oxford handbook of bioethics

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of elderly residents of a long term care facility to injected cancer cells (Katz 1972). During this time several states adopted laws that limited the kinds of research that could enroll persons who were residents of institutions or under legally appointed guardianship.

But conditions for the treatment of the mentally ill were changing. The National Commission noted in its report that ‘stereotyped notions’ about the causes and treatment of psychiatric illnesses no longer applied. The changes included a transformation in concepts of mental illness from psychodynamic to biological pathogenesis. Biological psychiatry saw the proposed guidelines as a barrier to valuable research. In addition, public policy for the care of the mentally ill was changing. States were adopting an approach of ‘deinstitutionalization’ of the mentally ill. In short, the National Commission wrote recommendations for an era that was coming to a close.

The second reason for the change in focus was that organized advocates for the mentally ill began to divide in their view of research. The general attitude was no longer that persons with mental illness should be protected from research. Instead, groups such as the National Alliance for the Mentally Ill (NAMI) advocated that more research was needed to improve the care of the mentally ill. NAMI advocated clinical trials in the United States to obtain FDA approval of the anti-psychotic clozapine for the treatment of acute psychosis (Fried 1998). Unlike clozapine, available anti-psychotic medications had the risk of a disabling movement disorder, but clozapine had the risk of a sudden decline in infection-fighting white blood cells. It is a testament to the power of a patient advocacy group aligned with a pharmaceutical company and investigators that the research necessary to obtain FDA approval occurred in spite of these risks and the absence of regulations to guide research that involves persons with acute psychosis, a condition that can cause cognitive impairment.

Related to this political transformation was a change in the understanding of how mental illness impacts on a person’s ability to make a decision. Prior to the 1980s much of the writing on informed consent focused on legal perspectives. For example, the National Commission invoked the concept of a ‘legally valid informed consent’, which referred to the competency of the person who granted it. But the law recognized at least three legal concepts of competency: a rational reasons standard, capacity to reach a reasonable result, and capacity to make a decision. It is notable that the third — the capacity to make a decision — was the view of only a minority of courts and would later become the most widely recognized standard.

Instead, the most widely recognized standards for competency assessment were the first two: a person is competent if his or her answer was what a reasonable person would choose or the person’s reasons were ‘rational’. While such a standard may have limited legitimacy in clinical care decisions when the balance of benefits clearly outweighs harms and risks, it is entirely inadequate for decisions where reasonable people disagree, such as the merits of enrolling in research.

Medicine and medical researchers had little if any interest in the issue of what it means to be competent to consent. For example, the Commission’s review of the informed consent practices for mental health research does not discuss if the investigators made an effort to assess the subject’s capacity to consent. In all likelihood, they did not. This reflected medicine’s and medical research’s attitude about informed consent that ranged from indifference to open hostility (Demy 1971; Ingelfinger 1972). Although psychiatrists were recognized as experts in judging competency, it was not until the 1980s that the field began to articulate a conceptual framework of competency and then develop a social science to validate it empirically.7

Medicine and medical research have transformed how they decide whether a person is competent to consent from judgments of competency that were based largely on the diagnostic label and whether the person makes a ‘reasonable’ or ‘rational’ choice — i.e. a person with acute schizophrenia is competent if he agrees to be hospitalized — to an assessment of the functional consequences of cognitive impairment: diminished decision making capacity. A key finding from decision making capacity research is that labels do not match how a person performs on a measure of capacity. Being labeled ‘mentally ill’ did not substantially equate with being not competent. For example, most persons hospitalized with schizophrenia perform as well on measures of their decision making abilities as age and education matched non-schizophrenic persons (Carpenter et al. 2000).

The recognition that the ability to make a decision, the foundation of being competent, could be assessed and measured has slowly influenced the practice of informed consent in clinical research. It was not until the latter part of the 1990s that researchers began to assess explicitly the ability of a potential subject to provide informed consent,8 and some medical journals required investigators to state how they obtained informed consent from the subjects (Charney et al. 1999).

In the years that followed the National Commission’s never-adopted guidelines, both public and private organizations repeatedly noted the lack of federal regulations to provide specific guidance for the conduct of research that involves adults with disorders that could impair their competency to provide an informed consent (Fletcher et al. 1985; Melnick et al. 1985; American College of Physicians 1989; National Institutes of Health, Office of Extramural Research 2001). As these organizations attempted to fill this gap, they struggled to settle on a coherent language to

7 The mental health network supported by the MacArthur Foundation were leaders in developing this conceptual framework (Appelbaum and Grisso 1988; Grisso and Appelbaum 1998b) and empirically testing it with instruments to assess the capacity to make research (Appelbaum and Grisso 1995) and treatment (Grisso and Appelbaum 1995) decisions.

8 At the Alzheimer’s Disease Center, where I conduct research, all persons with Alzheimer’s disease who enroll in clinical trials or greater than minimal risk research are required to complete a quiz that assesses their understanding of the key elements of the research project. This quiz is used to assist in the judgment of subject competency, and the informed consent form includes a section to document whether the subject is competent to consent, and, if not, is assenting to participation.

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describe what class of subjects they were trying to protect and the problem that precipitated the whole issue in the first place — the concept of competence to consent. For example, proposed guidelines issued by the American College of Physicians in 1989 addressed ‘cognitively impaired subjects’ (American College of Physicians 1989) and the last national effort to write guidelines, by the National Bioethics Advisory Commission (NBAC) in 1998, was titled ‘Research Involving Persons with Mental Disorders that May Affect Their Decisionmaking Capacity’ (National Bioethics Advisory Commission 1998). NBAC’s title reflects a tension between two views. On the one hand, there was the argument that the focus on ‘mental illness’ was necessary because of the stigma and history of abuse and exploitation such persons face. In contrast, persons schooled in the science of competency assessment argued that the focus simply perpetuated a historical stigma of mental illness while at the same time neglected the category of disorders that are not mental illnesses but can still impair decision making capacity, such as critical illness that requires sedation and ventilation.

Recent events suggest there is consensus on the focus of ethical concern: disorders that cause cognitive impairment (one of which is mental illness) that may impair the ability to make a decision. In 2002 the National Human Research Protections Advisory Committee, a multi-disciplinary advisory panel to the Federal office that oversees the regulation of human subjects research, the Office of Human Research Protections, issued recommendations modeled after the NBAC guidelines but changed the focus to research that involves all adults who lack decisional capacity for any reasons (National Human Research Protections Advisory Committee 2002). Similarly, a Department of Health and Human Services working group on the NBAC Report endorsed the position that the scope of the NBAC recommendations applies to all persons with decisional impairment, irrespective of the cause of the decisional impairment (National Institutes of Health, Office of Extramural Research 2001).

THE ET HIC A L FRA M E WOR K

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Competent adults are allowed extensive discretion in their choice of whether enrolling in research is in their best interests. These interests can include hopes for personal benefit or the fulfillment of altruistic values (Daugherty et al. 1995). The general ethical framework for research that involves cognitively impaired adults who are not capable of making this choice themselves does not grant their proxies or IRBs this same degree of discretion over another person’s life. Instead, proxy consent or even no informed consent is appropriate within a framework of subject protections that rely on further specification of the principles of research ethics.

The architecture of this framework is that the research is relevant to the subject’s condition, its risks and benefits fit within certain categories, and efforts are taken to

assess the subject’s competency and to protect the autonomy of the noncompetent subject. Each aspect of this framework is discussed below.

How Much Research Risk Is Permissible to Expose a Noncompetent Adult?

During the 1970s the National Commission addressed whether it is possible to conduct research ethically without the subject’s informed consent. The Commission addressed the ethics of research that involves selected subject populations from whom informed consent was not possible: children (Department of Health and Human Services 1991, subpart D) and persons with mental illness severe enough to warrant institutionalization (Department of Health Education and Welfare 1978). The Commission also addressed categories of research in which written informed consent from the subject was either not feasible (Department of Health and Human Services 1991, sect. 46.116), such as deception research, or seemed an excessive subject protection, such as a study that used existing samples taken for clinical purposes (Department of Health and Human Services 1991, sects. 46.117(c)(2), 101(b)(4) ).

The conceptual framework the Commission developed to address these situations was a substantial step away from the strict requirement for informed consent. By relaxing informed consent as an absolute requirement for all human subjects research the Commission established a standard that recognized that the social worth of research could outweigh a strict adherence to informed consent. In sum, vulnerable subject populations should have access to research and its potential benefits, and many kinds of valuable research not otherwise practicable without a waiver or modification of informed consent were viewed as being permissible.

The conceptual framework relied on more nuanced applications of the principles of beneficence and justice (Weijer 2000). Waivers and modifications of written informed consent from the subject are permissible if the research risks and potential benefits fulfilled specific criteria: the necessity requirement and specific categories of research risks and benefits. The ‘necessity requirement’ describes the finding that the research is relevant to the vulnerable subject population and could not be otherwise done with a nonvulnerable population who themselves can consent to be in the research. ‘Relevant’ means the research addresses a problem that is encountered in the daily lives of the vulnerable population. This requirement is an absolute requirement. In other words, no amount of other reasons or subject protections can justify research that does not fulfill the necessity requirement.

The second criterion addressed by the Commission described categories of research risk and benefit that circumscribe when it is appropriate to enroll a subject who cannot consent. The Commission proposed a framework based on three concepts: minimal risk, potential benefit, and the importance, or value, of the knowledge to be gained from the research. Proxy consent is appropriate if the

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research risks meet a criterion of minimal risk. In the case of greater than minimal risk research, further subclasses were created. The increment could be just a minor increment above minimal risk, or the research might have a reasonable prospect of potential benefit to the subject. If neither of these criteria could be met, then the research had to be reviewed and approved by a national panel. With the exception of emergency research, subsequent proposals for research that involves cognitively impaired adults (as well as children) have all used this basic framework.

The conceptual model for this framework justifies research risks based on balancing risks against two things: the potential benefits to the subjects and the importance of the knowledge that could reasonably be expected to result from the research. This model was consistent with two of the Commission’s recommendations in the general guidelines for human subjects research. The guidelines for IRB review of research required that the IRB judge risks reasonable to the potential benefits to subjects and to the importance of the knowledge that could reasonably result from the research (Department of Health and Human Services 1991, sect. 46.111(A)(2) ) and that the risks of research are minimized wherever possible by linking research procedures to existing procedures done for clinical purposes (Department of Health and Human Services 1991, sect. 46.111(A)(1) ). This model creates two risk assessments: a risk to potential benefit assessment and a risk to knowledge assessment.

But the Commission never addressed two shortcomings in its conceptual model. The failure to do so is the source of substantial disagreements in the ethics of research that involves noncompetent adults (Karlawish and Hall 1996; Weijer 2000; McRae and Weijer 2002). First, the Commission never clarified what risks should be balanced against the potential benefits to subjects and what risks should be balanced against the importance of the knowledge to be gained from the research. Consider the case of a clinical trial of a promising new intervention for sepsis that plans to enroll persons who are critically ill and therefore typically unable to communicate and thus to provide an informed consent. A common perspective on the risks and benefits of this study is that it is potentially beneficial and also presents risks that are greater than minimal but the subjects are so sick that those risks may not be too great. This ‘whole protocol’ approach to research risk assessment balances all the research risks against the potential benefits to the subjects. While such an approach makes sense in clinical care, it does not fit with the nature of research. Research studies inherently involve procedures designed not to benefit subject but to benefit science by producing generalizable knowledge. It is thus potentially exploitative to justify risks of interventions done solely to gather knowledge with the potential benefits of the intervention.

The second shortcoming in the Commission’s model was that it did not clearly articulate how to interpret the minimal risk definition: ‘The probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or the performance

of routine physical or psychological examinations or tests’ (Department of Health and Human Services 1991, sect. 46.102(i) ). A clear limitation in this definition is the absence of a comparison group, that is an anchor upon which an IRB could answer the question to whose daily life should the IRB compare the risks of the research? Should the IRB compare the risks of the research to the risks encountered in the daily lives of the potential subjects of the research or in the daily lives of healthy persons? The draft regulations stated healthy persons but this was dropped to yield the definition that makes reference to no comparison group (Department of Health Education and Welfare, Office of the Secretary 1979). The commentary to the final rule stated that the definition referred to the risks faced by the subjects of the research (Department of Health Education and Welfare, Office of the Secretary 1979). The authors of the regulations explained that this revision was intended to permit a waiver of informed consent for research that involved persons with head injury (McCarthy 1995). Unfortunately, this was a quick fix without the necessary public discussion of a substantial modification in the nature and intent of the rules for waiver and modification of informed consent in research that involves vulnerable subjects. It was politically ambitious and ethically simplistic to think that a single word modification in the definition of minimal risk with an explanation in the commentary section would settle the issue of when it is appropriate to waive informed consent.

Recent scholarship has attempted to reconcile the shortcomings in the conceptual model. The proposal developed by Charles Weijer and adopted by the National Bioethics Advisory Commission is called ‘component analysis’ (Weijer 2000). Component analysis begins with the recognition that research involves at least one of two kinds of distinct components: therapeutic and nontherapeutic. Therapeutic components describe interventions that may help subjects, such as a promising drug for which there is legitimate but uncertain evidence it is safe and effective. The risks and benefits of these interventions are justified by the epistemic condition of equipoise: the honest professional disagreement that a new intervention is at least as good as the current standard of care (Freedman 1987b). Research also includes interventions that are solely done to gather generalizable knowledge. These components, such as additional blood draws and randomization, are part of the nontherapeutic components of research. The risks of these interventions are justified by the value of the research results, that is, the importance of the knowledge to be gained from the research.

Component analysis provides a useful tool to answer the critical question in the ethics of research that involves the cognitively impaired: how much risk is appropriate to expose a noncompetent subject? The answer to this question is in the degree of nontherapeutic risk that is deemed acceptable. Persons who oppose exposing noncompetent subjects to any risk not justified by potential benefits to the subjects would answer ‘none’. Hence, noncompetent subjects, including children, could not be in any kind of research as all research involves some

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procedures that are done solely to generate generalizable knowledge, however trivial those procedures may be. The general consensus is that this position is extreme. Instead, assuming the research has passed the necessity requirement, it is acceptable to expose noncompetent subjects to risks that are no greater than minimal risk.

The remaining controversy is how to assess whether research risk is minimal risk. The definition lacks a comparison group, that is, an anchor upon which an IRB could answer the question to whose daily life should the IRB compare the risks of the nontherapeutic components of the research. A reasonable answer is based on what is the point of research: to create valuable knowledge that can benefit society. In accord with the principle of justice, the increment of risk noncompetent subjects face to contribute to society’s well being should be minimal and the assessment of this degree of risk should not be based on the severity of the subject’s illness. To base the assessment of minimal risk on the severity of the subject’s illness effectively means sicker subjects could be exposed to greater research risks because they are sick. Such an approach exploits subjects on the basis of their vulnerability. Instead, to determine whether the nontherapeutic components present minimal risk (or some accepted increment above it), the IRB should compare the risks of the nontherapeutic components to the risks faced in the routine medical and psychological tests encountered in the lives of an average person.

The failure to reconcile what risks apply to the minimal risk criteria and how to interpret the definition of minimal risk has led to incoherent standards for acceptable research risks. Perhaps the most egregious example is the emergency research regulations. The regulations created a category of permissible research risk and benefit called a ‘potential . . . to provide a direct benefit to the individual subjects’ (Department of Health and Human Services, Food and Drug Administration 1996). The IRB is instructed to judge whether a study met this standard based on a tripartite risk benefit assessment: ‘risks associated with the investigation are reasonable in relation to (1) what is known about the medical condition of the potential class of subjects, (2) the risks and benefits of standard therapy, if any, and (3) what is known about the risks and benefits of the proposed intervention or activity’ (Department of Health and Human Services, Food and Drug Administration 1996).

The standard suggests three risk assessments. Research risks should be compared to the severity of medical condition, the risks and benefits of standard therapy, and the risks and benefits of the proposed intervention. There are a number of shortcomings to this tripartite standard (McRae and Weijer 2002). First, it suggests that the potential benefits of a promising intervention can justify the risks of interventions that are designed to answer the research questions, such as additional monitoring, that is, the potential benefits of therapeutic components can justify the risks of nontherapeutic components. Second, the assessment of risk against the

severity of medical condition suggests that the sicker the subject population is, the more appropriate are increasing research risks. While this is accepted in clinical care, it is not at all appropriate that increasing vulnerability justifies exposing people to increasing risks of nontherapeutic components. Third, the balancing of ‘risks associated with the investigation’ to ‘risks and benefit for the proposed intervention’ is at least vague and even incoherent. What risks of the investigation are distinct from the risks of the proposed intervention? Fourth, the balance between risk and the importance of the knowledge that may reasonably result is entirely absent. In short, while the idea that some kinds of research can be potentially beneficial and present minimal risks to subjects is intuitively sensible and a justification for enrolling persons who themselves cannot consent, the emergency research risk and benefit standard shows how considerable conceptual ambiguity exists in how to make this assessment.

Component analysis clears up the kinds of conceptual ambiguity found in the emergency research regulations. Consider the case of a clinical trial of a promising new intervention for sepsis that plans to enroll persons who are critically ill and therefore typically unable to communicate and thus to provide an informed consent. A common perspective on the risks and benefits of this study is that it is potentially beneficial and also presents risks that are greater than minimal but the subjects are so sick those risks may not be too great.

Component analysis reaches a different and conceptually more coherent assessment. The therapeutic elements of the research — in this case the promising new intervention — may present substantial risks, such as a serious allergic reaction. But these risks are not part of the minimal risk assessment. They are justified by the potential benefits of the intervention and the equipoise condition. In contrast, the nontherapeutic interventions such as the additional tests done on the subjects to assure that the results are gathered in a manner that is scientifically rigorous are justified by the importance of the scientific question — a better treatment for sepsis. These risks should not be greater than minimal or perhaps some increment above minimal, depending on the comparison group used to interpret the minimal risk definition. This study would be considered potentially beneficial and minimal risk. Depending on the nature and extent of other subject protections, the waiver of informed consent or the use of proxy consent would be permissible.

The addition of risky research procedures to answer scientific questions demonstrates how component analysis provides a more coherent risk assessment than one that does not distinguish between therapeutic and nontherapeutic components and links the judgment that risks are acceptable to the severity of the subjects’ condition. Suppose the study included the placement of a right heart catheter to monitor how sepsis affected pulmonary pressures. This intervention is not part of the efficacy or safety assessments. It is done solely to gather knowledge about sepsis. Hence, it is part of the nontherapeutic components of the study and needs to pass the minimal

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risk standard. Such a procedure presents risks that are greater than those ordinarily encountered in the lives of reasonable persons. This potentially beneficial study is also greater than minimal risk. The waiver of informed consent or the use of proxy consent would be highly controversial or even prohibited.

In summary, the ethical framework of research risk and benefit assessment that articulates conditions when it is acceptable to obtain informed consent from someone other than the subject or even a waiver of informed consent relies on two features. First, there is the ‘necessity requirement’. The recruitment of the subject population must be necessary and not simply convenient. This avoids scandals such as the Jewish Chronic Disease Hospital case (Katz 1972). Second, the research risks and benefits should pass component analysis. Components that are part of therapeutic elements of research, such as the intervention and its control group, are justified if there is legitimate disagreement within the community over which intervention is beneficial. Components that are part of nontherapeutic elements of the research, such as the techniques to assure that the knowledge gained from the research is generalizable, should fulfill a standard of being no more than minimal risk or some acceptable increment above that threshold.

What Is an Appropriate Process for Assessing Research Risks and Benefits?

The standards outlined above describe the categories of research risks and benefits that are acceptable to allow investigators either to obtain informed consent from a proxy or to waive informed consent from the subject and proxy. The judgment that the research fits within the categories of potential benefit and minimal risk is informed not only by knowledge of the science of the intervention, but also by the experience of the daily lives of the subjects.

The need for the perspective of the daily lives of the subjects suggests that the research review process needs to include the perspective of the subject community and, for subjects who are vulnerable, the people who care for them. IRB membership must include a representative of the community and the IRB is empowered to bring in additional members as necessary to assist in reviewing a study (Department of Health and Human Services 1991, sect. 46.106) and is in particular encouraged (but not required) to call on a member of or advocate for any vulnerable study populations, but the process of research design and review may not adequately foster this kind of input. There are a number of reasons why.

Typically, studies are designed by the expert medical community and then reviewed by each study site’s IRB. This expert medical community often includes persons who have substantial interests in the commercialization of the results of the research. Hence, their judgments about whether legitimate uncertainty exists and the design of the trial that will settle this uncertainty are influenced not only by

the considerations of medical science but also by corporate concerns of profit and patent protection (Krimsky 2003). The IRB does not routinely seek the input of the potential subjects of the research. The results of IRB review are not routinely shared with other IRBs reviewing the same protocol. Although the point of research is to produce generalizable knowledge, public disclosure of results is not required, and, in the case of some research, it may not occur.

In the case of research that involves cognitively impaired adults, the principles of beneficence and justice warrant greater attention to involving the subjects in the research risk and benefit assessment. Perhaps the best example of the requirement for involving the subject community is the emergency research regulations (Department of Health and Human Services, Food and Drug Administration 1996). They require the study sponsor and investigator to consult with representatives of the communities from which the subjects will be drawn, and, prior to starting the research, public disclosure to these communities of the plans for the research and its risks and expected benefits. In the event that an IRB does not approve of a study, the regulations require the IRB to document why it cannot approve it, and the sponsor is required to disseminate this report to other investigators and IRBs who are involved in the research. During the course of the research, a data safety and monitoring board should review the conduct of the study. Finally, at the close of the research, the sponsor must disclose the results to the community where the research was conducted. The general theme of this process is an open and public discussion at both the start and the end of the social worth of the research.

Among these requirements, the most innovative are the requirements for community consultation and public disclosure and a sharing of other IRBs’ determinations. This model of democratic deliberation is novel to the social structure for research review, approval, and monitoring. The requirement that the sponsor and the investigator consult with representatives of the community from which subjects will be drawn includes suggestions for public meetings to discuss the protocol, creating a panel of community members from which the subjects will be drawn and consultants to the IRB, and adding community members who are not affiliated with the institution to the IRB. The goal of these efforts is to promote the public’s comprehension of the study and the proposed waiver of informed consent and elicit community opinions and input. While there are not formal requirements for the community to approve the research or alter its design, the acts of consultation and disclosure provide the community the opportunity to weigh in on what are permissible risks in the pursuit of research to develop new therapies.

Community consultation makes conceptual sense. The histories of AIDS and schizophrenia research suggest that there is a need to involve the community of potential subjects proactively into the process of research review (Epstein 1996; Karlawish and Lantos 1997). In AIDS research, patients with the disease sharply and vocally disagreed with the standard approach that investigators proposed to