Bioequivalence and Bioavailability Forum

Hi Aymanmy,

❝ my concern is the study is already submitted by the sponsor to the H.A, and the study results are known, also the samples are out of studied long term stability, can we just exclude the results of the affected subjects from the statistics?

Yes, that’s Dan’s sensitivity analysis. If it fails to show BE, expect uncomfortable discussions with the sponsor. If the study passes BE, it is up to the agency to accept the outcome – or not. There’s no guarantee.

❝ and plz to confirm that every individual subject should fulfil the less than 5% of Cmax criteria for the future?

It is not necessary that all subjects pass. The rule is simple:

• If the pre-dose concentration is ≤ 5% of the subject’s C_max, keep the subject in the analysis.
  
• If the pre-dose concentration is > 5% of the subject’s C_max, exclude the subject from the analysis.

But in order to make this assessment your method must be sensitive enough for all subjects (LLOQ = 5% of lowest observed C_max).

However, we don’t have a crystal ball. Sometimes our assumption is wrong. For such a case state in the protocol that you will exclude the subject anyhow. With any exclusion you will loose power. You don’t want to end up with a lot of excluded subjects. My personal rule of thumb: Up to 10–15% are OK, then it will start to hurt.
If possible improve the method / revalidate it instead (like Mittyri suggested). If you succeeed, the best approach.