Bioequivalence approaches for highly variable drugs and drug products.

Over the past decade, concerns have been expressed increasingly regarding the difficulty for highly variable drugs and drug products (%CV greater than 30) to meet the standard bioequivalence (BE) criteria using a reasonable number of study subjects. The topic has been discussed on numerous occasions at national and international meetings. Despite the lack of a universally accepted solution for the issue, regulatory agencies generally agree that an adjustment of the traditional BE limits for these drugs or products may be warranted to alleviate the resource burden of studying relatively large numbers of subjects in bioequivalence trials. This report summarizes a careful examination of all the statistical methods available and extensive simulations for BE assessment of highly variable drugs/products. Herein, the authors present an approach of scaling an average BE criterion to the within-subject variability of the reference product in a crossover BE study, together with a point-estimate constraint imposed on the geometric mean ratio between the test and reference products. The use of a reference-scaling approach involves the determination of variability of the reference product, which requires replication of the reference treatment in each individual. A partial replicated-treatment design with this new data analysis methodology will thus provide a more efficient design for BE studies with highly variable drugs and drug products.