Analysis of Time-to-Event Data with Nonuniform Patient Entry and Loss to Follow-Up under a Two-Stage Seamless Adaptive Design with Weibull Distribution

Abstract

In the pharmaceutical industry, a two-stage seamless adaptive design that combines two separate independent clinical trials into a single clinical study is commonly employed in clinical research and development. In practice, in the interest of shortening the development process, it is not uncommon to consider study endpoints with different treatment durations at different stages (Chow and Chang, 2006; Maca et al., 2006). In this study, our attention is placed on the case where the study endpoints of interest are time-to-event data where the durations at the two stages are different with nonuniform patient entry and losses to follow-up or dropouts. Test statistics for the final analysis based on the combined data are developed under various hypotheses for testing equality, superiority, noninferiority, and equivalence. In addition, formulas for sample size calculation and allocation between the two stages based on the proposed test statistic are derived.

Key Words:

• Loss to follow-up
• Nonuniform entry
• Sample size determination
• Time-to-event data
• Two-stage adaptive design
• Weibull model