Chapter 4: The Assessment of Risk and Potential Benefit
The Common Rule directs IRBs to ensure that research risks
are minimized through careful study design and that risks are
"reasonable in relation to anticipated benefits, if any, to
subjects, and the importance of the knowledge that may
reasonably be expected to result."177 Many commentators favor
placing additional constraints on acceptable risks in
research involving persons who, as a result of having certain
mental disorders, may sometimes lack decisionmaking
capacity.
This chapter discusses some of the conceptual and
practical problems that arise not only for IRBs, but also for
investigators and potential subjects who must make judgments
about the acceptability of risk in relation to the prospect
of benefit. It first discusses some of the difficulties
inherent in defining risk, followed by an explanation of
NBAC's rationale for urging IRBs to evaluate research
protocols involving this population under two categories:
minimal risk and greater than minimal risk. Next, it
discusses some of the difficulties in defining benefits.
Finally, it comments on the difficulties of assessing
research risks in relation to potential benefits. In
particular, this discussion focuses on the protections that
should be required for research involving greater than
minimal risk that holds out the possibility of direct medical
benefit to subjects, and for research involving greater than
minimal risk that does not hold out the possibility of direct
medical benefit to subjects. The final section of this
chapter also proposes procedures to minimize risks to
subjects.
Defining and
Assessing Risk
The concept of risk is generally understood to refer to
the combination of the probability and magnitude of some
future harm. According to this understanding, risks are
considered "high" or "low" depending on whether they are more
(or less) likely to occur, and whether the harm is more (or
less) serious. In research involving human subjects, risk is
a central organizing principle, a filter through which
protocols must pass; research evaluated by IRBs that presents
greater risks to potential research subjects will be expected
to include greater or more comprehensive protections designed
to reduce the possibility of harm occurring. The ethical
basis for this position was usefully summarized in the
National Commission's Belmont Report: "The requirement that
research be justified on the basis of a favorable
risk/benefit assessment bears a close relation to the
principle of beneficence, just as the moral requirement that
informed consent be obtained is derived primarily from the
principle of respect for persons."178 In contrast, relatively
little progress has been made in describing the criteria for
assessing risk by IRBs.179 In large part, this is due
to the multiple difficulties inherent in classifying risk
judgments, including the difficulty associated with risk
perception in general,180 and other aspects of objectively
quantifying risk.181
The purpose of having multiple categories of risk is to
trigger different requirements from IRBs, just as the
"minimal" and "greater than minimal" risk categories trigger
different types of minimal protections in the Common Rule.
The Common Rule does not specify that IRBs use three
categories of risk in making judgments about the
acceptability of risks in relation to potential benefits, nor
do the regulations specific to pregnant women or prisoners
specify that IRBs use three categories of risk.182 Only the
regulations pertaining specifically to children describe
three categories of risk.183 Indeed, IRBs are free to use
as many categories of risk as they deem appropriate in
assessing risk in relation to potential benefit. The Common
Rule categories are only for the purposes of establishing
minimum protections. NBAC recommends that IRBs use their
existing authority to determine whether to add protections
above the minimal regulatory requirements for all research
involving greater than minimal risk.
Minimal Risk and Greater than 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."184 Although the concept of
minimal risk remains controversial in academic and scholarly
discussion, it is widely used to determine which set of
protections are to be required for particular research
protocols. For example, when a research protocol is
determined to involve minimal risk, IRBs are given the
latitude to waive certain consent requirements, so long as
certain conditions are met. Moreover, IRBs may expedite the
review of research protocols - relying on the review by a
single member, such as the chair - that typically (though not
exclusively) involve minimal risk.185 Still, the application of
this concept can be difficult in practice. For example, a
"typical" minimal risk encountered in everyday life or in
clinical care may be perceived differently by some
individuals with certain disorders. It is important,
therefore, to establish a practical level of minimal risk
against which IRBs can measure proposed research protocols in
order to decide which protocols require additional
protections. The level of minimal risk will change (in one
direction or another) over time, as experience and additional
knowledge alter the way the research community, IRBs, and
research subjects perceive the acceptability of various
research risks. Under the current system, IRBs have complete
discretion to apply none or only some of the added
protections to protocols that they believe to be of greater
than minimal risk. Indeed, they are entitled to add
additional protections for protocols involving minimal risk
as well.
The DHHS addressed the issue of IRB latitude in its
regulations on research involving children by permitting IRBs
to approve research presenting no greater than minimal risk
as long as requirements for parental permission and child
assent are satisfied. Even in this case, an IRB could add
further protections if it thought it was appropriate to do
so. However, the regulations stipulate that studies
presenting greater than minimal risk must meet additional
requirements.
Like the DHHS regulations for children, many proposals on
research involving impaired or incapable adults employ the
concepts of minimal risk and minor increase over minimal
risk. Indeed, many public comments suggested that NBAC group
research protocols involving persons with mental disorders
into three categories of risk: (1) minimal risk; (2) minor
increase over minimal risk; and (3) greater than minimal risk
(which encompasses risks greater than a minor increase over
minimal risk). The ostensible purpose of this tripartite
division is to allow protocols involving only a minor
increase over minimal risks to proceed with only minimal
additional protections. Three categories of risk, it has been
argued, provide IRBs with more flexibility in requiring
certain protections. Two categories of risk, it has been
suggested, would prevent certain protocols from going forward
since IRBs may believe that the additional protections would
effectively bar research involving greater than minimal risk
without the prospect for direct medical benefit. As evidence
of this alleged difficulty, NBAC received correspondence from
NIH describing examples of research that might be limited by
retaining the Common Rule's two-level categorization of risk.
These examples included: affected sib-pair genetic linkage
studies in Alzheimer's disease, biological measures for the
purpose of treatment response prediction, neuroimaging
studies in developmental disorders, studies to improve
understanding of Alzheimer's disease, studies to improve
diagnosis of Alzheimer's disease, study of urinary
incontinence in severely demented nursing home residents,
studies of delirium in older patients, and studies of
aphasia. In several of these examples, research was
considered to involve minimal risk or a slight increment
above minimal risk. NBAC did not find these concerns
convincing. As explained above, the key point is that IRBs
should focus on the need for a continuous range of
protections that are related to the perceived level of risk,
and whether there are two or more levels should make little
difference. NBAC's view is that IRBs should perceive their
responsibility as requiring, where necessary, a set of
additional protections beyond those minimally required, from
a continuous spectrum that will be governed by the particular
nature of the proposed protocol. In short, NBAC is not
persuaded that three categories of risk are necessary for
accomplishing the twin goals of providing protection for
persons with mental disorders while allowing important
research to go forward. At least one professional
organization, the Alzheimer's Association, has adopted as
official policy the view that the three categories of risk
are not necessary.186
As noted above, providing clear meaning to these concepts,
poses serious practical difficulties. The Common Rule's
minimal risk definition, which refers to the risks of
everyday life and medical care encountered by the population
as a whole, often is praised for its flexibility: "It 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."187 The concept's reference to
"risks of everyday life" also conveys a defensible normative
judgment that the sorts of risks society deems acceptable in
other contexts may be acceptable in research as well.188
In contrast to the minimal risk concept's reference to the
life and medical experiences of the overall population, the
concept of minor increase over minimal risk is, in the case
of children, tied to the prospective subject's individual
situation. Because persons with mental disorders often
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.189 For subjects not accustomed to or in need
of such medical interventions, however, the same study could
present a higher level of risk.
In its Report on Research Involving Children, the National
Commission defended this approach to greater than minimal
risk research on grounds that it permitted no child to be
exposed to a significant threat of harm. Further, the
National Commission 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.
An example is venipuncture, which may be more stressful for
healthy children than for sick children who may be more
accustomed to the procedure.
Commentators have criticized both the Common Rule's
"minimal risk" definition and the category "minor increase
over minimal risk" in the children's regulations. Loretta
Kopelman provides perhaps the most detailed critique. First,
she finds the notion of "risks of everyday life" too vague 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 whose health problems dictate that they 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.190
Difficulties with the minimal risk standard may be due in
part to a historical confusion. Some contend that the
drafters of the definition of minimal risk deliberately
dropped the National Commission's reference to normal
individuals, intending to make the relevant comparison to
risks ordinarily encountered by the prospective research
subject. This approach would allow classifying research risks
as minimal if they were reasonably equivalent to those the
subject encountered in his or her ordinary life or routine
medical care. Using this approach with persons with mental
disorders who face higher-than-average risks in everyday life
and clinical care, a research intervention could be
classified as minimal risk for them, but classified as
greater than minimal risk for healthy persons. If this was
the intention of the drafters of the regulations, it is not
at all clear in the current Common Rule.
In August 1998, the major federal funding agencies in
Canada developed a policy statement on "Ethical Conduct for
Research Involving Humans" that explicitly adopts the
standard of relativizing risk to the potential subject in
question. It defines "normally acceptable risk" as "when the
possible harms (e.g., physical, psychological, social, and
economic) implied by participation in the research are no
greater than those encountered by the subject in those
aspects of his or her everyday life. . . ."191 The Canadian
policy statement goes on to insist that therapeutic risks
should be treated differently from nontherapeutic risks.
Therapeutic risks can be considered as minimal for
patient-subjects, since they are inherent in therapy and thus
the everyday life of the subject.
In some cases, procedures presenting greater than minimal
risks to people with mental disorders might be treated as
such, while in other cases (e.g., in persons with special
vulnerability to those procedures) they might not be. A
procedure classified as minimal risk at one institution could
be classified as higher risk at another, or even from one
study to another in the same institution. Also needed is
further clarification of acceptable risk in research
involving incapable adults whose ongoing health problems
expose them to risks in their everyday clinical setting.
Because some persons with mental disorders who are accustomed
to certain procedures may experience fewer burdens when
undergoing them for research purposes, some would argue that
it may be defensible to classify the risks to them as lower
than would be the case for someone unfamiliar with the
procedures.
We must guard against assumptions like these. The
psychological context of illness may well make some research
procedures, however familiar, more burdensome than they would
be to someone who enjoys good health. These procedures must
not be classified as lower risk for subjects who have had the
misfortune of enduring them in the treatment setting.192 Like
the level of minimal risk, the boundaries that separate
particular risk categories can be expected to shift over time
in response to many complex and interrelated factors. What is
required is a focus on the "package" of reasonably
interpreted risks, on the one hand, and a correspondingly
appropriate set of protections, on the other.
One way to reduce variation 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. For example, the Maryland draft
legislation includes in its definition of "minimal risk"
research those "types of research that are . . . identified
by the United States Department of Health and Human Services
as suitable for expedited IRB review."193 The Maryland
proposal effectively incorporates examples like venipuncture,
magnetic resonance imaging (MRI), electroencephalography, and
the study of existing biological specimens. This is
consistent with federal regulations; however, it should be
noted that while current federal regulations permit studies
involving MRI to be reviewed on an expedited basis, this does
not always imply that such studies always involve minimal
risk.
Perhaps over time, if there is adequate communication and
disclosure, it will become evident to the IRB community that
protocols tend to cluster in certain ways. For example, one
author proposes that lumbar punctures and PET "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."194 The Maryland draft
legislation designates research as presenting more than a
minor increase over minimal risk if, as a result of research
participation, the subjects would be exposed to more than a
remote possibility of "substantial or prolonged pain,
discomfort, or distress" or "clinically significant
deterioration of a medical condition."195
One proposed list of minimal risk procedures for dementia
patients includes "routine observation, data collection,
answering a questionnaire, epidemiological surveys,
venipuncture, and blood sampling," as well as
neuropsychological testing.196 Though some reportedly
classify lumbar punctures and bone marrow biopsies as
presenting a minor increase over minimal risk, Keyserlingk
and colleagues suggest 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.197
NBAC's review of a series of research protocols turned up
a good example of an IRB that sought expert assistance in
assessing risks. The protocol involved a challenge study
which entailed a higher than standard dosage of the challenge
agent, although the investigator described the study as
minimal risk in the consent form. The expert evidently
advised the IRB that the risks were in fact greater than
minimal due to the increased dosage and that the dosage
should be reduced and properly identified in the consent
form. An IRB that seeks expert opinion, where necessary, can
dramatically improve both research design and the bases for
subjects to provide informed consent.
The debate about the meaning of minimal risk will surely
persist because of the philosophical and practical
difficulties of defining it precisely. But this does not mean
that research involving persons with mental disorders cannot
be conducted. Rather, it means that research procedures that
would entail minimal risk for a general population must be
assessed in light of the specific research population. In no
case, however, should procedures classified as greater than
minimal risk for the overall population be classified as
minimal risk for this population. Therefore, research
proposals should be more highly scrutinized if they involve
persons with mental disorders, and special care may be
required to understand particular risk levels for this
population. NBAC believes that these special considerations
are important and should not prevent the most valuable
research from continuing within such constraints.
Assessing Risk
Strictly speaking, risk assessment is a technique used to
determine the nature, likelihood, and acceptability of the
risks of harm.198 In actual practice there is always a
great deal of controversy about how such assessments should
occur. Moreover, few IRBs conduct formal risk assessments,
and there may be good reasons for this: First, reliable
information about risks or potential benefits associated with
the relevant alternative interventions is often lacking. As a
result, highly accurate risk assessment is difficult and in
many cases impossible. Second, each component of risk
assessment - identification, estimation, and evaluation -
involves time and requires particular kinds of expertise.199 Even
at the conceptual level, it is a matter of both scientific
and philosophical debate as to whether risk assessment should
involve purely objective or purely subjective factors (or
both). The "objectivist" school argues that quantitative risk
assessment should be a value-free determination limited only
by the technical ability to derive probability estimates.200 In
contrast, the "subjectivist" school argues that the values of
those who conduct the assessment, those who interpret the
results, and those who bear the risks should play a role in
the overall assessment of risks.201 It is reasonable to hold
that both schools of thought ought to influence IRB decision
making, the former because risk judgments should be
empirically based insofar as possible, and the latter because
many who have an interest in research can contribute to these
assessments despite the lack of formal quantitative data.
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."202 Evaluating
risks to subjects with mental disorders requires familiarity
with how such subjects may respond, both generally and
individually, to proposed research interventions and
procedures. What may be a small inconvenience to ordinary
persons may be highly disturbing to those with decisional
impairments. 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."203 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.204 Because of the
special vulnerability to harm and discomfort that particular
subjects may have, risk assessment should anticipate the
range of reactions subjects may experience to certain
proposed study procedures. Difficult as it may be, careful
risk assessment is the key to deciding on the appropriate
level of protections.
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Defining Benefits
Research involving adult subjects can yield three types of
potential benefit:
- direct medical benefit to subjects;
- indirect benefit to subjects; and
- benefit to others.
Direct Medical Benefit
Particular research protocols may hold out the prospect of
direct medical benefit to the subjects themselves, even
though such benefit can never be assured. The potential
direct medical benefits to the subjects include health
improvements which may or may not be related to the disorder
responsible for the subject's incapacity.205 For example,
the National Commission stated that research offering
potential direct benefits to persons institutionalized as
mentally infirm could include:
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.206
According to the National 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..."207 A more recent statement on
dementia research limits direct medical 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.208
IRBs and other reviewers should carefully scrutinize
investigators' assertions that research offers the prospect
of direct medical benefit to subjects. Furthermore, the
protocols reviewed by NBAC reflected some confusion about the
definition of direct medical benefit. One protocol referred
to the challenge procedure as the "treatment phase." The
consent form that accompanied this protocol included in the
benefits of the assessment phase "a thorough psychological
evaluation at no cost, the results of which will be the basis
for a treatment recommendation either within or outside of
the treatment phase of the study. Benefits of the treatment
phase may include decreases in the . . . severity of . . .
symptoms." Unless the distinctions between direct medical and
indirect benefits are identified, and their relative
significance explored carefully, there is a danger that
investigators may construe the concept of direct medical
benefit too broadly.209
Finally, potential direct medical benefits to the subjects
participating in the research protocol not only must be
carefully evaluated but may not, by themselves, justify
experimental interventions that present risks to a subject
population. Instead, these possible benefits must be
considered in relation to the risks involved. Even though a
research protocol may offer potential direct medical benefits
to individual participants, it cannot be justified by the
possibility of that benefit alone.
Indirect Benefit
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."210
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."211 NBAC agrees with the view expressed by
one group that an indirect benefit may be acknowledged, but
should not be assigned as heavy a weight as direct medical
benefit in the IRB review and discussions with prospective
subjects and their representatives.212
There is a continuing debate about whether the
reimbursement subjects receive for their time and
inconvenience constitutes a direct or indirect benefit of
research participation. The benefits of financial incentives
for the subject are indirect in the strict sense that they do
not stem from the research interventions themselves, but the
subject may view them as very important. A secondary concern
here, as with research on other potentially vulnerable
populations, is who actually receives and controls the funds:
the subject or a third party who authorizes research
participation?
The principle that financial incentives should not exceed
"reimbursement" for the subject's time and expenses, so as
not to establish undue motivation to participate, is well
established but not always easy to apply. The problem is
complex because both healthy volunteers as well as some who
are ill may agree, for example, to pharmaceutical testing as
an important supplement to their income (if not their sole
income source) as their main reason for participating.
Remuneration must be appropriate to justify their commitment
of time and their submission to discomfort, but not be so
great as to lead them to take unreasonable risks. Similarly,
some who are suffering from an illness, especially those who
are uninsured, may be tempted to join a study if it appears
that the ancillary medical care will be superior to what they
can otherwise obtain.
Research Benefit to Others
This category encompasses benefit to subjects' families or
other caregivers, to persons with the same disorder as
subjects, and to persons who will suffer from the same
disorder in the future. When such research is invasive and
presents no realistic possibility of direct health benefit to
the subject, 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."213 Thus, it is necessary to examine
carefully how risk and potential benefits - especially to
others - can be balanced; and what protections should be in
place to minimize risk to subjects with mental disorders that
may affect decisionmaking capacity.
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Balancing Risks and Potential
Benefits
The National Commission was fully aware of the problems
inherent in making risk-benefit assessments when it wrote
that:
It is commonly said that the benefits and risks must be
"balanced" and shown to be "in a favorable ratio." The
metaphorical character of these terms draws attention to
the difficulty in making precise judgments. Only on rare
occasions will quantitative techniques be available for the
scrutiny of research protocols. However, the idea of
systematic, nonarbitrary analysis of risks and benefits
should be emulated insofar as possible.214
This chapter has described some of the difficulties with
defining risks and benefits in research; the following
describes the difficulties with evaluating their relationship
to each other in order for IRBs, as required by current
regulations, to assess the ratio of risks to benefits
involved in individual research protocols. Most researchers
and IRBs take the position that adults who lack
decisionmaking capacity may be involved in studies presenting
little or no risk, as long as requirements for third party
consent are met and the research protocol 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
that fail to offer subjects a reasonable prospect of direct
benefit.215
Research presenting greater than minimal risk to subjects
is generally classified into one of two categories. The first
category is research offering subjects the prospect of direct
medical benefit. The second category is research that is not
designed to offer the prospect of direct medical benefit to
subjects. Although these categories may seem to imply a
distinction between "therapeutic" and "nontherapeutic," that
is not the case and, in fact, is a serious misconception,
particularly if studies are described as beneficial on the
basis of a therapeutic component. Rather, it should be
understood that some research may hold out the prospect of
direct medical benefit for some individuals while some
research may not.
Research Protocols Involving Minimal Risk
NBAC recognizes that there are both practical and
philosophical difficulties with applying the concept of
minimal risk. However, NBAC's view is that research protocols
that involve minimal risk present fewer ethical issues for
IRBs, researchers, and potential subjects than those
protocols involving greater than minimal risk, where, in the
latter case, the harms or discomforts may be expected to
occur more often or are more serious. As NBAC recommends in
Chapter 5, an IRB may approve protocols that present only
minimal risk using several different routes for subject
enrollment: when the potential subject gives informed consent
(unless consent is waived); if the potential subject gives
permission in advance (which NBAC describes more fully below
as "Prospective Authorization") and a surrogate decision
maker has given permission; or if a surrogate decision maker
has given permission under certain conditions.
Research Protocols Involving Greater than Minimal Risk
that Offer the Prospect of Direct Medical Benefit to
Subjects
The general view is that it is permissible to include
persons with mental disorders that may affect decisionmaking
capacity in a research protocol that involves greater than
minimal risk, but does not offer the prospect of direct
medical benefit to subjects as long as the research presents
a balance of risks and expected direct benefits similar to
those available in the normal clinical setting.216 The ACP
guidelines allow 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, they suggest that 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)."217
In a similar vein, the Maryland draft legislation deems
"research involving direct medical benefit" permissible if an
agent or family member or friend acting as surrogate, or an
IRB-designated proxy, "after taking into account . . .
treatment alternatives outside of the research . . .
concludes that participation in the research is in the
individual's medical best interest."218 Likewise, with
the permission of an individual holding a DPA, or
court-appointed family guardian, the NIH Clinical Center
permits greater than minimal risk research offering a
prospect of direct subject benefit if there was 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."219
Research Protocols Involving Greater than Minimal Risk
that Do Not Offer the Prospect of Direct Medical Benefit to
Subjects
The ACP and other groups take the position that greater
than minimal risk research offering incapable subjects no
reasonable prospect of direct medical benefit should be
permitted only when authorized by a research advance
directive220 or after review and approval at the
national level, through a process resembling that set forth
in the current regulations governing research involving
children.221 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.222
However, others see this position as either too liberal or
too restrictive. In NBAC's view, the proposal of national
review has considerable merit, and is discussed below and in
Chapter 5.
On the one hand, based on the Nuremberg Code's and the
Declaration of Helsinki's convictions that vulnerable
unconsenting individuals should not be put at undue risk for
the sake of patient groups or society, some favor an absolute
prohibition on moderate- or high-risk research offering no
benefit to subjects but great promise of benefit to others.
Supporters of this position contend that when these documents
were created, "[i]t 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."223 Some explicitly label this stance the
most ethically defensible position.224
On the other hand, a position paper representing federally
funded Alzheimer's disease centers adopts a somewhat
different view: "Research 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."225 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 greater than minimal risk to
incapable subjects. While acknowledging that "there may be
some advantages" to national review, but contends 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."226
Special Review Panel
The regulations governing research involving children
subjects provide for a special review process to address
studies that offer the subjects no prospect of direct benefit
and that would pose greater than a minor increment over
minimal risk. The process begins by requiring that, an IRB
determine that a study in this category "presents a
reasonable opportunity to further the understanding,
prevention, or alleviation of a serious problem affecting the
health or welfare of children."227 Upon such a finding, the
Secretary may convene a panel of experts in pertinent
disciplines to review the study and should provide the public
an opportunity to review and comment on the study.228
After the panel's review and the public comment period, the
study may be approved if the Secretary has determined: (1)
that the study actually falls into a category of research
that the IRB could have approved on its own,229 or (2) that
the research does present the "opportunity to further the
understanding, prevention, or alleviation of a serious
problem affecting the health or welfare of children, that the
research will be conducted in accordance with sound ethical
principles, [and] that adequate provisions are made for
soliciting the assent of [the] children and the permission of
their parents or guardians."230
This type of process, if modified, offers an additional
route for assessing some protocols involving persons with
mental disorders. In NBAC's view, however, a more flexible
and accessible process is required. It would be appropriate
for the Secretary of DHHS to establish a Special Standing
Panel (SSP) which would have the authority to review and
approve particular protocols, involving greater than minimal
risk and do not offer the prospect of direct medical benefit
to potential subjects, that could not otherwise be approved
by IRBs. These protocols would be forwarded to the SSP by the
local IRB. The SSP, which is described more fully in Chapter
5, would also have the authority to establish guidelines over
time for delegating to local IRBs the authority to approve
certain types of protocols in this arena.
NBAC urges the Secretary of DHHS, when constituting the
SSP, to be mindful of the reports NBAC has received from the
research community asserting that a significant amount of
important research may fall into this category and that
medical progress for many suffering persons may very well
depend upon the ability of IRBs to approve appropriate
protocols in this area. In designing the SSP, the Secretary
also should take into account the experience of the current
panel mechanism identified in 45 CFR 46.407(b). In
particular, NBAC believes that it is essential for the SSP to
conduct its work in a timely and efficient manner. Although
the mechanism for special cases in research with children has
been used only twice, NBAC believes that a similar but
modified mechanism could fulfill its intended purpose in
research involving persons with mental disorders that may
affect decisionmaking capacity.
Therefore, NBAC strongly encourages the Secretary to
ensure sufficient administrative support of, and financing
for, the SSP and to adopt procedures for the operation of the
panel such that will: (a) make case-by-case decisions using a
process that is easily accessible to IRBs; and (b) develop as
appropriate, and issue, guidelines for categories of research
that then can be used by IRBs without having to utilize the
SSP. In addition, the process should include public
participation and a public written decision that explains the
SSP's rationale for each of its decisions. The system of
review recommended here will serve several important
functions. Most important to NBAC is that it will increase
protections for a subject population believed to have been
historically underprotected. Second, it will permit research
to go forward that has passed uniform expert and public
review of risks and benefits.
Opportunities to Enhance IRB Education and Decision
Making
Some have expressed concern that IRBs, if limited to two
categories of risk when making judgments about the
acceptability of risks in relation to potential benefits, may
be inclined to consider all projects involving greater than
minimal risk to require the most comprehensive
protections.
In particular, NBAC recognizes the concern expressed by
some that if research involving what are normally relatively
benign interventions (such as PET scans or MRIs) were
categorized as greater than minimal risk, this could result
in restrictions that might substantially delay or otherwise
limit research. NBAC believes, however, that the most
appropriate way to address this issue is not to focus on an
arbitrary line, which cannot be reliably established, but
rather to focus attention on improving the quality of IRB
judgments generally, and on the unavoidable responsibility of
IRBs to ensure an appropriate balance between risks and
benefits, but also an appropriate balance between risks and
protections. One possible strategy is for IRBs individually
and collectively to develop "research ethics case law," by
publicly disseminating the results of their deliberations so
that others may benefit.
The purpose of having a set of risk categories is to
establish certain minimal protections and to enable
individuals (in this case, IRB members) to discriminate more
precisely when making judgments about whether adequate
protections are in place, as well as when making judgments
about risk in relation to potential benefits. But since risks
will vary along a continuum that involves a number of
factors, and since IRBs currently have the authority to
require a variety of additional protections for persons
involved as subjects (even in minimal risk research), NBAC
was not persuaded by the assertion that an additional
category of risk is needed to assist in these decisions.
However, by limiting the categories of risk to two, NBAC is
not intending for IRBs to require all available protections
when they determine that a research protocol poses greater
than minimal risk.
A few empirical studies indicate that there is substantial
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 involving
children.231 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.232 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."233
NBAC recognizes the difficulty that IRBs may face when
making precise risk judgments, particularly about
non-physical harms. For this reason, IRBs may find it useful
to collect data on the types of protocols they review
involving persons with mental disorders, and to assess
whether any patterns emerge in which certain types of
protocols fall along a spectrum from the most benign to the
most dangerous. This could be accomplished within the context
of NBAC's proposed guidance regarding audit and disclosure
(see Chapter 5).
Independent Research Monitors
In the initial review process, IRBs evaluate a research
proposal's risks and expected benefits based both on study
design and on predictions of subject response, and it is
widely acknowledged that part of that overall evaluation will
include plans for safety and data monitoring. 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."234 After
evaluating human subject protections in schizophrenia
research conducted at UCLA, OPRR required the institution to
"establish one or more independent Data and Safety Monitoring
Boards . . . to oversee [DHHS]-supported protocols involving
subjects with severe psychiatric disorders in which the
research investigators or co-investigators are also
responsible for the clinical management of subjects."235 The
institution was directed to submit to federal officials a
proposal on creating and operating such monitoring
boards.
It is necessary to distinguish the process of monitoring
data and safety for the study as a whole from monitoring an
individual subject's safety. Data and Safety Monitoring
Boards (DSMBs) are well established devices, particularly for
multi-site studies, and often recommend the early termination
of a study because of evidence that one arm of the study is
safer or more efficacious than the other.236 But a major
question is how and when to implement individualized subject
monitoring, and whether such monitoring should be conducted
by someone who is independent of the research team. For
example, detailed provisions on monitoring are included in
Loma Linda University IRB guidelines on psychopharmacology
research in which placebos are administered. Investigators
must specify how often subjects will be assessed for
deterioration or improvement during studies. The most
appropriate quantitative instruments must be used for
assessment, and subjects must be withdrawn if their condition
deteriorates to a level "greater than that expected for
normal clinical fluctuation in a patient with that diagnosis
who is on standard therapy;" if they exhibit previously
specified behaviors indicating possible danger to self or
others; or if no signs of improvement in their condition are
evident after a specified time.237
Some have suggested that it would be appropriate to assign
monitoring responsibility to the incapable subject's
representative as well. According to the Belmont Report, the
representative "should be given an opportunity to observe the
research as it proceeds in order to be able to withdraw the
subject from the research, if such action appears in the
subject's best interest."238 In this spirit, the Maryland
draft legislation directs subject representatives to "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."239 Similarly, the U.S. Army
requires a "medical monitor" to "serve as an advocate for the
medical safety of volunteers."240
An important policy question is whether research team
members and subject representatives can provide sufficient
protection to impaired or incapable subjects. On the one
hand, research team members may face a conflict between
protecting subjects and maintaining the study population.241 On
the other hand, it is unlikely that subject representatives
will be present during every part of an incapable subject's
research involvement, and lay persons might not recognize
every indication of increased risk to subjects. In these
circumstances, IRBs would benefit from guidance on possible
approaches to monitoring harms and benefits to individual
subjects and on criteria for determining when the involvement
of an independent health care professional is needed.242 NBAC
believes that, at certain risk levels in research using
persons with mental disorders that may affect their
decisionmaking capacity, independent monitoring is essential,
and that such monitoring should be an ongoing process. In its
review of protocols, NBAC noted that some lacked sufficient,
ongoing monitoring. Although one study involved assigning
both clinical and home monitors to subjects, the protocol
included insufficient information for an IRB to evaluate how
monitoring was actually to occur. More frequently the
protocols failed to mention either monitoring or the risks of
certain procedures like drug washouts, during which a
subject's condition is likely to deteriorate. IRBs should
expect investigators to describe in their research proposals
(particularly in proposing research that involves greater
than minimal risk) how potential harms to subjects will be
monitored.
The first four chapters of this report examined several
critical scientific and ethical aspects of the research
involving subjects with disorders that may affect their
decisionmaking capacity. The final chapter presents NBAC's
recommendations for appropriate protections for this
population and the summary justifications for
recommendations.
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Footnotes