Bioequivalence and Bioavailability Forum

Dear D Labes,

thanks for the answer!

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

Yes – already decided. Even in the EU the five year DCP was painful. Summing up their internal costs answering deficiency letters, delayed approvals, and my honorary in the last years, the sponsor decided to be pragmatic.

❝ ❝ 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.

Yes. The compound is chiral, with different PK and PD. We expect to be able to measure C_min in ≈80 % of cases, but no way to go further down due to limitations of the linear range of the MS (right now we already have a range of 1:200).

❝ 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.

Agree. That was exactly what I’m planning to do.

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

Ahoy!