Estimands in clinical trials – broadening the perspective

Defining the scientific questions of interest in a clinical trial is crucial to align its planning, design, conduct, analysis, and interpretation. However, practical experience shows that oftentimes specific choices in the statistical analysis blur the scientific question either in part or even completely, resulting in misalignment between trial objectives, conduct, analysis, and confusion in interpretation. The need for more clarity was highlighted by the Steering Committee of the International Council for Harmonization (ICH) in 2014, which endorsed a Concept Paper with the goal of developing a new regulatory guidance, suggested to be an addendum to ICH guideline E9. Triggered by these developments, we elaborate in this paper what the relevant questions in drug development are and how they fit with the current practice of intention‐to‐treat analyses. To this end, we consider the perspectives of patients, physicians, regulators, and payers. We argue that despite the different backgrounds and motivations of the various stakeholders, they all have similar interests in what the clinical trial estimands should be. Broadly, these can be classified into estimands addressing (a) lack of adherence to treatment due to different reasons and (b) efficacy and safety profiles when patients, in fact, are able to adhere to the treatment for its intended duration. We conclude that disentangling adherence to treatment and the efficacy and safety of treatment in patients that adhere leads to a transparent and clinical meaningful assessment of treatment risks and benefits. We touch upon statistical considerations and offer a discussion of additional implications. Copyright © 2016 John Wiley & Sons, Ltd.     

Commentary on ‘Designs for dose–escalation trials with quantitative responses’

Bailey (Statist. Medi 2009; this issue) puts the focus on efficiency in dose‐finding studies and shows that some quite simple modifications to much current experimentation can lead to significant efficiency gains. Efficiency has not been the main focus of interest in this field, in particular when dealing with situations requiring other than healthy volunteers. Dr Bailey's results are important, both in theory and in practice and also raise the question as to what ought to be the guiding principle to statistical workers in this field. Safety, although escaping any simple definition, has mostly guided experimentation in dose‐finding studies; one reason being that the concept is one on which clinicians and statisticians can come to some broad agreement. Finding such agreement may still be the single major difficulty in these studies, alongside the establishment of criteria that all of the scientists involved believe are the most appropriate and useful ones. Copyright © 2009 John Wiley & Sons, Ltd.     

‘Good’ patient/‘bad’ patient: clinical learning and the entrenching of inequality

This article develops sociological understanding of the reproduction of inequality in medicine. The material is drawn from a longitudinal study of student experiences of clinical learning that entailed 72 qualitative in‐depth interviews with 27 medical students from five medical schools in the USA. To highlight the subtle, yet powerful, ways in which inequality gets entrenched, this article analyses ideas of the ‘good’ and the ‘bad’ patient. Bad patients question not only biomedical knowledge but also medical students’ commitment to helping people. Good patients engage with medical students in a manner that upholds biomedical knowledge and enables students to assume the role of the healer and the expert. At the same time, good patients possess cultural skills that align with those of medical practitioners. This alignment is, furthermore, central to definitions of the good patient. Distinctions drawn between good and bad patients thus both embody as well as enforce social inequality. The subtle reproduction of inequality is, however, difficult to discern because judgements about patients entwine with emotion.     

Destabilizing the ‘equipoise’ framework in clinical trials: prioritizing non‐exploitation as an ethical framework in clinical research

The framework of equipoise has been promulgated as an underlying requirement for conducting ethical clinical research. Equipoise is the term used for a state of indifference about which treatment intervention or innovation will provide the most benefit and the least harm to recipients. Drawing on healthcare, research, and ethics literature, this paper analyses the implications of equipoise from the perspective of several proponents and critics. Specifically the historical evolution of the concept based on Fried and Freedman's arguments is traced. A critique of the concept, informed by contrasting perspectives, is offered. An alternative framework of non‐exploitation as presented by Miller and Brody is argued to be superior in facilitating both the ultimate goals of research on human subjects and those of the healthcare professions'.