R. M. Veatch, âAbandoning Informed Consent,â Hastings Center. Report 25, no. ... www.medicine.ox.ac.uk/bandolier/booth/Risk/trasnsportpop.html. 32. Waisel et ...
29. R. M. Veatch, “Abandoning Informed Consent,” Hastings Center Report 25, no. 2 (1995): 5-12. 30. G. Li et al., “Epidemiology of Anesthesia-Related Mortality in the United States, 1999-2005,” Anesthesiology 110, no. 4 (2009): 759-65. 31. Bandolier, “Evidence-Based Thinking about Medicine,” http:// www.medicine.ox.ac.uk/bandolier/booth/Risk/trasnsportpop.html. 32. Waisel et al., “Ethical Issues in Pediatric Anesthesiology.” 33. R. M. Epstein, D. N. Korones, and T. E. Quill, “Withholding Information from Patients—When Less Is More,” New England Journal of Medicine 362 (2010): 380-81.
34. Presidential Commission for the Study of Bioethical Issues, Anticipate and Communicate: Ethical Management of Incidental and Secondary Findings in the Clinical, Research, and Direct-to-Consumer Contexts (Washington, D.C.: PCSBI, 2013). 35. L. Colloca and D. Finniss, “Nocebo Effects, Patient-Clinician Communication, and Therapeutic Outcomes,” Journal of the American Medical Association 307 (2012): 567-68. 36. Komesaroff, “From Bioethics to Microethics,” 81.
Should All Research Subjects Be Treated the Same? by Bar uch Brody, Stephen A . Migueles , and David Wendler
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ne of the founding principles of research ethics is that subjects should be treated equally.1 In the words of the Belmont Report, “equals ought to be treated equally.”2 This principle does not imply that all subjects should be treated exactly the same. Rather, subjects who are similar in relevant respects should receive similar treatment. Clinical status is clearly relevant to determining how subjects should be treated. Greater resources should be devoted to subjects who have worse diseases. In contrast, fame is irrelevant. Subjects should not receive greater resources simply because they are famous. A more challenging question, one that pervades clinical research yet has received almost no attention in the literature, is whether subjects’ level of scientific importance is relevant to determining how much support they should receive. This question was highlighted by a subject whose continued participation in research was regarded as extremely valuable to efforts to develop a vaccine against HIV infection. Development of a vaccine against HIV infection would have profound social value,3 but the subject’s erratic compliance was undermining his health, and further deterioration of his health could jeopardize his research eligibility. The investigators called a bioethics consultation to discuss whether it would be appropriate to continue to conduct research with the subject while his health was declining. If so, would it be appropriate, in an effort to keep him healthy and eligible for research, to devote more medical resources to him Baruch Brody, Stephen A. Migueles, and David Wendler, “Should All Research Subjects Be Treated the Same?,” Hastings Center Report 45, no. 1 (2015): 17-20. DOI: 10.1002/hast.414 January-February 2015
compared to the medical resources devoted to other subjects in the same study who have similar clinical needs, but are less important scientifically? Case Presentation
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r. J. was a sixty-year-old gentleman who had been diagnosed with HIV in 1990. His medical history was significant for hypertension, chronic renal insufficiency, lipid abnormalities, and diabetes mellitus. Mr. J had never received any treatment for HIV infection, yet his viral loads remained very low. In 2002, realizing that his disease course was unusual, Mr. J came to the National Institutes of Health and was enrolled in a study for individuals who have durable, immune-mediated control over HIV infection. Analysis of Mr. J’s serum revealed that it contained antibodies that neutralized the vast majority of diverse subtypes of HIV. The antibodies bound to the envelope spike of many different types of HIV and blocked their ability to enter CD4+ T-cells. The investigators hoped to use cells obtained from Mr. J to inform the development of a vaccine for HIV. While development of a vaccine continues to face many obstacles, Mr. J’s neutralizing antibody activity is among the broadest and most potent identified to date.4 As a result, his continued participation in research was considered extremely important to making advances toward an HIV vaccine. The study required Mr. J to undergo blood drawing and apheresis to collect white cells. Apheresis involved placing one or two intravenous lines in his arms and required him to lie still for ninety minutes. The risks of this procedure are low and include bruising, tenderness afterward, possible loss H AS TI N GS C EN TE R RE P O RT
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of some blood, and a very low chance of infection. There are no known long-term risks. Mr. J. understood that the research posed these risks to him and would not benefit him personally. Mr. J had a long history of erratic compliance with his clinical care, and he had been dismissed from several other studies because of his noncompliance. Mr. J’s erratic compliance was hard to explain, however. He understood that it threatened both his health and his participation in research, and this clearly upset him. He very much wanted to live and very much wanted to contribute to research. He felt that he could serve as a beacon of hope for future generations. He tolerated his medications well—when he took them—and repeated psychological evaluation failed to identify any factors that might explain his behavior. Numerous interventions were attempted to help Mr. J improve his compliance, including meetings with investigators, social workers, and diabetes educators. He was always apologetic. He wanted to stay healthy and promised to take his medications. Typically, he did well for a while but then became less compliant. The compliance problems undermined Mr. J’s health but did not make him ineligible for the study. On December 30, 2009, Mr. J came to the NIH for a study visit. He reported some increase in urination and stated that since running out of his diabetes medicines, he had been sharing his father’s oral medication. His blood pressure was 150 over 80, and his blood sugar was extremely high, although he was not diagnosed as being in a diabetic crisis. Given concern about the level of his blood sugar, the apheresis procedure was canceled. The staff expressed concern about obtaining cells and information from Mr. J while his health continued to decline. Was it appropriate to keep Mr. J in the research, given his erratic compliance and the consequent impact on his health? If so, would it be appropriate, in an effort to keep him healthy and eligible for research, to devote greater medical resources to Mr. J than to other subjects in the study who have similar clinical needs but are less important scientifically? Rather than check in once a week, as the nurses do with other subjects, they could call Mr. J once a day. The investigators could even hire a personal nurse for Mr. J, even though they could not afford to hire nurses for the other subjects in the study who could benefit from increased medical support and attention. Devoting greater medical resources to Mr. J makes sense from a scientific point of view. But the team was concerned that this practice would be unfair to other subjects. The team also was concerned about how this practice might be implemented. Should the investigators evaluate the scientific value of every subject and allocate resources accordingly? Two Possible Obligations
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to recognize, as Mr. J himself recognized, that the research offered him no potential for therapeutic benefit. The investigators were obtaining information and cells from Mr. J that ultimately might benefit future patients. It was acceptable to expose Mr. J to the risks of research because he understood the lack of personal benefit and gave his voluntary consent. There are restrictions on how we can treat research subjects, however, even when they are competent and give voluntary consent. The first restriction is that the risks cannot be excessive, even if the subjects are willing to accept them. That concern is not relevant in this case.6 Another is that investigators should not disregard subjects’ medical problems, especially when the subjects are deteriorating. The easy case is when the deterioration is due to an individual’s participation in research. In that case, we withdraw the person. The more complicated case involves a subject whose deterioration is independent of the research. Two claims could be put forward about possible obligations to subjects whose clinical status is deteriorating for reasons independent of the research. One is the “offer” claim: subjects should be offered treatment. An even stronger claim, the “successful receipt” claim, is that subjects should be allowed to continue in research only if they successfully receive therapy. There may be cases in which, for scientific reasons, someone has to take certain medications to be eligible for a study. They may need to take the treatment that is being studied, or they may need to take a secondary medication (such as one to keep their kidneys functioning properly) to be eligible. But we are considering someone who was eligible. Should we have required that he take medications, not for scientific reasons, but for his own health? One way to think about this question is this: would we impose that requirement if the researcher were the subject? If you think the answer to that question is no, then perhaps we should not impose that requirement on subjects who share the goals of the study. It seems acceptable to keep individuals in a study when doing so promotes their important personal goals, even though, for independent reasons, they are not promoting other important personal goals. This suggests that the continued conduct of research on subjects like Mr. J, whose condition was deteriorating due to his noncompliance with independently needed therapy, can be acceptable. Because treatment was available, and because the investigators tried hard and repeatedly to help Mr. J remain compliant, the offer claim was satisfied. (Some might wonder whether the offer claim was justified, but since it was satisfied, the justification question is irrelevant.) Everyone gets frustrated by people who do not take the steps necessary to protect their health, especially when they cannot even explain their behavior. But frustration is not the same thing as ethical concern, and it is important to distinguish them.
o address the questions raised by this case, it is important to remember that Mr. J was a research subject, not a patient. The obligations we have to research subjects are different from those we have to patients.5 It is also important 18 HASTI N G S C E N T E R R E P ORT
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Was it appropriate to devote greater medical resources to Mr. J than to other subjects in the study who have similar clinical needs but are less important scientifically? Fair Allocation of Resources
Implementation
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ow consider the question about the allocation of medical resources. Remember that Mr. J was a research subject and that the money devoted to him was research money—money allocated to the acquisition of knowledge. In general, research money should be used to maximize the social value of the knowledge acquired, provided it is done so ethically. Mr. J was an extremely valuable subject. Allocating more resources to him, if that was what was needed to keep him in the study, was one way to get more valuable results out of the research. This approach would have been problematic only if other subjects were deprived of something they were entitled to or if the devotion of extra resources were arbitrary or unreasonable. Research subjects are entitled to whatever has been promised them in the consent or in discussion with investigators. They also are entitled to what is required in regulations and to things that have strong ethical rationales. Providing Mr. J with extra resources would not require depriving other subjects in the study of anything to which they are entitled on any of these grounds. There are familiar examples of unequal but legitimate treatment of subjects. For example, efforts to increase the enrollment of indigent patients in research often encounter logistical problems. If the prospective subject lives a distance away, it is common to provide taxi fare. If the subject has young children, it is common to provide day care while the subject is on a study visit. These practices are acceptable as long as they are based on a generalizable rule. We are not acting arbitrarily because anyone who has difficulty getting there will be offered taxi fare. And we are acting reasonably as long as we are following a rule that makes sense in light of the purpose of the activity. When these conditions are met, the fact that greater resources are being devoted to some subjects is not morally problematic. The level of scientific importance also can be relevant to the allocation of medical resources to research subjects. Given the scientific importance of Mr. J, devoting greater medical resources to him would be acceptable as long as we would use comparable resources on other subjects of comparable scientific importance. In that case, devoting the resources to him would be neither unreasonable nor arbitrary, although it was likely to be controversial. It therefore would not be morally problematic, even when subjects with similar clinical needs in the same study receive fewer medical resources than Mr. J. January-February 2015
he investigators in this case were concerned that differential treatment of Mr. J posed a dilemma. Deciding on a case-by-case basis which subjects will receive greater medical resources given greater scientific importance runs the risk of treating subjects inconsistently across cases and across time. Yet employing a common set of criteria to evaluate the scientific importance of every subject does not seem feasible. It is relatively easy to identify those who live farther from the clinic. But which criteria would be used to determine which subjects are of greatest scientific importance? Investigators should not adopt a general policy, and they should not try to evaluate the scientific importance of every subject. That would be preposterous. Could one ever say that this subject has a value of 3.4 and thus gets five minutes of the social worker’s time and that that subject is a 4.6 and gets ten minutes? Instead, investigators must rely on their judgment. They should treat all subjects the same and consider this issue only when they encounter a subject who is very unusual and extremely important. In this way, the exceptional cases help to identify the boundaries and thereby characterize the extent of the obligation to treat research subjects equally. Research subjects should be treated equally in the sense that their claims, needs, interests, and rights should be given equal consideration. But this does not imply that investigators should treat all research subjects the same. The reason is simply that subjects’ circumstances may differ in relevant ways. Some subjects may need taxi fare because they live farther away or child care because they do not have the resources to pay for it. More controversially, analysis suggests that subjects’ level of scientific importance is also relevant to determining what medical resources they should receive. It can be acceptable to devote more medical resources to subjects who are of greater scientific importance compared to subjects who have the same clinical needs but are of less scientific importance. These differences are acceptable as long as they do not prevent subjects from receiving things to which they are entitled. It also is important for investigators to follow an approach that is reasonable, not arbitrary, and applies to all subjects equally. Disclaimer
The views expressed are those of the authors and do not represent the position or policy of the U.S. National Institutes of Health or of the Department of Health and Human Services. H AS TI N GS C EN TE R RE P O RT
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Acknowledgments
This article is based on an Ethics Grand Rounds session at the National Institutes of Health Clinical Center. We thank the participants for their comments, and the subject for providing permission to publish his story. This work was funded by the Department of Bioethics at the NIH Clinical Center and the intramural research program of the NIH. 1. Council for International Organizations of Medical Sciences, International Ethical Guidelines for Biomedical Research involving Human Subjects (Geneva, Switzerland: CIOMS, 2002). 2. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report: Ethical
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Principles and Guidelines for the Protection of Human Subjects of Research (Washington, D.C.: U.S. Government Printing Office, 1978). 3. M. I. Johnston and A. S. Fauci, “An HIV Vaccine: Challenges and Prospects,” New England Journal of Medicine 359 (2008): 888-90. 4. X. Wu et al., “Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1,” Science 329 (2010): 856-61. 5. R. J. Levine, “Clarifying the Concepts of Research Ethics,” Hastings Center Report 9, no. 3 (1979): 21-26. 6. E. Emanuel, D. Wendler, and C. Grady, “What Makes Clinical Research Ethical?,” Journal of the American Medical Association 283 (2000): 2701-11.
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