Article Text

Download PDFPDF

Paper
Is best interests a relevant decision making standard for enrolling non-capacitated subjects into clinical research?
  1. Jeffrey T Berger
  1. Correspondence to Dr Jeffrey T Berger, Associate Professor of Medicine, Stony Brook University School of Medicine, Director of Clinical Ethics and Chief Section of Hospice and Palliative Medicine, Winthrop University Hospital, 222 Station Plaza North, Suite 518, Mineola NY 11501, USA; jberger{at}winthrop.org

Abstract

The ‘best interests’ decision making standard is used in clinical care to make necessary health decisions for non-capacitated individuals for whom neither explicit nor inferred wishes are known. It has been also widely acknowledged as a basis for enrolling some non-capacitated adults into clinical research such as emergency, critical care, and dementia research. However, the best interests standard requires that choices provide the highest net benefit of available options, and clinical research rarely meets this criterion. In the context of modern norms of bioethics, the best interests standard rarely supports surrogate consent for research and should not be accepted as a routine provision.

  • Best interests
  • surrogate decision making
  • informed consent
  • research ethics
  • philosophy of medicine
  • third party consent/incompetents
  • research on special populations

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Introduction

‘Best interests’ is the decision making standard used in clinical care to make necessary health decisions for non-capacitated individuals for whom neither explicit nor inferred wishes are known.1 2 This ethical norm has been also widely acknowledged as a basis for enrolling some non-capacitated adults into clinical research such as emergency, critical care and dementia research.3–5 However, on closer examination, and in the context of modern bioethics, the best interests standard poorly supports surrogate consent for research.

Background

Clinical research is never primarily intended to provide direct benefit to its subjects. Rather, it is structured to test hypotheses and is intended to benefit both future persons and to serve the common good. Its great value notwithstanding, research is ethically complex since the risk of harm (to subjects) and the expected accrual of benefit (to future patients) are dissociated from each other. These complexities are compounded when research requires the involvement of persons whose capacity to consent is impaired. These and related concerns are addressed using a bioethical-legal framework that sets limits on research associated risks and emphasises respect for autonomy through informed consent.6 7 Decision making for persons without capacity follows a hierarchy of three standards crafted to maximally respect individual autonomy.1 8 9 These standards are known wishes, substituted judgements and best interests. Although none of these standards easily applies to decisions about research, the best interests standard is the most problematic.

The first standard, known wishes, requires that decisions follow persons' prior direct expression of preference. However, this standard is difficult to apply in research because research decisions are usually more complex than decisions about treatment, persons rarely anticipate these choices with specificity sufficient to meet this standard, and, at least according to US legal requirements, the degree to which consent for research must be informed is greater than it is for treatment.10 The next standard, substituted judgements, requires surrogates to make decisions that ‘reflect the patient's views and values’.1 However, as the American College of Physicians aptly notes, research surrogates' ‘substituted judgements as to participation in research are likely to be highly speculative, as most incompetent people … were never presented with such a choice in the past and are unlikely to have formulated and expressed opinions on the matter’.11

Lastly, the best interests standard is operational when ‘a surrogate does not have serviceable knowledge of the patient bearing on the treatment choice at hand’.8 It requires a determination of highest net benefit and, in the view of Beauchamp and Childress, surrogates should consider net benefits only as far as they affect of quality of life of the patient.1 However, as I will discuss, it is difficult, if not often impossible, to determine that enrolment into research offers the highest net benefit because, among other reasons, most clinical research is intended either to demonstrate absence of harm (early phase trials) or to establish benefit (later phase trials), and because research is never primarily intended to directly benefit its subjects. Moreno notes, there is an ‘…absence of reliable direct benefits to participation for the human subject’.12 Federal requirements for safeguards to minimise risk in non-capacitated research notwithstanding,10 benefits from research are often speculative. How then, does the best interests standard serve as an affirmative basis for surrogate decisions for research?

Normative positions on best interests in research

Numerous ethical and legal statements on the ethics of human subjects research allude to non-capacitated persons' best interests.13 The Belmont Report, issued in 1979 by the National Commission for the Protection of Human Subjects of Biomedical and Behavioural Research, states that ‘the third parties chosen should be those who are most likely to understand the incompetent subject's situation and to act in that person's best interest’.14 The American Geriatrics Society maintains that surrogates may withhold or withdraw consent for research if, in the surrogate's view, such participation is not in the person's best interests.4 The American College of Physicians stipulates that ‘a surrogate may properly consent to therapeutic research … if a careful weighing of the risks and benefits shows that foregoing standard treatment (or no treatment, if none exists) to participate is in the incompetent person's best interest.’11 Although the American College of Physicians' statement implies that both the likelihood and magnitude of benefits from participating in a particular research study can be reasonably assessed, it also states that ‘because the potential benefits of experimental or innovative therapy are to a substantial degree still speculative, exposing subjects to substantially greater levels of risk than those associated with standard treatment (or with no treatment, if none exists) would not be in the subject's best interests’.

The National Bioethics Advisory Commission, under the Clinton Administration, in its report Research involving persons with mental disorders that may affect decision making capacity concluded that ‘Where the LAR [legally authorised representative] lacks any evidence about the person's values and preferences, the LAR may not grant permission … unless judgements about that person's “best interests” could warrant such permission. Great caution is needed, however, because LARs also may succumb to the therapeutic misconception, and … make inappropriate judgements about the subject's best interests’.15 Its apt admonition notwithstanding, the Commission does not elucidate the many challenges to applying best interests determinations to research.

An exception to the inclusion of best interests in statements on research ethics may be found in a European Union directive. With respect to non-capacitated subjects, the directive explicitly states that ‘consent must represent the subject's presumed will’.16 This suggests decision making must conform to subjects' known or inferred wishes and seems to proscribe enrolment based merely on subjects' interests. However, some member states disagree with this restriction and maintain that exceptions to the ‘presumed will’ requirement are needed where the subject may directly benefit from enrolment.17

Reports that invoke best interests typically offer only passing and uncritical reference to this standard.18 In fact, there is little analysis of best interests as it pertains to treatment, let alone to research. The Encyclopedia of Bioethics states that the best interests standard, in the context of clinical care, requires surrogates to determine ‘what is in the patient's overall best interests by a more objective and communal standard’.19 Kopelman states that the best interests standard requires that a decision be based ‘on the action that is likely to produce the greatest balance of benefit over harm for the individual’, but notes that it is ‘a very conservative standard with conventional social mores usually selected as best.’20 According to Beauchamp and Childress, best interest refers to ‘the highest net benefit among the available options, assigning different weights to interests the patient has in each option and discounting or subtracting inherent risks or costs. The term best is used because the surrogate's obligation is to maximise benefit through a comparative assessment that locates the highest net benefit.’21

The relevance of the best interests standard to research has been considered by several commentators in ethics. Yarborough notes that ‘to treat adult research subjects with dementia with respect, we must abandon the best interests standard in favour of the substituted judgement standard’.18 Wendler also suggests that best interests is problematic as a basis for proxy consent for research.22 In order to determine one's highest net benefit in clinical research, the potential benefits, potential harms, and actual burdens associated with participation in a research protocol must be defined, described, and ranked. Kopelman acknowledges that ‘The less agreement about how to … assess harms and benefits, the harder it will be to apply the Best Interests Standard’.2 There remains no functional definition of best interests as it pertains to clinical research with its inherent discounting of individual benefit. Although subjects' assent and post-hoc consent are important ethical considerations in research neither have bearing on determining one's best interests.

Defining subjects' interests and locating the best one

Since the best interests standard is operational when subjects' own preferences cannot meaningfully inform decisions, subjects' interests must be assessed through values that are communally held and conservatively interpreted. Broadly shared interests include being free of distressing physical symptoms, being free of excessive psychological, emotional and existential suffering, to have dignity preserved and to live in a state that is generally regarded as not worse than death. Which of the many collectively held interests rises to the level of the best interest? The answer has been neither normatively established nor empirically well described for either clinical care or research.

When is non-voluntarily enrolling into research in one's best interest? There is scant empirical basis for the position that most persons view research enrolment, for a condition of cognitive incapacity, as serving their best interest. In fact, the converse is could be argued. For example, low risk research that increases rates of survival without improving morbidity may not satisfy best interests since many patients disvalue such outcomes and often prefer to limit life-sustaining interventions for disabled states. In fact, many patients prefer death to continued life in a dependent and non-capacitated state.23–26 To further illustrate, consider the clinical trials with the dementia drug tacrine.27 The expected benefit was improvement in cognition. It is not apparent that participation satisfies the ‘highest net benefit’ requirement, because benefit depends, in part, on how negatively one rates life with cognitive impairment. If dementia renders persons oblivious, unconcerned and content, is it in their interest to restore cognitive function sufficiently so that they are again aware of the affliction? Moreover, even for research that carries low risk of harm, net benefit beyond neutral is speculative unless the likelihood and magnitude of benefit is already defined, which is unusual in clinical research. Therefore, assessments about research participation seem unlikely to satisfy the highest net benefit criteria of the best interests standard.

Although some commentators on the best interest standard state that determinations of net benefit should be limited to quality of life considerations, there is variability about what determines quality of life.28 For example, some patients assess death as preferable to living with loss of autonomy, control, and dignity, even more strongly than for living with physical suffering.29 Some older persons prefer death to a life with dementia.24 Such data suggest that the natural inclination of some surrogates, clinicians and investigators to seek prolongation of life may not necessarily represent the preferences of now non-capacitated subjects. Therefore, enrolling non-capacitated subjects into research based on unanalysed assumptions of quality of life that underlie best interests determinations is highly problematic. Rather, for non-capacitated persons about whose values we know little, a conservative determination of highest net benefit may require the provision of excellent palliative care, through which symptom relief and upholding of dignity are the central and reliably achievable objectives. These presuppositions about quality of life and benefit require further study if the research enterprise wishes to continue to support the best interests standard.

Best interests in each of the four phases of clinical research

In therapeutic research, pharmaceutical, biologics and medical device trials are typically categorised as phase I, II, III, or post-marketing (phase IV) trials. Phase I studies are designed to demonstrate safety. Whereas, phase II studies are intended to evaluate for efficacy, and phase III trials are conducted to confirm preliminary evidence of efficacy. Post-marketing studies are intended to develop new information about already approved medications or to compare relative efficacy with other treatments. How does the best interests standard relate to each of these types of trials? The discussion that follows assumes that a consensus on net benefit exists.

Phase I trials

Entry into phase I trials based on best interests is fundamentally illogical because the best interests standard centres on net benefit and, by definition, not even the harms, let alone benefits, of phase I trial are known at the outset of these studies. Although some capacitated subjects report benefit from participation in phase I trials, such as psychological and existential ones,30 non-capacitated subjects are poorly situated to experience these benefits.

Phase II

At the outset of a phase II study efficacy is yet to be assessed. Therefore, there cannot be any reasonable speculation on benefit. Nonetheless, because quantification of harms has begun in the phase I trial, one may argue that a particular phase II study may pose no additional harms. If participation in the study poses no burdens and the research intervention does not pre-empt treatments or care plans of defined benefit, because of the possibility of benefit, participation may be in subjects' best interest. Alternatively, one may argue that upon entry into a phase II study harms are only preliminarily known based on the experiences of a small number of subjects. Since the risk of harm is preliminarily defined and benefit is not at all established, only a specious argument can be made that enrolment satisfies the criteria of serving the non-capacitated subject's best interests.

Phase III

Phase III trials are designed to confirm benefit that was preliminarily identified in phase II research. The notion of ‘prospect of direct benefit’ is used to justify the incurring of ‘greater than minimal risk’ in phase III research.31 Sometimes, the prospect of benefit is not borne out by the results of phase III trials, and, in fact, some harms are not fully identified until after phase IV studies are conducted.32 33

Furthermore, the likelihood of direct benefit to subjects in phase III trials is often over-estimated. Both researchers and laypersons, and even the courts, often suffer from the therapeutic misconception, in which the purpose of research is conflated with expectations of individual benefit.34–37 The widely used term ‘risk-benefit ratio’ holds a connotation favourable to research because it suggests only a possibility of harm but a certainty of benefit. This linguistic bias in favour of participation in research is joined by a more general bias in the medical literature that favours publication of studies demonstrating efficacy over studies demonstrating inefficacy.38–42

Liberal and optimistic assessments of benefit in phase III research foster the misapplication of the best interests standard. To logically base enrolment in a phase III study on best interests, one must conservatively calculate net benefit using preliminary results of efficacy, and then determine that the net benefit of the investigational intervention is also the highest net overall experiential benefit to the individual. These may be different. For example, participation in a study with a prospect of direct benefit may well improve the underlying malady with little side effect, thereby providing net benefit. However, the burdens associated with protocol driven monitoring, testing, and other evaluations may mitigate the narrow medical benefits. (Of course, placebo controlled trials offer some subjects only the procedural burdens of participation without the prospect of medical benefit). It might be in one's particular interest to enrol in a phase III trial when phase II data demonstrates no greater harm than standard treatment and standard treatment offers little benefit. However, it is more difficult to argue that it is in the best interest of non-capacitated persons generally to enrol into such research.

Phase IV

A best interests standard may be most relevant for phase IV studies that compare two accepted therapies, are not placebo controlled, have no medication washout periods and individual subjects cannot otherwise obtain either treatment. This last condition is necessary to satisfy the requirement of net benefit but also raises concerns of unfair treatment due to socioeconomic disparities.

Should best interests in research be salvaged or discarded?

Subjects' best interests is frequently an illogical and generally a weak basis for surrogate consent for entry into clinical research. It should be abandoned, absent the development of the substantive content and functional framework for determining best interests. Since the best interests standard is reserved for subjects for whom neither explicit nor inferred preferences about research are discernable, enrolment based on best interests requires that broadly held and conservatively drawn values have first been established at a community level and are used to guide research decisions for all similarly situated persons. Otherwise, as Moreno notes we are left with ‘a micro-consensus arrived at by family and physicians’, and that these decisions are of questionable moral authority.43 How ought the likelihood and magnitude of harms and benefits of research be assessed against all of the relevant interests of potential subjects? By what measures can we determine that entering into research produces maximal net benefit for non-capacitated individuals? If research participation clearly provided highest net benefit for a non-capacitated person, then would surrogates have strong moral ground to object to enrolment?

Assuming some consensus on the core issues were developed, who then ought to apply these to individual cases? Independent guardians? Regulators? Local institutional review boards? In fact, the US Federal Office of Human Research Protections expects review boards to make best interests determinations for subjects whose continued participation in a study is of question.44 Parenthetically, best interests are relied upon here without substantive and serviceable definitions.

Is there any ethically sound basis for conducting research with non-capacitated persons who have provided neither direct nor indirect preferences? Perhaps surrogates could enrol a subject based on shared values of trust and fidelity.45–47 Subjects' experiential interests would serve as a constraint to the sorts of burdens they may incur through participation in research. Further consideration of these aspects of research surrogacy falls outside the scope of this paper.

Likewise, enrolment of non-capacitated persons into research might be based on mutually held responsibilities and obligations of membership in society in order to share in the benefits of community membership. Implicit support for this notion may be found in US Federal regulations on paediatric research that allows children to be entered into more than minimal risk research to benefit future child patients with comparable maladies, even if there is no expectation for direct subject benefit.10 Similarly, the World Medical Association's Declaration of Helsinki states that incompetent individuals ‘must not be included in a research study that has no likelihood of benefit for them unless it is intended to promote the health of the population represented by the potential subject’.48 In fact, the current Declaration suggests no particular basis for surrogate consent for non-capacitated research other than community benefit. Nevertheless, a community values approach to research enrolment carries with it fatal problems. Beyond the improbability of a consensus on this issue generally,49–53 a community-based imperative for research must be applied across all research, capacitated and non-capacitated alike, in order to satisfy ethical requirements of fairness. This poses enormous and innumerable challenges including impingements on individual rights and how to equitably apportion the burdens of research across a community or society. Moreover, it is fantastic to believe this approach would be acceptable since an appeal to communal interests has often failed even for interventions involving far less individual risk and far greater societal benefit such as for presumed consent for organ retrieval.54

As it stands, the ethically sound involvement of non-capacitated subjects whose enrolment satisfies neither the known wishes standard nor substituted judgement standard is hobbled by the lack of a robust ethical framework. The best interests standard is often applied without critical assessment of its pertinence. Perhaps this oversight stems from the lack of an alternative approach to enrolment coupled with a strong imperative to advance medical science. Regardless, absent the development of a clinically operational definition of best interests, or an alternative ethical approach to enrolment, the best interests standard should not be routinely associated with clinical research. Subjects should not be enrolled on this basis unless a critical appraisal of the particular circumstance warrants it. Of course, this restriction will be uncomfortable for researchers whose efforts to populate clinical trials will be affected. It will present new but ethically appropriate limits on surrogates who are now permitted to authorise enrolment based on an arbitrary assessment of benefit.

Conclusions

Subjects' best interests is an ethically weak basis for enrolling non-capacitated persons into research. The largely uncritical view of the best interest standard in clinical research should yield to scholarly study and empiric investigation into the myriad of assumptions implicit in this arena of decision making. Absent this work, the ethics of research surrogacy will flounder and the best interests standard will remain an undefined standard in non-capacitated research.

Acknowledgments

The author thanks Evan G DeRenzo, PhD for comments on an earlier draft of this paper.

References

Footnotes

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.