ABSTRACT
In the United States (U.S.), for small-molecule drug products, when an innovative (brand-name) drug product is going off patent, pharmaceutical and/or generic companies may file an abbreviated new drug application (ANDA) for the approval of the generic copies of the brand-name drug. In 1984, the United States Food and Drug Administration (FDA) was authorized to approve generic drug products under the Drug Price Competition and Patent Term Restoration Act, which is also known as the Hatch-Waxman Act. For the approval of generic (small-molecule) drug products, the FDA requires that evidence of average of bioavailability, which is measured in terms of the rate and extent of drug absorption, be provided through the conduct of bioequivalence studies. As indicated by Chow and Liu (2008), the assessment of bioequivalence as a surrogate for evaluation of drug safety and efficacy is based on the so-called Fundamental Bioequivalence Assumption that if two drug products are shown to be bioequivalent in average bioavailability, it is assumed that they will reach the same therapeutic effect or that they are therapeutically equivalent. Many practitioners interpret that approved generics and the brand-name drug can, in most cases, be used interchangeably since they are therapeutically equivalent. Under the Fundamental Bioequivalence Assumption, regulatory requirements (e.g., FDA guidances), study design (e.g., a standard two-sequence, two-period crossover design), acceptance criteria (e.g., the 80/125 rule based on log-transformed data), and statistical methods (e.g., Shuirmann’s two one-sided tests procedure or the confidence interval approach) for the assessment of bioequivalence have been well established over the past several decades (see, e.g., Schuirmann, 1987; FDA, 2001, 2003; Chow and Liu, 2008).
