[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
[[Page 8378]]
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
[[Page 8379]]
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
