## Carrot and whip [Regulatives / Guidelines]

Dear Helmut! I'm grateful for your reply!

Ok, my HW was not perfect No I reread it. Still don't understand what to argue to the assessors...

By the way, there is a typo in f' (the graph is correct), first term should be with minus:

Do not bother yourself, EAEC experts had already translated it: "Количество отобранных образцов также должно быть достаточным, чтобы обеспечить надежную оценку длительности экспозиции. Это достигается, когда AUC

Though the statement is not scientifically based it is still in the list of regulator's requirements. So in case if some problems with the "80% covering rule" we have to justify somehow that the validity of the study should not be called into question - that's what I've asked about.

By the way, was this question ever discussed on the conferences on harmonization?

Usually the last sampling point divides completely by 12, so I may expect 48 to be the last sampling point or may be 60, but who is so crazy to leave 71 as the last point?

But there arising another interesting situation: imagine there is a IR drug with T

❝ Read the entire thread again.

Ok, my HW was not perfect No I reread it. Still don't understand what to argue to the assessors...

By the way, there is a typo in f' (the graph is correct), first term should be with minus:

\(\small{f'(x)=A(-k_{el}\cdot e^{-k_{el}\cdot x}+k_a\cdot e^{-k_a\cdot x})}\)}

and for AUC as the integral from 0 to a, "a" should go instead of x:\(\small{A \left ( (e^{k_a \cdot a}-1)/k_a - (e^{k_{el}\cdot a}-1)/k_{el} \right )}\)

❝ I’m referring to the EMA’s guideline. Too lazy to Google-translate the ones in Russian.

Do not bother yourself, EAEC experts had already translated it: "Количество отобранных образцов также должно быть достаточным, чтобы обеспечить надежную оценку длительности экспозиции. Это достигается, когда AUC

_{(0–t)}перекрывает не менее 80 процентов от AUC_{(0–∞)}."Though the statement is not scientifically based it is still in the list of regulator's requirements. So in case if some problems with the "80% covering rule" we have to justify somehow that the validity of the study should not be called into question - that's what I've asked about.

❝ Therefore, the FDA does not have such a bizarre “AUC0–t ≥ 80% AUC0–∞ rule

By the way, was this question ever discussed on the conferences on harmonization?

❝ ...71 h → AUC_{0–71}...

Usually the last sampling point divides completely by 12, so I may expect 48 to be the last sampling point or may be 60, but who is so crazy to leave 71 as the last point?

But there arising another interesting situation: imagine there is a IR drug with T

_{1/2}equals to 18 hours. 4*T_{1/2}=72 so we can leave 72 hours as the last sampling point. Which of the two parameters AUC_{last}or AUC_{72}should be used to choose the best strategy to confirm BE in this case? At first sight they should be equal but this is not true. The NCA software (like Phoenix) uses AUC_{partial}to calculate AUC_{72}, so for 72 hours it would be equal to AUC_{all}but not AUC_{last}! For some subjects the last sample could be below LLOQ, for them AUC_{all}>AUC_{last}with an area of triangle.—

"Being in minority, even a minority of one, did not make you mad"

"Being in minority, even a minority of one, did not make you mad"

### 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
- 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

- Science vs. regulations Achievwin 2020-05-07 22:59

- Science vs. regulations Helmut 2020-04-23 17:32

- Science vs. regulations cakhatri 2013-03-10 08:59
- 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 whipAstea 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

- OT: Bias of AUCt, AUCall, pAUC ElMaestro 2020-06-09 08:45

- OT: Bias of AUCt, AUCall, pAUC Helmut 2020-06-08 15:53
- Maxwell's demon Astea 2020-06-12 14:15

- Bizarre paper ElMaestro 2020-06-08 15:33

- Dead dogs Helmut 2020-06-08 10:40

- Aber meine Herren das ist keine physik Astea 2020-06-08 00:08

- Dead dogs mittyri 2020-06-07 20:32

- Gedankenexperiment Helmut 2020-06-07 12:41

- Carrot and whipAstea 2020-06-06 21:11

- So what? Helmut 2020-06-06 12:02

- AUCt not covering at least 80% of AUCinf Astea 2020-06-05 19:05

- AUCt not covering at least 80% of AUCinf ratnakar1811 2013-03-06 08:50

- AUCt not covering at least 80% of AUCinf d_labes 2013-03-05 11:12