Bioequivalence and Bioavailability Forum

Dear all,

yesterday EMA’s PK working party published Rev. 7 of the Q&A document. According to the new #14:

1. The expected analysis for the combined data in a two-stage design is ANOVA with terms for stage, sequence, sequence × stage, subject(sequence × stage), period(stage), formulation.
   
2. This model can be fitted provided that in each stage, there is at least one subject randomised to each sequence. This does not supersede the requirement for at least 12 subjects overall.
   
3. A term for a formulation × stage interaction should not be fitted.

If you have a Two-Stage study underway, amend your SAP.

Note 1: The CI in the pooled analysis is not affected if compared to a model without subject(sequence × stage) sequence × stage. For Potvin’s Example 2 I got p 0.7689 0.1539.*
Bonus question: What if p <0.05?

Note 2: Phoenix/WinNonlin-users: Such a setup was already needed for an ‘all fixed-effects’ model.
Model Specification > Fixed Effects > Stage+Sequence+Sequence*Stage+Subject(Sequence*Stage)+Period(Stage)+Treatment

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• Typos corrected. THX to Detlew – see this post.