The Centrality of Voluntary and Informed Consent

The principal topic addressed by this report—what are the ethical requisites for research involving persons with mental disorders that may affect their decisionmaking capacity?—raises fundamental questions about governmental and professional regulation of all research with human subjects. Although public attention in the United States to the ethics of research involving human subjects traces its history to the revelations in the trial of the Nazi doctors five decades ago at Nuremberg, the widespread acceptance of the necessity of public oversight of research was not evident for another two decades—arising from the disclosure of ethical lapses in the United States71 and elsewhere.72 The regulatory structure (as embodied in 45 CFR 46) and professional norms that have evolved over the past 30 years in the United States have been built on a central premise of the need to ensure respect for research subjects and to protect them from exploitation and unwarranted harm. The result has been a system of prior review of research protocols by Institutional Review Boards, or IRBs, to ensure their scientific and ethical quality and thus to weed out protocols that would expose subjects to inappropriate risks, exploit them, or use them without their informed consent.

In recent years, some have argued that ensuring access of all groups to experimental treatments should also become a goal of research regulation.73 In their view, insistence on obtaining the maximum benefit from research while minimizing the risk of harm to subjects unduly restricts some patients from obtaining new although experimental medical interventions for their conditions. Thus they argue that regulatory requirements should be adjusted to allow patient-subjects, especially those for whom existing therapies are inadequate, greater access to participation in research protocols.

While obvious and important differences exist between these two perspectives—protection versus access74—there is nevertheless widespread agreement by both sides on the need for voluntary informed consent of research subjects. The landmark Nuremberg Code, for example, makes such consent the first and essential requisite of ethical research. Similarly, the current demand for greater access to participation in research protocols rests on a model of respect for persons and patient self-determination. In either view, the basic presumption is that research protocols are not acceptable if subjects have not had the opportunity to be informed about the methods, objectives, potential benefits, and risks of research, and to decide whether or not to participate in a voluntary and informed fashion. NBAC notes, of course, that under existing federal regulations, informed consent can be waived, under very special circumstances. One permitted category of waiver requires the IRB to find and document that the research presents no greater than minimal risk, that the waiver will not adversely affect the subjects’ rights, that the research could not be practicably carried out without the waiver, and that the subjects will be provided with pertinent information after participation whenever appropriate.75

Plainly, then, the capacity of the human subject to participate in this process of informed decision making is a critical component, though not the total corpus, of the present system of public oversight of biomedical and behavioral research. Under a strict "protection model" those who lack the capacity to give informed consent, or whose capacity to do so is uncertain, may be excluded from participation as research subjects. Under the strict protection model such exclusion may seem appropriate since the underlying principle is that it is better to protect subjects from risks of harm, even at the cost of slowing the progress of scientific investigation, the development of new medical advances, and access to potentially beneficial but unproven therapies. In this model there would correspondingly be fewer opportunities to assess promising new clinical approaches to the diseases from which these potential subjects suffer. The obvious dilemma presented by such a strict protection standard is that research leading to therapies for those disorders would be slowed as a consequence of the limited capacity of those who suffer from such disorders to consent to participate in such research.

Conversely, under the "access model" a total barrier to research for persons with mental disorders is suspect precisely because it would prevent some people from obtaining the potential benefits that such research might offer them, either directly as a result of participating in the research or indirectly as a result of the improved understanding of their illness and of methods for treating it that may result from the research in question. From either perspective, however, informed consent is essential and therefore decisionmaking capacity is a pivotal issue that must be addressed. Voluntary, informed consent is normally an essential feature of ethically and legally acceptable research. It embodies, as already noted, the respect for persons that is one of the most fundamental principles on which all physician-patient interactions are based, and it is also seen as one of the critical means of protecting people from unwarranted research risks. As a general rule, therefore, the basic threshold that qualifies an individual for participation in the informed consent process is an adequate level of decisionmaking capacity. When this threshold cannot be met, because of decisional impairment or incapacity, other important considerations arise.

The use of the term "impaired decisionmaking capacity" implies a condition that varies from statistical or species-typical normalcy, especially in the context of discussions about the ethics of human subjects research. In this sense, for example, normal immaturity should not be regarded as a decisional "impairment" since the very young cannot be expected to have achieved the normative level of decisionmaking capacity. Conversely, normal aging need not involve impaired decision making, and assuming such an impairment is inappropriate. (Throughout this report the term "capacity" is used rather than the term "competence"—although the two are often used interchangeably—because the latter often refers to a legal determination made by a court, and the former refers to a clinical judgment.)76 Therefore, "decisional impairment" refers to a limitation or an incapacity that is not part of normal growth and development. For example, senile dementia and schizophrenia are conditions that deviate from regular developmental patterns (e.g., dementia is not part of the normal aging process) and are not captured under regulatory categories intended to address periods in the life cycle (e.g., fetuses and children) or certain defined groups (e.g., pregnant women or prisoners).

In practice, it is not usually difficult to determine whether a person lacks all ability to make decisions, so findings of incapacity in this global sense are not often subject to much disagreement. Much more challenging (and the subject of numerous "hard cases" in the law) is determining whether someone with limited decisional capacity has sufficient capacity to make a particular choice, thereby demonstrating a level of capacity that one, on moral principle, should honor.

Individuals who have some cognitive deficit that renders them incapable of making some treatment decisions may nevertheless be quite functional and independent in activities of daily living. Having a decisional impairment need not imply a particular social or legal status. As a functional term, decisional impairment is neutral with respect to other particular characteristics an individual may possess. Moreover, as Grisso and Appelbaum have noted, what counts as impaired decisionmaking capacity is partly determined by the standard of competence that is chosen.77

Capacity refers to an ability, or set of abilities, which may be situation- or context-specific. There is a growing consensus that the standards for assessing decisionmaking capacity include the ability to evidence a choice, the ability to understand relevant information, the ability to appreciate the situation and its consequences, and the ability to manipulate information rationally.78 These standards were developed initially with a focus on the capacity to consent to treatment, not research. Recently, however, the American Psychiatric Association approved guidelines for assessing decisionmaking capacity in potential research subjects, which substantially rely on these same standards.79 Whether the context is treatment or research, the particular standard or combination of standards selected for assessing capacity will determine what counts as impaired decision making. For instance, when more stringent standards are used, the result could be over inclusive and thereby deprive a large number of people of their rights to make treatment or research decisions. Thus, what counts as decisional capacity is dependent on a subtle set of assumptions and evaluations.

When a standard of capacity has been chosen, one must set the threshold that distinguishes those who meet the standard from those who do not. Of course, different mental disorders may have an effect on decisionmaking capacity in different ways—some, not at all; some, intermittently; some, more persistently. The decision regarding where the threshold of capacity is set is influenced in part by a society’s value system. In a liberal democratic society such as ours, in which the scope of state authority over individual lives is strictly limited and subject to careful scrutiny, this threshold tends to be low. But the selection of a threshold of decisional ability is not wholly a political one, as it must be justified by the individual’s ability to satisfy certain benchmarks.80

Another facet of decisional impairment that is often encountered in the clinical setting is the variable manifestation of such impairments. The gradual loss of capacity rarely follows a straight line, and in psychiatric illnesses such as bipolar disease, cycles of mania and depression sometimes follow substantial periods of lucidity.

In a certain sense, all of us are decisionally impaired at various times in our lives. When we have been exposed to anesthetic agents, when we have had too little sleep, when a life event disrupts our equilibrium, or when we have over-indulged in alcoholic beverages, our ability to process information and weigh alternatives in light of our values is likely to be reduced. These acute but temporary forms of decisional impairment are not usually matters of concern, because decisions about participation in a research project can normally wait until the impairment has passed.81 Rather, the impairments that raise the greatest concern are those that persist or can be expected to recur. Reference to a decisional impairment in this report relates principally, but not exclusively, to a relatively persistent condition, that is, a condition that is ongoing or that may periodically recur. There are other sources of decisional impairment that are normally more temporary, such as the transitory side effects of medical treatment, but that might also call for special planning if participation in a research protocol is being considered. Some of the discussion and recommendations in this report may be relevant to these other factors that may affect decisionmaking capacity but, again, the primary concern of this report is with the potential effect of neurologic or psychiatric conditions on the decisional capacity of potential research subjects.

Following a capacity assessment by a qualified professional, a person may be found to lack the capacity to make informed decisions. Such a condition, as noted above, can result from a variety of causes including medical illnesses, cognitive difficulties, or constraints on personal freedom due to institutionalization or dependency upon those who provide one’s treatment. The specific concern of this report, however, is with persons whose decisional impairments may be related to the presence of what we currently understand to be a mental disorder.

Nevertheless, it is neither ethically acceptable nor empirically accurate to presume that individuals with mental disorders are decisionally impaired. Less obviously, it is also inappropriate to suppose that those who exhibit some decisionmaking deficit cannot be helped to attain a level of functioning that would enable them to be part of a valid consent process. Once these facts are recognized, the special ethical obligations of scientific investigators and institutions sponsoring or carrying out research with persons who may be decisionally impaired become apparent.

Not only must psychological and medical factors affecting these potential research subjects be taken into account, but a full understanding of the nature of their impaired decision making is required. As previously noted, even those who would not normally be considered to be suffering from a decisional impairment may become disoriented if suddenly thrust into the role of a patient, with all of the attendant social inequities and feelings of vulnerability. Persons with a tendency toward impaired decision making due to a mental disorder may experience the consequences of institutionalization in an even more pronounced manner. Therefore, the conditions under which a consent process takes place, including how information is presented and who is responsible for obtaining consent, can be critical in influencing the quality and thus the ethical validity of the consent obtained. Appreciating these different perspectives may also provide practical insights that can improve the process, such as the use of peers (other persons with similar mental disorders who have already participated in the research) and/or their advocates in the consent encounter, or the use of written or visual aids to clarify the research details. It is imperative that all those who are engaged in the approval and conduct of research with persons with mental disorders enrich their appreciation of the importance of context in the consent process and thus set an appropriate foundation for ethically acceptable research involving persons from this population as subjects.

For all of these reasons, determining the proper standards and procedures to assess capacity poses a major challenge in formulating policy on research involving subjects with mental disorders that may affect decisionmaking capacity. Persons with such disorders vary widely in their ability to engage in independent decision making. They may retain such capacity, or possess it intermittently, or be permanently unable to make decisions for themselves. Individuals with dementia, for example, frequently retain decisionmaking capacity early in the course of the illness, but with time they may become intermittently and then permanently unable to make their own decisions. Some individuals with cognitive disabilities are capable of making many choices for themselves; others completely lack such capacity.82

Because of their moral consequences, incorrect capacity determinations can be inadvertently damaging—an assessment that a capable person is incapable of exercising autonomy is disrespectful, demeaning, and stigmatizing, and it may result in the unwarranted deprivation of an individual’s civil liberties.83 Conversely, a judgment that an incapable person is capable leaves that individual unprotected and vulnerable to exploitation by others.84 In addition, the presence of many marginal cases among members of the relevant populations triggers concern about the ability to make those capacity assessments for many individuals.

It is also important to recognize that investigators seeking to enroll subjects face conflicting interests, and some may become too willing, perhaps unconsciously, to label prospective subjects capable when this will advance their research objectives.85 Investigators also must be alert to the possibility—and to its subsequent ramifications—that a research subject’s decisionmaking status may change during the protocol. NBAC’s view is that existing federal policy fails to provide adequate guidance to investigators and IRBs on the many complexities related to capacity determinations in research involving persons who are the subject of this report. Currently, individual IRBs determine (or at least approve) how investigators are to address these matters. Without adequate education and guidance, however, IRB members are likely to, albeit inadvertently, vary criteria too much and fail to institute adequate safeguards for such research.86 NBAC’s review of protocols and consent documents failed to find evidence that researchers provide to IRBs an adequate description of how prospective subjects will be evaluated for their ability to consent. NBAC, along with some other commentators, supports more systematic and specific federal direction on capacity assessment,87 not only for defining decisional capacity in the research context but also for developing better procedures for assessing such capacity.

A capacity assessment process must adequately protect the interests of individuals with conditions that increase the risk of decisional impairment. To address this need a variety of approaches to capacity assessment are endorsed in the literature on research involving adults with cognitive impairment. Many commentators believe that IRBs should, at a minimum, require investigators to specify the method by which prospective subjects’ decisional capacity will be evaluated and the criteria for identifying incapable subjects.88

A complicating factor, however, is that any assessment tool measures capacity indirectly through manifest performance, and a person’s performance does not always adequately reflect his or her capacity or potential. Many factors can inhibit performance, including anxiety or environmental conditions, the quality of the assessment instrument itself, and other characteristics of the assessment process.89 Everyone can attest to the variation on one occasion or another between actual performance—as on an examination or in a job interview—and actual capacity. The problem is aggravated in populations whose conditions are partly characterized by fluctuating capacity. The capacity-performance distinction suggests why the context in which the capacity assessment is made (under what conditions or by whom, for example) is so important.

There is divergence of opinion on whether capacity assessment and information disclosure should be conducted by an individual not otherwise connected with the research project. The National Commission recommended that, "where appropriate," IRBs should appoint a "consent auditor" for research involving those persons institutionalized as mentally infirm.90 IRBs would be authorized to determine whether a consent auditor is indicated and how much authority the consent auditor would have. For example, in research involving greater than minimal risk without the prospect of direct benefit to the subjects, the National Commission recommended that the auditor observe and verify the adequacy of the consent and assent process, and in appropriate cases observe the conduct of the study to ensure the subjects’ continued willingness to participate.91 The Department of Health, Education and Welfare (DHEW) regulations proposed in 1978 contemplated mandating auditors for all projects involving this subject population,92 but opposition to this proposal reportedly was one reason the regulations never became final.93

More recent commentary includes a spectrum of views on the need for an independent consent auditor. Some echo the National Commission’s view that a requirement for an independent evaluator becomes increasingly justified as net research risks to subjects increase. A team of Canadian scholars took this position in its recent recommendations on dementia research,94 noting that the role of a consent assessor/monitor ordinarily can be filled by a researcher or consultant "familiar with dementias and qualified to assess and monitor competence and consent in such subjects on an ongoing basis." The individual should be knowledgeable about the project and its risks and potential benefits. If, however, the research team lacks a person with these qualifications, if there is "a real danger of conflict of interest" for team members who might evaluate and monitor capacity, or if the project involves greater than minimal risk and no prospect of direct benefit to subjects, an independent assessor/monitor should be appointed.95

Others also appear open to the general use of outside observers and examiners. Recent guidelines adopted by the Loma Linda University IRB state, "[c]onsent observers who are independent of the investigator and of the institution will be required by the IRB in those conditions where the potential subject’s decisionmaking capacity is suspect."96 In testimony before NBAC, representatives of Citizens for Responsible Care in Psychiatry and Research recommended that "[a]n independent psychiatrist . . . determine the capacity of [the] potential participant to comprehend the risks and benefits of enrolling in the proposed research study."97 Recent articles also endorse the participation of a "special research educator" in the disclosure and decision process, particularly to ensure that prospective subjects understand when advancement of general knowledge is the primary goal of the project at hand.98

A strong case has also been made for an independent patient-advocate’s involvement in making capacity determinations, as well as in assisting and monitoring decision making by family surrogates who are acting for incapable persons. Legal analyst Philip Bein notes that courts have demanded relatively strict procedural safeguards in the context of imposed psychiatric treatment and sterilization for persons with mental disabilities. He makes the following argument for a similar approach in the research context:

As with psychotropic medication and sterilization, several distinct features of experimentation suggest the need for special protections. First, the history of medical experimentation has been characterized by significant incidents of abuse, particularly where members of vulnerable populations have been enlisted as subjects. Second, the interest of medical researchers in securing participation in the experiment often conflicts with their duties as treating physicians to inform, advise, and act in the best interests of their patients. Third, experimentation is inherently highly intrusive and dangerous, as the nature and magnitude of risks involved are largely unknown and unknowable.99

Bein further suggests that courts have not demanded such safeguards for decisions on life-sustaining treatment, based on the comparative rarity of the potential abuses just described. He also argues that an IRB-administered system of patient-advocates would provide inadequate oversight because such a system would be too responsive to institutional interests.100

Other recent commentary proposes more diverse methods for avoiding inappropriate capacity determinations. Legal scholar Richard Bonnie opposes a federal requirement for any specific procedure, contending instead that "the regulations should provide a menu of safeguards" from which IRBs could choose, including "specially tailored follow-up questions to assess subject understanding, videotaping or audio-taping of consent interviews, second opinions, use of consent specialists, or concurrent consent by a family member."101

The American Geriatric Society (AGS), in its position statement, "Informed Consent for Research on Human Subjects with Dementia," suggests that capacity to give informed consent "should be assessed in each individual for each research protocol being considered." The AGS suggests that the ability to give informed consent to a research protocol is task-specific, and not automatically conferred on individuals affected by dementia.102

Many groups advise the involvement of a trusted family member or friend in the disclosure and decisionmaking process. For example, AGS states that investigators should rely on traditional surrogates to assist in research participation decisions because the surrogate has "loving and intimate knowledge of the subject’s wishes or value system."103 Capable subjects reportedly are often willing to permit such involvement. Dementia researchers frequently adopt a mechanism called "double" or "dual" informed consent when the capacities of prospective subjects are uncertain or fluctuating.104 This approach has the virtue of providing a concerned back-up listener and questioner who "may help the cognitively impaired individual understand the research and exercise a meaningful informed consent."105 However, others have suggested that the presence of a caregiving relative could in some cases put pressure on subjects to enter a research study.106

Another suggestion is to require a two-part consent. In this process, information about a study is presented to a prospective subject and a questionnaire administered to determine the individual’s comprehension. The subject is then provided with a copy of the questionnaire to refer to as needed. If the individual initially fails to demonstrate an adequate understanding of the material, written or oral information is presented again, and the subject is re-tested. This process is likely to yield more accurate judgments of subject capacity than a less systematic and rigorous inquiry.107

Finally, numerous ideas have been offered to make information more accessible to subjects capable of exercising independent choice. Simple perceptual aids, such as increasing the type size of printed material, may enhance the ability of elderly subjects to comprehend the necessary information. Information can also be delivered through videotape, slides, or pictorial presentations. Another promising suggestion is for investigators to ask representatives of the affected population to critique drafts of information materials prior to their actual research use.108

The literature offers fewer suggestions for ensuring genuine voluntariness. The current Declaration of Helsinki includes a provision stating that "[w]hen obtaining informed consent for the research project the physician should be particularly cautious if the subject is in a dependent relationship to him or her or may consent under duress." In these circumstances, "informed consent should be obtained by a physician who is not engaged in the investigation and who is completely independent of this official relationship."109 NBAC holds the view that, in a variety of other circumstances, it may be desirable to have someone discuss separately with consenting subjects their reasons for participating.

An autonomous choice to enter a research study is both informed and voluntary. To be capable of informed choice it is generally agreed, as already noted, that a prospective subject should demonstrate the ability "to understand the nature of the research participation; appreciate the consequences of such participation; exhibit ability to deliberate on alternatives, including the alternative not to participate in the research; and evidence ability to make a reasoned choice."110 Subjects also should "comprehend the fact that the suggested intervention is in fact research (and is not intended to provide therapeutic benefit when that is the case)," and that they may decide against participation "without jeopardizing the care and concern of health care providers."111

There is consensus that decisional capacity requires a certain level of cognitive ability. Less agreement exists on whether subjects should be judged incapable if they lack affective appreciation of the choice before them. In a recent article, Carl Elliott argues that some depressed persons "might realize that a protocol involves risks, but simply not care about the risks," or "as a result of their depression, may even want to take risks."112 Elliott believes that judgments about a person’s capacity to consent to research should take into account emotional attitudes like these. He also proposes that subjects failing to exhibit a "minimal degree of concern for [their] welfare" should be deemed incapable of independent decision making. Others oppose this position, contending that such an approach could represent excessive paternalism toward persons diagnosed with mental disorders, that insufficient data exist on the extent of incapacitating emotional impairment among depressed persons, that affective impairment is difficult to assess, and that normative consensus is lacking on "how much impairment we as a society are willing to accept before we consider someone incompetent."113

It is generally agreed that a prospective subject’s capacity to decide whether to participate in a particular research project cannot be determined through a general mental status assessment.114 Instead, investigators must develop and present the specific material relevant to that project and evaluate the prospective subject’s understanding and appreciation of that information.115 In its 1998 report on "Research Involving Individuals with Questionable Capacity to Consent," an NIH panel also concluded that "a key factor in potential participants’ decisionmaking is their appreciation of how the study applies to them (in the context of their lives)."116 Like other commentators, the NIH panel endorsed a "sliding-scale" approach to decisional capacity in the research setting.117 This approach demands an increasing level of understanding and appreciation as study risks increase and potential benefits to subjects decrease.118 Similarly, some suggest that many prospective subjects, incapable of independent research decision making, remain capable of selecting a research proxy, since "the decisionmaking capacity that is required to designate a proxy is far less than the capacity required to understand a detailed protocol."119 The level of capacity required to appoint a proxy need not be as great as that which would be required to consent to participate in research.

A decision to enroll in a research protocol should be both informed and voluntary. The Nuremberg Code provides descriptive characteristics of a voluntary decision,120 and the National Commission’s Belmont Report characterizes a voluntary decision as "free of coercion and undue influence." According to the Belmont Report, "[c]oercion occurs when an overt threat of harm is intentionally presented by one person to another in order to obtain compliance. Undue influence . . . occurs through an offer of an excessive, unwarranted, inappropriate or improper reward or other overture in order to obtain compliance." In addition, the Belmont Report notes, an inducement that is not overly persuasive to most adults could unduly influence the judgment of vulnerable subjects. The National Commission acknowledged that terms such as "unjustifiable pressure" or "excessive reward" cannot always be precisely defined, but that "undue influence would include actions such as manipulating a person’s choice through the controlling influence of a close relative and threatening to withdraw health services to which an individual would be otherwise entitled."121

Due to its limited congressional mandate, the National Commission only considered potential pressures to enroll in research persons institutionalized as mentally infirm. Recent commentary favors expanding this concern to all persons with mental disorders, regardless of where they live, because they are especially vulnerable to similar pressures.122 Prospective subjects with mental disorders, living in the community, frequently rely heavily on the assistance of professionals and family members and may perceive research participation as essential to maintaining the approval of their caregivers.123 Nevertheless, there remains considerable support for retaining special protections to persons in residential facilities due to their near-complete dependence on the goodwill of the staff.124

A final element of decisional capacity, implicit in the above discussion, is the subject’s continuing ability—during the research protocol—to make a voluntary and informed choice to continue to participate. Some persons with certain mental disorders can provide an adequately informed and voluntary consent to participate in a study, but subsequently lose their capacity for independent choice. As a result, they become unable to exercise their right to withdraw from a study. Study designs must, therefore, provide for this contingency.

There is some indication from NBAC’s review of protocols that practices in the field may not adequately reflect these concerns. Several protocols and corresponding consent forms gave the impression that investigators may have inappropriately used their positions in order to obtain subjects. Though the consent forms contained language intended to inform subjects that their right to treatment would be unaffected by a refusal to participate in research, persons with mental disorders that may affect decisionmaking capacity who are seeking treatment may nevertheless feel indebted to the provider, or suspect that they are confronted with a quid pro quo—research participation for treatment. For example, one of the protocols reviewed by NBAC offered free health care to persons who would enroll themselves in the research. None of the protocols discussed here described methods for ensuring voluntary, uncoerced participation.

The particular instrument and methods used to assess capacity have an important role in determining the outcome of such an assessment. IRBs should be aware of the special characteristics and implications of particular instruments and methods. Studies involving subjects with fluctuating or declining decisional capacity should include mechanisms to ascertain and address this possibility, including provision for appointment of a representative for subjects who become incapable.125 The next chapter discusses the issue of appointing representatives to assist in the consent process and considers other factors that need to be taken into account when informed consent from the potential subject cannot be obtained.

72 Maurice K. Pappworth, Human Guinea Pigs: Experimentation on Man, (Boston: Beacon Press, 1968).

73 See the discussion in Carol Levine, "Changing Views of Justice after Belmont: AIDS and the Inclusion of ‘Vulnerable’ Subjects," in Harold Y. Vanderpool, ed., The Ethics of Research Involving Human Subjects: Facing the 21st Century (Frederick, MD: University Publishing Group, 1996), 105–126.

74 Jeffrey P. Kahn, Anna C. Mastroianni, and Jeremy Sugarman, eds., Beyond Consent: Seeking Justice in Research (New York: Oxford University Press, 1998).

75 See 45 CFR 46.116(d) (1998). An IRB may also approve research in which the requirement to obtain informed consent is waived if it finds and documents that "(1) The research or demonstration project is to be conducted by or subject to the approval of state or local government officials and is designed to study, evaluate, or otherwise examine: (i) Programs under the Social Security Act, or other public benefit or service programs; (ii) procedures for obtaining benefits or services under these programs; (iii) possible changes in or alternatives to those programs or procedures; or (iv) possible changes in methods or levels of payment for benefits or services under those programs; and (2) The research could not practicably be carried out without the waiver or alteration." 45 CFR 46.116(c) (1998).

76 Berg and Appelbaum, "Subjects’ capacity to consent to neurobiological research."

77 Thomas Grisso and Paul S. Appelbaum, "Comparison of Standards for Assessing Patients’ Capacities to Make Treatment Decisions," American Journal of Psychiatry 152 (1995): 1033–37.

78 Paul S. Appelbaum and Thomas Grisso, "Assessing Patients’ Capacities to Consent to Treatment," New England Journal of Medicine 319 (1988): 1635–38.

79 American Psychiatric Association, "Guidelines for Assessing the Decisionmaking Capacities of Potential Research Subjects with Cognitive Impairments," American Journal of Psychiatry 155 (1998): 1649–50.

80 For a fuller discussion of certain strengths and weaknesses of capacity assessment instruments, see Elyn R. Saks, Competency to Decide on Treatment and Research: The MacArthur Capacity Instruments (paper commissioned for the National Bioethics Advisory Commission, 1998). See Volume II of this report.

81 The ethical problems of conducting research in emergency settings, in the face of the acute loss of decisionmaking capacity that often accompanies admission to a hospital emergency room, has recently been the subject of federal regulation. Regulations promulgated by the Food and Drug Administration (FDA) permit a narrow exception to the informed consent requirement for emergency research involving serious conditions for which "current treatment is unproven or unsatisfactory." See Informed Consent and Waiver of Informed Consent Requirements in Certain Emergency Research, Final Rules, 61 Fed. Reg. 51497, 51499 (1996) (codified at 21 CFR 50.24).

82 See, generally, David A. Thomasma, "A Communal Model for Presumed Consent for Research on the Neurologically Vulnerable," Accountability in Research 4 (1996): 227–39; Greg A. Sachs et al., "Ethical Aspects of Dementia Research: Informed Consent and Proxy Consent," Clinical Research 42 (1994): 403–12.

83 Elyn R. Saks, Competency to Decide, see Volume II of this report.

84 National Commission, Belmont Report, 4.

85 See, e.g., Daniel C. Marson et al., "Consistency of physician judgments of capacity to consent in mild Alzheimer’s disease," Journal of the American Geriatrics Society 45 (1997): 453–457, 455. See also Shamoo and Keay, "Ethical Concerns About Relapse Studies," 373.

86 Bonnie, "Research with Cognitively Impaired Subjects," 109.

87 E.g., id.

88 Vijaya L. Melnick et al., "Clinical Research in Senile Dementia of the Alzheimer Type," Journal of the American Geriatrics Society 32 (1984): 531–36, 533.

89 See, for example, Thomas Grisso and Paul S. Appelbaum, Assessing Competence to Consent to Treatment: A Guide for Physicians and Health Care Professionals (New York: Oxford University Press, 1998).

90 National Commission, Report on Those Institutionalized as Mentally Infirm, 8–11.

91 Ibid. p. 15.

92 Proposed Regulations on Research Involving Those Institutionalized as Mentally Disabled, 43 Fed. Reg. 53, 950 (1978) (proposed Nov. 17, 1978).

93 Bonnie, "Research with Cognitively Impaired Subjects," 108; Robert J. Levine, "Proposed Regulations for Research Involving Those Institutionalized as Mentally Infirm: A Consideration of Their Relevance in 1996," IRB 18, no. 5 (1996): 1–5.

94 Keyserlingk et al., "Proposed Guidelines."

95 Id. at 343–44. See also Melnick et al., supra.

96 Robert D. Orr, "Guidelines for the Use of Placebo Controls in Clinical Trials of Psychopharmacologic Agents," Psychiatric Services 47 (1996): 1262–64, 1263.

97 Adil E. Shamoo and Vera Hassner Sharav, "Unethical Use of Persons With Mental Illness in High Risk Research Experiments," 2, no. 2 BioLaw (1997): S:23–S:31.

98 Evan G. DeRenzo, "The Ethics of Involving Psychiatrically Impaired Persons in Research," IRB 16, no. 6 (1994): 7–10, 8. In a study of this approach, researchers found that the participation of a trained educator increased the comprehension of psychiatric patients asked to enroll in research. Paul S. Appelbaum et al., "False Hopes and Best Data: Consent to Research and the Therapeutic Misconception," Hastings Center Report 17, no. 2 (1987): 20–24, 20.

99 Philip Bein, "Surrogate Consent and the Incompetent Human Subject," Food Drug Cosmetic Law Journal 46 (1991): 739–71, 747–48.

100 Id. at 762.

101 Bonnie, "Research with Cognitively Impaired Subjects," 105–11.

102 The American Geriatrics Society, "Informed Consent for Research on Human Subjects with Dementia," Journal of the American Geriatrics Society 46 (1998): 1308–1310, 1308.

103 The American Geriatrics Society, "Making Treatment Decisions for Incapacitated Older Adults Without Advanced Directives." Journal of the American Geriatrics Society 44 (1996): 986–987.

104 Dallas M. High et al., "Guidelines for Addressing Ethical and Legal Issues in Alzheimer Disease Research: A Position Paper," Alzheimer Disease and Associated Disorders 8, supp. 4 (1994): 66–74. See also Bonnie, "Research with Cognitively Impaired Subjects," 110.

105 Jason H. T. Karlawish and Greg A. Sachs, "Research on the Cognitively Impaired: Lessons and Warnings from the Emergency Research Debate," Journal of the American Geriatrics Society 45 (1997): 474–481, 477.

106 Id.

107 Richard M. Ratzan, "Technical Aspects of Obtaining Informed Consent from Persons with Senile Dementia of the Alzheimer’s Type," in Vijaya L. Melnick and Nancy N. Dubler, Alzheimer’s Dementia: Dilemmas in Clinical Research (Clifton: NJ, 1985) (citing Miller and Willner, "The Two-Part Consent Form," New England Journal of Medicine 290 (1974): 964–66).

108 Vijaya L. Melnick, et al., "Clinical Research in Senile Dementia of the Alzheimer Type," Journal of the American Geriatrics Society 32 (1984): 531–36, 536.

109 World Medical Association, Declaration of Helsinki: Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects (1996) (reprinted in Journal of the American Medical Association 277 (1997): 925–26).

110 High et al., supra, 69. In discussing decisional capacity in the research context, many writers also cite the President’s Commission’s requirements for treatment decisionmaking capacity: (1) possession of a set of values and goals; (2) ability to communicate and comprehend information; and (3) ability to reason and deliberate about the choice at hand. See President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, Making Health Care Decisions: A Report on the Ethical and Legal Implications of Informed Consent in the Patient-Practitioner Relationship (Washington, D.C.: GPO 1982), 60.

111 Melnick et al., "Clinical Research in Senile Dementia," 533.

112 Elliot, "Caring About Risks," 114 (italics in original).

113 Paul S. Appelbaum, "Rethinking the Conduct of Psychiatric Research," Archives of General Psychiatry 54 (1997): 117–20, 119. See also R. M. Hirschfeld et al., "Protecting Subjects and Fostering Research," Archives of General Psychiatry 54 (1997): 121–123.

114 High et al., supra; Marson, Determining the Competency of Alzheimer Patients to Consent to Treatment and Research, Alzheimer’s Disease and Assoc. Disord. 8 (Supp. 4, 1994): 5.

115 The Common Rule provides that the information given to a subject "shall be in a language understandable to the subject or representative." A subject may not be involved in research without first providing legally effective informed consent, which requires that consent is sought in circumstances that allow the prospective subject or representative "sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence." Moreover, to meet the general requirements of informed consent the Common Rule requires that the following information regarding the research to be provided to the prospective subject: (1) that the study involves research; (2) the purposes of the research; (3) the expected length of time of research participation; (4) the procedures to be performed and which, if any, are experimental; (5) reasonably foreseeable risks and discomforts; (6) reasonably expected benefits to subjects or others; (7) alternatives, including treatment, that could benefit the individual more than research participation; (8) the level of confidentiality protecting any identifiable information recorded on the subject; (9) whether compensation and medical treatment will be available for injuries resulting from research; (10) the identity of the person(s) to notify if the subject has questions or suspects research-related injury; and (11) that participation is voluntary, refusal will not be penalized, and participation may cease at any time without penalty. See 45 CFR 46.116 (1998). See 45 CFR 46.116(b) (1998) for additional information that must be provided to a prospective subject, when appropriate, such as information about additional costs that a subject may incur as a result of participation in research.

116 Expert Panel Report to the National Institutes of Health, Research Involving Individuals with Questionable Capacity to Consent, 4.

117 Ibid.

118 Carl Elliott, "Mentally Disabled and Mentally Ill Persons: Research Issues," in Encyclopedia of Bioethics, ed. Warren T. Reich, rev. ed., (New York: Simon and Shuster, 1995); Paul S. Appelbaum, "Drug-Free Research in Schizophrenia: An Overview of the Controversy," IRB 118, no. 1 (1996) 1–5, 1; George J. Annas and Leonard H. Glantz, "Rules for Research in Nursing Homes," New England Journal of Medicine 315 (1986): 1157–58. See also Arthur Schafer, "The ethics of the randomized clinical trial," New England Journal of Medicine 307 (1982): 719–24.

119 Sachs et al., "Ethical Aspects of Dementia Research," 410.

120 See p. 5, above.

121 National Commission, Belmont Report, 6.

122 See, for example, Bonnie, "Research with Cognitively Impaired Subjects," and Levine, "Proposed Regulations."

123 Keyserlingk et al., "Proposed Guidelines," 323–24.

124 Elliott, supra; Dallas M. High and Mary M. Doole, "Ethical and Legal Issues in Conducting Research Involving Elderly Subjects," Behavioral Sciences and the Law 13 (1995): 319–35. See also American College of Physicians, "Cognitively Impaired Subjects," Annals of Internal Medicine 111 (1989): 843–48.

125 Appelbaum, "Drug-Free Research," 4.

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