History of Regulatory
Efforts in This Area

History of Regulatory Efforts in This Area

When the National Commission was created in 1974, the decisionally impaired were among the special populations that it intended to consider, partly because of the controversy about lobotomy. In its 1978 Report and Recommendations on Research Involving Those Institutionalized as Mentally Infirm,263 which came at the very end of its tenure, the National Commission rejected both the Nuremberg Code’s complete ban and the 1964 Declaration of Helsinki’s limitation on the involvement of incapable subjects in research. The members of the National Commission believed a less restrictive approach was justified to avoid indirect harm to incapable persons by crippling research efforts designed to yield potential treatment for these persons’ conditions. They introduced this idea as follows:

[S]ince some research involving the mentally infirm cannot be undertaken with any other group, and since this research may yield significant knowledge about the causes and treatment of mental disabilities, it is necessary to consider the consequences of prohibiting such research. Some argue that prohibiting such research might harm the class of mentally infirm persons as a whole by depriving them of benefits they could have received if the research had proceeded.264

This concept marked an important turning point in the social philosophy underlying the regulation of human subjects research; benefits to others (particularly those who now or someday may suffer from the same disorder) could now be given more weight. The National Commission concluded that the dual goals of benefiting mentally infirm persons and protecting individual subjects from undue harm could be met by a third approach: incapable subjects could be involved in studies offering them potential direct benefit, as well as studies that did not offer potential direct benefit, as long as the burdens and risks of research participation did not exceed a certain level.

Based on this general approach, the National Commission created a framework for evaluating research involving incapable subjects. Its proposals regarding children and institutionalized persons with mental impairments were similar, though with some variation. Their common elements included a requirement to justify the involvement of these subject groups rather than alternative but less vulnerable subject populations; a hierarchy of research categories establishing more rigorous substantive and procedural standards for proposals presenting more than minimal risk to incapable subjects; and a mechanism for incapable subjects to provide input in the form of "assent" or objection to study participation—that is, a simple yes or no when questioned about willingness to be in a study.

Differences in the recommendations on children and institutionalized persons were based on the National Commission’s recognition that some adults institutionalized as mentally infirm retain the ability to give an informed and voluntary decision. Because of concerns about the vulnerability of institutionalized persons, however, the National Commission recommended that IRBs be given discretion to appoint "an auditor to observe and assure the adequacy of the consent process for research" that presents greater than minimal risk. Moreover, the National Commission believed that such auditors should be required in projects presenting no prospect of direct benefit and more than minimal risk to subjects. Their proposals also gave incapable adults more authority than children to refuse study participation.265 Finally, because incapable adults usually lack the legal guardian that most children have, the National Commission noted that in some cases a court-appointed guardian would be required to authorize research participation.

In response to the National Commission’s work, DHEW proposed regulations to govern research on the two populations. Those affecting children were adopted by DHHS in June 1983,266 but those affecting persons institutionalized as mentally infirmed were not.267 In explaining why the latter were not adopted, the Secretary of DHHS pointed to a lack of consensus on the proposed regulatory provisions and a judgment that the general regulations governing human subjects’ participation sufficiently incorporated the National Commission’s recommendations.268 Robert Levine blames the reported lack of consensus on DHEW’s earlier failure to adhere to the National Commission’s recommendations.269 In particular, DHEW’s proposed regulations indicated that consent auditors might be mandatory for all research involving institutionalized mentally disabled persons, and suggested that the authorization of an additional person assigned the role of independent advocate might be necessary before an incapable person could become a research subject. During the public comment period, many respondents objected to these additional procedural requirements, presumably on the belief that they were unnecessary and overly burdensome to research.270

The 1981 DHHS rules largely followed from the National Commission’s work. In 1991, these rules were codified for 16 federal agencies that conduct or sponsor research with human subjects and are now known as the "Common Rule."271 In the United States today, research involving adults diagnosed with a condition characterized by mental impairment is governed by no special regulations, but falls instead under the Common Rule, in which a few provisions address research involving persons with mental disabilities. First, the Common Rule identifies "mentally disabled persons" as a vulnerable population, and directs IRBs to include "additional [unspecified] safeguards . . . to protect the rights and welfare" of mentally disabled research subjects. These safeguards could involve consultation with specialists concerning the risks and benefits of a procedure for this population, or special monitoring of consent processes to ensure voluntariness. It is not known how frequently IRBs actually implement such measures.272

The Common Rule also advises IRBs to ensure that "subject selection is equitable."273 In particular, "[i]f an IRB regularly reviews research that involves a vulnerable category of subjects, such as . . . mentally disabled persons, consideration should be given to the inclusion of one or more individuals who are knowledgeable about and experienced in working with these subjects."274 The Common Rule allows an incapable individual’s "legally authorized representative" to give valid consent to the individual’s research participation,275 but provides no definition of incapacity, no guidance on the identity or qualifications of a subject representative beyond "legally authorized," and no guidance on what ratio of risks to potential benefits is acceptable.

In the 1980s and 1990s, numerous groups and individuals expressed dissatisfaction with gaps in the existing regulations. After the ACHRE reviewed eight studies conducted in the early 1990s involving adult subjects with uncertain decisionmaking capacity, and found that four of the studies required subjects to undergo diagnostic imaging that offered them no prospect of direct benefit and that two appeared to present greater than minimal risk to the subjects, it noted, "there was no discussion in the documents or consent form of the implications for the subjects of these potentially anxiety-provoking conditions. Nor was there discussion of the subjects’ capacity to consent or evidence that appropriate surrogate decision makers had given permission for their participation."276 Inquiries into studies involving rapid medication withdrawal from persons diagnosed with schizophrenia have also raised questions about the adequacy of current federal policy and the ethical acceptability of certain research protocols.277

NBAC is not aware of strong evidence that IRBs are actively using, or not using, their existing discretionary authority when reviewing protocols involving individuals with mental disorders. In addition, although IRBs currently have authority to monitor research in progress, including research involving persons with mental disorders, it does not appear that such monitoring routinely occurs, possibly because institutional and other resources have not been devoted to this critical activity. Observers of the review process agree that although the workload of many IRBs at some of the largest research centers has greatly increased in recent years, the institutional support for IRB activities has often not kept pace.278 While some institutions have responded to this increase by establishing more than one board, the practice may not be widespread enough. According to the report of the DHHS Office of the Inspector General, monitoring of a protocol’s progress after its initial approval is practically nonexistent apart from investigators’ routine filing of annual progress reports. After the initial stages, local review has only minimal impact on actual research practices.279

The lack of more specific federal guidance on research involving persons with mental disorders has also meant that research not under federal jurisdiction has been subject to widely divergent state laws and regulations; most states have no rules that specifically apply to research involving this population while some states have quite restrictive regulations. Several states currently prohibit certain types of research on persons with mental disorders, such as research that presents greater than minimal risk without the prospect of direct benefit to subjects.280 This suggests that both IRBs and researchers may have trouble identifying (and thus following) the procedures required for ethical and legal investigations involving persons with mental disorders, even in states that have attempted to provide the badly needed guidance.

Uncertainty about legal and ethical norms can contribute to an adversarial tone in public discourse about this kind of research. Indeed, as events in New York State illustrate, advocacy of sharply differing ethical perspectives can result in litigation. In T.D. v. New York State Office of Mental Health, several individuals and organizations challenged regulations of the New York State Office of Mental Health with respect to participation in greater than minimal risk research by minors and persons who lacked the capacity to give informed consent. In 1995, the trial court invalidated the regulations on the grounds that the Office of Mental Health lacked statutory authority to adopt them.281 The next year, the intermediate appellate court in New York agreed with the trial court’s conclusion but added a far more wide-ranging critique of the regulations, indicating that they violated both constitutional due process rights and substantive protections granted these research subjects under New York’s statutory and common law.282 Finally, however, New York’s highest court narrowed the judicial holding to the original decision of the trial court.283

Cognizant of the tensions revealed in the New York case, officials in Maryland have undertaken a cooperative process of policy formulation. A working group under the auspices of the Maryland Attorney General has, over more than 2 years, produced a series of reports culminating in a proposed state statute that would govern the substantive and procedural aspects of research involving "decisionally incapacitated individuals."284

263 National Commission, Report on Those Institutionalized as Mentally Infirm.

264 Ibid., 58.

265 The National Commission required explicit court authorization to involve an objecting institutionalized person in research. In contrast, the group recommended that parents be permitted to authorize research over a child’s objection if the study presented a prospect of direct benefit to subject not available outside the research context.

266 Additional Protections for Children Involved as Subjects in Research, 48 Fed. Reg. 9,814 (1983) (codified at 45 CFR 46 Subpt. D).

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

268 President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, Implementing Human Research Regulations (Washington, D.C.: GPO, 1983): 24.

269 Levine, "Proposed Regulations," 1; Bonnie, "Research with Cognitively Impaired Subjects," 107.

270 Ibid.

271 Federal Policy for the Protection of Human Subjects, 56 Fed. Reg. 28,003 (1991) (codified by adopting agencies in various sections of the Code of Federal Regulations).

272 Expert Panel Report to the National Institutes of Health, Research Involving Individuals with Questionable Capacity to Consent, 14.

273 45 CFR 46.111(a)(3) (1998).

274 45 CFR 46.107(a) (1998).

275 45 CFR 46.116 (1998).

276 ACHRE, Final Report, 706–707.

277 See, for example, Shamoo and Keay, "Ethical Concerns About Relapse Studies."

278 Department of Health and Human Services, Office of the Inspector General, Institutional Review Boards: Their Role in Reviewing Approved Research (Washington, D.C.: DHHS, 1998).

279 U.S. General Accounting Office, Continued Vigilance Critical to Protecting Human Subjects, report to the Ranking Minority Member, Committee on Governmental Affairs, U.S. Senate (Washington, D.C.: Government Accounting Office, 1996).

280 These prohibitions include Alaska Stat. §47.30.830 (Michie 1996) (prohibiting experimental research on state mental health patients that involve "any significant risk of physical or psychological harm"); Del. Code Ann. tit. 16, §51.75(f) (1995) (prohibiting any resident of a state mental hospital from being approached "to participate in pharmaceutical research if [the] patient is incapable of understanding the nature and consequences of [the] patient’s consent"); Del. Code Ann. tit. 16, §51.74 (1995) (prohibiting certain classes of mental hospital residents, regardless of competency, from participating in pharmaceutical research); 405 Ill. Comp. Stat. Ann. 5/2-110 (West 1993) (providing that parent or guardian cannot consent to ward’s participation in any "unusual, hazardous, or experimental services" without approval by court and determination that such services are in the "best interests" of the ward); Mass. Regs. Code tit. 104, §13.01–.05 (1995) (prohibiting research on patients in mental facilities that will not provide direct, therapeutic benefit and prohibiting research on patients with mental disabilities where the risk is more than minimal and exceeds the benefit to the subject); MO. Ann. Stat. §6.30.115 (8) (West Supp. 1997) (preventing state mental health patients from being "the subject of experimental research," with exceptions, and prohibiting biomedical or pharmacological research from being performed on any individual with mental disabilities if that research will have no direct therapeutic benefit on the individual research subject); 12 Va. Admin. Code 5-20-40 (1998) (prohibiting "non-therapeutic research" using patients in facilities for the mentally ill or developmentally disabled if the research presents greater than minimal risk). See also, Diane E. Hoffmann and Jack Schwartz, "Proxy Consent to Participation of the Decisionally Impaired in Medical Research: Maryland’s Policy Initiative," Journal of Health Care Law and Policy 136, nos. 9 and 12 (1997) (citing state statutes which provide restrictions for research on the decisionally impaired).

281 T.D., et al. v. New York State Office of Mental Health, et al., 626 N.Y.S. 2d 1015 (N.Y. Sup. Ct. 1995).

282 T.D., et al. v. New York State Office of Mental Health, et al., 650 N.Y.S. 2d 173 (N.Y. App. Div. 1996).

283 T.D., et al. v. New York State Office of Mental Health, et al., 690 N.E. 2d 1259 (N.Y. 1997). According to the New York Court of Appeals, the intermediate appellate court’s discussion of constitutional, common law, and other statutory issues was "an inappropriate advisory opinion."

284 Office of the Maryland Attorney General. Final Report.

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