BIOEQUIVALENCE - AN UPDATED REAPPRAISAL ADDRESSED TO APPLICATIONS OF INTERCHANGEABLE MULTISOURCE PHARMACEUTICAL PRODUCTS

This paper reviews study procedures for bioequivalence trials, mainly addressed to the New Drug Application (NDA) of generic drugs, strictly referring to EU and USA guidelines on this matter Specific attention is devoted to the most appropriate experimental designs the size of th e volunteer sample, the ethical issues involved, statistics to assess bioequivalence and the accepted standard format for final research rep orts Some aspects which create serious problems in bioequivalence tria ls, most of which not fully covered by the EU and USA specific guideli nes, are comprehensively discussed. These include a) drugs with elevat ed variability; b) endogeneous substances and the management of baseli ne value, c) modified release formulations, d) prodrugs; e) restrictio ns to be contained in forthcoming guidelines on chiral medicinal produ cts, f) superbioavailability, g) drugs with elevated half-life and h) cases in which bioequivalence trials should not be needed. As generic drugs cost less than the innovator product, agencies have facilitated their NDA procedures by requiring a dossier on chemistry and pharmacy and a pivotal bioequivalence study to demonstrate that the generic for mulation is fully interchangeable with the innovates product. Bioequiv alence is thus the key requirement for an NDA of a generic drug, and t rials should be planned conducted and reported in the most appropriate way. With this in mind, this review is an up-to-date reappraisal that should stimulate the attention of scientists and regulatory authoriti es on some open questions on bioequivalence.