Bioequivalence and Bioavailability Forum

So what? [Regulatives / Guidelines]

posted by Helmut  – Vienna, Austria, 2020-06-06 14:02 (1689 d 20:24 ago) – Posting: # 21502
Views: 18,075

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.

• We are interested in comparing the in vivo characteristics (ƒ, k_a, t_lag) to detect potential biopharmaceutical differences of formulations. Differences in ƒ are reflected in AUC and all three* in C_max.
  
• However, what happens once absorption is complete, is a property of the drug and hence, not relevant in BE (we are assuming identical clearances). Therefore, the FDA does not have such a bizarre “AUC_0–t ≥ 80% AUC_0–∞ rule”.

❝ But consider a following case: […]

The t_max is ≤ 1 h and hence, t_½,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 t_max 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 AUC_0–t covers less than 80% of AUC_0–∞, 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% AUC_0–∞ as well. For an IR formulation you could have sampled longer and with AUC_0–72 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 → AUC_0–71 (< 80% AUC_0–∞ in all cases):
   Problem (why?).
   
2. t = 72 h → AUC_0–72 (assessment of AUC_0–t/AUC_0–∞ 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)
    30^th Annual Conference of the International Society fo Clinical Biostatistics.
    Prague, August 25^th, 2009.

---

• C_max is a composite metric (influenced by k_el) and hence, does not unbiased represent the absorption characteristics (k_a, t_lag). C_max/AUC would be a better metric. Lots of publications, ignored in guidelines.

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! 
Helmut Schütz


The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes

Complete thread:

• AUCt not covering at least 80% of AUCinf ratnakar1811 2013-03-05 08:30 [Regulatives / Guidelines] 
  • AUCt not covering at least 80% of AUCinf d_labes 2013-03-05 11:12
    • AUCt not covering at least 80% of AUCinf ratnakar1811 2013-03-06 08:50
      • AUCt not covering at least 80% of AUCinf ElMaestro 2013-03-06 11:10
        • ADME-tox? Helmut 2013-03-06 14:35
          • ADME-tox? ElMaestro 2013-03-06 16:40
            • OT Helmut 2013-03-06 17:19
              • OT ElMaestro 2013-03-07 17:19
                • OT Helmut 2013-03-07 17:26
      • Science vs. regulations Helmut 2013-03-06 14:30
        • Science vs. regulations cakhatri 2013-03-10 08:59
          • ratio = difference of logs! Helmut 2013-03-11 01:17
        • Science vs. (EMA) GL aka PK primer Helmut 2013-03-11 03:17
        • Science vs. regulations qualityassurance 2020-04-23 14:11
          • Science vs. regulations Helmut 2020-04-23 17:32
            • Science vs. regulations Achievwin 2020-05-07 22:59
              • Science vs. regulations Helmut 2020-05-07 23:54
      • AUCt not covering at least 80% of AUCinf Brus 2018-11-20 13:01
        • AUCt not covering at least 80% of AUCinf Astea 2020-06-05 19:05
          • So what?Helmut 2020-06-06 12:02
            • Carrot and whip Astea 2020-06-06 21:11
              • Gedanken­experi­ment Helmut 2020-06-07 12:41
                • Dead dogs mittyri 2020-06-07 20:32
                  • Aber meine Herren das ist keine physik Astea 2020-06-08 00:08
                    • Aber meine Dame, das ist alles Unsinn! Helmut 2020-06-08 01:04
                    • Bizarre paper Helmut 2020-06-08 12:43
                      • Bizarre paper ElMaestro 2020-06-08 15:33
                        • OT: Bias of AUCt, AUCall, pAUC Helmut 2020-06-08 15:53
                          • OT: Bias of AUCt, AUCall, pAUC ElMaestro 2020-06-09 08:45
                            • OT: Bias of AUCs; example Helmut 2020-06-09 14:07
                      • Maxwell's demon Astea 2020-06-12 14:15
                  • Dead dogs Helmut 2020-06-08 10:40