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Back to the forum  Query: 2017-09-23 22:00 CEST (UTC+2h)
 
yicaoting
Regular
Homepage
NanKing, China,
2017-08-22 18:01

Posting: # 17736
Views: 650
 

 Validation of FDA's RSABE on NTIDs [RSABE / ABEL]

Dear Helmut,
Hope you are well.

I am trying to manually calculate the upper 90% CL of sWT/sWR in US FDA's RSABE for NTIDs(Draft Guidance on Warfarin).

I use BEBAC's sample data (page 14 of the PPT from this site http://bebac.at/lectures/Mumbai2013WS3.pdf) to validate/verify my calculation steps.

Data set link
http://bebac.at/downloads/NTID.xls

It will be greatly appreciated if you can help me on the following questions:
1. I manually calculate the sWR and sWT in Excel sheet, they are 0.124392769, 0.055720909, respectively. Are my results EXACTELY right?

2. In your slides, you have present the upper 95% CL of sWT/sWR 0.68427 ≤2.5.
I have calculated
lower 95% CL of sWT/sWR = 0.293238292
upper 95% CL of sWT/sWR = 0.684266753 (this is nearly the same as your result)

As US FDA's Guidance on Warfarin required, the upper 90% CI should be used, I also calculate the following:
lower 90% CL of sWT/sWR = 0.322597242
upper 90% CL of sWT/sWR = 0.621992961

Are the above results right?

I use the function Finv(0.1,16,16) and Finv(0.9,16,16) for the calculation of 90% CL of sWT/sWR,
and Finv(0.05,16,16) and Finv(0.95,16,16) for the calculation of 95% CL of sWT/sWR. Do I use the right function?

2. Would you please guide (step by step) me how to calculate CVwr CVwt? As shown in your slides, they are CVWR 12.49%, CVWT 5.58%. Although these two values are not used in calculation of "upper 90% CL of sWT/sWR".

Thank you for your great sample dataset which provides us a valuable bridge for us to learn and discuss this sparely used procedure.
Helmut
Hero
Homepage
Vienna, Austria,
2017-08-22 20:25

@ yicaoting
Posting: # 17739
Views: 564
 

 Validation of FDA's RSABE on NTIDs

Hi Zhang Yong,

» Hope you are well.

THX! Below my results obtained in Phoenix WinNonlin 7.0 in full precision.

» I manually calculate the sWR and sWT in Excel sheet, they are 0.124392769, 0.055720909, respectively. Are my results EXACTELY right?

swR 0.124392768691665, swT 0.0557209092013223

» In your slides, you have present the upper 95% CL of sWT/sWR 0.68427 ≤2.5.
» I have calculated
» lower 95% CL of sWT/sWR = 0.293238292
» upper 95% CL of sWT/sWR = 0.684266753 (this is nearly the same as your result)

lower CL 0.293238291752988, upper CL 0.684266752752176

» As US FDA's Guidance on Warfarin required, the upper 90% CI should be used, I also calculate the following:
» lower 90% CL of sWT/sWR = 0.322597242
» upper 90% CL of sWT/sWR = 0.621992961
» Are the above results right?

The guidance might be confusing. See the last bullet point below the formula
  • here α = 0.1.
Hence, 1–0.05 and 1–0.95 are correct.

» I use the function Finv(0.1,16,16) and Finv(0.9,16,16) for the calculation of 90% CL of sWT/sWR,
» and Finv(0.05,16,16) and Finv(0.95,16,16) for the calculation of 95% CL of sWT/sWR. Do I use the right function?

I have only Excel 2000. :-D Up to v2003 the inverse distributions were wrong. Maybe you have to use F.inv(alpha,df1,df1) or the old workaround Finv(2*alpha,df1,df1). Duno. The correct F-values (ν12=16) are:
Fα∕2,ν12 2.33348362746764, F1−α∕2,ν12 0.428543825304327

» Would you please guide (step by step) me how to calculate CVwr CVwt? As shown in your slides, they are CVWR 12.49%, CVWT 5.58%. Although these two values are not used in calculation of "upper 90% CL of sWT/sWR".

According to the guidance sWR and swT are estimated from complete data only (not an issue with this data set) ignoring its structure (solely 'sequence' in the linear model). Your values are correct. Hence, as usual CVw = 100√w - 1. Therefore, we get CVwR 12.49% and CVwT 5.58%.

Personally I would prefer to run a mixed effects model with restricted maximum likelihood which takes the entire information into account (i.e., the FDA’s code of the 2001 guidance and also in the ABE-part of the progesterone guidance). In this model you could have incomplete data and the variances of R and T are simultaneously estimated. I guess that’s impossible in Excel (as it is in R)…
I got: CVwR 15.86% and CVwT 5.73%. Interesting.

Hope that helps.

[image]All the best,
Helmut Schütz 
[image]

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yicaoting
Regular
Homepage
NanKing, China,
2017-08-23 05:30

@ Helmut
Posting: # 17742
Views: 536
 

 Validation of FDA's RSABE on NTIDs

Hi, Helmut.
Thank you for your quick response.

» THX! Below my results obtained in Phoenix WinNonlin 7.0 in full precision.
» swR 0.124392768691665, swT 0.0557209092013223

Yes, sWR and sWT can be calculate manually. So my results are indentical to yours.

» lower CL 0.293238291752988, upper CL 0.684266752752176
Thay are identical to mine.


» The guidance might be confusing. See the last bullet point below the formula
  • here α = 0.1.
Hence, 1–0.05 and 1–0.95 are correct.
I am not sure the guidance is correct or not.
But from the formula in the guidance (page 4, line 5) with Alpha=0.1, I guess the guidance is right, it calulates 90% CI of Swt/Swr, but not 95% CI.

Need your clarification? or FDA is wrong?

» I have only Excel 2000. :-D Up to v2003 the inverse distributions were wrong. Maybe you have to use F.inv(alpha,df1,df1) or the old workaround Finv(2*alpha,df1,df1). Duno. The correct F-values (ν12=16) are:
» Fα∕2,ν12 2.33348362746764, F1−α∕2,ν12 0.428543825304327

In Excel 2003,
Finv(0.05,16,16) = 2.33348362835
Finv(0.95,16,16) = 0.428543825142279

In Excel 2013
Finv(0.05,16,16) = 2.33348362746764
Finv(0.95,16,16) = 0.428543825304327
F.inv(0.05,16,16) = 0.428543825304327
F.inv(0.95,16,16) = 2.33348362746764

» According to the guidance sWR and swT are estimated from complete data only (not an issue with this data set) ignoring its structure (solely 'sequence' in the linear model). Your values are correct. Hence, as usual CVw = 100√w - 1. Therefore, we get CVwR 12.49% and CVwT 5.58%.

Thanks.

» Personally I would prefer to run a mixed effects model with restricted maximum likelihood which takes the entire information into account (i.e., the FDA’s code of the 2001 guidance and also in the ABE-part of the progesterone guidance). In this model you could have incomplete data and the variances of R and T are simultaneously estimated. I guess that’s impossible in Excel (as it is in R)…
» I got: CVwR 15.86% and CVwT 5.73%. Interesting.

I guess your result of 15.86% and 5.73% are obtain from the sheet of "Final Variance Parameters" from ABE results using PHX WNL.

let
a = Var(Period*Formulation*Subject)_21 (the value is 0.024828963992548 from PHX WNL)
b = Var(Period*Formulation*Subject)_22 (the value is 0.003281299568883 from PHX WNL)
CVwr = 100 * SQRT(EXP(a)-1)
CVwt = 100 * SQRT(EXP(b)-1)

I got the same results sa you.

Here the CVwr and CVwt are different from those calculated from Swr and Swt.
I prefer the result calculated from Swr and Swt.
What's your opinion?
Helmut
Hero
Homepage
Vienna, Austria,
2017-08-23 15:00

@ yicaoting
Posting: # 17744
Views: 492
 

 Validation of FDA's RSABE on NTIDs

Hi Zhang Yong,

» But from the formula in the guidance (page 4, line 5) with Alpha=0.1, I guess the guidance is right, it calulates 90% CI of Swt/Swr, but not 95% CI.
» Need your clarification? or FDA is wrong?

The FDA is never wrong. But so am I. :-D The guidance asks to calculate an confidence interval but only the upper confidence limit is assessed. Simply: The 90% CI has an upper and lower 95% CL.

» » Personally I would prefer […] to run a mixed effects model with restricted maximum likelihood…
» » I got: CVwR 15.86% and CVwT 5.73%. Interesting.
»
» I guess your result of 15.86% and 5.73% are obtain from the sheet of "Final Variance Parameters" from ABE results using PHX WNL.

Correct.

» Here the CVwr and CVwt are different from those calculated from Swr and Swt.
» I prefer the result calculated from Swr and Swt.
» What's your opinion?

For my preferences see above. If you have to follow the guidance that’s not an option.

BTW, if you have Phoenix WinNonlin why bother fiddling around in Excel? I have some doubts whether an agency will accept that. At least the EMA wouldn’t. Quoting the Q&A document:

3.3. Alternative computer programs
[…] Results obtained by alternative, validated statistical programs are also acceptable except spreadsheets because outputs of spreadsheets are not suitable for secondary assessment.

BTW, Certara is working on a validated template for PHX WNL and it will be published in the near future.

[image]All the best,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
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yicaoting
Regular
Homepage
NanKing, China,
2017-08-30 14:33

@ Helmut
Posting: # 17756
Views: 323
 

 Validation of FDA's RSABE on NTIDs

Hi Helmut
For validation of statistical procedure or software in analysis of BE data of NTID. I am eagerly hope you publish such reference datasets, like those two papers published in AAPS J in 2015 for two way crossover and parallel design.
If you wish, please tell me If i can provide any help.
I now use WNL PHX and SAS and/or Excel to analysis NTID. Excel is used just for SigmaWR and SigmaWR/SigmaWT and it's upper llevel of %CI, not for ABE or RSABE in such case.

BTW, I have developed a program in VBA in Excel for BE analysis, it has passed all 2*2*2 and 2‖2 reference datasets you provided. This program is not intended for commercialization, but will be published for free use in future. Like PKSolver and DDSolver which have been published.
Helmut
Hero
Homepage
Vienna, Austria,
2017-08-30 15:04

@ yicaoting
Posting: # 17757
Views: 322
 

 Validation of FDA's RSABE on NTIDs

Hi Yong,

» I am eagerly hope you publish such reference datasets, like those two papers published in AAPS J in 2015 for two way crossover and parallel design.

We are working on a paper for the EMA’s ABEL. ;-) We will also provide an R-package. It is still a work in progress. Its current state on GitHub. In the inst/extdata folder our reference data sets. NTIDs are DS02.csv (TRR|RTR|RRT), DS05.csv (TRRT|RTTR), and DS10.csv (TRR|RTT). Sorry, none with TRTR|RTRT…

» I now use WNL PHX and SAS and/or Excel to analysis NTID. Excel is used just for SigmaWR and SigmaWR/SigmaWT and it's upper llevel of %CI, not for ABE or RSABE in such case.

Our results with replicateBE and the latest template for PHX/WNL:
DS05.csv: swT∕swR 1.0184, upper CL of σwTσwR 1.4344.
DS10.csv: swT∕swR 1.2566, upper CL of σwTσwR 2.3300.

» BTW, I have developed a program in VBA in Excel for BE analysis, it has passed all 2*2*2 and 2‖2 reference datasets you provided. This program is not intended for commercialization, but will be published for free use in future. Like PKSolver and DDSolver which have been published.

Great!

[image]All the best,
Helmut Schütz 
[image]

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