Bioequivalence and Bioavailability Forum • Which country?

Which country? [Two-Stage / GS Designs]

posted by Helmut – Vienna, Austria, 2019-09-10 01:17 (1953 d 00:59 ago) – Posting: # 20566
Views: 13,452

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
More information please.

Accepted by the FDA (Donald Schuirmann is a co-author of this paper and later ones) and Health Canada. Confirmed at the 2^nd/3^rd GBHI conferences (Rockville 2016, Amsterdam 2018) that any simulation-based method is acceptable.
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; 35^th 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 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
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Complete thread:

Appropriate wording for a protocol Elena777 2019-09-09 19:34 [Two-Stage / GS Designs]
- Appropriate wording for a protocol ElMaestro 2019-09-09 21:39
  - Appropriate wording for a protocol Helmut 2019-09-09 23:27
  - Appropriate wording for a protocol Ohlbe 2019-09-10 10:27
- Which country?Helmut 2019-09-09 23:17
  - Which country? Elena777 2019-09-11 20:24
    - EEU-rules, TSD-methods (lengthy answer) Helmut 2019-09-12 01:31
      - EEU-rules, TSD-methods (lengthy question) Astea 2019-09-14 14:56
        
        n2 based on PK metric with higher CV Helmut 2019-09-16 11:50
        
        Q&A ref Astea 2019-09-16 18:28
        
        The omniscient oracle has spoken Helmut 2019-09-17 12:27
        
        The omniscient oracle has spoken Astea 2019-09-17 20:34
        
        OT: Булга́ков Helmut 2019-09-18 12:12
        
        n2 based on PK metric with higher CV Elena777 2019-09-16 19:48
        
        AUC passes with 0.05 and Cmax with 0.0294 Helmut 2019-09-16 23:30
        
        AUC passes with 0.05 and Cmax with 0.0294 Mikalai 2019-09-18 16:56
        
        Hybrid B/C Helmut 2019-09-18 17:09
        
        AUC passes with 0.05 and Cmax with 0.0294 Elena777 2019-09-19 08:34
        
        Use data of all dosed subjects Helmut 2019-09-19 15:16
        
        Use data of all dosed subjects Elena777 2019-09-19 15:27
        
        ‘Method C’ ⇒ risky Helmut 2019-09-19 16:15
        
        EEU-rules, TSD-methods (lengthy question) Elena777 2019-09-16 19:35
        
        apple tree for two-stage Astea 2019-09-16 20:39
        
        overripe apples Helmut 2019-09-16 23:37
        
        override apples Astea 2019-09-17 06:14