Bioequivalence and Bioavailability Forum

Dear Dan!

❝ an assessor realized that the number of AEs differ between the treatment groups and he/she concluded that the tolerability of one product is worse than the other.

Oh no. I got the same question once – many, many years ago.

❝ I would reply that bioavailability in terms of peak and total exposure is taken as a surrogate parameter for efficacy and safety and I would point out that bioequivalence studies are not designed to investigate the safety profile in terms of AEs of one formulation in comparison to another.

Correct.

❝ Due to the small numbers of subjects and small number of AEs any differences become significant but statistically not relevant.

❝ Is this correct or do you have other suggestions?

First I would not accept the idea to simply compare the number of AEs. IMHO only a comparison of ADRs (relationship to IMP rated certainly or probably/likely) makes sense. Or would you include headache, which is known to occur in up to 30 % of subjects due to the setting of the study (less sleep, no breakfast until four hours, no coffee, ). Furthermore I would not pool ADRs (apples with oranges), but evaluate them separately. If done that way I would expect differences between treatments to diminish. Only if you still get significant differences, I would continue with your argument.