## ANVISA guidelines for two-stage design [Two-Stage / GS Designs]

Hi MS,

» Art.75. For two-stage studies, the following should be noted:
1. It is acceptable to use a two-stage approach to demonstrate bioequivalence based on unknowledgement of the intra-individual variability of the drug;
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2. An initial group of subjects can be treated and their data analyzed;
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3. If power is not sufficient and bioequivalence has not been demonstrated, an additional group can be recruited and the results of both groups will be combined in a final analysis;
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4. This second group must have, at least, 50% of the previous group;
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5. Type I error must be preserved and adjusted, and in order to demonstrate bioequivalence the level of confidence is 94.12%;
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6. In the protocol, the stopping criteria must be clearly defined before the study and the analysis of the first step must be treated as an interim analysis; and
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7. When analyzing the combined data from the two stages, the stage variable should be included in the ANOVA model and its influence verified

» In my opinion it could be better. So, I would like to hear your opinion.

It sounds like a derivative of Potvin's method B with both alphas 0.0294 (1-2*0.0294=0.9412=94.12%), but the performance isn't one that is published. It is not at all demianding to do this type of study assuming you can generally handle twop-stage approaches, but I am a little uncertain when you mention that the influence of stage should be verified, I don't quite know what this means. Do they talk about anova and assessment of the stage effect through a p-level, comparison of results with and with a stage term or what?
Mauricio, do you think there could be alternative translations of the sentence in question?

Hötzi, do you want to publish the performance of this approach in AAPSJ or JPPS with me if I do the simulations and draft the ms?

This week's list of things I absolutely detest: Corona virus, the which function in R, WIA-WIA interfaces for scanning under Windows 10, the Bee Gees, the smell of my fridge.

Best regards,
ElMaestro