Evaluation of the bioequivalence of highly-variable drugs and drug products

Purpose. To establish procedures for the effective evaluation of bioequival ence (BE) for highly-variable drugs and drug products (HVD/P). Methods. 2- and 4-period crossover BE studies with 24 subjects were simulat ed which generally assumed within-subject coefficients of variation of 40 % . The relationship between the fraction of studies in which BE was accepted (the statistical power) and the ratio of geometric means (GMR) of the two formulations was evaluated for various methods of analysis. These included, primarily, scaled average BE (ABE), the corresponding approach of expandin g BE Limits (BEL), and, for comparison, unscaled ABE and scaled individual BE (IBE). Results Scaled ABE and expanding EEL showed very similar properties in both 2- and 4-period studies. They had steeper power curves than scaled LEE. Un sealed ABE had very low statistical power. The acceptance of BE by unscaled and scaled ABE and expanding EEL was almost independent of subject-by-form ulation interaction and the ratio of within-subject variations of the two f ormulations. By contrast, the conclusions reached by scaled IBE were strong ly affected by these parameters. Conclusions. Scaled ABE and expanding EEL evaluate BE effectivelg for HVD/P in both 2- and 4-period investigations. However, additional, useful inform ation can be obtained from 4-period studies.