The World Health Organization (WHO) guidelines on evaluation of similar biotherapeutic products (SBPs; also called biosimilars) were adopted by the WHO Expert Committee on Biological Standardization (ECBS) in 2009. In 2019, the ECBS considered that a more tailored and potentially reduced clinical data package may be acceptable in cases where this was clearly supported by the available scientific evidence. The goal of this publication is to review the current clinical experience and scientific evidence and to provide an expert perspective for updating the WHO guidelines to provide more flexibility and clarity. As the first step, the relevant guidelines by other regulatory bodies were reviewed in order to identify issues that might help with updating the WHO guidelines. Next, a literature search was conducted for information on the long-term efficacy, safety, and immunogenicity of biosimilars to identify possible long-term problems. Finally, a search for articles concerning the role of clinical studies in the benefit-risk evaluation of biosimilars was conducted. The analysis of other guidelines suggested that the WHO guidelines may need more emphasis on the importance of the state-of-the-art physicochemical and structural comparability exercise and in vitro functional testing. The use of "foreign" reference product will also need clarifications. The value of in vivo toxicological tests in the development of biosimilars is questionable, and the non-clinical part needs revisions accordingly. The concepts of "totality of evidence," "stepwise development," and "residual uncertainty" were applied in the evaluation of the clinical sections of the guideline. The review of long-term safety and efficacy demonstrated the robustness of the current biosimilar development concept. The analysis of the roles of different development phases suggested that the large efficacy, safety, and immunogenicity studies are, in most cases, redundant. The residual uncertainty of safety, immunogenicity, and efficacy of biosimilars that has shaped the current regulatory guidelines is now substantially reduced. This will allow the re-evaluation of the non-clinical and clinical requirements of the current WHO main guideline. The shift of the relative impact of the development phases towards physico-chemical and in vitro functional testing will provide a relief to the manufacturers and new challenges to the regulators.

中文翻译：

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生物仿制药的监管评估：基于科学证据和临床经验完善原则。

世卫组织生物标准化专家委员会 (ECBS) 于 2009 年通过了世界卫生组织 (WHO) 类似生物治疗产品 (SBPs；也称为生物仿制药) 的评估指南。2019 年，ECBS 认为更具针对性且可能减少的在现有科学证据明确支持的情况下，临床数据包可能是可以接受的。本出版物的目的是审查当前的临床经验和科学证据，并为更新 WHO 指南提供专家观点，以提供更大的灵活性和清晰度。作为第一步，审查了其他监管机构的相关指南，以确定可能有助于更新 WHO 指南的问题。下一个，对有关生物仿制药的长期疗效、安全性和免疫原性的信息进行了文献检索，以确定可能存在的长期问题。最后，搜索了有关临床研究在生物仿制药效益-风险评估中的作用的文章。对其他指南的分析表明，WHO 指南可能需要更加强调最先进的物理化学和结构可比性练习以及体外功能测试的重要性。“外国”参考产品的使用也需要澄清。生物仿制药开发中体内毒理学试验的价值值得商榷，非临床部分需要相应修改。“证据总量”、“逐步发展”和“剩余不确定性”的概念 应用于指南临床部分的评价。对长期安全性和有效性的审查证明了当前生物仿制药开发概念的稳健性。对不同开发阶段的作用的分析表明，在大多数情况下，大规模的疗效、安全性和免疫原性研究是多余的。影响当前监管指南的生物仿制药安全性、免疫原性和有效性的残余不确定性现在已大大降低。这将允许重新评估当前 WHO 主要指南的非临床和临床要求。开发阶段的相对影响向物理化学和体外功能测试的转变将减轻制造商的负担，并给监管机构带来新的挑战。