Bioequivalence and Bioavailability Forum

Hi David,

you raised good points!

❝ Batch-to-batch variability is "random noise" imo, …

Yep. At least the EMA’s BE-GL specifically asks for products which are “similar” in their measured content (Δ ≤5%). Of course – due to inaccuracy/imprecision of the analytical method – even “suitable” batches might have a larger true difference. However, this will not affect the Type I Error – only increases the producer’s risk; Type II Error).

Is the risk for a patient to switch from Reference to Test substantially larger than between different batches of the reference (which happens all the time)? Duno. Educated guess: No.*
We must not forget that batch-to-batch variability (if theoretically tested in BE studies powered at 80%) will lead to failure in ¹/₅ of studies. And: Failure to demonstrate BE does not imply inequivalence.
IIRC, at the BioInternational ’94 (Munich) Les Benet suggested small (n=6) BE-studies evaluated by Bayesian methods for batch-release. Was not further considered due to the shouts of innovators.

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• Davit BM, Nwakama PE, Buehler GJ, Conner DP, Haidar SH, Patel DT, Yang Y, Yu LX, Woodcock J. Comparing Generic and Innovator Drugs: A Review of 12 Years of Bioequivalence Data from the United States Food and Drug Administration. Ann Pharmacother. 2009; 43(10): 1583-97. doi:10.1345/aph.1M141.