Flexible Seamless 2-in-1 Design with Sample Size Adaptation

TL;DR

This paper introduces a flexible 2-in-1 clinical trial design with sample size adaptation, enabling more efficient drug development by using interim data and surrogate endpoints, aligning with FDA initiatives.

Contribution

It proposes a novel adaptive 2-in-1 trial design that incorporates sample size flexibility and interim decision rules, improving efficiency over traditional fixed-sample designs.

Findings

Requires smaller sample sizes than traditional designs

Achieves similar statistical power with shorter timelines

Demonstrated effectiveness through a multiple myeloma case study

Abstract

2-in-1 design (Chen et al. 2018) is becoming popular in oncology drug development, with the flexibility of using different endpoints at different decision time. Based on the observed interim data, sponsors choose either to seamlessly advance a small phase 2 trial to a full-scale confirmatory phase 3 trial with a pre-determined maximum sample size, or to remain in a phase 2 trial. This approach may increase efficiency in drug development but is rigid and requires a pre-specified fixed sample size. In this paper, we propose a flexible 2-in-1 design with sample size adaptation, while retains the advantage of allowing intermediate endpoint for interim decision. The proposed design reflects the needs of recent FDA's Project FrontRunner initiative to encourage using an earlier surrogate endpoint to potentially support accelerated approval with conversion to standard approval with long term endpoint from the same randomized study. Additionally, we identify the interim decision cut-off to allow conventional test procedure at the final analysis. Extensive simulation studies showed the proposed design require much smaller sample size and shorter timeline than the simple 2-in-1 design, while achieving similar power. A case study in multiple myeloma is used to demonstrate the benefits of the proposed design.