The new European Medicines Agency guideline on the investigation of bioequivalence.

In this MiniReview, the main modifications made during the revision of the current Note for Guidance on the Investigation of Bioavailability and Bioequivalence are reviewed and justified. Several new features have been added to this guideline, as well as changes aimed at improving the clarity of the guidance provided. The first issue to be addressed was to limit the scope of the guideline to bioequivalence studies for immediate release dosage forms with systemic action. Therefore, the guideline refers to bioequivalence alone. Moreover, the new definition of Generic Medicinal Product has been incorporated. Clearer guidance covering more specific cases is now given on sections such as: fed/fasting conditions, use of metabolite data, enantiomers and strength to be used in the bioequivalence study. Steady-state design is now restricted and other designs, such as parallel group design, replicate design and two-stage design, are now incorporated in a more explicit form. New practical guidance on Highly Variable Drug Products and Narrow Therapeutic Index Drugs has been incorporated. The possibility for a biowaiver based on the Biopharmaceutics Classification System is now more explicit for Class I drugs and can be extended to Class III drugs under restricted conditions. We are aware that the initial goal of providing a very specific and clear guidance on these issues has not been entirely achieved, mainly because it is almost impossible to cover all individual cases and predict every possible situation that may arise. Demonstration of bioequivalence will still require in many instances a case by case approach.