Bioequivalence and Bioavailability Forum

Dear Ratnakar!

❝ From where to take the median Tmax?

You hit the critical point!

❝ Is it from the same study (i.e. after considering the subject who had emesis during the clinical phase PK and stat to be conducted and then based on the result his inclusion to be decided) or from the published literature? If it is from the same study we will have to continue the subject in the clinical phase which may be unethical if we are sure that this subject is definitely will fall in the said window (i.e. 2 times median Tmax) and if from the published literature then chances of getting different median Tmax value is also more.

The label of the RLD rarely states the median (quite often it's still the arithmetic mean). Furthermore the value depends on the sampling schedule.
I always interpreted 'median T_max of the reference' as a study-specific value, as mentioned in the http://www.fda.gov/cder/guidance/5356fnl.pdf guideline (Section III.A.8.a.) in the context of early exposure:

'[…] In this setting, the guidance recommends use of partial AUC as an early exposure measure. We recommend that the partial area be truncated at the population median of Tmax values for the reference formulation. We also recommend that at least two quantifiable samples be collected before the expected peak time to allow adequate estimation of the partial area.'

See also this comment of August 2002 from the GPhA on the draft version of the guideline and Canada's Notice to Industry for rapid onset drugs (June 2005).

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Edit: FDA-link corrected to latest archived copy. [Helmut]