Biosimilars have the potential to broaden patient access to biologics and provide cost savings for health care systems. During the development of a biosimilar, data that directly compare the proposed biosimilar with the reference product are required. Such comparative data are generated in a stepwise hierarchical process that begins with extensive laboratory-based structural analyses and functional assays. This initial analytical phase serves as the foundation for the demonstration of biosimilarity and is followed by nonclinical in vivo testing (if required) and then clinical evaluation, including a comparative pharmacokinetics/pharmacodynamics study that is usually conducted in healthy volunteers. The development program typically culminates with a comparative clinical efficacy study. The aim of this study is to confirm clinical equivalence of the potential biosimilar and reference product on the basis of prespecified margins, using a study population and efficacy end point that are sufficiently sensitive for detecting potential product-related differences. Such studies also include detailed analyses of safety as well as evaluation of immunogenicity. As biosimilars become more widely available in oncology, especially with recent regulatory approvals of rituximab, trastuzumab, and bevacizumab biosimilars, it is critically important that clinicians understand how the comparative clinical study differs from a traditional phase III efficacy and safety study in the development of a novel biologic originator product. Here, we review the role of comparative clinical studies in biosimilar development, with a focus on trials conducted to support approved trastuzumab biosimilars. We discuss the study populations and end points used, extrapolation of indications, and the confirmatory nature of these studies within the totality of evidence supporting biosimilarity.

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了解比较临床研究在肿瘤生物仿制药开发中的作用

生物仿制药有潜力扩大患者获得生物制剂的机会，并为医疗保健系统节省成本。在生物仿制药的开发过程中，需要直接将拟议的生物仿制药与参考产品进行比较的数据。此类比较数据是在逐步分层过程中生成的，该过程从广泛的基于实验室的结构分析和功能测定开始。该初始分析阶段是证明生物相似性的基础，随后进行非临床体内测试（如果需要）和临床评估，包括通常在健康志愿者中进行的比较药代动力学/药效学研究。开发计划通常以临床疗效比较研究结束。本研究的目的是使用对检测潜在产品相关差异足够敏感的研究人群和疗效终点，在预先指定的裕度的基础上确认潜在生物仿制药和参考产品的临床等效性。此类研究还包括安全性的详细分析以及免疫原性的评估。随着生物仿制药在肿瘤学领域的应用越来越广泛，特别是最近监管部门批准了利妥昔单抗、曲妥珠单抗和贝伐珠单抗生物仿制药，临床医生了解比较临床研究与传统 III 期疗效和安全性研究在开发新药方面有何不同至关重要。新颖的生物原创产品。在此，我们回顾了比较临床研究在生物仿制药开发中的作用，重点关注为支持已批准的曲妥珠单抗生物仿制药而进行的试验。我们在支持生物相似性的全部证据中讨论了所使用的研究人群和终点、适应症的外推以及这些研究的验证性质。