生物类似药物（biosimilar）是与原研药物(originator)高度相似，并且在纯度、活性和安全性上与后者没有任何临床意义差异的生物制品。但生物制品的结构复杂，生产工艺繁琐且可变性大，故生物类似药物与原研药物仅仅类似，却不完全相同。因此，对于生物类似药物的研发，只有通过理化性质检测、临床前研究和临床试验确认生物类似药物与原研药物之间的相似性，并经监管机构审批后，才可以作为Biosimilar推出。低分子量的生物类似药物于2006年开始面世，高分子量的单克隆抗体类生物类似药物直到2013年才被欧洲药监局（EMA）批准上市，未来10年将是全球生物类似药物研发的高峰时期。笔者试图通过介绍欧洲药监局对研发生物类似药物的指导原则，并以抗癌药物曲妥珠单抗（trastuzumab）的生物类似药物临床试验为例，阐述单抗类生物类似药物临床试验设计和应用中的多项关键问题，特别是临床试验敏感人群的选择、适应证外推、临床试验终点的确定、与原研药物可否互换、上市后监督及生物类似药物说明书中应列出商品名等问题。对用于治疗癌症等威胁生命的疾病的生物类似药的研发和审评，必须采取一种更为谨慎的做法，以确保生物类似药物与原研药物在安全性和有效性上高度相似。

A biosimilar product is defined as a biologic medical item that is highly similar to and clinically not different from the originator or reference product in terms of safety, purity, and potency. Given their structure complexity and manufacturing process variability, a biosimilar can only be defined as similar, but not identical. To support a demonstration of biosimilarity, a series of tests, including physicochemical analysis, pre-clinical studies and clinical trials, should be taken between the biosimilar and the originator, as well as approval by the authority before being marketed. The biosimlar of low molecular weight biologics was marketed in 2006, the new class of biosimilars, monoclonal antibodies (mAbs), was not approved by the European Medicines Agency (EMA) until 2013, next decade will be the fastigium of biosimilar development. In this paper, we will outline the EMA guidelines for monoclonal antibody biosimilar products and review the clinical trials of trastuzumab, an anti-HER2 monoclonal antibody indicated for breast cancer. A particular focus of discussion will be the clinical trial-related issues including trial design, selection and recruitment of sensitive study populations, extrapolation of indications, interchangeability with the reference product, post-authorization pharmacovigilance and final product labeling. Taking the EMA guidelines in account together with the lessons from previous clinical trials of trastuzumab, we strongly suggest that more precautions should be taken when biosimilar drugs are subject to evaluation and approval to ensure the efficacy and safety profiles are highly similar to those of their reference products for the safety of patients, particularly those with life-threatening diseases, such as cancer.

国家“重大新药创制”科技重大专项（No.2012ZX09304010，No.2014ZX09304311001）