Sequential monitoring of response-adaptive randomized clinical trials

TL;DR

This paper introduces a method to sequentially monitor response-adaptive randomized clinical trials, combining adaptive randomization and sequential analysis to improve trial efficiency while controlling error rates.

Contribution

It proposes a new procedure that allows for sequential monitoring of response-adaptive trials, with proven convergence properties and practical advantages demonstrated through simulations and a real case study.

Findings

Sequential test statistics converge to a Brownian motion.

The procedure maintains type I error control while improving power and sample size efficiency.

Simulation and case study validate the method's effectiveness.

Abstract

Clinical trials are complex and usually involve multiple objectives such as controlling type I error rate, increasing power to detect treatment difference, assigning more patients to better treatment, and more. In literature, both response-adaptive randomization (RAR) procedures (by changing randomization procedure sequentially) and sequential monitoring (by changing analysis procedure sequentially) have been proposed to achieve these objectives to some degree. In this paper, we propose to sequentially monitor response-adaptive randomized clinical trial and study it's properties. We prove that the sequential test statistics of the new procedure converge to a Brownian motion in distribution. Further, we show that the sequential test statistics asymptotically satisfy the canonical joint distribution defined in Jennison and Turnbull (\citeyearJT00). Therefore, type I error and other objectives can be achieved theoretically by selecting appropriate boundaries. These results open a door to sequentially monitor response-adaptive randomized clinical trials in practice. We can also observe from the simulation studies that, the proposed procedure brings together the advantages of both techniques, in dealing with power, total sample size and total failure numbers, while keeps the type I error. In addition, we illustrate the characteristics of the proposed procedure by redesigning a well-known clinical trial of maternal-infant HIV transmission.