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Conducting Research That Involves Subjects at the End of Life Who Are Unable to Give Consent
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Journal of Pain and Symptom Management
Vol. 25 No. 4 April 2003
Special Article
Conducting Research That Involves Subjects at the End of Life Who Are Unable to Give Consent Jason H.T. Karlawish, MD Department of Medicine; Division of Geriatrics; Leonard Davis Institute of Health Economics; Center for Bioethics; and Alzheimers Disease Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Abstract This paper examines the conditions that describe when it is appropriate to conduct research that enrolls a subject near the end-of-life who cannot provide an informed consent. Specifically, it describes conditions that justify when it is acceptable to expose a person to the risks, burdens or discomforts of an intervention that is not intended to benefit that person but to produce generalizable knowledge that will benefit other people. These conditions are: (1) acceptable research risks, (2) proxy decision making, (3) subject assent and dissent, and (4) subject advance consent. J Pain Symptom Manage 2003;25:S14–S24. © 2003 U.S. Cancer Pain Relief Committee. Published by Elsevier. All rights reserved. Key Words End-of life research, research ethics, informed consent, proxy decision making
Introduction Informed consent is a key requirement for the ethical conduct of human subjects research.1 Under what conditions is it appropriate to conduct research that enrolls a subject who cannot provide an informed consent? Regulations exist to guide ethical practice of research that involves children2 (Subpart D). But in the case of research that involves adults who cannot provide an informed consent, a coherent and widely accepted answer to this question has been elusive. Although Europe and Canada have enacted regulations that describe a matrix of subject protections,3,4 the United States’ reg-
Address reprint requests to: Jason H.T. Karlawish, MD, University of Pennsylvania, Division of Geriatric Medicine, Ralston-Penn Center, Rm. 234, 3615 Chestnut Street, Philadelphia, PA 19104-2676, USA. Accepted for publication: December 16, 2002. © 2003 U.S. Cancer Pain Relief Committee Published by Elsevier. All rights reserved.
ulatory structure is incomplete and even piecemeal. Federal regulations guide the conduct of research with the emergently-ill.5 But in the case of research that involves adults who are decisionally impaired but not emergently-ill—such as persons near the end-of-life—at least two national6,7 and two state-wide8,9 efforts to adopt regulations have not succeeded. Of course, regulations do not guarantee that activities done under their guidance are ethical. Their subsequent review may show that they are misguided, even unethical, and should be revised or even rescinded. But the failure to adopt regulations suggests that there is not sufficient coherence or consensus to agree upon a reasonable set of guidelines about how to conduct research that involves subjects who are unable to give consent. There are at least two costs to the failure to adopt a reasonable set of guidelines. First, research is often the most efficient and valid method to generate valuable knowledge that 0885-3924/03/$–see front matter doi:10.1016/S0885-3924(03)00098-8
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improves patient care. Without these data, what is done with therapeutic intent may actually harm patients and their family caregivers. Second, there is a need to address a dignitary wrong. The issue here is not whether the research exposes a subject to harm, but the moral wrong of using a person as a means to an end and only as a means to an end. The heart of the matter is as follows: Can we do this research in a manner that is moral or do we sin bravely?10 In other words, are there any conditions that justify proxy altruism? These questions are especially prescient in the case of research that involves patients at the end of life. Unlike patients in the early stages of chronic diseases or with diseases that wax and wane, the dying are a population who will likely not live to benefit from the knowledge they contributed to.
Brief Overview of the Literature Research that involves persons at the end of life who cannot provide an informed consent presents the following question. Under what conditions is it acceptable to expose a person to the risks, burdens or discomforts of an intervention that is not intended to benefit that person but to produce generalizable knowledge that will benefit other people? A useful side by side review of U.S., Canadian and European guidelines identifies six core safeguards that establish these conditions: institutional risk-benefit assessment, consent assessment, necessity requirement, proxy decision maker and sufficient evidence of patients’ remaining preferences and interests, respect for patient assent and dissent, and independent monitors.11 Casarett’s companion paper addresses the issues of consent assessment and independent monitors. This paper’s foci are: (1) acceptable research risks (institutional risk-benefit assessment and the necessity requirement), (2) proxy decision making, (3) subject assent and dissent, and (4) subject advance consent.
Acceptable Research Risks: The Risk-Benefit and Risk-Knowledge Assessments The categorization of research risks and benefits is at the core of determining that a research
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project that involves persons who cannot consent is ethically appropriate. These categories reflect the degree that the principle of beneficence is fulfilled. The less this is fulfilled, the more additional subject protections are required. In other words, increasing research risks warrant increasing subject protections such as Items 2 through 4 discussed below. A core construct to describe research risks is “minimal risk,” defined as “the probability and magnitude of physical or psychological harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life, or during the performance of routine physical or psychological examinations or tests2 (46.102(i)).” Minimal risk is critical for determining the moral appropriateness of research that involves a variety of vulnerable populations—children, prisoners, and fetuses2 (Subparts b–d). It is also an essential guide for waivers and modifications of informed consent in research that involves nonvulnerable populations2 (§46.116d). In the case of research that involves noncompetent adults, the general proposal is as follows. Greater than minimal risk research risks require additional subject protections. Noncompetent subjects need to either provide an assent, not dissent, or have provided an informed consent previously when competent— i.e., advance consent. The consent of a proxy is required as well. The specific combinations of these protections vary across proposals. They rely on a more finer risk assessment, in particular whether the research risks are a minor increment or greater than a minor increment above minimal risk. In the case of research risks that are greater than a minor increment above minimal risk, there is general agreement that proxy consent with subject assent is an insufficient subject protection. Instead, the research may require that the subject either provide an advance consent or it is prohibited. This matrix of risk and consent is appealing. It reflects the intuitively sensible concept that in life some level of risk is tolerated without substantive deliberation. But operationalizing this in the conduct of research that involves adults who cannot deliberate remains controversial. Two issues limn out the features of this controversy: how to interpret who is the subject of the definition of minimal risk and to what risks does minimal risk apply.12–14
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There are two perspectives on to whom the risks of daily life should be compared. One is that the risks and benefits of the research should be compared to the risks and benefits faced by the subjects. The other is that the risks and benefits should be compared to the risks and benefits faced by healthy persons. Out of each of these perspectives emerge very different risk assessments. Consider the case of a randomized and placebo-controlled trial to assess whether a psychostimulant will increase the alertness of patients with profound to terminal stage Alzheimer’s disease (AD). The perspective of the patient as the subject of the minimal risk definition leads to the following assessment. Patients with this stage AD face a number of risks as a result of both their illness—e.g., pressure ulcers, infections, aspiration—as well as efforts to care for them— e.g., combativeness when cared for. In a word, they are very sick. The proposed study has risks related to the medication, and tests to assess safety and efficacy, but when weighed against these every day risks and the potential benefits of the experimental medication, they are minimal. Hence, the study is likely minimal risk and could proceed with proxy consent with subject assent. In contrast, the perspective of healthy persons would regard the study risks as certainly outside the realm of usual and everyday risks in the care of healthy persons. The study would be greater than minimal risk and either require subject advance consent or simply be prohibited. These differing interpretations have been ever present. Until the 1991 revision of the Common Rule, the definition of minimal risk went through three versions that largely revolved around either stating that the subject of the definition was the research subject or healthy persons.13 The final version does not denote any subject, but the regulations’ comments section states that subject of the research is the subject of the definition. This would imply that vulnerable subjects could be exposed to greater risks because they are exceedingly ill. Such a conclusion perverts the very point of talking about research ethics in the first place: that vulnerable subjects deserve protections at least as good as those accorded to nonvulnerable subjects, such as healthy persons. In the 1990’s this perversion was at the core of the debate over the waiver of informed consent in emergency research. At first glance, this
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seems an entirely incongruous subject population to examine the ethics of research that involves persons at the end of life. But the two classes of subjects have morally relevant similarities—they are very ill and near death. A common remark about research that involves the dying is that they are so ill anyway, what is the added harm of the research? Hence, the different perspectives on how people assessed risks faced by the emergently-ill inform an assessment of risks faced by dying patients. In brief, investigators were using the subject of the research interpretation of minimal risk in order to waive informed consent on the basis of the Common Rule’s provisions for the waiver or modification of informed consent under conditions of minimal risk. This created the irony that a provision usually employed to waive informed consent for projects such as survey research or a single venous blood draw was being applied to randomized trials of cardiopulmonary resuscitation interventions. Federal officials argued that the definition was applied to healthy persons and exercised its authority to shut down emergency research that waived informed consent. Irate researchers demanded a solution. The result was a set of emergency research specific regulations that sidestepped the issue of how to interpret minimal risk5 (21CFR50.24). Instead, the regulations adopted a “whole protocol assessment” of research risks. Acceptable risk was based on balancing all the risks as well as benefits faced by the subjects: the risks of their medical condition, the risks and benefits of standard therapy and the risks and benefits of the proposed intervention. The problem with this whole protocol assessment is that it suggests that the more ill the patient, the more risk they can be exposed to.14 This upends the norm that vulnerable populations deserve protection that is at least commensurate with nonvulnerable populations. A rewording of this to focus on a comparison of the risks faced by healthy persons would have the opposite effect of rendering all research at least greater than a minor increment of minimal risk. In sum, the whole protocol approach leads to a quandary described by the extremes of either under or over protection. The way out of this quandary is to focus on the question of to what risks does minimal risk apply? The answer to this question is not
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readily apparent in any one set of research regulations or guidelines, or the companion papers that accompany them.15 The progression of the National Commission’s work illustrates that they were not developing a whole protocol model of research risk assessment, but instead a two-component model. The first component is all therapeutic research procedures. The risks of these procedures are justified by their potential benefits to the subjects. This condition is met if there is an honest disagreement in the expert community as to what is the preferred intervention, socalled equipoise.16 Assessment of this component determines whether the research is “potentially beneficial” to the subjects. The second component is the risks of nontherapeutic procedures. These are procedures that are done solely to produce generalizable knowledge. The risks of these procedures are justified by a risk-knowledge assessment. Specifically, they are balanced against the importance of the knowledge the research can reasonably produce. In the case of research that involves noncompetent subjects, this risk should be no more than either minimal or a minor increment above minimal risk. This assessment exposes plainly the core issue: what risks should people undergo to advance a common good? Hence, these risks should be compared to the risks healthy people face in medical care. A higher threshold of risk places vulnerable patients at increased risk of exploitation. The two-component model of research risk assessment has an appealing logic. It articulates the Common Rule’s requirement that risks are reasonable with respect to two kinds of benefits: (1) the anticipated benefits, if any, to the subjects, and (2) the importance of the knowledge that may reasonably be expected to result2 (§45CFR46.111(a)(2)). Research risks are demarcated into substantively different categories: those that are part of therapeutic interventions (benefit category #1) versus those that are part of nontherapeutic interventions (benefit category #2). Examples of therapeutic interventions include comparing a new drug to the standard of care drug or systematically recording patients’ routine pain scale scores. Examples of nontherapeutic interventions include comparing new drug to placebo in patients for whom a well established standard of care exists, or recording pain scale scores at
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a frequency greater than routine, such as to test interrater reliability of a new scale. But as appealing as this model is, it is difficult to operationalize. Specifically, what really are therapeutic research interventions? For example, if equipoise exists between the risks and benefits of standard drug A and drug B, are randomization and blinding part of the therapeutic risks or nontherapeutic risks? Are they even risks? If the routine for use of standard drug A is that no blood monitoring is necessary, then are all blood draws in the research part of the therapeutic or nontherapeutic risks? The intent of the blood draws is to monitor drug safety. If they classified as nontherapeutic, they create a disincentive to include them in the protocol. Despite these limitations, the two-component model is appealing over the whole protocol model that lumps together the risks the subjects face as part of their illness, the risks and benefits of standard care, and the risks and potential benefits of the research intervention. The whole component model suggests that sicker patients, such as the dying, can be exposed to more risks in the pursuit of knowledge. In contrast, the two-component model reflects that risks and benefits fit into substantively different categories. Research involves interventions that may either benefit the subject or interventions that are done as part of clinical care but their data is also being used for research. These risks are substantively different from research interventions that are done not as part of clinical care but only for research. This model has two implications. First, it guides interpreting the so-called “necessity requirement.” The term describes the requirement that research that involves adults who are unable to consent should only be done if the research cannot obtain the desired information by enrolling adults who can consent. This requirement attempts to operationalize the norm that the most vulnerable are the “last in line” for assuming risk in the advancement of science. But efforts to define “necessity” descend into a frustrating exercise of what proportion of eligible and competent subjects would warrant excluding noncompetent subjects: 1%, 10%, 50%? A more sensible approach uses the risk-knowledge assessment to guide whether a project exposes noncompetent subjects to excessive risks in the pursuit of
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knowledge. The IRB needs to determine the value of the knowledge that can be reasonably expected to result and the likelihood that the subjects will benefit from that knowledge.17 Will it benefit the subjects of the research, the class of subjects, or another class of subjects? Risks that are greater than minimal should only be pursued if the research will produce knowledge that will benefit the subjects of the research. In this way, the subjects stand a reasonable prospect of benefit, albeit at the end of the research. If this is not possible, investigators should explore alternative designs such as the techniques of quality improvement. The second implication of the two-component approach is that it radically transforms the disclosure of research risks and benefits in the informed consent form. Specifically, forms should clearly distinguish among risks and benefits that are part of therapeutic interventions versus risks that are purely research interventions. This is developed in the “Recommendations” section. The extensive text devoted to the assessment of research risks and the two-component model of research risk assessment seems odd in light of the regulations that guide the conduct of research that involves children. These regulations rely significantly on the concept of minimal risk. It is likely though that the controversy over the subject of the definition and assessment of research risks has been tolerated in pediatric research because of the well-established status of a second subject protection: parents as proxies. In the case of research that involves adults at the end of life, such a proxy is not as socially and legally evident.
Proxy Decision Making Proxy consent is a core protection in all proposals for research that involves persons who cannot consent. But the absence of clear legal guidance on who can serve as a proxy for research that involves adults frustrates investigators and IRBs. It is a situation analogous to the events that began in clinical care some 30 years ago.18 Then, the issue was who can decide to terminate life-sustaining treatment. Case and statutory law has developed a standard that a hierarchy of family members can decide and developed standards of evidence that featured the patient’s wishes (a substituted judgement)
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over best interests. An analogous situation is taking place in the similarly morally controversial realm of making decisions for others about research. Proxy consent focuses on two issues: (1) who should serve as a proxy? and (2) how should the proxy decide whether to enroll the noncompetent subject? These issues are especially important in the case of research that presents greater than minimal risk. In this case, absent clear guidance from the patient that they would want to participate in such research, how can it be in the patient’s best interests to enroll? Who should serve as a proxy? Guidelines and proposed regulations recommend that a close friend or family member serve as a proxy. “Closeness” denotes an important condition. In the care of persons who are noncompetent as a result of a chronic and progressive illness such as brain cancer or multiple sclerosis, there is typically at least one family member who has the role of “caregiver.” In this role, they typically perform at least one of the following tasks: serve as knowledgeable informant to health care professionals about the patient’s health, make decisions with or even for the patient, and assist the patient in activities of daily living. In addition, as a result of these caregiving roles they experience depression, distress and related morbidity.19 In sum, a caregiver is both socially and institutionally sanctioned. Collectively, these roles describe a person with substantive moral standing as a proxy. They have experience in making decisions and working with health care professionals for the good of the patient. They recognize that research risks and benefits to themselves and to the patient are interdependent.20 For example, if the research helps the patient, the caregiver will benefit by a less intense caregiving role, and if the research harms the patient, the caregiver will have an increased caregiving role and possibly too a feeling of culpability. The implication of these qualities is that the proxy is not so much acting as the agent of the subject but is acting as the subject. That is, their interdependence describes an interstitial autonomy. Certainly, this point needs much more explication of the constructs of agency, autonomy and interdependence, but the point remains that some caregiver-patient relationships (whether as spouse to spouse or adult child to parent) blur the separateness of the people. This
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“closeness” can be operationalized into policy recommendations for the kind of person who can serve as a proxy for enrolling a noncompetent subject in greater than minimal risk research. How should the proxy decide whether to enroll the noncompetent subject? The general consensus adopts the position of clinical care decisions. The proxy’s decision should reflect a substituted judgment, that is, what the person would decide if they could decide for themselves. Unfortunately, just as in clinical care decisions, the professional ethic does not match the ethic in practice. Evidence suggests that proxies do not routinely use a substituted judgment. In fact, some proxy’s may enroll a subject even though they believe that the subject himself would not want to enroll.21 But this evidence may not be as morally distressing as it appears. People may not feature a substituted judgement as their preferred standard for how a proxy should decide for them. In clinical care, a substantial number of people want their proxy to decide based not on a substituted judgment but instead on their best interests.22 Whether this is true in research remains a question for empirical study, including what counts as a best interests judgment for enrolling in greater than minimal risk, non beneficial research. Studies of how proxies and patients make research decisions raise a final point on proxy decision-making.20,23 There may well be instances when a researcher and a proxy disagree that a patient is not competent. In other words, the researcher thinks that the patient is not competent, the family member is providing the informed consent and the subject providing assent, but the proxy thinks the patient is competent and has made the decision. The disagreement is important because the proxy may not appreciate the moral weight their signature represents on a consent form.
Subject Assent and Dissent The noncompetent subject’s either assent or lack of dissent is a common requirement in several guidelines. Guidelines link this requirement to the research risk benefit assessment. Specifically, a subject should show some ability to decide whether to enroll in greater than minimal risk research. They differ on whether
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the requirement is the subject’s assent or failure to dissent.11 Implicit in this protection is the concept that decisionmaking abilities are dimensional as opposed to categorical constructs. This means that a person may not have sufficient abilities to be competent to provide an informed consent, but his performance on measures of decision-making ability may fit into either one of two categories: (1) it is adequate to the degree that he can either assent or dissent, or (2) it falls below this threshold. Guidelines do suggest the factors that influence the ability to assent or dissent. For example, in the case of pediatric research2 (§46.408), the ability to assent is determined by the child’s age, maturity and psychological state, in other words, the degree of cognitive development. Among adults, the degree of premorbid cognitive development as well as cognitive impairment caused by a disease determine this. But what is missing is a clear consensus on a standard to assess the ability to assent-dissent. There is a substantial literature that examines the reliability and validity of standards to assess the abilities to be competent to consent or refuse,24 but no studies report the validity or reliability of standards to assess the abilities to assent or dissent. A side-by-side comparison of recommendations and regulations suggests great variability. In the Federal regulations for research that involve children, the National Commission For the Protection of Human Subjects defines assent as “a child’s affirmative agreement to participate in research. Mere failure to object should not, absent affirmative agreement, be construed as assent2 (§46.402(b)).” This suggests that assent is the ability to choose. In contrast, in the Commission’s proposed regulations for adults who lacked the ability to consent, the National Commission defined assent as “the ability to know (1) what procedures will be performed in the research and that he or she may withdraw from participation, (2) choose freely to undergo these procedures, and (3) communicate this choice unambiguously.6 (pg. 11332)” This standard adds some aspects of the ability to understand to the pediatric requirement of the ability to choose. The Canadian Tri-Council standard is that the subject should “understand the nature and consequences of the research4 (article 2.7).”
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The point of this side-by-side comparison is that merely saying “yes” (or “no”) may be insufficient evidence of the ability to assent (or dissent). Some other abilities may be necessary, such as understanding key facts or appreciating key risks. Unfortunately, no clear consensus exists on what would constitute a meaningful assent or dissent. But the true motivation of respecting an assent or dissent may have nothing to do with it being a sufficient expression of subject’s abilities or capacities to think about their choice to enroll or not enroll in the research. It may have nothing to do with our effort to respect some autonomous choice by the subject. Instead, it may reflect our discomfort with enrolling a patient in research when that patient expresses either adamant opposition to participation or blissfully ignorant agreement. In short, it feels wrong to force someone kicking and screaming into a protocol.
Subject Advance Consent Proxy consent may not be adequate in the case of research that presents risks and potential discomforts without a reasonable prospect of benefit to the subjects’ health. On what ethical grounds can another person enroll that patient? A common proposal is a research advance directive (RAD).7–9 Prior to incapacity, the potential subject indicates the kinds of research they would or would not participate in. At first glance, RADs seem odd. Few people, if any, have them, and the small portion of persons who have clinical advance directives (10 to 20%) suggests that RADs might be just as uncommon.25,26 The net effect of a policy of prospective authorization is a hindrance in the progress of valuable research. But three lines of evidence suggest that research advance planning may have a role. First, research advance planning may be a useful way to assure that proxies use substituted judgments when they decide whether to enroll a patient in research. Studies that compare the preferences of the potential subject versus their potential proxy largely recapitulate the results of similar studies in clinical care27— there is generally poor agreement between patient and proxy.28,29 In addition, Warren reported the decisions of proxies deciding whether to enroll their relative who lived in a
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nursing home in research that presented no direct benefit.21 One-third (17/55) consented to enroll their relative in the study of urinary catheters even though these caregivers reported that they thought their relative would not want to enroll. These results suggest the need for RADs in order to minimize the dignitary harm of enrolling subjects in research that they do not want to be involved in. Second, RADs may assist proxies who are reluctant to decide. Warren reported that among the proxies who declined to allow their relative to participate in the study, 60% reported an important reason was their reluctance to decide for the patient. This suggests that research advance planning may be very useful to address a primary reason for not enrolling a patient—the lack of guidance about the patient’s wishes. Finally, research advance planning may be feasible, especially in end-of-life research. Breitbart and colleagues used advance consent to recruit subjects for a study to test the efficacy and safety of potential treatments for delirium in hospitalized AIDS patients.30 The investigators obtained informed consent from all subjects admitted to hospital who were not delirious. Subjects were then enrolled if they became delirious. Here the model is not an advance directive. Instead, the immediacy and specificity of the study make the decision an advance consent. Although they do not report the efficiency of an advance consent process (the number of subjects recruited versus those enrolled), this approach suggests how an advance consent maybe especially feasible in research that involves persons at the end of life. Unlike patients with chronic diseases marked by long periods of impaired decision making abilities, patients at the end of life have comparatively short periods of incapacity. Hence, an advance consent will be salient and specific. As useful as these data are for supporting the concept of a RAD, research suggests a series of paradoxes in people’s attitudes about the uses and value of a RAD. A survey of 226 persons with a family history of Alzheimers disease found the vast majority willing to execute an RAD, but when offered the opportunity to execute one few did it.26 The majority preferred to have RAD instructions followed over a family member’s choice, but the majority also permitted a family member to overrule a RAD in the
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case of potentially beneficial research. These results suggest the following issues need further investigation. First, how would subjects who make RADs want them followed? In particular, how would subjects regard a proxy overriding RAD instruction not to enroll them in research that is not potentially beneficial? In clinical care, many persons want their best interests taken into consideration with their directive, even if that means overriding the directive.22 But “best interests” are an unusual standard in research settings where there is either no plausible individual benefit or real chances of risk to the research participant. In these situations, “best interests” might be understandable only as an appreciation for the altruistic intents of either the subject or the proxy. The answers to these issues will not decide whether we should have RADs, but they will go a long way to explaining the acceptability and feasibility of their use.
Recommendations That Delineate Reasonable Protections and Questions in Need of Study The accompanying table is a core set of subject protections drawn from the common aspects of the proposed guidelines and regulations. A critical point about this table is that it reflects a two-component rather than a whole protocol assessment of research risks and benefits. Hence, the key focus is the management of research risks that are solely justified by the importance of the knowledge the research can reasonably be expected to produce. These risks are categorized using the concept of minimal risk. But in the case of research that is at least greater than minimal risk, the prospect of a potential to benefit the subjects does not mitigate the need to provide additional protections. Below, are additional recommendations for each of the core subject protections discussed above.
Acceptable Research Risks: The Risk-Benefit and Risk-Knowledge Assessments Recommendation 1: Researchers and IRBs should adopt the two-component model of risk assessment to organize their assessment and documentation of research risks and benefits.
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Recommendation 2: Informed consent forms should reflect the two-component analysis of research risks. Specifically, the forms should clearly differentiate between risks and benefits that are in the category of therapeutic research risks versus risks in the category of nontherapeutic research. Plain statements should (1) describe that the risks are judged minimal, a minor increment above minimal or greater than a minor increment above minimal, and (2) justify these risks based on assessment of the value of the knowledge the research is reasonable expected to produce. Recommendation 3: Assessments of value should detail whether the knowledge will benefit the class of subjects or the subjects of the research themselves. Collectively, these data will allow patients and proxies to make a candid assessment of the costs and value of the sacrifice the research asks of them. Recommendation 4: Protocols should include clear plans to feedback the results of the research to the subjects and their proxies. This will limit the dignitary harm of being “used solely as a means to an end.”
Research Questions: 1. Does the two-component risk assessment model work? That is, can investigators and IRB members achieve reasonable agreement when they apply the model? 2. What is the impact of a two-component disclosure of research risks and benefits on subject decisionmaking? Specifically, does this disclosure improve subject understanding, appreciation and reasoning and does it affect willingness to participate?
Proxy Decision Making Recommendation 5: Proxies should know that they are serving as a proxy. Hence, informed consent forms should include a clear documentation whether the subject’s signature represents an informed consent from a competent subject or an assent. Recommendation 6: The form should also include a section called “the role of a proxy in this study.” This will describe why they are acting as proxy and describe the substituted judgement and best interests standards of proxy decision-making.
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Table 1 Proposed Guidelines for Research That Involves Subjects Who Cannot Consent The following are guidelines for subject protections for nontherapeutic research risks. In the case of research that presents a reasonable prospect for direct benefit to the subjects, proxy informed consent is necessary. Any additional protections should be determined based on the level of nontherapeutic research risks Protections That Establish Permissible Research
Proxy Consent Nontherapeutic Minimal Riska Research Procedures Minor Increment Above Minimal Risk Greater Than a Minor Increment Above Minimal Risk
Subject Assent
Subject Dissent
Evidence of Advance Preference
Documentation can Not necessary Respected Not necessary be modified and even waived Documentedb Necessary Respected Evidence neededc Documentedb
Necessary
Respected Evidence needed
Other
d d,e
a Minimal
risk as defined in 45CFR46 with healthy persons as the comparison group. should have a history of making decisions for the patient, assisting with activities of daily living and serving as a knowledgeable informant with healthcare professionals. c If proxy fulfills criteria of #1, then it is reasonable to accept no evidence of subject’s prior preference. d Assessment of scientific value should determine that the knowledge that may reasonably be expected to result will benefit the subjects of the research. e This is a moral problematic category of research. It could be considered prohibited, or—if allowed—additional conditions are warranted such as consent auditor, review by a body outside the institution where the research is conducted. b Proxy
Recommendation 7: In the case of research that presents more than minimal risk, the proxy should fulfill other roles to assure that the proxy recognizes how the risks might impact the patient and has experience making decisions for the patient. In particular, the proxy should have a record of assisting the patient in activities of daily living, acting as decision maker and serving as a knowledgeable informant to health care professionals. This is as important as the legally authorized representative’s informed consent. Hence, some subjects may have two proxies: one who is recognized under the law and the other who fulfills the roles described above.
things to people who either object or agree but are not competent when they say so. Recommendation 8: Subject assent-dissent can be tied to the research risk-benefit assessment. In the case of greater than minimal risk research, subject assent is necessary. In the case of all kinds of research, subject dissent is respected. Recommendation 9: A protocol should specify a standard to assess assent-dissent. It would be especially useful if the standard indicated the abilities the person has to demonstrate. For example, the subject must understand this is research and appreciate that the research will provide no direct medical benefit to them.
Research Questions: 1. How well do professional judgments of competency match lay judgments? 2. Can subject communities develop legitimate representation that assists in a consensus on the socially acceptable level of nontherapeutic research risk?
Research Questions: 1. What is a reasonable standard to assess assent and dissent? 2. How reliable and valid are standards for judging the ability to assent or dissent?
Subject Assent and Dissent
Subject Advance Consent
Essential work needs to be done to clarify the validity of the construct of assent-dissent. However, reasonable protections are warranted that largely satisfy our discomfort with doing
Recommendation 10: In the case of research that enrolls subjects who have a reasonable prospect of losing their decision-making capacity during the course of
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the research, the investigator should have the subject designate a person who will serve as proxy for the subject. Recommendation 11: In the case of research that is greater than minimal risk and will enroll a subject upon the loss of capacity, investigators should attempt to obtain advance consent from the subject.
Research Questions: 1. Do people who are likely to face research decisions value a research advance directive? 2. Are persons who are at risk of losing their capacity capable of executing a research advance directive or advance consent? 3. How much leeway do potential subjects want their proxy to exercise in interpreting their substituted judgments? 4. What is the moral appropriateness of the transfer of altruistic goals from proxy to patient?
Conclusion This paper begins with the problem of the noncompetent person at the end of life who cannot provide an informed consent to enroll in research. The recommendations and research questions above are limned out in an attempt to compensate for the inability to fulfill the principle of respect for autonomy. But two points suggest the need to attend to other issues than fulfilling the principle of respect for autonomy. First, a political condition must exist. Key power brokers need to recognize the class of subjects as uniform and readily identifiable, such as children, and that other people can represent members of this group, such as parents for children. But subjects who are decisionally impaired, at the end of life, and are not emergently-ill are heterogeneous. They got to this state by very different illnesses. This includes persons with progressive neurodegenerative diseases, delirium, critical illness and chronic medical diseases. The challenges then are how to collect these people into a class or subclasses that can be regarded as uniform and readily identifiable, and who can represent them. Second, how much do our efforts to sustain the autonomy of the noncompetent subject re-
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flect and impact on the reasons why people enroll in research? These reasons include trust in the system that designs and conducts the research.20, 31 Efforts to document preferences, assess capacity, and solicit assent or dissent do little to address the conditions that establish trust, such as conflicts of interest, data ownership and the confusion of clinician-researcher roles.32 In fact, to the extent that they cultivate an ethos of voluni non fit injuria (i.e., “you signed up, so I’m not to blame”), they may even hinder trust. This is not to suggest that the protections discussed above are wrong or inappropriate. But society does not simply ask parents to sign permission forms. It takes steps to assure that parents can trust the people who educate, coach and otherwise supervise their children. So too, equal attention is warranted to establish conditions that allow a proxy to trust a researcher.
Acknowledgments Dr. Karlawish is supported by a Greenwall Faculty Scholars Award in Bioethics, a Paul Beeson Physician Faculty Scholars Award, and NIA grants K01 AG-00931 and P30-AG01024.
References 1. Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA 2000;283:2701–2711. 2. Department of Health and Human Services. Common Rule, 45 CFR 46. Federal policy for the protection of human subjects; Notices and rules. Fed Reg 1991;56:28003–28032. 3. Council of Europe. Convention for the Protection of Human Rights and Dignity of the Human Being with Regard to the Application of Biological and Medical Convention on Human Rights and Biomedicine. www.cm.coe.int/dec/1996/578/578.101.html. 4. Tri-Council Working Group. Code of Conduct for Research Involving Humans. www.ethics.ubc.ca/ code/ July 11, 2002. 5. Department of Health and Human Services. Food and Drug Administration. Protection of human subjects; Informed consent and waiver of informed consent requirements in certain emergency research; Final rules. Title 21, Code of Federal Regulation, Part 50.24. Fed Reg 1996;61:51528–51533. 6. Department of Health, Education and Welfare. Protection of human subjects. Proposed regulations on research involving those institutionalized as mentally-disabled. Fed Reg 1978;43:53950–53956. 7. National Bioethics Advisory Commission. Research involving persons with mental disorders that
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may affect their decision-making capacity. Vol. I: Report and recommendations. Rockville, MD: National Bioethics Advisory Commission, 1998. 8. Maryland Attorney General’s Working Group on Research Involving Decisionally Incapacitated Subjects. Final Report of the Attorney General’s Working Group on Research Involving DecisionallyImpaired Subjects. Baltimore, MD: Office of the Maryland Attorney General, 1998. 9. New York State Advisory Work Group on Human Subjects Research Involving the Protected Classes. Recommendations on the Oversight of Human Subject Research Involving the Protected Classes. Albany, NY: State of New York Department of Health, 1998. 10. Ramsey P. The enforcement of morals: Nontherapeutic research on children. Hastings Cent Rep 1976;6:21–30. 11. Wendler D, Prasad K. Core safeguards for clinical research with adults who are unable to consent. Ann Intern Med 2001;135:514–523. 12. Levine RJ. Research in emergency situations. The role of deferred consent. JAMA 1995;273:1300–1302. 13. Karlawish JHT, Hall JB. The controversy over emergency research: A review of the issues and suggestions for a resolution. Am J Respir Crit Care Med 1996;153:499–506. 14. McRae AD, Weijer C. Lessons from everyday lives: a moral justification for acute care research. Crit Care Med 2002;30:1146–1151. 15. Weijer C. The ethical analysis of risk. J Law Med Ethics 2000; 28:344–361. 16. Freedman B. Equipoise and the ethics of clinical research. N Engl J Med 1987;317:141–145. 17. Casarett D, Karlawish JHT, Moreno JD. How assessing value can contribute to human subjects protections. IRB: Ethics and Human Research. In press. 18. Meisel A. The Right to Die, 2nd ed. New York: Wiley, 1996. 19. Schulz R, O’Brien A, Bookwala J, Fleissner K. Psychiatric and physical morbidity effects of dementia caregiving: Prevalence, correlates, and causes. Gerontologist 1995;35:771–791. 20. Karlawish JHT, Casarett D, Klocinksi J, Sankar P. How do AD patients and their caregivers decide
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whether to enroll in a clinical trial? Neurology 2001; 56:789–792. 21. Warren JW, Sobal J, Tenney JH, et al. Informed consent by proxy: An issue in research with elderly patients. N Engl J Med 1986;315:1124–1128. 22. Sehgal A, Galbraith A, Chesney M, et al. How strictly do dialysis patients want their advance directive followed? JAMA 1992;267:59–63. 23. Sugarman J, Cain C, Wallace R, Welsh-Bohmer KA. How proxies make decisions about research for patients with Alzheimer’s Disease. J Am Geriatr Soc 2001;49:1110–1119. 24. Kim SYH, Karlawish JHT, Caine ED. Current state of research on decision-making competence of cognitively impaired elderly. Am J Geriatr Psychiatry 2002;10:151–165. 25. Emanuel LL, Barry MJ, Stoeckle JD, Ettelson LM, Emanuel EJ. Advance directives for medical care—a case for greater use. N Engl J Med 1991;324: 889–895. 26. Wendler D, Martinez RA, Fairclough D, Sunderland T, Emanuel E. Views of potential subjects toward proposed regulations for clinical research with adults unable to consent. Am J Psychiatry 2002;159: 585–591. 27. Sulmasy DP, Terry PB, Weisman CS, et al. The accuracy of substituted judgements in patients with terminal diagnoses. Ann Intern Med 1998;128:621– 629. 28. Sachs GA, Stocking CB, Stern R, et al. Ethical aspects of dementia research: informed consent and proxy consent. Clinical Res 1994;42:403–412. 29. Muncie HL, Jr., Magaziner J, Hebel R, Warren JW. Proxies’ decisions about clinical research participation for their charges. J Am Geriatr Soc 1997;45: 929–933. 30. Breitbart W, Marotta R, Platt MM, et al. A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry 1996;153:231–237. 31. Kass NE, Sugarman J, Faden R, Schoch-Spana M. Trust: The fragile foundation of contemporary biomedical research. Hastings Cent Rep 1996;26:25–29. 32. O’Neill O. Autonomy and Trust in Bioethics. Cambridge: Cambridge University Press, 2002.
Journal of Pain and Symptom Management
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Special Article
Conducting Research That Involves Subjects at the End of Life Who Are Unable to Give Consent Jason H.T. Karlawish, MD Department of Medicine; Division of Geriatrics; Leonard Davis Institute of Health Economics; Center for Bioethics; and Alzheimers Disease Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Abstract This paper examines the conditions that describe when it is appropriate to conduct research that enrolls a subject near the end-of-life who cannot provide an informed consent. Specifically, it describes conditions that justify when it is acceptable to expose a person to the risks, burdens or discomforts of an intervention that is not intended to benefit that person but to produce generalizable knowledge that will benefit other people. These conditions are: (1) acceptable research risks, (2) proxy decision making, (3) subject assent and dissent, and (4) subject advance consent. J Pain Symptom Manage 2003;25:S14–S24. © 2003 U.S. Cancer Pain Relief Committee. Published by Elsevier. All rights reserved. Key Words End-of life research, research ethics, informed consent, proxy decision making
Introduction Informed consent is a key requirement for the ethical conduct of human subjects research.1 Under what conditions is it appropriate to conduct research that enrolls a subject who cannot provide an informed consent? Regulations exist to guide ethical practice of research that involves children2 (Subpart D). But in the case of research that involves adults who cannot provide an informed consent, a coherent and widely accepted answer to this question has been elusive. Although Europe and Canada have enacted regulations that describe a matrix of subject protections,3,4 the United States’ reg-
Address reprint requests to: Jason H.T. Karlawish, MD, University of Pennsylvania, Division of Geriatric Medicine, Ralston-Penn Center, Rm. 234, 3615 Chestnut Street, Philadelphia, PA 19104-2676, USA. Accepted for publication: December 16, 2002. © 2003 U.S. Cancer Pain Relief Committee Published by Elsevier. All rights reserved.
ulatory structure is incomplete and even piecemeal. Federal regulations guide the conduct of research with the emergently-ill.5 But in the case of research that involves adults who are decisionally impaired but not emergently-ill—such as persons near the end-of-life—at least two national6,7 and two state-wide8,9 efforts to adopt regulations have not succeeded. Of course, regulations do not guarantee that activities done under their guidance are ethical. Their subsequent review may show that they are misguided, even unethical, and should be revised or even rescinded. But the failure to adopt regulations suggests that there is not sufficient coherence or consensus to agree upon a reasonable set of guidelines about how to conduct research that involves subjects who are unable to give consent. There are at least two costs to the failure to adopt a reasonable set of guidelines. First, research is often the most efficient and valid method to generate valuable knowledge that 0885-3924/03/$–see front matter doi:10.1016/S0885-3924(03)00098-8
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improves patient care. Without these data, what is done with therapeutic intent may actually harm patients and their family caregivers. Second, there is a need to address a dignitary wrong. The issue here is not whether the research exposes a subject to harm, but the moral wrong of using a person as a means to an end and only as a means to an end. The heart of the matter is as follows: Can we do this research in a manner that is moral or do we sin bravely?10 In other words, are there any conditions that justify proxy altruism? These questions are especially prescient in the case of research that involves patients at the end of life. Unlike patients in the early stages of chronic diseases or with diseases that wax and wane, the dying are a population who will likely not live to benefit from the knowledge they contributed to.
Brief Overview of the Literature Research that involves persons at the end of life who cannot provide an informed consent presents the following question. Under what conditions is it acceptable to expose a person to the risks, burdens or discomforts of an intervention that is not intended to benefit that person but to produce generalizable knowledge that will benefit other people? A useful side by side review of U.S., Canadian and European guidelines identifies six core safeguards that establish these conditions: institutional risk-benefit assessment, consent assessment, necessity requirement, proxy decision maker and sufficient evidence of patients’ remaining preferences and interests, respect for patient assent and dissent, and independent monitors.11 Casarett’s companion paper addresses the issues of consent assessment and independent monitors. This paper’s foci are: (1) acceptable research risks (institutional risk-benefit assessment and the necessity requirement), (2) proxy decision making, (3) subject assent and dissent, and (4) subject advance consent.
Acceptable Research Risks: The Risk-Benefit and Risk-Knowledge Assessments The categorization of research risks and benefits is at the core of determining that a research
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project that involves persons who cannot consent is ethically appropriate. These categories reflect the degree that the principle of beneficence is fulfilled. The less this is fulfilled, the more additional subject protections are required. In other words, increasing research risks warrant increasing subject protections such as Items 2 through 4 discussed below. A core construct to describe research risks is “minimal risk,” defined as “the probability and magnitude of physical or psychological harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life, or during the performance of routine physical or psychological examinations or tests2 (46.102(i)).” Minimal risk is critical for determining the moral appropriateness of research that involves a variety of vulnerable populations—children, prisoners, and fetuses2 (Subparts b–d). It is also an essential guide for waivers and modifications of informed consent in research that involves nonvulnerable populations2 (§46.116d). In the case of research that involves noncompetent adults, the general proposal is as follows. Greater than minimal risk research risks require additional subject protections. Noncompetent subjects need to either provide an assent, not dissent, or have provided an informed consent previously when competent— i.e., advance consent. The consent of a proxy is required as well. The specific combinations of these protections vary across proposals. They rely on a more finer risk assessment, in particular whether the research risks are a minor increment or greater than a minor increment above minimal risk. In the case of research risks that are greater than a minor increment above minimal risk, there is general agreement that proxy consent with subject assent is an insufficient subject protection. Instead, the research may require that the subject either provide an advance consent or it is prohibited. This matrix of risk and consent is appealing. It reflects the intuitively sensible concept that in life some level of risk is tolerated without substantive deliberation. But operationalizing this in the conduct of research that involves adults who cannot deliberate remains controversial. Two issues limn out the features of this controversy: how to interpret who is the subject of the definition of minimal risk and to what risks does minimal risk apply.12–14
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There are two perspectives on to whom the risks of daily life should be compared. One is that the risks and benefits of the research should be compared to the risks and benefits faced by the subjects. The other is that the risks and benefits should be compared to the risks and benefits faced by healthy persons. Out of each of these perspectives emerge very different risk assessments. Consider the case of a randomized and placebo-controlled trial to assess whether a psychostimulant will increase the alertness of patients with profound to terminal stage Alzheimer’s disease (AD). The perspective of the patient as the subject of the minimal risk definition leads to the following assessment. Patients with this stage AD face a number of risks as a result of both their illness—e.g., pressure ulcers, infections, aspiration—as well as efforts to care for them— e.g., combativeness when cared for. In a word, they are very sick. The proposed study has risks related to the medication, and tests to assess safety and efficacy, but when weighed against these every day risks and the potential benefits of the experimental medication, they are minimal. Hence, the study is likely minimal risk and could proceed with proxy consent with subject assent. In contrast, the perspective of healthy persons would regard the study risks as certainly outside the realm of usual and everyday risks in the care of healthy persons. The study would be greater than minimal risk and either require subject advance consent or simply be prohibited. These differing interpretations have been ever present. Until the 1991 revision of the Common Rule, the definition of minimal risk went through three versions that largely revolved around either stating that the subject of the definition was the research subject or healthy persons.13 The final version does not denote any subject, but the regulations’ comments section states that subject of the research is the subject of the definition. This would imply that vulnerable subjects could be exposed to greater risks because they are exceedingly ill. Such a conclusion perverts the very point of talking about research ethics in the first place: that vulnerable subjects deserve protections at least as good as those accorded to nonvulnerable subjects, such as healthy persons. In the 1990’s this perversion was at the core of the debate over the waiver of informed consent in emergency research. At first glance, this
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seems an entirely incongruous subject population to examine the ethics of research that involves persons at the end of life. But the two classes of subjects have morally relevant similarities—they are very ill and near death. A common remark about research that involves the dying is that they are so ill anyway, what is the added harm of the research? Hence, the different perspectives on how people assessed risks faced by the emergently-ill inform an assessment of risks faced by dying patients. In brief, investigators were using the subject of the research interpretation of minimal risk in order to waive informed consent on the basis of the Common Rule’s provisions for the waiver or modification of informed consent under conditions of minimal risk. This created the irony that a provision usually employed to waive informed consent for projects such as survey research or a single venous blood draw was being applied to randomized trials of cardiopulmonary resuscitation interventions. Federal officials argued that the definition was applied to healthy persons and exercised its authority to shut down emergency research that waived informed consent. Irate researchers demanded a solution. The result was a set of emergency research specific regulations that sidestepped the issue of how to interpret minimal risk5 (21CFR50.24). Instead, the regulations adopted a “whole protocol assessment” of research risks. Acceptable risk was based on balancing all the risks as well as benefits faced by the subjects: the risks of their medical condition, the risks and benefits of standard therapy and the risks and benefits of the proposed intervention. The problem with this whole protocol assessment is that it suggests that the more ill the patient, the more risk they can be exposed to.14 This upends the norm that vulnerable populations deserve protection that is at least commensurate with nonvulnerable populations. A rewording of this to focus on a comparison of the risks faced by healthy persons would have the opposite effect of rendering all research at least greater than a minor increment of minimal risk. In sum, the whole protocol approach leads to a quandary described by the extremes of either under or over protection. The way out of this quandary is to focus on the question of to what risks does minimal risk apply? The answer to this question is not
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readily apparent in any one set of research regulations or guidelines, or the companion papers that accompany them.15 The progression of the National Commission’s work illustrates that they were not developing a whole protocol model of research risk assessment, but instead a two-component model. The first component is all therapeutic research procedures. The risks of these procedures are justified by their potential benefits to the subjects. This condition is met if there is an honest disagreement in the expert community as to what is the preferred intervention, socalled equipoise.16 Assessment of this component determines whether the research is “potentially beneficial” to the subjects. The second component is the risks of nontherapeutic procedures. These are procedures that are done solely to produce generalizable knowledge. The risks of these procedures are justified by a risk-knowledge assessment. Specifically, they are balanced against the importance of the knowledge the research can reasonably produce. In the case of research that involves noncompetent subjects, this risk should be no more than either minimal or a minor increment above minimal risk. This assessment exposes plainly the core issue: what risks should people undergo to advance a common good? Hence, these risks should be compared to the risks healthy people face in medical care. A higher threshold of risk places vulnerable patients at increased risk of exploitation. The two-component model of research risk assessment has an appealing logic. It articulates the Common Rule’s requirement that risks are reasonable with respect to two kinds of benefits: (1) the anticipated benefits, if any, to the subjects, and (2) the importance of the knowledge that may reasonably be expected to result2 (§45CFR46.111(a)(2)). Research risks are demarcated into substantively different categories: those that are part of therapeutic interventions (benefit category #1) versus those that are part of nontherapeutic interventions (benefit category #2). Examples of therapeutic interventions include comparing a new drug to the standard of care drug or systematically recording patients’ routine pain scale scores. Examples of nontherapeutic interventions include comparing new drug to placebo in patients for whom a well established standard of care exists, or recording pain scale scores at
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a frequency greater than routine, such as to test interrater reliability of a new scale. But as appealing as this model is, it is difficult to operationalize. Specifically, what really are therapeutic research interventions? For example, if equipoise exists between the risks and benefits of standard drug A and drug B, are randomization and blinding part of the therapeutic risks or nontherapeutic risks? Are they even risks? If the routine for use of standard drug A is that no blood monitoring is necessary, then are all blood draws in the research part of the therapeutic or nontherapeutic risks? The intent of the blood draws is to monitor drug safety. If they classified as nontherapeutic, they create a disincentive to include them in the protocol. Despite these limitations, the two-component model is appealing over the whole protocol model that lumps together the risks the subjects face as part of their illness, the risks and benefits of standard care, and the risks and potential benefits of the research intervention. The whole component model suggests that sicker patients, such as the dying, can be exposed to more risks in the pursuit of knowledge. In contrast, the two-component model reflects that risks and benefits fit into substantively different categories. Research involves interventions that may either benefit the subject or interventions that are done as part of clinical care but their data is also being used for research. These risks are substantively different from research interventions that are done not as part of clinical care but only for research. This model has two implications. First, it guides interpreting the so-called “necessity requirement.” The term describes the requirement that research that involves adults who are unable to consent should only be done if the research cannot obtain the desired information by enrolling adults who can consent. This requirement attempts to operationalize the norm that the most vulnerable are the “last in line” for assuming risk in the advancement of science. But efforts to define “necessity” descend into a frustrating exercise of what proportion of eligible and competent subjects would warrant excluding noncompetent subjects: 1%, 10%, 50%? A more sensible approach uses the risk-knowledge assessment to guide whether a project exposes noncompetent subjects to excessive risks in the pursuit of
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knowledge. The IRB needs to determine the value of the knowledge that can be reasonably expected to result and the likelihood that the subjects will benefit from that knowledge.17 Will it benefit the subjects of the research, the class of subjects, or another class of subjects? Risks that are greater than minimal should only be pursued if the research will produce knowledge that will benefit the subjects of the research. In this way, the subjects stand a reasonable prospect of benefit, albeit at the end of the research. If this is not possible, investigators should explore alternative designs such as the techniques of quality improvement. The second implication of the two-component approach is that it radically transforms the disclosure of research risks and benefits in the informed consent form. Specifically, forms should clearly distinguish among risks and benefits that are part of therapeutic interventions versus risks that are purely research interventions. This is developed in the “Recommendations” section. The extensive text devoted to the assessment of research risks and the two-component model of research risk assessment seems odd in light of the regulations that guide the conduct of research that involves children. These regulations rely significantly on the concept of minimal risk. It is likely though that the controversy over the subject of the definition and assessment of research risks has been tolerated in pediatric research because of the well-established status of a second subject protection: parents as proxies. In the case of research that involves adults at the end of life, such a proxy is not as socially and legally evident.
Proxy Decision Making Proxy consent is a core protection in all proposals for research that involves persons who cannot consent. But the absence of clear legal guidance on who can serve as a proxy for research that involves adults frustrates investigators and IRBs. It is a situation analogous to the events that began in clinical care some 30 years ago.18 Then, the issue was who can decide to terminate life-sustaining treatment. Case and statutory law has developed a standard that a hierarchy of family members can decide and developed standards of evidence that featured the patient’s wishes (a substituted judgement)
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over best interests. An analogous situation is taking place in the similarly morally controversial realm of making decisions for others about research. Proxy consent focuses on two issues: (1) who should serve as a proxy? and (2) how should the proxy decide whether to enroll the noncompetent subject? These issues are especially important in the case of research that presents greater than minimal risk. In this case, absent clear guidance from the patient that they would want to participate in such research, how can it be in the patient’s best interests to enroll? Who should serve as a proxy? Guidelines and proposed regulations recommend that a close friend or family member serve as a proxy. “Closeness” denotes an important condition. In the care of persons who are noncompetent as a result of a chronic and progressive illness such as brain cancer or multiple sclerosis, there is typically at least one family member who has the role of “caregiver.” In this role, they typically perform at least one of the following tasks: serve as knowledgeable informant to health care professionals about the patient’s health, make decisions with or even for the patient, and assist the patient in activities of daily living. In addition, as a result of these caregiving roles they experience depression, distress and related morbidity.19 In sum, a caregiver is both socially and institutionally sanctioned. Collectively, these roles describe a person with substantive moral standing as a proxy. They have experience in making decisions and working with health care professionals for the good of the patient. They recognize that research risks and benefits to themselves and to the patient are interdependent.20 For example, if the research helps the patient, the caregiver will benefit by a less intense caregiving role, and if the research harms the patient, the caregiver will have an increased caregiving role and possibly too a feeling of culpability. The implication of these qualities is that the proxy is not so much acting as the agent of the subject but is acting as the subject. That is, their interdependence describes an interstitial autonomy. Certainly, this point needs much more explication of the constructs of agency, autonomy and interdependence, but the point remains that some caregiver-patient relationships (whether as spouse to spouse or adult child to parent) blur the separateness of the people. This
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“closeness” can be operationalized into policy recommendations for the kind of person who can serve as a proxy for enrolling a noncompetent subject in greater than minimal risk research. How should the proxy decide whether to enroll the noncompetent subject? The general consensus adopts the position of clinical care decisions. The proxy’s decision should reflect a substituted judgment, that is, what the person would decide if they could decide for themselves. Unfortunately, just as in clinical care decisions, the professional ethic does not match the ethic in practice. Evidence suggests that proxies do not routinely use a substituted judgment. In fact, some proxy’s may enroll a subject even though they believe that the subject himself would not want to enroll.21 But this evidence may not be as morally distressing as it appears. People may not feature a substituted judgement as their preferred standard for how a proxy should decide for them. In clinical care, a substantial number of people want their proxy to decide based not on a substituted judgment but instead on their best interests.22 Whether this is true in research remains a question for empirical study, including what counts as a best interests judgment for enrolling in greater than minimal risk, non beneficial research. Studies of how proxies and patients make research decisions raise a final point on proxy decision-making.20,23 There may well be instances when a researcher and a proxy disagree that a patient is not competent. In other words, the researcher thinks that the patient is not competent, the family member is providing the informed consent and the subject providing assent, but the proxy thinks the patient is competent and has made the decision. The disagreement is important because the proxy may not appreciate the moral weight their signature represents on a consent form.
Subject Assent and Dissent The noncompetent subject’s either assent or lack of dissent is a common requirement in several guidelines. Guidelines link this requirement to the research risk benefit assessment. Specifically, a subject should show some ability to decide whether to enroll in greater than minimal risk research. They differ on whether
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the requirement is the subject’s assent or failure to dissent.11 Implicit in this protection is the concept that decisionmaking abilities are dimensional as opposed to categorical constructs. This means that a person may not have sufficient abilities to be competent to provide an informed consent, but his performance on measures of decision-making ability may fit into either one of two categories: (1) it is adequate to the degree that he can either assent or dissent, or (2) it falls below this threshold. Guidelines do suggest the factors that influence the ability to assent or dissent. For example, in the case of pediatric research2 (§46.408), the ability to assent is determined by the child’s age, maturity and psychological state, in other words, the degree of cognitive development. Among adults, the degree of premorbid cognitive development as well as cognitive impairment caused by a disease determine this. But what is missing is a clear consensus on a standard to assess the ability to assent-dissent. There is a substantial literature that examines the reliability and validity of standards to assess the abilities to be competent to consent or refuse,24 but no studies report the validity or reliability of standards to assess the abilities to assent or dissent. A side-by-side comparison of recommendations and regulations suggests great variability. In the Federal regulations for research that involve children, the National Commission For the Protection of Human Subjects defines assent as “a child’s affirmative agreement to participate in research. Mere failure to object should not, absent affirmative agreement, be construed as assent2 (§46.402(b)).” This suggests that assent is the ability to choose. In contrast, in the Commission’s proposed regulations for adults who lacked the ability to consent, the National Commission defined assent as “the ability to know (1) what procedures will be performed in the research and that he or she may withdraw from participation, (2) choose freely to undergo these procedures, and (3) communicate this choice unambiguously.6 (pg. 11332)” This standard adds some aspects of the ability to understand to the pediatric requirement of the ability to choose. The Canadian Tri-Council standard is that the subject should “understand the nature and consequences of the research4 (article 2.7).”
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The point of this side-by-side comparison is that merely saying “yes” (or “no”) may be insufficient evidence of the ability to assent (or dissent). Some other abilities may be necessary, such as understanding key facts or appreciating key risks. Unfortunately, no clear consensus exists on what would constitute a meaningful assent or dissent. But the true motivation of respecting an assent or dissent may have nothing to do with it being a sufficient expression of subject’s abilities or capacities to think about their choice to enroll or not enroll in the research. It may have nothing to do with our effort to respect some autonomous choice by the subject. Instead, it may reflect our discomfort with enrolling a patient in research when that patient expresses either adamant opposition to participation or blissfully ignorant agreement. In short, it feels wrong to force someone kicking and screaming into a protocol.
Subject Advance Consent Proxy consent may not be adequate in the case of research that presents risks and potential discomforts without a reasonable prospect of benefit to the subjects’ health. On what ethical grounds can another person enroll that patient? A common proposal is a research advance directive (RAD).7–9 Prior to incapacity, the potential subject indicates the kinds of research they would or would not participate in. At first glance, RADs seem odd. Few people, if any, have them, and the small portion of persons who have clinical advance directives (10 to 20%) suggests that RADs might be just as uncommon.25,26 The net effect of a policy of prospective authorization is a hindrance in the progress of valuable research. But three lines of evidence suggest that research advance planning may have a role. First, research advance planning may be a useful way to assure that proxies use substituted judgments when they decide whether to enroll a patient in research. Studies that compare the preferences of the potential subject versus their potential proxy largely recapitulate the results of similar studies in clinical care27— there is generally poor agreement between patient and proxy.28,29 In addition, Warren reported the decisions of proxies deciding whether to enroll their relative who lived in a
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nursing home in research that presented no direct benefit.21 One-third (17/55) consented to enroll their relative in the study of urinary catheters even though these caregivers reported that they thought their relative would not want to enroll. These results suggest the need for RADs in order to minimize the dignitary harm of enrolling subjects in research that they do not want to be involved in. Second, RADs may assist proxies who are reluctant to decide. Warren reported that among the proxies who declined to allow their relative to participate in the study, 60% reported an important reason was their reluctance to decide for the patient. This suggests that research advance planning may be very useful to address a primary reason for not enrolling a patient—the lack of guidance about the patient’s wishes. Finally, research advance planning may be feasible, especially in end-of-life research. Breitbart and colleagues used advance consent to recruit subjects for a study to test the efficacy and safety of potential treatments for delirium in hospitalized AIDS patients.30 The investigators obtained informed consent from all subjects admitted to hospital who were not delirious. Subjects were then enrolled if they became delirious. Here the model is not an advance directive. Instead, the immediacy and specificity of the study make the decision an advance consent. Although they do not report the efficiency of an advance consent process (the number of subjects recruited versus those enrolled), this approach suggests how an advance consent maybe especially feasible in research that involves persons at the end of life. Unlike patients with chronic diseases marked by long periods of impaired decision making abilities, patients at the end of life have comparatively short periods of incapacity. Hence, an advance consent will be salient and specific. As useful as these data are for supporting the concept of a RAD, research suggests a series of paradoxes in people’s attitudes about the uses and value of a RAD. A survey of 226 persons with a family history of Alzheimers disease found the vast majority willing to execute an RAD, but when offered the opportunity to execute one few did it.26 The majority preferred to have RAD instructions followed over a family member’s choice, but the majority also permitted a family member to overrule a RAD in the
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case of potentially beneficial research. These results suggest the following issues need further investigation. First, how would subjects who make RADs want them followed? In particular, how would subjects regard a proxy overriding RAD instruction not to enroll them in research that is not potentially beneficial? In clinical care, many persons want their best interests taken into consideration with their directive, even if that means overriding the directive.22 But “best interests” are an unusual standard in research settings where there is either no plausible individual benefit or real chances of risk to the research participant. In these situations, “best interests” might be understandable only as an appreciation for the altruistic intents of either the subject or the proxy. The answers to these issues will not decide whether we should have RADs, but they will go a long way to explaining the acceptability and feasibility of their use.
Recommendations That Delineate Reasonable Protections and Questions in Need of Study The accompanying table is a core set of subject protections drawn from the common aspects of the proposed guidelines and regulations. A critical point about this table is that it reflects a two-component rather than a whole protocol assessment of research risks and benefits. Hence, the key focus is the management of research risks that are solely justified by the importance of the knowledge the research can reasonably be expected to produce. These risks are categorized using the concept of minimal risk. But in the case of research that is at least greater than minimal risk, the prospect of a potential to benefit the subjects does not mitigate the need to provide additional protections. Below, are additional recommendations for each of the core subject protections discussed above.
Acceptable Research Risks: The Risk-Benefit and Risk-Knowledge Assessments Recommendation 1: Researchers and IRBs should adopt the two-component model of risk assessment to organize their assessment and documentation of research risks and benefits.
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Recommendation 2: Informed consent forms should reflect the two-component analysis of research risks. Specifically, the forms should clearly differentiate between risks and benefits that are in the category of therapeutic research risks versus risks in the category of nontherapeutic research. Plain statements should (1) describe that the risks are judged minimal, a minor increment above minimal or greater than a minor increment above minimal, and (2) justify these risks based on assessment of the value of the knowledge the research is reasonable expected to produce. Recommendation 3: Assessments of value should detail whether the knowledge will benefit the class of subjects or the subjects of the research themselves. Collectively, these data will allow patients and proxies to make a candid assessment of the costs and value of the sacrifice the research asks of them. Recommendation 4: Protocols should include clear plans to feedback the results of the research to the subjects and their proxies. This will limit the dignitary harm of being “used solely as a means to an end.”
Research Questions: 1. Does the two-component risk assessment model work? That is, can investigators and IRB members achieve reasonable agreement when they apply the model? 2. What is the impact of a two-component disclosure of research risks and benefits on subject decisionmaking? Specifically, does this disclosure improve subject understanding, appreciation and reasoning and does it affect willingness to participate?
Proxy Decision Making Recommendation 5: Proxies should know that they are serving as a proxy. Hence, informed consent forms should include a clear documentation whether the subject’s signature represents an informed consent from a competent subject or an assent. Recommendation 6: The form should also include a section called “the role of a proxy in this study.” This will describe why they are acting as proxy and describe the substituted judgement and best interests standards of proxy decision-making.
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Table 1 Proposed Guidelines for Research That Involves Subjects Who Cannot Consent The following are guidelines for subject protections for nontherapeutic research risks. In the case of research that presents a reasonable prospect for direct benefit to the subjects, proxy informed consent is necessary. Any additional protections should be determined based on the level of nontherapeutic research risks Protections That Establish Permissible Research
Proxy Consent Nontherapeutic Minimal Riska Research Procedures Minor Increment Above Minimal Risk Greater Than a Minor Increment Above Minimal Risk
Subject Assent
Subject Dissent
Evidence of Advance Preference
Documentation can Not necessary Respected Not necessary be modified and even waived Documentedb Necessary Respected Evidence neededc Documentedb
Necessary
Respected Evidence needed
Other
d d,e
a Minimal
risk as defined in 45CFR46 with healthy persons as the comparison group. should have a history of making decisions for the patient, assisting with activities of daily living and serving as a knowledgeable informant with healthcare professionals. c If proxy fulfills criteria of #1, then it is reasonable to accept no evidence of subject’s prior preference. d Assessment of scientific value should determine that the knowledge that may reasonably be expected to result will benefit the subjects of the research. e This is a moral problematic category of research. It could be considered prohibited, or—if allowed—additional conditions are warranted such as consent auditor, review by a body outside the institution where the research is conducted. b Proxy
Recommendation 7: In the case of research that presents more than minimal risk, the proxy should fulfill other roles to assure that the proxy recognizes how the risks might impact the patient and has experience making decisions for the patient. In particular, the proxy should have a record of assisting the patient in activities of daily living, acting as decision maker and serving as a knowledgeable informant to health care professionals. This is as important as the legally authorized representative’s informed consent. Hence, some subjects may have two proxies: one who is recognized under the law and the other who fulfills the roles described above.
things to people who either object or agree but are not competent when they say so. Recommendation 8: Subject assent-dissent can be tied to the research risk-benefit assessment. In the case of greater than minimal risk research, subject assent is necessary. In the case of all kinds of research, subject dissent is respected. Recommendation 9: A protocol should specify a standard to assess assent-dissent. It would be especially useful if the standard indicated the abilities the person has to demonstrate. For example, the subject must understand this is research and appreciate that the research will provide no direct medical benefit to them.
Research Questions: 1. How well do professional judgments of competency match lay judgments? 2. Can subject communities develop legitimate representation that assists in a consensus on the socially acceptable level of nontherapeutic research risk?
Research Questions: 1. What is a reasonable standard to assess assent and dissent? 2. How reliable and valid are standards for judging the ability to assent or dissent?
Subject Assent and Dissent
Subject Advance Consent
Essential work needs to be done to clarify the validity of the construct of assent-dissent. However, reasonable protections are warranted that largely satisfy our discomfort with doing
Recommendation 10: In the case of research that enrolls subjects who have a reasonable prospect of losing their decision-making capacity during the course of
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the research, the investigator should have the subject designate a person who will serve as proxy for the subject. Recommendation 11: In the case of research that is greater than minimal risk and will enroll a subject upon the loss of capacity, investigators should attempt to obtain advance consent from the subject.
Research Questions: 1. Do people who are likely to face research decisions value a research advance directive? 2. Are persons who are at risk of losing their capacity capable of executing a research advance directive or advance consent? 3. How much leeway do potential subjects want their proxy to exercise in interpreting their substituted judgments? 4. What is the moral appropriateness of the transfer of altruistic goals from proxy to patient?
Conclusion This paper begins with the problem of the noncompetent person at the end of life who cannot provide an informed consent to enroll in research. The recommendations and research questions above are limned out in an attempt to compensate for the inability to fulfill the principle of respect for autonomy. But two points suggest the need to attend to other issues than fulfilling the principle of respect for autonomy. First, a political condition must exist. Key power brokers need to recognize the class of subjects as uniform and readily identifiable, such as children, and that other people can represent members of this group, such as parents for children. But subjects who are decisionally impaired, at the end of life, and are not emergently-ill are heterogeneous. They got to this state by very different illnesses. This includes persons with progressive neurodegenerative diseases, delirium, critical illness and chronic medical diseases. The challenges then are how to collect these people into a class or subclasses that can be regarded as uniform and readily identifiable, and who can represent them. Second, how much do our efforts to sustain the autonomy of the noncompetent subject re-
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flect and impact on the reasons why people enroll in research? These reasons include trust in the system that designs and conducts the research.20, 31 Efforts to document preferences, assess capacity, and solicit assent or dissent do little to address the conditions that establish trust, such as conflicts of interest, data ownership and the confusion of clinician-researcher roles.32 In fact, to the extent that they cultivate an ethos of voluni non fit injuria (i.e., “you signed up, so I’m not to blame”), they may even hinder trust. This is not to suggest that the protections discussed above are wrong or inappropriate. But society does not simply ask parents to sign permission forms. It takes steps to assure that parents can trust the people who educate, coach and otherwise supervise their children. So too, equal attention is warranted to establish conditions that allow a proxy to trust a researcher.
Acknowledgments Dr. Karlawish is supported by a Greenwall Faculty Scholars Award in Bioethics, a Paul Beeson Physician Faculty Scholars Award, and NIA grants K01 AG-00931 and P30-AG01024.
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