Limits for the scaled average bioequivalence of highly variable drugs and drug products.

PURPOSE: To provide a rational procedure for establishing regulatory bioequivalence (BE) limits that can be applied in determinations of scaled average BE for highly-variable (HV) drugs and drug products.
METHODS: Two-period crossover BE investigations with either 24 or 36 subjects were simulated with assumptions of a coefficient of variation of 10, 20, 30, or 40%. The decline in the fraction of accepted studies was recorded as the ratio of geometric means (GMR) for the two formulations was raised from 1.00 to 1.45. Acceptance of BE was evaluated by scaled average BE, assuming various BE limits, and, for comparison, by unscaled average BE. A procedure for calculating exact confidence limits in two-period studies is presented, and an approximate method, based on the linearization of the regulatory model, is applied.
RESULTS: A mixed model is proposed for average BE. Accordingly, at low variabilities, the BE limit is constant, +/-BELo, generally log(1.25). Beyond a logarithmic, limiting, "switching" variability (sigma(o)), in the region of HV drugs, the approach of scaled average BE is applied with limits of +/-(BEL(o)/sigma(o)). It is demonstrated that the performance of the mixed model corresponds to these expectations. The effect of sigma(o), and of the resulting BE limits is also demonstrated. Scaled average BE, with all reasonable limits for HV drugs, requires fewer subjects than an unscaled average BE. In two-period studies, the exact and approximate methods calculating confidence limits yield very comparable inferences.
CONCLUSIONS: Scaled average BE can be effectively applied, with the recommended limits, for determining the BE of HV drugs and drug products. The limiting, "switching" variability (sigma(o)) will have to be established by regulatory authorities.