Journal of biopharmaceutical statistics
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This article reviews nonparametric alternatives to the mixed model normal theory analysis for the analyses of multicenter clinical trials. Under a mixed model, the traditional analysis is based on maximum likelihood theory under normal errors. This analysis, though, is not robust to outliers. ⋯ These rank-based analyses offer a complete analysis, including estimation of fixed effects and their standard errors, and tests of linear hypotheses. Both rank-based estimates of contrasts and individual treatment effects are reviewed. We illustrate the analyses using real data from a clinical trial.
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While randomized, well-controlled, clinical trials have been viewed as the gold standard in the evaluation of medical products, including drugs, biological products, and medical devices, it is not uncommon for safety assessment to be performed using observational studies, for ethical or practical reasons. In observational studies, various biases could be introduced in every stage and aspect of study, and consequently the resulting statistical inference may carry a lower level of scientific assurance, compared to randomized trials. To ensure the objectivity of study design and interpretability of the results, it is critical to address the challenges of such studies. In this paper, we share regulatory considerations on the prospective design of observational studies to address safety issues using propensity score methodology.
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Comparative Study
A profile analysis approach using MMRM in acute schizophrenia: a comparison to some traditional approaches.
The analysis of schizophrenia studies is plagued by inefficiency and bias due to much missing data. Mixed-effect models for repeated measures designs help address these problems, but to gain even more efficiency it is desirable to judiciously use additional longitudinal data in such designs by comparing treatment groups over multiple time points. Simulations were conducted to compare a profile analysis approach to other commonly used analysis methods in the presence of data missing at random. One gains efficiency by using a composite contrast over multiple time points when the treatment effect over the time points is not substantially different.
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This article discusses the problem of selecting free parameters of multiple testing procedures in confirmatory Phase III clinical trials with multiple objectives, including hypothesis weights and hypothesis ordering. We identify classes of multiple testing procedures that provide different interpretations of these parameters. ⋯ We examine the behavior of different classes of multiple testing procedures in problems with unequally weighted hypotheses and a priori ordered hypotheses and provide practical guidelines for the choice of hypothesis weights and hypothesis ordering. The concepts discussed in the article are illustrated using case studies based on clinical trials with multiple endpoints, multiple dose-placebo comparisons, and multiple patient populations.
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In clinical trials, multiple outcomes are often collected in order to simultaneously assess effectiveness and safety. We develop a Bayesian procedure for determining the required sample size in a regression model where a continuous efficacy variable and a binary safety variable are observed. ⋯ The model accounts for correlation between the two variables. Through examples we demonstrate that savings in total sample size are possible when the correlation between these two variables is sufficiently high.