Real World Evidence and Patient Outcomes, CERobs Consulting, Wrightsville Beach, NC, USA.
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Ther Innov Regul Sci. 2024 Nov;58(6):1214-1232. doi: 10.1007/s43441-024-00693-8. Epub 2024 Sep 16.
Single-arm clinical trials (SAT) are common in drug and biologic submissions for rare or life-threatening conditions, especially when no therapeutic options exist. External control arms (ECAs) improve interpretation of SATs but pose methodological and regulatory challenges.
Through narrative reviews and expert input, we developed a framework for considerations that might influence regulatory use and likelihood of regulatory acceptance of an SAT, identifying non-oncology first indication approvals as an area of interest. We systematically analyzed FDA and EMA approvals using SATs as pivotal evidence. The framework guided outcome abstraction on regulatory responses.
We examined all non-oncology FDA and EMA drug and biologic approvals for first indications from 2019 to 2022 to identify those with SAT as pivotal safety or efficacy evidence. We abstracted outcomes, key study design features, regulator responses to SAT and (where applicable) ECA design, and product label content.
Among 20 SAT-based FDA approvals and 17 SAT-based EMA approvals, most common indications were progressive rare diseases with high unmet need/limited therapeutic options and a natural history without spontaneous improvement. Of the types of comparators, most were natural history cohorts (45% FDA; 47% EMA) and baseline controls (40% FDA; 47% EMA). Common critiques were of non-contemporaneous ECAs, subjective endpoints, and baseline covariate imbalance between arms.
Based on recent FDA and EMA approvals, the likelihood of regulatory success for SATs with ECAs depends on many design, analytic, and data quality considerations. Our framework is useful in early drug development when considering SAT strategies for evidence generation.
在治疗罕见或危及生命疾病的药物和生物制剂的药品申请中，单臂临床试验（SAT）较为常见，尤其是当没有治疗方法时。外部对照（ECA）可改善 SAT 的解读，但存在方法学和监管挑战。
通过叙述性综述和专家意见，我们制定了一个考虑因素框架，这些因素可能会影响 SAT 的监管使用和监管接受的可能性，并确定非肿瘤首次适应证批准为关注领域。我们使用 SAT 作为关键证据，对 FDA 和 EMA 的批准进行了系统分析。该框架指导了监管反应的结果提取。
我们检查了 2019 年至 2022 年所有非肿瘤学的 FDA 和 EMA 药物和生物制品的首次适应证批准，以确定那些使用 SAT 作为关键安全性或疗效证据的批准。我们提取了结果、关键研究设计特征、监管机构对 SAT 及（如适用）ECA 设计的反应以及产品标签内容。
在 20 项基于 SAT 的 FDA 批准和 17 项基于 SAT 的 EMA 批准中，最常见的适应证是进展性罕见疾病，这些疾病的需求未得到满足/治疗选择有限，且自然病史没有自发改善。在比较类型中，最常见的是自然病史队列（45%FDA；47%EMA）和基线对照（40%FDA；47%EMA）。常见的批评是 ECA 非同期、终点主观以及臂间基线协变量不平衡。
基于最近的 FDA 和 EMA 批准，有 ECA 的 SAT 监管成功的可能性取决于许多设计、分析和数据质量的考虑因素。我们的框架在药物开发早期考虑 SAT 策略以生成证据时很有用。
