• M Mushfiqur Rashid, Joseph W McKean, and John D Kloke.
• a Food and Drug Administration , Silver Spring , Maryland , USA.
• J Biopharm Stat. 2013 Jan 1; 23 (6): 1207-27.

AbstractThis 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. Robust, rank-based, Wilcoxon-type procedures are reviewed for a multicenter clinical trial for the mixed model but without the assumption of normality. These procedures retain the high efficiency of Wilcoxon methods for simple location problems and are based on a fitting criterion which is robust to outliers in response space. A simple weighting scheme can be employed so that the procedures are robust to outliers in factor (design) space as well as response space. 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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