Achievwin
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US,
2023-10-02 22:34
(150 d 01:25 ago)

Posting: # 23729
Views: 1,942
 

 Carry over and statistical adjustment in BE computations [General Sta­tis­tics]

If the forum can throw some light on the addressing following points on carry-over.
what I am trying to understand is how to answer - Unequal carryover (between Test and RLD) effect on potential inflation of Type-1 error and bias in the BE conclusions"
  1. How to measure carry-over (any particular PK parameters or in vitro measures?)
  2. How to assess equal or unequal carryover?
  3. Differences in 1st order or other order carry-over
  4. Is there a cut-off to call negligible carry-over
  5. What are the statistical tests to call it a unequal carry-over or no un-equal carry-over.
  6. How to factor or apply any corrections of observed carry-over in BE and RSABE calculations?
I realize these are loaded questions but any true insight that gets buying by EMA or FDA is much appreciated.
Helmut
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2023-10-02 23:06
(150 d 00:52 ago)

@ Achievwin
Posting: # 23730
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 Carry-over → 🚮

Hi Achevwin,

please delete carry-over from your vocabulary.
Statistically irrelevant and not required acc. to any guideline (FDA, EMA, WHO, ICH). See this article for details.

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Achievwin
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US,
2023-10-03 14:13
(149 d 09:46 ago)

@ Helmut
Posting: # 23731
Views: 1,619
 

 Carry-over → 🚮

Hi Helmut:

❝ please delete carry-over from your vocabulary.


Good point...... but CRLs won't leave you without these questions.... somehow regulators seems to be obsessed with that borderline "Carry-over"

Regards,

Achivewin
Helmut
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2023-10-03 14:48
(149 d 09:10 ago)

@ Achievwin
Posting: # 23732
Views: 1,561
 

 Carry-over → 🚮

Hi Achivewin,

❝ somehow regulators seems to be obsessed with that borderline "Carry-over"


Against obsession consider psychotherapy or hire an exorcist you trust. :-D
Seriously: Point them to the relevant guidance(s). Give the number of the page.

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dshah
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India/United Kingdom,
2023-10-03 18:34
(149 d 05:25 ago)

@ Achievwin
Posting: # 23734
Views: 1,576
 

 Carry-over

Dear Achivewin!

❝ Good point...... but CRLs won't leave you without these questions.... somehow regulators seems to be obsessed with that borderline "Carry-over"

How many % of subjects had carryover? If its more than 5% of Cmax, generally the exclusion criteria cover it so that subject is not considered for statistical evaluation. If more than 20% subject has carry over effect (more than 5%Cmax value), than an investigation would be needed but this indicates that washout period was insufficient.
Regards,
Divyen
Achievwin
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US,
2023-10-03 22:33
(149 d 01:25 ago)

@ dshah
Posting: # 23736
Views: 1,523
 

 Carry-over

Dear Divyan and Helmut:

Whether we like it or not this question keep popping, can you both or anyone answer my questions above (I have views but I want to hear what other alternatives are there - my views align mostly with Helmut view but.... regulators are regulators)

I am struggling with the basic question how to quantify carry-over? and for some products that <5% of Cmax rule is not applied (this is a news for me)

Thanks a lot

AchievWin
Helmut
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2023-10-04 10:31
(148 d 13:28 ago)

@ Achievwin
Posting: # 23737
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 Carry-over

Hi AchievWin,

❝ Whether we like it or not this question keep popping, can you both or anyone answer my questions above (I have views but I want to hear what other alternatives are there - my views align mostly with Helmut view but.... regulators are regulators)


Again, tell regulators to follow their own guidances. Be polite, if you can.

❝ I am struggling with the basic question how to quantify carry-over?


After a dose we know only one thing for sure:
The concentration is not zero.
1


A good part of Stephen Senn’s textbook2 can be understood as an essay against carryover in the model.

If you are really interested in the behavior of the drug/formulation, you could only try PK modeling. Good luck. Even if you succeed, then what? Subtract the estimated concentration-time course of previous period(s) from the observed ones to get the ‘true’ concentrations? No regulator would accept that.

See there (Case 1, slides 4–7). I subtracted the fitted concentrations and presented it as a supportive analysis (after some subjects with pre-dose concentrations in higher periods we amended the SAP). Luckily the total (between- + within-subject) variability was low. The German agency accepted the study based on the data of the first period evaluated as a parallel design (new primary analysis; we crossed fingers). The study passed but it was a close shave.
BTW, with the current ≤5% Cmax rule evaluation as a crossover would have been not be a problem…

❝ and for some products that <5% of Cmax rule is not applied (this is a news for me)


Are you talking about endogenous compounds? Nasty beasts.


  1. Harold Boxenbaum at: Analytical Methods Validation: Bioavailability, Bioequivalence and Pharma­co­ki­netic Studies. (Crystal City I Con­fe­rence). Arlington, VA. December 3–5, 1990.
  2. Senn S. Cross-over Trials in Clinical Research. Chichester: Wiley; 2nd ed. 2002. ISBN: 978-0-471-49653-3.

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Achievwin
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US,
2023-10-04 18:38
(148 d 05:20 ago)

@ Helmut
Posting: # 23741
Views: 1,484
 

 Carry-over

❝ Are you talking about endogenous compounds? Nasty beasts.


No, someone said "5% Cmax rule of pre-dose doesn't apply for LAI/Depo formulations ---- I know they were wrong but you can not argue with authority figures.

Harold Boxenbaum et. al: Nice to see my former Mentor Late Harold's name in this discussion.....;-);-)
dshah
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India/United Kingdom,
2023-10-04 13:22
(148 d 10:36 ago)

@ Achievwin
Posting: # 23738
Views: 1,504
 

 Carry-over

Hi AchievWin!

❝ <5% of Cmax rule is not applied (this is a news for me)


Any example-Pls give me? As suggested by Helmut- if you are talking about endogenous substance, then the base line correction method would play a significant role.

Honestly, I have seen some carry over- but the protocol does take care of it.
Can you share the protocol's inclusion/exclusion criteria for PK/stat part?

Regards,
Divyen
mittyri
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Russia,
2023-10-05 22:15
(147 d 01:44 ago)

@ dshah
Posting: # 23742
Views: 1,435
 

 more than 20% subject carry over effect investigation

Dear Divyen!

❝ If more than 20% subject has carry over effect (more than 5%Cmax value), than an investigation would be needed but this indicates that washout period was insufficient.


Could you please enlighten me - why 20%? Why 15% could not trigger investigation? Are 15% not enough to start investigation?

Kind regards,
Mittyri
Helmut
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2023-10-06 09:08
(146 d 14:51 ago)

@ dshah
Posting: # 23744
Views: 1,398
 

 carry over effect investigation based on what?

Hi Divyen,

❝ If more than 20% subject has carry over effect (more than 5%Cmax value), than an investigation would be needed but this indicates that washout period was insufficient.


I agree with what Mittyri wrote above. Is is possible that you mixed it up with the 20% of subjects with extrapolated AUC >20%?

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dshah
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India/United Kingdom,
2023-10-06 15:20
(146 d 08:39 ago)

@ Helmut
Posting: # 23746
Views: 1,319
 

 carry over effect investigation based on what?

Hi Helmut & Mittyri!


❝ I agree with what Mittyri wrote above. Is is possible that you mixed it up with the 20% of subjects with extrapolated AUC >20%?


Yes, Probability I may have mixed up the things.
But with carry over effect, there is high probability that the subject would not have ratio of AUCt/AUCinf>0.8? which can be due to insufficient washout period? So there is high chance that where carry over is observed, the AUCt/AUCinf> 0.8 is not achieved and thus the investigation on this.
mittyri
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Russia,
2023-10-05 22:34
(147 d 01:24 ago)

@ Achievwin
Posting: # 23743
Views: 1,455
 

 Outdated and wrong answers

Dear Achievewin!

15-20 years ago the answers could be the following
  1. How to measure carry-over (any particular PK parameters or in vitro measures?)
    Usually we say that unequal carryover exists, when the p-value for Sequence effect in ANOVA is less than 5% for any of parameters of interest.
    We say that equal carryover exists, when the p-value for Period effect in ANOVA is less than 5%.


  2. How to assess equal or unequal carryover?
    See above

  3. Differences in 1st order or other order carry-over

    Something like this (one carryover effect overrides the previous one)
    https://online.stat.psu.edu/stat509/lesson/15/15.5

  4. Is there a cut-off to call negligible carry-over
    If the sequence effect is more than 5%: the carry-over effect is negligible.

  5. What are the statistical tests to call it a unequal carry-over or no un-equal carry-over.
    ANOVA F test

  6. How to factor or apply any corrections of observed carry-over in BE and RSABE calculations?
    Apply BE for the 1st period only.


Please don't get me wrong. These answers could be correct decades ago.

Kind regards,
Mittyri
Helmut
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2023-10-06 09:19
(146 d 14:40 ago)

@ mittyri
Posting: # 23745
Views: 1,396
 

 Wrong answer

Hi Mittyri & Achievewin,

❝ 15-20 years ago the answers could be the following


Speaking from a regulatory perspective since 23 years (the EMA Guideline) wrong.

❝ 6. How to factor or apply any corrections of observed carry-over in BE and RSABE calculations?

Apply BE for the 1st period only.


Proven to be wrong in 1989.*


  • Freeman PR. The performance of the two-stage analysis of two-treatment, two-period cross-over trials. Stat Med. 1989; 8(12): 1421–32. doi:10.1002/sim.4780081202.

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