Externally controlled trials (ECTs), including single-arm studies augmented with historical data and hybrid randomized designs with partial external augmentation, are increasingly used when concurrent randomized controls are infeasible or unethical. Regulatory guidance from the FDA, EMA, and NMPA calls for sensitivity analysis of borrowing assumptions, yet provides no structured template for which analyses to run or how to interpret them together. We propose a three-pillar framework organized around three questions: was the borrowing appropriate, did it contribute meaningful value, and are the conclusions robust to perturbation? The framework comprises eight modular analyses covering heterogeneity diagnostics, source influence, no-borrowing references, effective sample size, prior sensitivity, tipping points, alternative borrowing methods, and structural model sensitivity. It is method-agnostic and applies to both Bayesian and frequentist borrowing in patient-level or hybrid settings. We illustrate the framework using simulated data that mimic a hybrid evidence synthesis from a historical approval of ethnic-bridging submission under a real-world-evidence regulatory pathway. That original analysis combined individual patient data from a global pivotal study and a regional real-world study with aggregate data from two published cohorts, fitted via a Bayesian longitudinal model with ethnic-difference parameters. The worked example provides a reproducible template for sensitivity analysis in ECT submissions.

翻译：外部对照试验（ECT）——包括利用历史数据增强的单臂研究以及部分外部增强的混合随机设计——在并行随机对照不可行或不符合伦理时日益得到应用。美国食品药品监督管理局（FDA）、欧洲药品管理局（EMA）及国家药品监督管理局（NMPA）发布的监管指南要求对借用假设进行灵敏度分析，但未提供需执行哪些分析或如何联合解读这些分析的结构化模板。我们提出一个围绕三个问题的三支柱框架：借用是否恰当？是否贡献了有意义的价值？结论对扰动是否稳健？该框架包含八项模块化分析，涵盖异质性诊断、来源影响、无借用参照、有效样本量、先验敏感性、临界点、替代借用方法及结构模型敏感性。该方法具有通用性，适用于患者层面或混合场景下的贝叶斯和频率学派借用。我们通过模拟数据演示该框架，模拟数据模仿了在真实世界证据监管路径下历史上获批的种族桥接申报中的混合证据合成过程。原分析结合了全球关键性研究中的个体患者数据、区域真实世界研究数据以及两个已发表队列的汇总数据，通过包含种族差异参数的贝叶斯纵向模型进行拟合。该实例为ECT申报中的灵敏度分析提供了可复现模板。