Bioequivalence and Bioavailability Forum

Dear vezz,

❝ in a recent study we observed few profiles with no measurable concentrations (i.e., all the concentrations were below the lower limit of quantification). I would like to ask you how these profiles are usually handled in the statistical analysis in your experience.

The EMA guidance states (page 14)
"Exclusion of data cannot be accepted on the basis of statistical analysis or for pharmacokinetic reasons alone, because it is impossible to distinguish the formulation effects from other effects influencing the pharmacokinetics.
The exceptions to this are:
1) A subject with lack of any measurable concentrations or only very low plasma concentrations for reference medicinal product. A subject is considered to have very low plasma concentrations if its AUC is less than 5% of reference medicinal product geometric mean AUC (which should be calculated without inclusion of data from the outlying subject). The exclusion of data due to this reason will only be accepted in exceptional cases and may question the validity of the trial ..."

A little bit curious for me is the underlined sentence. Taken literally it would not allow to exclude such profiles for the Test formulation .

❝ Someone suggested not to calculate the PK parameters (e.g., AUC C_max, etc.) based on these profiles, but to consider these concentrations only in the calculation of the descriptive statistics by time point in order to determine the mean profiles. I wonder if this approach may be reasonable.

The EMA guidance is not specific in respect to this.
I personally would calculate the PK metrics for such profiles as far as possible but drop them in the statistical analysis.
I would drop these profiles also from the mean curves.