Cancer Outcomes Research Program, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Cancer. 2014 Mar 1;120(5):761-7. doi: 10.1002/cncr.28470. Epub 2013 Dec 5.
Pain palliation resulting from antitumor therapy provides direct evidence of treatment benefit when combined with evidence of antitumor activity. The US Food and Drug Administration (FDA) previously issued guidance regarding the use of patient-reported outcome (PRO) measures to support labeling claims. The purpose of this article is to identify common challenges and key design strategies when measuring pain palliation in antitumor therapy clinical trials that are consistent with PRO Guidance principles.
Antitumor clinical protocols submitted to the FDA between 1995 and 2012 that included pain palliation as a primary or secondary endpoint were reviewed. Challenges in critical trial design components were identified. Design strategies consistent with PRO Guidance principles are proposed.
The challenges identified were measurement of pain intensity and analgesic use, enrollment eligibility criteria, data collection methods, responder definitions, missing data, and blinding. Strategies included the use of well-defined, reliable, PRO assessments of pain intensity and analgesics; ensuring that enrollment criteria define patients with clinically significant pain attributable to cancer on an optimal analgesic regimen; defining responders using both pain and analgesic use criteria; incorporating an analysis of tumor response to support evidence of pain response; and minimizing missing data and inadvertent unblinding.
Improvement in cancer-related pain resulting from antitumor therapy is an important treatment benefit that can support drug approval and labeling claims when adequately measured if study results demonstrate statistically and clinically significant findings. Sponsors are encouraged to discuss pain palliation assessment methods with the FDA early in and throughout product development.
抗肿瘤治疗引起的疼痛缓解与抗肿瘤活性的证据相结合，为治疗获益提供了直接证据。美国食品和药物管理局（FDA）曾发布过关于使用患者报告结局（PRO）测量来支持标签声明的指南。本文的目的是确定在与 PRO 指南原则一致的抗肿瘤治疗临床试验中测量疼痛缓解时常见的挑战和关键设计策略。
回顾了 1995 年至 2012 年期间提交给 FDA 的抗肿瘤临床方案，这些方案将疼痛缓解作为主要或次要终点。确定了关键试验设计组件中的挑战。提出了符合 PRO 指南原则的设计策略。
确定的挑战包括疼痛强度和镇痛药使用的测量、入组资格标准、数据收集方法、应答者定义、缺失数据和盲法。策略包括使用定义明确、可靠的 PRO 评估疼痛强度和镇痛药；确保入组标准定义了在最佳镇痛方案下归因于癌症的具有临床意义的疼痛的患者；使用疼痛和镇痛药使用标准定义应答者；纳入肿瘤反应分析以支持疼痛反应的证据；并最大限度地减少缺失数据和意外的未盲。
如果研究结果显示具有统计学和临床意义的发现，抗肿瘤治疗引起的癌症相关疼痛的改善是一个重要的治疗益处，可以支持药物批准和标签声明。鼓励赞助商在产品开发的早期和整个过程中与 FDA 讨论疼痛缓解评估方法。
