Date of Award
Doctor of Philosophy
Dr. Joseph W. McKean
Dr. Joshua D. Naranjo
Dr. Gary L. Neidert
Applicants submitting a new drug application (NDA) or new animal drug application (NADA) under the Federal Food, Drug, and Cosmetic Act (FDC Act) are required to document bioavailability (BA). A sponsor of an abbreviated new drug application (ANDA) or abbreviated new animal drug application (ANADA) must document first pharmaceutical equivalence and then bioequivalence (BE) to be deemed therapeutically equivalent to a reference listed drug (RLD). The Average (ABE), Population (PBE) and Individual (IBE) bioequivalence have been used to establish the equivalence in the pharmaco-kinetics of drugs.
The current procedure of PBE uses Cornish Fisher's (CF) expansion on small samples. Since area under the curve (AUC) and maximum dose (Cmax) are inherently skewed, a least squared (LS) normality based analysis is suspect. A bootstrap procedure is proposed which uses scale estimators. Since this bootstrap procedure works best for large samples, we propose a small sample analysis which uses robust scale estimators to compare least squares CF with Gini mean difference and inter quartile range.
Traditional ABE is univariate, two one-sided test which follows strict LS normality assumptions. We suggest small sample ABE utilizing AUC and Cmax in a multivariate setting with or without outliers using Componentwise rank method.
Nandakumar, Srinand Ponnathapura, "Statistical Procedures for Bioequivalence Analysis" (2009). Dissertations. 691.