Bioequivalence and Bioavailability Forum

Dear Detlew!

❝ 1) A subject with lack of any measurable concentrations or only very low plasma concentrations for reference medicinal product. A subject is considered to have very low plasma concentrations if its AUC is less than 5% of reference medicinal product geometric mean AUC (which should be calculated without inclusion of data from the outlying subject)."

Nitpicking: Note the singular!

❝ • May this be applied also in the truncated Area setting?

❝ • Is this also applicable for AUC(0-tau) in multiple dose studies?

Why not? Although I would expect to see outliers in MD less often (accumulation from previous doses).

❝ • What is the geometric mean in replicate cross-over studies? Overall or calculated for each replicate?

Good question. Overall?

❝ • What to do in case of crossover design with more than one Reference?

Oh no.

❝ • Should an algorithm implemented recursively (i.e. repeated after exclusion of identified outlier with respect to the 5% criterion in a first run)?

Sine the GL talks about a single outlier (why?) maybe not. I would say you can remove more than one, but only in the first ‘look’. We once had a case (15+ years ago), where two outliers were evident in the dataset and another one appeared after removing them. The agency asked us to remove this one as well. My gut feeling tells me that nowadays such a procedure would not be acceptable.