Bioequivalence and Bioavailability Forum

Dear Joy!

❝ Thanks for your kind and prompt attention.

You’re welcome!

❝ I understand we cannot get a reliable estimate of the CV by using a small sample size i.e. 6 subjects; […]

Not only the CV, but also the point estimate…

❝ […] but using 16 subjects for a pilot BE is analogous to doing a full-scale BE.

Only for CV<18.9%, ±5% deviation from the reference, 80% power
Seriously: as you have stated in your original post, the purpose of a pilot study is not solely statistical, but also to get information on the suitability of the sampling schedule and the appropriateness of the analytical method.

❝ What if the pilot BE using 16 indicates bioequivalence for the test product versus the reference product based on the 90% CI for Cmax and AUC - would this mean a full-scale BE is no longer needed?

No, since – strictly speaking - the purpose of the study was to get estimates of CV and the deviation from the reference, you should not even calculate the CI…
Less strictly speaking, the outcome is a serendipitous result and only descriptive, since the main target was estimating CV and PE – and not demonstration of BE.

Just to stay with yesterday’s example of 15% CV, n=16: 90% CI will be within 0.8-1.25, but you have a study with no sample size estimation, and an undefined target.

OK, now comes the courage of the sponsor in - and the country you are aiming at.
According to current guidelines you have to have information on variability and the expected deviation from the reference in order to perform a proper sample size estimation (otherwise it’s considered unethical to dose subjects with an unclear chance of outcome).
If you are quite sure that clinics/analytics are not in question – and the primary target in the pilot study is a statistical one – you may try to go for an add-on design (though personally I’m not happy with the potentially inflated patients’ risk).
Add-on designs are standard in Canada (since 1992) and Japan (since at least 1997), but are not acceptable according to some other regulations (e.g., USA, Brazil). The European Union lies somewhere in between, deciding on a case-to-case basis (not covered in the guideline), but the general practice is very restrictive.

It’s part of the job of a CRO to explain to sponsors that they must not only look at the budget for BE-studies, but also avoid time-delays in the approval process (which very often easily outweigh additional costs).
If you have a pilot study which ‘demonstrated BE’ this is not a BE study. Full stop.