Natural constant as usual; not for reference-scaling [Two-Stage / GS Designs]

posted by Helmut Homepage – Vienna, Austria, 2016-10-11 09:50  – Posting: # 16717
Views: 10,795

Hi ElMaestro,

very interesting. From the wording of the 2-period study I assume that the original analysis was performed according to “Method C”. I have seen similar requests by the MEB (i.e., post hoc changing to “Method B”). With budesonide the applicant was lucky enough to pass (lower CL 0.80; both of AUC and Cmax) but I have seen other cases. BTW, the GL tells us that the CI should be given in percent rounded to two decimals. Would this study still be accepted now?

BSWP:Some assessors I know:

“I accept studies with Potvin’s methods if the CI is not too close to the acceptance range.

Now to the fully replicated 4-period study:

» Alpha 2.94%. Approved in Germany, Sweden, Portugal, Iceland, Hungary, Italy, 2015 :-):-):-)

“Correct statistical analysis was conduced.” Hhm. Pocock’s natural constant. “Method B” applied outside its valid range (2×2×2 crossover, n1 12–60, CV 10–100%). Cmax of budesonide again a close shave.

Edit: Seems that the study was not intended for reference-scaling (page 10: “Cmax […] within the bioequivalence acceptance range of 0.80-1.25.”
The CV of Cmax was ~50%. If we assume that n1 (2×2×2) is 2n1 (2×2×4) we are again outside Potvin’s range (92 > 80). However, likely the TIE was controlled. Quick & dirty:

power.2stage(method="B", alpha=rep(0.0294, 2), n1=46*2,
             GMR=0.95, CV=0.5, targetpower=0.8,
             theta0=1.25, nsims=1e6)$pBE
[1] 0.040382

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