AUC <5% of TEST geometric mean AUC [Outliers]

posted by ElMaestro  – Denmark, 2019-02-13 09:36  – Posting: # 19904
Views: 465

Hi vezz,

» In a bioequivalence study on an orally inhaled product a case of AUC <5% of the geometric mean AUC was found for the test drug. At the time of the data review it was decided to exclude from the statistical analysis the data from this treatment period. Now the EMA is raising some concerns on this approach.
» Of course, we know that the EMA guideline (section 4.1.8) allows for similar exclusions only for the reference product. However, with inhaled products it is not unusual to encounter this kind of issues, often due to a poor inhalation technique of the subject (despite the trainings provided during the study). This situation is very different compared to, say, the intake of a tablet.

I am involved in a lot of inhaled trials. Most of them fail for a variety of reasons, but almost always on the PE not the width of the CI.
When you say your observation is most likely caused by bad technique then you maybe right but you may also be wrong. Most companies provide a lot of training, much more than patients will get when they after approval get their medication at a pharmacy. If they during the trial can't inhale properly then obviously this problem goes a bit beyond training and the subject her/himself.
If the technique is wrong during the actual dosing then it would be OK to have a checkbox on the CRF to note this and then to exclude the subject per protocol. Do that next time, please.

I can't fix the actual issue for you. But please check the Cmax vs the bioanalytical LLOQ. If the ratio is less than 20 then you may be able to exclude either the period or even the whole subject regardless of treatment. there is wording in the EMA guideline for this. It is not all to uncommon to see this done for OIPs and Nasals and it is widely accepted because of the wording of the guideline. Let me know how you fare with this idea.

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Best regards,

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