Clinical Safety Statistics, Merck & Co., Inc, Kenilworth, NJ, USA.
Clinical Safety, Moderna, Cambridge, MA, USA.
Ther Innov Regul Sci. 2022 May;56(3):423-432. doi: 10.1007/s43441-021-00349-x. Epub 2022 Feb 9.
Safety evaluation is a continual and iterative process throughout the drug development life cycle and requires long time horizons and large amounts of data to fully understand the safety profile of a medical product. Although randomized clinical trials (RCT) provide high-quality data for an initial assessment of safety signals, the safety signals may not all have been known at the time of approval because safety data collected from RCT only involve a relatively small number of subjects during a relatively short follow-up period. The increased accumulation of post-marketing real-world data (RWD) presents an opportunity to utilize them for safety decision-making; these include identifying new safety signals, further characterization of safety concerns that are raised in pre-marketing RCT, and further generalization of RCT findings to the broader patient populations not previously studied in RCT. In this paper, we use cardiovascular safety outcome trial for antidiabetic therapies as an illustrative example and discuss how integrative analysis of RCT and observational study data can answer regulatory concerns about cardiovascular risk in a post-marketing setting. A novel statistical analysis strategy is proposed to combine both sources of safety data in a data fusion approach. The proposed approach includes three stages: (1) feasibility analysis that uses an RCT to validate an observational study, applying estimand framework and emulating RCT with RWD; (2) integrative analysis that combines evidence from the RCT and observational study data cooperatively; and (3) sensitivity analysis that examines the consistency of the previous analyses. Two potential utilities of the proposed integrative analysis for the cardiovascular safety outcome trial are discussed.
安全性评估是药物研发生命周期中持续且反复的过程，需要长时间的研究和大量的数据来全面了解医疗产品的安全性概况。虽然随机对照试验（RCT）为安全性信号的初步评估提供了高质量的数据，但在批准时可能并非所有安全性信号都已被知晓，因为 RCT 中收集的安全性数据仅涉及相对较少的研究对象，且随访时间相对较短。越来越多的上市后真实世界数据（RWD）为安全性决策提供了利用这些数据的机会；这些机会包括识别新的安全性信号、进一步描述在上市前 RCT 中提出的安全性问题，并将 RCT 发现进一步推广到 RCT 之前未研究过的更广泛的患者群体。在本文中，我们以心血管安全性结局试验的抗糖尿病疗法为例，讨论如何综合分析 RCT 和观察性研究数据，以回答上市后心血管风险的监管关注。我们提出了一种新的统计分析策略，以数据融合的方法综合两种安全性数据来源。该方法包括三个阶段：（1）可行性分析，使用 RCT 验证观察性研究，应用目标框架和用 RWD 模拟 RCT；（2）整合分析，合作整合 RCT 和观察性研究数据的证据；（3）敏感性分析，检查先前分析的一致性。讨论了拟议的综合分析对心血管安全性结局试验的两个潜在用途。
