Bioequivalence and Bioavailability Forum

Dear Dan!

I agree with your points made about PEs ‘far away’ from unity. But if you expect a large deviation, IMHO the study should be powered for that – and not concealed by ‘overpowering’ for an unrealistic PE. The ‘old’ EU guideline was pretty specific (3.1 Design c):

The number of subjects required is determined by

1. the error variance associated with the primary characteristic to be studied as estimated from a pilot experiment, from previous studies or from published data,
   
2. the significance level desired,
   
3. the expected deviation from the reference product compatible with bioequivalence (∆) and
   
4. the required power.

Unfortunately the current guideline (4.1.3 Subjects / Number of subjects) reduced this section to :

The number of subjects to be included in the study should be based on an appropriate sample size calculation.

❝ There is a certain risk that the regulatory authority could refuse a marketing authorisation because only by overpowering the study became acceptable.

I wouldn’t expect that. BE is solely defined by inclusion of the CI within the acceptance range. I’m only concerned whether regulators might not accept the protocol – that’s where the term ‘forced BE’ has its place.

See also FDA’s guidance, Appendix C (though speaking about PBE and IBE, ∆ ≤5% is suggested):

Sample sizes for average BE should be obtained using published formulas. Sample sizes for population and individual BE should be based on simulated data. The simulations should be conducted using a default situation allowing the two formulations to vary as much as 5% in average BA with equal variances and certain magnitude of subject-by-formulation interaction. The study should have 80 or 90% power to conclude BE between these two formulations. Sample size also depends on the magnitude of variability and the design of the study. Variance estimates to determine the number of subjects for a specific drug can be obtained from the biomedical literature and/or pilot studies.