Bioequivalence and Bioavailability Forum

Dear Nathan,

I agree a number of things you wrote in your blog post, but not all. Most comments on this forum were in connection with bioequivalence trials. There, I agree with statements such as "Because PK is the primary endpoint, the blood draws for PK samples should take priority over all other activities and should occur on the scheduled time point before any other procedure". In a BE trial I couldn't care less if "when PK blood sampling is given priority, it can negatively affect other assessments such as vital signs, ECG measurements, and behavioral measures", unless there are PD parameters to be measured too. I prefer to see the blood sample collected at the correct time and vitals delayed by a few minutes, than the reverse.

❝ I still posit that it does not matter. As an example, if your sampling times are 0.5, 1, and 1.5 hours. The sample at 1 hour can be taken at 0.75, 1, or 1.25 hrs and still give reasonable results.

Sounds reasonable in a BA trial with PK modelling. But the PK analysis in BE trials is Mickey Mouse PK: model independent, and most people use the linear trapezoidal rule to calculate AUC (which makes Helmut regularly scream). The difference in AUC usually remains minimal, but you may miss Cmax.

Lastly, deviations in the sampling time in the last collected sample will affect AUC_0-t, which is one of the primary BE parameters. Unless of course you use an estimated Clast at the nominal sampling point.

I remain of the opinion that blood samples should be collected as close as possible to the nominal sampling time. Whether sampling time deviations should be recorded as protocol deviations, and the amount of associated paperwork, remains another discussion. Some people indeed overdo it.