Clin Pharmacol Ther. 2021 Oct 17. doi: 10.1002/cpt.2451. Online ahead of print.
ABSTRACT
The current regulatory criterion for bioequivalence of narrow therapeutic index (NTI) drugs in the European Union requires that the 90% confidence interval for the ratio of the population geometric means of the test product compared to the reference for AUC, and in certain cases Cmax , to be included within the tighter acceptance range of 90.00 – 111.11%. As a consequence, sponsors need to recruit a higher number of subjects to demonstrate bioequivalence and this may be seen as increasing the burden for the development of generics. This “one-size-fits-all” criterion is particularly questionable when the within-subject variability of the reference product is moderate-to-high. As an alternative, we propose a further refined statistical approach where the acceptance range is narrowed based on the within-subject variability of the reference product of the NTI drug, similar to the one used for widening the standard 80.00 – 125.00% acceptance range for highly variable drugs. The 80.00-125.00% acceptance range is narrowed, only if the within-subject variability is lower than 30%, down to the current NTI acceptance range of 90.00 – 111.11% when the within-subject variability is 13.93% or lower. Examples within the current EMA list of NTI drugs show a considerable reduction in required sample size for drugs like Tacrolimus and Colchicine, where the predicted within-subject variability is 20-30%. In these cases, this approach is less sample size demanding without any expected increase in the therapeutic risks, since patients treated with reference products with moderate-to-high within-subject variability are frequently exposed to bioavailability differences larger than 10%.
PMID:34657284 | DOI:10.1002/cpt.2451
