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

posted by DavidManteigas – Portugal, 2016-10-21 12:44 (3033 d 13:33 ago) – Posting: # 16749
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I'm feeling really dumb in this discussion since I can't figure it out how batch-to-batch variability migth be accounted for in bioequivalence trials in a smart way.

When I was in University studying pharmaceutical development I remember to hear about the Design Space when we talked about quality by design and as far as I remember batch-to-batch variability is expected within the design space. Even the test formulation will have that kind of variability and different batches of test and reference products may, or may not be bioequivalent. However, as far as both formulations keep the amount API within the approved design space (which I believe is defined based on the pk-pd relationship of the specific product) and bioequivalence has been proved by the traditional way, there is no increase in the chance of having more than 5% of bio-inequivalent products in the market. Batch-to-batch variability is "random noise" imo, and I don't see how one might control for it. Using different batches of reference product will increase the variability of the reference product and increase the sample size required for BE studies. Conducting an additional BE study in a different batch of the reference product will increase costs of an industry in which price is the competitive advantage without any significant advantage for patients.

Will we in the near future discuss how one should account for pill-to-pill variability? :-D

I think there are problems in clinical operations that inflate a lot more type I error rather than manufacturing issues. Subject behaviour between periods, subject behaviour during confinement, subject physical activity, the weather...

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