Study planning 101 [Regulatives / Guidelines]

posted by Helmut Homepage – Vienna, Austria, 2020-03-11 16:31 (202 d 17:30 ago) – Posting: # 21255
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Hi SKM,

» Pivotal is powered given the high ISCV.

May I ask how? Say the CV was 25% in the pilot study, it might be as well higher in the pivotal. Its upper CL is 32% (n=12, M+F) and 35% (n=8, M). If you follow the ‘carved in stone’ approach, you shoot yourself in the foot (see there).

» We took M:Fe in the ratio of 2:1 and this is a post hoc analysis.

So far, so good. That’s one of the purposes of a pilot. Learn sumfink. Any exploratory analysis is fine.

» We saw high ISCV and lower Cmax in Females as compared to Males.

Saw! Given the small sample size I have strong doubts that these differences are (statistically) significant. As ElMaestro wrote, subgroup analyses have been tried a lot. Didn’t work because studies were not sufficiently powered. See also this post and the reference within.

» We intend to submit the data in EU but I won't be surprised if the management decides to submit that data in FDA at a later date.

The management will be surprised when the study is rejected by the FDA’s OGD right away because not the RLD was used in the study. If you want to submit to both agencies, you need a 6×3 Willi­ams’ design with both a European reference and the RLD (see there).

» Should you suggest me to go ahead with same M:Fe::2:1 ratio for a powered pivotal?

Given the notorious high dropout-rate of female subjects in India I would (for the EMA) perform a 2×2×2 in males only. The FDA requires subjects to be ‘representative of the general population’. When I was in the US last December I didn’t get the impression that it is even close to 2:1. Lots of women around…

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