Critical considerations into the new EMA guideline on bioequivalence

The market of generic drugs has been greatly developing during the last 15 years in various European Union (EU) member states, mainly in the Mediterranean area, including non-EU countries, i.e., in the Middle East. This has required a more detailed support from EMA (European Medicines Agency) as guidelines are concerned. Previous EU guidelines on bioavailability and bioequivalence neglected some relevant issues often met in bioequivalence trials, defined in the literature as "open questions on bioequivalence". In the absence of EU specific directives these problems were managed by EU investigators in compliance with U.S. FDA (Food and Drug Administration) guidelines that had already considered some of these "open problems". The latest EMA guideline operating from August 1, 2010 focuses on various relevant issues, including directions on orodispersible tablets, how to operate in the case of high variability, or how to manage the carryover effect of plasma concentrations, but, e.g., it is still neglecting the issue of the multiple-peak phenomenon. In addition, comprehensive directions are still needed on how to manage clinical studies in which endogenous substances are involved. The present review focuses on situations now appropriately discussed in the latest EU guideline, as well as other situations that still need to be defined and need further attention by the regulatory agency in order to give additional adequate directions to the investigators.