Bioequivalence and Bioavailability Forum

Hello Smitha,

❝ 1. Sometimes, the last quantifiable concentration is higher than the preceding concentration in the elimination phase.

❝ a. What would be the impact of such a profile?

❝ b. Are there any regulatory requirements on how these need to be handled?

❝ c. If the guideline or the CRO SOP does not address this issue, is it acceptable to accept

❝ the data as is? Does it need to be addressed in an SOP/protocol?

There is no specific guidance on such matters. It is quite common see what you are observing here. I come across it reasonably often with inhalation and nasal products.
It is always a good idea to have an SOP, but what to put in that SOP is of course tricky. Unless you have a reason to distrust the point (a better reason than PK-expectation alone) then you will need to just work with the value you have. It may cause you to estimate a negative t½, and again, that is just how it is, however unlikely it otherwise that the body starts synthesizing an exogenous molecule.
If you have an SOP stating that in such cases you will do an investigation then you demonstrate ability to reflect and react objectively. Search the forum for aspects like reanalysis as part of the investigation and the difference between recording and reporting in the absence of a cause. It is a mine field and you need to decide whether you want to take guidelines literally or apply some degree of common sense with all the danger that entails

❝ 2. For a BE study, a window period is given for the sampling time points and usually most CROs use the scheduled time point if the sampling deviation is within the window period to plot the concentration-time graphs. The actual sampling time point is used in the graphs only if the sampling is outside the window period.

❝

❝ a. If the actual time-point is used even if the sampling deviation is within the window

❝ period, is it appropriate? Is there an impact on the PK data e.g AUC?

I think it is common to use the nominal point for both plotting and AUC-calculation when the sample is inside the window (note: not all CROs apply windows). Otherwise use actual time for both.

❝ b. Are there any regulatory requirements on how these need to be handled?

No guidance has that level of granularity, as far as I know.