Two-Stage Enrichment Clinical Trial Designs with Survival Outcomes and Adjustment for Misclassification in Predictive Biomarkers

• Activity Number: 318 - Adaptive (and Other) Clinical Trial Designs
• Type: Contributed
• Date/Time: Wednesday, August 11, 2021 : 3:30 PM to 5:20 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Yanping Chen* and Yong Lin and Shou-En Lu
• Companies: Bristol Myers Squibb and Rutgers University and Rutgers School of Public Health and Cancer Institute of New Jersey
• Keywords: Predictive Biomarker; Biomarker Misclassification; Enrichment Design; Adaptive design; Survival outcomes

Abstract

We propose a two-stage enrichment clinical trial design with survival outcomes. Specifically, we consider the situation where the assay and classification of the biomarker are possibly subject to error, and extend a stratified design with a futility analysis on the biomarker appeared negative cohort at the first stage. Depending on the result of the interim futility analysis, the second stage can be either a targeted design with only the biomarker appeared positive patients, or still the stratified design with both biomarker appeared strata. To account for the misclassification of the biomarker status, we develop the log rank statistics for the interim analysis and final analysis, with an adjustment for the sensitivity and specificity of the biomarker assay. Family-wise type I error control was achieved by considering correlations between adjusted log rank statistics from the same and/or different stages. R code is developed to calculate critical values, achieve global power, and marginal power, and to calculate sample size.