International Harmonization of Regulatory Bioequivalence Requirements

International harmonization of regulatory requirements for bioequivalence studies has made major progress during the last years, particular with regard to the bioequivalence range and statistical analysis. The multiplicative model and hence the logarithmic transformation of the primary extent and rate characteristics AUC and Cmax and - in consistency with this - the bioequivalence range of (0.80, 1.25) are now accepted by all major health authorities including the European CPMP, the U.S. FDA and the Canadian HPB. There is also far-reaching consensus that “pharmacokinetic lack of interaction” studies have to be handled as an equivalence problem. Such a consensus is still missing for “lack of food interaction” studies, although the same methodology has to be applied if a corresponding claim is made in the labeling of a particular formulation. Further applications of the equivalence concept include “batch-to-batch equivalence” and “pharmacokinetic dose linearity” studies. Replicate designs, which so far have been rarely used, may gain importance because they allow the assessment of the equivalence of intrasubject variability in addition to the equivalence of average bioavailability. A major issue to be addressed in the near future is the appropriate choice of clinically relevant bioequivalence ranges based on therapeutic ranges and intrasubject variabilities.