oxford handbook of bioethics

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determine whether a drug was a safe and effective AIDS treatment. The ensuing debate resulted in changes in the design and conduct of AIDS clinical trials. The NAMI was instrumental in convincing Sandoz Pharmaceuticals of the social worth of pursuing studies of clozapine for schizophrenia (Fried 1998).

Community consultation has a clear role to assure that the research risks are reasonable with respect to both potential benefits to subjects as well as the social worth of the research. But as appealing as community input into the research risk and benefit assessment is, the social structure of research is not set up to assure that subjects’ rights and interests are adequately represented. Research training does not include how to interact with the subject community. And disease advocacy groups, such as the Alzheimer’s Association and the NAMI, do not have a prespecified role in setting research policy. Moreover, their membership policies, leadership structure, and how they interact with researchers and the for-profit research industry are not uniform or deliberately structured to address the assessment of research risks and benefits. Hence, the legitimacy of any one group’s ‘representation’ may be questioned.

How Should We Decide that an Adult Cannot Provide an Informed Consent?

The review of research to assure that it fits within certain categories of risk and benefit and the conduct of that review to include input from the subject community are designed to assure that the principles of beneficence and justice are adequately fulfilled. This balances the relaxation or even waiver of respect for the subject’s autonomy by means of an informed consent. But all adults are presumed competent until proven otherwise. How do we arrive at the judgment that a person is not competent in a manner that does not rely on labels (such as mental illness) or judgments based on what the investigator thinks is a ‘reasonable choice’?

Substantial progress has occurred in the last thirty years on developing a conceptual model for competency to consent to research and treatment. The judgment that a person is not competent to consent relies on an assessment of the person’s decision-making capacity. This capacity is determined by their performance on four decision-making abilities: understanding, appreciation, choice, and reasoning (Grisso and Appelbaum 1998a). Understanding, the ability that is most widely recognized as essential for competence to consent, means knowing the meaning of the information disclosed. Appreciation describes recognizing how facts can apply to one’s personal situation. Reasoning describes inferring consequences of a choice to one’s life. Choice describes the ability to state a preference consistently.

An investigator can assess a potential subject’s performance on each of these abilities by asking the individual questions tailored to the specifics of the decision at hand. For example, to assess understanding, an investigator can ask a subject to

‘say back in their own words’ certain facts, such as how it is decided what subjects receive in the clinical trial. In the case of enrollment in a randomized clinical trial, the question ‘How is it decided what subjects receive in this study?’ assesses the ability to understand randomization. A subject who answers ‘You do it by chance, a flip of the coin’ would demonstrate adequate understanding of randomization.

Studies of persons with conditions that can cause cognitive impairment show that their performance on measures of decision making ability vary largely on the severity of their cognitive impairments. Much of this variance in performance is explained by the degree of impairment in executive function, a term that describes a person’s ability to organize, plan, and categorize information (Marson and Harrell 1999).

The constructs of capacity and decision-making abilities and the methods to assess them have had a tremendous impact on the judgment of competency. They provide structure and a conceptual framework for what can otherwise be a highly idiosyncratic judgment based on a variety of characteristics that have nothing to do with the decision at hand, such as whether the person is mentally ill or makes a choice other people consider ‘reasonable’. But there are two challenges to applying the conceptual model.

What Is the Best Way to Assess Capacity?

One of the most widely studied methods to assess a person’s decision making abilities, the MacArthur Competency Assessment Tool for Clinical Research (MacCAT-CR), uses a semi-structured interview (Appelbaum and Grisso 2000). For each ability, the subject’s answers to a set of questions are scored. The sum of scores constitutes a score for that ability. For example, the MacCAT-CR measure of understanding asks thirteen questions to assess understanding, each of which is scored 0, 1, or 2, generating an understanding score that ranges from 0 to 26. Should this twenty minute long interview be the standard for all kinds of research that involves cognitively impaired subjects? Alternative methods include a quiz that asks true – false or multiple choice questions or simply an informal interview modeled after MacCAT-CR style questions but that is not scored.

The general issue is how much rigor should an assessment of decision making abilities involve. A balancing principle is needed to assure that the capacity assessment does not take longer than participation in the actual research project. A reasonable guideline is that the rigor of an assessment should be commensurate with the degree of research risks to the subjects, especially risks of the nontherapeutic components. Hence, a study that involves developing a brief memory test arguably would require a minimal assessment of capacity, such as understanding that the project is research and that it involves a memory test. In contrast, a study that involves substantial research risks, such as a test of the pharmacology of a drug that

along a continuum of four abilities (understanding, appreciation, reasoning, and choice). Persons who are judged not competent may still coherently express aspects of these abilities. For example, while a substantial number of persons with mild to moderate Alzheimer’s disease may not be capable of an informed consent to enroll in a trial, many of them are capable of a choice and can embellish this choice with plausible reasons that draw on limited degrees of understanding, appreciation, and reasoning, and are involved in decision making with their family members (Karlawish et al. 2002a, b). The ethical consequences of this are substantial and the issue was a cause of dissenting views among members of both the National Commission and the National Bioethics Advisory Commission. What responsibility does an investigator have to listen to a potential subject’s assent, dissent, or attempt to withdraw, once enrolled?

The answer to this question engages an important but largely unsettled effort to respect the autonomy of persons who are not competent. Guidelines for research that involve the cognitively impaired differ on an investigator’s responsibility vis-a`- vis each of these. The National Commission argued that investigators had to obtain subject assent and respect dissent (Department of Health Education and Welfare 1978). In contrast, the National Bioethics Advisory Commission focused only on the investigator’s obligation to respect a subject’s dissent (National Bioethics Advisory Commission 1998). Each of these requirements — soliciting assent or respecting dissent — has intuitive appeal. It is good that people are in agreement with what is happening to them, even if they do not fully grasp the plan, and the indignity of forcing someone who says ‘no’ to undergo research procedures is prima facie unacceptable.

But assent and dissent are undifferentiated constructs. As such, investigators and IRBs do not have clear guidelines for how to operationalize them. Absent such guidance, as appealing as the sentiment of respecting an assent or dissent is, investigators cannot coherently apply it.

What constitutes an assent? The higher standard of competency to consent requires evidence of some degree of adequate understanding, appreciation, reasoning, and choice. How much less of these abilities does a person have who while not capable of consent, is still capable of assent? The National Commission described assent as authorization by a person ‘whose capacity to understand and judge is somewhat impaired by illness or institutionalization, but who remains functional’ (Department of Health Education and Welfare 1978, 11332). The Commission defined assent as the subject ‘know[s] what procedures will be performed in the research, choose[s] freely to undergo those procedures, communicate[s] this choice unambiguously, and [is] aware that subjects may withdraw from participation’ (Department of Health Education and Welfare 1978, 11332). Thus, according to the Commission, assent is not simply saying ‘yes’. It means having the ability to understand procedures and voluntariness, and the ability to choose.

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But why require only the ability to choose and to understand research procedures and voluntariness? Why not require more evidence of abilities in order to assent? For example, why not require that, in addition to the Commission’s standard, a subject also needs to reason about how enrolling in the research could affect his or her everyday life? The point of these questions is that the construct of assent is contingent upon what we decide it is. The only boundaries to its requirements are that they not be the same as consent and, at the other extreme, that there must be at least some evidence of a choice.

A more reasonable construct of assent ties it to the purpose of eliciting it in the first place. Assent is a means to assure subject protection from research risk. The general principle is that, as the risks of the research increase, there is a greater need to protect subjects and, hence, for a stricter standard that assures that the subject understands the risks of the research. Thus in a study involving only minimal risks, assent may simply be the choice to enroll and an understanding that the project is research. In the case of a greater than minimal risk project, assent will need additional requirements such as understanding the risks of the procedures that are an increment above minimal risk.

Dissent has not been operationalized with the same detail as assent. The NBAC proposal argued that ‘any potential or actual subject’s objection to enrollment or continued participation in a research protocol must be heeded in all circumstances’ (National Bioethics Advisory Commission 1998, recommendation 7). Hence, an investigator should respect as a valid dissent any utterance that suggests ‘no’. NBAC did not define a dissent in the detail that the National Commission defined assent. It defended this broad and undefined standard as a means to maximize subject protection from research risks and also effectively to eliminate the dignitary harm of enrolling someone in research who simply does not want to be in it.

NBAC’s standard effectively eliminates the unappealing image of restraining a subject who repeats ‘no’ and makes physical efforts to leave the research setting. But a blanket policy of respect for dissent of any kind and at any time in the course of a research project may be counterproductive to one of the justifications for the requirement. Specifically, blanket respect for dissent may not maximize subject protection from research risks if withdrawing from the research would place the subject at some risk as a result of withdrawing.

Consider the case of a subject who is enrolled in a study that involves the permanent placement of stem cell tissue in the brain of persons with Alzheimer’s disease. After seven months of being in the study, the subject is attending a clinical assessment and during the cognitive testing says ‘No — I don’t want to do this’. Is the research assistant who is doing the testing obligated there and then to cease the testing and notify the investigator that the subject has withdrawn from the research? Or is this ‘no’ only applicable to the testing session? It is reasonable that the assistant find out the reason for the objection and attempt to address it. It may be that the subject needs to take a break or simply does not want to do the cognitive

testing but will engage in the remainder of the study visit (such as the physical exam). Suppose the subject’s ‘no’ was about overall participation in the research. In such a case, it is reasonable that the investigator and the subject’s proxy discuss the subject’s dissent with the subject in order to make sure that dropping out is in the subject’s best interests.

The claim that enrolling in research can be in a subject’s best interests is controversial because research is not treatment. But once a person is in research, withdrawing may present risks. In this case example, the implanted cells are permanent. There is a need for continued monitoring for the purposes of safety assessment. Hence, an investigator should respect the decision of subject who consistently says ‘no’ and understands the risks of no longer being assessed. In the case of a subject who says ‘no’ but does not understand the risks of dropping out, there is a strong warrant to make sure the subject’s proxy and caregiver are aware of the dissent, to agree that the subject does not understand the consequence of dropping out, and to have a plan to make sure the subject continues to receive assessments necessary for safety. Additionally, the investigator has a responsibility to determine whether this ‘no’ is part of other behavioral problems. For example, it may be that the subject is not only resisting study procedures; the caregiver may report that the person is also resisting dressing and bathing. In such a case, the person may benefit from treatment for agitation. Options include environmental manipulations — including stopping the research, caregiver education, and even pharmacotherapy.

Guidelines on Who Can Serve in the Proxy Role and How the Proxy Should Make a Research Enrollment Decision

There are two instances in research that involves persons who are cognitively impaired and not competent that are especially ethically challenging: (1) research that proposes to enroll subjects who are not capable of an assent, and (2) research that presents risks that are greater than some acceptable threshold of risk, such as minimal risk. The combination of these two instances within a single research project, that is, enrolling subjects incapable of assent into greater than minimal risk research, creates an even greater ethical challenge.

The following case illustrates these ethical challenges. Mr Smith, a previously well man, becomes critically ill from a pneumonia. His treatments require mechanical ventilation and sedation. Throughout his stay in the intensive care unit, his physicians talk with his wife to make decisions for a variety of therapeutic interventions such as the placement of an arterial line in order to monitor closely Mr Smith’s labile blood pressure.

In general, society is comfortable with Mrs Smith serving in this role of making clinical care decisions on behalf of her husband. She does not need legal authorization. Instead, this role follows naturally from her close relationship

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with her husband. But what if an investigator wishes to recruit Mr Smith into a clinical trial to test a new critical care technique? Mr Smith is so cognitively impaired that he cannot grant an assent or express dissent. Is an informed consent from his wife an appropriate extension of her role as a proxy for clinical care decisions? This question raises two issues: whether she can serve in this role, and, even if she can, how she should make the decision.

Thirty years ago guidelines for research that involves persons who are cognitively impaired required Mrs Smith to have legal authorization to serve as a research proxy. Since then, there has been a general loosening of this requirement. Instead, guidelines argue that the model for clinical care decision making should apply to research decision making. Close family who serve as a proxy for clinical decisions can also serve as a proxy for research decisions (National Bioethics Advisory Commission 1998; National Human Research Protections Advisory Committee 2002).

But while requirements for who can serve in the role of a research proxy resemble the practice used in clinical care decision making, requirements for how that person should make a decision differ from clinical care guidelines. In clinical care, a proxy should exercise a substituted judgment. To refer to the case described above, this means that Mrs Smith should choose what Mr Smith would choose if he were capable of making that choice. If Mr Smith had previously written a document called a ‘living will’ that specifically sets out future preferences for care, Mrs Smith should follow that document. But what if Mrs Smith does not have sufficient information about her husband’s preferences to make a substituted judgment? Absent such knowledge, she is then expected to decide what is in her husband’s best interests.

This conceptual framework for clinical care decision making seems incompatible with research decision making. Absent a substituted judgment that the noncompetent person would have wanted to be in research, there is no best interests justification for enrolling a person in research. Research is not an activity designed solely for a subject’s best interests. It follows then that a proxy can only grant an informed consent to enroll a noncompetent person in research on the basis of a substituted judgment. This requirement for a substituted judgment as an absolute condition for research enrollment has led to the recommendation that a proxy can only enroll a noncompetent person in greater than minimal risk research that does not offer the prospect of benefit to the subjects if the person had previously executed an advance directive that expressed a willingness to be in such research (National Bioethics Advisory Commission 1998). In contrast, most guidelines accept that a substituted judgment is not necessary for proxy informed consent for minimal risk research. The defense of this position is based on a utilitarian argument that the value of the knowledge to society exceeds the risks to subjects and the dignitary harm of putting someone in research that they may not have wanted to participate

in. Thus, the degree of research risk is the central determinant of whether we take a stance of either strictly protecting autonomy or advancing the common good.

These requirements presume that they in fact do reflect how people would want their proxy to make research enrollment decisions. Studies of people’s willingness to grant their family members authority to serve as proxy decision makers suggest that this may not reflect their ethic. Most people are comfortable with granting trusted family members’ discretion in making choices that may even violate a research advance directive. Instead, people want their proxy to balance substituted judgment with what is in their best interests. A survey of family members of persons with Alzheimer’s disease found the vast majority willing to execute a research advance directive, but when offered the opportunity to execute one, few did it (Wendler et al. 2002). The majority preferred to have their research advance planning instructions followed over a family member’s choice, but the majority also permitted a family member to overrule these instructions in the case of potentially beneficial research.

Although the investigators did not examine the contentious issue of the discretion people would give to a proxy over enrollment in research that is judged nonpotentially beneficial or whose risks of nontherapeutic procedures are greater than minimal, these results suggest that the requirements that a proxy can only enroll a noncompetent person in more than minimal risk research on the basis of a substituted judgment or that a proxy can enroll persons in minimal risk research in the absence of a substituted judgment may not reflect how people conceptualize respect for their autonomy when they are themselves no longer capable of asserting their autonomy. ‘Best interests’ is an unusual standard in research settings where there is no plausible individual benefit or where there are real chances of risk to the research participant. In these situations, ‘best interests’ might be understandable only as an appreciation for the altruistic intents of either the subject or the proxy and the willingness of the subject to grant their proxy discretion in exercising this altruism regardless of the degree of research risk.

CONCLUSION

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Human subjects research presents an ethical dilemma between advancing the interests of society while protecting individuals from harms encountered in an effort to accomplish the research. Democratic society’s standard approach to resolving this dilemma is a procedural solution: informed consent. But in the case of research that involves subjects who have cognitive impairments this solution has unacceptable consequences, including an absolute prohibition on research on entire segments of the population. To avoid these consequences, society must find a standard that allows for vital research while at the same time providing adequate protection for vulnerable individuals.

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Thirty years of scholarship have proposed a set of subject protections that attempt to justify research with either proxy consent or even a waiver of any consent. The failure of these proposed protections to achieve a consensus reflects continued ambiguity in how to justify research risks, the meaning of an assent and dissent, and the ambiguity on whether substituted judgments are essential when a proxy makes a research decision.

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R E S E A R C H I N

D E V E LO P I N G

C O U N T R I E S

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flO R E N C I A LU NA

RESEARCH ethics already has a history of its own. Just as bioethics focused initially on autonomy and individual rights, and recently on questions about public health, justice, and social rights, research ethics has also turned from problems of autonomy and informed consent to more general ones that embrace obligations to research subjects and the community, such as nonexploitation. The situation of societies with vulnerable and marginal populations is now being analyzed thoroughly. For these populations, informed consent is merely the first step in a far more complex and problematic process. This shift in the focus of interest is related to the problems that developing countries have brought to the international debate.

In this chapter I examine the problems that research ethics confronts in developing countries and the impact that research in developing countries has had on research ethics. In order to show this I shall analyze the first paradigmatic cases that gave rise to the ‘classic’ analysis of research ethics. Hence, in this first part, many of the ethical concerns apply wherever research is conducted and are not particular to developing countries. Secondly, I shall describe the complex process of research by analyzing different research actors and their interests in the current research process. Thirdly, I shall sketch some of the recent cases that have prompted fierce ethical debate surrounding research in developing countries. I shall indicate a new battlefield: the ethical guidelines for research, in particular the Declaration