Bioequivalence and Bioavailability Forum

Dear All

Good morning

A few days back, have done a pilot BE study for a combination product of BCS class I (tmax range: 6-12 hrs) and II molecule (Tmax: 2-4 hrs).

After plasma sample analysis we have observed that a certain volunteer showed no measurable plasma conc. for both the components of the combination product following administration of the TEST formulation in Period II

The plasma profile shows that

1. Plasma concentration of molecule I is zero (All values below LLOQ)
   
2. concentration of molecule II is 1 % of the geomean (of reference and test)

It clearly indicates that the volunteer has splitted the tablet out after administration and as usual CRO came with a justification that There are no clinical or bio-analytical anomalies associated

Luckily this was a pilot BE study and the results excluding the volunteer was very nice (Mean T/R ratios 98-102 and CI limits 88-115) but data including volunteer for molecule II is disastrous (T/R=80% CI- 44-133 with ISCV 100%)

This gives us another lesson about the importance of the BE study monitoring and we would be more cautious for the Pivotal BE study.

As per EMEA, 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: 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 ay question the validity of the trial.

Now coming to the queries

1. What to do if we ran in the same situation again in Pivotal study (Zero concentration or AUC <5% for test product)? EMEA agrees for removing volunteers which show lack of any measurable concentrations or only very low plasma concentrations for reference medicinal product only. What about test product data?
   
2. What could be the other reasons of getting zero concentration?