Statistical evaluation of non‐profile analyses for the in vitro bioequivalence

Abstract

AbstractFor locally acting drug products such as nasal aerosols and nasal sprays, the 2003 US Food and Drug Administration (FDA) draft guidance suggests that bioequivalence between generic and brand‐name products be established through in vitro tests. In addition, for non‐profile analyses based on spray content uniformity, droplet size distribution, spray pattern, priming, and re‐priming, the draft US FDA guidance recommends that the population bioequivalence (PBE) between generic and innovator's products be demonstrated. However, the linearized criterion recommended in the draft FDA guidance does not take into consideration the variations due to batches, samples, and life stages. Hence, under a two‐stage nested random effects model, we apply the methods of modified large‐sample (MLS) and generalized pivotal quantities (GPQs) to construct the upper 95% confidence limit for in vitro PBE criterion with consideration of variance components as the statistical testing procedures for establishing the in vitro BE. A simulation study was conducted to compare empirical size and empirical power among the three methods. A numerical example illustrates the proposed methods. Copyright © 2010 John Wiley & Sons, Ltd.