This document presents the findings and proposals of a multi-agency Working Group (WG) convened by the Office of Science Policy, Office of the Assistant Secretary for Planning and Evaluation to develop a proposed response by the Department of Health and Human Services (HHS) to the National Bioethics Advisory Commission (NBAC) Report entitled Research Involving Persons with Mental Disorders That May Affect Decisionmaking Capacity (the “Report”). The Report makes 21 recommendations, which are variously directed to investigators or institutional review boards (IRBs); the National Institutes of Health (NIH) or other HHS agencies and offices; other Federal agencies that, along with HHS, have adopted the Common Rule*; State legislatures; health professionals; or others responsible for human subject protections.
The WG commends NBAC for its thoughtful and insightful report. The WG agrees that, despite significant improvement in human subject protection during recent decades, difficult issues related to the participation in research of individuals with impaired decisionmaking capacity need further consideration. NBAC has performed a valuable service in bringing these matters to the Nation’s attention.
The WG believes, with NBAC, that our goals must be “providing protection for persons with mental disorders while allowing important research to go forward.” (Report at 41). This position is in harmony with Mental Health: Report of the Surgeon General, which emphasizes the “importance of a solid research base for every mental health and mental illness intervention” because “establishing mental health policy on the basis of good intentions alone can make bad situations worse; [whereas] evaluating the practicality and effectiveness of new approaches is efficient and, more critically, is accountable to those for whom an intervention is intended.”** The WG agrees with many of NBAC’s concerns and recommendations and has developed proposals for how HHS might appropriately respond to the Report.
In addition, the WG recognizes that NBAC currently is conducting a review of the entire system of human subject protections and that, upon completing this comprehensive review, may make additional recommendations affecting human research subjects with impaired decisionmaking capacity. The WG was mindful of that possibility in developing its proposals.
SCOPE OF APPLICABILITY OF NBAC’S RECOMMENDATIONS
The WG found some ambiguity as to who is to be protected by the Report’s 21 recommendations. Certain NBAC recommendations refer to “persons [or subjects] with mental disorders that may affect decisionmaking capacity” (e.g., Recommendations 2 and 20), while others refer to “persons with mental disorders” (e.g., Recommendations 1, 3, and 18). Based upon an analysis of the entire Report, the WG interprets the intended scope of NBAC’s recommendations to be “persons with mental disorders that may affect decisionmaking capacity,” as listed in the title.
The WG agrees with NBAC that current procedures for human subject protection should be improved to adequately protect research participants whose decisionmaking ability is impaired because of a mental disorder. Because of the need to rely on surrogate decision-makers and concerns about a subject’s susceptibility to undue influence and coercion, a subject who has impaired decisionmakng capacity due to a mental condition may not be adequately protected by the current informed consent procedures.
However, the WG notes that some physical disorders or conditions also may result in impaired capacity to make decisions and therefore the ability to give voluntary informed consent to research. Either mental or physical conditions that impair decisionmaking capacity may make subjects vulnerable to coercion or undue influence and thus in need of protection. As NBAC observed, “many of the issues and concerns raised in this report (and, indeed, many of its recommended protections) could be applied to all persons with questionable or diminished capacity.” (Report at p. 5).
Further, the WG is concerned that limiting the scope of protections may be perceived to be stigmatizing. Approximately one in five Americans experiences a mental disorder during the course of a year,*** yet the preponderance are capable of making major life decisions. The WG agrees, and NBAC’s Report takes pains to. emphasize, that a person is not decisionally incapacitated to consent to research merely because that Person has a mental disorder or mental illness. However, the Report’s focus was not expressly extended beyond persons with mental disorders and that in itself may appear stigmatizing or could lead to inadvertent stigmatization in practice.
The WG therefore concludes that the scope of the Report’s recommendations seem appropriately applicable to all persons with decisional impairment, irrespective of diagnosis.
REGULATORY FRAMEWORK ENVISIONED BY NBAC
Four of NBAC’s recommendations work in concert to call for a new regulatory framework:
- Recommendation 2: Creation of a Special Standing Panel (SSP)
- Recommendation 10: Research Protocols Involving Minimal Risk
- Recommendation 11: Research Protocols Involving Greater than Minimal Riskthat Offer the Prospect of Direct Medical Benefit to Subjects
- Recommendation 12: Research Protocols Involving Greater than Minimal Risk that Do Not Offer the Prospect of Direct Medical Benefit to Subjects
The recommended framework would require IRBs to classify all proposed research involving persons with mental disorders that may affect decisionmaking capacity into one of the three categories specified by Recommendations 10-12. The current regulations do not require a classification of risk.
Further, if the proposed research does not offer the prospect of direct medical benefit and involves any degree of risk greater than minimal risk, the subject could not be enrolled in the research by a legally authorized representative (LAR), except under one of two sets of circumstances. In addition to IRB approval, either (1) the subject must have executed an advance directive to participate in that type of research or (2) the research must be reviewed by a “Special Standing Panel” (SSP) convened by the Secretary and that panel must conclude that the protocol “offers the possibility of substantial benefit to the population under study, that its risks to subjects are reasonable in relation to this possible benefit, and that it could not be conducted without the proposed population,” and the panel must be “satisfied that all appropriate safeguards are incorporated.” If the SSP subsequently were to promulgate guidelines covering certain instances of that type of protocol, then only IRB approval and surrogate consent would be required unless the guidelines were to require more.
The WG agrees with the principle, reflected in NBAC’s Recommendations 10, 11, and 12, that additional safeguards are warranted when research is directed toward subjects with mental or physical conditions that are associated with decisional impairment This principle is consistent with current requirements. However, the WG believes that widespread execution of Prospective Authorizations for research is unlikely and thus that the large number of proposed protocols that would require review by the SSP could make the envisioned regulatory framework impractical to implement Further, the WG notes that the envisioned regulatory framework would alter IRB authority in ways that could produce anomaloiis results. For example, under certain circumstances, NBAC’s recommendations not only would limit IRB authority more for adults than for children but also would narrow the types of benefits that an IRB may consider in determining whether a greater than minimal risk protocol offers a direct benefit.
With regard to Recommendations 2, 10, 11, and 12, the WG proposes that the Office for Human Research Protections (OHRP), working in consultation with Food and Drug Administration (FDA), solicit additional public comment regarding appropriate approval standards as a function of differing levels of risk in research directed toward subjects with mental or physical conditions that are associated with decisional impairment. The WG proposes in particular that a formal Federal Register solicitation request comment on (i) appropriate mechanisms for ensuring needed protections; (ii) appropriate regulatory frameworks for characterizing informed consent and IRB approval requirements as a function of differing levels of risk; and (iii) acceptability of certain overarching principles.
See “Discussion” and “Proposed Action” following Recommendation 12 for pertinent details regarding the form and content of the proposed solicitation of public comment.
RECOMMENDED PROTECTIONS INHERENT IN CURRENT REGULATIONS BUT POSSIBLY WARRANTING ADDITIONAL GUIDANCE
Eight of NBAC’s recommendations are consistent with but generally more specific than the current regulations:
- Recommendation 1: Institutional Review Board Membership
- Recommendation 3: Appropriate Subject Selection
- Recommendation 4: Justifying Research Designs and Minimizing Risks
- Recommendation 5: Evaluating Risks and Benefits
- Recommendation 7: Objection to Participation in Research
- Recommendation 8: Assessing Potential Subjects’ Capacity to Decide about Participating in a Research Protocol
- Recommendation 9: Notifying Subjects of Incapacity Determinations and Research Enrollment
- Recommendation 17: Involving Subjects’ Family and Friends
The WG agrees in principle regarding all eight recommendations, but for five of them (1, 4, 8, 9, and 17) it offers an alternative perspective on certain facets for consideration by OHRP and FDA.
The WG proposes that, after consideration of this Analysis and consultation with FDA, OHRP develop and issue additional interpretive guidance in response to Recommendations 1 and 3.
The WG proposes that, after consideration of this Analysis and consultation with FDA, OHRP take whatever actions it deems appropriate regarding Recommendations 4, 5, 7, 8, 9, and 17.
ADDITIONAL RESEARCH RELATED TO DECISIONAL IMPAIRMENT
Two of NBAC’s recommendations are related to additional research related to decisional impairment:
- Recommendation 19: Expanding Knowledge about Capacity Assessment and Informed Consent
- Recommendation 20: Institute of Medicine Review of Research Studies
Recommendation 19 is addressed explicitly to the NIH. For recommendation 20, the NIH is the appropriate lead agency for HHS.
The WG proposes that the Director, NIH determine and take whatever action is needed in regard to Recommendations 19 and 20.
STATE LAWS RELATED TO RESEARCH INVOLVING PERSONS WHOSE DECISIONMAKING CAPACITY MAY BE IMPAIRED
Four of NBAC’s recommendations address legal matters that fall substantially, if not entirely, within the province of States:
- Recommendation 13: Prospective Authorization
- Recommendation 14: Legally Authorized Representatives
- Recommendation 15: Expansion of the Category of Legally Authorized Representatives and of the Powers Granted under Statutes for Durable Powers of Attorney (DPA) for Health Care
- Recommendation 16: State Legislation Regarding Advanced Directives for Research
The WG recognizes that the options of the federal government in these areas are heavily dependent upon what actions, if any, States take.
The WG proposes’ that the Secretary make the States aware of NBAC’s Recommendations 13-16 and our proposed actions and encourage the States to consider them, by sending copies of NBAC’s Report and this Analysis to the States’ Attorneys General.
- Recommendation 6: Informed Consent
- Recommendation 18: Reviewing and Developing Educational Materials Regarding Research
- Recommendation 21: Increased Funding to Support Necessary Protections of Human Subjects)
Recommendation 6 requires no action. Recommendation 18 is directed to professional associations and organizations. Recommendation 21 is directed to all research sponsors, including HHS.
With regard to Recommendation 21, the WG proposes that HHS continue its efforts to increase the financial support available to IRBs.
* Most federal agencies that conduct or support research involving human subjects have adopted regulations based on the language set forth in Subpart A of 45 CFR 46. This set of common regulations is referred to as the Federal Policy (Common Rule) for the Protection of Human Subjects. The FDA regulations at 21 CFR Parts 50 & 56 are FDA’s equivalent to the Common Rule.
** Mental Health Report, Executive Summary p. viii.
*** Mental Health Report, Executive Summary, p. xii.