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Protecting Subjects with Decisional Impairment in Research

The Need for a Multifaceted Approach

University of Maryland School of Medicine, Baltimore, Maryland; University of California at San Francisco, San Francisco, California; and Office of the Maryland Attorney General, Baltimore, Maryland

Correspondence and requests for reprints should be addressed to Henry Silverman, M.D., M.A., Department of Medicine, University of Maryland School of Medicine, 10 South Pine Street, Suite 800, Baltimore, MD 21201. E-mail: hsilverm{at}medicine.umaryland.edu

Advances in the understanding and treatment of medical conditions such as psychiatric and cardiopulmonary illnesses depend on research involving persons who are cognitively impaired. Such persons have, or are at risk of having, decisional impairment and therefore might not be competent to give voluntary informed consent to participate in research. Consensus statements on research ethics assert that ethically acceptable research may proceed with such vulnerable subjects if additional safeguards, including appropriate proxy consent, are in place to minimize the risk of harm and exploitation (1–5).

Despite these consensus statements and the establishment of federal regulations and institutional review boards (IRBs), research involving subjects with decisional impairment who suffer from mental illnesses has led to adverse outcomes that have prompted lawsuits (6) and governmental sanctions (7). Recently, the Office of Human Research Protections (OHRP) (8), which is responsible for oversight of IRBs and for compliance with federal research regulations, conducted inquiries regarding the ethical appropriateness of research involving subjects who are critically ill and who might have had decisional impairments.

Research involving subjects with decisional impairment is problematic in part because of the uncertain legal foundation for proxy consent and the lack of guidance in the federal regulations (known as the "Common Rule" because 17 federal agencies have adopted it) on how to adequately protect vulnerable subjects (9–11). Furthermore, although two states have enacted statutes that eliminated the legal uncertainty regarding proxy consent for the participation of subjects with decisional impairment in research (12, 13), these statutes lack attention to certain key safeguards for vulnerable subjects. In the absence of the specification of at least essential safeguards, the protection of subjects with decisional impairment relies too heavily on the views of diverse IRBs, risking inadequate (8) and inconsistent safeguards (14).

In view of the prospect of increasing numbers of research protocols involving subjects with decisional impairment, we present a multifaceted and complementary approach through which the traditional expertise and domains of the important regulatory and oversight bodies at the federal, state, and institutional levels can ensure that such research is ethically appropriate. Our recommendations are applicable regardless of the basis for subjects' incapacity, be it due to psychiatric conditions or acute critical illnesses, because the need for additional safeguards depends on the condition of incapacity rather than its cause (15).

ROLE OF THE FEDERAL GOVERNMENT

The federal government's proposed regulations involving children, wherein essential safeguards linked to permissible risk categories are specified, were adopted by the Department of Health and Human Services in 1983. However, the government's more restrictive proposed regulations on mentally disabled persons were abandoned in the face of strong opposition (9, 16). Accordingly, research involving adults with decisional impairment is governed solely by the Common Rule's general provisions, which merely direct IRBs to include "additional safeguards...to protect the rights and welfare" of "mentally disabled persons" (17). Such generality might lead to inadequate protection of vulnerable subjects. For example, in its investigation of critical care trials, the OHRP found that most IRBs failed to require additional safeguards beyond that of requiring proxy consent (8).

Because, as we will discuss, state statutes will not likely specify essential safeguards for protecting vulnerable subjects, we recommend that the federal government offer a framework delineating safeguards linked to permissible risk levels. We present such a hierarchy of risk levels and their justifications in Table 1 . The concept of minimal risk is central to this risk categorization. Under the federal regulations, research may be characterized as minimal risk if "The probability and magnitude of harms or discomforts anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychologic examinations or tests" (18). This definition has been difficult to apply because of conceptual confusion whether "daily life" applies to healthy persons or to the target group of the research. A risk threshold linked to the daily life of the research group would allow ill subjects to be exposed to greater risks than healthy subjects. Such exposure would entail imposing disproportionate burdens of research on the ill without the possibility of benefit and provide weaker protections for them than for healthy persons, thus violating the ethical principle of justice.

The risk levels presented in Table 1 are fashioned after those outlined in the federal regulations for children (22) but depart from them in that rather than requiring the research study as a whole to be placed in a single risk category, they acknowledge that a research study may consist of two distinct components, procedures with and procedures without the prospect of direct benefits to individual subjects (23). Within a framework of a component analysis, a study should be acceptable only if the risks of each component of the research are justified separately. For example, procedures with a prospect of direct benefits are justified by (1) whether the risks are reasonable in relation to the potential benefits to the subjects and (2) whether the balance of risk and benefits of the procedures are similar to available, alternative methods of achieving the same outcome. The latter requirement is similar to that of clinical equipoise when human subjects participate in clinical trials (24). Procedures without a prospect of direct benefits, such as those done solely to gather data to answer a research question, are justified by their potential to generate scientific knowledge. In the absence of such a component analysis, procedures performed solely for research purposes might claim to be justified by the procedures that offer the prospect of direct benefits to subjects (23, 25). Finally, for research protocols that contain components that do not involve greater than minimal risk, it is sufficient that justification for either component derives from the scientific knowledge to be gained.

The Acute Respiratory Distress Syndrome (ARDS) Network late-phase corticosteroids trial can serve as an example of the application of a component analysis of risk (26). In this study, the potential risks of corticosteroids are justified by the anticipated benefits to the subjects, including reduced mortality and reduced time on the ventilator. At the same time, the risks associated with bronchoscopy to obtain brochoalveolar lavage samples, performed solely for research purposes, are justified only by the potential to generate scientific knowledge, not by the anticipated benefits of the administration of corticosteroids to the subjects receiving them.

Once risk levels are delineated and justified, essential safeguards to protect vulnerable subjects can be specified. These safeguards, shown in Table 1, consist of those mentioned in the pediatric regulations and additional safeguards to address the context of adults with decisional impairment. For research at all risk levels, we recommend that investigators outline a specific plan to assess the capacity of all potential subjects when groups that might involve persons with decisional impairment are targeted for research, for example, patients receiving mechanical ventilation. The failure to assess capacity can be problematic because incorrect judgments that persons with cognitive impairment are capable of exercising autonomy might involve subjects in research that is not sufficiently understandable to them.

Our recommendation for capacity assessments is consonant with recent actions by entities that provide research oversight. For example, in its inquiry into the ARDS Network clinical trials, the OHRP asked for a description of any procedures approved by IRBs for assessing subjects' cognitive status and capacity to provide initial effective informed consent. Recently, the Office of the President of the University of California issued guidelines requiring investigators to perform capacity assessments on prospective subjects who might be decisionally impaired (27). Capacity assessments can consist of asking potential subjects several questions to assess their understanding of the involved research. Alternatively, formal methods to assess capacity are available (28). We do not recommended any one method because it is not clear which method should be preferred.

We also recommend for all risk levels a process for reconsent, which entails that subjects who were previously impaired and who regain capacity should be asked for their personal consent, regardless of whether the procedures in the research are completed. This reconsent requirement, coupled with the requirement for capacity assessments mentioned previously, would require that patients who are critically ill undergo capacity assessments before enrollment and ongoing during the course of the trial. Finally, we recommend the requirement for assent found in the pediatric regulations, which entails that investigators obtain affirmative agreement to research participation from subjects whose capacity is considerably but not completely diminished. Such subjects might still be able to understand some aspects of a study, for example, the procedures that will be performed or the reasons for their performance. This assent requirement ensures that adults with mild to moderate decisional impairments have some involvement in the decision for their study participation. Because subjects who give assent have diminished capacity, permission from their proxies also should be obtained.

For research involving procedures that do not involve greater than minimal risk, no additional safeguards than those already mentioned are needed. For research involving possibly beneficial procedures that pose more than minimal risk, we recommend that an independent person be available to monitor the subject's involvement in the study, mainly to determine when it might be appropriate to withdraw the subject from the study. The subject's legally authorized representative should ordinarily fulfill this role of a participation monitor (11).

Regarding research involving procedures without a prospect of direct benefit, commentators have argued that the risk from such procedures should be capped at the level of minimal risk (4, 29, 30). This position reflects the concern that vulnerable subjects should not be put at undue risk for the sake of society and that such research is exploitative. We argue, however, that advocating such a risk ceiling would seriously impair important research. Also, there is justification for allowing research procedures without a prospect of direct benefit and no more than a minor increment above minimal risk. For example, with a concept of minimal risk reflecting an absolute standard linked to socially acceptable risks, procedures that involve a minor increment above minimal risk would pose no significant threat to the adult's health. Further justification for this risk level comes from a recent study involving caregivers of individuals with Alzheimer's illness, showing that nearly all of those surveyed would be willing to enroll in research that involved the performance of X-ray studies (31). Although this study sampled a selective population group, it suggests that research procedures that present a minor increment above minimal risk, even without prospects of direct benefits, are not inherently exploitative. Procedures common in critical care research relevant to this risk category would include the insertion of arterial and central venous catheters.

An additional safeguard for this risk level is a "necessity requirement." This requirement entails that subjects with decisional impairment should be enrolled in research only when their participation is scientifically necessary, for example, when the desired information cannot be obtained by enrolling adults who can consent. This requirement addresses the concern that subjects with decisional impairment might be enrolled in research merely because they cannot provide consent and are less able to protect themselves. When their enrollment is needed to address the scientific hypothesis, exploitation of their impairment is not present because they are being enrolled to obtain important information and not because they are unable to consent. The scope of the necessity requirement should not, however, be extended to research containing procedures that have a prospect of direct benefits because excluding those unable to consent may seem more like discrimination than protection (32).

To provide supplemental protection, some guidelines reinforce the necessity requirement with a "subject condition" requirement, whereby the research must involve a condition from which the subject suffers. Such a requirement has intuitive appeal, because it is based on an implicit assumption that individuals might be more likely to enroll in research investigating conditions similar to theirs. However, individuals' decisions to enroll in research might not be based on whether the condition they have is being studied. The recent survey study involving caretakers of patients with Alzheimer's disease cited earlier showed that similar numbers of persons were willing to participate in a study involving X-rays regardless of whether the research investigated conditions from which they suffered (31). Furthermore, a subject-condition requirement is overly restrictive in that certain types of research might require the participation of a class of subjects in which the condition being investigated is not related to their condition (32). For example, subjects with one type of cognitive impairment (e.g., Alzheimer's disease) might be needed to serve as control subjects for another cognitive impairment that is the main focus of a study (e.g., Down's syndrome) (32). We believe that the necessity requirement is sufficient to alleviate concerns about exposing vulnerable populations to risks for the benefit of others.

The most controversial category of research containing procedures with no prospect of direct benefits is that which presents more than a minor increment above minimal risk. Few, if any, critical care studies would fall within this category of risk. However, research involving persons with psychiatric illnesses might be relevant to this category, for example, drug withdrawal studies. Due to the potential for serious harm and exploitation, we recommend, as in the pediatric regulations, a federal-level approval process to ensure both the vital nature of the research and the specification of any additional safeguards (22).

ROLE OF THE STATES

Presently, a lack of clarity in the legal and regulatory landscape exists regarding proxy consent. The Common Rule states that "no investigator may involve a human being as a subject in research ... unless the investigator has obtained the legally effective informed consent of the subject or the subject's legally authorized representative" (33) and defines a legally authorized representative as "an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject's participation in the procedures(s) involved in the research" (34).

With this definition, the federal government requires proxies giving consent for subjects' participation in research to be legally authorized to provide such consent and that such authorization be accomplished "under applicable law." The phrase "applicable law" refers to a state or other local law, but it is ambiguous regarding the type of law that can be relevant. For example, applicable law can potentially refer to a state statute specifying proxy decision making in the research context, a statute on decision making in the clinical context, a guardianship statute, or common law. Such ambiguity in the federal regulations regarding "applicable law" is significant, as few states have laws addressing research decision making by allowable proxies.

In the absence of a clear state law on research decision making, most IRBs have relied on close family members and friends to serve as proxy decision makers in the research context (35). In its inquiry into the ARDS Network clinical trials, the OHRP requested the identification of "the applicable state and local laws that established" an individual who gave proxy consent for the subject's participation in the research "as the legally authorized individual" (8). The OHRP has defined examples of "applicable law" as being state statutes, regulations, case law, or formal opinion of a State Attorney General that addresses the issue of proxy consent to "medical procedures" (36). Accordingly, any "applicable law" that empowers proxies to provide consent in the clinical context would be applicable to provide consent for the subject's participation in the "procedures(s) involved in the research" (34). The OHRP has not allowed proxy consent for research when a state lacks a proxy consent law specifically for medical procedures, unless the proxy is a court-appointed guardian or has been authorized by a health care advance directive executed in accordance with state law (37). Despite the OHRP's ruling on the nature of applicable law, much uncertainty remains. For example, some institutions might be unwilling to incur the liability risk that inevitably accompanies a decision to proceed in the absence of an authoritative ruling, such as an explicit state law endorsing the applicability of a clinical surrogate consent law to the research context (38).

To redress the legal uncertainty regarding proxy research consent, states should develop statutes that specify the list of acceptable legally authorized representatives to reflect what is currently advocated (11) and allowed in practice by IRBs. These statutes should also identify the qualifications of legally authorized representatives and describe the substantive criteria that should guide their decision making, for example, substituted judgment or best interests standards. Such statutes at the state level would be appropriate for several reasons. First, local factors and specific opinions of state residents may be relevant to these issues. Second, states have traditionally been involved with empowering persons with decision-making authority for persons with decisional impairment, as evidenced by state statutes on guardianship and health care advance directives.

The California and Virginia statutes are examples of attempts to extend proxy consent for individuals with decisional impairment to the research context. In 2002, Virginia passed a law expanding such authority to family members in addition to legal guardians and those appointed in a research advance directive (12). The law allows proxy consent for research with a prospect of direct medical benefits and for "nontherapeutic" research that presents no more than a minor increase over minimal risk. In 2003, California enacted similar legislation granting research decision making authority to family members not previously appointed by the subject or the court. This law also requires that the subject's dissent or resistance to participation be honored and allows such proxy consent for research related to maintaining or improving the health of the subject or related to obtaining information about his or her condition (13).

For all their strengths, neither the Virginia statute nor the California statute delineates essential safeguards for vulnerable subjects. Several reasons can explain this absence. First, states have had little or no experience addressing the complex issues involved with the identification of risk categories and associated protection mechanisms in research. Second, there might be a desire to avoid a contentious political process similar to what occurred with a 1999 proposal in Maryland that elaborated detailed and restrictive protections for the decisionally impaired (39).

These statutes also fail to specify the decision making standards that should guide the decisions of legally authorized representatives. The California statute merely requires for nonemergency research that proxies should have "reasonable knowledge of the subject" (13). Traditionally, the standard carrying the most moral weight has been that of "substituted judgment" because decisions made under this standard are based on a good faith estimation of what subjects would have chosen if capable of making a decision by themselves. However, studies in both the clinical and research setting suggest that surrogates often do not know patients' previous preferences (40, 41). Rather than attaching exclusive importance to the substituted judgment standard, proxies should be instructed to also consider what would be in the "best interests" of patients.

ROLE OF IRBS
The traditional purview of IRBs has included the discretion to determine the appropriate risk level assessment and to specify additional safeguards for a given research study. This role is warranted because general principles, rules, and regulations are difficult to apply to complex research protocols and widely varying local conditions. Examples of additional safeguards that extend beyond those recommended in Table 1 include (1) the circumstances under which capacity assessments should be performed by individuals who are not members of the research team and (2) when independent consent auditors might be required to monitor the consent process.

The role of the IRBs in specifying additional safeguards coupled with the specific roles discussed previously for the federal and state governments would redress the serious gaps that presently exist in the system for protecting subjects with decisional impairment enrolled in research. Such a multifaceted and complementary approach is needed because isolated attempts at any one of these three levels will be inadequate for a robust system of protection for subjects with decisional impairment, including those who are critically ill.

Acknowledgments

The authors thank Nancy M. P. King, J.D. and Pamela Amelung, M.D. for their careful review of previous versions of this manuscript and their helpful suggestions.

FOOTNOTES

Conflict of Interest Statement: H.J.S. has no declared conflict of interest; J.M.L. has no declared conflict of interest; J.S. has no declared conflict of interest.

Received in original form March 26, 2003; accepted in final form October 17, 2003

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