Clinical trials : journal of the Society for Clinical Trials
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Aprotinin is a serine protease inhibitor used to limit perioperative bleeding and reduce the need for donated blood transfusions during cardiac surgery. Randomized controlled trials of aprotinin evaluating its effect on the outcome of perioperative transfusion have been published since 1987, and systematic reviews were conducted in 1992 and 1997. ⋯ This study demonstrates that investigators evaluating aprotinin were not adequately citing previous research, resulting in a large number of RCTs being conducted to address efficacy questions that prior trials had already definitively answered. Institutional review boards and journals could reduce the number of redundant trials by requiring investigators to conduct adequate searches for prior evidence and conducting systematic reviews.
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We describe different forms of clustering that may occur in individually randomized trials, where the observed outcomes for different individuals cannot be regarded as independent. We propose random effects models to allow for such clustering, across a range of contexts and trial designs, and investigate their effect on estimation and interpretation of the treatment effect. ⋯ Clustering is an important issue in many individually randomized trials. Ignoring it can lead to underestimates of the uncertainty and too extreme P-values. Even when there is little apparent heterogeneity across clusters, it can still have a large impact on the estimation and interpretation of the treatment effect.
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Randomized controlled trials almost always have some individuals with missing outcomes. Inadequate handling of these missing data in the analysis can cause substantial bias in the treatment effect estimates. We examine how missing outcome data are handled in randomized controlled trials in order to assess whether adequate steps have been taken to reduce nonresponse bias and to identify ways to improve procedures for missing data. ⋯ Our review shows that missing outcome data are a common problem in randomized controlled trials, and are often inadequately handled in the statistical analysis in the top tier medical journals. Authors should explicitly state the assumptions underlying the handling of the missing outcomes and justify them through data descriptions and sensitivity analyses.
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It is considered to be a fundamental ethical premise of human experimentation, that it should be carried out only where the effects of an intervention are unclear. The point at which it is considered that there is insufficient scientific and medical evidence to clearly state the superiority of an intervention has been termed equipoise. This concept has been the subject of much recent impassioned debate but little empirical research about the views of people involved in recruitment to randomized controlled trials (RCTs), and none in the particularly emotive area of neonatal intensive care. ⋯ Our findings suggest that the concept of equipoise goes beyond the idea of uncertainty. In part this is because it includes the balancing of benefit and harm; this balancing is part of a professional obligation and requires engagement with 'expert' knowledge. Equipoise could therefore be seen as 'active' or 'responsible' uncertainty. Elucidation of this difficult concept may help to facilitate recruitment for both clinicians and parents in future trials and thereby help to find answers to important clinical questions.
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Since 1992 the Office of Research Integrity (ORI) had reviewed investigations of scientific misconduct in research funded by the US Public Health Service (PHS). ORI defined scientific misconduct as "fabrication, falsification, plagiarism, or other practices that seriously deviate from those that are commonly accepted within the scientific community for proposing, conducting, or reporting research". ⋯ In clinical trials, junior employees may bear the burden of sanction for scientific misconduct. The most frequently applied sanction was the requirement that a plan of supervision of the sanctioned employees accompany any future application for funding which would include them. This imposition of sanction on an individual employee does not address possible causes of misconduct which may be inherent in the overall pattern of leadership, training and supervision in the trial. Furthermore, the definition of misconduct, as interpreted by the Departmental Appeals Board, excludes carelessness and other poor research practices that may lead to dissemination of more incorrect data than misconduct.