Bioequivalence and Bioavailability Forum

Dear Shireen,

❝ Question # 2

❝ Doesn't the above mentioned case indicate a problem in the method, or in the analysis of that specific drug itself?

If the interference is more than 5 % of Cmax, and less than LLOQ, it means that your LLOQ is more than 5 % of Cmax. Isn't this a first problem ? Will you be able to follow your concentrations long enough ?

You will be in trouble in future if this sentence in the draft revision of the EU guideline remains as such in the final version:
If there are any subjects for whom the pre-dose concentration is greater than 5 percent of the Cmax value for the subject in that period, the statistical analysis should be repeated with those subjects excluded. Results from both analyses should be presented, but the analysis with the subjects excluded should be considered as primary.

The text uses the word "concentration", not "signal", or "interference". Which means that you need to calculate a concentration. Meaning that it should be higher than LLOQ ! Which means in turn that your LLOQ should not be higher than 5 % of Cmax.

❝ "Any interference less that the LLOQ detected in the zero standard sample of the volunteers should not be repeated even if is more than the 5% of the Cmax of the phase, since the value obtained is not accurate and precise":

You may still wish to repeat these samples to check whether you still have a signal, and that it is not due simply to a contamination or carry-over. This may be part of your investigations to try and understand why you have these pre-dose concentrations higher than 5 % of Cmax (especially if you have them in the first period !).

Regards
Ohlbe