[Federal Register Volume 72, Number 171 (Wednesday, September 5, 2007)]
[Notices]
[Pages 50966-50970]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E7-17490]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES


Request for Information and Comments on Research That Involves 
Adult Individuals With Impaired Decision-making Capacity

AGENCY: Office for Human Research Protections, Office of Public Health 
and Science, Office of the Secretary, HHS.

ACTION: Notice.

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SUMMARY: The Office for Human Research Protections (OHRP), Office of 
Public Health and Science is seeking information and comments about 
whether guidance or additional regulations are needed to adequately 
protect adult individuals with impaired decision-making capacity who 
are potential subjects in research. This request for information and 
comments stems from the recommendation of an HHS working group, 
generated in response to the report published by the National Bioethics 
Advisory Commission (NBAC) entitled ``Research Involving Persons With 
Mental Disorders That May Affect Decision-making Capacity'' (December 
1998), and from subsequent recommendations by the National Human 
Research Protections Advisory Committee (NHRPAC).\a\
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    \a\ The National Human Research Protections Advisory Committee 
has been disbanded and replaced by the Secretary's Advisory 
Committee on Human Research Protections.
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    In addition, as part of its charge to provide expert advice and 
recommendations to the Secretary of Health and Human Services (the 
Secretary) and the Assistant Secretary for Health on issues and topics 
pertaining to or associated with the protection of human subjects, the 
Secretary's Advisory Committee on Human Research Protections (SACHRP) 
has formed a Subcommittee on Inclusion of Individuals with Impaired 
Decision-Making in Research. This SACHRP subcommittee is currently 
considering whether guidance or additional regulations are needed for 
research involving individuals with impaired decision-making capacity. 
The information and comments submitted in response to this notice will 
be shared with SACHRP to inform the Committee's recommendations to the 
Secretary and Assistant Secretary for Health.

DATES: Submit written or electronic information and comments by 
December 4, 2007.

ADDRESSES: Submit written comments to REQUEST FOR INFORMATION ON 
RESEARCH THAT INVOLVES ADULT INDIVIDUALS WITH IMPAIRED DECISION-MAKING 
CAPACITY, Office for Human Research Protections, The Tower Building, 
1101 Wootton Parkway, Suite 200, Rockville, MD 20852. Comments also may 
be sent via e-mail to [email protected], or via facsimile at 
301-402-2071. Comments received within the comment period, including 
any personal information provided, will be made available to the public 
upon request.

FOR FURTHER INFORMATION CONTACT: Julie Kaneshiro, Office for Human 
Research Protections, Department of Health and Human Services, The 
Tower Building, 1101 Wootton Parkway, Suite 200, Rockville, MD 20852; 
240-453-6900; e-mail [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    The Department of Health and Human Services (HHS) regulates 
research involving human subjects conducted or supported by HHS through 
regulations codified at 45 CFR part 46 which are administered by OHRP. 
The HHS regulations stipulate that in order to approve research covered 
by the regulations, an institutional review board (IRB) shall determine 
that when some or all of the subjects are likely to be vulnerable to 
coercion or undue influence, such as children, prisoners, pregnant 
women, mentally disabled persons, or economically or educationally 
disadvantaged persons, additional safeguards have been included in the 
study to protect the rights and welfare of these subjects. 45 CFR 
46.111(b). Apart from this broad requirement regarding vulnerable 
populations, the HHS regulations do not contain specific additional 
standards for the participation of adults with impaired decision-making 
capacity in research, nor do they define who should be considered as 
part of this population. In response to the recommendations by the 
National Commission for the Protection of Human Subjects of Biomedical 
and Behavioral Research (National Commission) that pertained to 
research involving individuals who are institutionalized as mentally 
infirm, in 1978, the Department of Health, Education, and Welfare (now 
HHS), issued proposed regulations on research involving those 
institutionalized as mentally disabled. However, these proposed 
regulations were never finalized or adopted due to a lack of consensus 
on the proposed regulatory provisions, and a judgment that the general 
HHS regulations governing human subjects' participation in research 
were sufficient to address the National Commission's recommendations.
    The impetus for this request for information and comments stems 
from a number of different sources. HHS is aware that some research 
currently conducted or supported by HHS involves adults with impaired 
decision-making capacity. HHS believes that research involving adults 
with impaired decision-making capacity is important and necessary in 
order to improve the health and well-being of such individuals. HHS and 
others have long recognized the potential vulnerability of these 
subjects, and that research involving this population needs to be 
conducted with adequate safeguards. At this time HHS believes it is 
appropriate to solicit the views of the public on whether the current 
human subject protection regulations are adequate in safeguarding these 
individuals. This request for information and comments also stems from 
recommendations of an HHS working group (HHS WG), generated in response 
to the report published by the former NBAC entitled ``Research 
Involving Persons with Mental Disorders That May Affect Decision-making 
Capacity'' (December 1998), and from subsequent recommendations by the 
former NHRPAC.

A. NBAC Report

    In its December 1998 report, the full text of which can be found on 
the Internet at http://bioethics.georgetown.edu/nbac, NBAC defined 
decisional impairment as a limitation or incapacity that is not part of 
normal growth and development. NBAC's report contained recommendations 
for helping to ensure adequate protections for people with decisional 
impairment who participate in research, but referred only to research 
involving persons with mental disorders

[[Page 50967]]

that may affect decision-making capacity.
    NBAC's recommendations called for a new regulatory framework 
requiring IRBs to classify into one of three categories all proposed 
research that involves people with impaired decision-making capacity 
due to mental disorders, based on the level of risk and potential for 
direct medical benefit to the research subject. NBAC identified three 
categories of research that pose: (1) Minimal risk to subjects; (2) 
greater than minimal risk to subjects and having the prospect of direct 
medical benefit; and (3) greater than minimal risk to subjects but 
having no prospect of direct medical benefit. NBAC recommended that the 
legally authorized representative of a subject with impaired decision-
making capacity be able to give permission for the subject's 
participation in research protocols that fall into either of the first 
two categories. However, NBAC recommended that research in the third 
category could not proceed unless one of two conditions occurred: 
Either (1) the research subject would have had to give Prospective 
Authorization for the particular class of research when competent, or 
(2) a Special Standing Panel (SSP), convened by the Secretary of HHS, 
would need to review the research and find it approvable or have issued 
guidelines about the class of research indicating that it was 
approvable. In NBAC's recommendations, Prospective Authorization would 
provide individuals, when competent, with an opportunity to express 
their preferences (if they have them) regarding future research 
participation, within certain limits. NBAC recommended that a 
Prospective Authorization should specify the ``particular class of 
research,'' and the degree of specificity in the Prospective 
Authorization should be correlated with the level of risk posed by the 
research. For example, a person with a diagnosis of early stage 
Alzheimer's Disease who is still competent to make decisions could 
express his or her preference to participate in greater than minimal 
risk clinical trials testing interventions for moderate or severe 
Alzheimer's Disease in the future, when he or she may not be competent 
to make decisions.

B. HHS Working Group

    The Office of Science Policy, Office of the Assistant Secretary for 
Planning and Evaluation, convened an HHS WG to analyze NBAC's 
recommendations and to develop a proposed HHS response to the NBAC 
report. The HHS WG's report can be found on the Internet at http://aspe.hhs.gov/sp/human.shtml. The HHS WG considered, among other things, 
NBAC's recommended framework described above. The HHS WG was concerned 
that this framework was not practical because it would lead to the use 
of either a Prospective Authorization or a SSP for a large number of 
research protocols involving subjects with impaired decision-making 
capacity. The HHS WG concluded that the widespread use of Prospective 
Authorizations is unlikely. Thus, unless the research involved the 
prospect of direct medical benefit to the participants, an SSP would 
need to review all research involving greater than minimal risk.
    The HHS WG compared NBAC's proposed regulatory framework to the HHS 
regulations governing the participation of children in research (45 CFR 
part 46 subpart D [hereafter referred to as ``subpart D 
regulations'']). The subpart D regulations allow an IRB to consider a 
broad range of different types of direct benefits to the subject, not 
just direct medical benefits, when weighing the risks posed by research 
involving greater than minimal risk that presents the prospect of 
direct benefit to the individual child. NBAC, on the other hand, 
recommended that benefits be limited to direct medical benefits only 
for research involving subjects with impaired decision-making capacity. 
The subpart D regulations also create an intermediate risk category, 
not included in NBAC's framework, called a ``minor increase over 
minimal risk.'' The HHS WG noted that an alternative regulatory 
framework modeled on subpart D could provide appropriate protection and 
also decrease the number of studies needing SSP review and thus may 
increase the feasibility of such reviews.
    The HHS WG decided that NBAC's recommended framework would limit an 
IRB's authority to approve research involving an adult with impaired 
decision-making capacity more than it would an IRB's authority to 
approve a child's participation in the same type of research. The HHS 
WG further noted that NBAC's framework would alter IRB authority in 
ways that could produce different results. For example, the subpart D 
regulations permit a child's parent or guardian to enroll the child in 
research that has no prospect of direct benefit and that poses a minor 
increase over minimal risk if an IRB determines the research, among 
other things, is ``likely to yield generalizable knowledge * * * of 
vital importance'' about the child's disorder or condition (45 CFR 
46.406). However, under NBAC's recommendations, the legally authorized 
representative of an adult with impaired decision-making capacity could 
not enroll the adult in the same type of research, unless the adult had 
signed a Prospective Authorization or the SSP approved or issued 
guidelines about the research. The HHS WG recognized that safeguards 
for children and adults with impaired decision-making capacity need not 
necessarily be identical, but noted that two different standards might 
be confusing to investigators and IRBs.
    In addition, in its 1998 report, NBAC considered how ethically 
acceptable research could be conducted with human subjects who suffer 
from mental disorders that may affect their decision-making capacity. 
The HHS WG interpreted the intended scope of NBAC's recommendations as 
applying to research involving ``persons with mental disorders that may 
affect decision making capacity,'' but determined that the scope of 
NBAC's recommendations seem appropriately applicable to research 
involving adults with decisional impairment, irrespective of the cause. 
The HHS WG noted that some physical disorders or conditions (e.g., 
cancer, sepsis, head injury) also might result in impaired capacity to 
make decisions, and therefore, an inability to give voluntary informed 
consent to participate in research. In addition, the HHS WG was 
concerned that limiting the scope of protections to research subjects 
whose decision-making capacity is impaired because of a mental disorder 
may be perceived to be stigmatizing to such individuals. Thus, the HHS 
WG concluded that adults with an impaired capacity to make a decision 
as a result of any disease or condition should receive the same 
protections as those individuals with an impaired decision-making 
capacity from a mental disorder.
    The HHS WG proposed that OHRP request public comment on the issues 
raised by the NBAC framework and the HHS WG's analysis of those issues. 
This request for information and comments is designed to accomplish 
that goal.

C. NHRPAC Report

    In response to NBAC's recommendations and the HHS WG's report, at 
OHRP's request, NHRPAC drafted a report entitled ``Informed Consent and 
the Decisionally Impaired.'' NHRPAC was an advisory committee to the 
Secretary of HHS, the Assistant Secretary for Health, the Director of 
OHRP, and other Departmental officials on a broad range of issues and 
topics pertaining to or associated with the protection of human 
research subjects. NHRPAC's draft report is available on the Internet 
at

[[Page 50968]]

http://www.hhs.gov/ohrp/nhrpac/documents/nhrpac10.pdf. NHRPAC's report 
applies to ``all potential subjects in biomedical and social/behavioral 
research who lack decisional capacity for any reason and is not limited 
to persons with mental disorders.'' In its report, NHRPAC recommended 
specific protections at different levels of risk and potential benefit 
for research with the decisionally impaired population. These risk-
benefit categories included:
    (1) Research that involves no more than minimal risk,
    (2) Research that involves greater than minimal risk but presents 
the prospect of direct benefit to the subjects,
    (3) Research that involves a minor increase over minimal risk that 
does not present the prospect of direct benefit but is likely to yield 
generalizable knowledge about the subject's condition or disorder, and
    (4) Research not otherwise approvable which presents an opportunity 
to understand, prevent, or alleviate a serious problem affecting the 
health or welfare of persons with impaired decision-making capacity, 
provided the Secretary of HHS makes specified determinations after 
consulting with a panel of experts and providing the opportunity for 
public review and comment.
    These risk categories are similar to those contained in the subpart 
D regulations governing research with children.

D. SACHRP Activities

    In October 2002, SACHRP was created by the Secretary to replace 
NHRPAC. SACHRP is charged to advise, consult with, and make 
recommendations to the Secretary and Assistant Secretary for Health on 
matters pertaining to the continuance and improvement of functions 
within the authority of HHS directed toward protections for human 
subjects in research. In carrying out its charge, SACHRP formed a 
Subcommittee on Inclusion of Individuals with Impaired Decision-Making 
Capacity in Research. Specifically, this SACHRP subcommittee will 
develop recommendations for consideration by SACHRP about whether 
guidance or additional regulations are needed for research involving 
individuals with impaired decision-making capacity. In making its 
assessment, the Subcommittee will review the relevant provisions of 
subpart A, 45 CFR part 46, including the provisions at 45 CFR 
46.111(b), and will seek additional information to formulate its 
decision as it deems necessary.
    The information and comments submitted in response to this notice 
will be shared with SACHRP to inform the Committee's recommendations to 
the Secretary and Assistant Secretary for Health.
    The reports of the National Commission, NBAC, and NHRPAC 
specifically address and endorse the inclusion of decisionally 
incapacitated subjects in clinical research with the provision of 
adequate protections for these subjects. Based on these recommendations 
and reports over the years, and SACHRP's current work on this issue, 
OHRP is seeking comment on whether it is necessary to develop 
additional safeguards to protect adult individuals with impaired 
decision-making capacity because these individuals may have diminished 
or no capacity to provide informed consent to their participation in 
research. The next section contains the specific questions of interest 
to HHS.

II. Request for Information and Comments

    OHRP is seeking information and comments from the public about 
whether guidance or additional regulations are needed to adequately 
protect adult individuals with impaired decision-making capacity who 
are potential subjects in research. The scope of this request for 
information and comments is limited to research involving adult 
subjects because additional protections for children involved as 
subjects in research already exists under the subpart D regulations. In 
addition, this notice is not directed toward consideration of emergency 
research involving the decisionally impaired that would be covered 
under the HHS's Secretarial waiver under 45 CFR 46.101(i) on the 
exception from informed consent requirements for emergency research 
(published in the Federal Register in 1996 at 61 FR 51531). OHRP 
believes that this existing provision already addresses the conduct of 
emergency research without informed consent that involves individuals 
with impaired decision-making capacity.
    OHRP specifically seeks information and comments on the following 
issues. Comments should also include a reference to the specific 
numbered question being addressed:
    1. What are investigators' and IRBs' current practices in regard to 
the conduct, review, and approval of research involving decisionally 
impaired adult individuals?
    1a. Have investigators' or IRBs' practices changed as a result of 
NBAC's or NHRPAC's recommendations? If not, why not?
    1b. If an IRB regularly reviews research proposals involving adult 
individuals with impaired decision-making capacity, do such IRBs 
include one or more members or consultants who are familiar with 
conditions that may affect decision-making capacity and with the 
concerns of the population being studied?
    1c. Are investigators proposing research targeting adult 
individuals with impaired decision-making capacity as subjects 
providing IRBs with a thorough justification for their proposed 
research design, including a description of the procedures that are 
designed to minimize risks to subjects?
    1d. If research protocols targeting adult individuals with impaired 
decision-making capacity as subjects are being approved by IRBs when 
the research could be done with other subjects, what are the reasons 
for IRBs approving such studies?
    1e. Are investigators proposing research targeting adult 
individuals with impaired decision-making capacity as subjects 
providing IRBs with a thorough evaluation of the risks and potential 
benefits to the subjects involved in the proposed research study?
    1f. For research involving adult individuals with impaired 
decision-making capacity as subjects, how are subjects' potential or 
actual objections to enrollment or continued participation in research 
being addressed by investigators and IRBs?
    1g. Are IRBs requiring investigators to have an assessment of a 
potential subject's capacity to consent, and if so, under what 
circumstances? If IRBs are requiring capacity assessments for some 
research, is the degree of risk presented by the research pertinent to 
the IRB's decision to require such assessments? What concerns have 
arisen in regard to capacity assessments?
    1h. For studies that have included an assessment of potential 
subjects' capacity to consent, how has this assessment been used in the 
informed consent process? Are subjects notified when they have been 
found to lack capacity to consent? When informed consent is sought from 
such a subject's legally authorized representative, are potential 
subjects provided an opportunity to assent or object to their 
participation in the research?
    1i. For research involving subjects who are able to provide 
informed consent, but are expected to have fluctuating, limited, or 
diminishing decision-making capacity during the course of the research 
study, what processes or procedures have investigators implemented, or 
have IRBs

[[Page 50969]]

required, in order to ensure that the rights and welfare of such 
subjects remains adequately protected?
    2. What problems or concerns have arisen for investigators, IRBs, 
or research subjects in the conduct or review of research involving 
decisionally impaired individuals as subjects?
    2a. To what extent, if any, has the absence of OHRP guidance or 
additional regulatory requirements given rise to unacceptable practices 
by IRBs or investigators reviewing or conducting research targeting 
adult individuals with impaired decision-making capacity as subjects, 
or created inappropriate barriers to the conduct of research involving 
individuals with impaired decision-making capacity as subjects?
    2b. Please describe the process used when a legally authorized 
representative is asked to consent on behalf of a prospective research 
subject for research involving adult individuals with impaired 
decision-making capacity as subjects. Do the legally authorized 
representatives use substituted judgment (decisions that reflect the 
views of the individual expressed while decisionally capable) or the 
best interest standard? Which seems more ethically justified?
    2c. How are advance directives for health care and for research 
used when a legally authorized representative is available?
    2d. Have any problems or concerns arisen in regard to seeking 
consent from a legally authorized representative on behalf of a 
prospective research subject for research involving adult individuals 
with impaired decision-making capacity as subjects? If so, please 
describe the issues that have arisen.
    3. The current requirement for IRB approval under the HHS 
regulations at 45 CFR 46.111(b), states:

    When some or all of the subjects are likely to be vulnerable to 
coercion or undue influence, such as children, prisoners, pregnant 
women, mentally disabled persons, or economically or educationally 
disadvantaged persons, additional safeguards have been included in 
the study to protect the rights and welfare of these subjects.

    Please describe the additional safeguards you have included in 
studies to protect the rights and welfare of subjects with impaired 
decision-making capacity.
    3a. Does the regulatory provision cited above provide sufficient 
protections for adult subjects with impaired decision-making capacity 
or are additional regulatory safeguards needed? If additional 
safeguards are needed, what should these additional protections be? 
Below please find a compendium of possible additional protections for 
subjects with impaired decision-making capacity. Please feel free to 
comment on any or all of them, and to suggest others. In your comments, 
please indicate if your comments are directed towards the issuance of 
either guidance or additional regulations:
     Consent auditor/independent consent monitor.
     Sliding scale of capacity, (i.e., protections should be 
proportional to the severity of capacity impairment, or to the 
magnitude of experimental risk, or both).
     Description of specific tasks to assess capacity (these 
may be study-specific).
     Independent assessment of decision-making capacity.
     Enhancement of IRB expertise such that the IRB includes 
members or consultants familiar with conditions that may affect 
decision-making capacity and with the concerns of the population being 
studied.
     Obtaining consent from legally authorized representative.
     Obtaining assent from subjects with impaired decision-
making capacity (may be limited to objecting to inclusion in the 
research study). This would be in addition to consent from the legally 
authorized representative.
     Use of advance directive for research where permitted by 
state/local law.
     Use of appropriate waiting periods (after research 
presented to the subject) before obtaining assent or consent as 
possible.
     Consent enhancements: Interventions to increase the 
subject's decision-making capacity.
     Other suggestions.
    3b. If the regulations at 45 CFR part 46 are sufficient, should 
OHRP issue additional guidance on how the regulations should be applied 
to protect adult subjects with impaired decision-making capacity?
    3c. If additional regulations are needed would a risk-based model, 
such as a model based on the subpart D regulations be appropriate? If 
not, what type of regulatory model would be appropriate?
    3d. If additional regulations are needed, would it be appropriate 
to develop additional regulations that would only apply to a subset of 
the population of adult subjects with impaired decision-making 
capacity? For example, would it be appropriate to develop additional 
regulations that would apply only to adult individuals who have no 
capacity to provide legally effective informed consent (e.g. comatose 
individuals or individuals in a persistent vegetative state)?
    4. How should the population of adults with impaired decision-
making be defined for the purposes of guidance or regulation? Note that 
the subpart D regulations contain a definition of the term 
``children,'' who are defined as `` * * * persons who have not attained 
the legal age for consent to treatments or procedures involved in the 
research, under the applicable law of the jurisdiction in which the 
research will be conducted.'' See 45 CFR 46.402(a). Does the definition 
of the term ``children'' in the subpart D regulations provide a helpful 
model for developing a definition of ``adults with impaired decision-
making capacity,'' or would a definition modeled on the definition of 
``children'' inappropriately exclude adult individuals who are at risk 
of decisional impairment, and those who suffer from some form of 
persistent, fluctuating, or progressive decisional impairment, but who 
nevertheless retain the capacity to give legally effective informed 
consent under the applicable law of the jurisdiction in which the 
research will be conducted? If a comparable definition of adults with 
impaired decision-making capacity was to be developed, such a 
definition could read: ``Adults with impaired decision-making capacity 
are persons who do not have the capacity to give legally effective 
informed consent to treatments or procedures involved in research/
clinical investigation, under the applicable law of the jurisdiction in 
which the research/clinical investigation will be conducted.''
    5. In some circumstances, certain adult subjects may develop 
impaired decision-making capacity (e.g. persistent, fluctuating, or 
progressive decisional impairment) after consenting and enrolling in 
research. In such cases, is guidance needed, or are additional 
regulations necessary, in order to adequately protect adult subjects 
who become decisionally impaired during their participation in 
research? For example, should guidance or additional regulations 
address when it would be appropriate for investigators to seek the 
consent of the subject's legally authorized representative to enable 
the subject's continued participation?
    6. If guidance or additional regulations are needed to adequately 
protect the rights and welfare of subjects with impaired decision-
making capacity, should such guidance or regulations address the issue 
of assent? Note that the subpart D regulations generally require that 
IRBs determine that adequate provisions are made for soliciting the 
assent of children when in

[[Page 50970]]

the judgment of the IRB the children are capable of providing assent. 
(See 45 CFR 46.408.)
    6a. If an adult with impaired decision-making capacity is capable 
of providing assent to participation in research, should the guidance 
or regulation indicate that the adult subject's assent should always be 
a condition for proceeding with the research? If there are 
circumstances when an adult subject's assent should not be necessary, 
what are those circumstances?

Melody Lin,
Deputy Director, Office for Human Research Protections.
 [FR Doc. E7-17490 Filed 9-4-07; 8:45 am]
BILLING CODE 4150-36-P