Group Sequential Design for Non-Proportional Hazards: Logrank, Weighted Logrank, and MaxCombo Methods

TL;DR

This paper develops group sequential design methods for non-proportional hazards in clinical trials, focusing on three NPH approaches and providing analytic tools for sample size calculation, with implementation in an R package.

Contribution

It introduces analytic design characteristics for three NPH methods and implements them in the gsDesign2 R package for improved trial planning.

Findings

Analytic forms for design characteristics under NPH scenarios.

Sample size calculation methods for group sequential designs.

Implementation of methods in the gsDesign2 R package.

Abstract

Non-proportional hazards (NPH) are often observed in clinical trials with time-to-event endpoints. A common example is a long-term clinical trial with a delayed treatment effect in immunotherapy for cancer. When designing clinical trials with time-to-event endpoints, it is crucial to consider NPH scenarios to gain a complete understanding of design operating characteristics. In this paper, we focus on group sequential design for three NPH methods: the average hazard ratio, the weighted logrank test, and the MaxCombo combination test. For each of these approaches, we provide analytic forms of design characteristics that facilitate sample size calculation and bound derivation for group sequential designs. Examples are provided to illustrate the proposed methods. To facilitate statisticians in designing and comparing group sequential designs under NPH, we have implemented the group sequential design methodology in the gsDesign2 R package at https://cran.r-project.org/web/packages/gsDesign2/.