Bioequivalence and Bioavailability Forum

Hi Shuanghe!

❝ Man. It's nice to be your own boss. lucky you.

Great that my boss pays for me. Stupid personal union.

❝ ❝ • According to the draft MD studies might be waived under certain circumstances:

❝ ❝ — AUC_t > 90% AUC_∞ and

❝ ❝ — BE demonstrated in SD for additional PK metrics, e.g., pAUCs (C_τ under discussion).

❝

❝ You meant AUC_τ, not AUC_t, right? The same goes for the following procedure in your post.

Oops, sure. AUC_(0-τ) – lines 593–595.

❝ […] let's say one Reference product has to be taken twice a day so dose interval would be 12 hours. In single dose BE study let's say sampling is up to 18 hours.

❝ Then AUC_τ is AUC_0-12 (and C_τ, in case we are allowed to use it to replace MD study in the future, would be C_{12 hours}), AUCt would be AUC_0-18.

Exactly. My mistake.

❝ In order to avoid MD study, […]

Correct interpretation.

❝ 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 wish that we could but probably not if "less food effect contradictory to the definition of generic... " is any indication. But I'd like to hear all thoughts from forum members anyway.

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

❝ While we were talking about parameter, I have another question.

❝ Since there're several C_min to choose (predose, post dose, true C_min...), C_min was defined as "the concentration at the end of the dose interval" (in steady state). However the guideline defined the C_τ,ss as such as well. So what's the difference between them?

In a generic application you always have to show BE of C_τ,ss. With a new formulation (first MR product or comparison with IR) the global C_min will be more interesting (that’s also the one you should use in the calculation of %PTF if you want).

❝ ❝ • If the MD study passes with the conventional metrics (AUC_τ, C_max, C_min), the fact that ‘shape’ metric(s) failed in SD will not lead to rejection of the application (rationale: BE demonstrated with conventional metrics both in SD and MD).

❝

❝ Nice. Is this a consensus and will be written in the final guideline or just our wish?

This was a consensus. Difficult to predict whether it will be that clearly stated in the final version. But there is a logic behind. You try to pass with the additional metrics in order to apply for a waiver. 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.

❝ ❝ There was a short discussion whether for delayed release AUC_0-T & AUC_T-t and for prolonged release AUC_0-T & AUC_T-∞ would be sufficient (dropping the respective other AUC-metrics). No consensus was reached.

❝

❝ No kidding. I was under the impression that pAUC will not be required for delayed-release formulation. I remembered that Dan Seiler (or someone else?) said so during the panel discussion on the 2nd day in the Budapest conference. Or I misunderstood it? D***, that would affect many of my projects.

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