KULLBACK–LEIBLER DIVERGENCE FOR EVALUATING BIOEQUIVALENCE: II. Simulation and Retrospective Assessment of Performance of the Proposed FDA metric and the Kullback-Leibler Divergence in Individual Bioequivalence Assessment

Methodology has been proposed for evaluating switchability of two formulations of a drug that encompasses bioequivalence aspects using Dragalin and Fedorov’s application of the KullbackLeibler Divergence (KLD) and a metric developed by the Food and Drug Administration (FDA) as measures of discrepancy between the distributions of the two formulations using two sequence replicate, crossover designs. Standards are proposed for implementation of the KLD as an alternative procedure for the evaluation of similarity between formulations using the same study design as that proposed in FDA guidance. Simulations are conducted to evaluate the performance of the KLD relative to the metric proposed in guidance by the Food and Drug Administration for the evaluation of individual bioequivalence. Previously published retrospective analyses using the FDA proposed metric are contrasted with those based on the KLD, and thoughts regarding future evaluations are explored. This investigation is conducted to provide an exploratory look into the properties of the two metrics in order to support a future, rigorous comparison. It is concluded that the KLD is a viable alternative to the FDA-proposed metric and that its mathematical properties make it a readily interpretable measure of the individual differences between formulations.