Bioequivalence and Bioavailability Forum

Hi Helmut, Thanks!

❝ ❝ What if AUC_τ/AUC_0-∞ is <90% for reference but >90% for test? So reference has risk of accumulation but test does not. Can we waive MD study?

❝

❝ Nope. See lines 594–595: “[…] demonstrated that the mean AUC_(0-τ) after the first dose covers more than 90% of mean AUC_(0-∞) for both test and reference…”

I know the guideline said both test and reference (I actually copied the phrase but somehow got deleted ).
What I was trying to ask is if anyone mentioned this point so we might get generic product with AUC_τ/AUC_0-∞ is <90% for reference but >90% for test. It's a long shot I know.

❝ Consensus amongst the members of the drafting group: “Better” is not “equivalent”. Article 10(3) instead of 10(1).

OK. What about "better alcohol effect" ?

We know in vitro dissolution with alcohol (0, 5, 10, 20%, and maybe 40% as well as FDA did) will be required and the "criterion" is "similar effect".
But for alcohol, maybe "better" and "equivalent" is not that contradictory? Not like the accumulation mentioned above, which I had doubt myself; for alcohol I'd say it should be allowed to have generic product release less in alcohol than reference. Anyone mentioned this in the discussion?

❝ Imagine two applications:

❝ • In the first the additional metrics were tried, failed, but passed the MD study.

❝ • The other one didn’t try at all and went straight for the MD.

❝ So at the end both showed BE with conventional metrics in SD and MD. Rejecting the first application would be difficult to defend.

When you put it this way, it's crystal-clear. thanks.

❝ Well, according to the draft Appendix III (lines 1170–1176) for DR no MD is required.

My bad. I didn't state it clearly. No MD study for DR dosage form, that's clear from the guideline (unless they change their mind of course).
What I meant to say was that Line 800 indicated that C_max, AUC_0-t, AUC_0-∞ and _partialAUC will be required for MR formulation in single dose study. My argument is that only the former 3 parameters should be required for DR formulation and all 4 parameters required for prolonged-release formulation in single dose study. That's impression I got from Budapest conference.

❝ However, this question was raised. The main concern is AUC_T-∞ instead of AUC_T-t for PR. Higher variability and not consistent with US/CAN. Whatever the outcome will be (and I don’t think MD will be required for DR) it will affect projects starting 1½ years from now (my guess about the timeline).

Not sure if I understood your message correctly, you mean that _pAUC (in single dose study) will be required for DR formulation as well?