## Which country? [Two-Stage / GS Designs]

Hi Elena,

» We are planning to conduct several BE studies with adaptive design using the drugs with uncertain intraCV. We have decided to use method C described by Potvin …

Whether Potvin’s Method C will be accepted depends on the jurisdiction you are bound to.a,b

1. Accepted by the FDA (Donald Schuirmann is a co-author of this paper and later ones) and Health Canada. Confirmed at the 2nd/3rd GBHI conferences (Rockville 2016, Amsterdam 2018) that any simulation-based method is acceptable.
2. For the EMA possible if BE already in stage 1, difficult if you proceeded to stage 2. Even Method B is tricky. The EMA dislikes (oh dear!) methods based on simulations and prefers ones which showed strict control of the type I error, i.e.,
1. König F, Wolfsegger M, Jaki T, Schütz H, Wassmer G. Adaptive two-stage bioequivalence trials with early stopping and sample size re-estimation. Vienna: 2014; 35th Annual Conference of the International Society for Clinical Biostatistics. Poster P1.2.88. doi:10.13140/RG.2.1.5190.0967.
2. Maurer W, Jones B, Chen Y. Controlling the type 1 error rate in two-stage sequential designs when testing for average bioequivalence. Stat Med. 2018;37(10):1–21. doi:10.1002/sim.7614.
BTW, implemented in the -package Power2Stage: functions power.2stage.in(), interim.tsd.in(), final.tsd.in() since October 2017.
The EMA’s Pharmacokinetics Working Party and the Biostatistics Working Party had two-stage design on their workplan for years (!) with any outcome. At last year’s BioBridges Paola Cop­pola (MHRA) showed this slide:

Dif-tor heh smusma 🖖
Helmut Schütz

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