What makes placebo-controlled trials unethical?

The leading ethical position on placebo-controlled clinical trials is that whenever proven effective treatment exists for a given condition, it is unethical to test a new treatment for that condition against placebo. Invoking the principle of clinical equipoise, opponents of placebo-controlled trials in the face of proven effective treatment argue that they (1) violate the therapeutic obligation of physicians to offer optimal medical care and (2) lack both scientific and clinical merit. We contend that both of these arguments are mistaken. Clinical equipoise provides erroneous ethical guidance in the case of placebo-controlled trials, because it ignores the ethically relevant distinction between clinical trials and treatment in the context of clinical medicine and the methodological limitations of active-controlled trials. Placebo controls are ethically justifiable when they are supported by sound methodological considerations and their use does not expose research participants to excessive risks of harm.     

Risk and Trust in Public Health: A Cautionary Tale

The leading ethical position on placebo-controlled clinical trials is that whenever proven effective treatment exists for a given condition, it is unethical to test a new treatment for that condition against placebo. Invoking the principle of clinical equipoise, opponents of placebo-controlled trials in the face of proven effective treatment argue that they (1) violate the therapeutic obligation of physicians to offer optimal medical care and (2) lack both scientific and clinical merit. We contend that both of these arguments are mistaken. Clinical equipoise provides erroneous ethical guidance in the case of placebo-controlled trials, because it ignores the ethically relevant distinction between clinical trials and treatment in the context of clinical medicine and the methodological limitations of active-controlled trials. Placebo controls are ethically justifiable when they are supported by sound methodological considerations and their use does not expose research participants to excessive risks of harm.     

Behavioral equipoise: a way to resolve ethical stalemates in clinical research

Randomized trials depend on clinicians feeling that they are morally justified in allowing their patients to be randomized across treatment arms. Typically such justification rides on what has been called "clinical equipoise"--when there is disagreement of opinion among the community of experts about whether one treatment is better than another, then physicians can ethically enter their patients into a clinical trial, even if individual physicians are not at equipoise. Recent debates over prominent studies, however, illustrate that controversy can be easily created rather than dispelled by trials, with many clinicians choosing not to use the proven therapy until they receive more convincing evidence of its superiority. In such situations, we propose that a new standard of equipoise be used to guide decisions about the ethical justifications for research trials--a standard of behavioral equipoise. Under behavioral equipoise, a trial is potentially justifiable if it addresses behavioral resistance to prior scientific evidence.     

临床均势原则辨析——对临床科研方法的伦理思考

随机对照试验作为一种评价新疗法的可靠设计方法,开始逐渐被世界范围内的临床医生所广泛接受和采用,成为目前最重要的试验方法之一。RCT的运用应该遵循一定的伦理准则,即临床均势原则。围绕临床均势原则这一主题,对随机对照试验的方法论进行较为深入的伦理学思考。并对临床均势的内涵、伦理意义,以及这一伦理要求在实践中所引发的各种伦理争论加以探讨。     

Both Sides of the Coin: Randomization from the Perspectives of Physician-Investigators and Patient-Subjects

Randomization is the "gold standard" design for clinical research trials, and is accepted as the best way to reduce bias. Although some controversy remains over this matter, we believe equipoise is the fundamental ethical requirement for conducting a randomized clinical trial. Despite much attention to the ethics of randomization, the moral psychology of this study design has not been explored. This paper analyzes the ethical tensions that arise from conducting these studies, and examines the moral psychology of this design from the perspectives of physician-investigators and patient-subjects. We conclude with a discussion of the practical implications of this analysis.     

Uncertainty and the Ethics of Clinical Trials

A probabilistic explication is offered of equipoise and uncertainty in clinical trials. In order to be useful in the justification of clinical trials, equipoise has to be interpreted in terms of overlapping probability distributions of possible treatment outcomes, rather than point estimates representing expectation values. Uncertainty about treatment outcomes is shown to be a necessary but insufficient condition for the ethical defensibility of clinical trials. Additional requirements are proposed for the nature of that uncertainty. The indecisiveness of our criteria for cautious decision-making under uncertainty creates the leeway that makes clinical trials defensible.     

Early stopping of clinical trials: charting the ethical terrain

The decision to terminate a clinical trial earlier than planned is often described as ethically problematic, but it is rarely systematically analyzed as an ethical issue in its own right. This paper provides an overview of the main ethical considerations at stake in such decisions and of the main tensions between these considerations. Arguments about informed consent and the impact of early stopping on research and society are explored. We devote particular attention to a familiar conflict that arises with special urgency when early data suggest that the experimental treatment is superior. Should the trial be stopped so that participants in the control group will not be allocated a seemingly inferior treatment, or should it continue in pursuit of evidence conclusive enough to improve the care of future patients? We scrutinize three ways to address this problem. Rather than dissolving the tension, they represent different trade-offs between the respective welfare interests of subjects and future patients.     

Clinical Equipoise and Moral Leeway: An Epistemological Stance

Clinical equipoise (CE) 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 (HR) 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.

     

Unique Ethical Concerns in Clinical Trials Comparing Psychosocial and Psychopharmalogical Interventions

In recent years, there has been a particular emphasis placed on conducting randomized controlled trials (RCTs) that compare the relative efficacy of psychosocial and pharmacological interventions. This article addresses relevant ethical considerations in the conduct of these treatment trials, with a focus on RCTs with children. Ethical concerns, including therapeutic misconception, treatment preference, therapeutic equipoise, structure of treatments, and balancing risks versus benefits, are introduced through a clinical scenario and discussed as they relate to psychotherapy versus medication RCTs. In each case, suggestions are made for researchers seeking to minimize the impact of these ethical concerns on research participants.     

Pulling the plug on clinical equipoise: a critique of Miller and Weijer

As clinicians, researchers, bioethicists, and members of society, we face a number of moral dilemmas concerning randomized clinical trials. How we manage the starting and stopping of such trials--how we conceptualize what evidence is sufficient for these decisions--has implications for both our obligations to trial participants and for the nature and security of the resultant medical knowledge. One view of how this is to be done, "clinical equipoise," recently has been given an extended defense by Paul Miller and Charles Weijer in their article "Rehabilitating Equipoise." The present paper critiques this position and Miller and Weijer's defense of it. I argue that their attempted rehabilitation fails. Their analysis suffers from a number of confusions, as well as a failure to make crucial distinctions, adequately to clarify key concepts, or to think through exactly what needs to be established to justify their claim. We are left with little reason to uphold the clinical equipoise criterion.     

Resituating the principle of equipoise: justice and access to care in non-ideal conditions

The principle of equipoise traditionally is grounded in the special obligations of physician-investigators to provide research participants with optimal care. This grounding makes the principle hard to apply in contexts with limited health resources, to research that is not directed by physicians, or to nontherapeutic research. I propose a different version of the principle of equipoise that does not depend upon an appeal to the Hippocratic duties of physicians and that is designed to be applicable within a wider range of research contexts and types, including health services research and research on social interventions. I consider three examples of ethically contentious research trials conducted in three different social settings. I argue that in each case my version of the principle of equipoise provides more plausible and helpful guidance than does the traditional version of the principle.     

Clinical Equipoise and Adaptive Clinical Trials

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: (1) 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 (2) 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 (i.e., frequentist and Bayesian), 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.

     

Contextualizing clinical research: the epistemological role of clinical equipoise

Since its introduction in 1987, Benjamin Freedman’s principle of clinical equipoise has enjoyed widespread uptake in bioethics discourse. Recent years, however, have witnessed a growing consensus that the principle is fundamentally flawed. One of the most vocal critics has undoubtedly been Franklin Miller. In a 2008 paper, Steven Joffe and Miller build on this critical work, offering a new conception of clinical research ethics based on science, taking what they call a “scientific orientation” toward the ethics of clinical research. Though there is much to recommend Joffe and Miller’s scientifically oriented conception of clinical research ethics, I believe that both the critical and constructive projects suffer from the same basic mistake: inattention to context. The internal norms of science cannot be fully specified, let alone satisfied, independently of contextual (external) factors that only come into view when we are attentive to the particular context of that form of inquiry.     

Equipoise: beyond rehabilitation?

Challenging the interpretation of Charles Fried's use of "equipoise" presented by Paul Miller and Charles Weijer in a recent issue of the Kennedy Institute of Ethics Journal, this commentary argues that Fried was in no way promoting the concept of equipoise. In fact, his key point was that patients have a right to know and to make their own decisions about participation in clinical trials, regardless of equipoise, however it is defined.     

CRISPR/Cas9 genome editing – new and old ethical issues arising from a revolutionary technology

Although germline editing has been the subject of debate ever since the 1980s, it tended to be based rather on speculative assumptions until April 2015, when CRISPR/Cas9 technology was used to modify human embryos for the first time. This article combines knowledge about the technical and scientific state of the art, economic considerations, the legal framework and aspects of clinical reality. A scenario will be elaborated as a means of identifying key ethical implications of CRISPR/Cas9 genome editing in humans and possible ways of dealing with them. Unlike most other discussions of CRISPR/Cas9 germline editing, which are generally based on deontological arguments, the focus in this case will be on a consequentialistic argument against certain applications of germline and somatic editing that takes not only the potential benefits and risks but also socioeconomic issues into consideration. The practical need for an indication catalogue, guidelines for clinical trials, and for funding of basic research will be pointed out. It will be argued that this need for regulatory action and discussion does not stem primarily from the fact that CRISPR/Cas9 germline editing is revolutionary in terms of its ethical implications and potential for human therapy, although this is the prevailing view in the current discussion. Understanding the value and interest dependency of arguments put forward by different stakeholders and learning from past debates related to similar technologies might prove a fruitful method of reaching judgments and decisions that come closer to a consensus upon which society as a whole can agree - which after all should be the true goal of an ethical debate and of bioethics.     

The harm-benefit tradeoff in "bad deal" trials

This paper examines the nature of the harm-benefit tradeoff in early clinical research for interventions that involve remote possibility of direct benefit and likelihood of direct harms to research participants with fatal prognoses, by drawing on the example of gene transfer trials for glioblastoma multiforme. We argue that the appeal made by the component approach to clinical equipoise fails to account fully for the nature of the harm-benefit tradeoff-individual harm for social benefit-that would be required to justify such research. An analysis of what we label "collateral affective benefits," such as the experience of hope or exercise of altruism, shows that the existence of these motivations reinforces rather than mitigates the necessity of justification by reference to social benefit. Evaluations of social benefit must be taken seriously in the research ethics review process to avoid the exploitation of research participants' motivations of hope or altruism and to avoid the possibility of inadvertent exploitation of high-risk research participants and the harms that would associate with such exploitation.     

The Science and Ethics of Placebo in Pediatric Psychopharmacology

Pediatric psychopharmacology is a relatively new science. Although the use of psychotropic medications in children has risen in the past decade, there are few standard treatments for serious psychiatric or developmental disorders of childhood. The relative absence of standard treatments is further complicated by the fact that many of the agents used in pediatric psychopharmacology have been adapted from other fields. Therefore, investigators have a responsibility to make incremental progress from concept through pilot studies and large-scale, multisite efficacy and safety trials. Thus, although there is a pressing need to conduct medication trials that can guide clinical practice, there are scientific and ethical considerations to bear in mind when designing clinical trials in pediatric psychopharmacology. This article reviews essential ethical and scientific issues that are relevant to designing clinical trials in children with psychiatric and developmental disorders. Using examples from recently published literature, the article describes the challenges and pitfalls of various clinical trial study designs. The application of sound ethical and scientific principles is necessary to ensure that clinical trials are properly conducted and to guard against ambiguous results that can not guide practice.     

An ethically justified framework for clinical investigation to benefit pregnant and fetal patients

Research to improve the health of pregnant and fetal patients presents ethical challenges to clinical investigators, institutional review boards, funding agencies, and data safety and monitoring boards. The Common Rule sets out requirements that such research must satisfy but no ethical framework to guide their application. We provide such an ethical framework, based on the ethical concept of the fetus as a patient. We offer criteria for innovation and for Phase I and II and then for Phase III clinical trials to improve the health of pregnant patients and of fetal patients and also criteria to responsibly manage the transition from investigation to clinical practice. Basing ethical criteria for research involving pregnant women on the ethical concept of the fetus as a patient insulates the proposed ethical framework and therefore research on pregnant women from the divisive and politicized concepts and discourses of personhood, fetal rights, and unborn child.     

Stopping speech suppresses the task-irrelevant hand

Some situations require one to quickly stop an initiated response. Recent evidence suggests that rapid stopping engages a mechanism that has diffuse effects on the motor system. For example, stopping the hand dampens the excitability of the task-irrelevant leg. However, it is unclear whether this ‘global suppression’ could apply across wider motor modalities. Here we tested whether stopping speech leads to suppression of the task-irrelevant hand. We used Transcranial Magnetic Stimulation over the primary motor cortex with concurrent electromyography from the hand. We found that when speech was successfully stopped the motor evoked potential from the task-irrelevant hand was significantly reduced compared to when the participant failed to stop speaking, or responded on non stop signal trials, or compared to baseline. This shows that when speech is quickly stopped, there is a broad suppression across the motor system. This has implications for the neural basis of speech control and stuttering.     

Predictability influences stopping and response control

Using a continuous tracking task, the authors examined whether stopping is resistant to expectancies as well as whether it is a representative measure of response control. Participants controlled the speed of a moving marker by continuously adjusting their response force. Participants stopped their ongoing tracking in response to auditory signals on 25%, 50%, 75%, or 100% of trials. Stopping was contrasted with accelerating, in which participants accelerated the marker in response to the signals. In Experiment 1, on each trial participants either stopped or accelerated, allowing a trade-off between the two. In Experiments 2 and 3, participants only stopped or only accelerated, thus decreasing the likelihood of a trade-off. When a trade-off was possible, stopping was resistant to expectancies. However, with little or no trade-off, expectancies influenced stopping and accelerating similarly. These findings contrast with the established view that stopping is insensitive to expectancies. In addition, when trade-offs are prevented, these results confirm that stopping is representative of other response adjustment measures.