Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
Center for Personalised Nanomedicine, University of Queensland, Brisbane, Queensland, Australia.
J Clin Oncol. 2020 Apr 1;38(10):1070-1080. doi: 10.1200/JCO.19.02953. Epub 2020 Feb 14.
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.
生物类似药有可能扩大生物制剂的患者可及性，并为医疗保健系统节省成本。在开发生物类似药的过程中，需要直接比较拟议的生物类似药与参比产品的数据。此类比较数据是通过逐步分层的过程生成的，该过程从广泛的基于实验室的结构分析和功能测定开始。这个初始分析阶段是证明生物类似性的基础，随后进行非临床体内测试（如果需要），然后进行临床评估，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。开发计划通常以比较临床疗效研究达到高潮。该研究的目的是根据预设的界限，基于足够敏感的研究人群和疗效终点，确认潜在生物类似药和参比产品的临床等效性，以检测潜在的与产品相关的差异。这些研究还包括对安全性的详细分析以及免疫原性评估。随着生物类似药在肿瘤学领域的应用越来越广泛，尤其是最近批准了利妥昔单抗、曲妥珠单抗和贝伐珠单抗生物类似药，临床医生必须了解比较临床研究与新型生物原创产品开发中的传统 III 期疗效和安全性研究的区别，这一点至关重要。在这里，我们回顾了比较临床研究在生物类似药开发中的作用，重点介绍了支持已批准的曲妥珠单抗生物类似药的试验。我们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在支持生物类似性的总体证据中的确证性质。
