Sounding Board
Equipoise and the Dilemma of Randomized Clinical Trials
N Engl J Med 2011; 364:476-480February 3, 2011DOI: 10.1056/NEJMsb1011301
- Article
In the 1980s, bioethics scholars defined the dilemma of randomized clinical trials as a central problem in clinical research ethics.1,2 How can physicians offer their patients optimal medical care at the same time that their treatment is selected by chance in the context of a randomized clinical trial? The solution that gained widespread acceptance appeals to “equipoise,” which has assumed canonical status in research ethics. Physicians can ethically randomly assign patients to treatments provided that equipoise — a state of professional uncertainty about their relative therapeutic merits — exists. If equipoise exists, no participant in a randomized clinical trial is knowingly given inferior treatment.
A major problem with the equipoise solution to the dilemma is that it narrowly locates the ethical concern about randomized clinical trials within the orbit of the doctor–patient relationship. The proponents of equipoise have characterized randomized clinical trials solely as tools to guide clinicians in making decisions about optimal medical care. In particular, they have argued that randomized trials are consistent with physicians' ethical duties to their patients if, and only if, equipoise exists.3 This “therapeutic orientation” to clinical research ignores the wider societal interest in evidence-based health policy, as reflected in regulatory decisions to approve new treatments for licensing and in health coverage decisions by national health systems and other payers.4 The requisite knowledge to make decisions about individual patient care, however, is not necessarily sufficient to guide the health policy decisions about licensing approval and coverage.
Clinicians make the best decisions they can for individual patients here and now, notwithstanding more or less uncertainty regarding the benefits and risks of alternative options. In contrast, regulatory authorities and health plans adopt a population perspective. In the United States, the Food and Drug Administration (FDA) is charged with determining that new drugs are safe and effective for defined groups of patients before they are approved. Public and private insurers make decisions about health coverage on the basis of “medical necessity,” which generally rests on convincing evidence that a treatment offers a net health benefit for a defined patient population.
Why Appeal to Equipoise Is Misguided
Regardless of whether equipoise, as it is traditionally understood, works to resolve the dilemma of randomized clinical trials,5 it fails to offer sound ethical guidance regarding the appropriateness of randomized clinical trials as tools to generate the knowledge needed for drug approval or coverage decisions. Five considerations that militate against appeal to equipoise as the arbiter of the ethical legitimacy of randomized trials to evaluate new treatments, even for life-threatening or highly debilitating conditions, are the following: the imprecision in defining the concept of equipoise, the reliance on expert opinion, the limitations of determining efficacy on the basis of surrogate outcomes, the high costs of new treatments, and the tendency toward premature termination of randomized clinical trials.
The reigning conception of equipoise is known as “clinical equipoise.” According to Freedman's classical formulation, clinical equipoise exists when “there is no consensus within the expert clinical community about the comparative merits of the alternatives to be tested.”3 Despite widespread endorsement of equipoise as an ethically necessary condition for randomized clinical trials, its proponents have not clarified how to determine when it exists. Assuming that the relevant expert community can be identified, what is the minimal proportion of members who must favor treatment A over treatment B as an appropriate therapy for patients with a given medical condition, thus justifying a randomized, clinical trial comparing the two? No authoritative answer has been provided. An approximately 50–50 split in expert opinion, which would best reflect the underlying idea of (collective) indifference reflected in the term “equipoise,” is unlikely. However, if only 1% of expert clinicians favor treatment A, it is difficult to see how the community is in equipoise. Where, between these extremes, do the boundaries of equipoise lie? Furthermore, however the presence of equipoise might be specified, systematic data are rarely available or developed to define the degree of consensus within the expert community to guide decisions about commencing or designing randomized clinical trials. Thus, operationally, equipoise fails as a guide to conduct.
More importantly, it is ironic that under the equipoise standard the permissibility of undertaking randomized clinical trials, which are intended to provide the most rigorous basis for clinical evidence, rests on mere expert opinion about the relative value of treatment options. Overwhelming support among experts for treatment A over treatment B, signifying a lack of equipoise, may or may not be grounded in sufficient evidence to guide policy, or even individual treatment, decisions. The well-known fallibility of expert opinion in support of the therapeutic value of treatments, without evidence from well-designed randomized clinical trials, is reflected in notable examples of widely used treatments that were subsequently proved to be ineffective or harmful. These treatments include antiarrhythmia drugs that were adopted on the basis of surrogate outcomes and proved to increase mortality as compared with placebo controls6; high-dose chemotherapy with bone marrow transplantation for metastatic breast cancer, which produced high rates of response in phase 2 trials but proved no more effective and more toxic than standard chemotherapy7; arthroscopic surgery for osteoarthritis of the knee, which was found to be no better than a sham intervention in relieving pain8; and hormone-replacement therapy, which was shown to lack benefit in promoting cardiovascular health and to be associated with multiple serious adverse outcomes.9,10 Moreover, the perception among clinicians that trial enrollment conflicted with equipoise probably delayed the recruitment of patients for some of these and other important randomized clinical trials.11
In the case of new treatments, expert opinion often rests on data from early-phase trials, which typically evaluate the agent's effect on surrogate end points. The limitations of drawing conclusions about efficacy on the basis of surrogate end points deserve emphasis.12,13 In the case of cancer treatments, single-group phase 1 or 2 trials may produce valid evidence of tumor response; however, the causal connection between this surrogate outcome and the clinical outcomes of improved survival and enhanced quality of life over time is open to question.14-18 When a lack of equipoise relating to a promising new treatment derives from such response data, it generally represents a weak consideration against conducting a rigorous randomized clinical trial to evaluate definitive measures of clinical benefit.
The high cost of new treatments for life-threatening or highly debilitating conditions reinforces the importance of rigorous evaluation of therapeutic value. Whether or not cost considerations are considered relevant to decisions about regulatory approval, decisions about health coverage should reflect judgments of cost-effectiveness. Failure to honestly face the challenge of treatments that provide insufficient therapeutic value to justify their expense is a principal reason for the burgeoning cost of health care in the United States — a level of spending far in excess of other countries, without commensurate benefits in terms of improved health outcomes. Even if decisions about approval and coverage are made without any explicit consideration of cost-effectiveness, high cost ought to be relevant to the assessment process. When treatments are likely to be very expensive, and their clinical benefits are uncertain based on current knowledge, it becomes all the more important to develop sufficiently rigorous evidence about their risks and benefits. However, the traditional understanding of the dilemma of randomized clinical trials and equipoise makes no reference to the costs of treatments, owing to the exclusive ethical focus on decisions about patient care in light of current knowledge. When the specter of cost receives due consideration, randomized clinical trials may be considered ethical to generate the rigorous knowledge needed to guide health policy decisions despite a lack of equipoise. Otherwise, there will be accelerated access to new treatments that may prove either to have unfavorable risk–benefit ratios as compared with available alternatives or to offer only marginal net benefits that do not justify their costs.
Finally, in addition to serious deficiencies in determining the ethical legitimacy of randomized clinical trials, equipoise promotes premature discontinuation of trials based on interim data relating to treatment benefit.19,20 According to the equipoise doctrine, trials should be terminated when equipoise has been disturbed.3 However, data-monitoring committees may determine that equipoise has been disturbed by interim trial results before these data are sufficient to guide health policy decisions. Systematic reviews have documented an increasing incidence of early termination of randomized clinical trials, resulting in overestimates of treatment benefit.21-23 Early discontinuation also impedes the development of rigorous evidence regarding adverse treatment effects. Together, these equipoise-driven consequences bias the evidence base relevant to risk–benefit assessment.
Application to a Controversial Clinical Trial
The problem with using equipoise to determine whether a randomized clinical trial is ethically appropriate is vividly illustrated by the recent controversy surrounding the development of a new agent for patients with metastatic melanoma, a uniformly fatal condition. The proportion of patients who have a response to dacarbazine, the current standard of care, averages 15%, with most responses associated with only partial tumor shrinkage.24 PLX4032 is an experimental targeted intervention that has undergone early-phase testing.25 On the basis of impressive rates and durations of response in a phase 1 trial among patients with melanoma that harbors a particular genetic mutation, the pharmaceutical company that developed the experimental agent has undertaken a randomized clinical trial designed as an open-label, head-to-head comparison between PLX4032 and dacarbazine.26 Because the primary end point of this trial is overall survival, crossover from dacarbazine to PLX4032 after disease progression is not allowed.
Is there equipoise between the two treatments of this randomized clinical trial? A recent New York Times article featuring this study suggests that equipoise is lacking.27 In light of current knowledge, if PLX4032 were clinically available outside the trial, it is reasonable to suppose that virtually all clinicians and informed patients would opt for this treatment over the marginally effective and toxic standard chemotherapy. The fact that some physician-investigators support the conduct of this trial does not prove that equipoise exists. These persons may represent only a very small minority of experts, and they may favor conducting the trial for various reasons despite the lack of equipoise. Assuming that there is no equipoise, does it follow that this trial, which is aimed at developing the knowledge needed for regulatory assessment of effectiveness, is unethical?
To be sure, one might argue that there are ethically preferable designs for randomized clinical trials that are likely to confer greater benefits for — or impose less toxicity on — study participants, while still answering the relevant scientific, clinical, and policy questions. One ethical requirement for clinical research is to maximize benefits to trial participants, provided that this requirement is consistent with promoting the social value and scientific validity of the research.28,29 Perhaps crossover to the experimental agent, in a trial designed to evaluate progression-free rather than overall survival as a primary end point, should be permitted for patients with disease that progresses while they are receiving dacarbazine. Or perhaps, given the toxicity and limited efficacy of dacarbazine, a straightforward placebo-controlled design is appropriate. Although the planned trial offers the best opportunity to assess survival benefit, the relative merits of alternative designs for randomized clinical trials are debatable. None of them, however, satisfy equipoise. Clinicians will not be indifferent to randomly assigning patients between the promising experimental agent and the current, marginally effective, standard treatment, even if crossover were an option for those with disease progression,30 nor would they be indifferent about the possibility of randomization to placebo.
Some observers might argue that PLX4032 should be approved without evaluation in a randomized clinical trial, based on the impressive evidence from the phase 1 trial. Additional, though less rigorous, evaluation of effectiveness might be accomplished by requiring that all patients receiving the new drug are enrolled in a data registry, with careful evaluation of outcomes to be compared with historical data from previous trials. If the marginal usefulness of the evidence that will result from a randomized clinical trial of PLX4032 for the purposes of making both clinical and policy decisions is limited, as compared with further observational research, then FDA approval without a randomized clinical trial would be justified, thus speeding access to the potential benefits of the new agent. PLX4032 is a genuinely difficult case, and reasonable people may differ over whether evaluation in a randomized clinical trial to clarify whether the drug offers a survival benefit is needed. For physicians and ethicists who adopt a therapeutic orientation to clinical trials and espouse equipoise, the answer is clear: a randomized clinical trial comparing PLX4032 with either the standard treatment or placebo is unethical because equipoise does not exist. From a health policy perspective, however, the answer depends on judging the knowledge value added by a suitably designed randomized clinical trial. In making this determination, equipoise is irrelevant.
Conclusions
Equipoise is fundamentally flawed as a criterion for determining whether a randomized clinical trial is justified to evaluate new treatments, even in the context of life-threatening or seriously debilitating conditions with marginally effective therapeutic options. As a rule, to inform regulatory and coverage decisions, rigorous evaluation of a new treatment before it is made available in clinical practice must be pursued beyond the point at which physicians and informed patients would choose it over the current standard treatment based on initial efficacy data. However, the examples of cisplatin for testicular cancer and bortezomib for multiple myeloma show that randomized clinical trials are not always required before new treatments are approved and covered.31-33 Several scientific and clinical criteria may provide support for validation of new treatments without randomized clinical trials (Table 1Table 1
Criteria Supporting the Approval of Agents for Life-Threatening Diseases on the Basis of Nonrandomized Evidence.). Nevertheless, evaluation in randomized clinical trials should be the default, with a heavy burden of proof before new treatments are approved and covered solely on the basis of evidence from uncontrolled trials. The expense of new treatments (e.g., between $4,000 and $8,000 per month for targeted therapies such as bevacizumab for metastatic breast cancer) augments the burden of proof.34,35 The resort to equipoise to guide decisions about evaluation of new treatments rests on a flawed intuition that study participants are harmed or wronged by being denied access to a promising but partially evaluated treatment. Participants are not harmed because they are not knowingly made worse off than they otherwise would be outside the trial, where presumably they would be offered standard treatment. They are not wronged because their right to evidence-based medical care is not violated: they are not entitled to experimental treatment that has yet to be adequately evaluated. Though they are psychologically and interpersonally challenging, trials of new treatments for life-threatening diseases that violate equipoise are both ethical and necessary for the development of evidence to support health policy decisions made on behalf of populations of patients.
The opinions expressed are those of the authors and do not necessarily reflect the position or policy of the National Institutes of Health, the Public Health Service, or the Department of Health and Human Services.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Source Information
From the Department of Bioethics, Clinical Center, National Institutes of Health, Bethesda, MD (F.G.M.); and the Department of Pediatric Oncology, Dana–Farber Cancer Institute, and the Department of Medicine, Children's Hospital Boston — both in Boston (S.J.).
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