FDA ER vs. IR: Global Cmax [Regulatives / Guidelines]

posted by Helmut Homepage – Vienna, Austria, 2020-05-09 11:54 (254 d 00:29 ago) – Posting: # 21410
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Hi Nathalie,

» […] which IR Cmax should be considered to assess the potential bioequivalence between an IR formulation administered BID and an XR formulation administered OD on day 1 and at steady-state. This is for a submission to FDA.
» 28 For example, when a 150-milligram (mg) ER product administered once daily (QD) is being developed that gives an approved 50-mg IR reference product administered three times a day (TID) or a 75-mg product administered two times a day (BID), a comparison of the 150-mg ER product administered as a single dose could be compared to either the 50-mg IR reference product administered TID or 75-mg IR reference product administered BID.
» In this case, the least common time interval is 24 hours.


» Based on this, I think that the first day dosing interval should be considered as a whole…


» …and that on both day 1 and at SS, the highest Cmax over the least common dosing interval should be taken for the reference, whether it is the first or the second Cmax.

SS correct. What do you mean by “day 1”? Do you want to sample full profiles in the multiple dose study both after the first dose and in steady state? That’s not required. The guidance recommends two studies: SD and MD. If you want to collapse the SD and MD studies into one, you may drain the subjects.

Even if the drug has a short half-live (i.e., little accumulation), for the IR formulation the Cmax after the last dose in the interval will likely* be the global Cmax anyhow. I performed studies like that (OAD XR vs. BID IR, European submission and for Health Canada). The t½ was <3 h, accumulation <1%. In all studies the second Cmax was the global one.
Another hint why the FDA requires the global Cmax only: For multiphasic products the FDA requires partial AUCs but only one Cmax (example). That’s different to the EMA, where additionally Cmax-values in each interval are required.

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Helmut Schütz

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