Bioequivalence and Bioavailability Forum

Dear Charl & Ohlbe,

❝ ❝ what is the minimum re-analysis points is accepted to demonstrate reproducibility from the whole incurred samples?

❝ That's a question FDA refused to answer, leaving it to your best scientific jugement... They didn't say exactly what they want, how they want it to be presented and how they will interpret it

Wonderful. The entire Section sounds like some kind of Voodoo to me; I’m not getting the point(s).

‘It is generally accepted that the chance of incurred sample variability is greater in humans than in animals, …’

Why the h... do they claim that the ’chance of incurred sample variability is greater in humans than in animals’?
I don’t think that this is

1. ‘generally accepted’, and
2. true at all (personally I would expect just the opposite).

The most disturbing fact is the open system like:
‘The final decision as to the extent and nature of the incurred sample testing is left to the analytical investigator, and should be based on an in-depth understanding of the method, the behavior of the drug, metabolites, and any concomitant medications in the matrices of interest…’

Even if ‘based on an in-depth understanding’ anything we plan will be entirely exploratory. We cannot set any specifications, because before having analysed our biosamples, we simply don’t know anything about the outcome. This may be acceptable for First-In-Man studies (which are exploratory in nature anyway), but will be considered poor taste in any pivotal trial.

‘It is recognized that accuracy of the result generated from incurred samples can be more difficult to assess.’
IMHO it’s not possible at all, as far as only re-analyis is considered. Or should we arbitrarily set the first result to 100% and report ±x% for the second result? The ‘true’ concentration of an unknown sample is (by definition) always unknown. We assign a concentration to a sample, nothing more. Therefore talking about accuracy is simply nonsense (unless we start dealing with standard additions).

‘First-in-human, proof-of-concept in patients, special population, and bioequivalence studies are examples of studies that should be considered for incurred-sample concentration verification.’
Here we are. FIM – OK, POC – why not, but BE?!
Everybody is measuring subject's test/reference samples in a cross-over manner in the same analytical batch – so what? Even if day-to-day precision of incurred samples is lousy, it does not influence the assessment of BE (maybe FDA’s agents should have sneaked across their border).