Guidances related to bioavailability and bioequivalence: European industry perspective

The investigations of bioavailability and bioequivalence can be classified according to three separate areas of information. Firstly, estimation of bioavailability judged on a drug substance's in vivo characteristics taking into account solubility, polymorphism, stability (especially under the conditions of the GI tract), gut wall permeability and first pass metabolism. Secondly, evaluation of formulation properties including dissolution profile in the GI tract and its contribution to exposure variability with respect to the desired absorption characteristics. Finally, maintaining quality during the market phase with respect to equivalence to the clinical trial formulations. While in the first two areas, the range of the estimated mean values and the intra- and inter-subject variabilities contain the desired information for proper medical decisions, in the third area the mean values and their confidence limits describe the quality with regard to the formulations of proven efficacy. Guidelines should clearly distinguish between the different areas in their recommendations regarding the intended information, e.g. mean values and/or ranges and confidence intervals. New approaches of granting limited waivers for BE studies (e.g. Biopharmaceutical Classification System (BCS)) should be expanded to consideration of pharmacokinetic properties of drugs (e.g. gastrointestinal metabolism, evidence for an absorption window, magnitude of first-pass effect; half-life) as already partly implemented in the German waiver concept, and further (scientifically) validated to achieve world-wide harmonisation (e.g. via ICH).