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.     

‘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.     

An early ‘clinical trial’ as a teaching exercise: the Book of Daniel 1.1–15 (1.1–20)

Summary. This article discusses a very early clinical trial from the Old Testament. One of Daniel's and his companions' tribulations in Babylonia is explicated within the framework of the modern clinical trial. Even if many, or maybe even most, guidelines for good clinical trial practice are violated (it can even be argued that this is not really a clinical trial), a discussion of this biblico-historical episode in, for example, a problem-based course in (clinical) epidemiology or a course in the critical appraisal of the literature, can be a useful (and possibly entertaining) exercise.     

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'.     

Are routine clinical chemistry analyses ‘in control’ according to shewhart's technique?

The clinical laboratory routinely uses quality control (QC) procedures. The Shewhart technique of charting control data, introduced in 1950, is usually applied in a much simplified manner. This reduces its power to distinguish between random errors and errors due to assignable causes. In a comparison of one of our routine charting procedures with a correct Shewhart procedure we checked 23 chemical tests. We found that using the latter 'a stable system of chance causes' did not exist for 6 tests. Both control procedures agreed well on the evaluation of reproducibility. For three of the tests, albumin, urea and uric acid, the instability was not detected by the routine procedure. Although charting of group means (mean i) and ranges (Ri) more readily detected instability, it did not lead to a negation of the practical utility of our patient data.     

A ‘stethoscope’ for the physician manager—conditions for clinical accountability in the nordic setting

An increasing interest in requiring clinical accountability, i.e. direct economical and managerial involvement of physicians, can be witnessed in the US and the UK, representing two extremes on the axis of private versus public service provision. The development is also taking place in the Nordic countries alongside a ‘decentralisation’ of financial and managerial decision making to smaller units. The essay discusses possibilities to introduce clinical accountability on the Nordic scene. As a background to the anlaysis, clinical accountability is defined in terms of production targets, budget limits and preset standards of quality of care. Arguments for not using clinical outcome as result measure are presented. The product analogy is suggested as a means for the physician manager to control both clinical policies and resource management. The conclusion is that the possibilities to introduce clinical accountability in the Nordic countries probably are better than in the US or UK, for the following reasons: physician attitudes, interpreted indirectly by shown interest in management training are not unfavourable; the organisational structure with physicians in a line organisation gives the financially accountable Department Head professional as well as managerial authority; management policy stressing decentralisation increases autonomy and stimulates interest to involve in management; product control information is readily available through reliable information systems. Obstacles are also identified. Finally it is argued that the organisation structure found in Nordic countries enables clinical accountability still preserving clinical freedom in the singular doctor patient relation.