Bioequivalence and Bioavailability Forum

Dear Ratnakar!

❝ It is not mentioned in the protocol but it has been mentioned in my SOP […]

My suggestion: Always describe ‘critical’ steps in great detail in the protocol – not only in an SOP. The protocol goes through approval (regulatory + IEC), whereas SOPs do not. If an assessor has questions later on, you have much better arguments if the processes are already described.

❝ […] and AUCinf is not a primary parameter as per protocol.

EMA doesn’t even ask for it as secondary. Report the GLSM (±CV) for test and reference only. AUC_(0-∞) is only required to assess the extrapolated AUC. EMA thinks that AUC_(0-t) is ‘the most reliable measure of extent of exposure’ if AUC_(0-t) ≥80% of AUC_(0-∞). Whilst it has been shown that this is not the case (sampling until 2 to 4×t_max is enough), it would be a tough job to convince EMA.

❝ I am asking about exclusion of subject only from AUCinf analysis and not from complete analysis, but guideline also says that “Exclusion of data cannot be accepted on the basis of statistical analysis or for pharmacokinetic reasons alone, because….” in the same section.

IMHO excluding a subject based on a too high residual AUC is neither based on statistics nor on PK, but only to fulfill EMA’s requirement. Personally I have no problem keeping the subject in the study, but truncate his/her AUC in the respective other treatment period as well.

❝ Further regarding the following sentence "This does not apply if the sampling period is 72 h or more and AUC_(0-72h) is used instead of AUC_(0-t)." I am confused about the word ‘..or more..', as in the situation of truncated study upto 72 hrs I can understand but what about the drugs where we have sampling period more than 72 hrs as mnetioned in the GL or drugs with small half life where AUCinf can be obtained before 72 or 96 hrs.

What? Sorry, but I don’t get the point.