Determining Equivalence for Generic Locally Acting Drug Products

For regulatory purposes, bioequivalence (BE) is defined as the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. The U.S. Food and Drug Administration may accept evidence from various approaches for determining the bioavailability (BA) or BE of a drug product, including in vivo pharmacokinetic studies, certain in vitro studies that are correlated with and predictive of human in vivo BA, and well-controlled clinical endpoint studies. In this article, we describe some of the statistical approaches used in clinical endpoint studies of bioequivalence for generic drugs. We outline a conventional design and statistical analysis for such studies, including the equivalence criteria. We exemplify this approach with a more detailed discussion of studies of nasal spray products for allergic rhinitis, pointing out some of the statistical issues particular to this area. Finally, we describe a new statistical approach to evaluating BE for topical, locally acting dosage forms (e.g., creams, ointments, and gels) studied in vitro using excised human skin, with a specific focus on unique issues in the design and statistical analysis of data from such studies.