Bioequivalence and Bioavailability Forum

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

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.