Legal and Ethical Complexities of Consent with Cognitively Impaired Research Subjects: Proposed Guidelines

Journal of Law, Medicine and Ethics

Volumn 24, Issue 1, 1996, Pages 18-35

  Berg, Jessica Wilen ^a  

^a UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADVISORY COMMITTEE; AMERICAN COLLEGE OF PHYSICIANS; ARTICLE; BIOETHICS; BIOMEDICAL AND BEHAVIORAL RESEARCH; COGNITIVE DEFECT; GOVERNMENT; GOVERNMENT REGULATION; HUMAN; HUMAN EXPERIMENT; INFORMED CONSENT; JURISPRUDENCE; LEGAL ASPECT; LIVING WILL; MENTAL CAPACITY; MENTAL HEALTH THERAPIES; MISCELLANEOUS NAMED GROUPS; NATIONAL INSTITUTES OF HEALTH; PRACTICE GUIDELINE; PROFESSIONAL STANDARD; RISK ASSESSMENT; UNITED STATES; VULNERABLE POPULATION;

AMERICAN COLLEGE OF PHYSICIANS; BIOMEDICAL AND BEHAVIORAL RESEARCH; MENTAL HEALTH THERAPIES; NATIONAL INSTITUTES OF HEALTH;

ADVANCE DIRECTIVES; ADVISORY COMMITTEES; BIOETHICS; COGNITION DISORDERS; ETHICS COMMITTEES, RESEARCH; FEDERAL GOVERNMENT; GOVERNMENT REGULATION; GUIDELINES; HUMAN EXPERIMENTATION; HUMANS; INFORMED CONSENT; JUDICIAL ROLE; MENTAL COMPETENCY; NONTHERAPEUTIC HUMAN EXPERIMENTATION; PERSONS; RISK ASSESSMENT; THERAPEUTIC HUMAN EXPERIMENTATION; UNITED STATES; UNITED STATES DEPT. OF HEALTH AND HUMAN SERVICES; VULNERABLE POPULATIONS;

EID: 0030093760     PISSN: 10731105     EISSN: None     Source Type: Journal    
DOI: 10.1111/j.1748-720X.1996.tb01830.x     Document Type: Article

References (147)

1. J. Katz, Experimentation with Human Beings (New York: Russell Sage Foundation, 1971): at 1.
2. The present federal regulations include pregnant women, fetuses, institutionalized persons, prisoners, and children as "vulnerable" populations that need additional protections. I do not deal with the issue of vulnerability in the sense of being susceptible to coercive pressures, rather I focus on the difficulties relating to informed consent in research with cognitively impaired subjects.
3. G. Annas and M. Grodin, "Introduction," in G.J. Annas and M.A. Grodin, eds., The Nazi Doctors and the Nuremberg Code: Human Rights in Human Experimentation (New York: Oxford University Press, 1992): at 3.
4. The Nuremberg Code (1947). See full text as reprinted in Katz, supra note 1, at 305-06.
5. J. Katz, "The Nuremberg Consent Principle: Then and Now," in G.J. Annas and M.A. Grodin, eds., The Nazi Doctors and the Nuremberg Code: Human Eights in Human Experimentation (New York: Oxford University Press, 1992): at 235 (Katz argues that the Nuremberg Military Tribunal's main concern was to prevent recurrence of the atrocities of Nazi experimentation, and thus they did not seek to balance the advancement of science and individual inviolability.).
6. "Incompetent" is used here to refer to incapacity to make medical decisions; it is not necessarily a legal determination of incompetence. Only a court can make a determination of "competence." "Capacity" determinations, on the other hand, are relegated to the medical or mental health professions.
7. World Medical Association, Declaration of Helsinki: Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects (1964). Reprinted in T. Mappers and J. Zembaty, eds., Biomedical Ethics (New York: McGraw-Hill, 1981): at 146-47.
8. World Medical Association, Declaration of Helsinki: Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects (1964). Reprinted in T. Mappers and J. Zembaty, eds., Biomedical Ethics (New York: McGraw-Hill, 1981): at 146-47.
9. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects in Research (Washington, D.C.: U.S. Government Printing Office, OS 78-0012, 1978).
10. Id. at 13 (the list included "infants and young children, mentally disabled patients, the terminally ill and the comatose").
11. Department of Health and Human Services, Rules and Regulations for the Protection of Human Research Subjects, 45 C.F.R. §§ 46.101-.409 (1983).
12. 45 C.F.R. § 46.116 (1991) (emphasis added).
13. 21 C.F.R. §§ 50.20-.48 (1993).
14. 43 Fed. Reg. 53,954 (Nov. 17, 1978).
15. See, for example, R Appelbaum, C. Lidz, and A. Meisel, Informed Consent: Legal Theory and Clinical Practice (New York: Oxford University Press, 1987).
16. 43 Fed. Reg. 53,954 (Nov. 17, 1978) ("'mentally disabled' individuals includes those who are mentally ill, mentally retarded, emotionally disturbed, psychotic or senile, regardless or their legal status or the reason for being institutionalized.").
17. See infra page 20.
18. See J. Horowitz, "For the Sake of Science: When Tony Lamadrid, a Schizophrenic Patient and Research Subject at UCLA, Committed Suicide, It Set Off a National Debate: What Is Acceptable in Human Experimentation and Who Decides?," Los Angeles Times Magazine, Sept. 11, 1994, at 16; and Office for Protection from Research Risks, "Evaluation of Human Subject Protections in Schizophrenia Research Conducted by the University of California Los Angeles" (May 11, 1994).
19. See, for example, J.C. Fletcher and A. Wichman, "A New Consent Policy for Research with Impaired Human Subjects," Psychopharmacology Bulletin, 23 (1987): 382-85.
20. Statement on Federal Funding for Research on Human Embryos, 30 Weekly Comp. Pres. Doc. 2459 (Dec. 2, 1994). No action was taken in 1995. It remains to be seen whether a commission will be established in 1996.
21. I use the terms research and experimentation interchangeably, except where specially noted. However, the two have different meanings, and it is useful to clarify exactly what is intended The Belmont Report points out that "[t]he fact that a procedure is 'experimental,' in the sense of new, untested, or different, does not automatically place it in the category of research" (National Commission for the Protection of Biomedical and Behavioral Research, supra note 8, at 3). Experimentation and research, however, both involve unknown consequences and thus both should be subject to increased scrutiny. P. McNeiil, The Ethics and Politics of Human Experimentation (New York: Oxford University Press, 1993). Even so, it is not realistic to require that every doctor who tries a new or experimental treatment on one patient get IRB approval. Thus the guidelines proposed here should only apply when the physician seeks systematically to gather general information, that is, when the doctor seeks not only to treat the individual patient but also to obtain information that will help treat other patients. Thus many "experimental treatments" may become research as they are repeatedly tested on different patients. IRB approval would not be avoided by categorizing each of a number of trials of an experimental medium or method as "individual treatment."
22. J. Katz, "Human Experimentation and Human Rights," St. Louis University Law Journal, 38 (1993): at 7.
23. Id. at 41. See also P. Williams, "Why IRBs Falter in Reviewing Risks and Benefits," IRB: A Review of Human Subjects Research, 6, no. 3 (1984): at 4 (listing possible reasons why IRBs fail to evaluate adequately risks and benefits, but noting that there is "no evidence that unduly dangerous protocols are actually passing committee review").
24. Id. at 41. See also P. Williams, "Why IRBs Falter in Reviewing Risks and Benefits," IRB: A Review of Human Subjects Research, 6, no. 3 (1984): at 4 (listing possible reasons why IRBs fail to evaluate adequately risks and benefits, but noting that there is "no evidence that unduly dangerous protocols are actually passing committee review").
25. Katz, supra note 21, at 158-59 ("In human experimentation, research ethics committees are ideal candidates to exercise discretion in the application of principles and rules to particular research proposals.... The degree of discretion exercised by committees should not mean that some committees can approve research on human subjects that is below the minimum ethical standard for such research. This position... requires an active national body to oversee the system of review and provide specificity in research guidelines.").
26. 45 C.F.R. §§ 46.101-.409 (1983); and 21 C.F.R. §§ 50.20-.48 (1993). More guidance at the national level on the meaning of these terms is necessary.
27. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, U.S. Department of Health, Education and Welfare, Institutional Review Boards: Report and Recommendations (Washington, D.C.: U.S. Government Printing Office, OS 78-0008, 1978): at 1.
28. American College of Physicians, "Cognitively Impaired Subjects," Annals of Internal Medicine, 111 (1989): at 843.
29. National Institutes of Health, Clinical Center Policy, Research Involving Impaired Human Subjects Clinical Center Policy for the Consent Process (Bethesda: National Institutes of Health, 1986).
30. M. Wicclair, Ethics and the Elderly (New York: Oxford University Press, 1993).
31. American College of Physicians, supra note 26, at 883.
32. Id.
33. J.C. Fletcher and F.G. Miller, The Promise and Perils of Public Bioethics (Baltimore: University of Maryland, 1994).
34. Id. at 13.
35. G. Dworkin, "Law and Medical Experimentation: Of Embryos, Children and Others with Limited Legal Capacity," Monash University Law Review, 13 (1987): 189-208.
36. Id. at 208.
37. B. Miller, "Autonomy and Proxy Consent," IRB: A Review of Human Subjects Research, 4, no. 10 (1982): at 1, 2.
38. Additional protections may also be necessary when the research presents a high risk of harm to the subjects, or when the subject population is considered unusually vulnerable to coercive tactics designed to induce participation.
39. Miller, supra note 35, at 3 (specific authorization; general authorization with instructions; general authorization without instructions; instructions without authorization; substituted judgment; and deputy judgment). He concludes that all but one of the models, deputy judgment, protects autonomy in one or more of the four aspects. I do not use Miller's categories; instead, I address the standards of proxy decision making (best interests and substituted judgment) allowed in different contexts. Miller's analysis of autonomy, however, is useful in explaining why one model of proxy consent is preferable over another.
40. Although Wicclair recognizes the existence of these documents, he does not specifically allude to them in his seven conditions. In his comments, however, he notes that "speculative judgments are discouraged by requiring explicit instructions and criteria to be given to surrogates." Wicclair, supra note 28, at 183.
41. American College of Physicians, supra note 26, at 884.
42. See T. Sunderland and R. Dukoff, "Informed Consent with Cognitively Impaired Patients: An NIMH Perspective on the Durable Power of Attorney," Accountability in Research (forthcoming, 1996) (evaluating the NIH Clinical Center Policy).
43. C. Sabatino, "Legislative Trends in Health-Care Decisionmaking," ABA Bioethics Bulletin, 3, no. 2 (1994): 10-11 (Advance directive is used in the study as an all encompassing term that includes living wills and DPAs).
44. See E. DeRenzo, "Surrogate Decision Making for Severely Cognitively Impaired Research Subjects: The Continuing Debate," Cambridge Quarterly of Healthcare Ethics, 3 (1993): at 543.
45. A number of states either do not permit a guardian to consent to research or only allow consent with prior court approval. Many of these states make a distinction between life-saving potentially therapeutic experimental treatments (which may be allowed) and nontherapeutic research. Alaska Stat. § 13.26.150 (1995); Fla. Stat. Ann. § 744.3215 (West 1995); Ill. Rev. Stat. ch. 405, para. 5/2-10 (1995); Minn. Stat. § 525.56 (Supp. 1995); Nev. Rev. Stat. § 159.0805 (1993); N.H. Rev. Stat. Ann. § 464-A:25 (1994); N.D. Cent. Code § 30.1-28-12(5-312) (1995); Okla. Stat. Ann. tit. 30, § 3-119 (Supp. 1995); and 20 Pa. Cons. Stat. Ann. § 5521 (1995). Other states either explicitly or implicitly allow guardians to consent to experimental treatment or research. Cal. Health & Safety Code § 24173 (Supp. 1995); D.C. Code Ann. § 6-1969 (1994); Ga. Code Ann. § 31-8-108 (Michie Supp. 1995); Kan. Stat. Ann. 59-3018 (Supp. 1995); Mo. Ann. Stat. § 431.064 (Vernon 1995); Mont. Code Ann. §§ 53-20-147, 53-21-147 (1993); N.J. Stat. Ann. S 30:6D-5 (West 1995); N.Y. Pub. Health Law § 2442 (McKinney 1995); Wis. Stat. Ann. § 51.61 (1995); P.R. Laws Ann. tit. 24, § 4020 (1990); S.D. Codified Laws Ann. § 27B-8-20 (Supp. 1995); and Va. Code Ann. § 32.1-162.16 (Supp. 1995) (if nontherapeutic only if minor increase over minimal risk).
46. 42 U.S.C. §§ 1395cc, 1396aa (1990).
47. See DeRenzo, supra note 42, at 546.
48. The term surrogate will be used rather than guardian. A guardian is a court-appointee who has much greater control over an incompetent individual's life than a surrogate decision maker. Casasanto, Simon, and Roman note a historical disagreement about whether a guardian should act in the ward's best interests or as a surrogate using a substituted judgment standard. M. Casasanto, M. Simon, and J. Roman, "A Model Code of Ethics for Guardians," Whittier Law Review, 11 (1989): at 545. Casasanto, Simon, and Roman suggest that a substituted judgment standard is preferable, and that a best interests standard only be used when there is no indication of the ward's preferences. Id. at 547. In addition, they state that the guardian should be careful not to act beyond the scope of his/her authority and should allow wards to make decisions on their own behalf when appropriate. Thus, in situations where the research subject has already had a guardian appointed, or in states where the only surrogate decision makers legally provided for are guardians, such guardians may function in essentially the same manner as any other surrogate decision maker. Their proposed model code's Rule 4 recognizes the guardian's responsibility to make medical decisions; it states, however, that the guardian cannot consent to "experimental treatment... without seeking review by the court or the ward's attorney or other representative." Id. at 561. This seems unnecessarily burdensome. The guardian in these situations should be as free to act as any other surrogate - being permitted to make decisions within the confines of the applicable guidelines.
49. A.A. Hamann, "Family Surrogate Laws: A Necessary Supplement to Living Will and Durable Powers of Attorney," Villanova Law Review, 38 (1993): at 106 ("All states have intestacy laws to provide for the distribution of the decedent's property without a will. A comparable alternative is needed to provide for those individuals who fail to execute a living will or a durable power of attorney.").
50. NIH Clinical Center Policy, supra note 27, cases 5, 6.
51. N. Dubler, "Some Legal and Moral Issues Surrounding Informed Consent for Treatment and Research Involving Cognitively Impaired Elderly," in M.B. Kapp, H.E. Pies, and A.E. Doudera, eds., Legal and Ethical Aspects of Health Care for the Elderly (Ann Arbor: Health Administration Press, 1986): 247-57. Dubler argues that the courts are an improper forum to make health care decisions; however, she states that "there is a class of patients, primarily the long-term institutionalized, retarded, and mentally ill, who are demonstrably so vulnerable that public judicial process is required." Id. at 252. There is no reason why these groups should be singled out for differential treatment. All cognitively impaired subjects face the same questions of informed consent and substitute decision making, some, perhaps, to a greater degree than others. The courts are no better arbiters of the research process for the groups identified by Dubler than for others; recourse to the judicial system merely lends a false sense of legitimacy. Rather, clear guidelines should be set forth that limit what types of research can be done with cognitively impaired persons, regardless of the source of the impairment. Furthermore, local review boards should be responsible for taking into account additional considerations that are unique to particular groups, for example, coercion in an institutionalized setting.
52. Sabatino, supra note 41, at 10-11. These statutes do not presently apply to research decision making. Missouri is the one exception as it specifies a hierarchy of proxy decision makers who can consent to research participation. Mo. Ann. Stat. § 431.064 (Vernon 1995).
53. Hamann, supra note 47, at 166. This has led to such anomalous scenarios as the Christian Fellowship of the Disabled being appointed as the guardian of a permanently unconscious individual who had no previous affiliation with the group, or the Americans United for Life Legal Defense Fund being allowed to argue against a family's decision to remove a feeding tube when the guardian ad litem was unable to find a physician to testify in favor of continuing treatment.
54. See infra notes 90-91 and accompanying text.
55. See Hamann, supra note 47 (arguing that the family is the most appropriate decision maker).
56. See, for example, Cruzan v. Director, Missouri Dep't of Health, 497 U.S. 261, 286-87 (1990) (recognizing that a number of states permit close family members to make surrogate treatment decisions, but holding that the U.S. Constitution does not require that a state do so in all circumstances).
57. See, for example, Illinois Health Care Surrogate Act, Ill. Rev. Stat. ch. 755, § 40/25 (1993); Tex. Code Ann. Health & Safety § 313.002(6) (Supp. 1995); and Va. Code 54.1-2986 (1994). Even under statutes that set out a hierarchy, it may be necessary to choose among people in a given class, for example, between a number of adult children or siblings. In such situations, some statutes authorize all the members of the class to make decisions and require either a majority or a consensus (Illinois). Others specify criteria, such as age, expressed interest, or availability of a particular member of the class (Virginia). Lastly, some statutes leave the ranking among class members unspecified, and thus open the possibility that the physician will have to exercise discretion (Texas). In situations where such a choice must be made, additional scrutiny may be appropriate.
58. American College of Physicians, supra note 26, at 845; NIH Clinical Center Policy, supra note 27, at 2; and Wicclair, supra note 28, at 182.
59. American College of Physicians, supra note 26, at 845; NIH Clinical Center Policy, supra note 27, at 2; and Wicclair, supra note 28, at 182.
60. American College of Physicians, supra note 26, at 845; NIH Clinical Center Policy, supra note 27, at 2; and Wicclair, supra note 28, at 182.
61. See generally, S. Busby-Mott, "The Trend Towards Enlightenment: Health Care Decisionmaking in Lawrence and Doe" Connecticut Law Review, 25 (1993): 1159-225.
62. Miller, supra note 35.
63. See, for example, American College of Physicians, supra note 26, at 844; and E.W. Keyserlingk et al., "Proposed Guidelines for the Participation of Persons with Dementia as Research Subjects," Perspectives in Biology and Medicine, 38 (1995): 319-62 (condition 10, at 352).
64. See, for example, American College of Physicians, supra note 26, at 844; and E.W. Keyserlingk et al., "Proposed Guidelines for the Participation of Persons with Dementia as Research Subjects," Perspectives in Biology and Medicine, 38 (1995): 319-62 (condition 10, at 352).
65. Compare Keyserlingk et al., supra note 59, at 351 (restricting the use of advance directives for research involving more than a minor increment over minimal risk except where the subject has experienced a similar level of pain or discomfort before consenting to the research).
66. States' laws vary on this point. For example, a judicial determination of incompetence may be necessary. Other states may require that a court scrutinize the proxy decision. Compare, for example, Superintendent of Belchertown State School v. Saikewicz, 370 N.W2d 417 (Mass. 1977) (requiring court review) with Matter of Quinlan, 355 A.2d 647 (N.J. 1976) (noting that court review of all decisions would be unduly burdensome).
67. The "evidence" may include written preferences, such as those found in a general advance care document; practices throughout the subject's life (that is, previous research participation); and verbal communications regarding research.
68. American College of Physicians, supra note 26, at 845.
69. Wicclair, supra note 28, at 182 (conditions 1(a), 2(a)).
70. Id. (condition 5).
71. See, for example, Cruzan v. Director, Missouri Dep't of Health, 497 U.S. 261, 286-87 (1990) (holding that a state may require clear and convincing evidence of an incompetent patient's wishes before allowing the withdrawal of life support). It is not clear that all courts will apply the clear and convincing evidentiary standard, even to life-support withdrawal. However, in the research context, more so than the life-support situations, it is better to err on the side of caution. In those cases with no therapeutic benefit, no harm comes from not allowing participation except the generalized harm of not allowing implementation of an autonomous decision. This is the price society has to pay for protecting individual autonomy, because one cannot perfectly substitute one person's judgment for another's. The suggestion to use evidentiary standards is not meant to imply that courts should be scrutinizing the evidence in each case; on the contrary, courts are the least appropriate forum for these types of decisions.
72. But see Keyserlingk et al., supra note 59, at 351 (allowing only the use of a written directive).
73. American College of Physicians, supra note 26, at 845.
74. Because the American College of Physicians paper only allows use of a subject's advance directive, this position does not allow a proxy decision maker to take into account other evidence of the subject's wishes. Thus a proxy could not consent for a subject who, although he/she had not executed an advance care document, has left other evidence that he/she would not want to participate in a research protocol, even if participation was in the subject's best interests. In this sense, the paper only permits a proxy to take into account evidence of a subject's negative wishes. By contrast, my position, outlined in the previous paragraphs, would allow a proxy also to consider evidence of a subject's positive attitude toward participation in research. Id.
75. Wicclair, supra note 28, at 182 (conditions 1(b), 2(b)).
76. American College of Physicians, supra note 26, at 844.
77. J. Lazarus, "Ethical Issues and Conflicts," Journal of the California Alliance for the Mentally Ill, 5 (1994) 20-21 (describing a patient who competently consented to research that involved taking him off medication, subsequently regressed and refused to take the experimental medication, and, later, after stabilizing again on the initial medication, "earnestly begged for another chance to try the experimental medication." Id. at 20.).
78. Id.; see also J. Warren et al., "Informed Consent by Proxy," N. Engl. J. Med., 315 (1986): 1124-28 (suggesting that investigators should reconsider when research begins, initiating contact while the subjects are still competent and thus can prospectively consent).
79. See, for example, Keyserlingk et al., supra note 59, at 349 (discussing the use of the "Ulysses Contract" (a self-binding psychiatric advance directive) in dementia research).
80. Fletcher and Wichman, supra note 18, at 383.
81. Wicclair, supra note 28, at 182 (condition 6).
82. If state law does not allow for treatment over an incompetent patient's refusal, research, even if it holds the potential for direct therapeutic benefit, would likewise be impermissible.
83. See infra pages 24-28.
84. State laws governing treatment refusals of incompetent patients would apply here. Thus it may be necessary to get a court order declaring the individual incompetent or to appoint a surrogate.
85. See, for example, Keyserlingk et al., supra note 59. A consent auditor and the research auditor may be the same person. The different titles simply highlight the different roles the consent auditor monitors the initial consent process to ensure that the subject has the ability to consent and actually understands the information. The research auditor would monitor the experiment to ensure that continued participation is appropriate given either changes in the protocol or changes in the subject's physical and mental state.
86. See Lazarus, supra note 72, at 21 (noting the "additional advocacy roles for family or friends of the patients").
87. National Commission for Protection of Human Subjects of Biomedical and Behavioral Research, supra note 8, at 5.
88. The phrase "research has the potential to produce direct therapeutic benefits" is used in place of "therapeutic research" to avoid confusion. The reason will become clear in the subsequent discussion of potential therapeutic benefits. Indirect benefits are not discussed in this analysis. Although they are likely to be included in a competent subject's evaluation about whether to participate in a study, they are unlikely to be appropriate considerations for a surrogate decision maker. See Keyserlingk et al., supra note 59, at 327-28 (identifying direct versus indirect benefits).
89. See, for example, A.D. Milliken, "The Need for Research and Ethical Safeguards in Special Populations," Canadian Journal of Psychiatry, 38 (1993): at 683 (discussing the need to balance risk and potential benefit). In this section, I will not go into detail about the risks that IRBs should consider when deciding whether to accept a particular protocol. For my purposes, I assume that the protocol has already passed IRB review and that at issue is whether cognitively impaired subjects should be allowed to participate. Because some protocols are designed to include only cognitively impaired subjects, in some sense the protocol approval will overlap with the analysis presented here. For example, it would be useless to "approve" a protocol involving severely cognitively impaired subjects, but not to allow proxy consent to participation.
90. Agreement also has not been reached on the definitions of more fundamental terms such as harm and risk. See, for example, E. Meslin, "Protecting Human Subjects from Harm Through Improved Risk Judgments," IRB: A Review of Human Subjects Research, 12, no. 1 (1990): 7-10 (comparing various definitions of harm and risk and proposing a model for risk judgments); and T. Beauchamp and J. Childress, Principles of Biomedical Ethics (New York: Oxford University Press, 1994) (discussing risk assessment, uncertainty, and risk perception).
91. Agreement also has not been reached on the definitions of more fundamental terms such as harm and risk. See, for example, E. Meslin, "Protecting Human Subjects from Harm Through Improved Risk Judgments," IRB: A Review of Human Subjects Research, 12, no. 1 (1990): 7-10 (comparing various definitions of harm and risk and proposing a model for risk judgments); and T. Beauchamp and J. Childress, Principles of Biomedical Ethics (New York: Oxford University Press, 1994) (discussing risk assessment, uncertainty, and risk perception).
92. 45 C.F.R. § 46.102(I) (1991); and 21 C.F.R. § 50.3(l) (1993).
93. A 1995 consensus statement regarding informed consent in emergency research proposed a new risk category - "appropriate incremental risk." This is defined as "any potential risk associated with participating in the research protocol relative to the natural consequences of the medical condition, or any potential risk associated with receiving the experimental intervention relative to receiving the standard intervention for the medical condition." M.H. Biros et al., "Informed Consent in Emergency Research: Consensus Statements from the Coalition Conference of Acute Resuscitation and Critical Care Researchers," JAMA, 273 (1995): at 1286. See also Keyserlingk et al., supra note 59, at 329 (noting that minimal risk must be evaluated in light of the subject's "everyday care and treatment." Thus the baseline of risk for a person with Alzheimer's would be higher than for a healthy person.).
94. A 1995 consensus statement regarding informed consent in emergency research proposed a new risk category - "appropriate incremental risk." This is defined as "any potential risk associated with participating in the research protocol relative to the natural consequences of the medical condition, or any potential risk associated with receiving the experimental intervention relative to receiving the standard intervention for the medical condition." M.H. Biros et al., "Informed Consent in Emergency Research: Consensus Statements from the Coalition Conference of Acute Resuscitation and Critical Care Researchers," JAMA, 273 (1995): at 1286. See also Keyserlingk et al., supra note 59, at 329 (noting that minimal risk must be evaluated in light of the subject's "everyday care and treatment." Thus the baseline of risk for a person with Alzheimer's would be higher than for a healthy person.).
95. Current DHHS regulations allow parents to consent to research involving their children that involves greater than minimal risk and no potential for direct therapeutic benefit when it is likely to yield generalizable information about the subject's condition. 45 C.F.R. § 46.406 (1991). The regulations state that the risk must "represent a minor increase over minimal risk." Id. Furthermore, the regulations require the approval of the secretary of DHHS. I suggest instead that when a research protocol involves risk that is too high for IRB approval, review Should be the responsibility of a national review board. See infra pages 28.
96. It is hard to quantify benefits. For example, how do you compare potential life-spans - living pain-free and out of the hospital for two weeks versus confinement to a hospital bed for two months? Notwithstanding, it is possible for IRBs to make general benefit calculations.
97. This simplifies the analysis greatly. The percentages, while being difficult to predict initially, may also not be this clear cut. For example, a drug could be likely to help 20 percent of the people 100 percent, 10 percent of the people 50 percent, and 2 percent of the people 30 percent. For the sake of argument, simple statistics are used.
98. As the potential for direct therapeutic benefit approaches zero, greater protections should apply.
99. I will not discuss protections in the treatment context. If these were to be changed or augmented, similar protections should be applied to the research context.
100. If the subject in question has been adjudicated as incompetent, he/she can neither consent to research nor execute an advance care document.
101. See generally, J. Robertson, "Taking Consent Seriously: IRB Intervention in the Consent Process," IRB: A Review of Human Subjects Research, 4, no. 5 (1982): 1-5 (describing ways in which IRBs could improve consent forms and the consent process through the use of competency testing, monitoring, and restructuring).
102. Therapeutic misconception refers to a phenomenon that occurs when the investigator is viewed as both a researcher and an attending physician. The result is a blurring of the two roles and a misconception that the research is primarily conducted for the direct therapeutic benefit of the patient-subject. Both physicians and patients are subject to this phenomenon.
103. P.S. Appelbaum, L. Roth, and C. Lidz, "The Therapeutic Misconception: Informed Consent in Psychiatric Research," International Journal of Law and Psychiatry, 5 (1982): 319-29.
104. P. Benson, L. Roth, and W. Winslade, "Informed Consent in Psychiatric Research: Preliminary Findings from an Ongoing Investigation," Social Science and Medicine, 20 (1985): 1331-41.
105. Id. at 1337.
106. B. Stanley, M. Stanley, and A. Lautin, "Informed Consent and Competency in Psychiatric Research," (unpublished manuscript, on file with the author, 1985) (medication use did not affect capacity, but diagnosis correlated with poorer decision making, that is, persons with schizophrenia were more likely chose to participate in high risk, low benefit studies).
107. Appelbaum, Lidz, and Meisel, supra note 14, at 248-58. See also F. Grinnell, "Endings of Clinical Research Protocols: Distinguishing Therapy from Research," IRB: A Review of Human Subjects Research, 12, no. 4 (1990): 1-3 (noting that many subjects at the end of a research protocol are unaware that a potentially beneficial treatment may be discontinued).
108. Appelbaum, Lidz, and Meisel, supra note 14, at 248-58. See also F. Grinnell, "Endings of Clinical Research Protocols: Distinguishing Therapy from Research," IRB: A Review of Human Subjects Research, 12, no. 4 (1990): 1-3 (noting that many subjects at the end of a research protocol are unaware that a potentially beneficial treatment may be discontinued).
109. See, for example, Robertson, supra note 94.
110. A low potential could mean either that the magnitude of benefit is low or that the percentage calculation approaches zero. The former should be treated cautiously because, as previously mentioned, it primarily involves an individual assessment. The latter could occur either because of the low probability that the treatment will help or because of the experimental design.
111. See National Commission for Protection of Human Subjects of Biomedical and Behavioral Research, supra note 8, at 5: "Respect for the immature or incapacitated may require protecting them as they mature or while they are incapacitated.... The extent of protection afforded should depend upon the risk of harm and the likelihood of benefit."
112. American College of Physicians, supra note 26, at 844.
113. To some extent, guidelines can carve out extremes along the continuum but not the middle. Thus one can specify restrictions on minimal and high-risk research, but appropriate protections for research that falls into the category of greater than minimal risk but lower than high risk should be determined by local IRBs. Factors to consider include the degree of risk (higher = greater protections) and the potential for direct therapeutic benefit (lower = greater protections).
114. See infra case 7.
115. Wicclair, supra note 28, at 182 (condition 4).
116. Id. at 182 (condition 3).
117. See, for example, American College of Physicians, supra note 26, at 844. This, in effect, is a situation where advance consent is sought from the subject in anticipation of later incompetence. For example, Alzheimer's patients in the first stage of the illness may want to consent to participation in high-risk research to be conducted during the later stages of the disease (for example, research designed to investigate the disease process in hopes of eventually finding a cure, but yielding no present direct therapeutic benefit to the subject). If a proxy is appointed to ensure that participation is still appropriate at a later date, such research should be allowed. As mentioned earlier, however, subject cooperation remains essential. In setting up these guidelines, I want to distinguish the court cases that have allowed a parent or guardian to consent to the donation of an organ of an incompetent person to a sibling. See, for example, J.B. Korins, "Curran v. Bosze: Toward a Clear Standard for Authorizing Kidney and Bone Marrow Transplants Between Siblings," Vermont Law Review, 16 (1992): 499-539. These holdings have been based on a stretching of the best interests analysis to include the emotional harm to the incompetent person that would result from the loss of a sibling. Although this is a dubious interpretation of best interests, it is not improbable that, in these extreme situations, a court may authorize such measures. Even so, I choose not to base my general recommendations on this practice.
118. See, for example, American College of Physicians, supra note 26, at 844. This, in effect, is a situation where advance consent is sought from the subject in anticipation of later incompetence. For example, Alzheimer's patients in the first stage of the illness may want to consent to participation in high-risk research to be conducted during the later stages of the disease (for example, research designed to investigate the disease process in hopes of eventually finding a cure, but yielding no present direct therapeutic benefit to the subject). If a proxy is appointed to ensure that participation is still appropriate at a later date, such research should be allowed. As mentioned earlier, however, subject cooperation remains essential. In setting up these guidelines, I want to distinguish the court cases that have allowed a parent or guardian to consent to the donation of an organ of an incompetent person to a sibling. See, for example, J.B. Korins, "Curran v. Bosze: Toward a Clear Standard for Authorizing Kidney and Bone Marrow Transplants Between Siblings," Vermont Law Review, 16 (1992): 499-539. These holdings have been based on a stretching of the best interests analysis to include the emotional harm to the incompetent person that would result from the loss of a sibling. Although this is a dubious interpretation of best interests, it is not improbable that, in these extreme situations, a court may authorize such measures. Even so, I choose not to base my general recommendations on this practice.
119. Compare the NIH Clinical Center Policy of having a bioethics consultant as a nonvoting member of an IRB. E. DeRenzo and A. Wichman, "A Pilot Project: Bioethics Consultants as Non-Voting Members of IRBs at the National Institutes of Health," IRB: A Review of Human Subjects Research, 12, no. 6 (1990): 6-8. In general, the use of such consultants was considered helpful (id.; and E. DeRenzo and F. Bonkovsky, "Bioethics Consultants to the National Institutes of Health's Intramural IRB System: The Continuing Evolution," IRB: A Review of Human Subjects Research, 15, no. 3 (1993): 9-10). However, most bioethics consultants will need additional training to serve in this capacity. DeRenzo and Wichman, id. at 8 ("individuals who were more familiar with the performance of human subjects research were appropriately perceived as better able to assist the ICRSs").
120. Compare the NIH Clinical Center Policy of having a bioethics consultant as a nonvoting member of an IRB. E. DeRenzo and A. Wichman, "A Pilot Project: Bioethics Consultants as Non-Voting Members of IRBs at the National Institutes of Health," IRB: A Review of Human Subjects Research, 12, no. 6 (1990): 6-8. In general, the use of such consultants was considered helpful (id.; and E. DeRenzo and F. Bonkovsky, "Bioethics Consultants to the National Institutes of Health's Intramural IRB System: The Continuing Evolution," IRB: A Review of Human Subjects Research, 15, no. 3 (1993): 9-10). However, most bioethics consultants will need additional training to serve in this capacity. DeRenzo and Wichman, id. at 8 ("individuals who were more familiar with the performance of human subjects research were appropriately perceived as better able to assist the ICRSs").
121. See 43 Fed. Reg. 53 (Mar. 17, 1978). The proposed regulations for research involving those "institutionalized as mentally infirm" stated that, in certain cases, the IRB should appoint a consent auditor to monitor consent. Current regulations refer to the obligation of the IRB or subject-advocates to oversee the consent process in connection with activities involving fetuses, pregnant women, or human in vitro fertilization. See 45 C.F.R. § 46.205(a)(2) (1991).
122. P.M. Bein, "Surrogate Consent and the Incompetent Experimental Subject," Food and Drug Cosmetic Journal, 46 (1991): 739-71.
123. Where there is no evidence of the subject's wishes, the best interests standard applies and participation would be barred. Likewise, where there is some but insufficient evidence, the high level of certainty needed would not be met and thus participation would be barred.
124. R. Delgado and H. Leskovac, "Informed Consent in Human Experimentation: Bridging the Gap Between Ethical Thought and Current Practice," UCLA Law Review, 34 (1986): at 116.
125. The above analysis assumes that the IRB has already approved the research. Thus, at issue here is whether the participation of an individual subject is permissible.
126. See NIH Clinical Center Policy, supra note 27, case 8.
127. Research that involves a significant degree of risk (that is, greater than minimal) and offers little or no therapeutic benefit would never be in a person's best interests. See American College of Physicians, supra note 26, at 845. Even if one assumes some altruistic gain from participating in experimentation, this would be outweighed by the high risk. Thus a surrogate decision maker using the best interests standard should never consent to such experiments.
128. See Miller, supra note 35, at 6 (arguing that "deputy judgment" where there is "no authorization of the agent by the principal, and the agent is not able to make a decision that is implied by the principal's values and attitudes... does not respect the autonomy of the principal in any of the four aspects of autonomy.").
129. H. Jonas, "Philosophical Reflections on Experimenting with Human Subjects," in P.A. Freund, ed., Experimentation with Human Subjects (New York: G. Braziller, 1970): at 3-4.
130. McNeill, supra note 20, at 155 (McNeill also notes that "[t]here needs to be an authority to define the cases to which the rule applies because it is not possible to specify in advance all the situations to which the rule or principle applies." Id. at 156). But see Keyserlingk et al., supra note 59, at 334 (arguing that even a national review board should not have the authority to allow research under these circumstances).
131. McNeill, supra note 20, at 155 (McNeill also notes that "[t]here needs to be an authority to define the cases to which the rule applies because it is not possible to specify in advance all the situations to which the rule or principle applies." Id. at 156). But see Keyserlingk et al., supra note 59, at 334 (arguing that even a national review board should not have the authority to allow research under these circumstances).
132. McNeill, supra note 20, at 155 (McNeill also notes that "[t]here needs to be an authority to define the cases to which the rule applies because it is not possible to specify in advance all the situations to which the rule or principle applies." Id. at 156). But see Keyserlingk et al., supra note 59, at 334 (arguing that even a national review board should not have the authority to allow research under these circumstances).
133. See DeRenzo, supra note 42, at 545 (discussing the benefits of a public forum).
134. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, supra note 25, at 1. See also Biros et al., supra note 87, at 1286 ("Because the local IRB has good insight into local medical practice, the local patient population, and the capabilities of local researchers, institutions, and resources, the IRB should be the monitoring body primarily responsible for maintaining vigilant oversight of clinical trials of emergency research.").
135. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, supra note 25, at 1. See also Biros et al., supra note 87, at 1286 ("Because the local IRB has good insight into local medical practice, the local patient population, and the capabilities of local researchers, institutions, and resources, the IRB should be the monitoring body primarily responsible for maintaining vigilant oversight of clinical trials of emergency research.").
136. National Institutes of Health Office for the Protection from Research Risks, Institutional Review Board Guidebook: Protecting Human Research Subjects (Washington: D.C.: U.S. Government Printing Office, 1993): 6-26 to 6-32.
137. Id. at 6-41.
138. Id. at 6-47.
139. Id. at 6-31 ("IRBs should be aware of any applicable law in their state particularly those relating to consent by family members on behalf of persons incapable of consenting on their own.").
140. See, for example, J. Kane, L. Robbins, and B. Stanley, "Psychiatric Research," in R. Greenwald, M.K. Ryan, and J. Mulvihill, eds., Human Subjects Research (New York: Plenum, 1982): 193-205 (proposing specific issues for IRBs to consider with regard to subjects who have a mental illness, but noting that "the population has much in common with other patient populations. Therefore issues such as risk-benefit ratio of the proposed research must be addressed as with nonpsychiatric research." Id. at 194.); and E.G. DeRenzo, "The Ethics of Involving Psychiatrically Impaired Persons in Research," IRB: A Review of Human Subjects Research, 16, no. 6 (1994): 7-9, 11.
141. See, for example, J. Kane, L. Robbins, and B. Stanley, "Psychiatric Research," in R. Greenwald, M.K. Ryan, and J. Mulvihill, eds., Human Subjects Research (New York: Plenum, 1982): 193-205 (proposing specific issues for IRBs to consider with regard to subjects who have a mental illness, but noting that "the population has much in common with other patient populations. Therefore issues such as risk-benefit ratio of the proposed research must be addressed as with nonpsychiatric research." Id. at 194.); and E.G. DeRenzo, "The Ethics of Involving Psychiatrically Impaired Persons in Research," IRB: A Review of Human Subjects Research, 16, no. 6 (1994): 7-9, 11.
142. See, for example, J. Kane, L. Robbins, and B. Stanley, "Psychiatric Research," in R. Greenwald, M.K. Ryan, and J. Mulvihill, eds., Human Subjects Research (New York: Plenum, 1982): 193-205 (proposing specific issues for IRBs to consider with regard to subjects who have a mental illness, but noting that "the population has much in common with other patient populations. Therefore issues such as risk-benefit ratio of the proposed research must be addressed as with nonpsychiatric research." Id. at 194.); and E.G. DeRenzo, "The Ethics of Involving Psychiatrically Impaired Persons in Research," IRB: A Review of Human Subjects Research, 16, no. 6 (1994): 7-9, 11.
143. See, for example, DeRenzo, supra note 127, at 9 (discussing the use of a "Ulysses Contract"-a self-binding psychiatric advance directive); and Casasanto, Simon, and Roman, supra note 46, at 549 (discussing the role of a guardian when the ward "has a cyclical impairment such as severe depression." Casasanto, Simon, and Roman conclude that "ethical principles favoring self-determination seem to dictate that the wishes expressed by the person be adhered to if a person is in a lucid state, despite the judicial determination that he is incompetent. [Thus the] Model Code recognizes... that a guardian is obligated, in limited situations, to respect the wishes of the ward even if contrary to the guardian's notion of best interest."). One danger that should be acknowledged is the guardian's potential liability. If the guardianship order is not limited, the guardian may be liable for allowing the ward to consent to a procedure that is not in his/her best interests. This can be avoided either by limiting the scope of the guardianship order or by expressly permitting the guardian to use a substituted judgment standard rather than a best interests analysis.
144. See, for example, DeRenzo, supra note 127, at 9 (discussing the use of a "Ulysses Contract"-a self-binding psychiatric advance directive); and Casasanto, Simon, and Roman, supra note 46, at 549 (discussing the role of a guardian when the ward "has a cyclical impairment such as severe depression." Casasanto, Simon, and Roman conclude that "ethical principles favoring self-determination seem to dictate that the wishes expressed by the person be adhered to if a person is in a lucid state, despite the judicial determination that he is incompetent. [Thus the] Model Code recognizes... that a guardian is obligated, in limited situations, to respect the wishes of the ward even if contrary to the guardian's notion of best interest."). One danger that should be acknowledged is the guardian's potential liability. If the guardianship order is not limited, the guardian may be liable for allowing the ward to consent to a procedure that is not in his/her best interests. This can be avoided either by limiting the scope of the guardianship order or by expressly permitting the guardian to use a substituted judgment standard rather than a best interests analysis.
145. See, for example, Letter to Ron Wyden from Subcommittee Staff (Mar. 11, 1994) (highlighting abuses in this context); Biros et al., supra note 87; and Protection of Human Subjects, 60 Fed. Reg. 49,086 (proposed Sept. 21, 1995).
146. See, for example, Letter to Ron Wyden from Subcommittee Staff (Mar. 11, 1994) (highlighting abuses in this context); Biros et al., supra note 87; and Protection of Human Subjects, 60 Fed. Reg. 49,086 (proposed Sept. 21, 1995).
147. Letter to Ron Wyden from Subcommittee Staff (Mar. 11, 1994). The present federal regulations appear to be inconsistent. Compare 45 C.F.R. § 46.116(d) (1991) with 21 C.F.R. § 50.23(a) (1993).