Bioequivalence and Bioavailability Forum

Hello John John,

❝ We had made a bioequivalence with more than 70 subjects divided into 7 groups. The statistical analysis has been like a normal bioequivalence. Regulatory agency asks us to include the covariable "group".

❝ Is this normal?

That's a fairly decent request. I guess if anything is not normal then it's probably your decision to divide into 7 groups. Anyways, including group as a fixed factor (not a covariate or random factor) takes your partitioning into consideration.

❝ From which number of groups/subjects would there be necessary to include it?

❝ It woul be possible to justify doesn't to do it?

When you specify group as a fixed factor the software should take care of the rest. Your model is then
ln(PK)=Subject+Sequence+Group+Period+Treatment+error

(at least if it is a crossover design; someone will probably suggest to make the model stuff overly complicated by using heavy nesting like subject in sequence in group etc - that is also correct but not really necessary for most practical purposes)

You will see up to 7 df's for Group depending on the type of SS you wish and your specific software but df=7 is only if you do type I SS without intercept and have Group specified lexically as the first factor.

Group is a between-factor. It will not affect the GMR and it will not increase the width of the CI. So the regulatory request is not a danger to the conclusion of BE, I believe.

I would not know how to justify not to do it when the agency specifically asks for it, and I do not see a reason to argue against it. In EU a relevant ref. is the requirement "The statistical analysis should take into account sources of variation that can be reasonably assumed to have an effect on the response variable" - that's simply the thinking behind the request from your regulator in this casee too, whether they are European or not.

Best regards,
ElMaestro ElMaestro