Bioequivalence and Bioavailability Forum

Dear Ohlbe,

❝ When you say that the study failed, do you mean to say that it failed to demonstrate bioequivalence ? Or just that as the bioanalytical results are not reliable you can't use them for PK / stats ? If you performed the stats and the study failed it will become difficult to convince the regulators that you are repeating the study because of a bioanalytical issue unseen before.

The PK/Stats analysis without repeat concentration data showed bioequivalence. The same with repeat concentration data did not prove bioequivalence, failing on lower side of AUC0-t. To investigate, the ISR was performed and majority of samples were not meeting the ISR acceptance limits.

❝ Shit happens. But storage over 55 days in a BE study is already quite long.

Long term stability results were not within acceptance limits and the molecule was found unstable in plasma, which was again confirmed by ISR.

❝ (1): OK, could be, but not my first hypothesis. And you would not see it with your stability QC samples. (2): yes, possible. You're supposed to have temperature records to confirm the storage conditions. (3): unless the problems happened during sample processing (bench top stability, dry extract stability) or added up to the degradation over time during long term storage, no. Stability is a characteristic of the analyte under specific conditions and is independent from the method used.

❝

❝ I would add reason 4: the analyte is not stable for more than 55 days in matrix at that temperature... Solutions: analyse faster; store at lower temperatures; add agents to stabilise.

I agree that the analyte is not stable in plasma. The stabilising agent was either incorrect or insufficient to maintain stability.

❝ I don't think this is a matter of guideline... It also goes back to the first question:

❝ - if you did not run the PK / stats but just stopped the analysis because of the stability issues, the study did not really "fail";

❝ - if you did the PK / stats and the study failed to show BE, and now you say there were stability issues, you can expect questions. Especially if there were no problems in your temperature records, the drug is described as stable in the literature, and you now have 80 days stability data.

The study failed because of bioanlaytical issues - lack of stability and improper stabilising agent. Required temperature was maintained all through. Would you be able to suggest a way forward.

Thank you

Regards
Ram