Evaluation of a Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European Union

Publication: Pharmaceutics


Bioequivalence (BE) of products containing narrow therapeutic index (NTI) drugs in theEuropean Union is currently established by demonstrating that the 90% confidence interval for theratio of the population geometric means of the test compared to the reference product’s AUC, and incertain cases Cmax, is included within the tighter acceptance range of 90.00–111.11%. An alternativecriterion, consisting of narrowed limits based on the within-subject variability of the reference product,was recently proposed. Its performance for a three-period partial replicate design was tested bysimulation in terms of power to show BE, type I error (T1E) and sample size requirements. A newcondition, a constraint on the test-to-reference geometric mean ratio (cGMR) to be contained withinthe range of 90.00–111.11%, was also tested. The probability of showing BE when the productsdiffer more than 10% was increased, but only if the reference product’s within-subject variability wasmoderate-to-high. The inclusion of the additional cGMR limited this. An increase in the T1E (<7%)was observed. The inclusion of the additional cGMR did not change the highest inflation of the T1E.Finally, a significant sample size reduction was observed and the inclusion of the cGMR usually didnot increase the required sample size.

By Paulo Paixão , Nuno Silva, Rita Bento Guerreiro, Kevin Blake, Milton Bonelli, José Augusto Guimarães Morais, Alfredo García-Arieta and Luís Filipe Gouveia