Individual bioequivalence revisited

For decades, the establishment of bioequivalence has generally relied on th e comparison of population averages between the test and reference formulat ions. In the early 1990s, individual bioequivalence was proposed to ensure that an individual could be switched from the reference product to the test product with unchanged efficacy and safety. Since 1997, the US Food and Drug Administration (FDA) has published three g uidance documents on the proposed criterion and statistical methodology for the individual bioequivalence approach. From a scientific stand-point, the individual bioequivalence criterion appears to offer several advantages fo r some drug products compared with the average criterion. It allows compari son of intraindividual variances, scaling the bioequivalence criterion to t he reference variability and detection of an important subject-by-formulati on interaction if it exists. Based on these considerations, the FDA has rec ently recommended replicate study designs for modified release dosage forms and highly variable drug products. The. new criterion also promotes inclus ion of a heterogeneous population of volunteers in bioequivalence studies. Despite all the advantages of the individual bioequivalence approach, quest ions remain on the optimal use of replicate study designs and the proposed criterion for evaluation of bioequivalence between formulations. In the fin alised guidance documents, therefore, the FDA maintains the average bioequi valence criterion while allowing other criteria under certain circumstances . Collection and analysis of bioequivalence data from replicate study desig ns may permit further assessment and resolution of these questions.