Bioequivalence and Bioavailability Forum

Hi Anbu,

❝ A subject had vomited within the 2 times of tmax period, as per pk person discussion, he continued and completed the study.

Always nice to have a discussion but what did the protocol state?

❝ After bioanalysis of the sample again pk persons, taking decision to withdraw a subject. does this procedure is fine?

No, it doesn’t look fine at all – even if the protocol would have stated sumfink like

“if a subject vomited within 2times median t_max of the reference product he will be excluded from comparative assessments based on the judgment of the pharmacokineticists”.

Not a good idea. It would be unacceptable after calculating the PE and CI – smells fishy / cherry-picking. Still doubtful if done before by “eye-ball PK” (i.e., looking at the profiles). 
You had two discussions. In the first one the pharmacokineticists concluded that vomiting would not matter. In the second one he revised his opinion. Now what?

Maybe you are interested in this recent guidance of the FDA. Under major BE deficiencies you will find:

• Inadequate or insufficient in vivo studies […] requiring submission of new studies. Examples include […] exclusion of study outliers […] and other PK […] issues.
  
• Insufficient justification for protocol deviations, such as inclusion or exclusion of subjects.

The EMA’s BE-GL is more specific:

In principle any reason for exclusion is valid provided it is specified in the protocol and the decision to exclude is made before bioanalysis.
Examples of reasons to exclude the results from a subject in a particular period are events such as vomiting and diarrhoea which could render the plasma concentration-time profile unreliable.
The permitted reasons for exclusion must be pre-specified in the protocol.
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.

I suggest that you perform two analyses:

1. All subjects (confirmatory).
   
2. Excluding the subject as a sensitivity analysis.

If both pass BE, #2 is supportive. If not (e.g., #1 fails and #2 passes), IMHO, cards are stacked against you.
Next time state the reasons for exclusion – before bioanalysis – in the protocol as suggested by the EMA.