Bioequivalence and Bioavailability Forum

Hi Mittyri,

❝ some time ago I was pleased to be invited on the session with Roger Jelliffe.

Congratulations! Roger is a guy of strong opinions.
When David Bourne’s PK/PD-List was still active, Roger regularly ranted about the LLOQ (examples). In PK modeling nobody simply ignores BLOQs. We still have no method dealing with “BQLs” in NCA (Martin ).
Essentially Roger is absolutely right (speaking also from my background in analytical chemistry).

BTW, on a similar note the best weighting scheme in calibration is 1/s² – and not 1/x, 1/x², 1/y, 1/y². They are all arbitrary and lack any justification. OK, in between those lines of the EMA’s BMV guideline …

A relationship which can simply and adequately describe the response of the instrument with regard to the concentration of analyte should be applied.

… it seems that it is recommended not only to assess calibration functions themselves (chromatography: linear, quadratic, …; LBA: 4-, 5-parameter logistic, …) but also different weighting schemes (based on the back-calculated concentrations’ accuracy & precision). Rarely done.
Of course, 1/s² requires at least duplicates (even after rejecting a measurement). In our lab we had this procedure: Validate the method with 1/s² and also the weighting scheme which gave the 2^nd best outcome. Sometimes sponsors didn’t like triplicate standards (money, money). Then – if we ended up with a singlet – we switched to the other weighting scheme. Regulators didn’t like that (“subjects are not treated equally”).

❝ My question is are there any steps forward in that direction?

I strongly doubt it.

❝ Even in analytical methodology (say QC samples): isn't possible to handle that values (as they are) for example for the mean evaluation for some level of QC sample?

Not sure what you mean here.