RESUMO
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.
Assuntos
Inaladores Dosimetrados , Modelos Estatísticos , Bases de Dados Factuais , Equivalência Terapêutica , Estados Unidos , United States Food and Drug AdministrationRESUMO
This study describes prewelfare reform child care use by 64 primarily low-income single mothers (65.6% African American) with preschoolers (half born preterm). Forty percent used child care for more than 75% of their children's lives, 20% did when not employed. Preschool children born preterm were more likely to receive child care from nonrelatives throughout their lives than children born full term. Children with health problems used a greater number of child care arrangements. Findings suggest addressing child care issues with both employed and nonemployed mothers and adequacy of child care for children with special needs.