Bioequivalence and Bioavailability Forum

Hello all,

what is the correct ANOVA model for extra-reference design?

Lets have a standard 2×2×2 crossover study that is extended by adding a third period in which all subjects receive the reference formulation only (i.e., extra-reference data in Period 3). If I analyze the data using the conventional ANOVA model with the four fixed effects (subject, sequence, period, and treatment), I obtain exactly the same PE as in the original 2×2×2 design. This remains true even when I simulate the reference data in Period 3 to be significantly lower (e.g., approximately half of the values observed in Periods 1 and 2).

This seems unreasonable, because the additional reference data contain some additional information about reference treatment and should therefore probably influence the PE?  So my question would be what is the correct statistical ANOVA model for an extra-reference design?

Best regards
BEQool