Advance Planning, |
For those whose decisionmaking capacity is impaired, truly informed consent may not be achievable but it remains the standard against which all efforts to obtain the ethical participation of individuals in research must be judged. While some persons with mental disorders are incapable of giving valid informed consent to participate in a research protocol, ethically acceptable research involving such persons is quite possible under appropriate circumstances and with special protections. In considering the special conditions that surround study design and consent processes in such cases, it is important to involve human subjects in the consent process as fully as possible given their individual circumstances. NBAC agrees with the National Commission’s conclusion in the Belmont Report that respect for persons unable to make a fully autonomous choice "requires giving them the opportunity to choose, to the extent they are able, whether or not to participate in research."126 In this vein, NBAC recognizes that certain opportunities already exist for maximizing subject choice in research, including the designation of appropriate substitute decision makers. It also recognizes that sensitivity and care must be exercised in establishing policy, lest blanket authority be given to enroll subjects in research without due consideration to their rights and interests.
This chapter discusses three mechanisms which have been proposed or used to enroll human subjects in research protocols, even if they are presently unable to give valid informed consent. These mechanisms are: (1) the use of assent or the lack of objection; (2) the use of advance planning and surrogate decision making; and (3) the use of legally authorized representatives (LARs).
The Role of Assent and Objection
The National Commission held that, under specified conditions, researchers could obtain assent to research participation from subjects incapable of independent decision making and, on the basis of this assent, enroll them in certain minimal risk studies. In its view, persons are capable of assent if they "know what procedures will be performed in the research, choose freely to undergo those procedures, communicate this choice unambiguously, and [know that they] may withdraw from participation."127 It defined assent as an authorization given by a person "whose capacity to understand and judge is somewhat impaired by illness or institutionalization, but who remains functional."128 In defining assent in this way, the National Commission explicitly acknowledged that full knowledge of all the risks involved in a particular protocol is not absolutely necessary to enroll subjects in certain minimal risk protocols if they choose freely to participate. In NBAC’s view, mere assent, however useful, is insufficient to enroll a subject in a research protocol.
Not all individuals who lack full decisional capacity can provide assent as defined by the National Commission, though some may satisfy certain elements of the standard.129 One question is whether the physical or verbal indications of persons deemed incapable of assent should be considered in research decision making. A related question is "whether the failure to actively object to participation in a protocol is enough to be interpreted as a tacit or implied form of assent or whether some more affirmative agreement is necessary."130 According to the National Commission, "mere absence of objection" ought not be interpreted as assent,131 and it recommended requiring the consent of a potential subject’s legal guardian to authorize greater than minimal risk research involving non-objecting persons incapable of assent.
Objection is also an important concept concerning persons’ involvement in research, regardless of their decisionmaking capacity. The National Commission also referred to a subject’s objection to participation, but it did not clearly define objection.132 The National Commission held that an incapable subject’s overt objection to initial or ongoing participation should preclude research involvement unless: (1) the study offers the subject a prospect of direct benefit and a court specifically authorizes the subject’s participation, and (2) the prospective benefit is available only in the research context.133 In addition, the National Commission recommended procedural mechanisms to apply these substantive provisions. In particular, it recommended the following: (1) IRBs should have discretion to appoint an independent auditor to verify the subject’s assent or lack of objection; (2) independent auditors should be required to monitor the incapable subject’s initial and ongoing assent in research presenting greater than minimal risk and no prospect of direct benefit to subjects; and (3) subjects should be removed from the study if they object at any time to this category of research.
Recent commentary generally supports a requirement for subject assent or, at a minimum, lack of objection, except in the unusual case when research participation offers the subject the possibility of direct medical benefits not otherwise obtainable in the clinical setting.134 Yet not all commentators agree that potential direct medical benefit should be sufficient to override the resistance (whether verbal or behavioral) of persons lacking decisional capacity regarding research participation. A Canadian group considering research involving persons with dementia recently noted:
Faced with an objection by a patient of impaired capacity, the justification advanced for nevertheless imposing the investigational intervention is that it holds out the prospect of direct (therapeutic) benefit. However, it is normally not legitimate to impose even established therapy on a patient refusing it. The case for proceeding may be stronger regarding the incompetent . . . patient who objects, but it is difficult to equate an intervention which is investigational in nature—whatever its potential for direct (therapeutic) benefit—with an intervention "which would be ordered in a purely therapeutic context."135
This group therefore was "not fully persuaded" that potential direct benefit provides an ethical justification for compelling an objecting person’s research participation. In this group’s view, this "is at best a position in need of further debate."136 The intermediate appellate court in the T.D. case (discussed in Appendix I) labeled as constitutionally deficient New York’s provision allowing the involvement of objecting incapable subjects in research protocols that hold out the potential of direct medical benefit, because the state regulations failed to provide them or their representatives notice and an opportunity to challenge such involvement.137 Although the constitutional portion of the judgment was eventually set aside by the Court of Appeals, these same provisions would not only be ethically objectionable according to the strict Nuremberg principle, among others, but would also continue to be legally suspect. The legislative proposal currently being developed in Maryland would bar investigators from conducting research with a decisionally incapable individual who expresses disagreement with, or who refuses to perform an action related, to the research.138
NBAC believes that once persons become part of a research study, they must always have the freedom to withdraw at any time without prejudice and without regard to their capacity. It is persuaded, however, that even in this case it is not necessary to always interpret such objections as permanent. To do so might unnecessarily limit research and fail to accomplish the goal of protection. The following example illustrates this view: consider a study involving certain patients with dementia, in which the only invasive intervention in an otherwise noninvasive long-term study is a single blood draw. Recognizing that some subjects may become irritable and object to this procedure—perhaps by recoiling from the needle—this objection, which must be heeded, should not necessarily be interpreted as an objection to continued participation in the entire study. Certainly the subject has objected to this portion of the study at this time. And, as previously noted, this objection must be heeded. Moreover, the researcher who would persist and attempt to take the blood would be acting illegally—by possibly committing battery—and unethically—by crossing the boundary from voluntary choice to coercion. However, after a reasonable amount of time, the researcher in this study should not be absolutely prohibited from returning to the person and ascertaining, with appropriate sensitivity, his or her willingness to now give blood. It is important to recognize and emphasize that the line between ascertaining a person’s willingness and badgering a person is not always clear.
The Role of Advance Planning and Surrogate Decision Making
Our society has long accepted the idea that people who have the capacity to decide their affairs should also be able to direct at least some aspects of their future as well. So, for example, the law of trusts and wills allows a person to control the disposition of property even after death. In addition, individuals may anticipate the consequences of a possible period of disability by designating someone, by means of a durable power of attorney (DPA), to handle their business and financial affairs during such a period. Over the past two decades, these advance planning concepts have been widely accepted in clinical medicine.
One can identify three types of anticipatory decision making in the clinical setting. The first might be called a projection of informed consent: a competent person’s decision whether to accept or decline a specific future treatment, made now because the person will or may be decisionally incapacitated when the treatment decision is to be implemented. A commonplace example is a patient’s decision whether to have immediate surgery should a biopsy reveal a malignancy. As a result of anesthesia, the patient would be incapable of informed consent when the decision actually presents itself. Yet the patient’s anticipatory decision, made prior to the biopsy, is no less an exercise of informed consent. This type of decision making about discrete, future clinical contingencies likewise occurs when a person fills out a "living will," the original advance directive document. The typical "living will" is an instruction that describes the specific end-of-life interventions a patient would want to have used (or not used) in the event of a terminal prognosis. Despite the difficulty in meshing this kind of instruction with what is often a more complex clinical situation, a "living will" nevertheless can serve as a self-executing embodiment of the person’s right to decide about these interventions.
The second type of anticipatory decision might be called a projection of personal values, rather than a projection of informed consent. Instead of making a treatment-specific decision meant to bind clinicians in the future, a person provides guidance for decision makers by emphasizing the comparative importance of different aspects of that person’s life. For example, a person might state in an advance directive his or her own view of what constitutes a life of sufficient quality to warrant the most aggressive treatment. This guidance would inform whoever was later deciding on a course of treatment after the person had lost the capacity for informed consent.
The third type of anticipatory decision might be called a projection of personal relationships. Just as someone may entrust another with responsibility for financial matters during a potential period of future disability, a person may designate a decision maker for health care matters. The legal instrument by which this designation is accomplished, the DPA for health care, has become a familiar feature of the clinical landscape. A recent study found about a 9 percent usage rate among residents of nursing homes in several states.139 This designation reflects trust in the integrity, judgment, and decision-making capacity of the chosen proxy. Of course, the designation can also be coupled with instructions or guidance about the choices that the proxy might face. Because giving effect to all three types of anticipatory decision making embodies respect for personal autonomy, NBAC believes that all three have a place in research involving persons with mental disorders.
First, a person who has given a valid informed consent to enroll in a particular research protocol should be allowed to continue to participate in that protocol, even after a loss of capacity, or in a future iteration of that or a substantially similar protocol (i.e., including similar procedures and similar risks) provided that suitable measures are in place to protect the person’s welfare during that research study. Second, a person who embodies in an advance directive his or her wishes about participation in research of certain kinds is entitled to have those wishes respectfully considered. However, this kind of advance directive, which does not reflect consideration of specific types of research risks, cannot itself serve as a self-executing instrument of informed consent or trump limitations on research participation that sound public policy requires. It also does not absolve the investigator and surrogate decision maker of responsibility for assessing the effect on the person’s welfare of participation in a particular research protocol. Third, a person may embody in an advance directive his or her choice of a decision maker concerning research participation. NBAC recognizes that people use advance directives to identify others with whom they have a relationship of trust. NBAC concludes, however, that this relationship in and of itself is sufficient to authorize participation in research studies only under certain conditions.
This summary account of the role of advance decision making in research is not intended to gloss over several important issues, such as whether advance directives can be adequately informed, how to safeguard a subject’s right to withdraw from research, and whether anticipatory decision making is a morally defensible basis for permitting otherwise prohibited levels of risk and burden in research involving incapable subjects.
The concept of advance research decision making was initially considered in the 1980s. In his volume on clinical research, Robert Levine discussed the "research living will" as an avenue for capable persons to authorize their future research involvement if they become incompetent.140 In 1987, the NIH Clinical Center formally adopted a policy, which is currently under review, in which persons "who are or will become cognitively impaired" are asked to complete a DPA document appointing a surrogate research decision maker.141 Such decision makers may authorize an incapable subject’s participation in research presenting greater than minimal risk that offers the prospect of direct benefit to subjects. In such cases, an ethics consultation is conducted to verify the decision maker’s capacity to understand information relevant to the research decision. If no DPA exists, the consent of a court-appointed family guardian is required. Research presenting greater than minimal risk is not permitted for subjects lacking a DPA or court-appointed guardian, except in a medical emergency when a physician may give therapy, including experimental therapy, if in his or her judgment it is necessary to protect the patient’s life or health.
In 1989, the American College of Physicians (ACP) gave qualified endorsement to instruction and proxy mechanisms permitting competent persons to register advance consent to research. According to the ACP, investigators seeking advance consent would be required to disclose to the competent person the usual information on a study’s purpose, methods, risks, and potential benefits. Moreover, the ACP recognized a need for greater caution regarding advance research decisions than advance treatment decisions:
In nonexperimental care, advance directives are generally used by patients to indicate their intent to refuse procedures . . . which they believe will be contrary to their interests. Respect for autonomy creates a strong presumption for adherence to instructions for nonintervention. In contrast, advance directives for research purposes would authorize interventions that do not benefit the subject in the case of nontherapeutic research, or that may not benefit the subject in the case of therapeutic research.142
Accordingly, the ACP took the position that research advance directives "may be abrogated if it is later determined that the proposed research would unduly threaten the subject’s welfare."143
Despite these cautions and restrictions, the ACP deemed an incapable subject’s prior consent an acceptable basis for allowing that subject’s involvement in higher risk research than is permitted for other incapable subjects. Its position paper states that incapable subjects who have given only informal instructions to a surrogate decision maker about their research preferences should not be involved in research of greater than minimal risk that offers no prospect of direct medical benefit. In contrast, subjects with formal advance directives may be involved in such studies, as long as the above limitations are observed. NBAC is sympathetic to this general approach; but as discussed below and in the recommendations, it supports the idea of advance planning and the appointment of substitute decision makers for research on mental disorders, not the direct use of advance directives as a self-sufficient basis for research enrollment.
In light of these various possibilities, many commentators agree that a third-party decision maker should be appointed to withdraw the subject from a study if previously unrecognized risks and burdens become apparent.144 They differ, however, on the standard that third parties should apply when exercising the subject’s right to withdraw from the research that the subject previously authorized. Some favor withdrawal only when the factual circumstances become materially different from those to which the individuals agreed in directives.145 Others contend that withdrawal should also occur if it becomes apparent to others that research participation threatens the incapable subject’s welfare. According to this position, a research proxy’s or surrogate’s:
obligation to respect the person’s prior wishes is limited by the obligation to protect the person. The function of the [third party decision maker] is to promote what subjects think are their best interests, which necessarily excludes consenting to being intentionally harmed or to being unreasonably exposed to the risk of harm.146
An intermediate position argues that an advance directive should be overridden if "no direct benefit is anticipated for the subject and it becomes apparent that enrollment or continued participation would seriously endanger that subject’s welfare to an extent not foreseen by the subject, or even if foreseen, to an extent judged by the substitute [decision maker] to be socially or morally unacceptable."147
Underlying this dispute is a disagreement about the appropriate scope of a capable person’s advance consent to research. Commentators are divided on whether policy should permit an incapable subject to be exposed to otherwise impermissible levels of research risks and burdens based on the subject’s prior instructions. In contrast to the ACP’s position, noted above, Moorhouse and Weisstub contend that directives should be restricted to authorizing research "with a negligible or less than substantial risk."148 Their position is based on the belief that capable individuals cannot predict with complete accuracy how they will experience research as incapable subjects. These authors also argue that the competent individual’s freedom to volunteer for research to advance the interests of others is qualified by society’s responsibility to protect vulnerable individuals from material harm.
Addressing dementia research, the Canadian group proposed that research directives should apply to studies offering no direct benefit to subjects only if the risk is minimal or a minor increase over minimal.149 They suggest one exception to this limit, however: "[i]f a subject who provides a directive specifying a willingness to undergo a higher-risk level also provides evidence of having already experienced a similar level of physical or psychological pain or discomfort in another therapeutic or research setting, then the cap of allowable risk for that subject could be raised accordingly."150
Berg, by contrast, supports full implementation of advance research directives without regard to the risk level. She argues, "[b]ecause competent subjects do not have limits placed on the types of research in which they can participate while they remain competent (as long as the protocol is approved by an appropriate review board), they should not have limits placed on the types of research in which they can consent, in advance, to participate should they become incompetent."151 Conversely, when an advance directive refuses research participation, Berg suggests that the subject’s refusal could be overridden if a study offers possible direct benefit unavailable in the clinical setting.
A few public policy developments are also relevant. Congress has limited the circumstances in which the Department of Defense (DoD) may accept the "consent" of a legal representative for the research participation of another.152 Currently, DoD is not permitted to fund research without the informed consent of the subject, or, in the case of "beneficial" research, without first obtaining the informed consent of either "the subject or a legal representative." Thus, Congress has prohibited DoD from conducting research that has no potential direct benefit for the human subjects, unless the subjects themselves provide informed consent—regardless of whether the research involves minimal or greater than minimal risk. A similar provision has governed DoD since 1972.
In 1996, the FDA adopted new regulations governing research involving incapable subjects in the emergency setting.153 These regulations allow research to proceed under certain conditions, in the absence of consent by a subject or an LAR. An IRB may approve such research if it finds and documents that there is no reasonable way to identify prospectively the individuals likely to become eligible for participation; the subjects are in a life-threatening situation and, because of their medical condition, cannot give their informed consent; the intervention must be administered before consent from an LAR is feasible; available treatments are unproven or unsatisfactory; the research is necessary to determine the safety and effectiveness of some new therapies; and various other conditions are met.154 According to agency officials, when IRBs determine that investigators can reasonably identify and seek prospective consent from persons likely to become eligible for a study, "[t]hose individuals who either did not make a decision or who refused would be excluded from participation in the investigation."155 In response to a public comment describing "the difficult task for potential subjects to imagine the kind of research they would want should they suffer a catastrophic illness," officials acknowledged possible difficulties in implementing the prospective decisionmaking process, but suggested that IRBs could adequately address these matters.156 As has been noted, similar problems apply to all advance directives for research participation.
The State of Maryland has initiated a policy effort relevant to advance research decision making. The draft legislation includes a framework for third-party decisions on research for decisionally incapacitated persons—i.e., research is permitted under some conditions with consent of an incapable subject’s "legally authorized representative." Unlike current federal policy, this proposal specifies who may fill this role. Subject representatives may be, in the following priority order: (1) a research agent designated in an advance directive for research; (2) a health care agent designated in an advance directive for treatment; (3) a surrogate—that is, a family member or close friend—authorized by statute to make health care decisions for an incapable person; or (4) a proxy decision maker designated by the IRB to act as a research decision maker for an incapable person.157
Thus, the Maryland draft gives substantial decisionmaking authority to third parties expressly chosen by an individual. In the absence of an instruction directive, only research agents and health care agents are authorized to consent to an incapable subject’s involvement in research presenting a minor increase over minimal risk and no expected direct benefit. Only a research agent may authorize an individual’s involvement in research presenting more than a minor increase over minimal risk and no direct benefit. The Maryland draft legislation also recognizes a limited role for instruction directives. A monitor may consent to an incapable individual’s participation in research presenting minimal risk and no direct benefit if the individual’s advance directive explicitly authorizes such participation. A research agent may permit an incapable subject to be involved in research presenting more than a minor increase over minimal risk only if "the research is unambiguously included in the individual’s advance directive" authorizing research participation.158 Thus, otherwise prohibited research risk is permitted based on the prior capable choice of a now incapable subject.
The Maryland draft legislation does not discuss the information that must be disclosed to a capable person making an advance research directive; it does address withdrawal from research, however. Any third party consenting to an incapable subject’s participation must:
Other groups and commentators have expressed general support for advance research decision making without addressing the concept in detail.160 In reviewing the advance directive’s potential application to dementia research, Greg Sachs speculates that it is unlikely that many individuals will prepare research directives. He notes that relatively few people make treatment directives, even though many fear excessive treatment at the end of life. Even fewer will make research directives, he predicts, because "the fear of missing out on being a subject in a promising dementia study, or of being inappropriately volunteered by one’s relatives, is simply not a prevalent or powerful concern."161
Although advance research decision making has been widely discussed in the literature and included in some recent state-based policy initiatives, numerous conceptual and practical questions remain. The matter could be made moot if very few persons prepare research directives. Further, even in the best circumstances, investigators and IRBs face challenges in providing competent individuals with all the necessary information about a future study. Finally, the literature reveals disagreement on the significance that should be assigned to the competent individual’s preferences about future research participation posing greater than minimal risk.
In sum, advance research decision making, although recognized as a potentially useful device, poses difficult issues concerning its scope and effect. In NBAC’s view, an advance directive can never serve as a "blank check" for future research participation. Indeed, an advance directive may itself serve as a sufficient basis for research participation only in very limited circumstances. That is, those in which the most important information relevant to informed consent about future research participation is already known and is presented to a capable person, who then gives consent, and there is no material change in the research protocol or the person’s clinical situation (apart from loss of decisionmaking capacity) by the time that research participation is actually to begin. If the person’s willingness to participate in research is stated more broadly—for example, in terms of a desire to participate in research about a disease—that statement should be given considerable weight by whoever has authority to authorize research participation, but it cannot by itself be considered sufficient for enrollment in a particular study. This type of prospective authorization can provide the basis for enrolling subjects in certain kinds of research. And, as we will discuss below, prospective authorization provides a necessary ground for enrolling a subject in research involving greater than minimal risk without the prospect of direct medical benefit—so long as certain standards for third party approval can be satisfied. We now turn to this issue.
Legally Authorized Representatives and Research Decision Making
Surrogate decision makers are frequently mentioned as one solution to ethical problems of enrolling persons from certain vulnerable groups in research. In its recent report on "Research Involving Individuals with Questionable Capacity to Consent," the 1998 NIH panel concluded that, "Individuals with questionable capacity (or clear incapacity) to consent may have a family member and/or LAR serve as a surrogate, with this role documented during the consent process." The panel further recommended that the surrogate’s research decisions reflect, to the greatest extent possible, the individual’s views prior to the period of incapacity.162
Although the term "surrogate" is frequently used in ethical discussions such as that in the NIH Panel Report, the Common Rule uses the phrase "legally authorized representative" (LAR). The concept of a LAR leaves many unanswered questions. Surrogates may be regarded as individuals who have had prior experience with the individual being represented, but LARs (for example, legal guardians) often do not have such experience. State laws addressing a somewhat broader area of concern contain general provisions on the standards and procedures governing appointment of guardians for persons declared legally incompetent. This report addresses only one aspect of this issue. Guardianship, for example, requires a judicial proceeding and ordinarily authorizes someone to make financial, personal, or both types of decisions for the incompetent person. Limited guardianships covering a narrower area of decisionmaking responsibility are also possible.
As mentioned previously, relatively few states have laws specifically addressing research decision making by legal guardians or other allowable surrogates. Moreover, existing legislation in some states limits the involvement of incapable subjects in research in various ways. A number of state laws, for example, require guardians to obtain specific court authorization to make decisions on a ward’s participation in a research protocol. In addition, several states currently prohibit certain types of research on persons with mental disorders, particularly research which presents greater than minimal risk and from which subjects are not intended to benefit. Wichman notes that if an IRB were to approve a study in a state that did not have such a statute, the IRB might choose to invoke certain protections, including additional monitoring of the study, requiring a consent auditor, or requiring educational activities for authorized representatives.163
Federal research policy is not intended to preempt or otherwise affect state or local laws applying to research, including those conferring additional protection on subjects participating in research protocols.164 Thus, investigators and IRBs in jurisdictions with specific laws governing the identity and authority of research decision makers for persons lacking decisional capacity must comply with those laws. Yet in the many states without clear law, it will be left to federal policy, investigators, and IRBs to determine who, if anyone, may act as a surrogate decision maker for a person who lacks decisional capacity. At present, legal guardianship is rarely, if ever, sought in the research setting. Instead, close family members, who may or may not have formal guardianship status, are the customary decision makers when the research participation of incapable adults is sought.
Should federal policy require formal legal guardianship for someone to be considered a suitable surrogate for decision making about research? The underlying question is whether such a requirement is necessary or sufficient to provide adequate protection against inappropriate involvement of a vulnerable population in research to advance the interests of others. The National Commission recommended that the permission of either a legal guardian or a judge be required to authorize the research participation of subjects institutionalized as mentally infirm in the following situations: the incapable subject objects to participation, or the subject is incapable of assent and the research presents greater than minimal risk.165
Subsequent commentary by others questions whether formal legal proceedings are necessary to provide adequate protection for subjects who lack capacity, particularly those not residing in an institutional setting. As one writer notes, IRBs requiring legal guardianship, "to be on the safe side," could end up contributing to a deprivation of general decisionmaking rights of subjects.166 Moreover, the guardian appointment process ordinarily will not address research participation issues in any explicit way. In most cases, a judicial decision to confer guardianship status on a particular person is made without consideration of that person’s suitability to make decisions regarding his or her ward’s participation in research protocols.
Dissatisfaction with a requirement for legal guardianship has led to alternative proposals for granting authority to act as an incapable person’s representative in research decision making. One option, which was discussed above, is to allow decisionally capable persons to authorize in advance a specific individual to make decisions regarding their research participation during a future period of incapacity. This device, which is modeled on the durable power of attorney for health care, has the virtue of promoting the capable individual’s autonomous views on who is best suited to act on his or her behalf in the research context. Its primary advantage, though, is the explicit authority granted by prospective subjects, who presumably will choose someone likely to express their values and protect their welfare. NBAC supports the place of personal values and wishes in making advance decisions about research participation. Designating a surrogate decision maker with whom the subject has a close, trusted relationship is one way to express how personal values and wishes should be applied to future decisions regarding research participation. As a practical matter, however, it is unclear whether many individuals will be interested in or willing to complete such a DPA. Moreover, the device cannot be applied to the population of persons with mental disorders who are currently incapable and not expected to recover capacity. Still NBAC recognizes that such a practice could, if accepted, result in more individuals appointing LARs explicitly for research purposes.
A second potential source of authority is an existing health care power of attorney. It is doubtful that an individual’s choice of a proxy to make treatment decisions in the event of incapacity can fairly be taken as an authorization for research decision making as well. Nevertheless, the choice does manifest a high degree of trust in the proxy, and that evidence of trust may entitle the health care proxy to a decisionmaking role in research. The NIH Clinical Center policy does allow previously chosen health care proxies to make some research decisions for subjects.167
A third alternative is to regard state legislation authorizing family members (and, in a few states, friends) to make certain treatment decisions on behalf of relatives as conferring authority for research decisions as well. It might be argued that such legislation recognizes that important health-related decisions for persons lacking decisional capacity are properly assigned to appropriate relatives. Perhaps it would be reasonable to extend the law’s application to a statutory proxy’s decision regarding research offering potential health benefit to an incapable subject.168 Others believe that these laws should not be interpreted so expansively and that amendments or new legislation would be required to provide explicit statutory authority for delegating to relatives decisions about the subject’s participation.169
A final possible option is to assign such decisionmaking authority based on the simple status of being a close relative or a trusted individual. Support for this alternative, especially as regards relatives, comes from the long-held tradition in health care of relying on families to make decisions for incapable persons, as well as from the belief that relatives are most likely to make decisions in accord with the incapable person’s values, preferences, and interests.170 This approach is easy to administer; moreover, it apparently has been and continues to be a common practice in many research settings.171
Each of these options presents advantages and drawbacks. Requiring judicial involvement may cause unproductive delays, raise the costs of research, and may not always advance respect for and protection of incapable persons. Requiring explicit durable powers of attorney for research poses some practical difficulties, since relatively few persons have or can be expected to complete these documents, and it may not be possible to describe the future research protocol completely. Another question is whether the power of DPAs to consent to research risks for an incapable individual should be equal to the power of capable adult subjects to consent to such risks for themselves. New legislation authorizing a relative or a trusted friend to make research decisions for incapable persons would require action by the states; such legislation, however, might emerge slowly or, in some states, not at all.
All of these alternatives also raise questions about the accuracy with which incapable subjects’ values and preferences as competent persons will be expressed by formal or informal representatives.172 There is also the problem of potential conflicts between subjects’ interests and those of their representatives. Those most likely to act as representatives are family members, who may see the subject’s research participation as an avenue "that may lighten the burden of care-giving or lead to treatment from which the family member may benefit."173 Two empirical studies found some family members willing to allow an incapable relative to be entered in a research study even though they thought the relative would refuse if competent. Some family members also stated they would allow an incapable relative to become a subject even though they would refuse to enroll in such a study themselves.174 At the same time, NBAC recognizes that these mechanisms might permit some important research to go forward. Moreover, NBAC is satisfied that the argument for encouraging the involvement of LARs is sound so long as there is a clear description of the role and authority of the LAR, and of the protections that must be in place in order for an IRB to assure itself that the LAR is appropriately acting on behalf of the incapable persons. In addition, there should be an ongoing evaluation of LARs in this context.
The Authority of the LAR
An LAR is an individual authorized by law (statutory or judicial) or previously published institutional rules to make medical decisions on behalf of another individual. There are two mechanisms by which an LAR can be involved in research decision making. One option might be to allow individuals, while competent, to designate their LAR to give permission to enroll them in research. This scenario requires the designation of an individual whose authority is limited to research involvement. Given the paucity of experience with research-specific LARs in this country, NBAC recognizes the burden that might be created by recommending that only this method be used. Another option would be to permit persons designated as DPAs (the many thousands of individuals who have already been appointed in this country to be health care decision makers for clinical decisions) to serve as LARs and be able to make certain decisions regarding the participation of subjects in research protocols. In both cases, the authority of the LAR requires careful description and limitation.
Three forms of substantive limits on this authority are commonly endorsed. One is to allow guardians, proxies, and informal surrogates to give valid permission for an incapable person’s participation only if the incapable person assents or, at the very least, fails to object to initial or ongoing research participation. The second is to require that third parties make research decisions consistent with the incapable subject’s prior instructions issued while capable. The third is to permit LARs to authorize the involvement of incapable subjects only in studies that meet certain risk-potential benefit standards. Many of the recommendations on research involving persons with mental disorders apply each of these limits, but combine them in a variety of ways.
Protections to Ensure that the LAR is an Ethically Valid Surrogate for Research Decision Making
Given the limited experience in this country with research-specific LARs (or for extending existing health care DPAs to research), NBAC is unwilling to recommend their adoption without also recommending certain protections and methods for their evaluation. In general, NBAC regards the IRB as the proper locus for determining whether these (or any other) protections are adequate. For an IRB to be assured that an LAR’s enrollment of a now incapable person with a mental disorder into a research study is acceptable, the IRB might consider requiring the following procedures:
With regard to the standard by which substitute decisions are made, NBAC suggests the following prioritization scheme. Any wishes previously expressed by the subject authorizing participation in a future study should be honored by the LAR. The more specific the authorization is, the easier it is to apply to a particular study. In the absence of a prior specific authorization by the subject, NBAC favors, in general, giving priority to those decisions by LARs that approximate most closely the now incapable subject’s previously expressed preferences. For example, statements about research "of this kind" or "involving these types of risks" should influence the LAR’s decision about enrollment. In the absence of this kind of information, LARs would have to rely on potential subjects’ general values as expressed in other kinds of choices or actions. NBAC is acutely aware of the difficulties this approach presents and explains the rationale in somewhat more detail in Chapter 5.
Ongoing Evaluation of LARs
The protections listed above could provide the IRB some assurance that the LAR has been assigned in a legally and ethically valid way. However, ongoing assessment of the LAR process would be of considerable value. IRBs intending to permit enrollment of a now incompetent subject on the basis of LAR decisions (regardless of how well documented this process might be) would be strongly encouraged to evaluate the effectiveness of LARs. There would be considerable value in having IRBs report on those studies involving greater than minimal risk research in which enrollment of decisionally incapable subjects with mental disorders was authorized by an LAR. In the absence of good empirical data about the effectiveness of the LAR mechanism in both permitting scientifically valuable research to go forward and, at the same time, ensuring appropriate protections of subjects from research harm, NBAC cannot fully endorse it. On balance, however, NBAC believes that it is appropriate to proceed by using the LAR mechanism only in certain situations. Nevertheless, NBAC strongly encourages the research community, led by NIH (in view of its experience in this area), to support studies on the possible roles of surrogate decision makers in research.
Independent Professional Support for Subjects and Surrogates
Although consent forms and research protocols normally provide thorough information about the study, they do not provide the individualized information that many people need to make a decision about their own participation. Also, some potential research participants, or their representatives, may be intimidated by the medical research environment, or feel unable to make an independent judgment due to the technical nature of medical research.
One way to provide intellectual and emotional support to these individuals is to ensure that, in appropriate circumstances, an independent and properly skilled health care professional is available as an advisor for each research participant or their surrogate. This independent advisor should not be involved with the study and preferably should have had a prior relationship with the potential subject. Subjects, or their representatives if subjects lack capacity, should be able to choose their responsible health care professionals. The advisor’s role would be to help a potential subject and representative decide whether participation in a particular research protocol is a good choice for that subject. For incapacitated persons whose research participation is contemplated, the health care professional could be an invaluable consultant to the LAR. Often this professional will be a physician; however, other professional caregivers may serve the same role—a nurse-clinician or a social worker, for example. The basic requirement is that such caregivers be familiar with the subject, understand the nature of the research protocol, not be part of the research team, and, if practical, not be part of the organization conducting the research.
It would be unreasonable to require independent health care professional advisors for all research protocols involving persons with mental disorders, but the advisors should be available for studies involving greater than minimal risk, and where the subject lacks capacity to decide or is expected to lose capacity during the course of a study. For any proposed research, subjects or their LAR should be informed that they may request the opinion of an independent health care professional about participation in research. In turn, investigators should make available any information the independent health care professional requests regarding the conduct of the protocol.
The British Law Commission recommended a similar system to the House of Commons in 1995, though its proposal applied only to individuals who lack capacity. It wrote: "In most cases the appropriate person to carry out an independent check [on research participation] will be a registered medical practitioner who is not involved in the research project. . . . The doctor who knows the person best, by virtue of having responsibility for his or her general medical care, will often be the best candidate."175 The Maryland proposal assigns this responsibility to a "medically responsible clinician" if research involves withdrawing a group of decisionally incapacitated subjects from a standard treatment or otherwise presents more than minimal risk.176 At the very least, it seems sensible for an LAR to have access to an independent health care professional advisor before entering an individual into such a research protocol.
For research protocols involving greater than minimal risk, whether or not direct medical benefit is anticipated, an IRB should consider whether to require that an independent health care professional should be available before the research begins. The subjects or their LARs may or may not choose to utilize the independent health care professional. When, as is usually desirable, the researcher is not the health care professional responsible for the care of the patient, the treating professional would be available to serve as the independent advisor to the patient once enrolled in the research.
This chapter has discussed some of the conceptual and practical problems that arise when informed consent cannot be obtained from potential research subjects, the place of assent/objection, the use of advance planning, and the role of LARs in permitting some research to go forward. The next chapter describes some of the difficulties that arise in assessing risk and potential benefit and offers some perspectives on their resolution.
126 National Commission, Belmont Report, 6.
127 National Commission, Report on Those Institutionalized as Mentally Infirm, 9.
129 Sachs et al., "Ethical Aspects of Dementia Research," 410.
130 Marshall B. Kapp, "Proxy Decision Making in Alzheimer’s Disease Research: Durable Powers of Attorney, Guardianship, and Other Alternatives," Alzheimer’s Disease and Related Disorders 8, supp. 4 (1994): 28–37, 34.
131 National Commission, Report on Those Institutionalized Mentally Infirm, 14.
134 E.g., Jessica Wilen Berg, "Legal and Ethical Complexities of Consent with Cognitively Impaired Subjects: Proposed Guidelines," Journal of Law, Medicine and Ethics 24 (1996): 18–35, 22; High and Doole, "Ethical and Legal Issues in Conducting Research Involving Elderly Subject"; High et al., "Guidelines for Addressing Ethical and Legal Issues in Alzheimer Disease Research"; Melnick et al., "Clinical Research in Senile Dementia of the Alzheimer Type," 534.
135 Keyserlingk et al., "Proposed Guidelines," 342.
137 T.D., et al. v. New York State Office of Mental Health et al., 650 N.Y.S. 2d 173, 192 (N.Y. App. Div. 1996).
138 Office of Maryland Attorney General, Final Report, A-23.
139 Joan M. Teno et al., "Changes in advance care planning in nursing homes before and after the Patient Self-Determination Act: report of a 10-state survey," Journal of the American Geriatrics Society 45 (1997): 939–944.
140 Robert J. Levine, Ethics and Regulation of Clinical Research, 2d ed., (Baltimore: Urban and Schwarzenberg, 1986), 270–74.
141 National Institutes of Health (NIH), Clinical Center Policy and Communications Bulletin, Consent Process in Research Involving Impaired Human Subjects No. 87-4 (1987) (available at NIH’s Office of Human Subject Protections homepage, http://helix.nih.gov:8001/ohsr, as of Dec. 31, 1998). See also, John C. Fletcher, F. William Dommell, and Daniel D. Cowell, "Consent to research with impaired human subjects," IRB 7, no. 6 (1985): 1–6.
142 American College of Physicians, "Cognitively Impaired Subjects," 844.
144 See, e.g., Anne Moorhouse and David V. Weisstub, "Advance Directives for Research: Ethical Problems and Responses," International Journal of Law and Psychiatry 107, no. 2 (1996) 107–41, 135.
145 Berg, "Legal and Ethical Complexities," 22.
146 Moorhouse and Weisstub, "Advance Directives for Research," 135; Shamoo and Sharav, "Unethical Use of Persons With Mental Illness in High Risk Research Experiments," S:29 (advance directives should not bind a subject to research participation).
147 Keyserlingk et al., "Proposed Guidelines," 352.
148 Moorhouse and Weisstub, "Advance Directives for Research," 134.
149 Keyserlingk et al., supra, at 351.
151 Berg, "Legal and Ethical Complexities," 22.
153 Informed Consent and Waiver of Informed Consent Requirements in Certain Emergency Research; Final Rules, 61 Fed. Reg. 51,498 (1996) (codified at 21 CFR 50.23 and 50.24 (1998)). The DHHS Secretary, at the same time, waived the general requirements for informed consent under conditions that are almost identical to FDA regulations. See Waiver of Informed Consent Requirements in Certain Emergency Research 61 Fed. Reg. 51,531 (1996).
155 61 Fed. Reg. 51498, 51510 (1996).
156 61 Fed. Reg. 51498, 51510–11 (1996).
157 Office of the Maryland Attorney General, Final Report, Parts VI, VII, VIII, and IX.
160 E.g., Melnick, et al., "Clinical Research in Senile Dementia of the Alzheimer Type," (endorsing research directives and implying that such documents could authorize otherwise questionable research presenting greater than minimal risk and no prospect of direct therapeutic benefit to subjects); Annas and Glantz, "Rules for Research in Nursing Homes," (competent person diagnosed with disorder expected to produce incapacity could designate proxy decision maker; such document could authorize participation in otherwise prohibited nontherapeutic studies posing "any risk of harm," but should be used only if instructions are specific and address "reasonably well defined" research and subject retains right to withdraw even after becomes incapable).
161 Greg A. Sachs, "Advance Consent for Dementia Research," Alzheimer Disease and Associated Disorders 8, supp. 4 (1994): 19–27, 22. Sachs refers to unpublished survey data finding that while 16 of 21 ethicists expressed enthusiasm for advance research directives, only 8 out of 74 investigators agreed that directives would be a workable approach. In a different survey of healthy elderly persons, many respondents indicated they would be unwilling to complete "blank checks" authorizing participation in a wide range of future studies. Respondents were more positive about advance directives authorizing research offering a reasonable prospect of direct benefit, but only if interventions were restricted to the specific procedures, pain, and discomfort set forth in the document. Keyserlingk et al., supra, 347.
162 Expert Panel Report to the National Institutes of Health, Research Involving Individuals with Questionable Capacity to Consent, 3.
163 Wichman, "Protecting Vulnerable Research Subjects," 94–95.
165 National Commission, "Research Involving Those Institutionalized as Mentally Infirm," 11-20. At least one commentator supports a requirement for explicit judicial authorization prior to an incapable subject’s enrollment in research if relatives are unwilling to act as subject representatives or if a subject-advocate questions a family surrogate’s good faith or decisionmaking capacity. Bein, "Surrogate Consent and the Incompetent Human Subject." Others have criticized this view as intrusive, unnecessarily adversarial, and too great an impediment to research. See, e.g., Berg, "Legal and Ethical Complexities of Consent with Cognitively Impaired Research Subjects," 21; and Kapp, "Proxy Decision Making in Alzheimer’s Disease Research," 33.
166 Office for Protection from Research Risks, Protecting Human Research Subjects: Institutional Review Board Guidebook (Washington, D.C.: GPO, 1993), 6–30. See also High and Doole, supra, 328.
167 NIH Clinical Center Policy, supra.
168 Bonnie, "Research with Cognitively Impaired Subjects," 110.
170 This position is endorsed in policy guidelines adopted by "Alzheimer’s Disease Centers" in the U.S. "Unless there is statutory or case law to the contrary, family members should be recognized as having surrogate authority without prerequisite appointment as guardians or proxies through the use of instruments such as durable powers of attorney." High et al., supra, 69.
171 Kapp, supra; High and Doole, supra.
172 See Sachs, "Advance Consent," 23 (" . . . I think it is fair to assume that most proxies [in the current consent process] know very little about their demented relative’s preferences regarding research participation").
173 Keyserlingk et al., "Proposed Guidelines," 346.
174 Sachs et al., "Ethical Aspects of Dementia Research"; J. W. Warren et al., "Informed Consent By Proxy," New England Journal of Medicine 315 (1986): 1124–28. There were also cases in which family members would not allow an incapable subject’s participation even though they thought the subject would consent if competent or the family members would enter such a study themselves.
175 The Law Commission, Mental Incapacity: Item 9 of the Fourth Programme of Law Reform: Mentally Incapacitated Adults (London: House of Commons, 1995), 101.