posted by Helmut Homepage – Vienna, Austria, 2020-02-03 13:25 (1536 d 07:12 ago) – Posting: # 21130
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Dear Osama,

I think that the GCC’s guideline is not that bad (following what the EMA’s Q&A of July 2006 required).
During the development of the EMA’s GL (and even in the June 2010 EGA/EMA joint workshop when the GL was already final) the industry lamented that for CVwR 30–40% one would need larger sample sizes than before. I kept my mouth shut because for years I was an advocate of reference-scaling. Although I was aware of the 2009 paper of the two Lászlós, it needed Detlew’s post of 2013 to comprehend the ugly problem of the inflated Type I Error.
Example: 2×2×4 design, assumed T/R ratio 0.90, powered for ≥80%; in ABE at CVwR 30% switching the BE limits from 80.00–125.00% to 75.00–133.33%.


For extreme CVs (say, 300% for some LALAs like mesalazine) sample sizes are nasty anyway (430 subject for the fixed wider limits and 224 for ABEL)…
I designed such studies (reference-scaling for the EMA and the FDA) and the problem is less the CV but the uncertain T/R ratio driving the sample size. If the T/R ratio drops from 0.90 to 0.85, the sample size doubles to 448.

❝ I would like only here really to express my sincere gratitude and thanks for the great excellent effort which you did and do. As a previous academic person who worked also in the industry and now in one of the regulatory body I still till the moment (I think better to say we still) learning a lot from you and other colleagues.

THX for the flowers!
BTW, you are not the only regulator here. We have members of different European agencies, the Eurasian Economic Union, ASEAN states, ANVISA, and – believe it or not – the FDA. :-D

❝ For all of yours, I wish and hope the continuously for this Forum to illuminate our problems in the dark BE world.

You should have typeset “dark” also in bold. ;-)

Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz

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