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The Moral Foundations of Equipoise and Its Role inInternational ResearchAlex John London aa Carnegie Mellon UniversityPublished online: 21 Sep 2006.

To cite this article: Alex John London (2006) The Moral Foundations of Equipoise and Its Role in International Research, TheAmerican Journal of Bioethics, 6:4, 48-51, DOI: 10.1080/15265160600755599

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Open Peer Commentaries

The Moral Foundations of Equipoise and Its Role

in International ResearchAlex John London, Carnegie Mellon University

In “The Real Problem With Equipoise,” Chiong (2006)raises two distinct, but interrelated issues concerning theconcept of equipoise. The first deals with the role ofequipoise in evaluating international clinical trials. HereChiong argues that an interpretation of equipoise that wasarticulated for this purpose by London (2001) rules out asunethical any effort to find medical interventions that aredistinctly suited to the needs of developing world popula-tions but that may be less effective than interventions areavailable in the developed world for the same medical con-dition. In the following discussion, I argue that Chiong’sanalysis highlights some important aspects of this concep-tion of equipoise that merit careful explication but that hisobjection is ultimately mistaken. The second issue raised byChiong deals with the moral foundation for the equipoiserequirement and, in particular, how the duty of personalcare or the therapeutic obligation ought to be understood. Iargue briefly that Chiong’s positive proposal seems to differlittle from the views of those who have followed Freedman’s(1990) view of the therapeutic obligation, such as Millerand Weijer (2003). As such, I suggest that Chiong’s con-cerns are predicated on an uncharitable reading of at leastone prominent version of the equipoise requirement. How-ever, I conclude by suggesting that there may be other rea-sons to resist grounding clinical equipoise in role-relatedobligations of either physicians or researchers.

EQUIPOISE IN INTERNATIONAL RESEARCH

In 1997 Marcia Angell published a provocative editorial inthe New England Journal of Medicine in which she chargedthat it was unethical to use a placebo control in clinical trialsof a short-course of zidovudine (AZT) to prevent perinataltransmission of HIV in a number of countries of the devel-oping world (Angell 1997). In particular, she argued thatuse of the placebo control violated the principle of equipoisebecause a regimen of AZT known as the 076 protocol hadalready been shown in clinical trials in the developed worldto cut the rate of maternal-fetal HIV transmission by morethan half. As another commentator succinctly stated the ar-gument, “The only way that these placebo-controlled trialsshould be allowed [in the developing world] is if there is agenuine doubt about the benefits of AZT. No such doubtexists in the United States” (Clark 1998, 162).

In “Equipoise and International Human Subjects Re-search,” I argued that the previously noted argumentis ambiguous (London 2001). If we assume that some

intervention (I) has been shown to be effective in treatingpatients with some condition (C) in one treatment setting(S), then in order to infer that no doubts exist about thebenefits of I for treating patients with C in some othertreatment setting (S∗), we must be confident that S and S∗are sufficiently similar that causal relationships that exist inthe former will obtain in the latter. This is because differ-ences in the context in which treatments are administeredmay affect our ability to reliably replicate in one settingthe causal relationships that can be achieved in some othersetting.

In order for Angell’s argument to be valid as stated, ithas to adopt what I call a narrow criterion of similarity betweentreatment contexts. In the narrow view, the relevant criterionof similarity between two treatment settings is the physio-logical equivalency of the individuals in the two treatmentpopulations. To be valid, therefore, Angell’s argument pre-supposes that the context of treatment in the United Statesand Uganda, for example, is relevantly similar just in casewe have no credible reason to doubt that AZT, as success-fully administered in the 076 protocol, would have the samebiological effects in both populations.

As Chiong correctly notes, I argued that, although thisview salvages the validity of Angell’s argument, it does soat great cost. In particular, not only does it rule out asunethical the placebo-controlled trial design that Angellopposed, but it rules out as unethical Angell’s preferredtrial design in which the short-course would be comparedwith the full 076 protocol. The reason is simply that, at thattime, credible doubt did not exist about the superiority ofthe 076 protocol over the short-course regimen.

Instead, I argued in favor of a broader criterion of sim-ilarity between treatment settings. Following Freedman(1990), I argued that what matters from a clinical stand-point when evaluating competing interventions for a partic-ular condition is the relative net-therapeutic advantage of thosedifferent interventions. The relative net-therapeutic advan-tage of an intervention is an all-things-considered measureof its attractiveness from a clinical standpoint comparedwith other treatment alternatives (Freedman 1990; London2001). This portmanteau measure, therefore, takes account ofthe brute biological action of the intervention discountedby its side-effect profile. It also takes account of any fea-tures of the intervention that may hinder the realizationof its full beneficial potential in actual clinical practice. Itis in light of this broader criterion of similarity between

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clinical contexts that I argued that equipoise might fail toexist between a set of interventions in one place, say a de-veloped country such as the United States, but may existin another setting, such as a developing world context. Thekey consideration for making this determination in any par-ticular instance hinges on the similarity of the treatmentsettings with respect to variables that affect the relative nettherapeutic advantage of the interventions in question.

Chiong argues that this approach faces the same objec-tion that I raised against Angell (1997). Chiong argues thatthe “patient-centered ‘duty of personal care,”’ on which theequipoise requirement rests requires that physicians “offertreatments that are in the best interests of their individualpatients” (2006, 37). Chiong continues:

From the perspective of a patient in a clinical trial, considera-tions of cost or sustainable implementation in her populationare irrelevant to the determination of her best interests—study participants are treated free of charge, and a partici-pant in a study would not have self-interested grounds forpreferring a less effective treatment because it is easier toimplement in her population. If a patient were enrolled ina trial comparing a short-course regimen to the long-course076 protocol, her interests (and her child’s interests) wouldbe best served by being in the 076 arm, and an unrestrictedlypartial physician would not allow her to be randomized to theshort-course arm. Thus, London’s proposal, with its appeal tothe relative merits of treatments among populations, cannotpreserve the traditional, fully patient-centered conception ofphysicians’ obligations that equipoise was intended to accom-modate (Chiong 2006, 37).

Chiong’s objection, however, rests on a misunderstand-ing of my position. In particular, it assumes that the broaderview of equipoise that I endorse compares the relative thera-peutic merits of a set of interventions relative to populationsof patients in a way that does not bear directly on the individualinterests of particular patients. This, however, is a mistake. Therelative net-therapeutic advantage of a set of interventionsshould be evaluated relative to individual trial participants.As such, what matters from the standpoint of equipoise isnot whether the range of considerations that affect the rela-tive net-therapeutic advantage of a set of interventions do soin the abstract, but whether they affect the therapeutic valueof these intervention for individual patients. This is an im-portant point about which I should have been more precisein my original article and that I discuss in detail elsewhere(London 2006a, 2006b; Evans and London 2006).

Consider, for example, two interventions. One consistsof a complex regimen of pills that must be taken at spe-cific times during the day, some on an empty stomach andsome with food, and some of which must be stored undercarefully controlled temperature conditions. The other is atwo-pill regimen, one that is taken in the morning and theother at night, neither of which requires careful temperature

control. Even if we have good reason to believe that the morecumbersome intervention is superior to the other on the nar-row measure of brute biological effectiveness, this does notmean that equipoise might not exist between the two in-terventions relative to specific individuals in one treatmentpopulation, but not relative to specific individuals anotherpopulation. For example, it may be that in a well-nourishedpopulation in a developed country, where refrigerators arewidely available and where there is a robust infrastructurefor healthcare delivery, the more cumbersome regimen ispreferred to the less cumbersome intervention when treat-ing individual patients. In contrast, equipoise may existbetween these interventions for individuals who live incommunities without a robust healthcare infrastructure,in which patients frequently have nutritional deficienciesas well as higher rates of secondary medical conditions andin which the infrastructure for refrigeration is not widelyavailable.

There may be many reasons why equipoise might existfor individuals in the latter context, but not the former. Forinstance, if nutritional status or secondary disease statusaffect the side-effect profiles of these interventions, thenthe ratio of risks to benefits for these interventions relativeto individual patients in these different populations mayvary as well. Similarly, limitations of the infrastructure inone community may make it more difficult for individualsin that setting to consistently take and tolerate the morecomplex regimen under conditions that ensure the potencyof those pills. Even for particular individuals, therefore,whether the clinical benefits of one of these interventionswill be greater than the other may be partly a functionof the extent to which those individuals have consistentand convenient access to refrigeration, small meals that canbe eaten at the relevant intervals, and practices of time-keeping or scheduling that are necessary for the effectiveimplementation of the one intervention, but not the other.

Chiong appears to go further, however, and claim thateven if such factors affect our estimation of the relativetherapeutic merits of a set of interventions for treating in-dividual patients in the clinical setting, they do not affectour estimation of the relative therapeutic merits of theseinterventions for particular individuals in the setting of a clin-ical trial. As Chiong points out, although the relative costof an intervention may be a factor in the ability of pa-tients to access it outside of a clinical trial, it would notbe such a factor within the context of a clinical trial. Inmy previous hypothetical example, however, the procure-ment costs of the interventions was not even a variable.Furthermore, although many of the variables that impactthe relative therapeutic merits of an intervention for indi-vidual patients within a particular treatment setting can bealtered with a sufficient expenditure of resources, in practicethis might amount to changing fundamental features of the

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The American Journal of Bioethics

socioeconomic context of the host community. As I sug-gest in the following discussion, however, even when suchchanges might be obligatory, it is questionable whether themoral obligation to make such changes can be derived fromthe role-related obligations of physicians.

EQUIPOISE AND THE HUMAN DEVELOPMENT

APPROACH TO INTERNATIONAL RESEARCH

To be absolutely clear, I have been claiming only thatChiong’s objection to my position is based on a misunder-standing of the way in which a range of variables may, underdifferent circumstances, affect the relative net-therapeuticadvantage of a set of interventions for specific individuals indifferent treatment settings. It is worth emphasizing thatthis is a general point about causal inference and the waythat our ability to achieve desired clinical outcomes witha particular intervention depends on a range of contextualfactors that can be relevant to the interests of individualsubjects at a variety of different levels. Although the inter-national context provides a setting in which the differencesbetween treatment settings may be particularly salient andacute, this simply represents a clear instance of a more gen-eral problem that can arise within, as well as across, nationalborders.

However, the previous point about causal inference isdistinct from the larger moral and political question aboutwhich of these variables should be accepted as given forindividuals in a treatment setting and which should be tar-geted for remediation. After all, equipoise is a necessarycondition for the initiation of a clinical trial, but it is notsufficient. As a result, the fact that equipoise exists betweeninterventions A and B for individuals in one treatment set-ting S∗ but not for individuals in another S, is not by itselfsufficient to justify conducting a clinical trial in S∗. Thisis because the proper response to this difference may be tochange features of S∗ as to make it relevantly similar to S.

Whether the proper response to this sort of case is tochange features of S∗ as to make it more relevantly similarto S or to conduct a clinical trial to see which interventionis best suited to the treatment of individuals under the cir-cumstances that obtain in S∗ cannot be decided by appealto the role-related obligations of physicians. First, this isbecause such issues raise questions of distributive justicethat fall outside of the narrow purview of the physician–patient or researcher–subject relationship. Second, this factis itself encoded within clinical medicine by a long tra-dition of distinguishing (1) the physician’s obligation toprovide the best care possible to each individual patient,given the resources to which that patient has a legitimatemoral claim, from (2) the idea that the individual physi-cian has an obligation to ensure that sufficient resourcesare in place to guarantee that each patient receives the bestpossible care, tout court.

The equipoise requirement cannot substitute, there-fore, for a systematic and explicit treatment of the fun-damental questions of distributive justice that routinelyarise in the context of international clinical research. Ihave argued elsewhere that basic questions about howto ensure that clinical trials are adequately responsive tothe health needs of individuals in the developing worldshould be addressed within what I call the human develop-ment approach to international research (London 2005). Thisapproach seeks to identify health needs of host commu-nities that constitute priorities for research because theycannot be more effectively or efficiently addressed by thedeployment of existing knowledge or resources. The moralmission of medical research, in this view, is to gener-ate the information that is necessary to bridge the gapsthat exist between the basic interests of community mem-bers and the capacity of basic social structures in thatcommunity to meet those needs. Within such a frame-work, I submit, the equipoise requirement has an im-portant role to play as a necessary condition for morallypermissible clinical research. The equipoise requirementcannot, however, obviate the need for such a broaderframework.

THE MORAL FOUNDATIONS OF EQUIPOISE

Quite apart from the various arguments that I have ad-vanced, Chiong’s critique of the equipoise requirement ispredicated on the assumption that proponents of equipoiseunderstand the therapeutic obligation in fairly demand-ing terms. However, those who follow Freedman (1990)do not accept such a demanding view of the therapeu-tic obligation. In fact, Chiong’s positive proposal that“the therapeutic obligation can be discharged by provid-ing good enough treatment” (Chiong 2006, 37; empha-sis in the original) seems simply to restate Miller andWeijer’s claim that, for Freedman (1990), this obliga-tion “does not require the provision of the best possi-ble care, rather it requires the provision of competentcare” (Miller and Weijer 2003, 101). It is true that ver-sions of the equipoise requirement have proliferated andthat this alone has generated confusion in the literature(London 2006b). But with respect to clinical equipoise atleast, I am concerned that the real problem with Chiong’scritique lies in its uncharitable interpretation of thatposition.

Having said that, I do think that there are funda-mental tensions between the traditional understanding ofthe therapeutic obligation and the requirements of clinicalequipoise. Although I continue to endorse something verysimilar to clinical equipoise, I do not think that we shouldground this moral requirement in role-related obligationsof either clinicians or researchers. What I call the integrativeapproach to clinical research grounds this requirement in a

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view of clinical research as one element within a larger so-cial division of labor that must be justified to communitymembers as operating in a way that respects the funda-mental moral equality of each of those community mem-bers (London 2006a, 2006b, 2006c). As such, I agree withChiong about at least this point: it is fundamentally impor-tant that proponents of the equipoise requirement under-take a searching reconsideration of the moral foundationsof that requirement. �

REFERENCES

Angell, M. 1997. The ethics of clinical research in the ThirdWorld. New England Journal of Medicine 337: 487–489.

Chiong, W. 2006. The real problem with equipoise. AmericanJournal of Bioethics 6(4): 37–47.

Clark, P. A. 1998. The ethics of placebo controlled trials for peri-natal transmission of HIV in developing countries. Journal ofClinical Ethics 9: 156–166.

Evans, E. L., and A. J. London. 2006. Equipoise and the criteriafor reasonable action. Journal of Law, Medicine & Ethics, InPress.

Freedman, B. 1990. Placebo-controlled trials and the logic ofclinical purpose. IRB 12(6): 1–6.

Miller P. B., and C. C. Weijer 2003. Rehabilitating equipoise.Kennedy Institute of Ethics Journal 13(2): 93–118.

London, A. J. 2001. Equipoise and international human-subjects research. Bioethics 15(4): 312–332.

London A. J. 2005. Justice and the human development ap-proach to international research. Hastings Center Report 35(1):24–37.

London, A. J. 2006a. Sham surgery and reasonable risks. InCutting to the core: Exploring the ethics of contested surgeries,ed. D. Benatar, 211–228. New York, NY: Rowman & Littlefield.

London, A. J. 2006b. Clinical equipoise: Foundational re-quirement or fundamental error? In The Oxford Handbook ofBioethics, ed. B. Steinbock. New York, NY: Oxford UniversityPress.

London, A. J. 2006c. Reasonable risks in clinical research: Acritique and a proposal for the integrative approach. Statisticsin Medicine, 25, in press.

Copyright c© Taylor & Francis Group, LLC

DOI: 10.1080/15265160600755599

Are There Three or Four Distinct Types of Medical

Practice?Howard Brody, Michigan State University

Franklin G. Miller and I initially came to the problemof clinical equipoise from our attempts to characterizethe internal morality of medicine or the dictates of pro-fessional integrity (Brody and Miller 1998; Miller andBrody 2001). We assumed at the outset of this inquirya three-part division among the activities of physicians—therapeutic care, clinical research and public health. Weconsidered each activity as distinct in its nature and goalsand therefore, in all probability, requiring somewhat dif-ferent ethical approaches. We initially confined our dis-cussions of physician integrity to the therapeutic realm.We then turned to the question of what counted as in-tegrity for the physician working in the clinical researchrealm. Through that inquiry, we concluded that clini-cal equipoise could not do the work for which it wasproposed.

Chiong (2006) now offers further support for one ofour arguments, that clinical equipoise is not defensible as arestraining principle on research involving human subjects.In the process, he poses a very interesting challenge to ourlarger body of work by proposing that our three-part schema

was, in fact, incomplete. According to his argument, weshould have realized that there was a fourth distinct realmof medical work: medical education.

In his article, Chiong adopts the terminology Millerand I proposed (Miller and Brody 2003). He calls the stancethat both clinical research and therapeutic medicine shouldbe grounded in the same (therapeutic) ethical frameworkthe “similarity position,” and the argument that they aredistinct types of activities requiring distinct ethical frame-works the “difference position.” If one tries to critiqueChiong’s argument, as I will in the following discussion, onefinds the “similarities” and “differences” tripping over eachother. That is, Chiong asserts that medical education andtherapeutic medicine are as different from each other as areclinical research and therapeutic medicine. Despite that dif-ference, both medical education and therapeutic medicine aregrounded in a similar ethical framework. Therefore the dif-ferences between clinical research and therapeutic medicinefail to justify the claim that the two should be groundedin different ethical frameworks, so in the end the similarityposition wins.

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