title: Methods for flexible sample-size design in clinical trials: Likelihood, weighted, dual test, and promising zone approaches.
abstract: Sample size plays a crucial role in clinical trials. Flexible sample-size designs, as part of the more general category of adaptive designs that utilize interim data, have been a popular topic in recent years. In this paper, we give a comparative review of four related methods for such a design. The likelihood method uses the likelihood ratio test with an adjusted critical value. The weighted method adjusts the test statistic with given weights rather than the critical value. The dual test method requires both the likelihood ratio statistic and the weighted statistic to be greater than the unadjusted critical value. The promising zone approach uses the likelihood ratio statistic with the unadjusted value and other constraints. All four methods preserve the type-I error rate. In this paper we explore their properties and compare their relationships and merits. We show that the sample size rules for the dual test are in conflict with the rules of the promising zone approach. We delineate what is necessary to specify in the study protocol to ensure the validity of the statistical procedure and what can be kept implicit in the protocol so that more flexibility can be attained for confirmatory phase III trials in meeting regulatory requirements. We also prove that under mild conditions, the likelihood ratio test still preserves the type-I error rate when the actual sample size is larger than the re-calculated one.
authors.affiliation: Department of Biostatistics, Rutgers School of Public Health, Rutgers University, Piscataway, NJ 08854, United States. Electronic address: w.joe.shih@rutgers.edu.
authors.forename: Weichung Joe
authors.initials: WJ
authors.lastname: Shih
authors.affiliation: Janssen Pharmaceutical Research and Development, Raritan, NJ 08869, United States.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Janssen Pharmaceutical Research and Development, Raritan, NJ 08869, United States.
authors.forename: Yining
authors.initials: Y
authors.lastname: Wang
mesh_terms: D002986:Clinical Trials as Topic; D006801:Humans; D016013:Likelihood Functions; D012107:Research Design; D018401:Sample Size; D013223:Statistics as Topic
keywords: Adaptive design; Conditional power; Flexible clinical trials; Group-sequential boundary; Sample size re-estimation; Two-stage designs