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. (shrink)

In this essay, I suggest that a slightly modified version of Freedman’s formulation of the clinical equipoise requirement is justified. I begin this essay with a brief discussion of the equipoise r...

Data monitoring committees often are employed to review interim findings of randomised controlled trials. Interim findings are kept confidential until the data monitoring committee finds that they provide sufficiently compelling evidence regarding efficacy, typically because they have crossed the pre-defined statistical boundaries, or they raise serious concerns about safety. While this practice is vital to maintaining the scientific integrity of controlled trials and thereby ensuring their social value, it has been criticised as unethical. Commentators argue that withholding interim findings from (...) research participants is deceptive, inconsistent with valid informed consent, and a violation of respect for participants’ autonomy. The present article examines these arguments, focusing specifically on confidential data monitoring for efficacy. This practice need not be deceptive provided its use is disclosed to prospective research participants. In addition, confidential data monitoring does not make research participants worse off than they would be in the clinical setting and represents an acceptable limitation on the options available to prospective research participants. Taken together, these considerations suggest confidential data monitoring, subject to adequate safeguards, is ethically acceptable. (shrink)

Ethical guidelines for conducting clinical trials have historically been based on a perceived therapeutic obligation to treat and benefit the patient-participants. The origins of this ethical framework can be traced to the Hippocratic oath originally written to guide doctors in caring for their patients, where the overriding moral obligation of doctors is strictly to do what is best for the individual patient, irrespective of other social considerations. In contrast, although medicine focuses on the health of the person, public health is (...) concerned with the health of the entire population, and thus, public health ethics is founded on the societal responsibility to protect and promote the health of the population as a whole. From a public health perspective, research ethics should be guided by giving due consideration to the risks and benefits to society in addition to the individual research participants. On the basis of a duty to protect the population as a whole, a fiduciary obligation to realise the social value of the research and the moral responsibility to distribute the benefits and burdens of research fairly across society, how a public health perspective on research ethics results in fundamental re-assessments of the proper course of action for two salient topical issues in research ethics is shown: stopping trials early for reasons of efficacy and the conduct of research on less expensive yet less effective interventions. (shrink)

BackgroundThe nature of the relationship between a clinical investigator and a research subject has generated considerable debate because the investigator occupies two distinct roles: clinician and scientist. As a clinician, the investigator has duties to provide the patient with optimal care and undivided loyalty. As a scientist, the investigator has duties to follow the rules, procedures and methods described in the protocol.Results and conclusionIn this article, I present a contextual approach to the investigator-subject relationship. The extent of the investigator's duty (...) to provide the patient/subject with clinical care can vary from one situation to the next, as a function of several factors, including: the research design, benefits and risks of the research; the subject's reasonable expectations, motivations, and vulnerabilities; the investigator's ability to benefit the subject; and the investigator's prior relationship with the subject. These and other factors need to be considered when determining the clinical investigator's obligations to provide clinical care to human research subjects. In some research contexts, the investigator has extensive clinical obligations to the patient/subject; in others, the investigator has minimal ones. (shrink)

Equipoise is advocated as a means of achieving high scientific and ethical standards in randomised trials. As used in the context of research the word describes a state of uncertainty characterised by the belief that in a trial no arm is known to offer greater harm or benefit than any other arm. Clinicians who lack personal equipoise are advised to accept clinical or communal equipoise, based on current unresolved disagreement among the medical profession. Equipoise is mainly discussed in the literature (...) as an issue for senior doctors and research directors. Limitations of professional equipoise are reviewed, and data on the neglected topic of patients' equipoise are reported using the example of breast cancer trials. In theory, a patient who gives informed and voluntary consent to enter a randomised trial has achieved the equilibrium of equipoise. In practice, equipoise among patients ranges from personal to proxy acceptance. (shrink)

The problem of collecting, analyzing and evaluating evidence on adverse drug reactions (ADRs) is an example of the more general class of epistemological problems related to scientific inference and prediction, as well as a central problem of the health-care practice. Philosophical discussions have critically analysed the methodological pitfalls and epistemological implications of evidence assessment in medicine, however they have mainly focused on evidence of treatment efficacy. Most of this work is devoted to statistical methods of causal inference with a special (...) attention to the privileged role assigned to randomized controlled trials in Evidence Based Medicine. Regardless of whether the RCT’s privilege holds for efficacy assessment, it is nevertheless important to make a distinction between causal inference of intended and unintended effects, in that the unknowns at stake are heterogonous in the two contexts. This point has been emphasized by epidemiologists in the last decade. Their main focus is methodological, and regards the fact that bias and confounding do not affect studies on intended and unintended effects in the same way. However, deeper concerns ground the intuition for such a distinction; these are related to the constraints which we impose on evidence and their epistemological justification. My thesis is that such constraints ought to be understood to be different in the case of evidence for risk vs. benefit assessment. I present the recent debate on the causal association between acetaminophen and asthma in order to illustrate the point at issue. (shrink)

Randomised controlled trials (RCTs) sometimes recruit participants who are desperate to receive the experimental treatment. This paper defends the practice against three arguements that suggest it is unethical first, desperate volunteers are not in equipoise. Second clinicians, entering patients onto trials are disavowing their therapeutic obligation to deliver the best treatment; they are following trial protocols rather than delivering individualised care. Research is not treatment; its ethical justification is different. Consent is crucial. Third, desperate volunteers do not give proper consent: (...) effectively, they are coerced. This paper responds by advocating a notion of equipoise based on expert knowledge and widely shared values. Where such collective, expert equipoise exists there is a prima facie case for an RCT. Next the paper argues that trial entry does not involve clinicians disavowing their therapeutic obligation; individualised care based on insufficient evidence is not in patients best interest. Finally, it argues that where equipoise exists it is acceptable to limit access to experimental agents; desperate volunteers are not coerced because their desperation does not translate into a right to receive what they desire. (shrink)

The “therapeutic obligation” is a physician’s duty to provide his patients with what he believes is the best available treatment. We begin by discussing some prominent formulations of the obligation before raising two related considerations against those formulations. First, they do not make sense of cases where doctors are permitted to provide suboptimal care. Second, they give incorrect results in cases where doctors are choosing treatments in challenging epistemic environments. We then propose and defend an account of the therapeutic obligation (...) that solves the problems that undermined previous efforts at formulating the TO. We conclude by considering how apparent problems with our proposal actually rest on difficulties with informed consent. (shrink)

The problem of collecting, analyzing and evaluating evidence on adverse drug reactions (ADRs) is an example of the more general class of epistemological problems related to scientific inference and prediction, as well as a central problem of the health-care practice. Philosophical discussions have critically analysed the methodological pitfalls and epistemological implications of evidence assessment in medicine, however they have mainly focused on evidence of treatment efficacy. Most of this work is devoted to statistical methods of causal inference with a special (...) attention to the privileged role assigned to randomized controlled trials in Evidence Based Medicine. Regardless of whether the RCT’s privilege holds for efficacy assessment, it is nevertheless important to make a distinction between causal inference of intended and unintended effects, in that the unknowns at stake are heterogonous in the two contexts. This point has been emphasized by epidemiologists in the last decade. Their main focus is methodological, and regards the fact that bias and confounding do not affect studies on intended and unintended effects in the same way. However, deeper concerns ground the intuition for such a distinction; these are related to the constraints which we impose on evidence and their epistemological justification. My thesis is that such constraints ought to be understood to be different in the case of evidence for risk vs. benefit assessment. I present the recent debate on the causal association between acetaminophen and asthma in order to illustrate the point at issue. (shrink)

This paper targets an orphan topic in research ethics, namely the so called principle of the primacy of the human being, which states that the interests of the human subject should always take precedence over the interests of science and society. Although the principle occupies the central position in the majority of international ethical and legal standards for biomedical research, it has been commented in the literature mainly in passing. With a few notable exceptions, there is little in-depth discussion about (...) the meaning and role of the principle. Several authors note that the principle is vogue, ambiguous and apparently conflicting with the accepted practice of conducting non-beneficial research on individuals unable to give consent. There are opinions that it is just “a vacuous figure of speech” and should be abandoned. This paper argues that the primacy principle is far from being “a vacuous figure of speech”, rather it should be seen as a threefold concept: a fundamental interpretative rule, a procedural rule, and a substantive rule aimed at protecting research subjects from instrumental treatment and unacceptable risks. This interpretation tracks back to the principle regulatory and normative origins in the Declaration of Helsinki of 1975, but also acknowledges changes in research ethics and practice, which took place at the turn on the twentieth and twenty-first centuries. Thus, the proposed reading of the principle is not only original, but also historically grounded and normatively fruitful. It provides a fresh and ethically rich perspective on extensively debated, but still controversial problem of an upper limit of permissible risks in non-beneficial studies. (shrink)

ABSTRACT In this essay, Paul Lauritzen examines Richard B. Miller's liberal account of pediatric ethics by asking if the duty to promote a child's basic interests is substantial enough to secure the well‐being of children. This question is raised in light of two case studies: daytime TV talk shows that broadcast interviews with sexually active children, and a medical study conducted to test the effect of growth hormone treatment on adult height in peripubertal children. In both cases, Lauritzen argues, children (...) are subjected to potential harms that are not easily explained, and therefore not easily prevented, by appeals to basic interests. (shrink)

It is almost universally acknowledged that risks have to be weighed against benefits, but there are different ways to perform the weighing. In conventional risk analysis, collectivist risk-weighing is the standard. This means that an option is accepted if the sum of all individual benefits outweighs the sum of all individual risks. In practices originating in clinical medicine, such as ethical appraisals of clinical trials, individualist risk-weighing is the standard. This implies a much stricter criterion for risk acceptance, namely that (...) the risk to which each individual is exposed should be outweighed by benefits for that same individual. The different choices of risk-weighing methods in different policy areas seem to have emerged from traditional thought patterns and social relations, rather than from explicit deliberations on possible justifications for the alternative ways to weigh risks against benefits. It is not obvious how the prevalent differences in risk-weighing practices can be reconstructed in terms of consistent underlying principles of preventive health or social priority-setting. (shrink)

Philosophical discussions have critically analysed the methodological pitfalls and epistemological implications of evidence assessment in medicine, however they have mainly focused on evidence of treatment efficacy. Most of this work is devoted to statistical methods of causal inference with a special attention to the privileged role assigned to randomized controlled trials (RCTs) in evidence based medicine. Regardless of whether the RCT’s privilege holds for efficacy assessment, it is nevertheless important to make a distinction between causal inference of intended and unintended (...) effects, in that the unknowns at stake are heterogonous in the two contexts. However, although “lower level” evidence is increasingly acknowledged to be a valid source of information contributory to assessing the risk profile of medications on theoretical or empirical grounds, current practices have difficulty in assigning a precise epistemic status to this kind of evidence because they are more or less implicitly parasitic on the (statistical) methods developed to test drug efficacy. My thesis is that (1) “lower level” evidence is justified on distinct grounds and at different conditions depending on the different epistemologies which one wishes to endorse, in that each impose different constraints on the methods we adopt to collect and evaluate evidence; (2) such constraints ought to be understood to be different in the case of evidence for risk versus benefit assessment for a series of reasons which I will illustrate on the basis of the recent debate on the causal association between acetaminophen (a.k.a. paracetamol) and asthma. (shrink)

In this essay, Paul Lauritzen examines Richard B. Miller's liberal account of pediatric ethics by asking if the duty to promote a child's basic interests is substantial enough to secure the well-being of children. This question is raised in light of two case studies: daytime TV talk shows that broadcast interviews with sexually active children, and a medical study conducted to test the effect of growth hormone treatment on adult height in peripubertal children. In both cases, Lauritzen argues, children are (...) subjected to potential harms that are not easily explained, and therefore not easily prevented, by appeals to basic interests. (shrink)