Clarification needed: Validation of FDA's RSABE on NTIDs [RSABE / ABEL]

posted by CECIF – Colombia, 2018-02-19 22:20 (1385 d 01:47 ago) – Posting: # 18436
Views: 12,573

(edited by CECIF on 2018-02-19 23:18)

I need some…clarifying, if you will.
I am also, trying to replicate the FDA guidance on warfarin. I am using R. However I am stuck in steps 2 and 3.
In step 2 I am able to calculate ((YR-YT)^2)-theta*swR2, but it says I should find the upper 95% CI using Howe´s method. Sincerely I just read Howe's method (from the reference in the FDA guidance) for like 4 hours and still can't understand how to use it (maybe it´s because I am not a certified statistician). Can somebody give me a step by step on how to do this?.
An additional comment on step 2: once I find the upper 95% CI, What I am supposed do to with it? it does not seem to appear on the subsequent steps (or at least not alone). I just saw your presentation on RSABEs, and you use the criteria "Bioequivalent If 95% upper CI <0" where does this criterion comes from?
In step 3 “every study should pass the scaled and unscaled and scaled bioequivalence limits”: “every study" refers to:
1. Period 1 vs period 2 (regular bioequivalence study)
2. Period 3 vs period 4 (replicated study)
3. Pooled analysis (Average periods 1 and 3 vs average period 2 and 4)
4. Repeated crossover analysis considering all four periods
Did I miss any?
And “scaled bioequivalence limits” refers to the upper 95% CI (supposedly found in step 2) with an additional (and respective) lower 95% CI?

In the study 4 mentioned above is it correct to use the same methods for calculation of BE limits as the others, but adding another factor for the variable of “replication” in the ANOVA?

And finally, is it necessary to comply with all four steps (and multiple criteria) of this guidance to demonstrate bioequivalence? What happens for example if one of them fails but the other 3 are correct?

I would really appreciate any light you can shed.

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