Citations

Abstract: To ensure that participants in randomized controlled trials are protected from harm, interim analyses and review of results by an independent data monitoring committee have become standard practice. If an analysis of accumulating data partway through a trial reveals an unanticipated degree of benefit or toxicity, or differences in outcomes between the intervention and control groups are so unimpressive that any prospect of a positive result with the planned sample size is extremely unlikely, investigators may stop the trial earlier than originally scheduled. The practice of stopping randomized controlled trials early is, however, problematic, especially if the trial is stopped for apparent benefit. Concerns in trials stopped early for apparent benefit include appropriate interpretation of results and ethical problems concerning trial participants, clinicians, and society as a whole. In this article, we review the epidemiology of trials stopped early and illustrate some of the problems and controversies associated with stopping randomized controlled trials early for apparent benefit. Finally, we offer guidance for clinicians, those running clinical trials, and authors of systematic reviews.

Abstract: Randomized controlled trials in orthopaedics are often underpowered to detect important differences in outcomes. Composite end points (CEPs) hold promise as a strategy to address this issue by combining multiple end points into one summary measure, thus increasing the observed event rate. The use of CEPs by trialists, however, can be problematic when they include components that vary greatly in importance to patients and when differences in apparent effect between components are large. We present an overview of CEPs with a focus on appropriate design and interpretation of results.

In this paper, we explore the relative value that different methods offer in answering some stereotypical comparative effectiveness research questions with the goal of informing development of a ‘translation table’ – a selection tool for choosing appropriate methods for specific comparative effectiveness research questions. This paper was written as a parallel effort to Greenfield and Kaplan (also in this volume) to support the endeavor described in the manuscript by Tunis et al. (also in this volume). Originally based on four cases, the current article has been shortened to two cases for the current discussion. These cases represent research priorities proposed to orient the work of the Patient-Centered Outcomes Research Institute, comparative clinical effectiveness and comparative health services.

We review controversies associated with randomized controlled trials (RCTs) stopped early for apparent benefit (truncated RCTs or tRCTs) and present our groups’ perspective. Long-established theory, simulations and recent empirical evidence demonstrate that tRCTs will on average overestimate treatment effects, and this overestimation may be large, particularly when tRCTs have small number of events. Theoretical considerations and simulations demonstrate that on average, meta-analyses of RCTs with appropriate stopping rules will lead to only trivial overestimation of treatment effects. However, tRCTs will disproportionally contribute to meta-analytic estimates when tRCTs occur early in the sequence of trials with few subsequent studies, publication of nontruncated RCTs is delayed, there is publication bias, or tRCTs result in a ‘freezing’ effect in which ‘correcting’ trials are never undertaken. To avoid applying overestimates of effect to clinical decision-making, clinicians should view the results of individual tRCTs with small sample sizes and small number of events with skepticism. Pooled effects from meta-analyses including tRCTs are likely to overestimate effect when there is a substantial difference in effect estimates between the tRCTs and the nontruncated RCTs, and in which the tRCTs have a substantial weight in the meta-analysis despite themselves having a relatively small number of events. Such circumstances call for sensitivity analyses omitting tRCTs.

Abstract Mortality in National Heart, Lung and Blood Institute–sponsored clinical trials of treatments for acute lung injury (ALI) has decreased dramatically during the past two decades. As a consequence, design of such trials based on a mortality outcome requires ever-increasing numbers of patients. Recognizing that advances in clinical trial design might be applicable to these trials and might allow trials with fewer patients, the National Heart, Lung and Blood Institute convened a workshop of extramural experts from several disciplines. The workshop assessed the current state of clinical research addressing ALI, identified research needs, and recommended: (1) continued performance of trials evaluating treatments of patients with ALI; (2) development of strategies to perform ALI prevention trials; (3) observational studies of patients without ALI undergoing prolonged mechanical ventilation; and (4) development of a standardized format for reporting methods, endpoints, and results of ALI trials.

Background. Statin Choice is a decision aid about taking statins. The optimal mode of delivering Statin Choice (or any other decision aid) in clinical practice is unknown. Methods. To investigate the effect of mode of delivery on decision aid efficacy, the authors further explored the results of a concealed 2 × 2 factorial clustered randomized trial enrolling 21 endocrinologists and 98 diabetes patients and randomizing them to 1) receive either the decision aid or pamphlet about cholesterol, and 2) have these delivered either during the office visit (by the clinician) or before the visit (by a researcher). We estimated between-group differences and their 95% confidence intervals (CI) for acceptability of information delivery (1—7), knowledge about statins and coronary risk (0—9), and decisional conflict about statin use (0—100) assessed immediately after the visit. Follow-up was 99%. Results. The relative efficacy of the decision aid v. pamphlet interacted with the mode of delivery. Compared with the pamphlet, patients whose clinicians delivered the decision aid during the office visit showed significant improvements in knowledge (difference of 1.6 of 9 questions, CI 0.3, 2.8) and nonsignificant trends toward finding the decision aid more acceptable (odds ratio 3.1, CI 0.9, 11.2) and having less decisional conflict (difference of 7 of 100 points, CI - 4, 18) than when a researcher delivered the decision aid just before the office visit. Conclusions. Delivery of decision aids by clinicians during the visit improves knowledge and shows a trend toward better acceptability and less decisional conflict.