Bioequivalence and Bioavailability Forum

Dear Kotu,

❝ ... suppose i got cv 32.5 and t/r ratio is 97%. how to decided the sample size for further study.

Since the sample size tables do not contain your values I would go with a conservative approach and use CV=35% and GMR=0.95. That would give N=
    3-period  4-period
EMA   29       20
FDA   24       18
if your desired power is 80% according to the tables in the paper.
If you are not satisfied with this approach interpolate in the tables.

❝ What approach Canada Regulatory follows?

Did you had a look into the Guidance documents the Forum's Admin has collected gratifyingly for You and all of us ?

AFAIK the current in effect guidance doesn't contain scaled ABE.
But there is no Acceptance range for the CI of Cmax in the guidance. Only the point estimator (GMR of T/R) has to be in the range 80% - 125%.

The Draft Guidance Document "Comparative Bioavailability Standards: Formulations used for Systemic Effects" states:
"7. Drugs with highly variable pharmacokinetics:
For the purpose of bioequivalence testing, there is no compelling need for a distinct category of "highly variable" drugs, given that there is sufficient permitted flexibility in study design to address exceptional cases.
Notwithstanding the potential need for relatively large numbers of subjects in some bioequivalence studies, the current requirements do not present an unreasonable barrier to product approval.
Furthermore, the ethical concern surrounding the exposure of a relatively large number of healthy subjects to study drugs does not outweigh the potential risk of exposing the patient population to a bio-inequivalent drug."
(emphasis by me)
Thus it seems scaled ABE will not be an issue for the Canadians also in the future.

You have to plan your study based on AUC as usual for conventional ABE, given your pilot estimate of the GMR for Cmax is within 80-125%, regardless of whichever design you use.