Chapter 3: Advance Planning, Surrogate Decision Making, and Assent or Objection
For those whose decisionmaking capacity is impaired, truly
informed consent may not be achievable but it remains the
standard against which all efforts to obtain the ethical
participation of individuals in research must be judged.
While some persons with mental disorders are incapable of
giving valid informed consent to participate in a research
protocol, ethically acceptable research involving such
persons is quite possible under appropriate circumstances and
with special protections. In considering the special
conditions that surround study design and consent processes
in such cases, it is important to involve human subjects in
the consent process as fully as possible given their
individual circumstances. NBAC agrees with the National
Commission ' s conclusion in the Belmont Report that respect
for persons unable to make a fully autonomous choice
"requires giving them the opportunity to choose, to the
extent they are able, whether or not to participate in
research."126 In this vein, NBAC recognizes that
certain opportunities already exist for maximizing subject
choice in research, including the designation of appropriate
substitute decision makers. It also recognizes that
sensitivity and care must be exercised in establishing
policy, lest blanket authority be given to enroll subjects in
research without due consideration to their rights and
interests.
This chapter discusses three mechanisms which have been
proposed or used to enroll human subjects in research
protocols, even if they are presently unable to give valid
informed consent. These mechanisms are: (1) the use of assent
or the lack of objection; (2) the use of advance planning and
surrogate decision making; and (3) the use of legally
authorized representatives (LARs).
The Role of
Assent and Objection
The National Commission held that, under specified
conditions, researchers could obtain assent to research
participation from subjects incapable of independent decision
making and, on the basis of this assent, enroll them in
certain minimal risk studies. In its view, persons are
capable of assent if they "know what procedures will be
performed in the research, choose freely to undergo those
procedures, communicate this choice unambiguously, and [know
that they] may withdraw from participation."127 It defined
assent as an authorization given by a person "whose capacity
to understand and judge is somewhat impaired by illness or
institutionalization, but who remains functional."128 In
defining assent in this way, the National Commission
explicitly acknowledged that full knowledge of all the risks
involved in a particular protocol is not absolutely necessary
to enroll subjects in certain minimal risk protocols if they
choose freely to participate. In NBAC's view, mere assent,
however useful, is insufficient to enroll a subject in a
research protocol.
Not all individuals who lack full decisional capacity can
provide assent as defined by the National Commission, though
some may satisfy certain elements of the standard.129 One
question is whether the physical or verbal indications of
persons deemed incapable of assent should 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."130
According to the National Commission, "mere absence of
objection" ought not be interpreted as assent,131 and it
recommended requiring the consent of a potential subject's
legal guardian to authorize greater than minimal risk
research involving non-objecting persons incapable of
assent.
Objection is also an important concept concerning persons'
involvement in research, regardless of their decisionmaking
capacity. The National Commission also referred to a
subject's objection to participation, but it did not clearly
define objection.132 The National Commission held that an
incapable subject's overt objection to initial or ongoing
participation should preclude research involvement unless:
(1) the study offers the subject a prospect of direct benefit
and a court specifically authorizes the subject's
participation, and (2) the prospective benefit is available
only in the research context.133 In addition, the National
Commission recommended procedural mechanisms to apply these
substantive provisions. In particular, it recommended the
following: (1) IRBs should have discretion to appoint an
independent auditor to verify the subject ' s assent or lack
of objection; (2) independent auditors should be required to
monitor the incapable subject's initial and ongoing assent in
research presenting greater than minimal risk and no prospect
of direct benefit to subjects; and (3) subjects should be
removed from the study if they object at any time to this
category of research.
Recent commentary generally supports a requirement for
subject assent or, at a minimum, lack of objection, except in
the unusual case when research participation offers the
subject the possibility of direct medical benefits not
otherwise obtainable in the clinical setting.134 Yet not all
commentators agree that potential direct medical benefit
should be sufficient to override the resistance (whether
verbal or behavioral) of persons lacking decisional capacity
regarding 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."135
This group therefore was "not fully persuaded" that
potential direct benefit provides an ethical justification
for compelling an objecting person's research participation.
In this group's view, this "is at best a position in need of
further debate."136 The intermediate appellate court in the
T.D. case (discussed in Appendix I) labeled as
constitutionally deficient New York's provision allowing the
involvement of objecting incapable subjects in research
protocols that hold out the potential of direct medical
benefit, because the state regulations failed to provide them
or their representatives notice and an opportunity to
challenge such involvement.137 Although the constitutional
portion of the judgment was eventually set aside by the Court
of Appeals, these same provisions would not only be ethically
objectionable according to the strict Nuremberg principle,
among others, but would also continue to be legally suspect.
The legislative proposal currently being developed in
Maryland would bar investigators from conducting research
with a decisionally incapable individual who expresses
disagreement with, or who refuses to perform an action
related, to the research.138
NBAC believes that once persons become part of a research
study, they must always have the freedom to withdraw at any
time without prejudice and without regard to their capacity.
It is persuaded, however, that even in this case it is not
necessary to always interpret such objections as permanent.
To do so might unnecessarily limit research and fail to
accomplish the goal of protection. The following example
illustrates this view: consider a study involving certain
patients with dementia, in which the only invasive
intervention in an otherwise noninvasive long-term study is a
single blood draw. Recognizing that some subjects may become
irritable and object to this procedure - perhaps by recoiling
from the needle - this objection, which must be heeded,
should not necessarily be interpreted as an objection to
continued participation in the entire study. Certainly the
subject has objected to this portion of the study at this
time. And, as previously noted, this objection must be
heeded. Moreover, the researcher who would persist and
attempt to take the blood would be acting illegally - by
possibly committing battery - and unethically - by crossing
the boundary from voluntary choice to coercion. However,
after a reasonable amount of time, the researcher in this
study should not be absolutely prohibited from returning to
the person and ascertaining, with appropriate sensitivity,
his or her willingness to now give blood. It is important to
recognize and emphasize that the line between ascertaining a
person's willingness and badgering a person is not always
clear.
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The Role of
Advance Planning and Surrogate Decision Making
Our society has long accepted the idea that people who
have the capacity to decide their affairs should also be able
to direct at least some aspects of their future as well. So,
for example, the law of trusts and wills allows a person to
control the disposition of property even after death. In
addition, individuals may anticipate the consequences of a
possible period of disability by designating someone, by
means of a durable power of attorney (DPA), to handle their
business and financial affairs during such a period. Over the
past two decades, these advance planning concepts have been
widely accepted in clinical medicine.
One can identify three types of anticipatory decision
making in the clinical setting. The first might be called a
projection of informed consent: a competent person's decision
whether to accept or decline a specific future treatment,
made now because the person will or may be decisionally
incapacitated when the treatment decision is to be
implemented. A commonplace example is a patient's decision
whether to have immediate surgery should a biopsy reveal a
malignancy. As a result of anesthesia, the patient would be
incapable of informed consent when the decision actually
presents itself. Yet the patient's anticipatory decision,
made prior to the biopsy, is no less an exercise of informed
consent. This type of decision making about discrete, future
clinical contingencies likewise occurs when a person fills
out a "living will," the original advance directive document.
The typical "living will" is an instruction that describes
the specific end-of-life interventions a patient would want
to have used (or not used) in the event of a terminal
prognosis. Despite the difficulty in meshing this kind of
instruction with what is often a more complex clinical
situation, a "living will" nevertheless can serve as a
self-executing embodiment of the person's right to decide
about these interventions.
The second type of anticipatory decision might be called a
projection of personal values, rather than a projection of
informed consent. Instead of making a treatment-specific
decision meant to bind clinicians in the future, a person
provides guidance for decision makers by emphasizing the
comparative importance of different aspects of that person's
life. For example, a person might state in an advance
directive his or her own view of what constitutes a life of
sufficient quality to warrant the most aggressive treatment.
This guidance would inform whoever was later deciding on a
course of treatment after the person had lost the capacity
for informed consent.
The third type of anticipatory decision might be called a
projection of personal relationships. Just as someone may
entrust another with responsibility for financial matters
during a potential period of future disability, a person may
designate a decision maker for health care matters. The legal
instrument by which this designation is accomplished, the DPA
for health care, has become a familiar feature of the
clinical landscape. A recent study found about a 9 percent
usage rate among residents of nursing homes in several
states.139 This designation reflects trust in the
integrity, judgment, and decision-making capacity of the
chosen proxy. Of course, the designation can also be coupled
with instructions or guidance about the choices that the
proxy might face. Because giving effect to all three types of
anticipatory decision making embodies respect for personal
autonomy, NBAC believes that all three have a place in
research involving persons with mental disorders.
First, a person who has given a valid informed consent to
enroll in a particular research protocol should be allowed to
continue to participate in that protocol, even after a loss
of capacity, or in a future iteration of that or a
substantially similar protocol (i.e., including similar
procedures and similar risks) provided that suitable measures
are in place to protect the person ' s welfare during that
research study. Second, a person who embodies in an advance
directive his or her wishes about participation in research
of certain kinds is entitled to have those wishes
respectfully considered. However, this kind of advance
directive, which does not reflect consideration of specific
types of research risks, cannot itself serve as a
self-executing instrument of informed consent or trump
limitations on research participation that sound public
policy requires. It also does not absolve the investigator
and surrogate decision maker of responsibility for assessing
the effect on the person's welfare of participation in a
particular research protocol. Third, a person may embody in
an advance directive his or her choice of a decision maker
concerning research participation. NBAC recognizes that
people use advance directives to identify others with whom
they have a relationship of trust. NBAC concludes, however,
that this relationship in and of itself is sufficient to
authorize participation in research studies only under
certain conditions.
This summary account of the role of advance decision
making in research is not intended to gloss over several
important issues, such as whether advance directives can be
adequately informed, how to safeguard a subject's right to
withdraw from research, and whether anticipatory decision
making is a morally defensible basis for permitting otherwise
prohibited levels of risk and burden in research involving
incapable subjects.
The concept of advance research decision making was
initially considered in the 1980s. In his volume on clinical
research, Robert Levine discussed the "research living will"
as an avenue for capable persons to authorize their future
research involvement if they become incompetent.140 In 1987, the
NIH Clinical Center formally adopted a policy, which is
currently under review, in which persons "who are or will
become cognitively impaired" are asked to complete a DPA
document appointing a surrogate research decision maker.141 Such
decision makers may authorize an incapable subject's
participation in research presenting greater than minimal
risk that offers the prospect of direct benefit to subjects.
In such cases, an ethics consultation is conducted to verify
the decision maker's capacity to understand information
relevant to the research decision. If no DPA exists, the
consent of a court-appointed family guardian is required.
Research presenting greater than minimal risk is not
permitted for subjects lacking a DPA or court-appointed
guardian, except in a medical emergency when a physician may
give therapy, including experimental therapy, if in his or
her judgment it is necessary to protect the patient's life or
health.
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 greater 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.142
Accordingly, the ACP 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."143
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. Its position
paper states that incapable subjects who have given only
informal instructions to a surrogate decision maker about
their research preferences should not be involved in research
of greater than minimal risk that offers no prospect of
direct medical benefit. In contrast, subjects with formal
advance directives may be involved in such studies, as long
as the above limitations are observed. NBAC is sympathetic to
this general approach; but as discussed below and in the
recommendations, it supports the idea of advance planning and
the appointment of substitute decision makers for research on
mental disorders, not the direct use of advance directives as
a self-sufficient basis for research enrollment.
In light of these various possibilities, many 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.144 They differ,
however, on the standard that third parties should apply when
exercising the subject's right to withdraw from the research
that the subject previously authorized. Some favor withdrawal
only when the factual circumstances become materially
different from those to which the individuals agreed in
directives.145 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 [third party 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.146
An intermediate position argues that an advance directive
should be overridden if "no direct benefit is anticipated for
the subject and it becomes apparent that enrollment or
continued participation would seriously endanger that
subject's welfare to an extent not foreseen by the subject,
or even if foreseen, to an extent judged by the substitute
[decision maker] to be socially or morally unacceptable."147
Underlying this dispute is a disagreement about the
appropriate scope of a capable 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. In contrast to the ACP's
position, noted above, Moorhouse and Weisstub contend that
directives should be restricted to authorizing research "with
a negligible or less than substantial risk."148 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.
Addressing dementia research, the Canadian group proposed
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.149 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 therapeutic or research setting, then the cap of
allowable risk for that subject could be raised
accordingly."150
Berg, by contrast, supports full implementation of advance
research directives 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."151 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.
A few public policy developments are also relevant.
Congress has limited the circumstances in which the
Department of Defense (DoD) may accept the "consent" of a
legal representative for the research participation of
another.152 Currently, DoD is not permitted to fund
research without the informed consent of the subject, or, in
the case of "beneficial" research, without first obtaining
the informed consent of either "the subject or a legal
representative." Thus, Congress has prohibited DoD from
conducting research that has no potential direct benefit for
the human subjects, unless the subjects themselves provide
informed consent - regardless of whether the research
involves minimal or greater than minimal risk. A similar
provision has governed DoD since 1972.
In 1996, the FDA adopted new regulations governing
research involving incapable subjects in the emergency
setting.153 These regulations allow research to
proceed under certain conditions, in the absence of consent
by a subject or an LAR. An IRB may approve such research if
it finds and documents that there is no reasonable way to
identify prospectively the individuals likely to become
eligible for participation; the subjects are in a
life-threatening situation and, because of their medical
condition, cannot give their informed consent; the
intervention must be administered before consent from an LAR
is feasible; available treatments are unproven or
unsatisfactory; the research is necessary to determine the
safety and effectiveness of some new therapies; and various
other conditions are met.154 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."155 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.156 As has been
noted, similar problems apply to all advance directives for
research participation.
The State of Maryland has initiated a policy effort
relevant to advance research decision making. The draft
legislation includes a framework for third-party decisions on
research for decisionally incapacitated persons - i.e.,
research is permitted under some conditions 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: (1) a research agent designated in
an advance directive for research; (2) a health care agent
designated in an advance directive for treatment; (3) a
surrogate - that is, a family member or close friend -
authorized by statute to make health care decisions for an
incapable person; or (4) a proxy decision maker designated by
the IRB to act as a research decision maker for an incapable
person.157
Thus, the Maryland draft gives substantial decisionmaking
authority to third parties expressly chosen by an 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 Maryland draft
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.158 Thus, otherwise prohibited research risk
is permitted based on the prior capable choice of a now
incapable subject.
The Maryland draft legislation does not discuss the
information that must be disclosed to a capable person making
an advance research directive; it does address withdrawal
from research, 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, including expectations
about potential benefits, if any, and risks presented by
the research; and withdraw consent if:
- the research was initially determined to present a
reasonable prospect of direct medical benefit to the
research subjects but no longer does so for the
individual;
- the research presents a higher level of risk to the
individual than initially expected; or
- considering all relevant circumstances, continued
participation would be detrimental to the individual's
well-being.159
Other groups and commentators have expressed general
support for advance research decision making without
addressing the concept in detail.160 In reviewing the advance
directive's potential application to dementia research, Greg
Sachs speculates that it is unlikely that many individuals
will prepare research directives. He notes that relatively
few people make treatment directives, even though many fear
excessive treatment 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."161
Although advance research decision making has been widely
discussed in the literature and included in some recent
state-based policy initiatives, numerous conceptual and
practical questions remain. The matter could be made moot if
very few persons prepare research directives. Further, even
in the best circumstances, investigators and IRBs face
challenges in providing competent individuals with all the
necessary information about a future study. Finally, the
literature reveals disagreement on the significance that
should be assigned to the competent individual's preferences
about future research participation posing greater than
minimal risk.
In sum, advance research decision making, although
recognized as a potentially useful device, poses difficult
issues concerning its scope and effect. In NBAC's view, an
advance directive can never serve as a "blank check" for
future research participation. Indeed, an advance directive
may itself serve as a sufficient basis for research
participation only in very limited circumstances. That is,
those in which the most important information relevant to
informed consent about future research participation is
already known and is presented to a capable person, who then
gives consent, and there is no material change in the
research protocol or the person's clinical situation (apart
from loss of decisionmaking capacity) by the time that
research participation is actually to begin. If the person's
willingness to participate in research is stated more broadly
- for example, in terms of a desire to participate in
research about a disease - that statement should be given
considerable weight by whoever has authority to authorize
research participation, but it cannot by itself be considered
sufficient for enrollment in a particular study. This type of
prospective authorization can provide the basis for enrolling
subjects in certain kinds of research. And, as we will
discuss below, prospective authorization provides a necessary
ground for enrolling a subject in research involving greater
than minimal risk without the prospect of direct medical
benefit - so long as certain standards for third party
approval can be satisfied. We now turn to this issue.
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Legally Authorized Representatives and
Research Decision Making
Surrogate decision makers are frequently mentioned as one
solution to ethical problems of enrolling persons from
certain vulnerable groups in research. In its recent report
on "Research Involving Individuals with Questionable Capacity
to Consent," the 1998 NIH panel concluded that, "Individuals
with questionable capacity (or clear incapacity) to consent
may have a family member and/or LAR serve as a surrogate,
with this role documented during the consent process." The
panel further recommended that the surrogate's research
decisions reflect, to the greatest extent possible, the
individual's views prior to the period of incapacity.162
Although the term "surrogate" is frequently used in
ethical discussions such as that in the NIH Panel Report, the
Common Rule uses the phrase "legally authorized
representative" (LAR). The concept of a LAR leaves many
unanswered questions. Surrogates may be regarded as
individuals who have had prior experience with the individual
being represented, but LARs (for example, legal guardians)
often do not have such experience. State laws addressing a
somewhat broader area of concern contain general provisions
on the standards and procedures governing appointment of
guardians for persons declared legally incompetent. This
report addresses only one aspect of this issue. Guardianship,
for example, requires a judicial proceeding and ordinarily
authorizes someone to make financial, personal, or both types
of decisions for the incompetent person. Limited
guardianships covering a narrower area of decisionmaking
responsibility are also possible.
As mentioned previously, relatively few states have laws
specifically addressing research decision making by legal
guardians or other allowable surrogates. Moreover, existing
legislation in some states limits the involvement of
incapable subjects in research in various ways. A number of
state laws, for example, require guardians to obtain specific
court authorization to make decisions on a ward's
participation in a research protocol. In addition, several
states currently prohibit certain types of research on
persons with mental disorders, particularly research which
presents greater than minimal risk and from which subjects
are not intended to benefit. Wichman notes that if an IRB
were to approve a study in a state that did not have such a
statute, the IRB might choose to invoke certain protections,
including additional monitoring of the study, requiring a
consent auditor, or requiring educational activities for
authorized representatives.163
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
participating in research protocols.164 Thus,
investigators and IRBs in jurisdictions with specific laws
governing the identity and authority of research decision
makers for persons lacking decisional capacity must comply
with those laws. Yet in the many states without clear law, it
will be left to federal policy, investigators, and IRBs to
determine who, if anyone, may act as a surrogate decision
maker for a person who lacks decisional capacity. At present,
legal guardianship is rarely, if ever, sought 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
for someone to be considered a suitable surrogate for
decision making about research? The underlying question is
whether such a requirement is necessary or sufficient to
provide adequate protection against inappropriate involvement
of a vulnerable population in research 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,
or the subject is incapable of assent and the research
presents greater than minimal risk.165
Subsequent commentary by others questions whether formal
legal proceedings are necessary to provide adequate
protection for subjects who lack capacity, 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.166 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 to make decisions regarding his or her
ward's participation in research protocols.
Dissatisfaction with a requirement for legal guardianship
has led to alternative proposals for granting authority to
act as an incapable person's representative in research
decision making. One option, which was discussed above, is to
allow decisionally capable persons to authorize in advance a
specific individual to make decisions regarding their
research participation during a future period of incapacity.
This device, which is modeled on the durable power of
attorney 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. Its
primary advantage, though, is the explicit authority granted
by prospective subjects, who presumably will choose someone
likely to express their values and protect their welfare.
NBAC supports the place of personal values and wishes in
making advance decisions about research participation.
Designating a surrogate decision maker with whom the subject
has a close, trusted relationship is one way to express how
personal values and wishes should be applied to future
decisions regarding research participation. As a practical
matter, however, it is unclear whether many individuals will
be interested in or willing to complete such a DPA. Moreover,
the device cannot be applied to the population of persons
with mental disorders who are currently incapable and not
expected to recover capacity. Still NBAC recognizes that such
a practice could, if accepted, result in more individuals
appointing LARs explicitly for research purposes.
A second potential source of authority is an existing
health care power of attorney. It is doubtful that an
individual's choice of a proxy to make treatment decisions in
the event of incapacity can fairly be taken as an
authorization for research decision making as well.
Nevertheless, the choice does manifest a high degree of trust
in the proxy, and that evidence of trust may entitle the
health care proxy to a decisionmaking role in research. The
NIH Clinical Center policy does allow previously chosen
health care proxies to make some research decisions for
subjects.167
A third alternative is to regard state legislation
authorizing family members (and, in a few states, friends) to
make certain treatment decisions on behalf of relatives as
conferring authority for research decisions as well. It might
be argued that such legislation recognizes that important
health-related decisions for persons lacking decisional
capacity are properly assigned to appropriate relatives.
Perhaps it would be reasonable to extend the law's
application to a statutory proxy's decision regarding
research offering potential health benefit to an incapable
subject.168 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 delegating to relatives decisions about the
subject's participation.169
A final possible option is to assign such decisionmaking
authority based on the simple status of being a close
relative or a trusted individual. Support for this
alternative, especially as regards relatives, 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.170 This approach is easy to administer;
moreover, it apparently has been and continues to be a common
practice in many research settings.171
Each of these options presents advantages and drawbacks.
Requiring judicial involvement may cause unproductive delays,
raise the costs of research, and may not always advance
respect for and protection of incapable persons. Requiring
explicit durable powers of attorney for research poses some
practical difficulties, since relatively few persons have or
can be expected to complete these documents, and it may not
be possible to describe the future research protocol
completely. Another question is whether the power of DPAs to
consent to research risks for an incapable individual should
be equal to the power of capable adult subjects to consent to
such risks for themselves. New legislation authorizing a
relative or a trusted friend to make research decisions for
incapable persons would require action by the states; such
legislation, however, might emerge slowly or, 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.172 There is also the problem of
potential conflicts between subjects' interests and those of
their representatives. 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 care-giving or lead to treatment from which the
family member may benefit."173 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.174 At the same time, NBAC recognizes that
these mechanisms might permit some important research to go
forward. Moreover, NBAC is satisfied that the argument for
encouraging the involvement of LARs is sound so long as there
is a clear description of the role and authority of the LAR,
and of the protections that must be in place in order for an
IRB to assure itself that the LAR is appropriately acting on
behalf of the incapable persons. In addition, there should be
an ongoing evaluation of LARs in this context.
The Authority of the LAR
An LAR is an individual authorized by law (statutory or
judicial) or previously published institutional rules to make
medical decisions on behalf of another individual. There are
two mechanisms by which an LAR can be involved in research
decision making. One option might be to allow individuals,
while competent, to designate their LAR to give permission to
enroll them in research. This scenario requires the
designation of an individual whose authority is limited to
research involvement. Given the paucity of experience with
research-specific LARs in this country, NBAC recognizes the
burden that might be created by recommending that only this
method be used. Another option would be to permit persons
designated as DPAs (the many thousands of individuals who
have already been appointed in this country to be health care
decision makers for clinical decisions) to serve as LARs and
be able to make certain decisions regarding the participation
of subjects in research protocols. In both cases, the
authority of the LAR requires careful description and
limitation.
Three forms of substantive limits on this authority are
commonly endorsed. One is to allow guardians, proxies, and
informal surrogates to give valid permission for an incapable
person's participation only if the incapable person assents
or, at the very least, 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 capable. The third
is to permit LARs to authorize the involvement of incapable
subjects only in studies that meet certain risk-potential
benefit standards. Many of the recommendations on research
involving persons with mental disorders apply each of these
limits, but combine them in a variety of ways.
Protections to Ensure that the LAR is an Ethically Valid
Surrogate for Research Decision Making
Given the limited experience in this country with
research-specific LARs (or for extending existing health care
DPAs to research), NBAC is unwilling to recommend their
adoption without also recommending certain protections and
methods for their evaluation. In general, NBAC regards the
IRB as the proper locus for determining whether these (or any
other) protections are adequate. For an IRB to be assured
that an LAR's enrollment of a now incapable person with a
mental disorder into a research study is acceptable, the IRB
might consider requiring the following procedures:
- Documentation that the subjects were competent to
designate an LAR. This would involve the independent
assessment of the capacity of the subjects, perhaps on more
than one occasion, including just prior to completing the
documentation assigning an LAR.
- Documentation that the subject and LAR understood the
scope of the authority being granted to the LAR. The
documentation referred to here would enable IRBs to satisfy
themselves that the now incapable subject and his or her
LAR had reasonably understood the scope of the type of
study being proposed. This places considerable emphasis on
the degree to which the IRB is assured that the prospective
subject (when capable) and his or her designated LAR
understood the difference between research and treatment
and, in research that imposes greater than minimal risk,
between that which offers the prospect of direct benefit to
the subject and that which does not. As noted below for
each of the two other protections listed, the value of this
particular protection is in need of ongoing empirical
testing and validation.
With regard to the standard by which substitute decisions
are made, NBAC suggests the following prioritization scheme.
Any wishes previously expressed by the subject authorizing
participation in a future study should be honored by the LAR.
The more specific the authorization is, the easier it is to
apply to a particular study. In the absence of a prior
specific authorization by the subject, NBAC favors, in
general, giving priority to those decisions by LARs that
approximate most closely the now incapable subject's
previously expressed preferences. For example, statements
about research "of this kind" or "involving these types of
risks" should influence the LAR's decision about enrollment.
In the absence of this kind of information, LARs would have
to rely on potential subjects' general values as expressed in
other kinds of choices or actions. NBAC is acutely aware of
the difficulties this approach presents and explains the
rationale in somewhat more detail in Chapter 5.
Ongoing Evaluation of LARs
The protections listed above could provide the IRB some
assurance that the LAR has been assigned in a legally and
ethically valid way. However, ongoing assessment of the LAR
process would be of considerable value. IRBs intending to
permit enrollment of a now incompetent subject on the basis
of LAR decisions (regardless of how well documented this
process might be) would be strongly encouraged to evaluate
the effectiveness of LARs. There would be considerable value
in having IRBs report on those studies involving greater than
minimal risk research in which enrollment of decisionally
incapable subjects with mental disorders was authorized by an
LAR. In the absence of good empirical data about the
effectiveness of the LAR mechanism in both permitting
scientifically valuable research to go forward and, at the
same time, ensuring appropriate protections of subjects from
research harm, NBAC cannot fully endorse it. On balance,
however, NBAC believes that it is appropriate to proceed by
using the LAR mechanism only in certain situations.
Nevertheless, NBAC strongly encourages the research
community, led by NIH (in view of its experience in this
area), to support studies on the possible roles of surrogate
decision makers in research.
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Independent Professional Support for
Subjects and Surrogates
Although consent forms and research protocols normally
provide thorough information about the study, they do not
provide the individualized information that many people need
to make a decision about their own participation. Also, some
potential research participants, or their representatives,
may be intimidated by the medical research environment, or
feel unable to make an independent judgment due to the
technical nature of medical research.
One way to provide intellectual and emotional support to
these individuals is to ensure that, in appropriate
circumstances, an independent and properly skilled health
care professional is available as an advisor for each
research participant or their surrogate. This independent
advisor should not be involved with the study and preferably
should have had a prior relationship with the potential
subject. Subjects, or their representatives if subjects lack
capacity, should be able to choose their responsible health
care professionals. The advisor's role would be to help a
potential subject and representative decide whether
participation in a particular research protocol is a good
choice for that subject. For incapacitated persons whose
research participation is contemplated, the health care
professional could be an invaluable consultant to the LAR.
Often this professional will be a physician; however, other
professional caregivers may serve the same role - a
nurse-clinician or a social worker, for example. The basic
requirement is that such caregivers be familiar with the
subject, understand the nature of the research protocol, not
be part of the research team, and, if practical, not be part
of the organization conducting the research.
It would be unreasonable to require independent health
care professional advisors for all research protocols
involving persons with mental disorders, but the advisors
should be available for studies involving greater than
minimal risk, and where the subject lacks capacity to decide
or is expected to lose capacity during the course of a study.
For any proposed research, subjects or their LAR should be
informed that they may request the opinion of an independent
health care professional about participation in research. In
turn, investigators should make available any information the
independent health care professional requests regarding the
conduct of the protocol.
The British Law Commission recommended a similar system to
the House of Commons in 1995, though its proposal applied
only to individuals who lack capacity. It wrote: "In most
cases the appropriate person to carry out an independent
check [on research participation] will be a registered
medical practitioner who is not involved in the research
project. . . . The doctor who knows the person best, by
virtue of having responsibility for his or her general
medical care, will often be the best candidate."175 The Maryland
proposal assigns this responsibility to a "medically
responsible clinician" if research involves withdrawing a
group of decisionally incapacitated subjects from a standard
treatment or otherwise presents more than minimal risk.176 At
the very least, it seems sensible for an LAR to have access
to an independent health care professional advisor before
entering an individual into such a research protocol.
For research protocols involving greater than minimal
risk, whether or not direct medical benefit is anticipated,
an IRB should consider whether to require that an independent
health care professional should be available before the
research begins. The subjects or their LARs may or may not
choose to utilize the independent health care professional.
When, as is usually desirable, the researcher is not the
health care professional responsible for the care of the
patient, the treating professional would be available to
serve as the independent advisor to the patient once enrolled
in the research.
This chapter has discussed some of the conceptual and
practical problems that arise when informed consent cannot be
obtained from potential research subjects, the place of
assent/objection, the use of advance planning, and the role
of LARs in permitting some research to go forward. The next
chapter describes some of the difficulties that arise in
assessing risk and potential benefit and offers some
perspectives on their resolution.
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Footnotes