Bioequivalence and Bioavailability Forum

Tough job [Two-Stage / GS Designs]

posted by Helmut  – Vienna, Austria, 2012-08-31 20:37 (4678 d 09:17 ago) – Posting: # 9135
Views: 21,838

Hi GSD!

❝ […] I will then run the actual simulation and for each run query the result tables. Assuming I use 10^4 simulations, the production of all these tables should take no longer than 2 weeks.

Yes, but as I said at the end of my post not only the grid is too coarse, but IMHO 10⁴ sim’s are not enough.

❝ When I simulate from a normal distribution with mean centered on ln(0.8) or ln(1.25) and employ the different models based on the different sample CVs, I get a wildly inflated type I error.

A technical question: How do you define the mean and CV in log-scale? Maybe this post helps.

❝ Let’s just start with the usual 1-stage design with a full replicate model and consider EMA scaling. If I simulate as above, I get an empirical type I error of 5.1%, 8.5% 25.4%, 36.9%, 47.1% and 49.8% for CVs of 10%, 30%, 35%, 40%, 50% and 70% respectively. (The sample size that I used in each case was powered at 80%).

Terrible – and surprising. With a CV of 10% we should expect to very rarely have to employ the ABEL model. Stupid question: Which one of Potvin’s methods are you aiming at? With Method B I would not expect such a large inflation. Right now I’m re-calculating their tables (up to 50% CV with a narrower grid and the exact method rather than the shifted t). Here is a Krig-surface in order to interpolate sim’s which are not completed yet:



The critical region runs from [n₁ 12 – 21 | CV 26] to [n₁ 44 - 50 | CV 60 – 48]. Below CV 12% (n₁ 12) and 30% (n₁ 60) the framework is extremely conservative (α_emp. ~ α_adj.).

❝ Should I try instead to find the center of the distribution that would allow me to control the type I error at exactly 5%? For example, when the CV is 40%, if I simulate from a normal distribution with mean centered on 0.748, it will give me an empirical type I error of ~5%.

Doesn’t make sense. ln(0.8)/ln(1.25) are fixed margins and we are testing for no inflation there. 0.748 is outside the margin and the GMR-restriction would reject all studies.

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! 
Helmut Schütz


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Complete thread:

• Potvin’s 2-stage adaptive design GSD 2012-08-17 20:56 [Two-Stage / GS Designs] 
  • Potvin’s 2-stage adaptive design + RSABE/ABEL Helmut 2012-08-18 00:39
    • Potvin’s 2-stage adaptive design + RSABE/ABEL GSD 2012-08-31 16:30
      • Tough jobHelmut 2012-08-31 18:37
        • Tough job GSD 2012-08-31 19:23
          • C/D for EMA? Good luck! Helmut 2012-09-01 15:09
        • Surprise? d_labes 2012-09-05 12:57
          • Got it. Ages for sims to complete Helmut 2012-09-05 13:35
            • Life belt d_labes 2012-09-05 14:51
              • Life belt Helmut 2012-09-05 15:20
    • Power for Two stage Design K2K 2013-10-07 14:43
      • Power for Two stage Design Helmut 2013-10-07 14:59
        • Power for Two stage Design K2K 2013-10-08 14:35
          • “Interim power” Helmut 2013-10-08 14:58
            • “Interim power” K2K 2013-10-09 12:39
              • Validation of PowerTOST Helmut 2013-10-09 14:10
              • Phoenix/WinNonlin - power d_labes 2013-10-09 16:11
                • Phoenix/WinNonlin - power Helmut 2013-10-09 18:19
                  • power K2K 2013-10-10 08:36