Critical Remarks on Reference-Scaled Average Bioequivalence.

More than a decade ago the option to assess highly variable drugs / drug products by reference-scaled average bioequivalence was introduced in regulatory practice. Recommended approaches differ between jurisdictions and may lead to different conclusions even for the same data set. According to our knowledge, implemented methods have not been directly compared for their operating characteristics (Type I Error and power). We performed Monte Carlo simulations to assess the consumer risk and the clinically relevant difference for the recommended regulatory settings. In all methods for reference-scaled average bioequivalence the Type I Error can be inflated with a consequently compromised consumer risk. Furthermore, the clinically relevant difference could vary between studies performed with the same reference product. Only average bioequivalence with fixed - widened - limits would both maintain the consumer risk and offer an unambiguously defined clinically not relevant difference. As long as such an approach is not implemented in regulatory practice, we recommend adjusting the level of the test a.