Bioequivalence and Bioavailability Forum

Hi John,

❝ Since both SAS and WinNonlin results are submittable for FDA (EMA?), …

EMA:

❝ … what if my results are borderline passing the 90% CI with SAS and borderline failing the 90% CI with WinNonlin?

❝ Just an example: SAS gives 79.85% - 99.93%, while WinNonlin gives 80.15% - 100.52%.

Some ideas:

• Conventional 2×2 cross-over: Since Phoenix/WinNonlin only speaks REML, you have to exclude incomplete data. Unlike in SAS GLM (which ignores such cases) you have to filter for complete data in Phoenix first. Otherwise you are in mixed-effects model limbo. For the EMA you have to treat all effects fixed. In Phoenix that means: Delete subject(sequence) in the variance structure / random1 tab and add it to the fixed effects.
  
• Higher-order Xover (say two references). Same as above, but for the EMA you have to exclude the “uninteresting” treatment, while for the FDA I guess (!) you keep all in the model and report only the relevant pair. That’s independent from the software you use.
  
• Replicate designs / scaling: Cave – FDA and EMA have different models.

With the correct coding I never saw different results from SAS and PHX. Is this a hypothetical example or from the ‘real world’? On the other hand different results in higher-order Xovers are possible (again independent from software). In your example substitute SAS by FDA and WinNonlin by EMA. The former comes from the full model with a pooled variance of all formulations, whereas the latter pools only variances of test and the European reference. If the US RLD has a lower variance than the European reference, in the EMA’s model you will get a wider CI because the ‘dampening effect’ of the US RLD is not applicable.