Bioequivalence and Bioavailability Forum

Dear all,

recently Dr_Dan asked about feasibility of a parallel two-stage BE study. I can't think of any reason not to do it but there's at present zero documentation. Of course, I couldn't help thinking a little bit about how such documentation can be produced.

Let's for a second forget the discussion about unequal variances - better do that in another thread.

The evaluation with a simple (one-stage) parallel study is a normal linear model with a single factor (treatment) of two levels (Test or Ref). For stage two we need to calculate sample size, and here I am not so sure what to do. For evaluation at stage 2, I imagine -and I'd really love to hear your opinion- that the factors are treatment (two levels) + stage (two levels) + stage x treatment.
Stage is in this regard the joker. In a two-stage 2,2,2-BE study stage is a between-subject factor, so this factor itself does not affect the residual. In a parallel two-stage evaluation, stage is also a between-subject factor, and hence it does affect the residual. Should one therefore take that fact into consideration when calculating sample size for stage 2? If yes, any idea how?

I would be inclined to say we argue that a well-planned and executed study should not have any significant stage effect, and hence we can ignore the latter issue and just calculate sample size as if it were a just the one-factor situation. But on the other hand, if the anova after stage 2 comes out with a significant p-value for stage as a factor, would this then be bad? I think not, I'd prefer to just look at it as a nuisance and conclude that if the 90% CI is good and stage has a significant p-value then we were perhaps little lucky because our assumption used to calculate sample size was violated but there's nothing wrong with the conclusion towards BE per se.


Is this thinking all wrong or completely irrelevant like most of my utterings? Does anyone have any views to share?
Many thanks.