WHO bioequivalence guidelines (TRS No. 1003, Annex 6) allow for the use of reference-scaled BE criteria for Cmax from replicate design bioequivalence studies conducted with highly variable drug products. For the past five years, on a trial basis, PQT/MED has considered a priori scientific justifications from applicants to permit the reference-scaling/widening of the AUC acceptance criteria for data from full replicate design bioequivalence studies. This trial period has allowed PQT/MED to better understand the risks associated with extending the possibility for scaling/widening for the AUC parameter, beyond its use for the Cmax parameter as per WHO guidelines.
Going forward, PQT/MED will accept the reference-scaled widening of the acceptance range, not only of the Cmax but also for the AUC for data from four-period, full replicate design bioequivalence studies, if this approach is pre-defined and justified in the study protocol.