Department of Statistics, Rice University, Houston, Texas, USA.
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Stat Med. 2024 Jul 10;43(15):2972-2986. doi: 10.1002/sim.10093. Epub 2024 May 15.
The U.S. Food and Drug Administration (FDA) has launched Project Optimus to shift dose selection from the maximum tolerated dose (MTD) to the dose that produces the optimal risk-benefit tradeoff. One approach highlighted in the FDA's guidance involves conducting a randomized phase II trial following the completion of a phase I trial, where multiple doses (typically including the MTD and one or two doses lower than the MTD) are compared to identify the optimal dose that maximizes the benefit-risk tradeoff. This article focuses on the design of such a multiple-dose randomized trial, specifically the determination of the sample size. We generalized the standard definitions of type I error and power to accommodate the unique characteristics of dose optimization and derived a decision rule along with an algorithm to determine the optimal sample size. The resulting design is referred to as MERIT (Multiple-dosE RandomIzed Trial design for dose optimization based on toxicity and efficacy). Simulation studies demonstrate that MERIT has desirable operating characteristics, and a sample size between 20 and 40 per dosage arm often offers reasonable power and type I errors to ensure patient safety and benefit. To facilitate the implementation of the MERIT design, we provide software, available at https://www.trialdesign.org.
美国食品和药物管理局（FDA）已经启动了“Optimus 项目”，将剂量选择从最大耐受剂量（MTD）转移到产生最佳风险效益权衡的剂量。FDA 指南中强调的一种方法是在完成 I 期试验后进行随机 II 期试验，其中比较多个剂量（通常包括 MTD 和一个或两个低于 MTD 的剂量），以确定最大限度地提高风险效益权衡的最佳剂量。本文重点介绍了这种多剂量随机试验的设计，特别是样本量的确定。我们将 I 型错误和功效的标准定义推广到适应剂量优化的独特特征，并推导了一个决策规则以及一个算法来确定最佳样本量。由此产生的设计被称为 MERIT（基于毒性和疗效的多剂量随机试验设计进行剂量优化）。模拟研究表明，MERIT 具有理想的操作特性，每个剂量臂的样本量在 20 到 40 之间通常可以提供合理的功效和 I 型错误，以确保患者的安全和获益。为了促进 MERIT 设计的实施，我们提供了软件，可在 https://www.trialdesign.org 上获得。
