Bioequivalence and Bioavailability Forum

Hi,

❝ What does it mean?

❝ "We recommend you to perform 3-period study. By the way you can perform simple 2-period study and it's enough"

…

It does look strange. It seems like the paragraph that you quoted is a generalization. To me it seems like the actual recommendations are listed in the next 2 paragraphs.

John

Dear mittyri
You are right, this inconsistency is confusing. But you will find something similar also in the guideline for MR products (draft). On the one hand the EMA would like to see a study to assess the food effect (MR) or the effect of water (your case) and on the other hand EMA commits that this effect doesn't matter as long as you are bioequivalent in a simple 2 way cross over (or two 2 way for MR). My suggestion is to conduct the simple study and to discuss arguments which led to the refusal of the 3 way study in modul 2.5 Clinical Overview of the dossier.
I hope this helps
Dr_Dan

❝ However, if bioequivalence between ODT taken without water and reference formulation with water is demonstrated in a 2-period study, bioequivalence of ODT taken with water can be assumed."

What about such a situation:
- ODT without water (w-) and IR with water (w+) have indeed the same bioavailability, as mentioned in the guidance:
(1) F_ODT|w- / F_IR|w+ = 1
- Taking ODT with water results in a biovailability decreased by 30%:
(2) F_ODT|w+ / F_ODT|w- = 0.7
- Then, the bioavailability of ODT with water relative to IR with water is:
F_ODT|w+ / F_IR|w+ = (1) x (2) = 0.7
=> ODT with water can certainly NOT be assumed bioequivalent to IR with water

The assumption (2) above does not seem unrealistic, as the rationale for developing an ODT alternative to an existing oral formulation could be to improve the bioavailability by increasing its absorption by the buccal mucosa and then limiting some acidic degradation in the stomach or a strong 1^st-pass effect.

So, either I miss completely the point somewhere, or the guidance actually does not care about BE with water... even if it tries to convince us of the opposite ???