subject inclusion question in replicate design for ANVISA [RSABE / ABEL]

posted by Shuanghe  – Spain, 2019-09-04 12:48  – Posting: # 20539
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Dear all

From discussion in this and this post, ANVISA accepts reference scaled approach with replicate design, with possibility of method A/B from EMA's guideline. However, I didn't find anything mentioned about the inclusion of subject in statistical analysis.

We recently sent to one of our clients a BE protocol (intended for ANVISA submission) with 2x2x4 design following EMA's guideline, where it states that all subjects who complete at least two periods with at least one period of reference product will be included in the statistical analysis, i.e., if subject has data of 1T+0R or 2T+0R, he/she will be excluded since T/R does't cross at least once, otherwise they will be included (e.g., if he/she has data of 1T+1R, 1T+2R, 2T+1R, 2T+2R). Subject with 0T+2R will also be included for the estimation of intra-subject variability of reference. However, the client's statistical consultant commented that only subjects who complete all 4 period (2T+2R) should be included, otherwise, they should be excluded even if they completed 3 period. I really doubt this would be the ANVISA's intention for analysis the replicate design, given they are willing to follow EMA/WHO's guideline. The only possibility that I see for this to make some sense is that if we have to use US FDA's SAS code as detailed in progesterone guidance.

Of course, best way is to ask ANVISA's opinion before the start of the study. However, I was told by the client's BE consultant that ANVISA might take 6 months to give feedback!

Can any of you, especially colleagues from Brazil, share your opinion/experience on this topic?
Thanks!

By the way, Helmut, does this belong to Study Assessment or Regulative/Guideline category?

All the best,
Shuanghe

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