Bioequivalence and Bioavailability Forum

Dear Dr. Gunasakaran & Sandeep!

❝ EMA may not accept Reference scaled approach for fully replicate design. But, you can submit Expandable BE limits for the same.

4.1.10 Highly variable drugs or drug products

Those HVDP for which a wider difference in Cmax is considered clinically irrelevant based on a sound clinical justification can be assessed with a widened acceptance range. If this is the case the acceptance criteria for C_max can be widened to a maximum of 69.84 – 143.19%.
The extent of the widening is defined based upon the within-subject variability seen in the bioequivalence study using scaled-average-bioequivalence according to [U, L] = exp [±k·s_WR], where U is the upper limit of the acceptance range, L is the lower limit of the acceptance range, k is the regulatory constant set to 0.760 and s_WR is the within-subject standard deviation of the log-transformed values of C_max of the reference product.
It is acceptable to apply either a 3-period or a 4-period crossover scheme in the replicate design study.

(my emphases)
It’s important to apply EMA’s ‘Method A or B’ stated in the Q&A-document. ‘Method C’ (from FDA’s 2001 guidance) or the currrent one (in the progesterone guidance) are not acceptable.