Bioequivalence and Bioavailability Forum

Hi Clare,

❝ 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.

Almost correct (as Dr. Gunasakaran already pointed out). Currently you have to state in the protocol:

1. Intention to widen the acceptance range based on [L, U] = ℯ^{∓0.760·s_WR} if CV_WR >30% (and limited with 50%) – GMR within 80.00–125.00%;
   unscaled AR (80.00–125.00%) otherwise.
   
2. Sound justification that the widening is clinically irrelevant.

Don’t forget the second point.

❝ Nevertheless, there are UKPARs showing that widened acceptance limits have been allowed without a replicate study design.

Since the Q&A-document (July 2006) CV_WR >30% in a replicate design was required in order to widen the limits (for C_max only) to 75.00–133.33%.
Before it was possible to widen the limits to e.g. 75.00–133.33% without a replicate design. Note the “e.g.”! There were many products approved with an AR of 70.00–142.86%. In exceptional cases widening was also accepted for AUC…