Bioequivalence and Bioavailability Forum

Dear Helmut,

❝ According to the 1999 MR-NfG C_min is one of the required PK metrics, which gives me a headache.

Do you consider a multiple dose study? Although it was considered not necessary in EU? For answering Chinese, Saudis etc. ?

❝ Essentially no accumulation is expected, but the metric will be highly variable. …

Of course. And in most / many / all cases not reliable estimable.
With the common rule values reported as <LLOQ set to zero the ratios T/R for subjects are inf, 0 or not defined as you know.

❝ What would you do? Treat the formulation according the IR-GL (following the arguments used in the original MA) and forget about C_min, report it only, or what else? From a clinical point of view it does not matter,❝ because the formulation is intended for chronic use and according to the SmPC patient's are to be titrated for the effect.

I would take all your arguments (including that from the scientific advice and from the new guidance) over to the study protocol to justify why C_min and or C_last is considered not an useful PK metric for that product and is expected not estimable in most subjects ... And therefore can at the best only reported.

Eventually our "regulator" EM has a good EMphylistic text suggestion for you if he is debarked .