Bioequivalence and Bioavailability Forum

Hi PJS,

❝ The applicant has provided suitable justification for the use of the adjusted confidence interval 96.7 % instead of a confidence limit 90%.

❝

❝ What could be the reason to use 96.7% CI

Smells of Bonferroni’s adjustment for three simultaneous comparisons.

❝ (decreasing the patient risk ??? increasing the faith in product???)

Neither nor. To preserve the patient’s risk at ≤0.05.

   unadjusted (nominal)   adjusted for multipl.
k   α      CI    FWER       α       CI    FWER
1  0.05  90.00  0.0500    0.0500  90.00  0.0500
2  0.05  90.00  0.0975    0.0250  95.00  0.0494
3  0.05  90.00  0.1426    0.0167  96.67  0.0492

k is the number of tests, α the level of the test, CI the confidence interval calculated as 100(1–2α), and FWER the familywise (type I) error rate according to 1–(1–α)^k.
If three tests are performed at 0.05 the FWER might increase to ~14%. With an adjusted level of 0.05/3=0.0166 (96.66% CI) the FWER is preserved at ~4.9%.

❝ and what justification would have been given.

The Bonferroni correction is in general considered the most conservative amongst multiplicity adjustment methods and therefore, requires the least (if any substantial) justification. Might be more demanding to convince regulators about using others (e.g., Šidák. Holm, Hochberg,…).
It is not evident from the PAR why the company used it (BE of a solution vs. an IR formulation).
I’ve applied it when showing BE at one dose level and in the same study assessed dose proportionality of the test. Example:

dose   T  R
 10    ☒  ☐
 20    ☐  ☐
 40    ☒  ☐
 60    ☐  ☐
 80    ☒  ☒

BE of T vs. R at 80mg, dose proportionality of T shown at 10/40/80mg. Biowaivers for 20/60mg.