Alternative Approaches for Assessing Bioequivalence regarding Normality Assumptions

Abstract

This paper concerns several alternative approaches for the assessment of bioequivalence between two formulations (a test formulation and a reference formulation) of a drug with respect to various situations depending upon whether the normality assumptions for the random subject and random error terms are met. When the two terms are both normal, a new approach is proposed by constructing an exact confidence region for (μ_R, μ_T), where μ_T and μ_R are means for the test and reference formulations, respectively. The constructed confidence region is then compared with the acceptance region which is bounded by μ_T = 0.8μ_R and μ_T = 1.2μ_R. This approach is shown to more rigorously meet the Food and Drug Administration (FDA) requirement compared with the customary method. When the random subject term follows a skewed but unknown distribution, an alternative approach is derived based on the individual subject ratios. A nonparametric bootstrap procedure is also proposed for situation where the distributions of the two terms are both unknown. Two examples concerning two-way crossover experiments for the comparison of bioavailability between two formulations are presented. A brief discussion regarding tests for normality assumptions and future research in this area is given.