Paper Two: Research Involving Persons With Mental Disabilities: A Review of Policy Issues and Proposals
Author(s):
Rebecca Dresser, John Deaver Drinko-Baker
Introduction
Developing a federal policy to govern research involving
adults with cognitive impairment poses numerous challenges.
Some challenges are related to the diverse abilities and
situations of individuals in this population. Due to this
diversity, relatively detailed standards and procedures are
required to discern which persons are capable of independent
decisions to enter and remain in a study, and which need the
assistance of another to act as research decision maker.
Challenges also arise from the effort to show respect for the
varied present and former preferences of decisionally
incapable persons. Additional challenges are posed by the
lack of clear consensus concerning the acceptable balance of
risk and expected benefit in studies involving incapable
subjects.
Practical challenges face those creating federal policy on
research involving adults with mental disabilities as well.
Some proposals in the literature may be too complex for
real-world application. Federal policy must be reasonably
attainable by, and conveyed in language comprehensible to,
Institutional Review Board members, researchers, clinicians,
and lay persons.
I begin by describing the historical context of the
current debate over research involving adults with mental
disabilities. Then, with the goal of delineating the choices
before you, I discuss six basic concepts relevant to
potential policy. Though the concepts merit separate
analysis, they often are combined in various policy
proposals. For example, some proposals favor a higher
standard for capacity to enter a research study when the
risks of participation are significant; other suggest that
higher risk studies for incapable subjects should be
permitted only as long as the subject affirmatively assents
or previously consented while competent to participate.
The following is a list of basic questions to be addressed
in the deliberations on appropriate federal policy for
research involving adults with mental disabilities:
- What capacity standard(s) should apply to persons
deciding about research participation? (Should a lower
standard be applied to persons?)
- What procedures, if any, should be required to ensure
that an individual' s decision to enter (and remain in)
research is capable, informed, and voluntary? Should
special procedures be required only in certain cases, such
as research presenting no prospect of direct benefit? When,
if ever, should an independent monitor be involved in such
evaluations?
- Should federal policy encourage or require specific
qualifications for persons making research decisions for
incapable individuals (e.g., legal guardianship, prior
designation as research or health care proxy, legislative
authorization to make health care decisions)?
- Should substantive standards be adopted for decisions
by subject representatives (e.g., choose according to
subject' s prior express wishes or general values and
preferences, or subject's best interests)?
- Should requirements be adopted for education and
screening of subject representatives? (If so, who should
perform these tasks?)
- Should affirmative subject assent (always/sometimes/
never) be required? Should research ever be permitted when
subjects appear partially or completely incapable of
assent? If so, when? What constitutes an objection
sufficient to block continued participation? When, if ever,
may research proceed despite an incapable subject's
objection?
- What procedures should be applied to monitor an
incapable subject's continued willingness to participate in
research? When, if ever, should an independent monitor be
required?
- Should research advance directives be encouraged or
required? If so, what constitutes informed advance consent
to research participation? How should the subject's right
to withdraw be respected in this situation? When, if ever,
should a research directive be a permissible basis for
conducting research presenting greater risk to an incapable
subject than is ordinarily permitted?
- Should policy specify the appropriate direct benefits,
indirect benefits, and risks to be weighed in evaluating
studies involving incapable subjects?
- Should policy incorporate the concepts of "minimal
risk" and "a minor increase over minimal risk"? If so,
should the concepts be defined with greater precision than
in current federal policy? Should limits be placed on the
degree of risk permissibly presented in research involving
incapable subjects? What prospect of direct benefit to
subjects or benefit to society is sufficient to justify
various degrees of research risks? Should a national review
process be adopted to consider the justification for
certain categories of research with risk-expected benefit
ratios unfavorable to incapable or questionably capable
subjects?
- Should monitoring procedures be required to ensure that
acceptable risk-expected benefit standards are observed in
ongoing research?
- Should IRBs be required to include representatives of
relevant subject groups when reviewing studies involving
mentally disabled persons? Should policy direct IRBs or
investigators to arrange for notice to, and consultation
with, representatives of affected communities regarding
proposed, ongoing, and completed research?
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>Historical
Context
International Developments
The subject's informed and voluntary consent is the
strongest basis for enrollment in a research study. Certain
persons diagnosed with psychiatric disorders, developmental
disabilities, dementia, and other conditions associated with
mental disability possess the necessary cognitive abilities
and are sufficiently independent of others to provide
informed and voluntary consent. Many others, however, are
not. A basic moral and policy question is whether these
individuals should ever be involved in research.
The Nuremberg Code, the first international document on
human subjects research, appears to forbid such research.
According to the Code,"[t]he voluntary consent of the human
subject is absolutely essential." Adequate consent requires
the subject's:
- "legal capacity to consent"
- ability "to exercise free power of choice without the
intervention of any element of force, fraud, deceit,
duress, or over-reaching, or other ulterior form of
constraint or coercion"
- "sufficient knowledge and comprehension of the elements
of the subject matter involved," including "the nature,
duration, and purpose of the experiment; the method and
means by which it is to be conducted; all inconveniences
and hazards reasonably to be expected; and the effects upon
his health or person which may possibly come from his
participation in the experiment." 1
Absent from the Code is any provision authorizing
surrogate consent to research on behalf of subjects incapable
of producing a decision that meets these criteria.
Later research codes and policies have rejected the
Nuremberg Code's apparent position that informed and
voluntary consent is an absolute prerequisite to a human
subject's research participation. Two justifications are
offered for this rejection. One rests on an interpretation of
the Code in light of its historical origins. The Code was
formulated in response to the Nazi experiments conducted on
competent subjects without their consent. The judges issuing
the Code may not have intended to take a specific position on
research involving incapable subjects.2 The second
justification for rejecting a ban on research involving
incapable subjects is based on moral considerations. Because
new treatments must eventually be tested in persons suffering
from the relevant condition, a policy totally excluding
incapable subjects from research would preclude the
development of improved treatment for persons with serious
psychiatric disorders, dementia, and other mentally
debilitating conditions.
The next major international research code reflects these
views. The World Medical Association's Declaration of
Helsinki, first issued in 1964, provides for limited research
involvement of incapable human subjects. The most recent
version of the Declaration states," [i]n the case of legal
incompetence, informed consent should be obtained from the
legal guardian in accordance with national legislation."3 The
Declaration divides research into two categories:
"therapeutic" and "non-therapeutic." The Declaration appears
to rule out the participation of incapable subjects in
research that fails to offer them the possibility of direct
benefit. When research has the advancement of knowledge for
the benefit of others as its sole objective, the Declaration
states,"[t]he subjects should be volunteers ...."
Two other recent documents address research involving
incapable human subjects. The International Ethical
Guidelines for Biomedical Research, issued in 1993 by the
Council for International Organizations of Medical Sciences
(CIOMS) and the World Health Organization (WHO), allow an
incapable individual's research participation to be
authorized by a "legal guardian or other duly authorized
person." The guidelines permit research involving incapable
subjects only if "the degree of risk attached to
interventions that are not intended to benefit the individual
subject is low" and "interventions ...intended to provide
therapeutic benefit are likely to be at least as advantageous
to the individual as any alternative." Incapable subjects'
objections to participation must be respected; the sole
exception would be the rare case in which "an investigational
intervention is intended to be of therapeutic benefit to a
subject, ... there is no reasonable medical alternative, and
local law permits overriding the objection."4
Last November, the Council of Europe's Committee of
Ministers adopted the Convention for the Protection of Human
Rights and Dignity of the Human Being With Regard to the
Application of Biology and Medicine. This document allows
persons without the capacity to consent to be involved in
research if all the following conditions are met:
- "the results of the research have the potential to
produce real and direct benefit to his or her health"
- "research of comparable effectiveness cannot be carried
out on individuals capable of giving consent"
- participation is authorized by the incapable person's
"representative or an authority or a person or body
provided by law"
- the incapable person does not object to
participation.
The document also permits research that fails to offer
subjects potential direct health benefit if the study meets
conditions two through four, above, and:
- is designed to produce knowledge for the benefit of
persons with the same condition;
- "entails only minimal risk and minimal burden for the
individual concerned."5
U.S. Policy Development
In the aftermath of Tuskegee and other disturbing studies
by U.S. researchers, Congress enacted legislation
establishing the National Commission for the Protection of
Human Subjects in 1974. Besides its work addressing the
ethics of human subjects research in general, the commission
produced analyses of the ethical and legal issues raised by
the involvement of certain groups deemed especially
vulnerable to inappropriate research practices. These groups
included children, who are legally incompetent to make
independent decisions, and persons institutionalized as
mentally infirm, whose mental impairment and
institutionalized status can prevent them from making
informed and voluntary decisions to participate in
research.6
In its 1977 Report and Recommendations on Research
Involving Children,7 and its 1978 Report and Recommendations on
Research Involving Those Institutionalized as Mentally
Infirm,8
the commission rejected both the Nuremberg Code's complete
ban and the Helsinki Declaration's limitation on the
involvement of incapable subjects. The commissioners believed
a less restrictive approach was justified to avoid harm to
incapable persons as a group:
since some research involving the mentally infirm cannot be
undertaken with any other group, and since this research
may yield significant knowledge about the causes and
treatment of mental disabilities, it is necessary to
consider the consequences of prohibiting such research.
Some argue that prohibiting such research might harm the
class of mentally infirm persons as a whole by depriving
them of benefits they could have received if the research
had proceeded.9
The commissioners concluded that the dual goals of
benefiting the class of mentally infirm persons and
protecting individual subjects from undue harm could be met
by a third approach: incapable subjects could be involved in
studies offering them potential direct benefit, as well as
studies failing to offer potential direct benefit, as long as
the burdens and risks of research participation did not
exceed a certain level.
Based on this general approach, the commission created a
framework for evaluating research involving incapable
subjects. The commissioners' proposals regarding children and
institutionalized persons with mental impairments were
similar, though with some variation. The proposals had in
common the following:
- a requirement to justify the involvement of these
subject groups rather than alternative, less vulnerable
subject populations
- a hierarchy of research categories establishing more
rigorous substantive and procedural standards for proposals
presenting more than minimal risk to incapable
subjects
- a mechanism for incapable subjects to provide input in
the form of "assent" or objection to study
participation.
Differences in the recommendations on children and
institutionalized persons were based on the commissioners'
recognition that some adults institutionalized as mentally
infirm retain the ability to issue an informed and voluntary
decision. Because of concerns about the vulnerability of
institutionalized persons, however, the commission
recommended that IRBs be given discretion to appoint "an
auditor to observe and assure the adequacy of the consent
process for research" presenting greater than minimal risk.
Moreover, the commissioners believed such auditors should be
required in projects presenting no prospect of direct benefit
and more than minimal risk to subjects. The commission's
proposals also gave incapable adults more authority than
children to block study participation.10 Finally, because
incapable adults lack the clear legal guardian that most
children have, the commission noted that in some cases a
court-appointed guardian would be required to provide
adequate authority for research participation.
In response to the commission's work, the Department of
Health, Education and Welfare (DHEW) proposed regulations to
govern research on the two populations. The regulations on
research involving children were adopted by the Department of
Health and Human Services (DHHS) in June, 1983.11 Proposed
regulations on persons institutionalized as mentally disabled
were never adopted, however.12
The Secretary of DHHS attributed the government's failure
to issue final regulations on research involving
institutionalized persons to "a lack of consensus" on the
proposed regulatory provisions and to a judgment that the
general regulations governing human subjects participation
sufficiently incorporated the commission's recommendations.13 Robert
Levine blames the reported lack of consensus on DHEW's
earlier failure to adhere to the commission's
recommendations. The agency's proposed regulations indicated
that consent auditors might be mandatory for all research
involving institutionalized, mentally disabled persons.
Moreover, they suggested that the authorization of an
additional person, assigned the role of independent advocate,
might be necessary before an incapable person could become a
research subject. During the public comment period, many
responded negatively to these additional procedural
requirements, presumably on the belief that they were
unnecessary and overly burdensome to research.14
Current U.S. Regulations
At this time, no special regulations govern research
involving adults diagnosed with a condition characterized by
mental impairment. Such research is governed by the "Common
Rule," 15 the general federal provisions governing
human subjects research. A few Common Rule provisions address
research involving persons with mental disabilities. The rule
identifies "mentally disabled persons" as a vulnerable
population. Institutional review boards are directed to
include "additional [unspecified] safeguards ... to protect
the rights and welfare" of mentally disabled research
subjects; IRBs are also advised to ensure that "subject
selection is equitable," and that mentally disabled persons
are not involved in research that could be conducted on a
less vulnerable group.16 Finally,"[i]f an IRB regularly reviews
research that involves a vulnerable category of subjects,
such as ... mentally disabled persons, consideration should
be given to the inclusion of one or more individuals who are
knowledgeable about and experienced in working with these
subjects."17 The rule allows an incapable individual's
"legally authorized representative" to give valid consent to
the individual's research participation,18 but provides no
definition of incapacity, no guidance on the identity or
qualifications of a subject representative, and no statement
on acceptable riskexpected benefit ratios for research
involving decisionally incapable subjects.
In the 1980s and 1990s, numerous groups and individuals
expressed dissatisfaction with gaps in the existing
regulations. These included the Advisory Committee on Human
Radiation Experiments, which reviewed eight studies conducted
in the early 1990s involving adult subjects with questionable
decisionmaking capacity. Four of these studies required that
subjects undergo diagnostic imaging that offered them no
prospect of direct benefit, and two appeared to present
greater than minimal risk. Yet, as the Committee noted,
"there was no discussion in the documents or consent form of
the implications for the subjects of these potentially
anxiety-provoking conditions. Nor was there discussion of the
subjects' capacity to consent or evidence that appropriate
surrogate decision makers had given permission for their
participation."19 Inquiries into studies involving medication
withdrawal from persons diagnosed with schizophrenia also
have raised questions about the adequacy of existing federal
policy.20
Dissatisfaction with the current regulatory system also
has driven many organizations and individuals to offer
proposals for additional provisions to govern research on
mentally disabled persons in general, as well as on
particular subgroups, such as persons with dementia and
persons diagnosed with psychiatric disorders. These
proposals, and their underlying positions on the major
ethical issues, are discussed in the remainder of this
paper.
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Capacity
Assessment
Determining the proper standards and procedures to govern
capacity assessment poses a major challenge in formulating
policy on research involving subjects with mental
disabilities. Persons with mental disabilities vary widely in
their ability to engage in independent decision making.
Persons with psychiatric disorders may retain such capacity,
possess it intermittently, or be permanently unable to make
decisions for themselves. Individuals with dementia
frequently retain decisionmaking capacity early in the course
of the illness, but with time they become intermittently, and
then permanently, unable to make their own decisions. Some
individuals with developmental disabilities are capable of
making many choices for themselves; others completely lack
such capacity.21
Incorrect capacity determinations are problematic because
of their moral consequences. A judgment that a capable person
is incapable of exercising autonomy is disrespectful,
demeaning, and stigmatizing to that individual. Conversely, a
judgment that an incapable person is capable leaves that
individual unprotected and vulnerable to exploitation by
others.21 The presence of many "borderline" cases
among members of the relevant populations triggers concern
about the adequacy of subject capacity assessments. Although
it is important to accord due respect to mentally disabled
persons capable of autonomous choice, it is also important to
recognize that investigators seeking to enroll subjects may
be too willing to label prospective subjects capable when
this will advance their research objectives.23
Existing federal policy fails to provide guidance to
investigators and IRBs on the appropriate substantive and
procedural standards applicable to capacity determinations in
research involving mentally disabled subjects. In the current
situation, individual IRBs determine how investigators are to
address these matters. The likely result is substantial
variation in the criteria and safeguards applied to this form
of research.24 Most of the commentary supports more
systematic and specific federal direction on capacity
assessment.25 Greater guidance is needed on defining
decisional capacity in the research context, and procedures
for assessing such capacity.
Substantive Requirements for Research Decision Making An
autonomous choice to enter a research study is both informed
and voluntary. To be capable of informed choice, it is
generally agreed that a prospective subject should
demonstrate the ability "to understand the nature of the
research participation; appreciate the consequences of such
participation; exhibit ability to deliberate on alternatives,
including the alternative not to participate in the research;
and evidence ability to make a reasoned choice."26 Subjects also
should "comprehend the fact that the suggested intervention
is in fact research (and is not intended to provide
therapeutic benefit when that is the case)," and that they
may decide against participation "without jeopardizing the
care and concern of health care providers."27
There is consensus that decisional capacity requires a
certain level of cognitive ability. Less agreement exists on
whether subjects should be judged incapable if they lack
affective appreciation of the choice before them. In a recent
article, Carl Elliott argues that some depressed persons
"might realize that a protocol involves risks, but simply not
care about the risks," or "as a result of their depression,
may even want to take risks."28 Elliott believes that judgments
on a person's capacity to consent to research should take
into account such emotional attitudes. He also proposes that
subjects failing to exhibit a "minimal degree of concern for
[their] welfare" should be deemed incapable of independent
decision making. Others oppose this position, contending that
such an approach could yield excessive paternalism toward
persons diagnosed with mental disorders, insufficient data
exist on the extent of incapacitating emotional impairment
among depressed persons, affective impairment is difficult to
assess, and normative consensus is lacking on "how much
impairment we as a society are willing to tolerate before we
consider someone incompetent."29
It is generally agreed that a prospective subject's
capacity to decide whether to participate in a particular
research project cannot be determined through a general
mental status assessment. 30 Instead, investigators must
present the specific material relevant to that project and
evaluate the prospective subject's ability to understand and
appreciate that information.31
Some commentators endorse a "sliding-scale" approach to
decisional capacity in the research setting. This approach
demands an increasing level of understanding and appreciation
as study risks increase and potential benefits to subjects
decrease.32 Similarly, some suggest that many
prospective subjects incapable of independent research
decision making remain capable of selecting a research proxy,
since "the decisionmaking capacity that is required to
designate a proxy is far less than the capacity required to
understand a detailed protocol."33
Besides being informed, a decision to enter research
should be voluntary. The Nuremberg Code provides descriptive
characteristics of a voluntary decision.34 The National
Commission's Belmont Report characterizes a voluntary
decision as "free of coercion and undue influence." According
to the report, "[c]oercion occurs when an overt threat of
harm is intentionally presented by one person to another in
order to obtain compliance. Undue influence ... occurs
through an offer of an excessive, unwarranted, inappropriate
or improper reward or other overture in order to obtain
compliance." In addition, the report notes, an inducement
that is not overly persuasive to most adults could unduly
influence the judgment of vulnerable subjects. The
commissioners acknowledged that unjustifiable external
influence cannot always be precisely defined, but that "undue
influence would include actions such as manipulating a
person's choice through the controlling influence of a close
relative and threatening to withdraw health services to which
an individual would be otherwise entitled."35
Due to its limited congressional mandate, the National
Commission considered only the potential pressures on
institutionalized persons to enroll in research. Recent
commentary favors expanding this concern, on grounds that
persons with mental disabilities are especially vulnerable to
such pressures no matter where they reside.36 Prospective
subjects living in the community frequently rely heavily on
the assistance of professionals and family members and may
perceive research participation as essential to maintaining
the approval of their caregivers.37 Some support also remains for
providing special protections to persons in residential
facilities, due to their near-complete dependence on the
goodwill of the staff.38
A final element of decisional capacity, implicit in the
above discussion, is the subject's ongoing ability to make a
voluntary and informed choice to participate. Some persons
with psychiatric disorders and dementia can issue an
adequately informed and voluntary consent to participate in a
study, but subsequently lose their capacity for independent
choice. As a result, they become unable to exercise their
right to withdraw from a study. Studies involving subjects
with fluctuating or declining decisional capacity must
include mechanisms to ascertain and address this possibility,
including provision for appointment of a representative for
subjects who become incapable.39
Procedures for Capacity Assessment and Information
Disclosure
Existing federal regulations acknowledge that mentally
disabled persons may be vulnerable to undue influence or
coercion, but leave the adoption of special safeguards up to
individual IRBs. The regulations also fail to provide
guidance on the process that should govern capacity
assessments and information disclosure.
Shortcomings in the process of capacity assessment were
cited in a recent New York appellate court decision
invalidating state regulations governing nonfederally funded
research involving incapable adult residents of facilities
operated and licensed by the New York State Office of Mental
Health. Plaintiffs in the case were involuntarily
hospitalized individuals deemed incapable of making treatment
decisions who feared they would also be labeled incapable of
research decision making and then "forced" to participate in
greater than minimal risk studies.
The New York regulations gave the IRB "complete discretion
in designating the individual or individuals who will make
the assessment [of subject] capacity and who will thereafter
review the researcher's initial assessment." This
flexibility, together with the absence of "appropriate and
specific provisions for notice to the potential subject that
his or her capacity is being evaluated and for appropriate
administrative and judicial review of a determination of
capacity" contributed to the court's conclusion that the
regulations violated the due process requirements of the New
York State Constitution and the Fourteenth Amendment to the
U.S. Constitution.40 This decision raises questions about the
constitutional status of the existing federal regulations as
well, since they closely resemble the invalidated New York
regulations.41
A variety of approaches to capacity assessment are
endorsed in the literature on research involving adults with
cognitive impairment. Most commentators believe that IRBs
should at minimum require investigators to specify the method
by which prospective subjects' decisional capacity will be
evaluated and the criteria for identifying incapable
subjects.42 A major point of contention, however, is
whether capacity assessment and information disclosure should
be conducted by an individual not otherwise connected with
the research project.
The National Commission recommended that IRBs have
discretion to require an independent "consent auditor" for
projects presenting greater than minimal risk to persons
institutionalized as mentally infirm. The auditor would
observe and verify the adequacy of the consent and assent
process, and in appropriate cases observe the conduct of the
study to ensure the subject's continued willingness to
participate.43 The commission recommended that such
auditors be required for projects presenting greater than
minimal risk and no prospect of direct benefit to subjects.
The DHEW regulations contemplated mandating auditors for all
projects involving this subject population, but opposition to
this proposal reportedly was one reason the regulations never
became final.
More recent commentary includes a spectrum of views on the
need for an independent consent auditor. Some echo the
National Commission's view that a requirement for an
independent evaluator becomes increasingly justified as net
research risks to subjects increase. A Canadian group took
this position in its recent recommendations on dementia
research.44 According to this group, the role of
consent assessor/monitor ordinarily can be filled by a
researcher or consultant "familiar with dementias and
qualified to assess and monitor competence and consent in
such subjects on an ongoing basis." This individual should be
knowledgeable about the project and its risks and potential
benefits. On the other hand, if the research team lacks a
person with these qualifications, if there is "a real danger
of conflict of interest" for team members who might evaluate
and monitor capacity, or if the project involves greater than
minimal risk and no prospect of direct benefit to subjects,
an independent assessor/monitor should be appointed.45
Others appear open to general use of outside observers and
examiners. Recent guidelines adopted by the Loma Linda
University IRB state, "[c]onsent observers who are
independent of the investigator and of the institution will
be required by the IRB in those conditions where the
potential subject's decisionmaking capacity is suspect."46 In
testimony before the National Bioethics Advisory Commission,
representatives of Citizens for Responsible Care in
Psychiatry and Research recommended that "[a]n independent
psychiatrist ... determine the capacity of [the] potential
participant to comprehend the risks and benefits of enrolling
in the proposed research study."47 Recent articles also endorse
the participation of a "special research educator" in the
disclosure and decision process, particularly to ensure that
prospective subjects understand that advancement of general
knowledge is the primary goal of the project at hand.48
A 1991 article makes a strong case for an independent,
federally employed patient-advocate's involvement in capacity
determinations, as well as in assisting and monitoring
decision making by family surrogates for incapable persons.
Philip Bein notes that courts have demanded relatively strict
procedural safeguards in the context of imposed psychiatric
treatment and sterilization for persons with mental
disabilities. He makes the following argument for a similar
approach in the research context:
As with psychotropic medication and sterilization, several
distinct features of experimentation suggest the need for
special protections. First, the history of medical
experimentation has been characterized by significant
incidents of abuse, particularly where members of
vulnerable populations have been enlisted as subjects.
Second, the interests of medical researchers in securing
participation in the experiment often conflicts with their
duties as treating physicians to inform, advise, and act in
the best interests of their patients. Third,
experimentation is inherently highly intrusive and
dangerous, as the nature and magnitude of risks involved
are largely unknown and unknowable.49
In contrast, Bein suggests that courts have not demanded
such safeguards for decisions on life-sustaining treatment,
based on an absence of the above features in the treatment
setting. He also argues that an IRB-administered system of
patient advocates would provide inadequate oversight because
such a system would be too responsive to institutional
interests.50
Other recent commentary proposes more diverse methods for
ensuring against inappropriate capacity determinations.
Bonnie opposes a federal requirement for any specific
procedure, rather "the regulations should provide a menu of
safeguards" from which IRBs could choose, including
"specially tailored follow-up questions to assess subject
understanding, videotaping or audiotaping of consent
interviews, second opinions, use of consent specialists, or
concurrent consent by a family member."51
Many groups advise the involvement of a trusted family
member or friend in the disclosure and decisionmaking
process. Capable subjects reportedly are often willing to
permit such involvement. Dementia researchers frequently
adopt a mechanism called "double" or "dual" informed consent
when the capacities of prospective subjects are uncertain or
fluctuating. 52 This approach has the virtue of providing a
concerned back-up listener and questioner who "may help the
cognitively impaired individual understand the research and
exercise a meaningful informed consent."53 On the other
hand, the presence of a caregiving relative could, in some
cases, put pressure on subjects to enter a research study.54
Another suggestion is to require the use of a two-part
consent process. In this process, information about a study
is presented to a prospective subject and a questionnaire
administered to determine the individual's comprehension. The
subject is then provided with a copy of the questionnaire to
refer to as needed. If the individual initially fails to
demonstrate an adequate understanding of the material,
written or oral information is presented again, and the
subject retested. This process is likely to yield more
accurate judgments of subject capacity than a less systematic
and rigorous inquiry.55
Finally, numerous ideas have been offered to make
information more accessible to subjects capable of exercising
independent choice. Simple perceptual aids, such as
increasing the type size of printed material, may enhance the
ability of elderly subjects to comprehend the necessary
information. Information can be delivered through videotape,
slides, or pictorial presentations. A creative suggestion is
for investigators to ask representatives of the affected
population to critique drafts of information materials prior
to their actual research use.56
The literature offers fewer suggestions for ensuring
adequate voluntariness. The Helsinki Declaration includes a
provision advising "the physician obtaining informed consent
for the research project [to] be particularly cautious if the
subject is in a dependent relationship or him or her may
consent under duress." In these circumstances, "informed
consent should be obtained by a physician who is not engaged
in the investigation and who is completely independent of
this official relationship."57 To guard against pressure from
family or other caregivers, someone should talk separately
with consenting subjects on their reasons for participating.
Again, the issue is whether a research team member,
independent evaluator, or IRB representative should be given
this responsibility.
Research Decisions for Persons Incapable of Independent
Choice
Many persons diagnosed with mentally disabling conditions
are unable to make their own decisions on research
participation. Others may become incapable while they are
participating in a study. In these circumstances, persons
other than the incapable individual must make the choice for
or against that individual's research involvement. Decisions
on the permissible conditions for enrolling and retaining
incapable subjects must be made at the policy level, as well
as by IRBs and the subject's personal representative.
Existing federal policy is largely silent on these
matters. According to the Common Rule, the risks presented by
any proposal to involve human subjects must be reduced to the
minimum necessary to obtain the desired data, and must be
"reasonable in relation to anticipated benefits, if any, to
subjects, and the importance of the knowledge that may
reasonably be expected to result."58 No additional limits or
criteria for evaluating permissible risk in research
involving incapable subjects are included in the rule.
Special DHHS regulations establish such conditions for
research involving children, but research involving incapable
adults is governed solely by the Common Rule's general
provisions.
Existing federal policy also gives little direction on who
should act as the incapable subject's personal representative
in making decisions on research participation. The Common
Rule simply provides that "[i]nformed consent will be sought
from each prospective subject or the subject's legally
authorized representative."59 The rule fails to address the
desirable qualifications of a representative or the
substantive criteria that should guide that person's choices.
The Belmont Report simply states that third-party decision
makers "should be those who are most likely to understand the
incompetent subject's situation and act in that person's best
interest."60
Improvements in current policy will require attention to
five areas:
- selection of an incapable subject's representative
- substantive criteria governing the subject
representative's decision making
- the incapable subject's assent or objection to research
participation
- the incapable subject's preferences while capable
- permissible levels of risk in research involving
incapable subjects
Although these areas are discussed in separate sections,
they are significantly related, and are likely to be combined
in any policy revision.
The Incapable Subject's Representative
The Common Rule's use of the phrase "legally authorized
representative" leaves many unanswered questions. State laws
contain general provisions on the standards and procedures
governing appointment of guardians for persons declared
legally incompetent. Guardianship requires a judicial
proceeding and ordinarily authorizes someone to make
financial decisions, personal decisions, or both types of
decisions for the incompetent person. Limited guardianships
covering a narrower area of decisionmaking responsibility are
also possible.
Relatively few states have laws specifically addressing
the area of research decision making by legal guardians.
Existing state legislation limits the involvement of
incapable subjects in research in various ways; a number of
laws require guardians to obtain specific court authorization
to make decisions on a ward's research participation.61
Federal research policy is not intended to preempt or
otherwise affect state or local laws applying to research,
including those conferring additional protection on
subjects.62 Thus, investigators and IRBs in
jurisdictions with specific law governing the identity and
authority of research decision makers for incapable subjects
must comply with that law. Yet in the many states without
clear law, it will be left to federal policy, investigators,
and IRBs to determine who may act as an incapable subject's
surrogate decision maker in research.
The literature indicates that at present legal
guardianship is rarely, if ever, mandated in the research
setting. Instead, close family members, who may or may not
have formal guardianship status, are the customary decision
makers when the research participation of incapable adults is
sought. Should federal policy require formal legal
guardianship? The underlying question is whether such a
requirement is necessary or sufficient to provide adequate
protection against inappropriate research use of a vulnerable
population to advance the interests of others. The National
Commission recommended that the permission of either a legal
guardian or a judge be required to authorize the research
participation of subjects institutionalized as mentally
infirm in the following situations:
- the incapable subject objects to participation
- the subject is incapable of assent (see below) and the
research presents more than minimal risk to subjects.63
Later commentary questions whether formal legal
proceedings are necessary to provide adequate protection for
incapable subjects, particularly those not residing in an
institutional setting. As one writer notes, IRBs requiring
legal guardianship "to be on the safe side" could end up
contributing to a deprivation of general decisionmaking
rights of subjects.64 Moreover, the guardian appointment process
ordinarily will not address research participation issues in
any explicit way. In most cases, a judicial decision to
confer guardianship status on a particular person is made
without consideration of that person's suitability as a
research decision maker.
Dissatisfaction with a requirement for legal guardianship
has led to proposals of alternative mechanisms for granting
authority to act as an incapable person's representative in
research decision making. One option is to allow decisionally
capable persons to authorize in advance a specific individual
to make decisions on research participation during a future
period of incapacity. This device, which is modeled on the
durable power of attorney (DPA) for health care, has the
virtue of promoting the capable individual's autonomous views
on who is best suited to act on his or her behalf in the
research context.
The primary advantage of the research DPA is the explicit
authority granted by the subject, who presumably will choose
someone likely to express her values and protect her welfare.
Intramural research at the National Institutes of Health
(NIH) Clinical Center is governed by a policy that encourages
this approach.65 The American College of Physicians and
numerous others express support for use of these devices.66 As a
practical matter, however, it is unclear whether many
individuals will be interested in or willing to complete such
a document.67 Moreover, the device cannot be applied to
the population of persons with mental disability who are
currently incapable and not expected to recover capacity.68
A second potential source of authority is an existing
health care power of attorney. In this situation, the
now-incapable subject previously exercised an autonomous
choice to delegate medical decision making to a particular
person. The question is whether an individual's choice of a
friend or relative to make treatment decisions in the event
of incapacity is defensibly interpreted as an authorization
for research decision making as well. The NIH Clinical Center
policy allows previously chosen health care proxies to make
research decisions for subjects.69
A third alternative is to regard state legislation
authorizing family members to make certain treatment
decisions on behalf of relatives as conferring authority for
research decisions as well. It might be argued that such
legislation embodies a recognition that important
health-related decisions for decisionally incapacitated
persons are properly assigned to relatives. Most reasonable
would be to extend the laws' application to a close
relative's decision regarding research offering potential
health benefit to an incapable subject.70 Others believe
that these laws should not be interpreted so expansively and
that amendments or new legislation would be required to
provide explicit statutory authority for delegation of
research decision making to relatives.71
The final possible option is to assign research
decisionmaking authority based on the simple status of being
a close relative. Support for this alternative comes from the
long-held tradition in health care of relying on families to
make decisions for incapable persons, as well as from the
belief that relatives are most likely to make decisions in
accord with the incapable person's values, preferences, and
interests.72 This approach also is easy to administer;
moreover, it apparently has been, and continues to be, a
common practice in the actual research setting.73
Each of the above options presents advantages and
drawbacks. Requiring judicial involvement raises the costs of
research and does not necessarily advance respect for, and
protection of, incapable persons. Requiring explicit DPAs for
research poses practical difficulties, since relatively few
persons have, or can be expected to complete, these
documents. Another question is whether the power of DPAs to
accept research risks to an incapable individual should be
equal to the power of competent adult subjects to consent to
such risks for themselves (see below). New legislation
authorizing relatives to make research decisions for
incapable persons would require action by the states; such
legislation would emerge slowly and in some states, not at
all.
All of these alternatives also raise questions about the
accuracy with which incapable subjects' values and
preferences as competent persons will be expressed by formal
or informal representatives.74 The problem of potential
conflicts of interest between subjects' interests and those
of their representatives exist as well. Those most likely to
act as representatives are family members, who may see the
subject's research participation as an avenue "that may
lighten the burden of caregiving or lead to treatment from
which the family member may benefit."75 Two empirical
studies found some family members willing to allow an
incapable relative to be entered in a research study even
though they thought the relative would refuse if competent.
Some family members also stated they would allow an incapable
relative to become a subject even though they would refuse to
enroll in such a study themselves.76
One response to the above concerns is to conduct screening
and education of subject representatives, with the goal of
ascertaining inappropriate decision makers and enhancing the
likelihood that representatives will make choices that
adequately respect the subject's competent preferences and
current interests.77 Adopting a requirement for screening and
training would raise the further question of whether this
procedure should be conducted by a member of the research
team, the IRB, or someone otherwise independent of the
project.78
An alternative or additional approach is to limit the
authority of any third party to consent to research
participation by an incapable subject. Three forms of
substantive limitations are commonly endorsed. One is to
allow guardians, proxies, and informal surrogates to give
valid consent to studies if the incapable subject assents or
fails to object to initial or ongoing research participation.
The second is to require that third parties make research
decisions consistent with the incapable subject's prior
instructions issued while competent. The third is to permit
subject representatives to authorize the involvement of
incapable subjects only in studies that meet certain
riskpotential benefit standards. Many of the recommendations
on research involving persons with mental disabilities apply
each of these limits, but combine them in a variety of
ways.
The Incapable Subject's Research Preferences
According to the Belmont Report, respect for persons
incapable of fully autonomous choice "requires giving them
the opportunity to choose to the extent they are able,
whether or not to participate in research."79 Consistent with
this view, the National Commission recommended that under
specified conditions, researchers should obtain assent to
research participation from subjects incapable of independent
decision making. According to the commissioners, persons are
capable of assent if they" know what procedures will be
performed in the research, choose freely to undergo these
procedures, communicate this choice unambiguously, and [know]
that they may withdraw from participation."80
The commission recommended that an incapable subject's
overt objection to initial or ongoing participation should
rule out research involvement unless the study offers the
subject a prospect of direct benefit and a court specifically
authorizes the subject's participation. The commissioners
also stated that an objecting incapable subject should be
involved in research presenting a prospect of direct benefit
and more than minimal risk only when the benefit is available
solely in the research context.
The commissioners recommended procedural mechanisms to
ensure application of these substantive provisions. They
stated that IRBs should have discretion to appoint an
independent auditor to verify the subject's assent or lack of
objection. They also recommended that independent auditors be
required to monitor the incapable subject's initial and
ongoing assent in research presenting more than minimal risk
and no prospect of direct benefit to subjects; if subjects
object at any time to this category of research, they should
be removed from the study.
Not all incapable individuals can provide assent as
defined by the National Commission. Some persons may satisfy
certain elements of the standard, but not all of them.81 Should
the physical or verbal indications of persons incapable of
assent be considered in research decision making? A related
question is "whether the failure to actively object to
participation in a protocol is enough to be interpreted as a
tacit or implied form of assent or whether some more
affirmative agreement is necessary."82 According to the National
Commission, "mere absence of objection" ought not be
interpreted as assent.83 The commission recommended requiring the
consent of a subject's legal guardian to authorize more than
minimal risk research involving nonobjecting subjects
incapable of assent. Whether this situation might be
adequately addressed through less formal procedural
safeguards, or by imposing special limits on research risks,
remains unsettled in the existing literature.
There is general agreement that the sole potential
justification for imposing research interventions on actively
resisting subjects would be to advance the goal of
protection; that is, to provide a potential material health
benefit unavailable outside the study. Recent commentary
generally supports a requirement for subject assent, or at
minimum, lack of objection, except in the unusual case when
research participation offers the subject direct benefits not
otherwise obtainable in the clinical setting.84 Yet not all
commentators agree that potential direct benefit should be
sufficient to override the incapable subject's behavioral
resistance to research participation.
A Canadian group considering research involving persons
with dementia recently noted:
Faced with an objection by a patient of impaired capacity,
the justification advanced for nevertheless imposing the
investigational intervention is that it holds out the
prospect of direct (therapeutic) benefit. However, it is
normally not legitimate to impose even established therapy
on a patient refusing it. The case for proceeding may be
stronger regarding the incompetent ... patient who objects,
but it is difficult to equate an intervention which is
investigational in nature - whatever its potential for
direct (therapeutic) benefit - with an intervention "which
would be ordered in a purely therapeutic context." 85
This group was "not fully persuaded" that potential
therapeutic benefit provides ethical justification for
compelling an objecting subject's research participation. In
their view, this "is at best a position in need of further
debate." 86
Draft legislation under consideration in Maryland
completely bars investigators from conducting research
involving a decisionally incapable individual "who refuses to
perform an action related to the research." 87 The T.D. case
labeled constitutionally deficient New York's provision
allowing the involvement of an objecting incapable subject in
potentially therapeutic research because the state
regulations failed to provide patients or their
representatives notice and an opportunity to challenge this
involvement.88
The Incapable Subject's Preferences While Competent
Various groups and individual commentators have explored
the relevance of advance decision making in the research
context. Two types of research advance directives are
discussed. Through an instruction directive, a competent
person may consent to or refuse future research involvement
during a period of temporary or permanent incapacity. Through
a proxy directive (also known as a research DPA), a competent
individual may choose someone else as her research decision
maker if she subsequently loses decisional capacity.
As in the treatment area, advance research decision making
is supported as a means of extending respect to the
autonomous choices of capable individuals. Advance decision
making is also seen as protective in that it can prevent a
surrogate from authorizing an incapable subject's involvement
in research the subject previously deemed unacceptable. The
primary issues raised by research advance directives are:
- whether advance decisions can be adequately
informed
- how to safeguard the subject's right to withdraw from
research
- whether advance choice is a morally defensible basis
for permitting otherwise prohibited levels of risks and
burdens in research involving incapable subjects.
The concept of advance research decision making was
initially discussed in the 1980s. In his volume on clinical
research, Robert Levine discussed the "research living will"
as an avenue for competent persons to authorize future
research involvement while incompetent.89 In 1987, the NIH
Clinical Center adopted a policy in which persons "who are or
will become cognitively impaired" are asked to complete a
durable power of attorney (DPA) document appointing a proxy
research decision maker.90 Such proxies may authorize an incapable
subject's participation in research presenting greater than
minimal risk to subjects. In such cases, an ethics
consultation is conducted to verify the proxy's capacity to
understand information relevant to the research decision. If
no DPA exists, the consent of a court-appointed family
guardian is required. The Clinical Center policy deems a
subject's prior exercise of choice an acceptable basis for
permitting higher risk research than is otherwise permitted
for subjects lacking court-appointed family guardians.91
In 1989, the American College of Physicians (ACP) gave
qualified endorsement to instruction and proxy mechanisms
permitting competent persons to register advance consent to
research. According to the ACP, investigators seeking advance
consent would be required to disclose to the competent person
the usual information on a study's purpose, methods, risks,
and potential benefits. Moreover, the ACP recognized a need
for more caution regarding advance research decisions than
advance treatment decisions:
In nonexperimental care, advance directives are generally
used by patients to indicate their intent to refuse
procedures ... which they believe will be contrary to their
interests. Respect for autonomy creates a strong
presumption for adherence to instructions for
nonintervention. In contrast, advance directives for
research purposes would authorize interventions that do not
benefit the subject in the case of nontherapeutic research,
or that may not benefit the subject in the case of
therapeutic research.92
Accordingly, this group took the position that research
advance directives "may be abrogated if it is later
determined that the proposed research would unduly threaten
the subject's welfare."93
Despite these cautions and restrictions, the ACP deemed an
incapable subject's prior consent an acceptable basis for
allowing that subject's involvement in higher risk research
than is permitted for other incapable subjects. The position
paper states that incapable subjects with informal proxies
should not be involved in greater than minimal risk research
offering no prospect of direct benefit. In contrast, subjects
with advance directives may be involved in such studies, as
long as the above limitations are observed.
Other groups and commentators have expressed general
support for advance research decision making without
addressing the concept in detail.94 Four articles published between
1994 and 1996 present more lengthy analyses of advance
research directives and are discussed below.
In reviewing the advance directive's potential application
to dementia research, Greg Sachs suggests it is unlikely that
many individuals will prepare research directives. He notes
that relatively few person make treatment directives, even
though many fear overtreatment at the end of life. Even fewer
will make research directives, he predicts, because "the fear
of missing out on being a subject in a promising dementia
study, or of being inappropriately volunteered by one's
relatives, is simply not a prevalent or powerful concern."95
Federal policy establishes stringent disclosure
requirements for investigators recruiting competent persons
for research. An individual considering whether to authorize
future research participation ought to be informed about a
prospective study as well. But problems in information
delivery are posed by the time lapse between a capable
individual's decision to enter a future study and the onset
of actual participation. As a Canadian group points
out,"[t]he research intervention, process, or technology may
have evolved; the risk of harm may have increased beyond what
was originally predicted; the patient's medical conditions,
relationships, level of family support, and daily routine may
have changed and deteriorated."96
In light of these possibilities, commentators agree that a
third-party decision maker should be appointed to withdraw
the subject from a study if previously unrecognized risks and
burdens become apparent.97 They differ, however, on the standard third
parties should apply when exercising the subject's right to
withdraw from research the subject previously authorized.
Some writers favor withdrawal only when the factual
circumstances become materially different from what the
individual agreed to in a directive.98 Others contend that withdrawal
should also occur if it becomes apparent to others that
research participation threatens the incapable subject's
welfare. According to this position, a research proxy's or
surrogate's obligation to respect the person's prior wishes
is limited by the obligation to protect the person. The
function of the [thirdparty decision maker] is to promote
what subjects think are their best interests, which
necessarily excludes consenting to being intentionally harmed
or to being unreasonably exposed to the risk of harm.99
This dispute is related to disagreement on the appropriate
scope of a competent person's advance consent to research.
Commentators are divided on whether policy should permit an
incapable subject to be exposed to otherwise impermissible
levels of research risks and burdens based on the subject's
prior instructions. Moorhouse and Weisstub contend that
directives should be restricted to authorizing research" with
a negligible or less than substantial risk." 100 Their position
is based on the belief that capable individuals cannot
predict with complete accuracy how they will experience
research as incapable subjects. These authors also argue that
the competent individual's freedom to volunteer for research
to advance the interests of others is qualified by society's
responsibility to protect vulnerable individuals from
material harm.
A Canadian group addressing dementia research proposes
that research directives should apply to studies offering no
direct benefit to subjects only if the risk is minimal or a
minor increase over minimal.101 They suggest one exception
to this limit, however: "[i]f a subject who provides a
directive specifying a willingness to undergo a higher risk
level also provides evidence of having already experienced a
similar level of physical or psychological pain or discomfort
in another research setting, then the cap of allowable risk
for that subject could be raised accordingly."102
Berg supports full implementation of advance research
instructions without regard to the risk level. She argues,
"[b]ecause competent subjects do not have limits placed on
the types of research in which they can participate while
they remain competent (as long as the protocol is approved by
an appropriate review board), they should not have limits
placed on the types of research in which they can consent, in
advance, to participate should they become incompetent."103
Conversely, when an advance directive refuses research
participation, Berg suggests that the subject's refusal could
be overridden if a study offers possible direct benefit
unavailable in the clinical setting. She fails to explain why
concern for the incapable subject's best interests justifies
disregarding a directive in one situation and not the
other.
A few public policy developments are relevant to this
topic as well. In 1996, the Food and Drug Administration and
NIH adopted new regulations governing research involving
incapable subjects in the emergency setting.104 The new
regulations allow research to proceed in the absence of
consent by a subject or subject representative if a number of
conditions are met. One such condition is that investigators
cannot reasonably obtain prospective consent from competent
individuals likely to be candidates for later study
enrollment.105
The regulations and agency comments do not address the
rationale for, or implementation issues raised by,
prospective consent. The commentary implies that the ordinary
disclosure requirements for informed consent govern advance
research decision making.106 According to agency
officials, when IRBs determine that investigators can
reasonably identify and seek prospective consent from persons
likely to become eligible for a study, "[t]hose individuals
who either did not make a decision or who refused would be
excluded from participation in the investigation." 107 In
response to a public comment describing "the difficult task
for potential subjects to imagine the kind of research they
would want should they suffer a catastrophic illness,"
officials acknowledged possible difficulties in implementing
the prospective decisionmaking process, but suggested that
IRBs could adequately address these matters.108 The New York
court decision invalidating regulations governing research at
the state's mental health facilities also expressed support
for prospective decision making on research participation. In
T.D., the appellate court took the position that without an
incapable subject's previous consent or the consent of
someone the subject specifically chose as her research
decision maker, "[i]t may very well be that ... there is at
present no constitutionally acceptable protocol for obtaining
the participation of incapable individuals" in studies posing
greater than minimal risk and no prospect of therapeutic
benefit.109 By implication, then, the court deemed
advance consent or the consent of a specifically authorized
research proxy a constitutionally adequate basis for an
incapable subject's participation in research posing more
than minimal risk and no prospect of direct benefit to
subjects.
The court's position was based on earlier New York
decisions addressing surrogate decision making on
life-sustaining treatment for incapable patients. These
decisions established a rule that" in the absence of specific
legislation, and where there is no evidence of personal
intent, a surrogate has no recognized right to decide ...
that treatment should be withheld...."110 Because
"participation in studies involving greater than minimal risk
exposes the subjects to possible harmful, and even fatal,
side effects," the court determined that explicit legislation
or the subject's prior expression of intent should be
required in the research context as well.111
The state of Maryland has initiated a third policy effort
relevant to advance research decision making. Draft
legislation includes a framework for third-party decisions on
research for decisionally incapacitated persons. Research is
permitted with consent of an incapable subject's" legally
authorized representative." Unlike current federal policy,
this proposal specifies who may fill this role. Subject
representatives may be, in the following priority order:
- a research agent designated in an advance directive for
research
- a health care agent designated in an advance directive
for treatment
- a surrogate authorized by statute to make health care
decisions for an incapable person
- a monitor designated by the IRB to act as a research
decision maker for an incapable person.112
The draft gives greater decisionmaking authority to third
parties expressly chosen by an incapable individual. In the
absence of an instruction directive, only research agents and
health care agents are authorized to consent to an incapable
subject's involvement in research presenting a minor increase
over minimal risk and no expected direct benefit. Only a
research agent may authorize an individual's involvement in
research presenting more than a minor increase over minimal
risk and no direct benefit.
The legislation also recognizes a limited role for
instruction directives. A monitor may consent to an incapable
individual's participation in research presenting minimal
risk and no direct benefit if the individual's advance
directive explicitly authorizes such participation. A
research agent may permit an incapable subject to be involved
in research presenting more than a minor increase over
minimal risk only if "the research is unambiguously included
in the individual's advance directive authorizing research
participation."113 Thus, otherwise prohibited research risk
is permitted based on the prior competent choice of a now
incapable subject.
The draft does not discuss the study information that must
be disclosed to a capable person making an advance research
directive.Withdrawal from research is addressed, however. Any
third party consenting to an incapable subject's
participation must
- take reasonable steps to learn whether the experience
of the individual in the research is consistent with the
expectations of the legally authorized representative at
the time that consent was granted
- withdraw consent if continued participation would,
considering all relevant circumstances be detrimental to
the well-being of the individual.114
In sum, advance research decision making has been widely
discussed in the literature and included in some recent
policy initiatives. Numerous conceptual and practical
questions remain unresolved, however. The number of persons
willing to prepare research directives may be small,
especially if rigorous standards for information disclosure
are observed. Investigators and IRBs face challenges in
providing competent individuals with up-to-date information
on a future study. Finally, the literature reveals
disagreement on the significance policy should assign to the
competent individual's preferences about future research
participation posing more than minimal risk to incapable
subjects.
Should federal policy regard the incapable subject's past
competent instructions as an acceptable basis for initial or
ongoing participation in studies that otherwise would be
prohibited? To answer this question, policy makers must first
decide whether certain types of studies are too risky or
burdensome to conduct on incapable subjects who have not
prepared advance research directives. This issue is discussed
in the next section.
Balancing Risks and Expected Benefits in Research
Involving Incapable Subjects
A generally accepted principle is that research risks to
human subjects must be justified by expected benefits to
subjects, to others, or to both. The Common Rule directs IRBs
to ensure that research risks are minimized and are
"reasonable in relation to anticipated benefits, if any, to
subjects, and the importance of the knowledge that may
reasonably be expected to result."115 These provisions govern all
research involving human subjects. Many commentators and
organizations, as well as the international documents
described above, favor placing additional constraints on
acceptable risks in research involving decisionally incapable
subjects.
As was noted earlier, the National Commission proposed a
research review framework in which greater substantive and
procedural demands would be applied to research presenting
relatively high risks to children and incapable individuals
institutionalized as mentally infirm. The current DHHS
regulations governing research involving children incorporate
such a framework.116 The regulations classify research using
the somewhat controversial concept of "minimal risk."
According to the Common Rule, a study presents minimal risk
if "the probability and magnitude of harm or discomfort
anticipated in the research are not greater in and of
themselves than those ordinarily encountered in daily life or
during the performance of routine physical or psychological
examinations or tests."117
The DHHS regulations on research involving children permit
IRBs to approve research presenting no more than minimal risk
as long as requirements for parental permission and child
assent are satisfied. Studies presenting greater than minimal
risk must meet additional requirements. If a study in this
category also offers a prospect of direct benefit to
subjects, criteria for IRB approval include:
- a finding that the risk is justified by the prospective
direct benefit
- a finding that the research presents at least as
favorable a risk-expected benefit ratio for subjects as
that presented by available alternatives in the clinical
setting.
If a study presenting more than minimal risk offers no
prospect of direct benefit to child subjects, criteria for
IRB approval include:
- a finding that the research presents a minor increase
over minimal risk
- a finding that "the intervention or procedure presents
experiences that are reasonably commensurate with those
inherent in their actual or expected medical, dental,
psychological, social, or educational situations"
- a finding that the study is likely to produce
generalizable and vitally important information on the
subjects'condition.
The regulations also provide for a special review process
to address an otherwise unapprovable study determined by an
IRB to offer "a reasonable opportunity to further the
understanding, prevention, or alleviation of a serious
problem affecting the health or welfare of children." The
Secretary of DHHS may approve such a study if, after
consultation with experts in relevant fields and the
opportunity for public review and comment, he or she concurs
with the IRB's finding on research significance and
determines that "the research will be conducted in accordance
with sound ethical principles."118
These regulations, the National Commission's
recommendations on research involving children and
institutionalized persons, and the literature on research
involving incapable adults present the following policy
matters for consideration:
- the appropriate definitions of risk and benefit to be
adopted in policy on research involving incapable adult
subjects
- the appropriate limitations on risk for research
involving this population
- the appropriate procedures for ensuring that the chosen
substantive standards are observed during the research
process.
Defining Risks and Benefits in Research Involving
Incapable Subjects
Risks
Incapable subjects are vulnerable to a variety of possible
harms when they participate in research. Risks to incapable
subjects "range from physical injury and pain at one extreme,
to discomfort and inconvenience at the other, including at
various points along the continuum such effects as
frustration, dislocation, confusion, and shame."119 The Common
Rule's definition of minimal risk refers to "harm or
discomfort," which seems clearly to include experiential
burdens as well as health risks.
The most thorough published analysis on risks and
potential benefits in research involving incapable adults
suggests that review committees should consider "physical,
social, psychological, and economic," risks, including
"foregone benefits, ... violations of privacy, ... effects
upon the subject's relationship with family members, [and]
the new anxiety associated with being invited to participate
in ... research before having come to terms with one's
affliction."120 Risk assessment also involves probability
judgments: "[t]he quantification of risk involves an
examination of both the degree or magnitude of harm that
could occur and the possibility that such harm will occur."121
Evaluating risks to incapable subjects requires
familiarity with how subjects in the relevant population may
respond, both generally and as individuals, to proposed
research interventions and procedures. What may be a small
inconvenience to ordinary persons may be highly disturbing to
some incapable subjects. Thus, for example, a diversion in
routine can for some dementia patients, "constitute real
threats to needed order and stability, contribute to already
high levels of frustration and confusion, or result in a
variety of health complications."122 Similarly, as the National
Commission observed, some subjects institutionalized as
mentally infirm may "react more severely than normal persons"
to routine medical or psychological examinations.123
Because of this special vulnerability to harm and
discomfort, risk evaluation should incorporate reliable
knowledge on the range of anticipated reactions subjects may
have to study procedures. Though conceding that precise risk
and benefit assessments rarely are attainable, the Belmont
Report states, "the idea of systematic, nonarbitrary analysis
of risks and benefits should be emulated as far as
possible."124 The National Commission's Report on
Research Involving Children advised IRBs to assess risks from
the following points of view: "a common-sense estimation of
the risk; an estimation based upon investigators' experience
with similar interventions or procedures; any statistical
information that is available regarding such interventions or
procedures; and the situation of the proposed subjects."125
Like the current DHHS regulations on research involving
children, many proposals on research involving incapable
adults employ the concepts of minimal risk and minor increase
over minimal risk. Giving substance to these concepts poses
difficulties, however.
The Common Rule's minimal risk definition is tied to the
risks of ordinary life and medical care. The minimal risk
concept is praised for its flexibility: "[i]t is inescapable
and even desirable that determinations of risk level (and its
acceptability when balanced with benefit consideration) are
matters of judgment rather than detailed definition,
judgments which are patient-specific, context-specific, and
confirmed after consideration and debate from many points of
view."126 In addition, the concept's reference to
"risks of everyday life" is supported as conveying a
defensible normative judgment that the sorts of risks society
deems acceptable in other contexts may be acceptable in
research as well.127
In contrast to the minimal risk concept's reference to the
life and medical experiences of ordinary persons, the DHHS
regulations' concept of minor increase over minimal risk is
tied to the prospective subject's individual situation.
Because persons with psychiatric and other disorders undergo
treatment and tests involving some discomfort and risk, a
study presenting similar procedures and potential for harm
may qualify as presenting a minor increase over minimal risk
to them.128 For subjects not accustomed to or in need
of such medical interventions, however, the same study would
present a higher level of risk.
In its Report on Research Involving Children, the majority
of National Commission members defended this approach on
grounds that it permitted no child to be exposed to a
significant threat of harm. Further, they noted that the
approach simply permits children with health conditions to be
exposed in research to experiences that for them are normal
due to the medical and other procedures necessary to address
their health problems. One member was highly critical of this
approach, however, contending that it was wrong to take a
more permissive approach to research risk in children with
health problems than in other children. He argued that the
only morally defensible differential treatment of sick and
healthy children would be one that was more permissive about
research risks to healthy children than to children already
burdened by their health problems.129
Commentators have criticized both the Common Rule's
"minimal risk" definition, and the DHHS regulations' term
"minor increase over minimal risk." Loretta Kopelman provides
the most detailed critique. First, she finds the risks of
ordinary life too vague a notion to provide a meaningful
comparison point for research risks. Ordinary life is filled
with a variety of dangers, she notes, but "[d]o we know the
nature, probability, and magnitude of these 'everyday'
hazards well enough to serve as a baseline to estimate
research risk?" Second,though the comparison to routine
medical care furnishes helpful guidance regarding minimal
risk, it fails to clarify whether procedures such as "X rays,
bronchoscopy, spinal taps, or cardiac puncture," which
clearly are not part of routine medical care, could qualify
as presenting a minor increase over minimal risk for children
with health problems who must undergo these risky and
burdensome procedures in the clinical setting. Kopelman
argues that the phrase minor increase over minimal risk
should be replaced or supplemented by a clearly defined upper
limit on the risk IRBs may approve for any child subject.130
A few empirical studies indicate that there is a real
possibility of variation in how IRBs and investigators
classify protocols using the current federal risk categories.
For example, a 1981 survey found differences in how pediatric
researchers and department chairs applied the federal
classifications to a variety of procedures commonly used in
research.131 Similarly, there was substantial
disparity in how the nine members of a special NIH review
panel applied the federal classifications to a trial of human
growth hormone in which healthy short children were
subjects.132 A survey asking research review committee
members and chairs in Canada to classify four different
dementia studies" confirmed that there is considerable
disagreement and uncertainty about what risks and benefits
mean and about what is to be considered allowable risk."133
In sum, if policy on research involving incapable adults
incorporates the concepts of minimal risk and minor increase
over minimal risk without providing further guidance to
investigators and IRBs, the concepts may be interpreted in
materially different ways. A study classified as minimal risk
at one institution could be classified as higher risk at
another. Also needed is more discussion and clarification of
acceptable risk in research involving incapable adults whose
health problems expose them to risks in the clinical setting.
Incapable persons accustomed to certain procedures may
experience fewer burdens when undergoing them for research
purposes. Thus, it is defensible to classify the risks to
them as lower than they would be for someone unfamiliar with
the procedures. On the other hand, some procedures entail
material burdens each time they are administered. Procedures
of this sort ought not be classified as lower risk for
subjects who have had the misfortune of enduring them in the
treatment setting.134
One way to reduce variance in risk classification would be
to provide examples of studies that ordinarily would be
expected to present a certain level of risk to members of a
certain research population. The discussion could also
include general considerations relevant to risk
classification. For example, one author proposes that lumbar
punctures and positron emission tomography "can be reasonably
viewed as having greater than minimal risk for persons with
dementia because 1) both procedures are invasive, 2) both
carry the risk of pain and discomfort during and after, and
3) complications from either procedure can require surgery to
correct."135 The Maryland draft legislation states
that an IRB may not classify a study as presenting minimal
risk if the study would expose incapable subjects to "a loss
of dignity greater than that ordinarily experienced by
individuals who are not decisionally incapacitated during the
performance of routine physical or psychological examinations
or tests."136 The draft legislation also prohibits IRBs
from applying the minimal risk or minor increase over minimal
risk categories to studies exposing incapable subjects to
possible "severe or prolonged pain or discomfort" or
"deterioration in a medical condition."137
Another document lists as minimal risk for dementia
patients "routine observation, data collection, answering a
questionnaire, epidemiological surveys, venipuncture, and
blood sampling," as well as neuropsychological testing.138
Though some reportedly classify lumbar punctures and bone
marrow biopsies as presenting a minor increase over minimal
risk, this document suggests that such procedures may present
"greater risks for some patients with dementia who are unable
to understand or tolerate the pain or discomfort"
accompanying the interventions.139 Finally, the document notes
that repeated performance of procedures ordinarily qualifying
as minimal risk could at some point create sufficient burdens
to subjects to merit a higher risk classification.
Benefits
Research involving incapable adults may yield three types
of benefit: direct benefit to subjects, indirect benefit to
subjects, and benefit to others. Direct benefit to subjects
includes health improvements which may or may not be related
to the disorder responsible for the subject's incapacity.140 The
National Commission stated that research offering potential
benefits to persons institutionalized as mentally infirm
includes studies to improve existing methods of biomedical or
behavioral therapy, or to develop new educational or training
methods. The studies may evaluate somatic or behavioral
therapies, such as research designed to determine
differential responsiveness to a particular drug therapy, or
to match particular clients with the most effective
treatment. Studies may also assess the efficacy of techniques
for remedial education, job training, elimination of
self-destructive and endangering behaviors, and teaching of
personal hygiene and social skills.141
According to the commission, "[t]o be considered 'direct,'
the possibility of benefit to the subject must be fairly
immediate [and t]he expectation of success should be
well-founded scientifically."142 A more recent statement on
dementia research limits direct benefit to:
a short or long-range improvement, or a slowing of a
degenerative process, in the specific medical condition of
the relevant subject, whether in the patient's condition of
dementia, a medical symptom associated with dementia, or
another physical or mental condition unrelated to dementia.
Such direct benefits include those resulting from
diagnostic and preventative measures.143
Subjects may obtain other forms of benefit from research
participation. As the National Commission noted,"[e]ven in
research not involving procedures designed to provide direct
benefit to the health or well-being of the research subjects,
...there may be incidental or indirect benefits." 144
Examples of indirect benefits are, "diversion from routine,
the opportunity to meet with other people and to feel useful
and helpful, or ... greater access provided to professional
care and support."145 According to one group, indirect benefit
may be acknowledged, but should not be assigned the same
weight as direct benefit in research review and discussions
with prospective subjects and their representatives.146
The T.D. decision criticized New York's failure to include
a more precise definition of direct subject benefit in the
regulations the court invalidated. The regulations referred
to "direct benefit that is important to the general health or
well being of the subject and is available only in the
context of the research." Because otherwise applicable
limitations and safeguards could be waived if a study offered
potential direct benefit to subjects,147 the court
seemed to favor a narrow definition encompassing only
expected benefits produced by the research procedure, related
to the incapable subject's psychiatric condition, and
reasonably equivalent to those provided by currently
available treatments.148
The court's response supports, at minimum, a need to
scrutinize investigators' characterizations of research
offering potential direct benefit to subjects.149 Such claims
require careful scrutiny by IRBs and other reviewers.
Specific definitions of direct and indirect benefit, and a
statement on the relative significance of the two, could
assist investigators and reviewers in evaluations of the
benefits anticipated from particular studies. The decision
also questions the justification for a policy adopting less
rigorous limits and safeguards for studies offering
prospective direct benefit to subjects, if direct benefit is
defined as broadly as it was in the New York regulations.
Research benefit to others encompasses benefit to a
subject's family or other caregivers, to persons with the
same disorder as subjects, and to persons diagnosed with the
disorder in the future. This category of research presents
the greatest challenge for those seeking the appropriate
balance between subject protection and the welfare of others.
As one group noted, when such research is invasive and
presents no realistic possibility of direct health benefit,
it "poses in the most dramatic form the conflict between the
societal interest in the conduct of important and promising
research and the interests of the potential subject."150
Acceptable Risk-anticipated Benefit Ratios in Research
Involving Incapable Subjects
Proposed policies on research involving incapable adults
generally engage in a balancing of risks and potential
benefits to determine when such research is acceptable. Most
proposals take the position that incapable adults may be
involved in studies presenting little or no risk to them, as
long as requirements for third party consent are met and the
research offers a reasonable prospect of advancing knowledge
or benefiting the subject, or both. There is substantial
support, however, for adopting additional restrictions and
review requirements for studies presenting higher risk,
particularly for higher risk studies failing to offer
subjects a reasonable prospect of direct benefit.
Research presenting more than low risk to subjects is
generally classified into one of two categories. The first
category is research offering subjects a reasonable prospect
of direct benefit. Though the moral justification for such
research is enhanced by the potential for improving subjects'
health or welfare, most proposals incorporate the view that
limits on risk are still needed to provide adequate
protection to incapable individuals.
Greater than Minimal Risk Research Offering Direct
Subject Benefit
The general view is that it is permissible to include
incapable subjects in potentially beneficial research
projects as long as the research presents a balance of risks
and expected direct benefits similar to that available in the
clinical setting.151 This position is adopted in current DHHS
regulations on research involving children.152 It is also
endorsed in most of the proposals on incapable adults.
The American College of Physicians' document allows
surrogates to consent to research involving incapable
subjects only "if the net additional risks of participation
(including the risk of foregoing standard treatment, if any
exists) are not substantially greater than the risks of
standard treatment (or of no treatment, if none exists)." In
addition, there should be "scientific evidence to indicate
that the proposed treatment is reasonably likely to provide
substantially greater benefit than standard treatment (or no
treatment, if none exists)."153
The Maryland draft legislation deems "expected medical
benefit" research permissible if an agent or surrogate,
"after taking into account treatment alternatives outside of
the research, ... concludes that participation is in the
individual's medical best interest."154 The NIH
Clinical Center permits greater than minimal risk research
offering a prospect of direct subject benefit with the
consent of a DPA or court-appointed family guardian,
following an ethics consultation to ensure that the
third-party decision maker understands the relevant
information. For subjects without a DPA or court-appointed
guardian, this form of research is permitted, "if the
situation is a medical emergency, when a physician may give
therapy, including experimental therapy, if in the
physician's judgment it is necessary to protect the life or
health of the patient."155
Greater than Minimal Risk Research Offering No Reasonable
Prospect of Direct Subject Benefit
The American College of Physicians and other groups take
the position that greater than minimal risk research offering
subjects no reasonable prospect of direct benefit should be
permitted only when authorized by a research advance
directive156 or after review and approval at the
national level, through a process resembling that set forth
in the current regulations governing research involving
children.157 The National Commission also recommended
a national review process for studies that could not be
approved under its other recommendations on research
involving persons institutionalized as mentally infirm.
However, others see this position as either too liberal or
too restrictive.
On one hand, some favor an absolute prohibition on
moderate or high-risk research offering no benefit to
subjects but great promise of benefit to others, based on the
Nuremberg Code's and Helsinki Declaration's "conviction that
vulnerable and unconsenting individuals should not be put at
undue risk for the sake of patient groups or society."158
Supporters of this position contend that when these documents
were created, "it was presumably well understood that a price
of that prohibition would be that some important research
could not proceed, some research answers would be delayed,
and some promising therapies and preventive measures would
for the time being remain untested and unavailable."159 Some
writers explicitly label this stance the most ethically
defensible position.160
A position paper representing federally funded Alzheimer
Disease Centers adopts a somewhat different view: "[r]esearch
that involves potential risks and no direct benefit to
subjects may be justified if the anticipated knowledge is
vital and the research protocol is likely to generate such
knowledge."161 This group also believes that a national
review process is not necessarily the best way to decide
whether to permit research presenting no potential direct
benefit and more than minimal risk to incapable subjects.
They acknowledge that "there may be some advantages" to
national review, but contend that "immediate and direct
monitoring of such research and on-site assurance of its
humane ethical conduct are at least as important as the
process of evaluation and approval of any proposed
research."162
In sum, there is a range of opinion on how federal policy
should address risks to incapable subjects in studies
conducted solely for the benefit of others. The literature
presents at least three options:
- adopt an absolute risk limit, such as minimal risk or
minor increase over minimal risk
- require approval at the national level for studies
exceeding a specific risk level
- preserve the status quo and allow IRBs to determine
acceptable risk levels. If the decision to limit risks is
made, consideration should be given to providing more
specific definitions than exist in current policy
provisions on minimal risk and minor increase over minimal
risk.
Maintaining Acceptable Risk-expected Benefit Ratios in
the Research Process
In the initial review process, IRBs evaluate a research
proposal's risks and expected benefits based on predictions
of subject response. In many cases, a range of responses
among subjects will be predicted. In some cases, predictions
may prove inaccurate as research progresses, for some or even
all subjects. As a result, subjects' health status and
experiences must be evaluated on an ongoing basis to ensure
that subjects can be removed if risks become excessive.
The need for subject monitoring is widely acknowledged.
The Common Rule directs IRBs to ensure that "[w]hen
appropriate, the research plan makes adequate provision for
monitoring the data collected to ensure the safety of
subjects."163 Commentators also refer to the importance
of monitoring.164 The major question is how to implement