Achievwin
★★  

US,
2023-10-02 22:34
(975 d 02:15 ago)

Posting: # 23729
Views: 14,285
 

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

Post reply
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
★★★
avatar
Homepage
Vienna, Austria,
2023-10-02 23:06
(975 d 01:43 ago)

@ Achievwin
Posting: # 23730
Views: 12,743
 

 Carry-over → 🚮

Post reply
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.
—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

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

US,
2023-10-03 14:13
(974 d 10:36 ago)

@ Helmut
Posting: # 23731
Views: 12,736
 

 Carry-over → 🚮

Post reply
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
★★★
avatar
Homepage
Vienna, Austria,
2023-10-03 14:48
(974 d 10:01 ago)

@ Achievwin
Posting: # 23732
Views: 12,653
 

 Carry-over → 🚮

Post reply
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.
—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

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

India,
2023-10-03 18:34
(974 d 06:15 ago)

@ Achievwin
Posting: # 23734
Views: 12,703
 

 Carry-over

Post reply
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
★★  

US,
2023-10-03 22:33
(974 d 02:16 ago)

@ dshah
Posting: # 23736
Views: 12,590
 

 Carry-over

Post reply
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
★★★
avatar
Homepage
Vienna, Austria,
2023-10-04 10:31
(973 d 14:18 ago)

@ Achievwin
Posting: # 23737
Views: 12,544
 

 Carry-over

Post reply
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.
—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

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

US,
2023-10-04 18:38
(973 d 06:11 ago)

@ Helmut
Posting: # 23741
Views: 12,610
 

 Carry-over

Post reply

❝ 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
★★  

India,
2023-10-04 13:22
(973 d 11:27 ago)

@ Achievwin
Posting: # 23738
Views: 12,547
 

 Carry-over

Post reply
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
★★  

Russia,
2023-10-05 22:15
(972 d 02:34 ago)

@ dshah
Posting: # 23742
Views: 12,673
 

 more than 20% subject carry over effect investigation

Post reply
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
★★★
avatar
Homepage
Vienna, Austria,
2023-10-06 09:08
(971 d 15:41 ago)

@ dshah
Posting: # 23744
Views: 12,466
 

 carry over effect investigation based on what?

Post reply
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%?
—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

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

India,
2023-10-06 15:20
(971 d 09:29 ago)

@ Helmut
Posting: # 23746
Views: 12,418
 

 carry over effect investigation based on what?

Post reply
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.
 
Mahmoud
★    

Jordan,
2025-12-09 11:47
(176 d 12:02 ago)

@ Achievwin
Posting: # 24525
Views: 3,458
 

 Carry-over → 🚮

Post reply
Dear Helmut

This is not true to delete carry-over from your vocabulary

some crosover designs need carry-over in the model

Please do not write anythings without refs

your not statistician

❝ ❝ 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"


Edit: correction in 2nd post merged with first. You can edit your post within 24 hours from the original submission, please see FAQ #3 [Ohlbe]
 
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2025-12-10 11:38
(175 d 12:10 ago)

@ Mahmoud
Posting: # 24529
Views: 3,354
 

 Carry-over → 🚮

Post reply
Hi Mahmoud,

❝ your not statistician

At least this is correct – just an interested amateur with 44+ years of experience in the field.
—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

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

Jordan,
2025-12-11 06:11
(174 d 17:38 ago)

@ Helmut
Posting: # 24531
Views: 3,291
 

 Carry-over → 🚮

Post reply
Dear Helmut

If you need understanding the carry over effects.please read the paper

Optimal and Efficient Crossover Designs Under Different Assumptions About the Carryover Effects
A. S. Hedayat a & John Stufken c
Journal of Biopharmaceutical Statistics

Vol. 13, No. 3, pp. 519–528, 2003
 
mittyri
★★  

Russia,
2023-10-05 22:34
(972 d 02:15 ago)

@ Achievwin
Posting: # 23743
Views: 12,558
 

 Outdated and wrong answers

Post reply
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
★★★
avatar
Homepage
Vienna, Austria,
2023-10-06 09:19
(971 d 15:30 ago)

@ mittyri
Posting: # 23745
Views: 12,414
 

 Wrong answer

Post reply
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.
—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
 
UA Flag
Activity
 Admin contact
23,653 posts in 4,991 threads, 1,571 registered users;
419 visitors (0 registered, 419 guests [including 40 identified bots]).
Forum time: 00:49 CEST (Europe/Vienna)

There are in fact two things, science and opinion;
the former begets knowledge, the latter ignorance.    Hippocrates

The Bioequivalence and Bioavailability Forum is hosted by
BEBAC Ing. Helmut Schütz
HTML5