Bioequivalence and Bioavailability Forum

Hi NK,

The ICH’s M13A will soon supersed the FDA’s guidance. However, a similar procedure is stated in its Section 2.2.3.3 Carry over.

❝ In a BE study of FDC (or drug with two isomers), If any subject had pre-dose > 5 percent of the Cmax for one drug (or one isomer), What should be followed

❝  1.Drop the subject from the statistical analysis of both the drug (or both the isomer) or

❝  2. Drop only for the statistical analysis of a drug (or a isomer) for which the pre-dose observed was > 5 percent of the Cmax and include for other drug (or isomer).

The idea of assessing the predose concentrations in higher period(s) is to check whether the washout was sufficiently long. The treatment comparison in the presence of unequal carryover would – unavoidably – be biased and there is no statistical method to adjust for it. For details see this article.
In a FDC half lives of components are generally different. In a drug with two isomers the half lives are likely different as well. Therefore, #2 because the washout was long enough for the respective other drug / isomer.