Bioequivalence and Bioavailability Forum

Hi Scopy,

❝ I am trying to get my head around why reanalyzing a blank sample because it had values above LLOQ in the initial analysis is not considered reanalysis for pharmacokinetic reason.

Congratulations for discovering this inconsistency.

❝ My thinking is...if a pre-dose sample gives a detectable peak area on analysis and on evaluation, there seem to be no explanation for this, why is it okay to reanalyze it again?

That’s against scientific thinking. If regulators read this: Sorry to say, no offense intended.

❝ Isn't it not considered reanalysis based on PK?

Actually it is. At least in a drug-naïve subject in the first period it should be zero. See Harold Boxenbaum’s quote in this post. In any higher period we hope that the washout was sufficiently long enough…
If there would be a true unequal carry-over, we have no means to get an unbiased estimate of the treatment effect.

❝ Could it be because the concentration at time t = 0 is not used in calculating AUC?

No. A limited carry-over is acceptable. That means:

• If C₀ ≤5% C_max of a subject in this particular period the concentration is used as it is in the calculation of AUC (the first partial AUC is indeed a trapezoid and not a triangle).
  
• If C₀ >5% C_max the subject (or if in a replicate design, data of this period) can be excluded.

❝ Also please what are the examples of reanalysis that are considered reanalysis due to PK reasons?

According to the current guidelines (EMA 2011, FDA 2018, ICH draft 2019) it is no more acceptable. IMHO, bad science. See the two case studies in this presentation (slides 22–35). The first one was an obvious sample mix-up in the clincal phase and the second one likely an – undocumented – problem in sample handling. However, in both cases samples were reanalyzed (good scientific practice = ignoring the GL) and results confirmed. That reveals a common problem: In most cases errors occur in the clinical phase and not in bioanalytics. Now what?
In the past it was acceptable to perform a blinded review of data and have rules for reanalysis / exclusion in the protocol. Regrettably, those days are gone and – understandable – paranoia (driven by the many cases of fraud) prevails.
Nowadays reanalysis is only acceptable for the obvious reasons: Concentration >ULOQ, batch not valid, poor chromatography* (e.g., interference, degraded column), malfunctioning equipment, forgotten to add IS or derivatization reagent, etc.

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• Funny term. What is ‘rich chromatography’?