Bioequivalence: tried and tested

Two drug products are considered bioequivalent 'if their bio-availabilities ... are similar to such a degree that their effects, with respect to both efficacy and safety, will essentially be the same'. 1 The bioequivalence of two drug products is generally demonstrated through a clinical study in healthy volunteers, the so-called bioequivalence study. If bioequivalence is shown for two drug products, therapeutic equivalence of the drug products is implied. Chow and Liu 2 call this assumption, namely that bioequivalence implies therapeutic equivalence, the 'fundamen-tal bioequivalence assumption'. Most drug products on the market today have been subjected to bioequivalence assessment at various stages in their development. As is well known, generic drug products require the demonstration of bioequivalence to the relevant innovator product for regulatory approval. What is perhaps less well known is that most innovator products, too, require some form of bioequivalence testing. New drugs typically undergo pharma-cokinetic dose-proportionality studies, and drug–drug and drug– food interaction studies, all of which use the bioequivalence concept. The site of development and production of the drug product could be changed. Most importantly, when the innovator formulation to be marketed is different from the formulation used previously in pivotal efficacy trials, as is often the case, bioequivalence of the marketed formulation to the clinical trial formulation must be shown. In this sense, many innovator drug products on the market are in fact 'generic copies' of the clinical trial formulation for which therapeutic efficacy and safety had been shown in patients. Consumers of drug products, therefore, of both generic and innovator products, need assurance on the question whether bioequivalence implies therapeutic equivalence. All drug manufacturers of either generic or innovator products need to know whether the bioequivalence concept and bioequivalence methodology serve their products well during development. On both these questions relatively recent developments have shed some light. Public concern and ongoing discussion about bioequivalence started in the early 1970s with reports about digoxin intoxica-tions. At the time, generic digoxin formulations were increasingly prescribed in the United States, and a change in the manufacturing process of a company in Great Britain led to an unintentional increase in the bioavailability of one brand of digoxin tables. 3,4 It became clear that drug products that are pharmaceutically equivalent, that is, products that contain the same drug in the same dose, are not necessarily bioequivalent. 5 Over the years, various regulatory guidelines on the design, conduct and statistical analysis …