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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.

Biosimilarity and Interchangeability in the Biologics Price Competition and Innovation Act of 2009 and FDA's 2012 Draft Guidance for Industry