Bioequivalence and Bioavailability Forum

Hi ElMaestro!

❝ A BE study generally has three possible outcomes: Bioeequivalent, bioinequivalent (CI entirely outside acceptance range) or inconclusive (overlap with the acceptance range, meaning not proven bioinequivalent and not proven bioequivalent).

Statistically speaking there are just two outcomes. The Null is bioinequivalence, which is either rejected (consumer risk with a probability of α) or not. The “grey zone” is related to the producer’s risk (with a probability of 1–β), which is important in study planning. Post hoc we get only this ‘bad luck’ feeling (in German: dumm gelaufen).

❝ If I were the FDA and had the funds I would certainly run a new study with more subjects in order to reach a firm conclusion.

Given the safety profile of budeprion I wouldn’t do that (at least not in healthy subjects as the FDA did in their study). For the sample size see below. I’m wondering why the FDA asked Teva to run a study in patients who showed safety/efficacy problems after switching from Wellbutrin XL 300 mg. It should have been foreseeable that they will run into massive recruitment problems. Why didn’t the FDA ask for a simple BE study in patients already back in 2007?

❝ […] how to calculate the sample size when the previous T/R was lower than 80% is an issue, but let's not go there.

Of course conventional sample size estimation will not work. Maybe Detlew can consider adding sampleN.inf() to PowerTOST. But leaving power aside and assuming that we can exactly reproduce the ratio (75.2%) and CV (29.8%) of C_max it would need 227 (!) subjects in order to squeeze the upper CL below 80% (Null not rejected, bioinequivalent).

❝ Bioinequivalence hasn't been shown until the CI is entirely out of the acceptance range, and […] they also do not use wording suggesting that the products are truly inequivalent. In stead they just correctly suggest that BE has not been shown.

Yep.

❝ Another case of 'aggregate weight of evidence', I imagine.

Makes sense since already in 2007 they had 85 supportive cases of therapeutic inequivalence (though anecdotal). Likely much more as of now.