Bioequivalence and Bioavailability Forum

Dear all,

maybe you can help me getting answers to a tricky question.
The drug has a half-life of 2-3 hours; the formulation is a double pulse MR, consisting of an IR part and a MR part for OAD administration. The 20 mg strength was BE to a conventional 10 mg IR formulation administered twice a day with a dosage interval of 4 hours (AUC_t, C_max, AUC_0-4, AUC_4-24, C_max,0-4, C_max,4-24). Dose linearity was shown between 5/10/20/30/40 mg strengths. Since the profiles of MR OAD were superimposable to IR TAD after 8-12 hours and no accumulation is possible (0.7 % higher C_max in steady state), it was agreed in a scientific advisory meeting at the German BfArM a couple of years ago not to perform a multiple dose study.
The MRP was a pain in the ass, since some member states missed the steady state study according to the MR-guideline. But finally the MA was granted. Same story in the DCP five years later. Now the sponsor is tired of answering deficiency letters from Saudia Arabia, China, etc.
In the course of a line extension (50/60 mg) we have already shown BE of the 60 mg formulation to 2×30 mg after a single dose. Now for the question:
According to the 1999 MR-NfG C_min is one of the required PK metrics, which gives me a headache. Essentially no accumulation is expected, but the metric will be highly variable. The drug/formulation shows low variability (≈15 %) for C_max and extremely low variability for AUC (≈7 %). We had already the 100 %-not-included-in-the-CI issue in the past… In a simulation I got a CV of ≈32 % for the global C_min and ≈75 % for C_last (preferred by some regulators). C_min was removed from the current IR-GL for exactly these reasons. The recently published concept paper states:

3.1 The necessity to combine the current guideline with existing documents touching different aspects of modified release products […] implies several aspects. The newly revised Note for Guidance on the Investigation of Bioequivalence (EWP/QWP/1401/98 rev1), the emergence of science as well as applications on new types of formulations require thorough discussions on:

• requirements for steady-state studies,
  
• primary pharmacokinetic parameters,
  
• possibility of widening (and narrowing) of acceptance ranges,
  
• requirements for specific formulations, e.g. “timed – released” dosage forms

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.