Moving Ahead in
This report stands in a long line of statements, reports, and recommendations by governmental advisory groups and professional organizations on the ethical requirements of research involving human subjects. Each of these has left an important legacy. For example, in 1947 the Nuremberg Code established the importance of voluntary consent to research participation. The Declaration of Helsinki in 1964 distinguished between research intended partly to benefit the subject and research intended solely for others benefit. The Guidelines developed by the Council of International Organizations of Medical Sciences allow legal guardians to consent to low-risk research that is potentially beneficial to the human subject involved. In addition to proposing ethical principles that should govern all human subjects research and developing guidelines for research with special populations, the National Commission in 1978 proposed additional protections for those institutionalized as "mentally infirm." Even though these protections resembled those proposed by the National Commission for research with children (which were adopted), the proposed protections for those institutionalized as mentally infirm were never adopted in federal regulations (See Appendix I).
Much has changed since the National Commissions work 20 years ago. There is a greater sensitivity on the part of many to the variety of mental disorders and an improved understanding of the ways that these disorders can be recognized and ameliorated. Diagnostic procedures and treatments have progressed, sometimes in breathtaking ways, with the promise of still greater breakthroughs on the horizon. More research is being conducted than ever before, and the research environment has become far more complex, involving both a larger societal investment and a greater role for the private sector. While by no means vanquished, the stigmatization of those who suffer from mental illnesses shows signs of abating due to greater understanding of these disorders and, in some cases, the underlying biological and genetic etiology of these disorders.
NBAC hopes that the legacy of this report will be to bring persons with mental disorders more fully and specifically under appropriate additional research protections, such as those that have been extended to other potentially vulnerable persons. It recommends these new protections with the deepest respect for those involved in research on these disorders: the person with a disorder that may affect decisionmaking capacity, whose autonomy must be protected and, when possible, enhanced; the clinical investigators who are dedicated to the alleviation of these terrible afflictions; and informal caregivers, whose own lives are often absorbed by the tragedy that has befallen their loved ones. In view of the ethical uncertainties noted by those involved in such researchas investigators, subjects, or family membersNBAC believes that enhanced protections will promote broad-based support for further research by engendering greater public trust and confidence that subjects rights and interests are fully respected. This concluding chapter presents NBACs recommendations and identifies, where possible, those who should be responsible for their implementation.243
Concerns have been expressed that requiring new protections in research involving persons with mental disorders might limit such research and thereby impede the development of new methods of diagnosis or treatment.244 It is difficult to evaluate such claims because there is, to date, insufficient evidence to support or reject them. NBAC does not believe, however, that the additional protections recommended in this report will excessively burden research or hamper the development of effective new treatments. Moreover, it is useful to note that many share the responsibility to protect the interests of those without whom this research could not be doneespecially those who may be unable to give full informed consent and who may not themselves directly benefit from the research. All research involving human beings must satisfy appropriate ethical standards. That is, both the means and ends of individual studies must be morally acceptable. This moral imperative is especially acute for potentially vulnerable populations such as children, pregnant women, prisoners, or, NBAC believes, individuals with mental disorders that may affect decisionmaking capacity.
A cogent case can be made for requiring additional special protections in research involving as subjects persons with impaired decisionmaking capacity. Indeed, most of the additional protections NBAC recommends could also be considered for research in that larger population. However, NBAC has chosen to focus this report on persons with mental disorders, in part because of this populations difficult history of involvement in medical research. NBAC believes that in addition to the regulations that are already applicable, IRB deliberations about research involving subjects with mental disorders that may affect decisionmaking capacity should be governed by other specific regulations.
Recommendations for New Regulations
In the United States, regulations have provided perhaps the most important means of protecting the rights and welfare of human subjects. But they have not been the only means. Clearly, for example, widely accepted and enduring professional norms have also played a role. The desirability of additional governmental regulation depends not only on the nature and importance of the problems the proposed new rules aim to address, but also on the regulations ultimate efficacy. Presumably, the least complex measures taken by governmental entities are the preferred ones, as long as those measures can achieve the important societal goals that have been identified. Many who are familiar with the federal regulations currently governing human subjects research complain that they are already too complex and bureaucratic. Some of those engaged in research on conditions related to mental disorders fear that further regulation will unnecessarily slow scientific progress and inappropriately stigmatize individuals who may be suitable and appropriate research subjects.
Whatever ones view of the current regulations, the period since their adoption has been, in the judgment of some, largely free of the sorts of large-scale problems and abuses that led to their initial promulgation. Others, however, stress that the issues discussed in this report illustrate some of the shortcomings of the Common Rule. In this context, NBAC was obliged to determine whether the outstanding issues and problems in research involving persons with mental disorders warrant new regulations and/or whether some or all of the required reforms could be advanced through other mechanisms. These might include statements of principle; the adoption of guidelines by those individuals or professional groups involved in reviewing, regulating, and carrying out these projects; and the development of educational materials for all relevant parties.
Although NBAC proposes a number of recommendations that would require changes in the language of the Common Rule, it is mindful that the time frame for such reforms might be long and the process labor intensive. Many of the regulatory proposals made by NBAC could, however, also be accomplished by the creation of a new subpart in 45 CFR 46. Adoption of a subpart has the advantage of permitting affected federal agencies to act as expeditiously as they choose to change the regulatory requirements for their own intramural and extramural research. Regardless of which regulatory route is taken, NBAC encourages researchers and institutions to adopt the spirit and substance of these recommendations immediately.
NBAC proposes 21 recommendations. A number propose the development of new federal regulations for the protection of human subjects; others are directed to investigators and IRBs, state legislatures, NIH, DHHS, health professionals, federal agencies subject to the Common Rule, and others responsible for human subjects protection. These recommendations provide both a set of requirements that NBAC believes must be satisfied in all research protocols involving persons with mental disorders, and several additional or optional protections that may be appropriate in particular circumstances. Taken together, these recommendations would both enhance existing protections and facilitate broad public support for continued research on mental disorders.
The several recommendations for changes in federal regulations and for other governmental, institutional, and organizational actions are interconnected. Even though only a few recommendations are explicitly cross-referenced, it is important to view each recommendation in the context of the others. Only then is it possible to see exactly how NBAC proposes to protect human subjects with mental disorders that may affect decisionmaking capacity and also allow important research to proceed. Finally, in some cases, only brief justifications, explanations, and interpretations follow each recommendation in this chapter; additional support and explication appear in the preceding four chapters. The following recommendations are clustered into six sections relating to: review bodies; research design; informed consent and capacity; categories of research; surrogate decision making; and education, research, and support.
I. Recommendations Regarding Review Bodies
Institutional Review Board (IRB) Membership
Recommendation 1. All IRBs that regularly consider proposals involving persons with mental disorders should include at least two members who are familiar with the nature of these disorders and with the concerns of the population being studied. At least one of these IRB members should be a member of the population being studied, a family member of such a person, or a representative of an advocacy organization for this population. These IRB members should be present and voting when such protocols are discussed. IRBs that only occasionally consider such protocols should involve in their discussion two ad hoc consultants who are familiar with the nature of these disorders and with the concerns of the population being studied; at least one of these consultants should be a member of the population being studied, a family member of such a person, or a representative of an advocacy organization for this population.
The issues considered in this report are as complex and as multifaceted as the research protocols designed to advance medical knowledge about mental disorders. Some of these issues are likely to arise routinely in protocols involving research subjects with such disorders. By increasing the representation of the subject population on IRBs and involving them in planning clinical research relevant to their disorders, investigators and their research institutions increase the likelihood that protocols will be both better designed and more responsive to the interests of the affected groups.245 It is for these reasons that the Common Rule directs IRBs that regularly review research involving a vulnerable subject group to consider including as reviewers persons "knowledgeable about and experienced in working with these subjects."246 This provision is advisory only. Another provision permits an IRB to seek assistance in the "review of issues which require expertise beyond or in addition to that available on the IRB," but disallows these individuals of special competence from voting with the IRB.247 Thus, some agencies and research institutions have already required the inclusion of such individuals on IRBs. For example, the Department of Educations National Institute for Disability and Rehabilitative Research (NIDRR) must comply with a regulation that, "[w]hen an IRB reviews research that purposefully requires inclusion of children with disabilities or individuals with mental disabilities as research subjects, the IRB must have at least one person primarily concerned with the welfare of these research subjects."248
After evaluating schizophrenia studies at UCLA, OPRR took the stronger measure of directing the UCLA School of Medicines IRB to "engage one or more subject representatives as IRB members who will assist the IRB in the review of issues related to the rights and welfare of subjects with severe psychiatric disorders."249 OPRR issued this directive even though the IRB already had a psychiatrist and a psychologist as members.250
NBACs recommendation aims to ensure that the special concerns and knowledge of this population are represented in IRB deliberations and conveyed, as appropriate, to investigators. Persons who have suffered from mental disorders, or those who are familiar with the problems caused by these disorders, are often uniquely helpful for evaluating the potential problems posed by a specific research protocol.
Creation of a Special Standing Panel (SSP)
Recommendation 2. The Secretary of the Department of Health and Human Services should convene a Special Standing Panel (SSP) on research involving persons with mental disorders that may affect decisionmaking capacity. The panels tasks should include:
- reviewing individual protocols that cannot otherwise be approved under the recommendations described in this report, that have been forwarded by IRBs to the SSP for its consideration. If the SSP finds that a protocol offers the possibility of substantial benefit to the population under study, that its risks to subjects are reasonable in relation to this possible benefit, and that it could not be conducted without the proposed population, then the SSP may approve the protocol if it is satisfied that all appropriate safeguards are incorporated. Under no circumstance, however, should the SSP approve a protocol that reasonable, competent persons would decline to enter;
- promulgating guidelines that would permit local IRBs to approve protocols that cannot otherwise be approved under the recommendations described in this report. Such guidelines could suggest that a particular class or category of research, using specified research interventions with certain identified populations, could be considered by local IRBs without the need to resort to the SSP for further approval. Under no circumstances, however, should the SSP promulgate guidelines permitting IRBs to approve research that would enroll subjects who lack decisionmaking capacity in protocols that reasonable, competent persons would decline to enter.
The SSP should have members who can represent the diverse interests of potential research subjects, the research community, and the public. The panels protocol approvals and guidelines should all be published in an appropriate form that ensures reasonable notice to interested members of the public.
Those federal agencies that are signatories of the Common Rule should agree to use the SSP, and the SSPs effectiveness should be reviewed no later than five years after inception.
In the case of research involving greater than minimal risk that does not hold out the prospect of direct medical benefit to subjects, there may be protocols that, while not meeting the requirements of Recommendation 12 below, nevertheless may present a compelling balance of risks and benefits, and thus warrant further review. IRBs could refer such protocols to the SSP, which would review them on a case-by-case basis. Over time, the SSP could also set guidelines for entire categories of research. Once these guidelines were promulgated, protocols consistent with these guidelines could be reviewed and approved by the local IRB. In reviewing individual protocols and considering particular categories of research, the SSP should determine whether the protocol is of substantial importance, its risks are reasonable in relation to the potential benefits, and it could not be conducted without involving subjects with mental disorders. In addition, the SSP should specify (1) any special procedures or protections needed to ensure that the risks to subjects are minimized; (2) the means to maximize the informed and voluntary nature of participation, including the permission obtained from subjects LARs; and (3) the IRBs special obligations to monitor the progress of the research and the ongoing adequacy of the protection afforded subjects. The SSP should include members from among the following groups: persons with mental disorders, members of their families, advocates for the rights and welfare of this population of persons, experts in the law and ethics of experimentation, researchers, and clinicians with expertise in the area of research.
This recommendation is intended to provide some genuine flexibility for the system to respond to new knowledge and to create a greater uniformity of understanding in what is a controversial area. As stressed throughout this report, there remain certain concerns about the adequacy of protections for persons with mental disorders in research. NBAC believes, however, that with advances being made in research, and the increased sensitivity of investigators and IRBs to ethical issues arising in research involving persons with mental disorders, there will be more examples of research that promises either significant scientific benefits for persons with mental disorders or significant increases in understanding their conditions. By assessing these examples on a case-by-case basis through an open consensus process, the Secretary would have access to a gradually evolving list of research examples (including the procedures used and any special protections required). Such a process might eventually result in an informed delegation to IRBs of the authority to approve a particular class of research protocols.
NBAC believes that the SSP could provide careful and timely evaluation of controversial research protocols that could not otherwise be approved under the other recommendations in this report. As already noted, the Secretarys authority within the regulations pertaining to research with children includes a provision for a special review process, which has been rarely used. The intent of NBACs recommendation is to provide the Secretary with a more viable and flexible mechanism to address important concerns of researchers and the public: How, if at all, can potentially important research that involves greater than minimal risk and does not hold out the prospect of direct benefit to subjects be conducted on persons with mental disorders who lack decisionmaking capacity, when the very ability of the individual subjects to assess the risks of such research may be lacking? How can potential subjects and their families be assured that their rights and welfare are protected? This mechanism may provide a way forward for some protocols in this area.
II. Recommendations Regarding Research Design
Appropriate Subject Selection
Recommendation 3. An IRB should not approve research protocols targeting persons with mental disorders as subjects when such research can be done with other subjects.
One important justification for research involving those with mental disorders is the need for progress in the treatment of these very conditions. However, because of this populations potential vulnerability, we should prohibit research targeting them if that research can be conducted equally well with other subjects. At least two reasons support this prohibition. First, it is important, on grounds of justice and fairness, to discourage any tendency to engage these persons in research simply because they are in some sense more available than others. Second, this prohibition would further reinforce the importance of informed consent in human subjects research. The principles of justice and respect for persons jointly imply that IRBs should not approve research protocols targeting persons with decisional impairments due to mental disorders when the research does not, by design, require such subjects.
There are circumstances, however, under which the use of subjects without these disorders may not be scientifically valid or appropriate. For example, if the research bears directly on a disorder that underlies the subjects decisional impairment, and the disorder is commonly associated with such an impairment, then it may not be possible to learn how to improve diagnosis and treatment for that disorder without, at some stage, involving subjects who are so affected. But if the research involves new ways to protect against diseases that are also common among those who do not have mental disorders that affect their decisionmaking capacity, then individuals with impaired decisionmaking capacity should not be targeted for recruitment. To do so would be a form of exploitation.251
NBAC is not suggesting that individuals with mental disorders should be precluded from participating in research unrelated to their mental disorder. These same individuals, if they are able to consent, would be permitted, as any person would, to choose to enter a study unrelated to their condition. This recommendation is in line with current regulations, which provide additional protections to certain potentially vulnerable populations to ensure that they are not unfairly burdened with involvement in research simply because, for example, they may be more easily available.
Justifying Research Design and Minimizing Risks
Recommendation 4. Investigators should provide IRBs with a thorough justification of the research design they will use, including a description of procedures designed to minimize risks to subjects. In studies that are designed to provoke symptoms, to withdraw subjects rapidly from therapies, to use placebo controls, or otherwise to expose subjects to risks that may be inappropriate, IRBs should exercise heightened scrutiny.
The protection of human subjects begins with an ethical study design that not only ensures the scientific validity and importance of the proposed protocol (ensuring the moral acceptability of its objective) but that also minimizes risks to subjects while still allowing the study objectives to be met. This process is accomplished by a variety of approaches, including the use of prior scientific evaluation by established peer review groups and review by an IRB. In many institutions, separate scientific review precedes an IRBs assessment of a protocol. In some institutions, IRBs also ensure the scientific merit of a protocol through using their own members or outside consultants. Whatever procedure is used, investigators and IRBs must consider ways to assess how the particular proposed research protocol would affect subjects in order to determine that a protocol will incorporate appropriate protections.
Because several specific designs used in research on mental disorders have raised concerns about increased risks to subjects, whenever an ethically controversial research design is proposed, the investigators are obligated to make every effort to minimize its associated risks. In particular, IRBs should require a clear justification for studies that include symptom provocation, placebo controls, or washout periods (particularly those involving rapid medication withdrawal), and should review carefully the criteria for including or excluding individuals from a study as well as the likely reasons for subject withdrawal, and the availability of follow-up care. In such research, the researcher and the IRB have a special obligation to ensure that the subjects or their legally authorized representatives are fully cognizant of the nature of the research design and its possible consequences.
Because many decisional impairments are associated with mental disorders that can be managed symptomatically with anti-psychotic medication, it can be argued that it is unethical to include a placebo arm in the study when a known risk is the return of symptoms. Thus, some contend that new drug investigations should always use standard therapy as a control, in spite of the additional methodological difficulties of such designs.252 Relevant grounds for excluding placebo arms in particular studies include the following: (1) an individualized assessment reveals that certain patients would be at high risk for relapse if a current or prospective therapeutic regimen were discontinued; (2) a washout period would not be contemplated for these patients if they were not enrolling in a study; or (3) standard therapy has previously proven to be effective.
When drug-free research is considered necessary, it is important to control risks and to follow subjects who are at risk for relapse. IRBs currently have the authority to follow-up studies that they approve. In studies in which patients are at risk of relapse, IRBs should give particular attention to exercising this authority.
Evaluating Risks and Benefits
Recommendation 5. Investigators should provide IRBs with a thorough evaluation of the risks and potential benefits to the human subjects involved in the proposed protocol. The evaluation of risks includes the nature, probability, and magnitude of any harms or discomforts to the subjects. The evaluation of benefits should distinguish possible direct medical benefits to the subject from other types of benefits.
This recommendation reaffirms what is already in the federal regulations, with a particular emphasis on tailoring the risk assessment to the population under study. The assessment should include consideration of the particular procedures proposed and their relationship to the specific conditions of the individuals who may be involved as study subjects. IRBs should be alert to the possibility that researchers and subjects may not evaluate the risks and benefits of a particular study in the same way.
Because there has been some confusion about what the current federal regulations say about levels of risk, it must be emphasized that only the regulations relating to children, found at Subpart D of the DHHS regulations (and the comparable set of regulations in the Department of Education), refer to three levels of risk. These regulations are not part of the Common Rule (which is limited only to Subpart A), and hence are not applicable to all agencies that are signatories to the Common Rule. Under current regulations agencies, investigators, and IRBs may voluntarily choose to adopt a three-tiered approach to risk assessment, should they find it to be useful. In NBACs view, no change is needed in this component of the Common Rule, but greater attention should be given to the assessment of the nature and levels of risk by IRBs and investigators so that judgments of risk in relation to potential benefit and the level of protection provided to subjects can be more appropriately related to the risks inherent in the protocols themselves. In particular, this will be important for research in which disagreement exists about whether the risk is minimal. Although the regulations contain language that defines minimal risk, care is needed when determining whether (or how) the definitional category applies to research involving persons with mental disorders.
The risk categories in the current regulations do not automatically apply to particular procedures, but must be applied contextually in light of specific study conditions. Recently, OPRR published a revised list of the categories that may be reviewed by IRBs using an expedited review procedure.253 The need for sensitivity in the application of risk categories is especially great when persons with mental disorders are among the potential subjects of a study. For some persons with mental disorders, their limited ability to understand the rationale for a specific intervention could cause them more distress than it would someone who fully understood the reason for the intervention. For example, repeated venipunctures (blood draws), which might be innocuous to many people, could be quite disturbing to persons with limited understanding. Thus, a procedure that per se presents minimal risk could nonetheless be highly threatening to those who are unable to appreciate the procedures context or the nature of their current situation.
In particular, those who lack the practical ability to function autonomously, as in the case of institutionalized persons, may have distorted perceptions of otherwise minor interventions. Those whose treating doctor is also the researcher may feel unable to withdraw from a study and may feel more threatened by the risks of a procedure than is objectively the case. Thus, a priori assessments of risk levels to the subject population as a whole may need to be adjusted according to the circumstances of individual subjects. Even within a given protocol, the same intervention may entail different risk levels for different individuals depending on their particular condition. When the level of risk may be perceived to be higher for some subjects than for others, the determination of risk for the entire subject group should be made conservatively. Moreover, the range of special protections should increase as the level of risk increases. Both investigators and IRBs should be sensitive to different levels of risk and adjust the required set of protections accordingly. As a consequence, investigators who propose to involve persons with mental disorders as subjects in research must carefully articulate to IRBs the nature of their risk evaluation procedures for potential subjects.
III. Recommendations Regarding Informed Consent and Capacity
Informed Consent to Research
Recommendation 6. No person who has the capacity for consent may be enrolled in a study without his or her informed consent. When potential subjects are capable of making informed decisions about participation, they may accept or decline participation without involvement of any third parties.
Regardless of a diagnosis of a mental disorder, persons capable of making informed decisions cannot be enrolled in a study without their informed consent unless, of course, consent is waived under existing regulations. Indeed, nothing in this report is intended to supplant federal rules governing consent waivers, which may be granted for minimal risk research that meets certain criteria. This merely reaffirms what is already in the federal regulations. A third party, such as a relative or friend, may not override the informed decisions of capable people. This is an implication of respect for persons, including their autonomous choices. Special moral and practical difficulties may arise, however, when a persons capacity can be expected to decline, either temporarily or permanently, or to fluctuate during the period of the protocol. In such cases, IRBs should ensure that the potential subject will be offered the opportunity to appoint a legally authorized representative (LAR) to make decisions, consistent with Recommendation 14 below, if the subjects decisionmaking capacity becomes impaired or is lost. As part of an informed consent process, such potential subjects must be able to understand all the usual information about the nature and purpose of the research, the procedures involved, the reasonably foreseeable risks or discomforts, potential benefits, and other relevant items.
In addition, they should also understand that consent to participate in a research protocol constitutes an agreement to take part in a project that will occur over a specified and perhaps extended period of time, during which their autonomous decisionmaking capacity may become impaired, either temporarily or permanently. Finally, investigators should be awareand IRBs should remind themof their responsibility to provide reasonable accommodations so that persons with impairments can, if possible, make their own decisions about research participation.
It is often possible for investigators and others to enable persons with some decisional impairments to make voluntary and informed decisions to consent or refuse participation in research. Creative measures include repetitive teaching, group sessions, videotapes, computer programs, and involvement of family members, among other approaches. Of course, some potential subjects simply cannot be enabled to make their own decisions, whatever approach is used. But creative approaches should be tried because, as Paul Appelbaum stresses, "one way of protecting peoples rights and interests is to help them make decisions for themselves."254 (See also the discussion of Recommendation 8 below.)
Objection to Participation in Research
Recommendation 7. Any potential or actual subjects objection to enrollment or to continued participation in a research protocol must be heeded in all circumstances. An investigator, acting with a level of care and sensitivity that will avoid the possibility or the appearance of coercion, may approach people who previously objected to ascertain whether they have changed their minds.
Even when decisionmaking capacity appears to be severely impaired, respect for persons must prevail over any asserted duty to serve the public good as a research subject. Hence, a potential or actual subjects objection must be heeded, regardless of the level of risk or potential benefit, just as it would in the case of an individual who clearly retains decisional capacity. Respect for persons requires that we avoid forcing an individual to serve as a research subject, even when the research offers the possibility of direct medical benefit to the individual, when his or her decisional capacity is in doubt, or when the research poses no more than minimal risk. While objection must always be respected, situations may arise in which the investigator could legitimately return to the subject at a later point to ascertain whether the previous objection still stands.
Assessing Potential Subjects Capacity to Decide about Participating in a Research Protocol
Recommendation 8. For research protocols that present greater than minimal risk, an IRB should require that an independent, qualified professional assess the potential subjects capacity to consent. The protocol should describe who will conduct the assessment and the nature of the assessment. An IRB should permit investigators to use less formal procedures to assess potential subjects capacity if there are good reasons for doing so.
All potential human subjects are presumed to be capable of making decisions for themselves unless there is a particular reason to suspect that a capacity assessment will be necessary. Because of this presumption, capacity assessments are usually undertaken only when there are reasons to believe that potential subjects may not be capable of making voluntary and informed decisions about research participation. IRBs should be aware, however, that decisional impairment and incapacity may be more frequent among some people with certain mental disorders than in the general population. It is thus appropriate for IRBs to assume that capacity assessments may be needed more often in certain populations and to require investigators to explain why such assessments would be unnecessary for a particular group, especially if the research protocol poses greater than minimal risk.
Therefore, for research protocols that involve as subjects persons with mental disorders that may affect decisionmaking capacity and that also pose greater than minimal risk, NBAC believes that IRBs should generally require investigators to use independent and qualified professionals to assess whether potential subjects have the capacity to give voluntary, informed consent. As a result, investigators should provide in their research protocols a description of who will perform the assessment and what instruments they will use in doing so.
NBAC recognizes that a range of professionals may be qualified to assess capacity, and thus does not indicate which professionals should perform the assessment. NBAC also does not recommend any particular method of capacity assessment, since there is vigorous debate about methods, in part because of their different presuppositions. Instead, it recommends that investigators include in their research protocols a description of the nature of the capacity assessment that will be used as well as an indication of who will perform it. The IRB should consider, in particular, not only whether the proposed professional is qualified to perform the assessment but also whether he or she is sufficiently independent of the research team and institution. This requirement of independence is based on NBACs conviction that conflicts of interest can, in some cases, distort professional judgment, and that they should be eliminated whenever possible.
IRBs would have the discretion to permit investigators to use less formal procedures for capacity assessment when there are good reasons for doing so. Such good reasons might include considerations of feasibility; for example, no independent, qualified professionals are available in a particular area. Less formal procedures could include the ways professionals often make judgments about capacity in routine interactions.
Requiring a formal procedure for capacity assessment, administered by an independent professional, for all potential research subjects with mental disorders does not appear to be necessary. It would perpetuate an incorrect assumption about individuals with mental disorders, namely that they are incapable unless assessed as capable. In a practical sense, requiring that IRBs approve research protocols (irrespective of their risk level), only when a formal capacity assessment will be undertaken, would impose additional and unnecessary burdens on researchers. Of course, if potential subjects appear to lack capacity, their capacity should be assessed before recruiting them for participation in research protocols.
NBAC notes that for research involving only minimal risk, IRBs would, of course, have the authority to require that a particular study include a capacity assessment if there are reasons to believe that potential subjects capacity may be impaired. The value of such a capacity assessment prior to enrollment of a subject in a minimal risk study is clear: by finding a potential subject incapable of deciding about participation in such a study, investigators would then be obligated, unless there is a consent waiver, to ensure that such a person is enrolled only when permission has been obtained from an LAR in light of what that person would have chosen if he or she had been capable of making a decision.
Notifying Subjects of Incapacity Determinations and Research Enrollment
Recommendation 9. A person who has been determined to lack capacity to consent to participate in a research study must be notified of that determination before permission may be sought from his or her LAR to enroll that person in the study. If permission is given to enroll such a person in the study, the potential subject must then be notified. Should the person object to participating, this objection should be heeded.
To be found decisionally incapable and then enrolled as a subject in a research protocol on the basis of alternative decisionmaking arrangements is to have certain rights curtailed, however justifiable the curtailment may be. Thus, whenever potential research subjects are found to be decisionally incapable, investigators should notify them of this determination prior to approaching their LAR for permission to enroll them as subjects in research (in accord with the relevant recommendations below).255 Such a notification process might seem, at times, to be an empty ritual that could undermine researchers respect for the regulatory system. Nevertheless, ethical treatment of human subjects demands that this process be observed; failure to do so may deprive the subject of the right to seek review of the decision and to pursue possible judicial intervention. People deserve to know that they have been found to lack the capacity to make a decision for themselves. At a minimum, this is a gesture of respect. Furthermore, it will allow them to assent or object to participation in research. Thus, only with unconscious persons is this interaction no more than an empty ritual.
IV. Recommendations Regarding Categories of Research
Research Protocols Involving Minimal Risk
Recommendation 10. An IRB may approve a protocol that presents only minimal risk, provided that:
- consent has been waived by an IRB, pursuant to federal regulations; or
- the potential subject gives informed consent; or
- the potential subject has given Prospective Authorization, consistent with Recommendation 13, and the potential subjects LAR gives permission, consistent with Recommendation 14; or
- the potential subjects LAR gives permission, consistent with Recommendation 14.
Persons who are capable of giving informed consent may choose to participate in research protocols that present minimal risk, whatever the prospect of direct benefit. The types of risk falling into this category of minimal risk are defined by federal regulation: "the probability and magnitude of harm or discomfort anticipated in the research are not greater in or of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests."256 This report has previously examined some of the difficulties in determining minimal risk. Additional guidance can be gleaned from the recent revision to the categories of research that may qualify for expedited IRB review. For instance, it might be argued that studies involving magnetic resonance imaging now fall within the category of minimal risk because federal regulations consider it a type of research that is approvable through expedited IRB review. But NBAC stresses, as do the federal regulations themselves, that the procedures qualifying for expedited review are not to be considered minimal risk solely because they appear on this list.257 In the end, the determination that a procedure is less than, equal to, or greater than minimal risk rests with the local IRB, and it must take into account the specific conditions and vulnerabilities of the particular subject population. A flow chart describing this recommendation is found in Appendix II.
Research Protocols Involving Greater than Minimal Risk that Offer the Prospect of Direct Medical Benefit to Subjects
Recommendation 11. An IRB may approve a protocol that presents greater than minimal risk but offers the prospect of direct medical benefit to the subject, provided that:
- the potential subject gives informed consent; or
- the potential subject has given Prospective Authorization, consistent with Recommendation 13, and the potential subjects LAR gives permission, consistent with Recommendation 14; or
- the potential subjects LAR gives permission, consistent with Recommendation 14. The research must also comply with Recommendations 7, 8, and 9.
Some important research cannot be done without the involvement of persons with mental disorders and some of that research may offer the prospect of direct medical benefit to those who participate. An example is the study of dopamine receptor function and schizophrenia, for which there are currently no suitable alternative models, and which could aid the treatment of individuals participating in the study.258
No one is obligated to participate in a study, even if it may be of direct medical benefit to him or her. Therefore, in order for research in this category to go forward, (1) the potential subjects informed consent must be obtained, or (2) the potential subject must have given Prospective Authorization to participate and his or her LAR must give permission, or (3) the potential subjects LAR must give permission in accord with what that person would have chosen if he or she had been capable of deciding. Recommendations that follow, particularly 13 and 14, indicate the circumstances under which prospective authorization and LAR permission can be given. Persons have the right to object to research participation before or during the research, and their objection must be heeded, even if they gave prior consent or Prospective Authorization, the LAR gives permission, and the research offers the prospect of direct medical benefit. A flow chart describing this recommendation is found in Appendix II.
Research Protocols Involving Greater than Minimal Risk Research that Do Not Offer the Prospect of Direct Medical Benefit to Subjects
Recommendation 12. An IRB may approve a protocol that presents greater than minimal risk but does not offer the prospect of direct medical benefit to the subject, provided that:
- the potential subject gives informed consent; or
- the potential subject has given Prospective Authorization, consistent with Recommendation 13, and the potential subjects LAR gives permission, consistent with Recommendation 14; or
- the protocol is approved on the condition of its approval by the panel described in Recommendation 2, or falls within the guidelines developed by the panel, and the potential subjects LAR gives permission, consistent with Recommendation 14. The research must also comply with Recommendations 7, 8, and 9.
As the most controversial category of research involving subjects with mental disorders, research protocols that present greater than minimal risk but do not offer the prospect of direct medical benefit require special attention. Such research should be conducted only under the conditions outlined in this recommendation.
First, potential subjects who have the capacity to decide whether they want to participate in such a study cannot be enrolled without their informed consent. This condition expresses what is implied by the principle of respect for persons, including their autonomous choices.
Second, potential subjects who now lack the capacity to give informed consent may be enrolled in such research if, while capable, they gave Prospective Authorization for participation in a particular class of research and their LAR now gives permission in accord with that authorization. The requirements for Prospective Authorization and LAR permission are spelled out in subsequent recommendations, especially Recommendations 13 and 14.
The third possibility (C) is for the research protocol to pass the scrutiny of the SSP proposed in Recommendation 2or to fall within the guidelines developed by that paneland for the potential subjects LAR to give permission in accord with the conditions specified in Recommendation 14.
For (B) and (C) above, the subject must be notified of the results of a formal capacity determination and of the LARs decision to enroll him or her in research. The subjects objection to participation in the research protocol at the outset or during the research must be heeded. A flow chart describing this recommendation is found in Appendix II.
V. Recommendations Regarding Surrogate Decision Making
Recommendation 13. A person who has the capacity to make decisions about participation in research may give Prospective Authorization to a particular class of research if its risks, potential direct and indirect benefits, and other pertinent conditions have been explained. Based on the Prospective Authorization, an LAR may enroll the subject after the subject has lost the capacity to make decisions, provided the LAR is available to monitor the subjects recruitment, participation, and withdrawal. The greater the risks posed by the research protocol under consideration, the more specific the subjects Prospective Authorization should be to entitle the LAR to permit enrollment.
The principle of respect for persons, including respect for their autonomous choices, extends to their choices made while capable to cover future periods of mental impairment or incapacity. NBAC believes that one of the ways in which individuals can be respected in their choices is to provide them opportunity to express their preferences (where they have them) regarding future research participation, within certain limits.
This Prospective Authorization cannot be a "blank check" for research participation. Hence, NBAC limits valid Prospective Authorization to "a particular class of research" and then only if the potential subject, while capable, understood the "risks, potential direct and indirect benefits, and other pertinent conditions" of this particular class of research. Furthermore, the degree of specificity of the Prospective Authorization should correlate with the level of risk of the research protocol for which the person is a potential subject: as the research protocols level of risk rises, so must the degree of specificity of the prospective authorization before the LAR may legitimately grant permission for research participation.
Finally, the prospective authorization is not by itself valid for enrollment in research. It must be accompanied by the LARs permission and availability for monitoring. The conditions for the LARs permission are further specified in Recommendation 14.
Legally Authorized Representatives (LARs)
Recommendation 14. An LAR may give permission (within the limits set by the other recommendations) to enroll in a research protocol a person who lacks the capacity to decide whether to participate, provided that:
- the LAR bases decisions about participation upon a best estimation of what the subject would have chosen if capable of making a decision; and
- the LAR is available to monitor the subjects recruitment, participation, and withdrawal from the study; and
- the LAR is a person chosen by the subject, or is a relative or friend of the subject.
Currently, 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. Sometimes it is appropriate for the LAR to give permission for a currently incapable person to be enrolled in a research protocol. This recommendation sets forth the basis on which the LAR should grant or withhold such permission; the requirement that the LAR be available to serve as monitor during the research; and some limits on who may serve as an LAR.
The standard for LAR decisions should be what the potential subject would have chosen if they had been capable of making a decision. Often called "substituted judgment," this standard requires that the surrogate decision maker, the LAR, make a decision according to his or her "best estimation" of what the subject would have chosen. Where the potential subject made a Prospective Authorization, the LAR can be more confident about conveying what he or she would have chosen. And, in accord with Recommendation 13, as the level of research risk increases, it is important that the Prospective Authorization be more specific. In the absence of a Prospective Authorization, the LAR must rely on other sources of information about the potential subjects values and preferences. Where the LAR lacks any evidence about the persons values and preferences, the LAR may not grant permission to investigators to enroll him or her in research unless judgments about that persons "best interests" could warrant such permission. Great caution is needed, however, because LARs also may succumb to the therapeutic misconception, and, in the absence of information about the subjects values or choices, make inappropriate judgments about the subjects best interests.
Another necessary condition (B) is the LARs availability for appropriate involvement with the research subject through the process of recruitment for participation in and withdrawal from the research protocol. If the LAR is not available for such a role, then his or her permission to enroll the potential subject in research should not be accepted.
Finally, the LAR should be someone selected for this role by the potential subject or "a relative or friend" of the potential subject, as authorized by state law or institutional rules. Ideally, the LAR should be chosen by the potential subject. Potential subjects are often able to select their LARs even when they lack the capacity to make a voluntary, informed decision about research participation or a Prospective Authorization for research participation. If the LAR is assigned by state law or institutional rules, rather than selected by the potential subject, investigators should rely on that LARs permission only if he or she is a relative or a friend of the potential subject. Such a relationship may increase the likelihood that the available LAR will in fact conscientiously "monitor the subjects recruitment, participation, and withdrawal from the study" as well as being "available" to do so.
Expansion of the Category of Legally Authorized Representatives and of the Powers Granted under Statutes for Durable Powers of Attorney (DPA) for Health Care
Recommendation 15. In order to expand the category of LARs:
- an investigator should accept as an LAR, subject to the requirements in Recommendation 14, a relative or friend of the potential subject who is recognized as an LAR for purposes of clinical decision making under the law of the state where the research takes place.
- states should confirm, by statute or court decision, that:
Recommendation 16. States should enact legislation, if necessary, to ensure that persons who choose to plan for future research participation are entitled to choose their LAR.
Although their scope varies considerably, statutes in 36 states and the District of Columbia authorize surrogates (without need of judicial appointment) to make health care decisions when a person lacks decisionmaking capacity. In the other states, custom recognizes family members as surrogates. Most statutes relating to substitute decision making do not explicitly refer to research, although they may be construed as implicitly authorizing surrogate consent for participation in research that holds out the prospect of direct medical benefit. NBAC is not aware of any state statutes that authorize a third party to enroll an incapable person in research that does not offer the prospect of direct medical benefit, even if the risk is minimal. In addition, every state recognizes the DPA for health care or an equivalent proxy designation mechanism. As is true of laws relating to substitute decision making, no state statutes authorize a proxy designated under a clinical DPA to consent to the patient-subjects participation in research that does not hold out the prospect of direct benefit to the subjects.
Although NBAC does not endorse the idea of authorizing third parties to enroll incapable subjects in research involving greater than minimal risk without the prospect of direct medical benefit, it is undoubtedly true that matters related to proxy decision making are ordinarily the province of state law, and principles of federalism suggest that deference be given to these state policy judgments. Here, however, each state has already decided to give clinical decisionmaking authority to these proxies. It would do no violence to state prerogatives if, for the reasons stated in this report, the federal government were to extend the authority of these proxies so that they could grant permission for participation in certain federally conducted or funded research. This could be accomplished by an amendment to the Common Rule that would define the term "legally authorized representative" to include those who, under the law of the state where the research is conducted, may serve as proxy decision makers for clinical care. Without Prospective Authorization, the authority of the LAR to enroll subjects would, however, extend only to minimal risk research or research involving greater than minimal risk where there is a prospect of direct medical benefit. Where research involves greater than minimal risk and does not hold out the prospect of direct medical benefit, and where the protocol has not been approved by the panel described in Recommendation 2, the authority of the LAR would extend only to permitting continued enrollment, withdrawing the subject, or enrolling the subject pursuant to the subjects Prospective Authorization.
Involving Subjects Family and Friends
Recommendation 17. For research protocols involving subjects who have fluctuating or limited decisionmaking capacity or prospective incapacity, IRBs should ensure that investigators establish and maintain ongoing communication with involved caregivers, consistent with the subjects autonomy and with medical confidentiality.
This report has stressed several times the important role of "involved caregivers," especially family members. Communication between these caregivers and the research team may be important in the relationships between both parties and the research subject. It may, for example, enable involved caregivers to respond more appropriately to the subjects particular needs, some of which may be affected by participation in the research protocol, and it may provide researchers with helpful information about the subjects responses during the research. Such communication should, of course, be limited by the ethical and legal requirements of respect for personal autonomy and medical confidentiality. Concerned parties, including professional and patient/family organizations, should begin discussions about ways to improve communication while, at the same time, respecting subjects choices about confidential information.
VI. Recommendations Regarding Education, Research, and Support
Reviewing and Developing Educational Materials Regarding Research
Recommendation 18. Professional associations and organizations should develop (or review their existing) educational materials pertaining to research involving persons with mental disorders to ensure that they are adequate to inform the health care community and the public of ethical issues related to the involvement of such persons as research subjects, and to convey the importance of measures to ensure that their rights and welfare are adequately protected.
A serious commitment to ethical research must be maintained at all levels of the research endeavor. Educational outreach through public and private organizations can serve as a valuable tool for ensuring the continuation of this commitment in the field. Agencies should develop educational materials on research ethics for IRB members and investigators involved in research with persons who have mental disorders. These materials should emphasize that many persons with mental disorders have the capacity to make decisions for themselves. NBAC further supports the development of educational materials to assist the general public (specifically populations of personsand their familieswho may encounter difficulties with decisionmaking capacity) in deciding about research participation. These materials should include information about risks and potential benefits of participation, and should offer guidelines for making informed choices about research participation (e.g., how to protect oneself as a research subject, what questions to ask, who to ask). NBAC recommends that all materials be circulated widely in order to encourage a more general public dialogue regarding the social and scientific issues engendered by research in this field.
Expanding Knowledge about Capacity Assessment and Informed Consent
Recommendation 19. The National Institutes of Health (NIH) should sponsor research to expand understanding about decisionmaking capacity, the best means for assessing decisionmaking capacity, techniques for enhancing the process of informed consent, and the possible roles of surrogate decision makers in research. It should sponsor research to evaluate the risks of various research interventions, and the attitudes of potential subjects toward the prospect of participating in research. Particular attention should be paid to attitudes toward participating in research of greater than minimal risk that does not offer the prospect of direct medical benefit to subjects. These data may be of particular value to the panel described in Recommendation 2.
The NIH should ensure that proposals for training grants and center grants include appropriate provisions for training and technical assistance in the issues discussed in this report. Where appropriate, NIH and OPRR should consider using consensus development conferences or workshops to advance discussion of these issues.
NIH has been active in sponsoring research on informed consent,259 in supporting training opportunities and grants for courses in research ethics, and in sponsoring a helpful meeting on the subject of research involving persons of questionable capacity, which has been extensively referenced in this report. In NBACs view, NIH is ideally positioned to support further intensive research on many of the issues identified in our report.
Institute of Medicine Review of Research Studies
Recommendation 20. The Department of Health and Human Services should contract with the Institute of Medicine (IOM) to conduct a comprehensive review and evaluation of the nature and extent of challenge, washout, and placebo controlled studies with subjects with mental disorders that may affect decision making.
Recommendation 4 requires investigators to submit a "thorough justification" of their research design and IRBs to exercise "heightened scrutiny" when examining research protocols that involve drug challenges, drug washout, and placebo controls. It would be helpful to investigators, IRBs, and the SSP to have comprehensive data available about the extent of research involving these designs, the actual and potential contributions of research using these designs, the medical conditions of the persons who are commonly recruited, and the process of obtaining informed consent or permission (including the use of consent forms). Data about symptom provocation and washout studies are needed, because these are controversial designs for which few data are currently available. Moreover, NBAC heard the greatest expression of concern from the public about these designs. Since NBAC does not have the resources or authority to conduct a comprehensive study, a focused effort by the IOM would be very valuable. The proposed review and evaluation should also include placebo-controlled research, about which there is also considerable controversy, especially when effective treatments are available for some disorders.
Increased Funding to Support Necessary Protections of Human Subjects
Recommendation 21. Compliance with the recommendations set forth in this report will require additional resources. All research sponsors (government, private sector enterprises, and academic institutions) should work together to make these resources available.
Several recommendations, for example, the requirement for independent capacity assessment and the establishment and use of additional review procedures, may require funds over and above the direct and indirect costs usually provided through federal grants. In NBACs view, these additional protections are necessary, and important research should not be thwarted because the resources are not available to provide the necessary protections.
Additional Guidance for IRBs
It will take time for the regulatory recommendations listed above to be considered, further evaluated, and perhaps implemented in whole or in part. Meanwhile, NBAC hopes that individual IRBs will adopt, on a voluntary basis, the spirit and substance of many of the additional protections described above. Those IRBs that choose not to adopt such policies should consider publicly disclosing their reasons and the resulting differences in their policies.260
The Research Context
IRBs should further consider whether the particular context of a proposed research protocol would tend to undermine the capacity of persons with mental disorders to provide informed consent due to their psychosocial vulnerability or to their misconception of therapeutic efficacy. IRBs should be alert to potential conflicts arising from the dependence that in-patient or continuing-care subjects may have on their institutions, or from the dual role played by the potential subjects physician as a member of the research team (e.g., as a recruiter or as a source of names of potential subjects).
Considerations in Research Design
Subjects with serious illnesses are often more vulnerable than others to exploitation when they are involved in randomized clinical trials. Although the study itself must satisfy the condition of clinical equipoise, and may offer the prospect of direct medical benefit, there will be instances in which the experimental arm of a study turns out to be more beneficial to subjects than the placebo arm (or standard care). One way to ameliorate this problem is to incorporate into the study design a non-research or "wraparound phase" which, following the conclusion of the research period, could provide the subject with some beneficial intervention independent of the study itself. Using such a wraparound phase can be problematic, however, because it may shift the balance of protection in the opposite and equally problematic direction by providing an inappropriate incentive to participate in studies, that is, to derive perceived benefits without having to pay for the treatment. Nevertheless, wraparound phases are suitable follow-ups to certain kinds of research, including those that provoke symptoms. In appropriate circumstances, IRBs could require a wraparound phase as part of the overall study design.
Subjects who are included in study arms in which they receive an experimental drug are also vulnerable to unfair treatment if the research results indicate that the drug is effective, but the subjects do not receive it after the study concludes. In such circumstances, IRBs could condition study approval on the manufacturers commitment to continue to supply the medication to research participants (including any subjects, such as placebo or standard therapy controls, who did not receive it during the study). Here again, such a condition would have to be considered carefully in view of its potential for inappropriate inducement.
Possible Additional Protections for the Consent Process
The use of a consent auditor has been suggested as an additional procedural protection in the recruitment of research subjects who may be decisionally impaired. A consent auditor, who cannot be a member of the study team but may be, for example, a member of the IRB or an institutional ethicist, witnesses the consent process and then either certifies it as valid or informs the principal investigator that, due to the inadequacy of the process, an individual is not able to give valid consent. IRBs could require consent auditors for potential subjects who have conditions often associated with a decisional impairment. A system of audited consent would involve a substantial investment by research institutions, but the requirement could be limited to studies that have certain characteristics, such as those that involve greater than minimal risk and/or those that do not offer the prospect of direct medical benefit to the subject.
In addition, studies with subjects who are decisionally impaired may take place over extended periods. One of the essential conditions of ethical research is the subjects continued voluntary participation, but those who are deeply involved with and dependent on the health care system may feel unable to withdraw from a study. A requirement for periodic re-consenting would help ensure that a patients continued involvement is truly voluntary, would provide the occasion to reassess decisionmaking capacity and, if necessary, would trigger an advance directive or surrogate arrangement. Re-consent arrangements conform with the spirit of informed consent as a process rather than a single event, and with the view that human research participants are partners in the study process rather than passive subjects.261
Although re-consenting is another potentially labor-intensive measure that might add to the cost and complexity of the human research system, some long-term studies supported by the National Institute on Aging already include such a procedure.262 IRBs should consider attaching a re-consent requirement to certain studies based on their length, on their risks and benefits, and on the potential decisional impairment of persons participating as subjects, such as those with progressive neurological disorders or fluctuating capacity.
Further Considerations about LARs
In NBACs view, an LAR ideally should be appointed by the potential subject. As the above recommendations reflect, the twin goals of appropriate protection of subjects and the conduct of high-quality research can often be accomplished by utilizing a carefully described advance planning process. Anticipatory planning for research participation is not a "research advance directive" but a version of the standard informed consent process. A critical difference between the planning and informed consent process is that the planning process should include the prospect of a loss of decisionmaking capacity during the study period, a consideration that is not routinely part of an informed consent process. Planning for research participation should involve the following elements: (a) the identification of an LAR; and (b) the completion of a DPA document, which identifies the person designated as an LAR, and provides any specific and relevant information that would assist the LAR in making research decisions on behalf of the subjects should they later become incapable of deciding about research participation on their own.
For persons with fluctuating capacity and those who are at risk for loss of capacity during a study, NBACs view is that comprehensive anticipatory planning for research participation should involve identifying an LAR who can function as a surrogate decision maker. There is always the possibility that unanticipated incidents will occur in a research study, incidents that a surrogate may find relevant to the subjects continued welfare and his or her participation in research. The surrogate could be an informal caregiverfor example, a family member or close friendbut not a member of the study team. Because of its concern that LARs could, at times, have some significant self-interest in enrolling a now incapable person into a study, NBAC recommends that IRBs request documentation of the designation of the LAR.
In such anticipatory planning, the potential subject must understand that he or she has appointed an LAR as a surrogate to make decisions concerning continuing research participation in a particular class of research protocols should the subject become unable to make these decisions. The subject must further understand that the LAR may never overrule the subjects wish not to participate in the research protocol or in any part of it, but may overrule the subjects instructions to continue participation, under certain conditions. Potential subjects must be aware that they have given the researchers permission to provide their LAR and their health care provider with information about treatment. They should also appreciate that, should their preferences change, they may alter their instructions at any time they have the capacity to do so, and that they may withdraw from the study at any time, whatever their level of decisionmaking capacity.
In turn, the researchers should agree to discuss information about the research site and the subjects treatment in the study (e.g., possibilities of decompensation, description of likely symptoms, data about medications and potential side effects, and possible danger to self or others) with the LAR. The research team should also make adequate provision for a thorough diagnostic assessment of the subjects current clinical status and develop an appropriate continuing treatment plan should the subject decompensate, become unable to cooperate, and drop out of the study.
During the course of the study, it is highly desirable for the subjects LAR to work closely with the subjects independent health care professional to ensure the subjects welfare. This health care professional should have no relationship with the research and, therefore, should be concerned only with subjects well-being and interests, should follow the subjects treatment, and should be in communication with the surrogate.
Independent Health Care Professional Advisors
For greater than minimal risk research, whether or not direct medical benefit is possible, IRBs should consider whether to require that an independent health care professional be identified in advance of the research to serve as a consultant to the subject or their representative. Subjects or their LARs may or may not choose to utilize the independent health care professional. Investigators should consider making available or accessible (to the subject or the LAR) any information the independent health care professional requests in relationship to the protocol.
IRBs may consider, alone, with other IRBs, or in collaboration with professional organizations, voluntarily adopting NBACs recommendations and then, after a suitable period of time, assessing their effect on the quality of the IRB review process. For example, since there has been considerable discussion in this report about the appropriateness of using two levels of risk in IRB review, it might be worthwhile to review protocols using this strategy, as compared with a strategy in which three (or more) risk levels are explicitly used. Where this evaluation is conducted in a more formal manner, the results could be published and shared with the IRB and research communities.
Guidance for Institutions
While investigators and IRBs bear a considerable responsibility for ensuring the ethical conduct of research involving human subjects, the institutions in which research occurs share some of this responsibility. In particular, since federal grants are awarded to institutions, not individual investigators, and since an Assurance of Compliance is negotiated between an institution and OPRR, the behavior of institutions may be thought of as the foundation upon which ethical practice is built.
Audit and Disclosure
The policies of IRBs and the institutions they serve play a central role in protecting human subjects, particularly vulnerable populations. Thus, IRBs should consider voluntarily undertaking a series of measures to open their activities to greater public view and accountability. In this regard, NBAC makes the following general recommendations.
It is NBACs view that IRBs can effectively use the mechanisms of audit (both internal and external) and disclosure to improve accountability and inspire public confidence in their oversight activities. Indeed, these oversight tools can be an excellent substitute for a wide variety of excessively detailed rules and regulations. Furthermore, such mechanisms can be used by all institutions, for all research involving human subjects.
243 The conclusions and recommendations directly address research that involves adult patients or subjects in research. They do not supplant the regulations governing research involving children.
244 Expert Panel Report to the National Institutes of Health, Research Involving Individuals with Questionable Capacity to Consent, 1.
245 Expert Panel Report to the National Institutes of Health, Research Involving Individuals with Questionable Capacity to Consent, 3.
246 45 CFR 46.107(a) (1998).
247 45 CFR 46.107(f) (1998).
248 34 CFR 356.3(c)(2) (1998).
249 Office for Protection from Research Risks, supra, 2122.
251 An individual with impaired decisionmaking ability who, for any reason, is not otherwise an appropriate subject for a particular protocol may have a life-threatening condition for which there is no satisfactory treatment. Under these circumstances, when the protocol is designed to ameliorate or potentially cure the life-threatening condition, current regulations permit these individuals, on compassionate grounds, to obtain the investigational treatment. Therefore, as a matter of justice, all persons, regardless of their decisionmaking capacity, whose best therapeutic alternative may be an innovative treatment, should have access to that treatment. The specific term used in the regulations is "treatment use." Criteria for "permitting an investigational drug to be used for treatment use under a treatment protocol or treatment IND" are: "(1) FDA shall permit an investigational drug to be used for a treatment use under a treatment protocol or treatment IND if: (i) The drug is intended to treat a serious or immediately life-threatening disease; (ii) There is no comparable or satisfactory alternative drug or other therapy available to treat that stage of the disease in the intended patient population; (iii) The drug is under investigation in a controlled clinical trial under an IND in effect for the trial, or all clinical trials have been completed; and (iv) The sponsor of the controlled clinical trial is actively pursuing marketing approval of the investigational drug with due diligence." 21 CFR §312.34(b) (1998).
252 Donald Addington, "The Use of Placebos in Clinical Trials for Acute Schizophrenia," Canadian Journal of Psychiatry 40 (1995): 17176; Kenneth J. Rothman and Karin B. Michels, "The Continued Unethical Use of Placebo Controls," New England Journal of Medicine 331 (1994): 39498.
253 See, Categories of Research That May Be Reviewed by the Institutional Review Board (IRB) Through An Expedited Review Procedure, 63 Fed. Reg. 60,364 (1998) (to be codified at 45 CFR 46).
254 Paul S. Appelbaum, "Missing the Boat: Competence and Consent in Psychiatric Research," American Journal of Psychiatry 155 (1998): 148688, 1488.
255 Another way to express this issue is whether the assent of incapable subjects should be required. Rebecca Dresser, Research Involving Persons With Mental Disabilities: A Review of Policy Issues and Proposals (contract paper for the National Bioethics Advisory Commission, September 1997). See volume II of this report.
256 45 CFR 46.102(i) (1998).
257 45 CFR 46.110(b)(1) (1998).
258 See, for example, Anthony F. Lehman et al., "Translating research into practice: the Schizophrenia Patient Outcomes Research Team (PORT) treatment recommendations," Schizophrenia Bulletin 24 (1998): 110.
259 See for example: Informed Consent in Research Involving Human Subjects, NIH Guide to Grants and Contracts, RFA-OD-97-001, vol 25, no. 32. (September 27, 1997).
260 NBAC is currently reviewing the federal system for overseeing human subjects protection, including the IRB system, and will issue a separate report on this subject. For this reason, this report offers only a few additional areas of guidance for IRBs; other, more comprehensive, recommendations for IRBs will appear in this later report.
261 An expert panel convened by NIH also notes that "repeated exposure to information in small doses over time may greatly improve comprehension." Expert Panel Report to the National Institutes of Health, Research Involving Individuals with Questionable Capacity to Consent, 14.
262 One such example is the Baltimore Longitudinal Study of Aging (BLSA). The protocol for reconsenting participants was described to NBAC as follows: "At this time, competency evaluations are done by a working group in the Laboratory of Personality and Cognition composed of Susan Resnick (NIA neuropsychologist), Claudia Kawas (a collaborating neurologist from JHMI), Jeff Metter (physician), and if necessary Chester Schmidt (Chief of Psychiatry at JHBMC). Each BLSA participant has a baseline cognitive assessment done upon entry to the study. Cognition is not formally assessed by serial determinations until participants are 55 years of age when most patients undergo the cognitive battery administered by the Cognition Section of LPC. Once patients enter this phase of the study, their test results are reviewed and if substantial loss of cognitive function is suspected the participant and his/her records (medical and psychometric) are reviewed by Drs. Resnick, Kawas, and Metter. At this time, Dr. Kawas performs a formal neurological evaluation to determine a medical cause of the cognition decline. In the case in which affective disorders are suspected, Dr. Schmidt will be consulted. Family members are immediately involved in the status of the evaluation and if competency is judged to be impaired, family members are asked to provide consent for further participation if the patient is agreeable and the family members believe that participation is in the interest of the patient. Since the BLSA is an observational study, not an interventional clinical one, issues of study-related risks (morbidity and mortality) have not been raised in terms of greater than minimal risk. Personal communication, Dr. Terrie Wetle, Deputy Director, National Institute on Aging, July 2, 1998.
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