How to deal with multiple treatment or dose groups in randomized clinical trials?
Multiplicity adjustment in general is currently a controversial topic. This review focuses on the proof of efficacy in randomized clinical trials. The ICH guidelines mandate control of the familywise error rate. Confidence intervals are clinically more appropriate than P-values or yes/no decisions. Therefore, simultaneous confidence intervals are proposed for several designs and aims in clinical trials. The computation of simultaneous confidence intervals for the difference or the ratio is demonstrated by means of real data examples using the R-packages multcomp and mratios. A special problem is the evaluation of dose-finding trials with and without the assumption that the effects increase with increasing doses. Simultaneous intervals are presented not only for one-way layouts and normal distributed endpoints, but also for higher way layouts, generalized linear models, and mixed models. Under importance ordering, the conditional testing of all hypotheses at level alpha will be shown using the intersection-union test principle. Other multiplicity issues (i.e. multiple endpoints, multiple analyses, and subgroup analyses) are discussed.
Hothorn
L A
LA
Institute of Biostatistics, Leibniz University of Hannover, Herrenhaeuser Str. 2, D-30419 Hannover, Germany. hothorn@biostat.uni-hannover.de
D002985:Clinical Protocols; D016001:Confidence Intervals; D035061:Control Groups; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015233:Models, Statistical; D016032:Randomized Controlled Trials as Topic / Q000379:methods / Q000706:statistics & numerical data*; D012107:Research Design