Abstract

During the last thirteen years, the author has investigated a relevant number of bioequivalence trials, for the approval of generics, which in the Mediterranean area show an increasing business trend. In his activity the author has faced several problems, most of them not considered in operating guidelines, defined “open questions on bioequivalence”. They deal with the most appropriate procedures to adopt in case of studies on drugs with long half-lives, of ethics problems, high data dispersion, endogenous substances, presence of active metabolite(s), prevalent metabolites and reversible metabolism, very low plasma concentrations, multiple peak phenomenon, titre differences, polymorphic metabolism, stereogenic atoms. The relevance of a pilot trial, mainly for modified-release formulations, and the problem of frauds are discussed as well. These open questions are discussed in the present review taking into account EU and US FDA guidelines, current literature and personal experience. In most cases suitable approaches are suggested. Appropriate procedures should be planned and defined in the study protocol and extensively discussed in the final report. An appropriate approach to the “open questions” is a requisite to achieve a clearly defined bioequivalence/bioinequivalence conclusion.

Keywords: Bioequivalence, clinical trials, guidelines