either treatment interventions or placebo controls.
PLACEBO-CONTROLLED TRIALS Placebo-controlled trials have been seen as ethically problematic whenever they withhold proven effective treatment or the established standard of care. As the passage quoted from Freedman and colleagues above indicates, such trials are contrary to clinical equipoise and thus considered unethical because they randomize patients to treatment known or believed to be inferior. Nevertheless, placebo-controlled trials, despite proven treatment, are common to evaluate novel or previously untested symptomatic treatments for a wide range of medical conditions, including mood and anxiety disorders, migraine headaches, irritable bowel syndrome and a host of chronic pain conditions. These conditions typically are associated with high rates of placebo response in RCTs, and treatment efficacy is typically assessed in terms of subjective, patient-reported outcomes. Accordingly, double-blind trials comparing new treatments to placebo controls for such conditions are believed to be methodologically indicated to achieve valid results. Consider the following RCT designed to evaluate the efficacy of the popular herbal treatment St. John’s wort in major depression, sponsored by the U.S. National Center for Complementary and Alternative Medicine and the National Institute of Mental Health.10 St. John’s wort had previously been shown to be superior to placebo for mild depression in some placebo-controlled trials. It was unknown whether it was effective for major depression, despite widespread use. The trial enrolled 340 patients randomized to 3 arms: St. John’s wort, placebo or sertraline, a Food and Drug Administration (FDA)-approved agent for major depression. Examining this trial from the perspective of equipoise, it would be reasonable to judge that there was equipoise between St. John’s wort and placebo, given the lack of previous evaluation of the herbal treatment in major depression. Was there equipoise between St. John’s wort and sertraline? It is not clear whether psychiatrists and primary care physicians who treat patients with major depression would be in clinical equipoise between an oftenprescribed FDA-approved agent for major depression and an herbal remedy available over-the-counter. In any case, it is clear that this trial violated equipoise by virtue of randomizing patients with major depression to a placebo control, despite proven effective treatment for this condition. Freedman et al7 have recommended active-controlled equivalence trials (ACTs) instead of placebo-controlled trials
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when proven effective treatment exists for the disorder under study. They are alleged to be ethically superior not only because the placebo-controlled trials withhold effective treatments. When proven effective treatments exist, the clinically relevant question for RCTs is how a new treatment compares with standard treatment, not whether it is better than nothing. If this were true, then Freedman et al would be correct that the no-inferior-treatment principle is equivalent to the honest null hypothesis. This stance, however, fails to withstand critical scrutiny. There were good reasons for evaluating whether St. John’s wort is superior to a placebo control because many depressed individuals use this treatment, and it was unknown whether it is effective in ameliorating the symptoms of depression. Moreover, ACTs suffer from serious methodological problems in evaluating symptomatic treatments with high rates of placebo response, such as major depression.11 Suppose that the St. John’s wort trial was designed as an ACT evaluating the equivalence or noninferiority of this herbal treatment and sertraline. If no statistically significant difference was observed between these 2 treatments in reducing symptoms of major depression, does it follow that St. John’s wort is just as effective or not inferior in efficacy (by an acceptable margin) to sertraline? Although this conclusion seems intuitively plausible, the ACT design is not able to rule out the hypothesis that neither St. John’s wort nor sertraline was effective (ie, better than placebo) in this sample of depressed patients. Indeed, proven effective agents for major depression frequently fail to beat placebo in particular trials.11 Without a placebo control, such a trial lacks internal validity because it is not able to demonstrate rigorously the efficacy of St. John’s wort in treating major depression. In fact, the results of the actual St. John’s wort trial bear this out. Neither St. John’s wort nor sertraline was superior to placebo in reducing symptoms of depression. If this study had been designed instead as an ACT evaluating equivalence, the study results might have led to the erroneous inference that St. John’s wort had been shown to be effective and equivalent to sertraline. Proponents of equipoise might object that this alleged methodological defect in ACTs is merely a function of underpowered trials. Although this National Institutes of Health– sponsored trial was not a small study relative to other antidepressant RCTs, it could be argued that in a sufficiently large trial, it would be highly unlikely for sertraline to fail to be effective. Accordingly, if there were no significant difference in observed effectiveness between St. John’s wort and sertraline in a sufficiently large trial, equivalence could be validly inferred. The problem with this objection is that it is unclear how large trials would need to be to ensure valid results in evaluating symptomatic treatments. Examining trial results for another natural product in a different medical condition is instructive. Saw palmetto is a widely used treatment for male urinary symptoms associated with benign prostatic hyperplasia. A recent Cochrane systematic review of saw palmetto concluded that it is no better than placebo, based on a meta-analysis of placebo-controlled trials encompassing a large number of patients.12 Nevertheless, 2 European ACTs comparing saw palmetto to 2 different FDA-approved agents for benign prostatic hyperplasia found no difference between either of these drugs and saw palmetto in reducing urinary symptoms. The first trial compared saw palmetto with finasteride in 1098 patients13; the second compared it with tamsulosin in 704 patients.14 The upshot is that the methodological problems with ACTs are not limited to small-scale RCTs. Volume 342, Number 4, October 2011
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Suppose, however, that we could be confident that large ACTs would not pose this problem of internal validity. Avoiding placebo-controlled trials of symptomatic treatments in the face of proven effective treatments by implementing large ACTs would add great expense to clinical trial evaluation and expose large numbers of patient-subjects to potentially ineffective treatments. Given the lack of efficiency in large trials, and the lack of clarity regarding the sample size necessary to avoid the methodological defects of ACTs, rigorous trials to evaluate the equivalence or noninferiority of symptomatic treatments, other things being equal, should also include a placebo control to ensure the efficacy of the investigational treatment. Furthermore, small-scale early phase efficacy trials of symptomatic treatments, designed to detect signals of benefit, should test novel treatments solely against placebo before undertaking larger head-to-head comparisons with standard treatments. In sum, placebo-controlled trials are both methodologically indicated and clinically relevant in the evaluation of novel or untested symptomatic treatments, despite the existence of proven effective treatments. The equipoise doctrine, animated by a misplaced therapeutic orientation to clinical trials, poses the wrong ethical question regarding placebo-controlled trials. Instead of asking whether particular trials compromise medical care of enrolled patients by randomizing them to treatments known to be inferior, we should ask whether these trials expose consenting patient-subjects to unreasonable net risks of harm from placebo assignment. In other words, examination of the merits of placebo-controlled trials of symptomatic treatments reinforces the normative deficiency of equipoise with respect to riskbenefit assessment that is appropriate to the research context. What are the risks to which patient-subjects are exposed in placebo-controlled trials of major depression? Although this is a serious medical condition, it does not follow that short-term RCTs that withhold proven effective treatment in the context of careful monitoring of subjects pose unreasonable risks of harm. A meta-analysis of the antidepressant trials in the FDA database, encompassing thousands of patients, showed that, compared with patients receiving active drugs, those randomized to placebo are at no greater risk of suicide or attempted suicide.15 Moreover, mean symptom reduction for subjects on placebo was 31% versus 41% on active drugs. Although this difference is highly significant statistically, it is not large. Antidepressants are only partially effective in reducing symptoms. Those receiving placebo in RCTs also show mean symptom reduction, which amount to 75% of that in patients who receive active drugs. From an ethical perspective, it is significant that depressed patients are not made worse off (than their baseline condition) in the aggregate by being exposed to placebo in short-term trials. Placebo-controlled trials of symptomatic treatments that withhold proven effective treatment are not risk free. Compared with receiving standard treatment, those randomized to placebo may be more likely to experience symptomatic worsening, and (as in the case of major depression) they may be less likely to experience the same degree of symptomatic improvement as those randomized to novel or untested active treatments. Riskbenefit assessment involves determining whether these risks in the light of careful monitoring of the condition of subjects are acceptable for the purpose of obtaining scientifically valid and clinically relevant knowledge from placebo-controlled trials. Such judgments are necessarily contextual and should be guided by available evidence. (There is scant systematic data across diverse medical conditions about the risks of harm from © 2011 Lippincott Williams & Wilkins
placebo assignment in RCTs that withhold proven effective treatment.) However, the mere fact that proven effective treatment is withheld is not ethically dispositive. Recognition of the methodological limitations of placebo-controlled trials has led to a revision of the Declaration of Helsinki. In 2000, the declaration precluded the use of placebo controls when proven effective treatments exist. As of 2008, the revised declaration permits placebo-controlled trials in the face of proven effective treatments under the following conditions: “Where for compelling and scientifically sound methodological reasons the use of placebo is necessary to determine the efficacy or safety of an intervention and the patients who receive placebo or no treatment will not be subject to any risk of serious or irreversible harm.”16 Whereas the adequacy of this particular guidance is open to question, it is clear that this leading international set of principles for clinical research now departs from equipoise as a necessary condition for the design of RCTs.
PREMATURE STOPPING OF RCTS Equipoise is understood not only as governing the design of RCTs but also as guiding decisions to stop trials earlier than planned based on interim data. When these data indicate that equipoise has been disturbed, such that continuing the trial will randomize patients to treatment now known to be inferior, it becomes ethically imperative to stop the trial. Proponents of equipoise, however, have not provided clear guidance on how to determine when equipoise is disturbed. More significantly, Gifford17 has argued that it is likely that equipoise, no matter how it is understood, will be judged to be disturbed before adequate data have been obtained to inform policy decisions regarding the net benefit of treatments under investigation for the purpose of licensing new drugs or health coverage. Data Monitoring Committees are charged with interim monitoring of the results of RCTs, especially multicentered trials. One of the purposes of interim monitoring is to decide whether the study must be terminated early owing to evidence that one of the treatment interventions is superior to the other. Generally, these decisions are made in accordance with stringent guidelines of statistical significance. If interim efficacy data cross the stipulated boundary for statistical significance, the decision typically is made to stop the trial early. The equipoise doctrine provides the normative foundation for early stopping for reasons of benefit. However, equipoise-driven early stopping is problematic from the perspective of health policy. A 2005 systematic review noted that “RCTs stopped early for benefit are becoming more common and show implausibly large treatment effects, particularly those with few events.”18 As an explanation for this trend, the authors suggested that “A commitment to promptly offer participants in the less favorable group the better treatment choice may motivate investigators, patients and their advocates and the DSMB.”18 When interim data indicate statistically significant superiority of one treatment over the other, equipoise appears disturbed because continuing trial enrollment or follow-up would involve a proportion of patient-subjects receiving what would seem to be inferior treatment. The following example is instructive regarding the problems with early stopping. In 2004, a placebo-controlled trial of letrozole, an aromatase inhibitor evaluated as an adjuvant therapy for postmenopausal women with breast cancer, was stopped early (after an average of 2.4 years of a planned 4-year follow-up).19 The trial was powered to detect a 2.5% difference in the primary endpoint of disease-free survival. In the letrozole
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group, an estimated 92.8% of the subjects experienced diseasefree survival after 4 years versus 86.8% in the placebo group. The 95% confidence intervals for this 6% difference were 2.0 to 10.1. Although there was no significant difference in overall survival, the trial was stopped early by the Data Monitoring Committee, as the interim results had crossed the preset boundary of statistical significance with respect to the primary outcome. This early stopping decision proved controversial. An editorial in the New York Times described the decision as “ethical overkill.”20 The National Breast Cancer Coalition, a patient advocacy group, complained that the trial was stopped before sufficient data had been obtained regarding the toxicity of letrozole.20 The principal investigators of the letrozole study defended the decision to stop the trial early in a Times letter to the editor: “The only ethical option was to unblind the study medication and offer treatment to all participants.”21 The only ethical option? Those who subscribe to equipoise as an ethically necessary condition for trial conduct and judge that equipoise was disturbed on the basis of these interim data will view early stopping as the only acceptable option in this case. Nevertheless, when interim data indicate that treatment A is more beneficial than treatment B, or a placebo control, there still may be insufficient data to assess the risk-benefit ratio of treatment A. In the letrozole trial, there was an observed trend for a higher incidence of new diagnoses of osteoporosis in the letrozole group, which may have become statistically significant if the trial had been continued to its planned completion.19 Stopping trials early for benefit may result in widespread use of a treatment ultimately found on the basis of future research to have an unfavorable risk-benefit ratio. In sum, the application of the equipoise doctrine to interim monitoring of RCTs arguably encourages premature stopping of trials with potentially deleterious consequences for health policy.22 The ethical imperative to terminate the letrozole trial early is open to question. Because benefit is only one component of a treatment’s risk-benefit ratio, it is not clear that continuing this trial in the face of the observed superior disease-free survival associated with letrozole would have exposed patient-subjects to unreasonable risks of harm. Relatively small apparent benefit in terms of disease-free survival should be balanced against the potential for adverse effects. It is noteworthy that the lower bound of the 95% confidence interval for the primary outcome was less than the 2.5% absolute difference in disease-free survival that the trial was designed to detect. This suggests that the investigators and trial sponsors saw this difference as representing a minimal clinically significant benefit. However, the results at the time of stopping did not rule out a potentially smaller magnitude of benefit with 95% confidence. Setting equipoise aside, it is difficult to see that it was ethically necessary to stop this trial early. In sum, it would have been reasonable to continue the trial until the planned follow-up had been reached or until substantially more pronounced evidence of therapeutic benefit emerged. To be sure, equipoise proponents might argue that equipoise should be understood as a function of the overall therapeutic merits of a treatment, not just effectiveness in terms of a clinically relevant outcome. Accordingly, some might judge that the interim results of the letrozole trial did not disturb equipoise, all things considered, despite crossing the stopping guidelines for benefit. But, then, how do we determine operational stopping guidelines in light of equipoise? Adherents of
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equipoise who intend this principle to offer practical guidance cannot escape this question.
EQUIPOISE AND HEALTH POLICY The problem of premature stopping underscores the generic defect in the equipoise doctrine. As argued above, equipoise reflects a misguided therapeutic orientation to clinical trials, such that they are considered ethical only when consistent with the ethics of the physician-patient relationship. But this fails to give due attention to the central role of clinical trials in guiding health policy. As Gifford noted, “The reason the RCT dilemma exists in the first place is that there is a difference between the amount of evidence needed to justify decisions to act at the present patient and policy levels.”17 The equipoise doctrine fails to provide a satisfactory solution to the RCT dilemma, biasing ethical judgments about trial design and conduct on individual, patient-centered therapeutic grounds at the expense of the knowledge needed for health policy in the areas of licensing approval of novel drugs and health coverage decisions. In addition to the misguided implications of equipoise for placebo-controlled trials and for interim monitoring of trial results, this normative stance arguably impedes the conduct of socially valuable RCTs for promising, but unproven, new potential therapies for life-threatening conditions without good treatment options. Clinicians are unlikely to be in a state of equipoise between a biologically plausible novel treatment that provides impressive signals of benefit with respect to a surrogate outcome such as tumor shrinkage in early phase uncontrolled studies and an existing standard treatment that offers a small prospect of survival benefit with substantial toxicity. A recent New York Times article featuring an RCT underway for an experimental targeted treatment for metastatic melanoma exemplifies this issue.23 Although these situations are ethically challenging, equipoise provides one-sided guidance that fails to do justice to the societal interest in rigorous evaluation of new treatments before they are introduced into clinical practice. The problem is only compounded when the high costs of novel treatments are considered. In health systems undergoing rapid and ultimately unsustainable cost increases, rigorous evaluation of net benefit is all the more crucial from a societal perspective. On the other hand, equipoise also provides dubious guidance for clinical trials of alternative treatments that lack support within the established medical community. Although controversial, the case of Laetrile for treatment of advanced cancer is an example. Noting the implications of clinical equipoise, Freedman3 argued that clinical trials of Laetrile would be unethical owing to a lack of support for this treatment within the expert clinical community. In fact, some expert physicians supported the use of Laetrile.24 But even if no established experts endorsed the therapeutic potential of Laetrile, or a comparable untested alternative treatment, it arguably still would be desirable from the perspective of public health to evaluate its efficacy and safety, despite lacking any solid scientific rationale. With support from the FDA, Laetrile was tested by the National Cancer Institute and found ineffective in a phase II clinical trial.25 Another example is secretin for autism. After media attention to a report of a child with autism who experienced dramatic improvements in behavior and language after intravenous administration of secretin, many children received this treatment.26 Despite the lack of support for this treatment in the expert medical community, a randomized, placebo-controlled trial was conducted that found no significant improvement in any of the outcome measures compared with Volume 342, Number 4, October 2011
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placebo.25 Notwithstanding the absence of equipoise, such trials have social value in promoting public health by demonstrating the lack of efficacy and potential harm in widely used treatments.
CONCLUSION It is time to dispense with equipoise. Not only does equipoise provide fundamentally flawed normative guidance for the design and conduct of clinical trials, the principles of research ethics have adequate resources to guide ethical judgment without invoking equipoise. RCTs should address valuable questions, the answers to which have the potential to contribute to improving medical care or promoting public health. They must be designed in accordance with statistically valid methods, which will require placebo controls to test symptomatic treatments for many conditions despite the existence of proven effective treatment. The design and conduct of RCTs must protect subjects from unreasonable risks of harm, but this does not mean that it is unethical to expose them to any net risks from withholding proven effective treatment. And patient-subjects must be given a fair opportunity to provide informed consent to research participation, without coercion, undue influence or deception. Regardless of equipoise, when these principles are satisfied, clinical research is ethical. REFERENCES 1. Hellman S, Hellman DS. Of mice but not men: problems of the randomized controlled trial. N Engl J Med 1991;324:1585–9. 2. Gifford F. The conflict between randomized clinical trials and the therapeutic obligation. J Med Philos 1986;11:347– 66. 3. Freedman B. Equipoise and the ethics of clinical research. N Engl J Med 1987;317:141–5. 4. Miller FG, Rosenstein DL. The therapeutic orientation to clinical trials. N Engl J Med 2003;348:1383– 6. 5. Emanuel EJ, Miller FG. The ethics of placebo-controlled trials—a middle ground. N Engl J Med 2001;345:915–9. 6. Anderson JA, Kimmelman J. Extending clinical equipoise to phase 1 trials involving patients: unresolved problems. Kennedy Inst Ethics J 2010;20:75–98. 7. Freedman B, Glass KC, Weijer C. Placebo orthodoxy in clinical research. II. Ethical, legal, and regulatory myths. J Law Med Ethics 1996;24:252–9. 8. Miller FG, Brody H. A critique of clinical equipoise: therapeutic misconception in the ethics of clinical trials. Hastings Cent Rep 2003; 33:19 –28.
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