[Federal Register Volume 64, Number 33 (Friday, February 19, 1999)]
[Notices]
[Pages 8376-8380]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-4190]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES


Notice of Publication of the Executive Summary of the Report, 
Research Involving Persons With Mental Disorders That May Affect 
Decisionmaking Capacity by the National Bioethics Advisory Commission 
(NBAC)

SUPPLEMENTARY INFORMATION: The President established the National 
Bioethics Advisory Commission (NBAC) on October 3, 1995 by Executive 
Order 12975 as amended. The functions of NBAC are as follows:
    (a) provide advice and make recommendations to the National Science 
and Technology Council and to other appropriate government entities 
regarding the following matters:
    (1) the appropriateness of departmental, agency or other 
governmental programs, policies, assignments, missions, guidelines, and 
regulations as they relate to bioethical issues arising from research 
on human biology and behavior; and (2) applications, including the 
clinical applications, of that research.
    (b) identify broad principles to govern the ethical conduct of 
research, citing specific projects only as illustrations for such 
principles.
    (c) shall not be responsible for the review and approval of 
specific projects.
    (d) in addition to responding to requests for advice and 
recommendations from the National Science and Technology Council, NBAC 
also may accept suggestions of issues for consideration from both the 
Congress and the public. NBAC may also identify other bioethical issues 
for the purpose of providing advice and recommendations, subject to the 
approval of the National Science and Technology Council. The members of 
NBAC are as follows:

Harold T. Shapiro, Ph.D., Chair
Patricia Backlar
Arturo Brito, M.D., Alexander M. Capron, LL.B.
Eric J. Cassell, M.D., M.A.C.P.
R. Alta Charo, J.D.
James F. Childress, Ph.D.
David R. Cox, M.D., Ph.D.
Rhetaugh G. Dumas, Ph.D., R.N.
Laurie M. Flynn
Carol W. Greider, Ph.D.
Steven H. Holtzman
Bernard Lo, M.D.
Lawrence H. Miike, M.D., J.D.
Thomas H. Murray, Ph.D.
Diane Scott-Jones, Ph.D.

Executive Summary, Research Involving Persons With Mental Disorders 
That May Affect Decisionmaking Capacity

    In this report, the National Bioethics Advisory Commission (NBAC) 
considers how ethically acceptable research can be conducted with human 
subjects who suffer from mental disorders that may affect their 
decisionmaking capacity; whether, in this context, additional 
protections are needed; and, if so, what they should be and how they 
should be implemented. In addition, this report provides an opportunity 
for investigators, Institutional Review Board (IRB) members, persons 
with mental disorders and their families, and the general public to 
become better informed about the importance of such research and what 
we believe are the appropriate protections for the human subjects 
involved.
    This report stands in a long line of statements, reports, and 
recommendations by governmental advisory groups and professional 
organizations on the ethical requirements of research involving human 
subjects that have been developed in the United States and elsewhere. 
Much has changed in the research environment since the National 
Commission for the Protection of Human Subjects of Biomedical and

[[Page 8377]]

Behavioral Research completed its work 20 years ago, and yet one 
finding is as true today as it was then: all research involving human 
beings as subjects must satisfy appropriate ethical and scientific 
standards. This moral imperative is especially acute for potentially 
vulnerable populations such as children, pregnant women, prisoners, or, 
NBAC believes, individuals with mental disorders that may affect their 
decisionmaking capacity. Mental disorders--which can be heartbreakingly 
burdensome for patients and their families and frustrating for the 
professionals who treat them--have in recent years been the focus of 
research studies that have produced important new methods of diagnosis 
and treatment. At the same time, some of these investigations have 
generated public controversy, government sanctions, and at times 
lawsuits. Although existing federal regulations for research involving 
human subjects provide special protections for certain populations that 
are regarded as particularly vulnerable, persons with mental disorders 
(who may have impaired capacity to make decisions about research 
participation) have not received any such special protections. NBAC 
believes that a cogent case can be made for requiring additional 
special protections in research involving as subjects persons with 
impaired decisionmaking capacity, but has chosen to focus this report 
on persons with mental disorders, in part because of this population's 
difficult history of involvement in medical research. Moreover, NBAC 
believes that in addition to the regulations that are already 
applicable, research involving subjects with mental disorders that may 
affect decisionmaking capacity should be governed by specific further 
regulations.
    In its consideration of these issues over 18 months, NBAC received 
input through public comments provided at every meeting, expert 
testimony, commissioned papers, interactions with professional and 
patient groups, and a 45-day comment period during which interested 
parties could submit written comments on the final draft report. In 
addition, NBAC reviewed a sampling of research protocols and consent 
forms relevant to research on individuals whose decisionmaking capacity 
might be affected by mental illness. Based on these varied inputs and 
careful deliberations, NBAC came to the following conclusions:
     During the nearly two decades in which the current federal 
regulations for the protection of human subjects have been in place, 
important scientific research on the cause and treatment of mental 
disorders has continued and expanded. Further, NBAC believes that 
important opportunities to develop new therapies will continue to 
emerge, and that the research community may be on the verge of some 
momentous breakthroughs. NBAC's challenge, therefore, was to develop 
recommendations that would sustain the continued acquisition of new 
knowledge and the development of new therapies, while ensuring the 
protection of those who participate as subjects in such research.
     Although IRBs have considerable authority and discretion 
to review, approve, and monitor research involving persons with mental 
disorders, they have received little practical guidance for reviewing 
such protocols. However, more than additional guidance is needed. 
Because of significant gaps in the current federal regulation 
additional regulations are necessary at this time. NBAC believes that 
enhanced protections will promote broad-based support for further 
research by engendering greater public trust and confidence that 
subjects' rights and interests are fully respected.
     More research is being conducted than ever before, and the 
research environment has become far more complex, involving both a 
larger societal investment and a greater role for the private sector. 
NBAC shares what it believes to be a broad base of support for 
continuing efforts to more fully understand and treat mental disorders. 
NBAC recommends additional new protections with the deepest respect for 
the many people involved in research on these disorders: those with a 
disorder that may affect decisionmaking capacity, whose autonomy must 
be protected and, when possible, enhanced; the clinical investigators 
who are dedicated to the alleviation of these disorders; and informal 
caregivers, whose own lives are often absorbed by the tragedy that has 
befallen their loved ones. NBAC does not believe, however, that the 
additional protections recommended in this report will excessively 
burden research or hamper the development of effective new treatments. 
Moreover, it is useful to note that many share in the responsibility to 
protect the interests of those without whom this research could not be 
done--especially those who may be unable to give full informed consent 
and who may not themselves directly benefit from the research.

Overview of the Report

    The report is divided into five chapters. Chapter 1 provides an 
overview of the issues that arise in research involving persons with 
mental disorders. It discusses the justification for the scope of the 
report, the nature of mental disorders, and the values that should 
guide research in these populations. Chapter 2 discusses informed 
consent and limitations on decisionmaking capacity. Chapter 3 examines 
the mechanisms that may be used to permit enrollment of persons who are 
now incapable of providing an informed consent: advance planning and 
surrogate decision making. It also considers the role of assent and 
objection. Chapter 4 explains NBAC's views on the assessment of risk 
and potential benefit in research. In particular, this chapter provides 
the rationale for distinguishing research protocols involving minimal 
risk, protocols involving greater than minimal risk that do not offer 
the prospect of direct medical benefit to the subjects, and protocols 
involving greater than minimal risk that do offer the prospect of 
direct medical benefit to the subjects. Chapter 5 presents NBAC's 
recommendations for regulatory reform and suggested additional guidance 
to IRBs and institutions.
    The several recommendations for changes in federal regulations and 
for other governmental, institutional, and organizational actions are 
interconnected. Even though only a few recommendations are explicitly 
cross-referenced, it is important to view each recommendation in the 
context of the others. Only then is it possible to see exactly how NBAC 
proposes to protect human subjects with mental disorders that may 
affect decisionmaking capacity and also allow important research to 
proceed.

Recommendations

    This report presents not only NBAC's recommendations but identifies 
where possible those who should be responsible for their 
implementation. Twenty-one recommendations are proposed. A number 
propose the development of new regulations for the protection of human 
subjects; others are directed to investigators and IRBs, state 
legislatures, the National Institutes of Health (NIH), the Department 
of Health and Human Services (DHHS), health professionals, federal 
agencies subject to the Federal Policy for the Protection of Human 
Subjects (``the Common Rule''), and others responsible for human 
subjects protection. These recommendations provide both a set of 
requirements that NBAC believes must be satisfied in all research 
protocols involving persons with mental disorders, and several 
additional or optional protections that may be

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considered, as appropriate, in particular circumstances. Taken 
together, these recommendations would both enhance existing protections 
and facilitate broad public support for continued research on mental 
disorders.
    Although NBAC proposes a number of recommendations that would 
require changes in the Common Rule, it is aware that the time frame for 
such reforms might be long and the process labor intensive. Many of the 
regulatory proposals made by NBAC could, therefore, be accomplished by 
the creation of a new subpart in 45 CFR 46. Regardless of which 
regulatory route is selected, NBAC encourages researchers and 
institutions to voluntarily adopt the spirit and substance of these 
recommendations immediately. The recommendations are clustered into six 
sections related to: review bodies; research design; informed consent 
and capacity; categories of research; surrogate decision making; and 
education, research, and support.

I. Recommendations Regarding Review Bodies

Institutional Review Board (IRB) Membership
    Recommendation 1. All IRBs that regularly consider proposals 
involving persons with mental disorders should include at least two 
members who are familiar with the nature of these disorders and with 
the concerns of the population being studied. At least one of these IRB 
members should be a member of the population being studied, a family 
member of such a person, or a representative of an advocacy 
organization for this population. These IRB members should be present 
and voting when such protocols are discussed. IRBs that only 
occasionally consider such protocols should involve in their discussion 
two ad hoc consultants who are familiar with the nature of these 
disorders and with the concerns of the population being studied; at 
least one of these consultants should be a member of the population 
being studied, a family member of such a person, or a representative of 
an advocacy organization for this population.
Creation of a Special Standing Panel (SSP)
    Recommendation 2. The Secretary of the Department of Health and 
Human Services should convene a Special Standing Panel (SSP) on 
research involving persons with mental disorders that may affect 
decisionmaking capacity. The panel's tasks should include:
    (A) Reviewing individual protocols that cannot otherwise be 
approved under the recommendations described in this report, that have 
been forwarded by IRBs to the SSP for its consideration. If the SSP 
finds that a 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, then the SSP may approve the 
protocol if it is satisfied that all appropriate safeguards are 
incorporated. Under no circumstance, however, should the SSP approve a 
protocol that reasonable, competent persons would decline to enter;
    (B) Promulgating guidelines that would permit local IRBs to approve 
protocols that cannot otherwise be approved under the recommendations 
described in this report. Such guidelines could suggest that a 
particular class or category of research, using specified research 
interventions with certain identified populations, could be considered 
by local IRBs without the need to resort to the SSP for further 
approval. Under no circumstances, however, should the SSP promulgate 
guidelines permitting IRBs to approve research that would enroll 
subjects who lack decisionmaking capacity in protocols that reasonable, 
competent persons would decline to enter.
    The SSP should have members who can represent the diverse interests 
of potential research subjects, the research community, and the public. 
The panel's protocol approvals and guidelines should all be published 
in an appropriate form that ensures reasonable notice to interested 
members of the public.
    Those federal agencies that are signatories of the Common Rule 
should agree to use the SSP, and the SSP's effectiveness should be 
reviewed no later than 5 years after inception.

II. Recommendations Regarding Research Design

Appropriate Subject Selection
    Recommendation 3. An IRB should not approve research protocols 
targeting persons with mental disorders as subjects when such research 
can be done with other subjects.
Justifying Research Design and Minimizing Risks
    Recommendation 4. Investigators should provide IRBs with a thorough 
justification of the research design they will use, including a 
description of procedures designed to minimize risks to subjects. In 
studies that are designed to provoke symptoms, to withdraw subjects 
rapidly from therapies, to use placebo controls, or otherwise to expose 
subjects to risks that may be inappropriate, IRBs should exercise 
heightened scrutiny.
Evaluating Risks and Benefits
    Recommendation 5. Investigators should provide IRBs with a thorough 
evaluation of the risks and potential benefits to the human subjects 
involved in the proposed protocol. The evaluation of risks includes the 
nature, probability, and magnitude of any harms or discomforts to the 
subjects. The evaluation of benefits should distinguish possible direct 
medical benefits to the subject from other types of benefits.

III. Recommendations Regarding Informed Consent and Capacity

Informed Consent To Research
    Recommendation 6. No person who has the capacity for consent may be 
enrolled in a study without his or her informed consent. When potential 
subjects are capable of making informed decisions about participation, 
they may accept or decline participation without involvement of any 
third parties.
Objection to Participation in Research
    Recommendation 7. Any potential or actual subject's objection to 
enrollment or to continued participation in a research protocol must be 
heeded in all circumstances. An investigator, acting with a level of 
care and sensitivity that will avoid the possibility or the appearance 
of coercion, may approach people who previously objected to ascertain 
whether they have changed their minds.
Assessing Potential Subjects' Capacity To Decide About Participating in 
a Research Protocol
    Recommendation 8. For research protocols that present greater than 
minimal risk, an IRB should require that an independent, qualified 
professional assess the potential subject's capacity to consent. The 
protocol should describe who will conduct the assessment and the nature 
of the assessment. An IRB should permit investigators to use less 
formal procedures to assess potential subjects' capacity if there are 
good reasons for doing so.
Notifying Subjects of Incapacity Determinations and Research Enrollment
    Recommendation 9. A person who has been determined to lack capacity 
to consent to participate in a research study must be notified of that

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determination before permission may be sought from his or her legally 
authorized representative (LAR) to enroll that person in the study. If 
permission is given to enroll such a person in the study, the potential 
subject must then be notified. Should the person object to 
participating, this objection should be heeded.

IV. Recommendations Regarding Categories of Research

Research Protocols Involving Minimal Risk
    Recommendation 10. An IRB may approve a protocol that presents only 
minimal risk, provided that:
    (A) Consent has been waived by an IRB, pursuant to federal 
regulations; or
    (B) The potential subject gives informed consent; or
    (C) The potential subject has given Prospective Authorization, 
consistent with Recommendation 13, and the potential subject's LAR 
gives permission, consistent with Recommendation 14; or
    (D) The potential subject's LAR gives permission, consistent with 
Recommendation 14.
Research Protocols Involving Greater Than Minimal Risk That Offer the 
Prospect of Direct Medical Benefit to Subjects
    Recommendation 11. An IRB may approve a protocol that presents 
greater than minimal risk but offers the prospect of direct medical 
benefit to the subject, provided that:
    (A) The potential subject gives informed consent; or
    (B) The potential subject has given Prospective Authorization, 
consistent with Recommendation 13, and the potential subject's LAR 
gives permission, consistent with Recommendation 14; or
    (C) The potential subject's LAR gives permission, consistent with 
Recommendation 14.
    The research must also comply with Recommendations 7, 8, and 9.
Research Protocols Involving Greater Than Minimal Risk Research That Do 
Not Offer the Prospect of Direct Medical Benefit to Subjects
    Recommendation 12. An IRB may approve a protocol that presents 
greater than minimal risk but does not offer the prospect of direct 
medical benefit to the subject, provided that:
    (A) The potential subject gives informed consent; or
    (B) The potential subject has given Prospective Authorization, 
consistent with Recommendation 13, and the potential subject's LAR 
gives permission, consistent with Recommendation 14; or
    (C) The protocol is approved on the condition of its approval by 
the panel described in Recommendation 2, or falls within the guidelines 
developed by the panel, and the potential subject's LAR gives 
permission, consistent with Recommendation 14.
    The research must also comply with Recommendations 7, 8, and 9.

V. Recommendations Regarding Surrogate Decision Making

Prospective Authorization
    Recommendation 13. A person who has the capacity to make decisions 
about participation in research may give Prospective Authorization to a 
particular class of research if its risks, potential direct and 
indirect benefits, and other pertinent conditions have been explained. 
Based on the Prospective Authorization, an LAR may enroll the subject 
after the subject has lost the capacity to make decisions, provided the 
LAR is available to monitor the subject's recruitment, participation, 
and withdrawal. The greater the risks posed by the research protocol 
under consideration, the more specific the subject's Prospective 
Authorization should be to entitle the LAR to permit enrollment.
Legally Authorized Representatives (LARs)
    Recommendation 14. A LAR may give permission (within the limits set 
by the other recommendations) to enroll in a research protocol a person 
who lacks the capacity to decide whether to participate, provided that:
    (A) The LAR bases decisions about participation upon a best 
estimation of what the subject would have chosen if capable of making a 
decision; and
    (B) The LAR is available to monitor the subject's recruitment, 
participation, and withdrawal from the study; and
    (C) the LAR is a person chosen by the subject, or is a relative or 
friend of the subject. 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 15. In order to expand the category of LARs:
    (A) An investigator should accept as an LAR, subject to the 
requirements in Recommendation 14, a relative or friend of the 
potential subject who is recognized as an LAR for purposes of clinical 
decision making under the law of the state where the research takes 
place.
    (B) States should confirm, by statute or court decision, that:
    (1) An LAR for purposes of clinical decision making may serve as an 
LAR for research; and
    (2) Friends as well as relatives may serve as both clinical and 
research LARs if they are actively involved in the care of a person who 
lacks decisionmaking capacity.
    Recommendation 16. States should enact legislation, if necessary, 
to ensure that persons who choose to plan for future research 
participation are entitled to choose their LAR.
Involving Subjects' Family and Friends
    Recommendation 17. For research protocols involving subjects who 
have fluctuating or limited decisionmaking capacity or prospective 
incapacity, IRBs should ensure that investigators establish and 
maintain ongoing communication with involved caregivers, consistent 
with the subject's autonomy and with medical confidentiality.

VI. Recommendations Regarding Education, Research, and Support

Reviewing and Developing Educational Materials Regarding Research
    Recommendation 18. Professional associations and organizations 
should develop (or review their existing) educational materials 
pertaining to research involving persons with mental disorders to 
ensure that they are adequate to inform the health care community and 
the public of ethical issues related to the involvement of such persons 
as research subjects, and to convey the importance of measures to 
ensure that their rights and welfare are adequately protected.
Expanding Knowledge About Capacity Assessment and Informed Consent
    Recommendation 19. The National Institutes of Health (NIH) should 
sponsor research to expand understanding about decisionmaking capacity, 
the best means for assessing decisionmaking capacity, and techniques 
for enhancing the process of informed consent, and the possible roles 
of surrogate decision makers in research. It should sponsor research to 
evaluate the risks of various research interventions, and the attitudes 
of potential subjects toward the prospect of participating in research. 
Particular attention should be paid to attitudes toward participating 
in research of greater than minimal risk that does not offer the 
prospect of direct medical benefit to subjects. These data may be of 
particular value to the panel described in Recommendation 2.

[[Page 8380]]

    The NIH should ensure that proposals for training grants and center 
grants include appropriate provisions for training and technical 
assistance in the issues discussed in this report. Where appropriate, 
the NIH and the Office for Protection from Research Risks (OPRR) should 
consider using consensus development conferences or workshops to 
advance discussion of these issues.
Institute of Medicine Review of Research Studies
    Recommendation 20. The Department of Health and Human Services 
should contract with the Institute of Medicine to conduct a 
comprehensive review and evaluation of the nature and extent of 
challenge, washout, and placebo controlled studies with subjects with 
mental disorders that may affect decisionmaking capacity.
Increased Funding To Support Necessary Protections of Human Subjects
    Recommendation 21. Compliance with the recommendations set forth in 
this report will require additional resources. All research sponsors 
(government, private sector enterprises, and academic institutions) 
should work together to make these resources available.

For Further Information About the Report Contact: Eric M. Meslin, 
Ph.D., Executive Director, National Bioethics Advisory Commission or to 
obtain copies of the report contact: Ms. Patricia Norris, National 
Bioethics Advisory Commission, 6100 Executive Boulevard, Suite 5B01, 
Rockville, Maryland 20892-7508, telephone 301-402-4242, fax number 301-
480-6900. Copies may also be obtained through the NBAC website: 
www.bioethics.gov.

    Dated: February 12, 1999.
Eric M. Meslin,
Executive Director,
National Bioethics Advisory Commission.
[FR Doc. 99-4190 Filed 2-18-99; 8:45 am]
BILLING CODE 4160-17-M