Bioequivalence and Bioavailability Forum

Hi Loky do,

❝ […] one volunteer showed no measurable concentration of empagliflozin for the test product, although a measurable concentration of metformin was observed in the same individual. […]

❝ We attempted to include this subject in the statistical calculations; however, SAS and WinNonLin automatically excluded the subject due to the missing concentration for empagliflozin, resulting in a passed study.

Of course.

❝ As the CRO, we have raised concerns, viewing the lack of measurable concentration for empagliflozin in the fed state as a potential issue regarding product conformity.

I would be concerned as well.

❝ How can we configure the statistical software to include this subject in the analysis, potentially yielding a failed study outcome?

Actually \(\lim_{x \to 0}\log(x)\small{=-\infty}\) and therefore, if we ask to calculate log(0) we will get -Inf as the – mathematically correct – answer. Nice, though not helpful if we want to use such a value in further calculations. Only by convention we say that \(\log(0)\) is ‘undefined’. There­fore, any \(\small{x\leq0}\) is either excluded in software or throws an error. There is no way to get around it.
You could only perform a sensitivity analysis setting all BQLs to say, LLOQ/2. Unless the study is not very large and the CV very small, quite likely it would fail.

❝ Alternatively, what rationale could we provide in the study documentation to ensure regulatory acceptance of our approach and prevent potential questions for the CRO?.

Well, the fact that you had measurable concentrations of one drug and none of the other in the same subject clearly demonstrates that there was no problem with the administration of the FDC.* You should discuss that in the report. The agency likely would raise questions about content uniformity. But these questions will go to the sponsor. Not your problem.

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• According to the guidelines reanalysis is not acceptable based on PK (only the predose-sample). However, I would do it in order to have an argument in discussions with the sponsor. Otherwise, they will blame you to have screwed up in bioanalytics.