There is no modified release formulation of the study drug in the market. How can I proceed according to EU guidelines?
immediate release formulation dont used to comparator for modified release because u also know drug release time very short for immediate release. you may take your different batch formulation to conduct BE study. just what i know given as answer for you, i dont know is correct r not
a true modified release formulation cannot be expected to be bioequivalent to an immediate release formulation. that is like comparing i.v. injection vs. s.c.. if you are the first to formulate your study drug as modified release, a BE study is not suitable unless you just want to know how much your new formulation differes from the conventional one
Please go the following link
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/03/WC500140482.pdf
How do I interpret which study to follow/conduct?
Thank you
For regulatory comparative bioequivalence for marketing approval? No. To characterize respective dosing schedules and dose-response curves for comparable therapeutic steady state plasma concentrations, and hence therapeutic equivalence of the two formulations already on the market? Maybe. In any case, there is no pharmaceutical logic in investigating bioequivalence between the two formulations. As you know, they are designed to release the active at different rates and to different extents per unit time. Even the elimination half-life from the body is different for the same molecule in the two types of formulation - the rate of release from the formulation is the elimination rate-limiting step.
Dear Tohlang,
Please let me know from the following
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/03/WC500140482.pdf
In this draft they clearly say that you can use modified release as comparator. But, which studies to conduct?
Dear Imran,
Thanks for alerting me to the reference. From what I read from it, the most relevant sections for your project are, firstly section 5.1 for comparative kinetics, and then section 5.2 for comparative efficacy and safety. But, there's a provision to waive comparative efficacy and safety requirements IF it can be proven by multi-dose kinetic studies that the two formulations are bioequivalent in terms of steady state AUC, Cmin, and Cmax. I suggest you read the two sections carefully, keeping in mind the known immediate release pharmacokinetics of the molecule you're dealing with, e.g. does it accumulate - which will affect half-life and hence the dosing schedule to reach comparative steady sate, e.t.c. Trust it helps a bit.
Thanks Tohlang.
I have read the draft earlier and I had come to the same conclusions which you have suggested.
I just wanted to confirm whether I am going in correct direction.
Thanks a lot.
Regards,
Imran
Depends on the nature of the active principle. If Cmax and Tmax are critical for efficacy and/or safety (i.e drugs requesting high blood levels to achieve the desired compartment) then apart from testing comparability of AUC further studies will be required. But for many drugs the two first variables are secondary issues and then a comparable BA test (AUC) with the immediate release formulation can be done (i.e. comparing tablets vs drinkable solutions). Take care with active principles in which AUC is affected by first pass effects or other PK variable.
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