Bioequivalence and Bioavailability Forum

Dear all,

According to the EMA BE guidance “…the decision to exclude a subject from the statistical analysis must be made before bioanalysis”.

We currently discuss the interpretation of “before bioanalysis”, considering two options:

Option 1:
“Before bioanalysis” will be interpreted as “prior to availability of bioanalytical data”
(assuming the processes will guarantee that the clinical and statistical teams and whoever will be involved in the allocation of subjects to analysis sets will not have any access to bioanalytical data prior to fixed and documented decisions on the allocation of subjects to analysis sets).

Option 2:
“Before bioanalysis” will be interpreted as “prior to start of any bioanalytical assessments”.

We wonder whether anybody in this forum can report any negative experiences (which may in worst case include rejections or at delays of regulatory approvals) from applying option 1 rather than the more strict interpretation (option 2).

Please note, that this discussion wants to fully recognize that the allocation of subjects to analysis sets (i.e. the potential exclusion of subjects from the PK set) has to happen at a time point when the clinical and statistical teams (and whoever else may be involved in this process) have not yet seen any bioanalytical data (and would not even have the chance to do so; Option 1 is to be discussed under these requirements only).
I.e., the discussion does not wish to question the need for a high-quality allocation/decision process, at all.

It is just a question about timelines and total study duration (sponsors prefer, of course, not to wait with the start of bioanalytical assessments longer than necessary).
Option 2 means that the start of bioanalysis has to wait more or less until DB lock (clinical data). Option 1 would allow running assays earlier as long as the data and information flow can be clearly separated.

For some compounds the start of bioanalysis cannot wait for technical / analytical reasons (stability etc.) that long as option 2 may request. In those cases only option 1 will be feasible. However, this will not be an issue, anyway, if option 1 is accepted in general.

We can share with this forum that, so far, we are not aware of any negative experiences when applying option 1. However, this does not mean that anybody else might have run into such an experience.

Any feedback / opinion / reporting of negative experiences (if any) is highly appreciated.

Many thanks and best regards,

Dirk Lehnick