Bioequivalence and Bioavailability Forum • Validated frameworks; observed GMR not relevant

Validated frameworks; observed GMR not relevant [Two-Stage / GS Designs]

posted by Helmut – Vienna, Austria, 2017-02-22 13:03 (3054 d 02:33 ago) – Posting: # 17096
Views: 15,143

Hi Yura,

❝ If the ratio of AUC and Cmax T / R beyond 0.95 - 1.05, whether it is a violation of the conditions of the calculation for algorithm of adaptive design? :confused:

Adjusted alphas of the published frameworks are only valid for certain ranges of n₁/CV-combinations, fixed GMRs, and target powers assessed (see this presentation, slide 20). F.i. Potvin’s α_adj 0.0294 in ‘Method B’ (“Type 1”) is valid for n₁ 12–60, CV 10–100%, fixed GMR 0.95, and target power 80%. The maximum Type I Error is generally seen at small stage 1 sample sizes and low CVs. Hence, even if the n₁ and/or CV were outside the validated range on the upper end (say for ‘Method B’ >60 and/or >100%) you can be pretty sure that the patient’s risk is still controlled. However, in such a case picky assessors might ask for simulations.
I would avoid performing the first stage in 12 subjects. Due to dropouts one may end up outside the validated range. Example for ‘Method B’:

library(Power2Stage) power.2stage(CV=0.2, n1=12, alpha=c(0.0294, 0.0294), theta0=1.25, targetpower=0.8, pmethod="shifted", nsims=1e6)$pBE # [1] 0.046352 #n₁ within validated range: TIE <0.05.
power.2stage(CV=0.2, n1=10, alpha=c(0.0294, 0.0294), theta0=1.25, targetpower=0.8, pmethod="shifted", nsims=1e6)$pBE # [1] 0.048389 #n₁ outside validated range: higher TIE but still <0.05.

The GMR observed in the first stage is not relevant.

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Complete thread:

Data for 2nd stage of Potvin’s designs BE-proff 2017-02-18 06:40 [Two-Stage / GS Designs]
- Data for 2nd stage of Potvin’s designs ElMaestro 2017-02-18 10:20
  - Data for 2nd stage of Potvin’s designs BE-proff 2017-02-18 13:29
    - GMR = fixed! Helmut 2017-02-18 16:23
- “Type 1” slightly higher power than “Type 2” for the same adj. α Helmut 2017-02-18 11:51
  - “Type 1” slightly higher power than “Type 2” for the same adj. α BE-proff 2017-02-18 13:31
    - Terminology Helmut 2017-02-18 16:27
      - Terminology Yura 2017-02-20 11:28
        
        Which GMR to plug in ElMaestro 2017-02-20 11:46
        
        Which GMR to plug in BE-proff 2017-02-21 11:35
        
        Which GMR to plug in ElMaestro 2017-02-21 11:47
        
        Validated frameworks; observed GMR not relevantHelmut 2017-02-22 12:03
        
        Validated frameworks; observed GMR not relevant Silva 2017-03-09 01:26
        
        GMR, theta 0 and that all d_labes 2017-03-09 09:21
        
        GMR, theta 0 and that all Silva 2017-03-09 12:38
        
        GMR, theta 0 and that all ElMaestro 2017-03-09 12:56
        GMR, theta0 and that all d_labes 2017-03-09 13:55
        
        GMR, theta0 and that all Silva 2017-03-09 18:01
  - “Type 1” slightly higher power than “Type 2” for the same adj. α BE-proff 2017-02-21 11:31