Just as there are rational requirements on thought, there are rational requirements on action. This book defends a conception of ethics, and a related conception of human nature, according to which altruism is included among the basic rational requirements on desire and action. Altruism itself depends on the recognition of the reality of other persons, and on the equivalent capacity to regard oneself as merely one individual among many.

This new edition of Charles Fried's Medical Experimentation includes a general introduction by Franklin Miller and the late Alan Wertheimer, a reprint of the 1974 text, an in-depth analysis by Harvard Law School scholars I. Glenn Cohen and D. James Greiner, and a new essay by Fried reflecting on the original text and how it applies to the contemporary landscape of medicine and medical experimentation.

Our decision-making is often subject to framing effects: alternative but equally informative descriptions of the same options elicit different choices. When a decision-maker is vulnerable to framing, she may consent under one description of the act, which suggests that she has waived her right, yet be disposed to dissent under an equally informative description of the act, which suggests that she has not waived her right. I argue that in such a case the decision-maker’s consent is simply irrelevant to the (...) permissibility of proceeding. I then consider two alternative views. According to the first, people susceptible to framing are able to give valid consent so long as they are sufficiently informed. This suggestion, I argue, maintains an overly narrow focus on mere quantity of information to the exclusion of other choice-affecting factors. A second response, which appeals to hypothetical consent, is likewise of little use in resolving the moral problem posed by framing effects. I conclude that if susceptibility to framing undermines the validity of consent, we may have good reason to reconsider whether consent has the rights-waiving function commonly attributed to it. (shrink)

In this article, I review and expand upon arguments showing that Freedman's so-called "clinical equipoise" criterion cannot serve as an appropriate guide and justification for the moral legitimacy of carrying out randomized clinical trials. At the same time, I try to explain why this approach has been given so much credence despite compelling arguments against it, including the fact that Freedman's original discussion framed the issues in a misleading way, making certain things invisible: Clinical equipoise is conflated with community equipoise, (...) and several versions of each are also conflated. But a misleading impression is given that, rather than distinct criteria being arbitrarily conflated, a puzzle is solved and a number of features unified. Various issues are pushed under the rug, hiding flaws of the "clinical equipoise" approach and thus deceiving us into thinking that we have a solution when we do not. Particularly significant is the ignoring of the crucial distinction between the individual patient decision and the policy decision. (shrink)

It is widely maintained that a clinical trial is ethical only if some form of equipoise between the treatments being compared obtains. To be in equipoise between two treatments A and B is to be cognitively indifferent between the statement ‘A is strictly more effective than B’ and its negation. It is natural to claim that equipoise regarding A and B is necessary for randomised assignment to treatments A and B to be beneficent and non‐maleficent and is sufficient for such (...) an assignment to be fair. Cashing this out precisely is difficult, and various forms of equipoise have been discussed which consider whose equipoise is relevant to the decision. This is to make judgement of equipoise something to be managed socially, while its prima facie significance is supposedly cognitive. Recent reconstructions of equipoise‐like concepts in epistemology give clues about how to understand equipoise cognitively. In this paper I examine some of this work and discuss how successful it has been. I suggest that while this work is promising, it still has far to go, and that while equipoise remains the best theory we have of the cognitive justification for clinical trials, it is nonetheless incoherent. (shrink)

: The "therapeutic misconception," described by Paul Appelbaum and colleagues more than 20 years ago, refers to the tendency of participants in clinical trials to confuse the design and conduct of research with personalized medical care. Although the "therapeutic misconception" has become a term of art in research ethics, little systematic attention has been devoted to the ethical significance of this phenomenon. This article examines critically the way in which Appelbaum and colleagues formulate what is at stake in the therapeutic (...) misconception, paying particular attention to assumptions and implications that clinical trial participation disadvantages research participants as compared with receiving standard medical care. After clarifying the ethical significance of the therapeutic misconception with respect to the decision making of patients, we offer policy recommendations for obtaining informed consent to participation in clinical trials. (shrink)

: "Therapeutic misconception" has been misconstrued, and some of the newer, mistaken interpretations are troublesome. They exaggerate the distinction between research and treatment, revealing problems in the foundations of research ethics and possibly weakening informed consent.

From the earliest application of modern randomized controlled trials in medical research, scientists and observers have deliberated the ethics of randomly allocating study participants to trial control arms. Adaptive RCT designs have been promoted as ethically advantageous over conventional RCTs because they reduce the allocation of subjects to what appear to be inferior treatments. Critical assessment of this claim is important, as adaptive designs are changing medical research, with the potential to significantly shift how clinical trials are conducted. Policy-makers are (...) swiftly moving to encourage greater use of adaptive designs. In 2016, the newly enacted 21st Century Cures Act instructed the Food and Drug Administration to help product sponsors incorporate adaptive methods into proposed clinical trial protocols and applications for investigational drugs and also biological products. In this article, we review the ethical justifications commonly offered for adaptive designs, explore these arguments in the context of actual trials, and contend that clinical equipoise is a useful standard for adaptive-trial ethics. We distinguish between theoretical and clinical equipoise and explain why ethical arguments related to adaptive trials tend to focus on the former. Yet we contend that theoretical equipoise can be an unreliable standard for adaptive ethics. While we contend that clinical equipoise is the most critical principle for the primary ethical concerns posed by adaptive trials, we suggest ethical approaches to deal with some additional concerns unique to adaptive designs. (shrink)

In an adaptive clinical trial , key trial characteristics may be altered during the course of the trial according to predefined rules in response to information that accumulates within the trial itself. In addition to having distinguishing scientific features, adaptive trials also may involve ethical considerations that differ from more traditional randomized trials. Better understanding of clinical trial experts’ views about the ethical aspects of adaptive designs could assist those planning ACTs. Our aim was to elucidate the opinions of clinical (...) trial experts regarding their beliefs about ethical aspects of ACTs. (shrink)

Clinical equipoise has been proposed as an ethical principle relating uncertainty and moral leeway in clinical research. Although CE has traditionally been indicated as a necessary condition for a morally justified introduction of a new RCT, questions related to the interpretation of this principle remain woefully open. Recent proposals to rehabilitate CE have divided the bioethical community on its ethical merits. This paper presents a new argument that brings out the epistemological difficulties we encounter in justifying CE as a principle (...) to connect uncertainty and moral leeway in clinical ethics. The argument proposes, first, that the methodology of hypothetical retrospection is applicable to the RCT design and that it can accommodate uncertainty. As currently understood, however, HR should give up its reliance on the assumption of uncertainty transduction, because the latter assumes the principle of indifference, which does not accommodate uncertainty in the right way. The same principle is then seen to distort also the received interpretations of CE. (shrink)

In a recent article in The Journal of Clinical Ethics, David Wendler argues that worries about the therapeutic misconception (TM) are not only misconceived, but detract from the larger agenda of a proper informed consent for subjects involved in clinical research. By contrast, we argue that Wendler mischaracterizes those who support TM research, and that his arguments are fragmentary, often illogical, and neglect a critical difference between clinical care and clinical research. A clear explanation about the chief aim of research (...) is, in fact, what gives the other elements in a consent process their meaning. We argue that informed consent must be both trial-specific and context-sensitive, and that concern about the TM is needed now more than ever. (shrink)

The notions of individual and collective ethics were first explicitly defined in the biostatistical literature in 1971 to motivate a mathematical solution to a posed ethical dilemma. This paper reviews key antecedents to these concepts and traces explicit references to them over time, primarily in the biostatistical literature. Following a historical exposition of these texts, a critical thematic analysis shows the following: the normative force of these concepts has not been adequately argued. Individual and collective ethics do not solve the (...) problem of how to use accumulating data to inform ethical action. The notions of the "individual" and the "collective" are too vague to prompt clear moral imperatives, especially in difficult cases. These concepts have not been successfully linked to a standard ethical framework. Finally, the paper concludes with the observation that a systematic, comprehensive ethical framework must be identified to fulfill the intuitions behind individual and collective ethics. (shrink)

It is commonly believed in research ethics that some form of equipoise is a necessary condition for justifying randomized clinical trials, that without it clinicians are violating the moral duty to do what is best for the patient. Recent criticisms have shown how complex the concept of equipoise is, but often retain the commitment to some form of equipoise for randomization to be justified. This article rejects that claim. It first asks for what one should be equally poised (scientific or (...) clinical equipoise), then asks who should be equally poised (scientist, clinician, or subject), and finally asks why any of these players need be equally poised between treatment options. The article argues that only the subject's evaluation of the options is morally relevant and that even the subject need not be equally poised or indifferent between the options in order to volunteer for randomization. All that is needed is adequately informed, free, and unexploited consent. It concludes equipoise is irrelevant. (shrink)

To give substance to the rhetoric of ‘learning health systems’, a variety of novel trial designs are being explored to more seamlessly integrate research with medical practice, reduce study duration and reduce the number of participants allocated to ineffective interventions. Many of these designs rely on response adaptive randomisation. However, critics charge that RAR is unethical on the grounds that it violates the principle of equipoise. In this paper, I reconstruct critiques of RAR as holding that it is inconsistent with (...) five important ethical principles. I then argue that these criticisms rest on a faulty view of equipoise encouraged by the idea that a RAR study models the beliefs of a single rational agent about the relative merits of the interventions being studied. I outline a view in which RAR models an idealised health system in which diverse communities of fully informed experts shrink or grow as their constituent members update their expert opinions in light of reliable medical evidence. I show how a proper understanding of clinical equipoise can reconcile this conception of RAR with these five ethical principles. This analysis removes an in-principle objection to RAR and sheds important light on the relationship between clinical equipoise and transient diversity in the scientific community. (shrink)

The doctrine of clinical equipoise is appealing because it appears to permit physicians to maintain their therapeutic obligation to offer optimal medical care to patients while conducting randomized controlled trials (RCTs). The appearance, however, is deceptive. In this article we argue that clinical equipoise is defective and incoherent in multiple ways. First, it conflates the sound methodological principle that RCTs should begin with an honest null hypothesis with the questionable ethical norm that participants in these trials should never be randomized (...) to an intervention known to be inferior to standard treatment. Second, the claim that RCTs preserve the therapeutic obligation of physicians misrepresents the patient-centered orientation of medical care. Third, the appeal to clinical equipoise as a basic principle of risk-benefit assessment for RCTs is incoherent. Finally, the difficulties with clinical equipoise cannot be resolved by viewing it as a presumptive principle subject to exceptions. In the final sections of the article, we elaborate on the non-exploitation framework for the ethics clinical research and indicate issues that warrant further inquiry. (shrink)

In a typical comparative clinical trial the randomization scheme is fixed at the beginning of the study, and maintained throughout the course of the trial. A number of researchers have championed a randomized trial design referred to as ‘outcome-adaptive randomization.’ In this type of trial, the likelihood of a patient being enrolled to a particular arm of the study increases or decreases as preliminary information becomes available suggesting that treatment may be superior or inferior. While the design merits of outcome-adaptive (...) trials have been debated, little attention has been paid to significant ethical concerns that arise in the conduct of such studies. These include loss of equipoise, lack of processes for adequate informed consent, and inequalities inherent in the research design which could lead to perceptions of injustice that may have negative implications for patients and the research enterprise. This article examines the ethical difficulties inherent in outcome-adaptive trials. (shrink)

Ethically permissible clinical trials must not expose subjects to risks that are unreasonable in relation to anticipated benefits. In the research ethics literature, this moral requirement is typically understood in one of two different ways: as requiring the existence of a state of clinical equipoise, meaning a state of honest, professional disagreement among the community of experts about the preferred treatment; or as requiring an equilibrium between individual and collective ethics. It has been maintained that this second interpretation makes it (...) mandatory to minimize the number of patients receiving the treatment that will eventually be shown to be inferior by the trial. This requirement has led to the development of adaptive trials, i.e., trials in which treatment allocation is determined by data accumulated during interim analysis. Many statisticians argue that in some circumstances—typically with potentially high benefits, as in the much discussed ECMO trial—adaptive design is the only ethically permissible experimental design. Nevertheless, some proponents of clinical equipoise argue that adaptive trials are neither ethically required nor permissible. More specifically, they argue that clinical trials using adaptive designs fail to meet the moral requirement of clinical equipoise, since these trials presuppose an epistemic state that is incompatible with a physician’s duty of care to her subjects. This paper emphasizes that the debate is to a large extent resting on an epistemological confusion. Specifically, I argue that this response conflates two different conceptions of statistical evidence, and that recognizing this distinction elucidates an epistemological framework in which adaptive trials are both consistent with and recommended by the moral requirement of clinical equipoise. (shrink)

Recent policy in relation to clinical research proposals in the UK has distinguished between two types of review: scientific and ethical. This distinction has been formally enshrined in the recent changes to research ethics committee structure and operating procedures, introduced as the UK response to the EU Directive on clinical trials. Recent reviews and recommendations have confirmed the place of the distinction and the separate review processes. However, serious reservations can be mounted about the science/ethics distinction and the policy of (...) separate review that has been built upon it. We argue here that, first, the science/ethics distinction is incoherent, and, second, that RECs should not only be permitted to consider a study’s science, but that they have anobligation do so. (shrink)