P18 Multi-arm and multi-stage superiority clinical trial design for negative binomial count data

Recurrent events or count data frequently serve as primary endpoints to assess treatment effects across diverse disease domains. Recently, statistical methodologies for group sequential design, adaptive design including sample size re-estimation with count data are discussed in the literature. However, the situation of multi-arm and multi-stage design incorporating both sample size re-estimation and arm dropping has not been explored for count data. In this research motivated by the need of designing a pediatric trial, a two-stage seamless phase 2/3 study design with count data as primary endpoint will be discussed. In stage 1, the participants will be randomized to low dose, high dose, and placebo. When pre-planned first part of stage 1 subjects (N11) completed a shorter treatment duration D1, an interim analysis will be conducted for both sample size re-estimation and dose selection. After dose is selected and final updated sample size is determined based on the interim analysis results and desired conditional power, stage 2 enrollment will begin by randomizing stage 2 participants into the selected dose and placebo. In order not to create any enrollment gap, from the cutoff date of interim analysis to start of stage 2 enrollment of N2 participants, additional stage 1 participants (N12) could be enrolled. All stage 1 and 2 participants (N11+N12+N2) will complete a longer treatment duration D2 (where D2>D1) and their data will be combined for the final analysis. The multiplicity adjustment approach accounting for dose selection and sample size re-estimation for the final analysis of comparing selected dose vs placebo for the primary efficacy endpoint using data from both stages will be discussed. Simulation studies will be presented to illustrate the operational characteristics under different enrollment assumptions, dose response curves and interim analysis timings.

Clinical Trial Design (e.g., Innovative/Complex Design, Estimands, Master Protocol)

ASA Biopharmaceutical Section Regulatory-Industry Statistics Workshop 2024