Bioequivalence and Bioavailability Forum

Dear Helmut,

This being my first or second post, I didn't post in proper topic, sorry for it. can we now tranfer this message to guidance topic.

now i am having a question for you regarding diarrhea

❝ ❝ ... does any guidelines says that "subject should be excluded from PK/Statistical Analysis if subject had diarrhea (gastro-intestinal disturbance)",...

I just gone through EMEA Question and Answers on BA/BE guidline, Q3 regarding outlier

3. Outliers. When can subjects classified as outliers be excluded from the analysis in bioequivalence studies?
Under 3.6.3 the NfG states that "Post-hoc exclusion of outliers is generally not accepted" but at the same time acknowledges that "the protocol should also specify methods for identifying biologically implausible outliers".
Unbiased assessment of results from randomised studies requires that all subjects are observed and treated according to the same rules that should be independent from treatment or outcome. In consequence, pharmacokinetic data can only be excluded based on non-statistical reasons that have been either defined previously in the protocol or, at the very least, established before reviewing the data.
Acceptable explanations to exclude pharmacokinetic data or to exclude a subject would be protocol violations like vomiting, diarrhoea, analytical failure, etc. The search for such explanations must apply to all subjects in all groups independently of the size of the observed pharmacokinetic parameters or its outlying position. Exclusion of data can never be accepted on the basis of statistical analysis or for pharmacokinetic reasons alone, because it is impossible to distinguish between formulation effects and pharmacokinetic effects.
Exceptional reasons may justify post-hoc data exclusion but this should be considered with utmost care.
In such a case, the applicant must demonstrate that the condition stated to cause the deviation is present in the outlier(s) only and absence of this condition has been investigated using the same criteria for all other subjects.
Results of statistical analyses with and without the group of excluded subjects should be provided.

As per above explanation subject will be excluded from PK/Statistical Analysis if he had diarrhea during the study. If this is the case why can't we exclude subject from continuing in the study if he had diarrhea during study (at time of sampling schedule) instead of making him outlier and exluding post hoc'kly i.e giving unnecessary pain to subject if continued in the study. I think guideline is not clear on this issue.

with regards
Ram mohan