So what? [Regulatives / Guidelines]

posted by Helmut Homepage – Vienna, Austria, 2020-06-06 14:02 (1273 d 14:18 ago) – Posting: # 21502
Views: 12,061

Hi Nastia,

❝ Until now I thought that the rule of 80% AUCinf was invented in order to demonstrate that the total duration of sampling is sufficient.

Read the entire thread again. ;-)
I’m referring to the EMA’s guideline. Too lazy to Google-translate the ones in Russian.
The phrase in the EMA’s guideline “The sampling schedule should also cover the plasma concentration time curve long enough to provide a reliable estimate of the extent of exposure…” is nonsense. Why it was invented [sic] is beyond my intellectual reach.

❝ But consider a following case: […]

The tmax is ≤ 1 h and hence, t½,a ≤ 30 minutes. It means that at four hours ≥ 99.6% were already absorbed. That’s what we are interested in. What follows shows that we have a two-compartment model (and possibly additional enterohepatic recycling). Nice to know, but already described by the innovator, right?
Any () AUC after 2–4times tmax is a reliable estimate of the extent of exposure. Full stop.

❝ So I may conclude, although the rule was not followed, the duration of the sampling time was sufficient. In this case the rule may indicate: too large distance between sample time points (48-24=24) that is an error in study planning or too large LLOQ. Am I right in this conclusion?

EMA: “Subjects should not be excluded from the statistical analysis if AUC0–t covers less than 80% of AUC0–∞, but if the percentage is less than 80% in more than 20% of the observations then the validity of the study may need to be discussed.”

OK, discuss it. It’s quite possible that even with an additional sampling point at 36 h (≥ LLOQ) you would have ended with < 80% AUC0–∞ as well. For an IR formulation you could have sampled longer and with AUC0–72 this entire extrapolation business would disappear.
Let’s play the devil’s advocate. IR formulation, drug has a fast distribution and long elimination, the LLOQ is sufficient to measure all samples at the last sampling time t; two studies:
  1. t = 71 h → AUC0–71 (< 80% AUC0–∞ in all cases):
    Problem (why?).
  2. t = 72 h → AUC0–72 (assessment of AUC0–t/AUC0–∞ not required):
    No problem (why not?).

❝ How can regulators interpret this issue?

Can or will? Regulators have the whip hand and therefore, can do whatever they like. If the assessor is a “checkbox-bureaucrat”, cards are stacked against you. If the assessor is a scientist, IMHO, good chances.

Science should always be the basis
of regulatory requirements.

    Joachim Röhmel (former head of biostatistics/BfArM)
    30th Annual Conference of the International Society fo Clinical Biostatistics.
    Prague, August 25th, 2009.

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