Division of Biostatistics, Center for Devices and Radiological Health, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
J Biopharm Stat. 2024 May;34(3):441-452. doi: 10.1080/10543406.2023.2220398. Epub 2023 Jun 18.
An in vitro diagnostic device (IVD) that is essential for the safe and effective use of a corresponding therapeutic product is commonly referred to as companion diagnostic device. Clinical trials using companion diagnostic devices (tests) together with therapies can yield the information necessary to address whether both products are safe and effective. A clinical trial ideally assesses safety and effectiveness of a therapy, where the clinical trial enrolls subjects based on the final market ready companion diagnostic test (CDx). However, such a requirement may be difficult to accomplish or impractical to achieve at the time of the clinical trial enrollment, due to unavailability of the CDx. Instead, clinical trial assay(s) (CTA), which are not the final marketable product, are often used in enrollment of patients in a clinical trial. When CTA is used for subject enrollment, a clinical bridging study provides a mechanism to bridge the clinical efficacy of the therapeutic product from CTA to CDx. This manuscript reviews some issues and challenges commonly associated with clinical bridging studies, including missing data, use of local tests for enrollment, prescreening before enrollment, and evaluation of CDx for low positive rate biomarkers, with particular focus on clinical trials using a binary endpoint and provide alternative statistical methodologies to assess effectiveness of CDx.
体外诊断设备（IVD）是安全有效使用相应治疗产品的必备条件，通常被称为伴随诊断设备。使用伴随诊断设备（检测）和治疗进行临床试验，可以提供必要的信息，以确定这两种产品是否安全有效。临床试验理想情况下评估治疗的安全性和有效性，临床试验根据最终市场准备好的伴随诊断检测（CDx）入组受试者。然而，由于 CDx 不可用，在临床试验入组时，可能难以实现或不切实际地实现这一要求。相反，临床试验检测（CTA）通常用于临床试验中患者的入组，CTA 不是最终可销售的产品。当 CTA 用于受试者入组时，临床桥接研究提供了一种机制，可将治疗产品的临床疗效从 CTA 桥接到 CDx。本文综述了一些与临床桥接研究相关的常见问题和挑战，包括缺失数据、入组时使用本地检测、入组前预筛选，以及对低阳性率生物标志物的 CDx 评估，特别关注使用二分类终点的临床试验，并提供替代的统计方法来评估 CDx 的有效性。
