Bioequivalence and Bioavailability Forum

Dear all,

recently I saw a response to a request of one of my clients concerning reference-scaling:

“In consideration of your request, we clarify that the Anvisa has accepted the use of the statistical method for scaling proposed by the European Agency (EMA, 2010), with the exception that for An­­visa scaling can only be applied […] in the cases that the intra-subject coefficient of variation (CV%) exceeds 40% for the originator product.
Please be advised, however, that the clinical protocol must be previously submitted to the tech­ni­cal evaluation of Therapeutic Equivalence Coordination (Anvisa) before conducting the bio­equi­va­lence study that you want to consider the scaling.”

Interesting. As usual the devil is in the details. IMHO, two interpretations are possible.

1. Use EMA’s regulatory constant k 0.760 which is derived from the regulatory standard deviation σ₀ based on the switching condition CV_WR of 30%:
   σ₀ = √ln(0.30²+1) = 0.2936
   k = ln(1.25)/σ₀ ≈ 0.760
   Scale according to EMA’s formula [L, U] = ℯ^±k·s_WR but apply widening of the acceptance range only if CV_WR >40%. This would lead to a discontinuity (similar to FDA’s “implied BE limits” based on a switch­ing condition of ~25.4% [σ₀ 0.25] applied at ≥30%):
   CVWR      AR (%)
0.20  80.00 125.00
0.25  80.00 125.00
0.30  80.00 125.00
0.35  80.00 125.00
0.40  80.00 125.00
0.45  72.15 138.59
0.50  69.84 143.19
0.55  69.84 143.19
0.60  69.84 143.19
   
   
2. If ANVISA wants 40% as the switching condition that would translate into σ₀ 0.3853 and k 0.579. No discontinuity but very little gain in terms of the acceptance range:
   CVWR      AR (%)
0.20  80.00 125.00
0.25  80.00 125.00
0.30  80.00 125.00
0.35  80.00 125.00
0.40  80.00 125.00
0.45  77.99 128.23
0.50  76.07 131.46
0.55  76.07 131.46
0.60  76.07 131.46
   

Any experiences from our members? In any case, the sample size estimation will be challenging…