ABSTRACT
When a brand-name drug is going off-patent, generic drug companies may file abbreviated new drug applications for generic drug approval. An approved generic drug can be used as a substitute for the brand-name drug. In 1984, the FDA was authorized to approve generic drugs through bioavailability and bioequivalence studies under the Drug Price and Patent Term Restoration Act. Bioequivalence testing is usually considered as a surrogate for clinical evaluation of drug products based on the Fundamental Bioequivalence Assumption that when two formulations of the reference product (e.g., a brand-name drug) and and the test product (a generic copy) are equivalent in bioavailability, they will reach the same therapeutic effect. In vivo bioequivalence testing is commonly conducted with a crossover design on healthy volunteers to assess bioavailability through pharmacokinetic (PK) responses such as area under the blood or plasma concentration-time curve (AUC) and maximum concentration (Cmax). For some locally acting drug products such as nasal aerosols (e.g., metered-dose inhalers) and nasal sprays (e.g., metered-dose spray pumps) that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action. Bioequivalence related to these products is called in vitro bioequivalence and is usually studied under a parallel design. Statistical procedures for some types of bioequivalence studies are described in the FDA guidances (FDA, 2000, 2001). Chow and Shao (2002) provided a review of statistical procedures for bioequivalence studies that are not provided by the FDA.
