Bioequivalence and Bioavailability Forum

Hi all,

We have been looking at some past BE studies which have been submitted to various agencies as well as the publicly-available assessment reports. We have seen many BE studies (pre-2010) where the acceptance limits for Cmax were widened for a highly-variable drug such as atorvastatin. However, in many of such studies, a conventional 2-period, 2-sequence study design was used, and not a replicate study design. If I have understood the current EMA guidelines correctly, the acceptance limits can only be widened if the intra-subject CV > 30% in the BE study and if prospectively specified in the protocol. Nevertheless, there are UKPARs showing that widened acceptance limits have been allowed without a replicate study design. Can someone please help me understand this?

Thanks!