Clinical Informatics and Medical Statistics Research Center and Graduate Institute of Clinical Medicine, Chang Gung University, Tao-Yuan, Taiwan.
Stat Med. 2013 Feb 10;32(3):449-61. doi: 10.1002/sim.5565. Epub 2012 Aug 22.
Biological drug products are therapeutic moieties manufactured by a living system or organisms. These are important life-saving drug products for patients with unmet medical needs. Because of expensive cost, only a few patients have access to life-saving biological products. Most of the early biological products will lose their patent in the next few years. This provides the opportunity for generic versions of the biological products, referred to as biosimilar drug products. The US Biologic Price Competition and Innovation Act passed in 2009 and the draft guidance issued in 2012 provide an approval pathway for biological products shown to be biosimilar to, or interchangeable with, a Food and Drug Administration-licensed reference biological product. Hence, cost reduction and affordability of the biosimilar products to the average patients may become possible. However, the complexity and heterogeneity of the molecular structures, complicated manufacturing processes, different analytical methods, and possibility of severe immunogenicity reactions make evaluation of equivalence between the biosimilar products and their corresponding reference product a great challenge for statisticians and regulatory agencies. To accommodate the stepwise approach and totality of evidence, we propose to apply a parallel assay to evaluate the extrapolation of the similarity in product characteristics such as doses or pharmacokinetic responses to the similarity in binary efficacy endpoints. We also report the results of simulation studies to evaluate the performance, in terms of size and power, of our proposed methods. We present numerical examples to illustrate the suggested procedures.
生物制品是由活系统或生物体制造的治疗性分子。对于有未满足医疗需求的患者来说，这些是重要的救命药物。由于成本高昂，只有少数患者能够获得救命的生物制品。大多数早期的生物制品将在未来几年内失去专利。这为生物制品的仿制药提供了机会，称为生物类似药。美国 2009 年通过了《生物制品价格竞争与创新法案》，2012 年发布了草案指南，为与 FDA 批准的参比生物制品具有生物相似性或可互换性的生物制品提供了一种审批途径。因此，生物类似药的成本降低和普通患者的可负担性可能成为可能。然而，分子结构的复杂性和异质性、复杂的制造工艺、不同的分析方法以及严重免疫原性反应的可能性，使得评估生物类似药与其相应参比产品之间的等效性对统计学家和监管机构来说是一个巨大的挑战。为了适应逐步方法和整体证据，我们建议应用平行测定法来评估产品特性（如剂量或药代动力学反应）相似性外推到二元疗效终点相似性的情况。我们还报告了模拟研究的结果，以评估我们建议的方法在大小和功效方面的性能。我们提出了数值示例来说明建议的程序。
