Title: Estimands for Randomized Discontinuation Designs in Oncology Show Chinese title

Title: 肿瘤学中随机退出设计的估计目标

Abstract: Randomized discontinuation design (RDD) is an enrichment strategy commonly used to address limitations of traditional placebo-controlled trials, particularly the ethical concern of prolonged placebo exposure. RDD consists of two phases: an initial open-label phase in which all eligible patients receive the investigational medicinal product (IMP), followed by a double-blind phase in which responders are randomized to continue with the IMP or switch to placebo. This design tests whether the IMP provides benefit beyond the placebo effect. The estimand framework introduced in ICH E9(R1) strengthens the dialogue among clinical research stakeholders by clarifying trial objectives and aligning them with appropriate statistical analyses. However, its application in oncology trials using RDD remains unclear. This manuscript uses the phase III JAVELIN Gastric 100 trial and the phase II trial of sorafenib (BAY 43-9006) as case studies to propose an estimand framework tailored for oncology trials employing RDD in phase III and phase II settings, respectively. We highlight some similarities and differences between RDDs and traditional randomized controlled trials in the context of ICH E9(R1). This approach aims to support more efficient regulatory decision-making. Show Chinese abstract

Abstract: 随机撤除设计（RDD）是一种常用于解决传统安慰剂对照试验局限性的富集策略，尤其是延长安慰剂暴露带来的伦理问题。 RDD 包括两个阶段：一个初始开放标签阶段，在此阶段所有符合条件的患者均接受研究性药物（IMP），随后是一个双盲阶段，在此阶段应答者被随机分配继续使用 IMP 或切换到安慰剂。 该设计旨在测试 IMP 是否能提供超出安慰剂效应的好处。 ICH E9(R1) 中引入的估计量框架通过明确试验目标并与适当的统计分析对齐，加强了临床研究利益相关方之间的对话。 然而，其在采用 RDD 的肿瘤学试验中的应用仍不清楚。 本文以 III 期 JAVELIN 胃癌 100 试验和 II 期索拉非尼（BAY 43-9006）试验作为案例研究，分别提出适用于 III 期和 II 期设置中采用 RDD 的肿瘤学试验的估计量框架。 我们强调了在 ICH E9(R1) 的背景下，RDD 和传统随机对照试验之间的某些相似性和差异。 这种方法旨在支持更高效的监管决策。