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Abstract

Clinical equipoise is a core concept in the ethics of research involving human participants. It is an ethical precondition for the permissibility of enrolling patients in a randomized controlled trial (RCT). According to Freedman, a state of clinical equipoise obtains when there exists “an honest, professional disagreement among expert clinicians about the preferred treatment” (Freedman, New England Journal of Medicine, 317(3), 144, 1987). Historically, the concept evolved in response to the question: how can a physician, consistent with the duty of care to the patient, offer her enrollment in a randomized controlled trial? Clinical equipoise addresses this ethical difﬁculty, in part, through the recognition that a physician’s judgment is drawn from, and constrained by, the realm of professional knowledge. When there is disagreement in the professional community as to the preferred treatment, random allocation to one or other treatment in an RCT is consistent with the physician’s duty of care to the patient.

Introduction

Randomized controlled trials (RCTs) are a key methodology in evidence-based medicine. They are an integral part of assessing the safety and efﬁcacy of new medical treatments, and their results inﬂuence drug regulators, policy makers, and practitioners. In an RCT, a novel treatment is compared to a treatment used routinely in practice or, if no standard treatment exists, to a placebo. Patients are randomly assigned to various treatment arms, or “conditions,” in the trial. The experimental condition is the new treatment, and the control condition is the standard treatment or placebo. In the study, patients are followed for a deﬁned period of time and information is collected on speciﬁc measures (such as cure or survival) set out in the study protocol. At the end of the RCT, the new treatment is deemed effective if patients in the experimental condition outperform patients in the control condition.

Randomization is an important part of the methodological strength of RCTs. It protects the study from bias, helps ensure that patients in the experimental and control condition are similar, and provides the foundation for statistical tests of signiﬁcance. However, randomization also presents an ethical dilemma for both physician researchers and research ethics committees. The physician’s ethical and legal duty of care demands that she promote the medical interests of her patient. Yet, historically, it has proven difﬁcult to reconcile the physician’s duty of care with the manifest importance of enrolling patients in RCTs. This ethical dilemma can be encapsulated as follows: how can a physician, consistent with the duty of care, offer her patient enrollment in an RCT? The answer to this question is of paramount importance for the continued progress of evidence-based medicine and the protection of research participants. Clinical equipoise is a concept that has evolved out of various attempts at providing a solution to this ethical dilemma. The historical context in which clinical equipoise was conceived is of considerable importance for understanding its contemporary meaning and varied applications.

This essay examines the historical origins of the concept of clinical equipoise, focusing on the work of Charles Fried and Benjamin Freedman. It reviews contemporary debate, including criticisms of clinical equipoise and revisions to the concept. It describes the role of clinical equipoise in the ethical analysis of study beneﬁts and harms. Finally, it considers the implications of clinical equipoise for debate about the ethics of RCTs in low and middle-income countries.

Historical Evolution Of Clinical Equipoise

Charles Fried

Charles Fried is widely recognized as the progenitor of the term “equipoise.” In his book Medical Experimentation: Personal Integrity and Social Policy, Fried argued that the ethical foundation of the relationship between physician and patient is trust (Fried 1974). A trust relationship is deﬁned by structural inequality: a more powerful party (trustee) has discretionary power over a signiﬁcant practical interest of a less powerful party (truster). Due to the ensuing vulnerability, the trustee has an obligation to use her personal – often, professional – judgment to protect the truster’s interests. Trust relationships are not unique to the physician-patient relationship; they are also found in relationships between lawyers and clients, teachers and students, and chief executive ofﬁcers and shareholders.

Fried looked to ﬁduciary law, which regulates socially important trust relationships, to provide a practical foundation on which to conceptualize the ethical obligations that govern the physician patient relationship and the implications these obligations may have for enrolling patients in RCTs (Fried 1974, p. 8). His analysis led him to conclude that the physician owes “a duty of strict and unreserved loyalty to his client” (Fried 1974, p. 33). The physician “may not pursue activities that either do in fact conﬂict with the exercise of his judgment as a ﬁduciary, or might conﬂict or inﬂuence the exercise of his judgment, or might appear to do so, without explicit consent” (Fried 1974, p. 34).

Fried was among the ﬁrst to draw attention to the ethical dilemma that arises when the physician adopts the dual role of physician and researcher. The “paradox of professional knowledge,” as he called it, refers to the conﬂict between a physician’s ethical obligation to exercise her judgment in providing personal care to her patient and the need to enroll patients in RCTs to advance medical knowledge (Fried 1974, p. 151).

Fried’s solution to this ethical dilemma was to propose a particular understanding of the equipoise requirement. Speciﬁcally, Fried understood the duty of care as requiring the physician to exercise individualized judgment on behalf of her patient (a “duty of personal care,” in Fried’s words). It would seem that this dilemma is bridged in cases in which the physician has no treatment preference for the patient. In Fried’s words:

[W]here the balance of [the physician’s] opinion is in equipoise, there is no sense to the accusation that the prescribing of one or the other of the equally eligible treatments can constitute a withholding of anything or can constitute doing less than one’s best (the alternative being no better). (Fried 1974, p. 51)

Fried recognized, however, that this understanding of equipoise required further reﬁnement if it were to serve as a practical solution to the ethical problem of randomization. He pointed out that such a state of affairs would rarely, if ever, obtain in practice (Fried 1974, p. 52). If equipoise were to plausibly resolve the ethical dilemma posed by randomization, it would have to take into account the particular circumstances of the patient. However, when a treatment choice is considered with regard to a patient “with a particular set of symptoms, a particular diagnostic picture and a particular set of values and preferences .. .one may doubt how often a physician.. .would conclude that the risks and beneﬁts are truly equal” (Fried 1974, pp. 52–53). Equipoise so understood is thus considerably more difﬁcult to satisfy than the initial formulation might suggest. Indeed, Fried goes as far as to say that in those cases in which equipoise appears to obtain, it is more likely that one has simply not inquired “too closely into the particular circumstances of the particular patient, proceeding rather on the balance of risks and beneﬁts as they pertain to a larger group” (Fried 1974, p. 53).

Fried offered a crucial – and commonly overlooked – qualiﬁcation to this demanding criterion. He pointed out that the physician’s judgment “is limited by the professional norms that constrain the doctor’s judgment and constrain it in the name of good medicine generally” (Fried 1974, p. 151). A physician acts in his capacity as physician only to the extent that he does what “good medicine prescribes” (Fried 1974, p. 151). Good medicine requires physicians to practice in accord with professional norms and medical knowledge. Fried argued that the “distinctive feature of medical knowledge as professional knowledge is its insistence on professional, impersonal (or transpersonal) validation” and “for all these reasons, the conception of what is good medicine is the product of a professional consensus” (Fried 1974, p. 150).

Fried’s equipoise, properly understood, is not disrupted by the capricious hunches or intuitions of the physician or even by preliminary trial result. A physician’s duty of care requires a degree of self-restraint when it comes to exercising personal judgment. Indeed, “even where the doctor loyally seeks to do his ‘best’ for the particular patient his understanding of what that best might be is strongly and properly determined by professional standards and criteria” (Fried 1974, p. 149). Thus,

the choice between two therapies.. .becomes considerably more plausible when viewed in conjunction with the concept of professional knowledge. One or the other of the two therapies may not seem quite equally eligible to the patient’s doctor, but then as a good professional he would demur, saying that professionally he had no basis for preferring one to the other, and thus was justiﬁed in viewing them as being in equipoise. (Fried 1974, p. 153)

Despite the importance of this insight, Fried never stated precisely what it meant for physician judgment to be “constrained by professional knowledge.” A practical answer to the ethical problem of randomization must operationalize this insight in terms that can be assessed independently.

Benjamin Freedman

In the years following the publication of Fried’s Medical Experimentation, equipoise was widely regarded as a potential solution to the ethical problem of randomization, and many authors understood equipoise to require that the physician be genuinely uncertain as to the preferred treatment for a patient. For instance, Peto and colleagues wrote that

Physicians who are convinced that one treatment is better than another for a particular patient cannot ethically choose at random which treatment to give, they must do what they think best for the patient. For this reason, physicians who feel they already know the answer cannot enter their patients into a trial. If they think, whether for a wise or silly reason, that they know the answer before the trial starts, they should not enter any patients. (Peto et al. 1976, p. 606)

As Fried pointed out, however, one might wonder how often physicians are genuinely uncertain about the preferred treatment for a patient, especially when the circumstances of the patient are considered carefully.

Recognition of the demanding nature of the equipoise requirement so understood predictably led to skepticism about its utility. Indeed, some authors came to view the problem of randomization as insoluble. Schafer argued that it is the patient who chooses the treatment, not the physician. Regardless of the physician’s opinion regarding the best treatment for the patient, if the patient consents to study participation then the patient’s values “restore equipoise” (Schafer 1982). Meier claimed that it is acceptable to enroll patients in an RCT even if they receive inferior treatment as a result. He argued, “most of us would be quite willing to forego a modest expected gain in the general interest of learning something of value” (Meier as quoted in Freedman 1987, p. 142). Marquis went so far as to argue, “[p]erhaps what is needed is an ethics that will justify the conscription of subjects for medical research. Nothing less seems to justify present practice” (Marquis 1983, p. 47).

Freedman viewed these proposals as “frank counsels of desperation.. .that resolve the ethical problems of equipoise by abandoning the need for equipoise” (Freedman 1987, pp. 142–143). He traced the problem to a faulty understanding of equipoise that he called “theoretical equipoise.” Theoretical equipoise obtained when “the evidence on behalf of two alternative treatment regimens is exactly balanced” (Freedman 1987, p. 143). The kinds of evidence relevant to this weighing are wide ranging, including “data from the literature, uncontrolled experience, considerations of basic science and fundamental physiological processes, and perhaps a ‘gut feeling’ or ‘instinct’ resulting from (or superimposed on) other considerations” (Freedman 1987, p. 143).

Theoretical equipoise suffers from a number of problems. It is overwhelmingly fragile; the slightest accretion of evidence in favor of one treatment will disturb it. And even if theoretical equipoise did obtain at the beginning of an RCT, it would certainly be disrupted by the data that accumulates once the trial begins. Thus, theoretical equipoise is “balanced on a knife’s edge” (Freedman 1987, p. 143). Beyond this, theoretical equipoise is both personal and idiosyncratic, and it may be disturbed by a hunch that lacks any substantive evidentiary foundation. Thus, Freedman argued that a different understanding of equipoise was required.

Freedman called his alternative conception “clinical equipoise.” Clinical equipoise exists when “there is a current or imminent conﬂict in the clinical community over what treatment is preferred for patients in a deﬁned population” (Freedman 1987, p. 143). For example, suppose there are two widely used treatments in a clinical setting, with some physicians preferring one treatment while other physicians prefer the other. In these cases “each side recognizes that the opposing side has evidence to support its position, yet each still thinks that overall its own view is correct” (Freedman 1987, p. 144). Thus, when clinical equipoise exists and there is “an honest, professional disagreement among expert clinicians about the preferred treatment,” a clinical trial may be conducted “with the aim of resolving this dispute” (Freedman 1987, p. 144).

In order to legitimately resolve this dispute, two “formal conditions” must be met: “[1] at the start of the trial, there must be a state of clinical equipoise regarding the merits of the regimens to be tested, and [2] the trial must be designed in such a way as to make it reasonable to expect that, if it is successfully concluded, clinical equipoise will be disturbed” (Freedman 1987, p. 144). In other words, an RCT is initiated in response to a dispute about the preferred treatment, and the results of a successful trial ought to be convincing enough to resolve the dispute among clinicians. For Freedman, “convincing enough” means that no open-minded physician informed of the results would favor the other treatment.

The strength of clinical equipoise lies in its appeal to the collective norms of the medical community. Clinical equipoise allows individual physicians to have treatment preferences : so long as there exists genuine disagreement in the community of expert practitioners. Furthermore, clinical equipoise is not as vulnerable to disruption due to the interim results of a trial; on the contrary, clinical equipoise will more often than not require the successful completion of a trial if the results are to be considered persuasive by clinicians. Finally, in setting out clear criteria that appeal to the state of professional knowledge, Freedman provided a solution to the ethical problem of randomization that could be operationalized in terms that might be assessed independently.

Despite the efforts of both Fried and Freedman to resolve this dilemma, important questions remained. At the time they were writing, patients were commonly enrolled in RCTs by physicians who were acting simultaneously as researchers. Today, many patients enter RCTs in ways that do not involve the physician acting as either researcher or intermediary. If a patient enters an RCT without a preexisting relationship with the researcher, does the latter have a duty of care to the former? If so, in what is the duty of care grounded? If not, what are the ethical obligations of researchers to patients in RCTs? These questions are central to recent debates about the merits of clinical equipoise.

Criticisms Of Clinical Equipoise

After the publication of Freedman’s article, clinical equipoise was – at least for a period of time – widely regarded as the deﬁnitive solution to the ethical problem of randomization. Since 2002, however, researchers’ duty of care and the validity of clinical equipoise have been the subject of vigorous debate. Critics can be divided into three categories: those who endorse the duty of care but deny clinical equipoise, those who endorse clinical equipoise but deny the duty of care, and those who deny both clinical equipoise and the duty of care.

Critics in the ﬁrst category understand the duty of care to involve the exercise of individual judgment by the physician. Freedman, by contrast, interpreted the duty of care in terms of the professional norms of the medical community. Insofar as clinical equipoise fails to capture the centrality of individual physician judgment, critics argue that it fails to satisfy the demands of the duty of care and that Freedman’s suggestion that a physician might enroll a patient in a trial despite her own opinion as to the preferred treatment amounts to an abnegation of the duty of care. Based on these inconsistencies, Hellman and Hellman concluded that the ethical problem of randomization is insurmountable, and that RCTs are ethically impermissible (Hellman and Hellman 1991).

Critics in the second category agree that clinical equipoise is an appropriate constraint upon the design and conduct of RCTs but question whether it can be grounded in the physician’s duty of care to her patient. London agrees with those critics who believe that clinical equipoise seems incompatible with the exercise of individual physician judgment (London 2007). He argues that the importance of clinical equipoise as a concept requires that the duty of care be rejected and a new foundation established for clinical equipoise. Kukla points to a different limitation in grounding clinical equipoise in the physician’s duty of care to the patient. In public health and knowledge translation trials, for instance, the researchers may not be physicians at all. Kukla points out that “[t]o the extent that one grounds research ethics on the ethics of therapeutic clinical medicine, these other kinds of research will be left in an unconstrained ethical vacuum” (Kukla 2007, p. 172). Finally, research ethics committees review RCTs prior to the enrollment of any patients, and thus prior to any researcher-patient relationship. If clinical equipoise is a concept that is meant to guide research ethics committees, it seems that a different moral foundation is required.

Critics in the third category reject both the duty of care and clinical equipoise. F.G. Miller and Brody claim that “the basic goal and nature of the activity determines the ethical standards that ought to apply” (Miller and Brody 2003, p. 21). Medical practice and research have differing goals. Medical practice, on the one hand, aims to promote the health of the patient; research, on the other hand, aims to produce generalizable knowledge. F.G. Miller and Brody endorse the duty of care as a central norm of the physician-patient relationship. The researcher-patient relationship, however, has differing goals, and hence it must have different norms. While physician researchers may have a variety of obligations to patients, a duty of care is not one of them. If there is no duty of care, the ethical problem of randomization vanishes, and clinical equipoise is not required.

If physician-researchers do not have a duty of care, what obligations do they have to patients?

According to F.G. Miller and Brody, physician researchers must ensure that the RCT addresses an important question, the methodology is sound, the beneﬁts outweigh the risks to patients, informed consent is obtained, and patients are not exploited (Miller and Brody 2003). Notably absent from this list is any reference to the protection or promotion of the patient’s medical interests which, for F.G. Miller and Brody, may be sacriﬁced for the ends of science. As they explain it, “[c]linical research is dedicated primarily to promoting the medical good of future patients by means of scientiﬁc knowledge derived from experimentation with current research participants – a frankly utilitarian purpose” (Miller and Brody 2003, p. 21).

The ethical use of placebos in RCTs illustrates this point. The use of a placebo control may mean that fewer patients are required, studies are cheaper to conduct, and results are easier to interpret. Clinical equipoise constrains the ethical use of placebo controls to circumstances in which there is no proven standard treatment or eligibility is restricted to patients who have failed to respond to standard treatment. F.G. Miller and Brody argue that placebo-controlled trials have advantages that outweigh the medical interests of patients (Miller and Brody 2003). They advocate the use of placebo controls even in serious and treatable medical conditions, including schizophrenia or depression. So long as the scientiﬁc question is important and valid informed consent is obtained, patients may be legitimately deprived of needed treatment.

Together these criticisms reveal important theoretical and practical inadequacies of Freedman’s concept of clinical equipoise. The next section examines the various reactions and responses to these criticisms and the consequent revisions to clinical equipoise that they have motivated.

Revising Clinical Equipoise

Proponents of clinical equipoise have made various attempts to respond to the criticisms described above (Miller and Weijer 2003). In doing so, they have addressed three main issues. First, they have attempted to provide a moral foundation for clinical equipoise that does not rely solely upon a duty of care. Second, they have attempted to explain why physician-researchers have a duty of care to patients in RCTs without appealing to the physician-patient relationship. Third, and ﬁnally, they have attempted to provide a clear account of the role of individual physician-researcher judgment in protecting and promoting the medical interests of patients in RCTs.

B. Miller and Weijer argue that clinical equipoise has a foundation in the trust relationship that exists between the state and the patient in research. RCTs are an important part of assessing the safety and efﬁcacy of novel medical treatments, and the resulting evidence base for medicine is a “critical public beneﬁt” (Miller and Weijer 2006, p. 543). P.B. Miller and Weijer argue that patients who volunteer for RCTs “reasonably trust that the state will protect them in exchange for their contribution to the public good of science” (Miller and Weijer 2006, p. 543). Given the trust shown by the patient and the public beneﬁt to be gained from their participation in clinical research, “the state is morally obliged to exercise its powers to protect their interests” (Miller and Weijer 2006, p. 543).

The state fulﬁlls this trust-based obligation to protect the interests of patients in RCTs by promulgating regulatory safeguards and ensuring that they are adequately enforced (Miller and Weijer 2006, p. 543). Research ethics committees are responsible for reviewing RCTs to ensure that they comply with regulations. Given this, research ethics committees are “best understood as an arm of the state that ensures protection of the liberty and welfare of citizens who give of themselves to further medical knowledge” (Miller and Weijer 2006, p. 543).

Research ethics committees are responsible for reviewing the relative merits of treatment arms in a proposed clinical trial; they must ensure that there is sufﬁcient evidence to support the experimental condition in light of available evidence and current medical practice. They must also ensure that the control condition is not known to be inferior to the experimental condition. In other words, research ethics committees must conclude that a state of honest, professional disagreement in the community of expert practitioners exists (or would exist, were the evidence widely known) as to the preferred treatment. If clinical equipoise obtains, then study conditions conform to professional standards for the treatment of patients.

P.B. Miller and Weijer also argue that the physician-researcher has a trust relationship with the patient in an RCT (Miller and Weijer 2006). As noted above, a trust relationship is characterized by a number of features, including: structural inequality, discretionary power over the signiﬁcant practical interests of another, and ensuing vulnerability that generates various trust-related duties.

The relationship between physician-researcher and patient in an RCT has all of these features. First, the relationship between physician researcher and patient is one of structural inequality. Medical treatments are part of the experimental and control conditions of an RCT, and the patient relies on the medical expertise of the physician-researcher. Indeed, the power to prescribe such treatments is restricted, and only the physician-researcher is socially authorized to do so. Second, by consenting to enrollment in an RCT, the patient has granted discretionary power over his medical interests to the physician researcher. The physician-researcher is authorized to: collect health information about the patient; determine study eligibility; administer or withdraw study treatments; administer procedures, such as blood draws or questionnaires; and recommend alternate therapy should the patient’s medical condition so require. Third, the patient who volunteers to participate in an RCT is vulnerable, and this implies that the physician researcher has trust-related obligations. Physician-researchers exercise considerable discretion in terms of determining study eligibility and judging whether it is appropriate to administer protocol-deﬁned treatment. As a result, the physician-researcher has an obligation to protect and promote the medical interests of the patient.

How ought the physician-researcher fulﬁll her duty of care to the patient? As previously noted, the research ethics committee plays an important role in determining that the RCT meets the requirement of clinical equipoise. This ensures that sufﬁcient evidence supports the experimental condition and that the control condition does not knowingly involve the provision of substandard care. While it is appropriate for the physician researcher to rely on the judgment of the research ethics committee, there are limits to the ability of the committee to protect patient interests. Clinical equipoise involves a judgment that the various treatment arms are consistent with competent medical care for the eligible population of patients. It does not, however, entail the moral acceptability of enrolling or continuing particular patients in an RCT. Here, the physician-researcher must exercise individualized judgment.

Thus, provided that a research ethics committee has determined that an RCT fulﬁlls clinical equipoise, the physician-researcher may enroll or retain a patient unless (1) she believes it would be medically irresponsible to do so and (2) this belief is supported by evidence that would be convincing to colleagues (Miller and Weijer 2006). P.B. Miller and Weijer describe this ethical requirement as the “clinical judgment principle” and argue that it is a more robust variant of Fried’s equipoise. Thus, protecting the medical interests of patients in RCTs requires that both clinical equipoise and the clinical judgment principle be satisﬁed.

Contemporary Applications Of Clinical Equipoise

Component Analysis

Clinical equipoise plays a key role in component analysis, a systematic approach to the ethical analysis of the risks and potential beneﬁts of research (Weijer and Miller 2004). As noted above, the research ethics committee plays an important role in protecting the liberty and welfare interests of research participants. Prior to the development of component analysis, research ethics committees were criticized for inconsistent decision-making, due in part to “reliance on the vagaries of intuition to interpret.. .regulation on acceptable risks and potential beneﬁts” (Weijer and Miller 2004, p. 570). In the absence of a deﬁned framework, research ethics committees are left to make intuitive assessments as to the acceptability of the beneﬁts and harms of the proposed research.

Component analysis begins with the recognition that clinical research often involves a mixture of therapeutic and nontherapeutic procedures. Therapeutic procedures are administered with therapeutic warrant, that is, “they are administered on the basis of evidence sufﬁcient to justify the belief that they may beneﬁt research subjects” (Weijer and Miller 2004, p. 570). Therapeutic procedures may include drugs, surgical procedures, or psychological interventions. Nontherapeutic procedures, on the other hand, are administered without therapeutic warrant and aim only to answer the scientiﬁc question at hand. Nontherapeutic procedures may include blood draws, additional imaging procedures, or the collection of information.

Importantly, different ethical standards apply to therapeutic and nontherapeutic procedures in research. Broadly, therapeutic procedures are constrained by moral conditions that protect the patient’s interest in receiving competent medical care. Nontherapeutic procedures are constrained by moral conditions that protect the patient’s interest not to be exposed to unreasonable risk solely for the beneﬁt of others.

Therapeutic procedures must fulﬁll the requirement of clinical equipoise. In other words, the research ethics committee must determine that, with respect to the various therapeutic procedures in the RCT, there exists a state of honest, professional disagreement in the community of expert practitioners as to the preferred treatment. Recall that a research ethics committee review is prospective in nature – it antedates any relationship between physician-researcher and patient. It is therefore “appropriate for the [research ethics committee] to evaluate therapeutic procedures in the light of the state of the community opinion on the comparative merits of available treatments” (Weijer and Miller 2004, p. 544). When there is genuine disagreement in the expert community as to the comparative merits of therapeutic procedures, the research ethics committee may justiﬁably conclude that the RCT will not expose study participants to substandard treatment.

Nontherapeutic procedures are performed without therapeutic warrant, and different moral standards apply. First, nontherapeutic risks must be minimized, consistent with sound scientiﬁc design (Weijer and Miller 2004, p. 571). This may involve the substitution of clinically indicated procedure for a research intervention. For example, a blood draw purely for research purposes might be coupled with a clinically indicated blood draw in order to reduce research-related risk. Second, the research ethics committee must determine that nontherapeutic risks stand in reasonable relation to the knowledge to be gained. In other words, the research ethics committee must “judge the study’s scientiﬁc value sufﬁcient to justify risks to subjects” (Weijer and Miller 2004, p. 571). This highlights the importance of including community representatives on the research ethics committee in order to ensure adequate “appraisal of social priorities” (Weijer and Miller 2004, p. 571).

Finally, when an RCT involves a vulnerable population, such as pregnant women, prisoners, children, or incapable adults, an additional moral standard is applied, namely, limiting the scope of nontherapeutic procedures to a “minor increase above minimal risk” (Weijer and Miller 2004, p. 571). Minimal risk is deﬁned as the risks of daily life. Reasoning by analogy, the research ethics committee must determine either that the risks of nontherapeutic procedures are in fact part of the risks of daily life, or that they are sufﬁciently similar and may be regarded as such. However, “whether the daily lives referred to by the minimal risk standard ought to be those of healthy or sick people remains controversial” (Weijer and Miller 2004, p. 544). Only when the moral standards for both therapeutic and nontherapeutic procedures have been satisﬁed may the research ethics committee reasonably conclude that study beneﬁts outweigh risks.

RCTs In Low-and Middle-Income Countries

One of the greatest challenges in the world today is the lack of access to adequate health care in low-and middle-income countries (LMICs). Treatment routinely used in high-income countries may not be affordable in low resource settings, or there may be inadequate evidence to support its use due to biological and environmental differences. RCTs provide critical evidence to ensure that treatments used in LMIC settings are both affordable and effective. While it is broadly accepted that ethical standards for research are universal, there may be differences in application of key concepts from one setting to the next. In high-income countries, clinical equipoise protects the welfare interests of patients in RCTs. But when research is conducted in a LMIC setting, should research ethics committees appeal to a local or global standard of care in clinical equipoise determinations?

Consider the controversial RCT that compared short-course zidovudine to placebo for the prevention of perinatal transmission of human immunodeﬁciency virus (HIV) in sub-Saharan Africa and Thailand. In countries with a high prevalence of HIV, maternal-fetal transmission is a major source of new HIV cases: approximately 25 % of HIV-infected mothers transmit the virus to their child during pregnancy or childbirth. A new prevention regimen (called the “ACTG 076 regimen”), involving oral treatment with zidovudine for 12 weeks before birth, intravenous treatment during labor, and oral treatment for 6 weeks for the newborn, was shown to reduce HIV transmission by two-thirds. But the applicability of the ACTG 076 regimen to LMIC settings in which antenatal care and intravenous administration of medications is not available was questioned. The short-course zidovudine trial sought to evaluate a cheaper version of the regimen that involved only oral zidovudine.

Lurie and Wolfe argued that the use of a placebo control in the short-course zidovudine trial violated clinical equipoise (Lurie and Wolfe 1997). Given that the ACTG 076 regimen was known to be effective, they argued that the use of a placebo control was unethical. Furthermore, they claimed a subgroup analysis within the original RCT endorsing the ACTG 076 protocol provided sufﬁcient evidence to support the use of the short-course zidovudine regimen. As a result, “researchers should have had every reason to believe that well-designed shorter regimens would be more effective than placebo” (Lurie and Wolfe 1997, p. 854). They concluded that “these ﬁndings seriously disturb the [clinical] equipoise.. .necessary to justify a placebocontrolled trial on ethical grounds” (Lurie and Wolfe 1997, p. 854).

Defenders of the short-course zidovudine trial also framed their response in terms of clinical equipoise. Crouch and Arras pointed out that the fundamental purpose of a clinical trial is to resolve a dispute within the expert community as to the preferred treatment (Crouch and Arras 1998). They further noted that, “within such a framework, clinical trialists should be concerned with the compendious evaluation of the [zidovudine] regimen’s effects: reduction of HIV transmission, safety, ease of administration, and, importantly, cost” (Crouch and Arras 1998, p. 27). Recognition of the pragmatic purpose of clinical trials demands a different interpretation of the short-course zidovudine trials:

the question is not merely whether short course [zidovudine] is better than nothing. Rather, the study question is whether the shorter [zidovudine] regimen is safe in these populations, and, if so, whether the demonstrated efﬁcacy is large enough, as compared to the placebo group, to make it affordable to the governments in question. (Crouch and Arras 1998, p. 27)

Crouch and Arras concluded that the practical aim of RCTs demands that clinical equipoise obtain with respect to a local, as opposed to a global, clinical community.

While Crouch and Arras’ defense of the shortcourse zidovudine trial is compelling, we might nonetheless worry that an unqualiﬁed local standard of care position may lead to exploitation and injustice. London (2000) distinguishes between a de facto and de jure local standard of care. The de facto local standard of care is “set by the actual medical practices of that community,” whereas the de jure local standard of care “is set, not by what physicians in some locality actually do, but by the judgment of experts in the medical community as to which diagnostic and therapeutic practices have proven most effective against the illness in question” (London 2000, pp. 383–384).

London argues that the de jure, and not the de facto standard of care, ought to be used in interpreting clinical equipoise for RCTs in LMICs. There are good reasons to think that local variations in treatment accessibility may be the result of unjust distribution of resources, inefﬁciency, and corruption. Unscrupulous investigators may seize upon such conditions to justify an RCT involving substandard care. A de jure local standard of care prevents such abuses by using the stated goals of the health system to benchmark the standard of care for clinical equipoise determinations.

Conclusion

The formulations of equipoise discussed in the preceding article constitute attempts to answer the question, “how can a physician, consistent with her duty of care, offer her patient enrolment in a RCT?” Fried argued that equipoise ought to be grounded in a physician’s duty of personal care and the exercise of professional judgment. Importantly, he realized that the requirements of good medicine, and the knowledge upon which it is based, act as a restraint on professional judgment. Freedman’s concept of clinical equipoise acknowledges this intuitive appeal to the collective norms of the medical community and allows for the ethical permissibility of RCTs only when there exists “honest, professional disagreement among expert clinicians about the preferred treatment” (Freedman 1987, p. 144).

After a period of widespread acceptance, Freedman’s concept of clinical equipoise became subject to criticism and attempts at reﬁnement and revision. P. B. Miller and Weijer argued that clinical equipoise is founded on trust between the state and the research participant and between the physician-researcher and the patient. Research ethics committees, acting as an arm of the state, exercise a duty of care by requiring that clinical equipoise obtain prior to the enrollment of research participants in RCTs. A physician researcher, meanwhile, exercises a duty of care by ensuring that enrollment in a RCT is consistent with the medical interests of her patient. The physician-researcher’s duty of care is fulﬁlled when both the clinical equipoise and “clinical judgment principle” requirements are met.

Clinical equipoise thus remains an essential methodological tool in the design and conduct of RCTs and plays a central role in component analysis, harm-beneﬁt analysis, and the ethical permissibility of RCTs in LMICs.

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