Open questions in bioequivalence

Bioequivalence studies are mainly required to demonstrate the interchangeability of multisource pharmaceutical products, usually called generics. A pivotal investigation projected and conducted in compliance with specific guidelines allows a replicative company to register a generic drug via an ANDA (abbreviated new drug application) procedure. Serious problems are often encountered in planning and conducting these studies, which are not covered by operating guidelines, and call for protocols to be set up on a case-by-case basis. The main problems involve the high variability of some active ingredients, how to manage baseline with endogenous substances, drugs with a long terminal half-life, drugs under genetic polymorphic metabolism, drugs possessing stereogenic centre(s), and drugs which cannot ethically be given to healthy volunteers. These problems are extensively covered in this paper and, where appropriate, possible solutions are suggested.