Bioequivalence and Bioavailability Forum

Dear Joshua!

The answer is a strict and clear No.

Reference scaled average bioequivalence (regardless of using the FDA reference scaled criterion described in the progesteron guidance or the widening of the BE acceptance limits according to the EMA) is defined based on the within-subject variability of the Reference.

Moreover the classification of a highly variable drug or drug product (formulation) is also based on the within-subject variability with a CV >30%.

Within a parallel group study you are not able to extract the within-subject variability. You only can get the total variability (sum of between and within). Regardless of using two groups ( how, why) with reference administered as you suggest. Therefore you don't have any foundation to apply the reference scaling approach.

BTW: The term "Reference Scaled Averaging" is quite sloppy in describing what you intend. There is no such "averaging" in the underlying methods.

BTW2: How do you distinguish the "two groups" treated with Reference? Do you have any feature different between them? If yes you have a 3-group parallel design with two distinct References and one Test.