Bioequivalence and Bioavailability Forum

Dear d_labes,

❝ So once again: Any idea how to do that? The Bear way, i.e same model as for 2x2? Helmuts suggestion? Any other?

Neither. If I had to do something with a dossier based on a replicated study it would be the following:

1. Carry on with a linear mixed model.
   
2. Construct the CI's and stuff as you ordinarily did before this guidance document was published.
   
3. Wait and see!

If anyone has the guts to trigger an EU referral, this would still be a good outcome. Not the quickest way for the product in question, but it would be good to have this issue debated at CMD and, much better, at CHMP.
So if the product is referred to CMD, there will be limited scientific discussion there because CMD is mainly a regulatory comittee. They are highly skilled in all procedural problems, but they are not statisticians or pharmacokinetophystians or what it's called (they can bring experts, but there is a limitation to that, too). So either approval or referral to the CHMP. This would be a great chance for you. Because you can openly address it and ask them to show you how one can analyse replicated studies without a mixed model and still get unbiased separate withins for T and R. Gotcha!

I have the greatest respect for the PK-subgroup, the CMD, the CHMP and EU regulators in general for all the work they undertake. But in this specific case I think the PK-subgroup has produced a document that is self-contradictory and not on par with current standards and which may result in rejection of equivalent products if the word of the guideline is followed. For that reason, I think that medicine consumers in Europe would have a potential benefit if someone like you engages the regulators in a game of chicken. It is only one sentence that needs to be changed in the guidance in order for everything to be ok.

Best regards
EM.