Monte Carlo simulations were performed to examine all possible relationships between the tested products. Four types of percent BE acceptances are defined and evaluated: (a) % BA1, when generic T1 is compared to the R product, (b) % BA2, in cases of comparison of generic T2 with the R product, (c) % BA21, when generic T2 is compared to another generic T1, and finally (d) % BA21C which is the conditional probability of percent bioequivalence acceptance of generic T2versus another generic T1 given that both T1 and T2 are declared bioequivalent to the same R formulation. The simulations were expanded to study concomitantly the performance of T1 and T2 when compared to the same R formulation. In each case, the 2 ¡Á 2 cross-over design was used and evaluation of BE was based on the classic BE limits (0.80-1.25) and the stricter BE limits (0.90-1.11) for narrow therapeutic index (NTI) drugs. A number of 24 and 48 subjects were assumed to participate in the simulated trials, while the coefficient of variation for the within-subject variability (CVw) was 20 % and 40 % . A number 40,000 BE trials were simulated under each condition. The T1/R and T2/R ratios ranged from 0.80 to 1.25 using a step of 0.05.
Even though two generics (T1 and T2) can be declared bioequivalent to the same R product, this does not ensure that they are always mutually bioequivalent. On the contrary, two generic products which differ substantially from the R product can still have a high probability to be truly interchangeable. The two generics (T1 and T2) can be switched from one to another when the T1/R and T2/R ratios are close to the same value, the CVw of the drug is low, and each BE study of T1-R and T2-R was conducted using a relatively large number of subjects. In the same context, two generic NTI drugs which differ more than 10 % from the R product can still be declared bioequivalent to one another depending on the relative T1/R and T2/R ratios. Switchability between generics assessed at the 0.90-1.11 interval is safer, but not always ensured.