Generics and cost-effective prescribing in Belgium: does bioequivalence always translate in therapeutic equivalence?

As many other countries, Belgium has a policy to promote the use of generic pharmaceutical products. In order to protect consumers, these generic products must be demonstrated to be essentially similar to the previously approved product, typically an innovator product. The therapeutic equivalence of a generic and an innovator product is most commonly based on the demonstration of bioequivalence, i.e. clinically insignificant differences in the rate and extent of drug absorption usually assessed from pharmacokinetic measurements, in a normal and healthy population. This article reviews the bioequivalence requirements for generic products and examines whether bioequivalence always adequately substantiates therapeutic equivalence and interchangeability. Clinical practice has identified a number of drug classes for which generic substitution should be approached with caution. Current bioequivalence requirements are based on a measure of average bioequivalence. There are fears that use of this measure may be inappropriate in the case of a drug with a narrow therapeutic range or high intrasubject or intersubject variability. Under these circumstances, measures of individual and population bioequivalence are proposed to be more accurate than measures of average bioequivalence. Bioequivalence issues are discussed together more general concerns about generic drug substitution, such as differences in product and packaging appearance and differences in excipients.