Bioequivalence and Bioavailability Forum

Hi all,


I am reading all this with great interest, but also with a bit of apprehension.

Regulators have over the years received so much garbage from CROs and companies that they have to set some rules to protect the patients. More generally, I am firmly in the camp of people who think it is absolutely necessary to restrict and regulate an applicant's ability to change reported values, simply because history has shown that certain industrial players can't handle such a privilege in a way that is favorable to patients.

It sends shivers down my spine when I hear those "what if"-type of arguments (hypothetical case studies), which are from the outset designed to refute an idea, good or bad. Show me any solution to any problem in the field of BE and I can probably conjure up some kind of hypothetical example which purportedly shows that the solution is bad. I dare you, come on do it!
But, and here is the absolutely salient point, my refutation that shows that the solution is bad might not apply generally.

Perspective: "Linear up, linear down" vs "linear up, log down" in NCA. If someone wants to convince me that "linear up, linear down" is disadvantageous then the approach will be to show me that T/R is biased when using it. The argument is not won by showing me a profile and explaining that the area is upward biased or whatever (an upward bias, or a downward one for that matter, does not necessarily affect T/R unless it affects T and R unequally. It is the latter point that is the deal-breaker).

So let's get real, and let's get general:
I think that patients are well protected if CROs apply healthy rules equally to T and R because then T/R is not expected to be biased. CROs can be trusted to do so, if the rules are defined a priori. Ideally if they are applied blindedly. I will make a point out of saying that I think there is difference between recording and reporting. I think scenarios exist in which a re-analysis is a potentially useful tool as part of an investigation (they are rare, though), but that should not necessarily affect the reported value. A PK-value for reporting should only be changed if there is proof that the original value is tainted. The proof is not by itself just that the value looks odd.
I have some degree of sympathy for people who say that investigations almost never give rise to identification of errors, they are for display only. For the same reason I see why some high-quality labs by principle simply do not do re-analyses as part of an investigation. They invest in doing the analysis well from the outset in stead.

Got a weird value, no root cause, and no SOP or healthy rule for re-analysis? Well, it simple then. Report the value, submit the dossier, and let the regulator decide what is fair in that situation. In the meantime, spending the energy on writing an SOP and helping colleagues perform in the lab so that their work does not produce funky values in the future, those are are good investments.