## Pseudo-periods [Design Issues]

Dear Helmut,

In your old but still-useful post (excerpt below), you describe generating pseudo-sequences and pseudo-periods when assessing ABE.

» A 6×3 design is needed in order to ‘extract’ two 2×2 tables, which are also balanced. Although the full 6×3 table will be used in the analysis of AUC and Cmax, you will need these 2×2s for the nonparametric analysis of tmax (unfortunately there’s no confidence interval based nonparametric method available for more than two formulations/periods). The asterisks * denote pseudo-sequences and pseudo-periods, e.g. P1* means only that the treatment was given in a period prior to P2* – irrespective of the true study period:

Your post preceded the EMA's Guideline on the Investigation of Bioequivalence by a few years, but it appears to agree with their stipulation:

In studies with more than two treatment arms (e.g. a three period study including two references, one from EU and another from USA, or a four period study including test and reference in fed and fasted states), the analysis for each comparison should be conducted excluding the data from the treatments that are not relevant for the comparison in question.

I completely understand the use of pseudo-sequences in this situation. But what about pseudo-periods? The EMA guidelines aren't too specific.

On the one hand, if you wish to display your data with pseudo-sequences, you would want to use pseudo-periods too (so that the timing of treatments is consistent within pseudo-sequence). On the other hand, the ANOVA doesn't care whether your pseudo-sequences are logically consistent with your period.

If there is no period effect, the difference between using period and pseudo-period will be minimal (use a few more df in the ANOVA table with period than pseudo-period). But what if there is a serious period effect? You would miss it (wrong sum of squares for period) by using pseudo-periods.

Opinions?