The Biologics Price Competition and Innovation Act (BPCIA), Congress's first authorization of a biosimilar therapeutic approval pathway, was signed into law in March 2010.1 The BPCIA creates a two-tier regulatory pathway for abbreviated licensing of a biologic therapeutic. A biosimilar is “highly similar” to the innovator biologic that serves as the reference product, and the two have no “clinically meaningful” differences.2 An interchangeable biologic must not only meet the biosimilarity standard, but also must be “expected to produce the same clinical result as the reference product in any given patient.”3 The terms “biosimilar” and “interchangeable” are new in the context of biologics, and Congress has left FDA and the courts considerable latitude in defining these terms. This article evaluates alternative interpretations of “biosimilar” and “interchangeable” within the scope of the BPCIA, with an emphasis on FDA's non-binding position on this question. Whereas abbreviated review of traditional small-molecule drugs was allowed under the Hatch-Waxman Amendments of 1984,4 an equivalent pathway for biologics was conspicuously absent until the BPCIA was enacted. The majority of approved therapeutics are small-molecule drugs, which often consist of fewer than 50 atoms covalently bound in a known arrangement. Biologics occupy the upper end of the complexity scale and are exemplified by recombinant therapeutic proteins.5,6 The structure of a recombinant protein is described not only by its amino acid sequence, but by additional chemical modification, such as glycosylation, phosphorylation, acetylation, and disulfide bonds.7 Additional complexity arises because every amino acid chain folds into a complex three-dimensional structure that is partially—but not completely—determined by the underlying amino acid sequence.8 To further complicate matters, these structural attributes need not be identical in every protein within a given sample.9 For these reasons, a recombinant protein is a vastly more complex specimen than a small-molecule drug. Despite the challenges associated with complex biologics, biotechnology and pharmaceutical companies have brought a number of important biologics to market in recent years. In 2011 in the U.S., 23% of spending on therapeutics went toward biologics.10 Although biologics and molecular entities each span a considerable price scale, a rough estimate places biologics at twenty-fold more expensive to the patient than molecular entity drugs.11 In 2011, six new Biologic License Applications (BLAs) were approved.12 Because of the efficacy and profitability of biologics, the number of biologics brought to market seems likely to increase.

中文翻译：

---

2009 年生物制品价格竞争和创新法案和 FDA 2012 年工业指南草案中的生物相似性和互换性

生物制品价格竞争和创新法案 (BPCIA) 是国会对生物类似药治疗批准途径的首次授权，于 2010 年 3 月签署成为法律。1 BPCIA 为生物治疗药物的简化许可创建了一个两级监管途径。生物仿制药与作为参考产品的创新生物制剂“高度相似”，两者没有“临床意义”差异。2 可互换的生物制剂不仅必须符合生物相似性标准，而且必须“预期生产在任何给定患者中与参考产品相同的临床结果。”3“生物仿制药”和“可互换”这两个术语在生物制剂的背景下是新的，国会在定义这些术语时给 FDA 和法院留下了相当大的自由度。本文评估了 BPCIA 范围内对“生物仿制药”和“可互换”的替代解释，并强调了 FDA 在这个问题上的非约束性立场。尽管 1984 年的 Hatch-Waxman 修正案允许对传统小分子药物进行简短审查，4 但在 BPCIA 颁布之前，明显缺乏生物制剂的等效途径。大多数批准的治疗剂是小分子药物，通常由少于 50 个以已知排列共价结合的原子组成。生物制剂占据了复杂度的上端，例如重组治疗性蛋白质。 5,6 重组蛋白质的结构不仅通过其氨基酸序列来描述，还通过额外的化学修饰来描述，例如糖基化、磷酸化、乙酰化、和二硫键。7 额外的复杂性出现了，因为每个氨基酸链折叠成一个复杂的三维结构，该结构部分（但不完全）由基础氨基酸序列决定。8 更复杂的是，这些结构属性不需要完全相同在给定样品中的每种蛋白质中。9 由于这些原因，重组蛋白质是比小分子药物复杂得多的样本。尽管复杂生物制剂面临挑战，但近年来生物技术和制药公司已将许多重要的生物制剂推向市场。2011 年在美国，23% 的治疗支出用于生物制剂。 10 尽管生物制剂和分子实体各自跨越了相当大的价格范围，