title: Comparison of conditional bias-adjusted estimators for interim analysis in clinical trials with survival data.
abstract: Group sequential designs are widely used in clinical trials to determine whether a trial should be terminated early. In such trials, maximum likelihood estimates are often used to describe the difference in efficacy between the experimental and reference treatments; however, these are well known for displaying conditional and unconditional biases. Established bias-adjusted estimators include the conditional mean-adjusted estimator (CMAE), conditional median unbiased estimator, conditional uniformly minimum variance unbiased estimator (CUMVUE), and weighted estimator. However, their performances have been inadequately investigated. In this study, we review the characteristics of these bias-adjusted estimators and compare their conditional bias, overall bias, and conditional mean-squared errors in clinical trials with survival endpoints through simulation studies. The coverage probabilities of the confidence intervals for the four estimators are also evaluated. We find that the CMAE reduced conditional bias and showed relatively small conditional mean-squared errors when the trials terminated at the interim analysis. The conditional coverage probability of the conditional median unbiased estimator was well below the nominal value. In trials that did not terminate early, the CUMVUE performed with less bias and an acceptable conditional coverage probability than was observed for the other estimators. In conclusion, when planning an interim analysis, we recommend using the CUMVUE for trials that do not terminate early and the CMAE for those that terminate early. Copyright © 2017 John Wiley & Sons, Ltd.
authors.affiliation: Data Science Department, Taiho Pharmaceutical. Co., Ltd., Tokyo, Japan.|Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Masashi
authors.identifier: 0000-0003-1233-4588
authors.initials: M
authors.lastname: Shimura
authors.affiliation: Department of Clinical Trial and Clinical Epidemiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Gosho
authors.affiliation: Biostatistics and Bioinformatics Section, Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hirakawa
mesh_terms: D015982:Bias; D003627:Data Interpretation, Statistical; D057239:Early Termination of Clinical Trials / Q000379:methods* / Q000706:statistics & numerical data; D006801:Humans; D018447:Medical Futility; D015233:Models, Statistical; D016032:Randomized Controlled Trials as Topic / Q000379:methods / Q000706:statistics & numerical data; D016019:Survival Analysis; D016896:Treatment Outcome
keywords: conditional estimation; group sequential design; unbiased estimator