Bioequivalence and Bioavailability Forum

Hi Sundar,

❝ Is it possible to design the reference scaled approach following parallel study (single period)?

By definition reference-scaling is applicable if the within-subject variability of the reference is >30%. CV_wR is not accessible in a parallel design (not even CV_w…).

❝ If yes, how to design the study, randomization and statistical procedures?

Tóthfalusi and Endrényi proposed a method for studies in a parallel design.¹ However, in a follow-up paper² they didn’t mention parallel designs any more. Given the troubles we already are facing with replicate designs (inflation of the Type I Error, convergence issues in the partial replicate) I guess the chance of a rather exotic approach to be accepted by any agency is practically zero.

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1. Tóthfalusi L, Endrényi L. An Exact Procedure for the Evaluation of Reference-Scaled Average Bioequivalence. AAPS J. 2016;18(2):476–89. doi:10.1208/s12248-016-9873-6. PMC Free Full text.
   
2. Tóthfalusi L, Endrényi L. Algorithms for evaluating reference scaled average bioequivalence: Power, bias, and consumer risk. Stat Med. 2017;36(27):4378–90. doi:10.1002/sim.7440.