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What's the problem? [Regulatives / Guidelines]

posted by ElMaestro - Denmark, 2017-05-17 03:30  - Posting: # 17361
Views: 10,698

Hi DM,

» For the sake of curiosity, in your opinion should a regulator approve a generic submited as "highly variable" although all the previous trials reported low CV's? Technically, the criteria are well defined and no objection should be raised in principle. However, should a study that reports an high variation, when all the previous information reports otherwise, be considered scientifically sound for the demonstration of bioequivalence?

The CV we observe is influenced by bioanalytical variability and possibly by factors noone understands well. For example, it has not -to the best of my knowledge- been much studied if certain populations are more within-variable than others. It is in my opinion entirely likely that if we go about studying a drug product in different places we will observe different CV's for some reason or other or by chance, even if we take great care with our experiment.
Of course assessments should reflect the applicant's observations.
Additional factors to consider: With time assays often get better, by and large - a CV obtained from a CRO using the API3000 10 years ago is in my opinion likely to be higher than if it were obatined today with an API6500 due to S:N phenomena (but I am not implying anything about "how much"), all other factors equal.
CV for Cmax (possibly also CV for AUC) may perhaps only be justifiably compared if the time points for blood sampling are the same (they rarely are between studies).

» Ideally, regulators would publish in their product-specific guidelines which compounds could be considered "highly variable"...

They already did that in the general guideline. Those with an observed CV above 30%. Simple as that.:-) But you are right, some degree of common sense is also necessary. If you have 20 reports with a CV of 11% and one with a CV of 41% then you start wondering. A few aberrant subject T/R's can easily inflate a CV, whether they occur by chance or not.

This is the sort of thing that is not covered by much literature and probably won't be for another 20 years?!

if (3) 4

Best regards,
ElMaestro

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