- IRB: ETHICS & HUMAN RESEARCH
The notion of exploitation frequently crops up in discussions about the ethics of biomedical research. A standard concern about clinical trials is that they exploit research subjects for the benefit of future patients. This concern is particularly emphasized when participants in clinical trials are drawn from vulnerable social groups and when research takes place in developing countries.1Some suggest that a major rationale behind ethical principles and guidelines governing research with humans is to avoid exploitation.2Yet it is unclear what exploitation means in the research context. The lack of clarity is hardly surprising, since exploitation is not as well-established a part of the bioethics toolbox as other concepts, like autonomy and harm. Exploitation has also received comparatively little philosophical attention outside of bioethics, and philosophers who have analyzed it disagree considerably about what exploitation is, when it is wrong, and why.3
Although some authors in research ethics have questioned the usefulness of exploitation discourse,4recent works have shed new light on the meaning of exploitation in clinical research, and several common misconceptions have been identified and dispelled.5However, more conceptual clarification is needed. This paper is not an attempt to develop a full account of exploitation in research, nor will I try to systematically apply any more general theory to this particular case. I will instead challenge one influential way of talking about exploitation in the research context: the so-called nonexploitation framework that a group of leading research ethicists have proposed in several recent papers.6I contend that one core element of the framework—the idea that nonexploitation in research requires that participants are not exposed to excessive risk—while seemingly sound, is in fact quite mistaken and misleading. A reflection on exploitation in other practices reveals why this is so.
The Nonexploitation Framework
The nonexploitation framework is proposed as an alternative to the long-prevailing view that clinical research should be guided by clinical equipoise.7There are different interpretations of the clinical equipoise doctrine, but the central tenet is that conducting a clinical trial is only justified when there is uncertainty about which of the trial interventions is better. On this view, randomization of research participants to different trial arms is unethical when the intervention in one of the arms is clearly inferior to the intervention in another arm (or to some other intervention available in clinical practice). This is because physician-investigators have an obligation to act in the best medical interest of each patient-subject8—an obligation oftherapeutic beneficence.
Proponents of the nonexploitation framework claim that the requirement of clinical equipoise is too strong and threatens to inhibit the progress of medical science. Medical care and clinical research are two different activities, they argue, and the obligation of therapeutic beneficence that governs the former does not apply to the latter. Instead, investigators have a weaker obligation: to protect research subjects from exploitation.
In order to get at what this might mean, consider a scenario that may raise worries about exploitation, and that advocates of the nonexploitation framework themselves discuss.9In this “early stopping scenario”—a somewhat simplified outline of a situation that may arise in real research10—a phase III trial investigates the efficacy of a new intervention for breast cancer that looks promising, judging from earlier phase trials, as well as laboratory and animal studies. Half of the trial participants are randomly allocated to the experimental intervention and the other half to the intervention that is currently the standard of care for patients of their kind. The effects of the intervention in the experimental group and the control group are compared. The trial is designed to enroll thousands of women and follow them up for five years. After two years have elapsed, an interim analysis of the data accumulated so far is conducted. The analysis indicates not only that the experimental intervention is superior to the standard one, but also that the difference between them is even greater than the difference the investigators expected to detect. The evidence is not beyond dispute, however; some think that it is less reliable and less complete than the evidence that might be gained if the trial is allowed to continue for as long as originally planned.
Suppose the investigators decide not to stop the trial on the basis of the evidence from the interim analysis, but instead to continue the trial until more reliable evidence about the effectiveness of the experimental intervention emerges. Here concerns about exploitation might arise. Are the participants in the control group being exploited for the sake of more evidence because they continue receiving an intervention that some evidence shows is inferior to another intervention that they might receive instead?
According to proponents of the nonexploitation framework, the answer to this question depends on two things. First, what is the magnitude of the risks participants in the control group who are denied access to the apparently superior intervention will face? And second, did participants enroll in the study with the understanding that the trial might continue despite early evidence that the experimental intervention is superior to the control intervention?11Franklin Miller and Howard Brody express the idea in more general terms: “Patients . . . are not being exploited if 1. they are not being exposed to excessive risks for the sake of scientific investigation; and 2. they understand that they are volunteering to participate in an experiment rather than receiving personalized medical care directed at their best interests.”12In short, nonexploitation is understood in terms of two standard research ethics requirements: nonmaleficence and informed consent.
Exploitation and Excessive Risk
Nonmaleficence and informed consent are certainly sound ethical requirements. But does satisfying these requirements avoid exploitation in research? Because others have explored the relationship between exploitation and informed consent in research,13I focus here on the first of the cited conditions of nonexploitation: that research subjects should not be exposed to excessive risk. Now, what does “excessive risk” mean? In the context of a stopping scenario, David Buchanan and Franklin Miller contend, “The risks associated with temporarily delaying access to a new experimental treatment must not be disproportionate to the potential benefits of having better knowledge about its safety.”14Miller and Brody offer a similar elaboration: “risks that are not compensated by medical benefits to participants should not exceed a tolerable threshold, which may vary somewhat depending on the value of the anticipated scientific knowledge.”15
The idea here is that the potential benefits of research—new or improved medical treatments—should outweigh the risks that research participants are exposed to. Greater risks require greater benefits. It is important here to remember that the risks are borne and the benefits enjoyed by two (largely) distinct groups: research participants and future patients, respectively. Thus, as Buchanan and Miller put it, “the potential harm associated with withholding the perceived benefits from participants . . . must be balanced against the value of the knowledge to be gained . . . for the vastly larger population of future patients.”16That is, risks to the first group should be proportional to the benefits to the second group. This, too, is a well-established ethical requirement of medical research.17Let us call it theproportionality requirement.
The proportionality requirement is not without problems. It allows risks to some people to be traded off against benefits to other people, and to what extent such tradeoffs are justifiable is controversial.18Regardless of what merit the requirement has, however, it is unsatisfactory as an explication of the idea that participants in clinical research should not be exploited.19Let us grant that participants are exploited if they are exposed to excessive risks, and that excessive risks are risks that are not sufficiently outweighed by benefits to other people. This implies that exploitation in research can be avoided or reduced in two ways: by decreasing risks to participants, and by increasing the benefits of the research to others. While the first way of avoiding exploitation appears to make sense, the second clearly does not.
To see why, consider a paradigm example of exploitation from another context. An industrialist hires a worker to perform heavy labor in unsafe conditions during exceedingly long days for very little pay. The value of what the worker produces far exceeds the cost to the industrialist of employing him. There are no other, better jobs available, and because the worker lives in a very poor country, not working at all would mean that he and his family would starve. If the work is heavy enough, the conditions bad enough, the days long enough, and the pay small enough, surely most would agree that the worker is being exploited. Now, suppose that the industrialist invests in newer and better machines that allow him to extract much more profit than before. The worker’s situation, however, remains unchanged: he continues to work just as hard, for as many hours and the same pay as before, and the conditions remain as unsafe. Would we now be less inclined than before the investment to say that the worker is being exploited? Surely not.
In fact, we are likely to think that the transaction ismoreexploitative after the investment than before. Different theories of exploitation would account for this belief in different ways. On one type of Marxist theory, capitalists are exploiters because the value that they extract from their workers’ labor exceeds what the workers get in return.20So one might expect Marxists to say that the greater the disparity between what the capitalist and the worker gets, the more rampant the exploitation. Perhaps more interestingly, Alan Wertheimer’s celebrated, decidedly non-Marxist account—the theory of exploitation that proponents of the nonexploitation framework themselves endorse21—suggests a similar explanation of the same belief. According to Wertheimer, A exploits B when A takes unfair advantage of B, where fairness is understood in a distributive sense.22A transaction between two parties (e.g., an industrialist and a worker) is exploitative when it effects a distribution of benefits between the parties that is advantageous to one of them (the industrialist) and unfair to the other (the worker). It plausibly follows that the more the benefits to the unfairly advantaged party (the industrialist) increase, the greater the unfairness, and hence the more exploitative the transaction.
It does not really matter whether the investment makes usmoreinclined to think that the industrialist exploits the worker, or merely notlessinclined to think so. The point is that we cannot make a transaction less exploitative by increasing the benefits from the transaction to parties other than the exploited party. (It could perhaps be suggested that greater benefits to these other partiesjustifyexploitation, but that is a different claim.)
This point is generalizable to other transactions and relationships that are sometimes described as exploitative. Consider two more examples. Many claim that prostitution involves the exploitation of the prostitute by the pimp. And some claim that universities exploit student athletes by offering them educational opportunities that may not benefit them in exchange for their athletic performance, from which the universities often derive significant financial gain. The validity and grounds of these claims may be contested. However, most would agree that increasing the pimp’s profit does not make prostitution any less exploitative. Most would also agree that universities do not avoid exploiting student athletes just because the universities gain enough from the athletes’ performance.
If this is correct, then by analogy, protecting research subjects from exploitation is not a matter of making sure that the benefitsto othersfrom the research are sufficiently large, either. In the early stopping scenario, for instance, the worry that participants in the control arm might be exploited if the trial continues should not be eased by the fact that continuing the trial might improve the care of other cancer patients in the future. Yet this is precisely what proponents of the nonexploitation framework suggest, quite counterintuitively and apparently contradicting the theory of exploitation that they themselves endorse.
The analogy that I draw between exploitation in clinical research and exploitation in labor, prostitution, and education might seem imperfect in two ways. First, whereas employers, pimps, and universities supposedly gain themselves from their exploitative relationships to workers, prostitutes, and student athletes, respectively, those who may gain from the exploitation of research subjects are arguably not researchers themselves but a third party: future patients. Even granted that there is such a difference, however, it is not a morally relevant difference. As Wertheimer notes, A is not any less guilty of exploitation if he takes unfair advantage of B on behalf of C, rather than to benefit himself.23It does not matter, for instance, whether the industrialist discussed earlier takes advantage of the worker in order to keep the profit for himself or in order to give it away to charity. The relationship is equally exploitative in both cases, and in neither case is it rendered less exploitative by increasing the profit. So the suggestion that researchers can avoid exploiting research participants by seeking to benefit others is not any less implausible because the others who will benefit are not the researchers themselves, but future patients.
Second, with clinical research, it is more difficult to distinguish benefited groups from harmed or burdened groups than in other practices sometimes described as exploitative. Workers, prostitutes, and student athletes are typically not among the beneficiaries of the increased profits that their employers, pimps, and universities make. On the other hand, the class of future patients who eventually benefit from research may include patients who actually participated in the relevant clinical trial or trials. To return again to the early stopping scenario: some of the participants in the control group at risk of receiving an inferior intervention because the trial wasn’t stopped may eventually benefit from the stronger evidence about the effectiveness of the experimental intervention that continuing the trial might yield.
This observation—which is no doubt correct—does seem to complicate claims about exploitation in clinical research. We are probably less inclined to think that participants are exploited in risky trials if we learn that they are likely to later benefit from the tested interventions. This complication is, however, perfectly compatible with my argument. I have no quarrel with the suggestion that a research participant might not be exploited because she is likely to belong to the group of future beneficiaries of the results of the trial. The problem with the nonexploitation framework is that it also entails the distinct claim that she might not be exploited because wholly different patients benefit, even when she herself does not.
One might think that little of practical relevance hinges on the correct use of the term exploitation. But my argument is not just a quibble over words. How we describe ethical problems and approaches, in clinical research and elsewhere, matters. As mentioned at the outset, concerns about exploitation in clinical research abound. By virtue of its label, the nonexploitation framework appears to speak directly to these concerns. However, when people worry about exploitation in research, they presumably worry about how research participants are treated. Advocates of the framework, by contrast, suggest that part of the problem with exploitation is that research may not benefit other parties sufficiently. They thus pick up a concern for the situation of research participants and transform it into something very different—a concern for the long-term social good of research. This move possibly reflects their avowedly utilitarian conception of research ethics,24but it dangerously misleads us about what avoiding exploitation requires. Promoting the social good of research and protecting research participants are not so easily reconciled. On the contrary, much of the controversy in research ethics stems from the long-acknowledged fact that these two admirable concerns pull in opposite directions.25The nonexploitation framework threatens to conceal rather than address this tension, thus disarming the worries about exploitation that it engenders.
This work was supported by a grant from the Swedish Cancer Society. I thank members of the Stockholm Centre for Healthcare Ethics and two anonymous reviewers for this journal for their helpful comments.
Erik Malmqvist, PhD,is Postdoctoral Research Fellow in Health, Ethics, and Law at the Centre for Research on Meaning, Ethics and Society (CERSES), Université Paris Descartes, in Paris, France.
1. Hawkins JS, Emanuel EJ, eds.Exploitation and Developing Countries: The Ethics of Clinical Research. Princeton, NJ: Princeton University Press, 2008.
2. Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical?JAMA2000;283:2701-2711.
3. Cohen GA. The labor theory of value and the concept of exploitation.Philosophy and Public Affairs1978;8:338-360; Wood AW. Exploitation.Social Philosophy and Policy1995;12:136-158; Wertheimer A.Exploitation. Princeton, NJ: Princeton University Press, 1996; Wilkinson S.Bodies for Sale: Ethics and Exploitation in the Human Body Trade. London, UK: Routledge, 2003.
4. Macklin R. After Helsinki: Unresolved issues in international research.Kennedy Institute of Ethics Journal2001;11:17-36.
5. See ref. 1, Hawkins and Emanuel 2008; Resnik DB. Exploitation in biomedical research.Theoretical Medicine and Bioethics2003;24:233-259.
6. Miller FG, Brody H. What makes placebo-controlled trials unethical?American Journal of Bioethics2002;2(2):3-9; Miller FG, Brody H. A critique of clinical equipoise: Therapeutic misconception in the ethics of clinical trials.Hastings Center Report2003;33(3):19-28; Miller FG, Brody H. Clinical equipoise and the incoherence of research ethics.Journal of Medicine and Philosophy2007;32:151-165; Buchanan DR, Miller FG. Principles of early stopping of randomized trials for efficacy: A critique of equipoise and an alternative nonexploitation ethical framework.Kennedy Institute of Ethics Journal2005;15:161-178; Buchanan DR, Miller FG. A public health perspective on research ethics.Journal of Medical Ethics2006;32:729-733.
7. Freedman B. Equipoise and the ethics of clinical research.NEJM1987;317:141-145.
8. Miller PB, Weijer C. Rehabilitating equipoise.Kennedy Institute of Ethics Journal2003;13:93-118.
9. See ref. 6, Buchanan and Miller 2005; Buchanan and Miller 2006.
10. Baum M, Buzdar A, Cuzick J, et al. Anastrozole alone or in combination with Tamoxifen versus Tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: First results of the ATAC randomized trial.Lancet2002;359:2131-2139.
11. See ref. 6, Buchanan and Miller 2005.
12. See ref. 6, Miller and Brody 2002, p. 5.
13. Wendler D. Informed consent, exploitation and whether it is possible to conduct human subjects research without either one.Bioethics2000;14:310-339; Martin AM.Hope and exploitation.Hastings Center Report2008;38(5):49-55.
14. See ref. 6, Buchanan and Miller 2005, p. 173.
15. See ref. 6, Miller and Brody 2002, p. 5.
16. See ref. 6, Buchanan and Miller 2006, p. 730.
17. World Medical Association. Declaration of Helsinki. October 2008,http://www.wma.net/en/30publications/10policies/b3/index.html; Council for International Organizations of Medical Sciences.International Ethical Guidelines for Biomedical Research Involving Human Subjects. Geneva, Switzerland: CIOMS, 2002.
18. Hansson SO. Weighing risks and benefits.Topoi2004;23(2):145-152.
19. Jansen LA. A closer look at the bad deal trial: Beyond clinical equipoise.Hastings Center Report2005;35(5):29-36.
20. See ref. 3, Cohen 1978.
21. See ref. 6, Buchanan and Miller 2005; Miller and Brody 2007.
22. See ref. 3, Wertheimer 1996.
23. See ref. 3, Wertheimer 1996.
24. See ref. 6, Miller and Brody 2007.
25. Marquis D. Leaving therapy to chance.Hastings Center Report1983;13(4):40-47.