Bioequivalence and Bioavailability Forum • R code for analysis of data from partial replicate design "2x3x3" BE study

mahmoud-teaima Regular 2017-06-08 17:45 Posting: # 17468 Views: 6,692	R code for analysis of data from partial replicate design "2x3x3" BE study [R for BE/BA] Post reply
	Hello all, Can any of our R-coding experts advise me with an R code to do data analysis of partial replicate design "2x3x3" BE study according to FDA and EMA guidelines. Greetings. — Mahmoud Teaima, PhD.

Helmut
Hero

Vienna, Austria,
2017-06-10 01:44

@ mahmoud-teaima
Posting: # 17480
Views: 6,192

R code for the EMA’s ABEL

Post reply

Hi Mahmoud,

» […] an R code to do data analysis of partial replicate design "2x3x3" BE study according to FDA and EMA guidelines.

Good news: The EMA’s ‘Method A’ and ‘Method B’ are fairly easy to implement in R. I have code covering the following designs: RTRT|TRTR, RTTR|TRRT, RTR|TRT, RTT|TRR, RRT|RTR|TRR. The code handles balanced/unbalanced sequences and complete/incomplete data (i.e., periods missing). Example output:

This code is copyright © by Helmut Schütz, Michael Tomashevskiy, Detlew Labes. This code is open source; you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foun- dation; either version 3, or (at your option) any later version. See the GNU GPL for more details. Copies of the GPL-3 versions are available at: http://www.gnu.org/licenses/gpl-3.0.html ╔════════════════════════════════════════════════════════════════════════════╗ ║ Program offered for Use without any Guarantees and Absolutely No Warranty. ║ ║ No Liability is accepted for any Loss and Risk to Public Health Resulting ║ ║ from Use of this R-Code. ║ ╚════════════════════════════════════════════════════════════════════════════╝ Directory : E:/Public/Documents/BEBAC/Publications/AAPS J/RepVal/Data/ File [sheet] : DS.xls [01] System : BEBAC-PC User : HS Operating System : Windows 7 x64 build 7601, Service Pack 1 R version : 3.4.0 (2017-04-21) readxl version : 1.0.0 (2017) PowerTOST version : 1.4.5 (2017) EMA_methodAB vers. : 0.95 (2017-06-11) ────────────────────────────────────────────────────────────────────── Function : CV.calc(); exec. 2017-06-11 18:10:33 CEST Fixed effects : sequence + subject(sequence) + period Data : treatment = R Function : method.A(); exec. 2017-06-11 18:10:33 CEST Fixed effects : sequence + subject(sequence) + period + treatment Data : all ────────────────────────────────────────────────────────────────────── Data set I given by the EMA (Q&A document) available at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002963.pdf Analysis performed on column ‘PK’ (data internally log-transformed) Sequences (design) : RTRT|TRTR (4-period full replicate) Subjects / sequence: 38|39 (unbalanced) Missings / sequence: 3|7 (incomplete) Missings / period : 0|1|7|2 (incomplete) Subjects (total) : 77 Sub’s with T and R : 77 (calculation of the CI) Sub’s with two Ts : 71 Sub’s with two Rs : 73 Degrees of freedom : 217 alpha : 0.05 (90% CI) Switching CV : 30.00% Scaling cap : 50.00% Regulatory constant: 0.760 GMR restriction : 80.00% ... 125.00% CVwT : 35.16% CVwR : 46.96% (reference-scaling applicable) Expanded limits : 71.23% ... 140.40% Recalculation due to presence of 2 outliers (subj. 45|52) ───────────────────────────────────────────────────────── CVwR (outl. excl.) : 32.16% (reference-scaling applicable) Expanded limits : 78.79% ... 126.93% Assessment based on original CVwR 46.96% ──────────────────────────────────────── Confidence interval: 107.11% ... 124.89% (pass) Point estimate : 115.66% (pass) Overall conclusion : pass Assessment based on recalculated CVwR 32.16% ──────────────────────────────────────────── Confidence interval: pass Point estimate : pass Overall conclusion : pass This code is copyright © by Helmut Schütz, Michael Tomashevskiy, Detlew Labes. This code is open source; you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foun- dation; either version 3, or (at your option) any later version. See the GNU GPL for more details. Copies of the GPL-3 versions are available at: http://www.gnu.org/licenses/gpl-3.0.html ╔════════════════════════════════════════════════════════════════════════════╗ ║ Program offered for Use without any Guarantees and Absolutely No Warranty. ║ ║ No Liability is accepted for any Loss and Risk to Public Health Resulting ║ ║ from Use of this R-Code. ║ ╚════════════════════════════════════════════════════════════════════════════╝ Directory : E:/Public/Documents/BEBAC/Publications/AAPS J/RepVal/Data/ File [sheet] : DS.xls [01] System : BEBAC-PC User : HS Operating System : Windows 7 x64 build 7601, Service Pack 1 R version : 3.4.0 (2017-04-21) readxl version : 1.0.0 (2017) PowerTOST version : 1.4.5 (2017) nlme version : 3.1.131 (2017) EMA_methodAB vers. : 0.95 (2017-06-11) ───────────────────────────────────────────────────────────────────────────────── Function : CV.calc(); exec. 2017-06-11 18:10:37 CEST Fixed effects : sequence + subject(sequence) + period Data : treatment = R Function : method.B(option=2): nlme/lme; exec. 2017-06-11 18:10:37 CEST Fixed effects : sequence + period + treatment Random effect : subject(sequence) Data : all ───────────────────────────────────────────────────────────────────────────────── Data set I given by the EMA (Q&A document) available at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002963.pdf Analysis performed on column ‘PK’ (data internally log-transformed) Sequences (design) : RTRT|TRTR (4-period full replicate) Subjects / sequence: 38|39 (unbalanced) Missings / sequence: 3|7 (incomplete) Missings / period : 0|1|7|2 (incomplete) Subjects (total) : 77 Sub’s with T and R : 77 (calculation of the CI) Sub’s with two Ts : 71 Sub’s with two Rs : 73 Degrees of freedom : 217 alpha : 0.05 (90% CI) Switching CV : 30.00% Scaling cap : 50.00% Regulatory constant: 0.760 GMR restriction : 80.00% ... 125.00% CVwT : 35.16% CVwR : 46.96% (reference-scaling applicable) Expanded limits : 71.23% ... 140.40% Recalculation due to presence of 2 outliers (subj. 45|52) ───────────────────────────────────────────────────────── CVwR (outl. excl.) : 32.16% (reference-scaling applicable) Expanded limits : 78.79% ... 126.93% Assessment based on original CVwR 46.96% ──────────────────────────────────────── Confidence interval: 107.17% ... 124.97% (pass) Point estimate : 115.73% (pass) Overall conclusion : pass Assessment based on recalculated CVwR 32.16% ──────────────────────────────────────────── Confidence interval: pass Point estimate : pass Overall conclusion : pass

I will send you the code by PM.

Bad news: Evaluation of replicate designs which will give exactly the same results as SAS’ PROC MIXED according to the FDA’s progesterone guidance is not (and likely will never be) possible in R. Too different philosophies.

Edit: Updated the output according to v0.95 of the R-code.

—
Cheers,
Helmut Schütz

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

mahmoud-teaima Regular 2017-06-10 22:48 @ Helmut Posting: # 17484 Views: 5,904	R code for the EMA’s ABEL Post reply
	Salam Alikum Hilmut, Thanks for the code! Waiting you send it to me through email. Greetings. — Mahmoud Teaima, PhD.

Helmut
Hero

Vienna, Austria,
2017-06-11 01:24

@ mahmoud-teaima
Posting: # 17485
Views: 5,918

R code for the EMA’s ABEL

Post reply

Salam Mahmoud,

» Waiting you send it to me through email.

I’ve sent it already yesterday afternoon to the e-mail address you used in registering to the forum. Please check your inbox.
I just sent it again to the three other addresses I found at your faculty’s website. This e-mail contains more explanations. Since you are working on MacOS I adapted the output: The file is encoded in UTF-8 with line endings CR (ASCII 13). Please report back whether it works (I don’t have a Mac to test it).

—
Cheers,
Helmut Schütz

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

mahmoud-teaima
Regular

2017-06-11 03:01

@ Helmut
Posting: # 17486
Views: 5,944

R code for the EMA’s ABEL

Post reply

Salam Helmut,

» I’ve sent it already yesterday afternoon to the e-mail address you used in registering to the forum. Please check your inbox.
» I just sent it again to the three other addresses I found at your faculty’s website. This e-mail contains more explanations. Since you are working on MacOS I adapted the output: The file is encoded in UTF-8 with line endings CR (ASCII 13).

I got the mail, thanks.

» Please report back whether it works (I don’t have a Mac to test it).

Sure, will check it and report back to you.

Many thanks.

Greetings to all participants in this effort.

—
Mahmoud Teaima, PhD.

Yura Regular Belarus, 2017-09-04 21:22 @ Helmut Posting: # 17773 Views: 5,086	R code for the EMA’s ABEL Post reply
	Dear Helmut I use combined R and SAS (I use the EMA approach) to calculate the replicative design Is it possible to get from you the implementation code in R of the above described constructions? thank you very much for any answer Best regards!

Helmut Hero Vienna, Austria, 2017-09-05 01:55 @ Yura Posting: # 17774 Views: 5,034	R code for the EMA’s ABEL Post reply
	Hi Yura, » Is it possible to get from you the implementation code in R of the above described constructions? It’s on GitHub: https://github.com/Helmut01/replicateBE Installation analogous to PowerTOST. See Detlew’s post. — Cheers, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes

Yura Regular Belarus, 2017-09-05 22:21 @ Helmut Posting: # 17783 Views: 5,009	R code for the EMA’s ABEL Post reply
	Thank you it remains only to run

Helmut Hero Vienna, Austria, 2017-09-06 14:24 @ Yura Posting: # 17785 Views: 4,996	R code for the EMA’s ABEL Post reply
	Hi Yura, » it remains only to run If you have questions, please post here. If you think that you discovered a bug, keep it. No, seriously: Navigate to https://github.com/Helmut01/replicateBE/issues and click on New issue. — Cheers, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes

Yura Regular Belarus, 2017-09-08 08:54 @ Helmut Posting: # 17794 Views: 4,925	R code for the EMA’s ABEL Post reply
	Yes, Captain Best regards! Edit: ElMaestro is our capt’n. I’m just a deckhand. [Helmut]

Bioequivalence and Bioavailability Forum 16:55 CEST

R code for analysis of data from partial replicate design "2x3x3" BE study [R for BE/BA]

R code for the EMA’s ABEL

R code for the EMA’s ABEL

R code for the EMA’s ABEL

R code for the EMA’s ABEL

R code for the EMA’s ABEL

R code for the EMA’s ABEL

R code for the EMA’s ABEL

R code for the EMA’s ABEL

R code for the EMA’s ABEL