Bioequivalence and Bioavailability Forum

Dear All,

according to the new EMA-Guideline we want to perform a study in a 2 Formulation - 3 Periods replicative crossover design to extent Cmax acceptance limits.

In Literature and FDA-Guideline (1999) only following sequences are recommended:
RTR (2 Times R)
TRT (2 Times T)

This design was needed for individual bioequivalence (because you need the CVintra of the Reference and the Test Formulation.

To extend the acceptance limit (average bioequivalence) we only need the intrasubject CV of the reference formulation. Therefore it is more sufficient to use only sequences with '2 Times R', for example

Proposal 1:
TRR
RRT

or

Proposal 2:
TRT
RTR
TRR

The answers in the comments to the EMA-Guideline allow this design.

Is there any statistical disadvantage of that design ?

Proposal 2 is the better one. But it is possible to use proposal 1, or are the disadvantages to big ?

Thank you for you response in advance

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Edit: Category changed. [Helmut]