title: Maximum type 1 error rate inflation in multiarmed clinical trials with adaptive interim sample size modifications.
abstract: Sample size modifications in the interim analyses of an adaptive design can inflate the type 1 error rate, if test statistics and critical boundaries are used in the final analysis as if no modification had been made. While this is already true for designs with an overall change of the sample size in a balanced treatment-control comparison, the inflation can be much larger if in addition a modification of allocation ratios is allowed as well. In this paper, we investigate adaptive designs with several treatment arms compared to a single common control group. Regarding modifications, we consider treatment arm selection as well as modifications of overall sample size and allocation ratios. The inflation is quantified for two approaches: a naive procedure that ignores not only all modifications, but also the multiplicity issue arising from the many-to-one comparison, and a Dunnett procedure that ignores modifications, but adjusts for the initially started multiple treatments. The maximum inflation of the type 1 error rate for such types of design can be calculated by searching for the "worst case" scenarios, that are sample size adaptation rules in the interim analysis that lead to the largest conditional type 1 error rate in any point of the sample space. To show the most extreme inflation, we initially assume unconstrained second stage sample size modifications leading to a large inflation of the type 1 error rate. Furthermore, we investigate the inflation when putting constraints on the second stage sample sizes. It turns out that, for example fixing the sample size of the control group, leads to designs controlling the type 1 error rate.
authors.affiliation: Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria; Competence Center for Clinical Trials, University of Bremen, Linzer Strasse 4, 28359, Bremen, Germany.
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Graf
authors.forename: Peter
authors.initials: P
authors.lastname: Bauer
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Glimm
authors.forename: Franz
authors.initials: F
authors.lastname: Koenig
mesh_terms: D001699:Biometry / Q000379:methods*; D002986:Clinical Trials as Topic / Q000379:methods*; D003657:Decision Making; D006801:Humans; D012107:Research Design; D018401:Sample Size
keywords: Conditional error function; Interim analysis; Maximum type 1 error; Sample size reassessment; Treatment selection
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