chapter  1
16 Pages


ByIsadore Kanfer

INTRODUCTION The introduction and application of bioequivalence testing as a surrogate indicator of safety and efficacy has had an enormous impact on the development and formulation of solid oral dosage forms in particular, not only for generic product manufacturers but also for the innovator or “brand” companies. Using bioequivalence as a tool to establish therapeutic equivalence between a test (generic) and a reference product certainly forms the basis for market approval of multisource drug products, the latter being products marketed by more than one manufacturer and containing the same active pharmaceutical ingredient (API) in the same dosage form intended to be administered by the same route of administration. The reference product is usually the comparator product developed and marketed by a so-called “innovator” or brand company, where their product had been approved on the basis of clinical trials to support claims for safety and efficacy. It is however a little-known fact that many innovator products that eventually become available on a particular market were in fact approved on the basis of a bioequivalence study (1) between the formulation used in the clinical trials (as reference) and an amended formulation of the same active(s), that is, the test product. Hence, it is apparent that using bioequivalence methodology and sound scientifically based acceptance criteria to show therapeutic equivalence overcomes the need to redo clinical trials that are expensive and time consuming, often taking several years to produce outcomes. As mentioned previously, it is in the area of solid oral dosage forms where the major benefits of bioequivalence testing occur since plasma drug concentrations can be measured following oral administration of a test and reference product in a cross-over fashion in healthy human subjects. This procedure is feasible and scientifically sound for drugs, which are intended to be absorbed into the systemic circulation since the underlying principle is that a link exists between drug concentrations in the blood and therapeutic effect. However, for other dosage forms, particularly those intended for other routes of administration and more specifically those which are not intended to be absorbed into the systemic circulation, generally no such link exists between drug concentrations in blood and effect. Although some specific methodologies have been developed and validated, such as the human skin blanching assay (HSBA) for topical corticosteroid products, to date relatively few surrogate measures to assess bioequivalence of such dosage forms have been accepted by regulatory agencies. It is thus apparent that the main objective of bioequivalence testing is to compare the formulation performance between a test and reference product with the premise that if bioequivalence is proven, there

is unlikely to be any significant differences in clinical outcomes between such products.