title: Methods of designing two-stage winner trials with survival outcomes.
abstract: In drug development, especially for oncology studies, a recent proposal is to combine a costly phase II dose selection study with a subsequent phase III study into a single trial that compares the selected (winning) dose from the first stage with the control group. This design may also be used in phase III trials, in which the winning active treatment regimen, selected at the first stage, is compared with the control group at the second stage. This design is known as a two-stage winner design, as proposed by Shun et al. (2008) for continuous outcomes. Time-to-event data are often analyzed in oncology trials. In order to derive the critical value and power of this design, per Shun et al. (2008), it is essential to calculate the asymptotic covariance and correlation of the log-rank statistics for survival outcomes between the two stages. In this paper, we derive the asymptotic covariance and correlation, and provide additional approximate design parameters. Examples are given to illustrate the method, and simulations are performed to evaluate the veracity of these approximate design parameters.
authors.affiliation: Bayer Healthcare Pharmaceuticals, Inc., Montville, NJ, 07045, U.S.A.
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
authors.forename: Weichung J
authors.initials: WJ
authors.lastname: Shih
authors.forename: Yulin
authors.initials: Y
authors.lastname: Li
authors.forename: Jay
authors.initials: J
authors.lastname: Yang
authors.forename: Xiaosha
authors.initials: X
authors.lastname: Zhang
mesh_terms: D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data; D017326:Clinical Trials, Phase III as Topic / Q000706:statistics & numerical data; D006801:Humans; D017063:Outcome Assessment, Health Care / Q000706:statistics & numerical data*; D012107:Research Design / Q000706:statistics & numerical data; D013223:Statistics as Topic / Q000379:methods*; D016019:Survival Analysis
keywords: asymptotic correlation; log-rank statistic; survival outcome; two-stage winner design