Type I error inflation caused by batch-to-batch variability of Reference? [Design Issues]

posted by Dr_Dan  – Germany, 2016-10-20 14:06 (3032 d 19:01 ago) – Posting: # 16739
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Hi
If a RLD shows such a high in-vivo batch-to-batch variability, why should this be the problem of the generic industry?

From a regulatory point of view I would say that a batch-to-batch variability which leads to bio-in-equivalence of batches of the same product is a serious risk to public health and the product should not be approvable (how can you transfer the safety and efficacy results gained with clinical batches to marketed batches/product?). IMHO the originator should be obliged to change the product specification and demonstrate bioequivalence within his formulation.

However, if such a RLD is notwithstanding approvable then high batch-to-batch variability should not matter, right? Otherwise the logic consequence would be
alternative 1: that generics need to show bioequivalence to each originator batch, or
alternative 2: do not need to show bioequivalence at all.

In the 2015 Meeting Report entitled “Pharmacokinetics of Orally Inhaled Drug Products” a recommendation seemingly attributed to an FDA speaker states “To include batch-to-batch and intra-subject variability of the reference product, the comparison of one batch of the test product with two batches of the R product, with one R batch being repeated, was suggested.”

hmmm, if the two R products are not bioequivalent, what would be the advantage of such a design?

I guess this will lead to interesting discussions....

Kind regards and have a nice day
Dr_Dan

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