Performance of the Population Bioequivalence (PBE) Statistical Test Using an IPAC-RS Database of Delivered Dose from Metered Dose Inhalers.

This article reports performance characteristics of the population bioequivalence (PBE) statistical test recommended by the US Food and Drug Administration (FDA) for orally inhaled products. A PBE Working Group of the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) assembled and considered a database comprising delivered dose measurements from 856 individual batches across 20 metered dose inhaler products submitted by industry. A review of the industry dataset identified variability between batches and a systematic lifestage effect that was not included in the FDA-prescribed model for PBE. A simulation study was designed to understand PBE performance when factors identified in the industry database were present. Neglecting between-batch variability in the PBE model inflated errors in the equivalence conclusion: (i) The probability of incorrectly concluding equivalence (type I error) often exceeded 15% for non-zero between-batch variability, and (ii) the probability of incorrectly rejecting equivalence (type II error) for identical products approached 20% when product and between-batch variabilities were high. Neglecting a systematic through-life increase in the PBE model did not substantially impact PBE performance for the magnitude of lifestage effect considered. Extreme values were present in 80% of the industry products considered, with low-dose extremes having a larger impact on equivalence conclusions. The dataset did not support the need for log-transformation prior to analysis, as requested by FDA. Log-transformation resulted in equivalence conclusions that depended on the direction of product mean differences. These results highlight a need for further refinement of in vitro equivalence methodology.