The revised EMA guideline for the investigation of bioequivalence for immediate release oral formulations with systemic action

Abstract

On August 1, 2010, a revised guidance regarding bioequivalence (BE) assessment for the approval of innovator (bridging studies, variations, line extensions) and generic medicinal products in the EU came into effect. This revised guideline specifies the requirements for BE assessment for immediate release oral dosage forms with systemic action. Compared to the previous BE guideline of the EMA, clearer guidance is now given on several topics. For example, for highly variable drugs/drug products, i.e. a within-subject variability for AUC and/or Cmax of 30% or more, the EMA now recommends to use a crossover, replicate design which allows widening of the acceptance limits for Cmax (not for AUC), if clinically justified, by using the scaled average BE approach. This approach allows scaling of the usual acceptance limits of 80.00-125.00% to a maximum of 69.84-143.19%, based on the within-subject variability of the reference product. The use of metabolite concentrations to assess BE is now only accepted in the exceptional case that no bioanalytical method exists, or can be developed using state-of-the-art methodology, which is sensitive enough to reliably determine the AUC of the parent compound. According to this revised EMA guidelance biowaivers based on in vitro dissolution tests are not only possible for BCS class I substances, but also for class III substances if a number of additional conditions, e.g. concerning the excipients used in the test product compared to the reference product, are met. Moreover, specific questions related to BE assessment are more elaborately addressed in a Questions & Answers document (EMA/618604/2008 Rev. 3, 26 January 2011).