SEQUENTIAL MONITORING OF RESPONSE-ADAPTIVE RANDOMIZED CLINICAL TRIALS

• 成果类型: Article
• 署名作者: Zhu, Hongjian; Hu, Feifang
• 署名单位: University of Virginia
• 刊物名称: ANNALS OF STATISTICS
• ISSN/ISSBN: 0090-5364
• DOI: 10.1214/10-AOS796
• 发表日期: 2010
• 页码: 2218-2241
• 关键词: biased coin designs; play-winner rule; LIMIT-THEOREMS; urn models; variability

摘要

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 (2000). 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.