He Philip, Ma Haijun, Lu Chengxing Cindy, Ananthakrishnan Revathi, Mi Gu, Gwise Thomas, Fernandes Laura, Yang Hui, Leung David, Ren Natalie, Chaudhry Sohail
Biostatistics,Daiichi Sankyo Inc., 211 Mt Airy Rd, Basking Ridge, New Jersey, USA.
Biostatistics, Exelixis, CA, USA.
Ther Innov Regul Sci. 2025 Aug 5. doi: 10.1007/s43441-025-00848-1.
Time-to-event endpoints, such as progression free survival (PFS) and overall survival (OS), are critical in assessing therapeutic efficacy in oncology drug development. However, their quality and interpretability are frequently challenged by a range of factors, from protocol design and intercurrent events (ICE) to inconsistent data collection and missing follow-up data. These methodological and operational complexities can obscure the true treatment effect. Discontinuation of study treatment, initiation of subsequent anticancer therapy, lost to follow-up and withdrawal of consent can introduce significant bias, limiting the robustness of survival endpoints and complicating regulatory decision making. Adopting a prospective ICH E9(R1) estimand framework helps mitigate risks associated with data collection, analysis methodology and interpretability. This facilitates clearer discussions with regulators and stakeholders. Although both the FDA guidance on oncology endpoints and the EMA guideline on anticancer medicinal product evaluation outline key principles in evaluating PFS and OS endpoints, integration of ICH E9(R1) offers a harmonized strategy that is important for the design and conduct of randomized late phase oncology clinical trials. In this article, we investigate the quality and interpretability of the endpoints of PFS and OS according to the ICH E9(R1) framework and present some practical recommendations for designing and conducting robust oncology clinical trials.
至事件发生终点，如无进展生存期（PFS）和总生存期（OS），在评估肿瘤药物研发中的治疗效果时至关重要。然而，它们的质量和可解释性经常受到一系列因素的挑战，从方案设计和并发事件（ICE）到数据收集不一致和随访数据缺失。这些方法学和操作上的复杂性可能会掩盖真实的治疗效果。研究治疗的中断、后续抗癌治疗的开始、失访和同意撤回可能会引入显著偏差，限制生存终点的稳健性并使监管决策复杂化。采用前瞻性的国际人用药品注册技术协调会（ICH）E9（R1）估计量框架有助于降低与数据收集、分析方法和可解释性相关的风险。这有助于与监管机构和利益相关者进行更清晰的讨论。尽管美国食品药品监督管理局（FDA）关于肿瘤终点的指南和欧洲药品管理局（EMA）关于抗癌药品评估的指南都概述了评估PFS和OS终点的关键原则，但整合ICH E9（R1）提供了一种统一的策略，这对于随机晚期肿瘤临床试验的设计和实施非常重要。在本文中，我们根据ICH E9（R1）框架研究了PFS和OS终点的质量和可解释性，并提出了一些设计和实施稳健的肿瘤临床试验的实用建议。
