Bioequivalence and Bioavailability Forum

Hi Shuanghe!

❝ I know the guideline said both test and reference.

❝ 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.

Nobody raised this question. In my understanding you will get an approval, only the MD study will be mandatory. Up to you to send a comment to the EMA.

❝ 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".

I didn’t take notes, so we have to wait for the presentations at EUFEP’s website. Maybe Dan does remember? In a recent line extension we were asked for 0, 5, 20, and 40% at pH 1.2 for two hours.

❝ But for alcohol, maybe "better" and "equivalent" is not that contradictory? […] for alcohol I'd say it should be allowed to have generic product release less in alcohol than reference.

I would support that.

❝ Anyone mentioned this in the discussion?

Not that I recall. However, there was a lengthy discussion whether the GL should concentrate on “intended use” or “misuse”. Food effects and alcohol-related dose dumping are different.

• Independent from what is stated in the SmPC (no food effect, without/with food, or even specific type of food, e.g., light breakfast) in real life administration contrary to the SmPC will happen regularly. So this is a very important issue.
  
• Intake together with alcohol might range from “possible” to “almost never”. As you know this issue has its origin in the oxycodone-story. Quite often terminal cancer patients take opiates together with strong spirits. On the other hand chances that this might happen with a pediatric formulation are close to nil.

I would say the requirement should be case-by-case and not a general one. Another point to comment.

❝ ❝ Imagine two applications:

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

Sometimes I fail to make myself clear in the first place. Sorry.

❝ […] 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.

Gotcha. Does _partialAUC in line 800 mean only the first one (singular; like the FDA’s/TGD’s early exposure)? Seems so, because for prolonged release (line 805) the EMA uses the plural: “early and terminal _partialAUCs”. Another ambiguity which calls for a comment. There was some dis­cussion whether this section should be extended to:

“AUC_(0-t), AUC_(0-∞), C_max and a representative parameter of the shape of the curve, e.g., (early and terminal _partialAUCs)”

Depending on the formulation pAUCs might not be optimal metrics. Example: Flat profiles with ill-defined t_max. Henning and I voted for the plateau time¹ or HVD.² Unfortunately we have only few published data of pAUCs (especially AUC_T-t; exception: some multiphasic for­mu­la­tions). On the other hand for MR theophylline we have a lot of data about t_75%. Hen­ning gave the FDA’s example of requiring all MR studies to be performed in a replicate design in order to explore the subject-by-formulation interaction. This requirement was in force for ~two years. After reviewing the data, the FDA concluded that S×F is unlikely and lifted the requirement. Hen­ning suggested to have additional metrics³ as exploratory ones for a limited period of time (should not lead to rejecting an application if failed) and after reviewing the performance clari­fy­ing requirements. No need to update the GL; could be done in the Q&A document. Perso­nally I’m skeptic whether the EMA will follow this track…

❝ ❝ 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?

For DR I guess only the first pAUC will be required (line 800); see also what I wrote above.

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1. Plateau time (t_75%) or Peak Occupancy Time (POT-25): Time period during which concentrations are within 25% of C_max.
   
2. Half-value duration (HVD), POT-50: Time period during which con­cen­trations are within 50% of C_max. According to László Endrényi (EUFEPS, Barcelona 2010) more stable than POT-25.
   
3. Besides #1 and #2, other metrics suggested in Barcelona:
   C_apical: Average of concentrations within POT.
   AUC_apical: Average of AUCs within POT.
   MDT: Median duration time.
   For the cut-off time point of early exposure Endrényi et al. (1998) suggested the earlier t_max calculated for each subject.

• Endrényi L, Csizmadia L, Tóthfalusi L, Balch AH, Chen M-L. The Duration of Measuring Partial AUCs for the Assessment of Bioequivalence. Pharm Res. 1998; 15(3): 399–404. doi:10.1023/A:1011916113082