Equivalence analyses of dissolution profiles with the Mahalanobis distance.

Abstract

For some postapproval changes, the manufacturer has to demonstrate that the dissolution profile of the drug product before the change is statistically equivalent to the dissolution profile after the change. Guidelines suggest the so-called similarity factor f2 as standard approach for the equivalence analysis. f2 is a statistically questionable transformation of the Euclidean distance between both profile means and does not allow a control of the type I error rate. An alternative multivariate distance measure for quantifying the dissimilarity between both profile groups is the Mahalanobis distance. Current equivalence procedures based on the Mahalanobis distance implicate some practical problems in the dissolution context: either one chooses an exact method but the determination of a product independent equivalence margin will not be practically feasible or one chooses an approximate alternative that suffers from the bias of the Mahalanobis distance point estimate. This paper suggests the T2EQ approach for dissolution profile comparisons. T2EQ is a practically feasible equivalence procedure based on the Mahalanobis distance with an internal equivalence margin for comparing dissolution profiles. The equivalence margin is compliant with current dissolution guidelines. The operating characteristics (size, robustness, and power) are investigated via simulation: T2EQ meets the needs of both authorities and industry: not affected by the bias of the point estimate the type I error rate can be reliably controlled for various distribution assumptions and the power of T2EQ exceeds the power of methods recently discussed in the literature. These results were presented for the first time at CEN-ISBS 2017.