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NewInPK ☆ 2009-03-27 04:09 (6292 d 13:17 ago) Posting: # 3405 Views: 9,222 |
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Hello everyone, Thank you for maintaining this forum, it is very helpful. I am another novice attempting to get a grasp of PK. After a few sort or regular courses and a lot of googling, I got to a level where I have some understanding, but still a lot of questions. I hope that one day I will be able to look back and laugh at my questions. My most recent roadblocks are the following: 1) Text in WinNonlin help menu: "Measures for each individual should be displayed in parallel for the formulations tested. In particular, for each BE measure the ratio of the individual geometric mean of the T product to the individual geometric mean of the R product should be tabulated side by side for each subject." I understand "for each BE measure" to refer perhaps to let's say Cmax. What I don't understand is what geometric mean could there be for each subject? Are they referring to replicate studies? If the study is not replicate, then one should tabulate simply the BE measure (such as Cmax, AUC etc) for each subject? 2) When using the BE wizard in WinNonlin, in the "Bioequivalence Fixed Effects" window, what does "Fixed Effect Confidence Level" refer to? For a crossover (1 treatment and reference) what are the fixed effects? 3) I read this example: http://www.ajpe.org/legacy/pdfs/aj630215.pdf and I was able to understand the step-by-step calculations, but when looking at the WinNonlin output, I don't find a confidence interval of the difference, instead I assume the CI of the ratio is listed. My guess is that I interpret to have bioequivalence if the value of the Ratio[% Ref] is included in the CI_90Lower and CI_90_upper. Is this right? 4) I am not clear if the 95% confidence level from the "Bioequivalence Fixed Effects" window of the BE wizard is related to the 90% confidence interval from the "Bioequivalence Options" window. I'll stop here, thank you in advance for your patience. |
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SDavis ★★  UK, 2009-03-27 11:52 (6292 d 05:33 ago) @ NewInPK Posting: # 3406 Views: 8,170 |
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Hi NewInPk, I'm just answering one of these briefly as I am sure (KNOW!) there are much better statisticians on this forum and I have to go to a meeting in 2 minutes. Regarding your point number 1 I think it is suggesting you to look at the output tab "Ratio Test=Tablet" where you see individual values for Cmax etc. and their ratio (Test/Reference) so it's an additional listing but not necessarily your end point that the Help file is discussing in that section. Simon. — Simon Senior Scientific Trainer, Certara™ [link=https://www.youtube.com/watch?v=xX-yCO5Rzag[/link] https://www.certarauniversity.com/dashboard https://support.certara.com/forums/ |
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NewInPK ☆ 2009-03-28 23:18 (6290 d 18:07 ago) @ SDavis Posting: # 3409 Views: 7,928 |
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Thank you, Simon. My main confusion comes from the word "mean" when referring to individual subjects. Have a nice weekend! |
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Helmut ★★★  Vienna, Austria, 2009-03-30 21:04 (6288 d 21:22 ago) @ NewInPK Posting: # 3419 Views: 8,410 |
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Hi NewInPK (nice nick...)! ❝ Thank you for maintaining this forum, it is very helpful. Thanks. ❝ After a few sort or regular courses and a lot of googling, [...] Consider the old-fashioned way: reading! Some textbooks are given in this post. ❝ 1) Text in WinNonlin help menu: "Measures for each individual should be ❝ displayed in parallel for the formulations tested. In particular, for each ❝ BE measure the ratio of the individual geometric mean of the T product to ❝ the individual geometric mean of the R product should be tabulated side by ❝ side for each subject." Your quote from the online-help starts with: "This is in response to the FDA guidance"... Pharsight refers to FDA's guideline from 2001, which states this sentence in  ❝ 2) When using the BE wizard in WinNonlin, in the "Bioequivalence Fixed ❝ Effects" window, what does "Fixed Effect Confidence Level" refer to? For a ❝ crossover (1 treatment and reference) what are the fixed effects? You see them below 'Model Specification'; for a 2×2×2 cross-over they are: sequence, treatment, and period. They are fixed, because they are given by the design of the study. Since we want to infer from our study (a random sample) to the general population, in the next window you find the random effect: subject(sequence). ❝ 3) [...] but when looking at the WinNonlin output, I don't find a ❝ confidence interval of the difference, instead I assume the CI of the ❝ ratio is listed. Look at 'Depent Variables Transformation' in the BE wizard which defaults in WinNonlin to ln(x). Since many biological metrics are skewed to the right this transformation makes sense (apart from this empiric observation there are pharmacokinetic and bioanalytical reasons as well). Therefore the ANOVA (or LME or any other parametric statistical method) is done on the differences of the logs (which are the ratios of untransformed values, since ln(x)-ln(y)=x/y). ❝ My guess is that I interpret to have bioequivalence if the value of the ❝ Ratio[% Ref] is included in the CI_90Lower and CI_90_upper. Is this right? No. The point estimate is always within it's own confidence interval. BE is demonstrated if the confidence interval is included in the acceptance range. The acceptance range has to be stated in the statistical protocol and agreed upon with the competent authority. See the third window of the BE wizard: 'Percent of Reference to Detect' which in WinNonlin defaults to 20%. For this example the lower acceptance limit is given with 100%-20% and the upper with 1/(100%-20%)=125%. 20% are conventionally applied, but may be smaller for NTIDs in some legislations (Canada, Denmark), where e.g., 10% is required (lower: 90%, upper: 111.1...%), or wider (EU and many other countries for Cmax of HVDs) as well (lower: 75%, upper: 133.3...%). If you are testing more than one formulation simultaneously (e.g., for dose proportionality) Bonferroni-adjusted alphas may be needed. If at least one confidence limit lies outside the acceptance range, BE is not demonstrated (deviation of test from reference and/or CVintra higher than expected in study planning, more drop-outs than expected,...). Only if the entire CI lies outside the acceptance range BioINequivalence is shown. ❝ 4) I am not clear if the 95% confidence level from the "Bioequivalence ❝ Fixed Effects" window of the BE wizard is related to the 90% confidence ❝ interval from the "Bioequivalence Options" window. Forget it, nobody will require these CIs.  Edit: Link corrected for FDA’s new site. [Helmut] — Dif-tor heh smusma 🖖🏼 Довге життя Україна! ![[image]](https://static.bebac.at/pics/Blue_and_yellow_ribbon_UA.png) Helmut Schütz ![[image]](https://static.bebac.at/img/CC by.png) The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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d_labes ★★★ Berlin, Germany, 2009-03-31 10:17 (6288 d 08:09 ago) @ Helmut Posting: # 3420 Views: 7,987 |
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Dear Helmut, ❝ Forget it, nobody will require these CIs. With the exception of the Great Mahatma EMEA. If this piece of the new DRAFT BE guideline survives  :"Statistical analysis, lines 512-514 [...] In addition, tests for difference and the respective confidence intervals for the treatment effect, the period effect, and the sequence effect should be reported for descriptive assessment. [...]" — Regards, Detlew |
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Helmut ★★★ Vienna, Austria, 2009-03-31 18:38 (6287 d 23:48 ago) @ d_labes Posting: # 3427 Views: 7,922 |
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Dear D Labes! ❝ ❝ Forget it, nobody will require these CIs. Oh, wishful thinking. ❝ With the exception of the Great Mahatma EMEA. [...] ❝ "Statistical analysis, lines 512-514 [...]" In my comments sent to EMEA I suggested to simply delete this sentence. We can only cross our fingers and wait... — Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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NewInPK ☆ 2009-04-08 13:55 (6280 d 04:30 ago) @ Helmut Posting: # 3499 Views: 7,991 |
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Hi HS, Thanks a lot for your excellent reply and for your patience. I am traveling and I don't have WinNonlin installed on this laptop, but as soon as I get back I will go over your reply again. In the meantime I'll try to rephrase my first question: "Measures for each individual {I assume it refers to a person/subject} should be displayed in parallel for the formulations tested. In particular, for each BE measure the ratio of the individual {I assume "individual" here refers to a single measure, such as Cmax) geometric mean of the T product to the individual geometric mean of the R product should be tabulated side by side for each subject." How can there be a geometric mean for a BE measure of a subject? One subject has only one value for a BE measure for one product. Many thanks again, NewInPK :) |
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Helmut ★★★ Vienna, Austria, 2009-04-08 15:07 (6280 d 03:18 ago) @ NewInPK Posting: # 3501 Views: 7,846 |
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❝ I am traveling [...] Sayonara, NewInPK! ❝ In the meantime I'll try to rephrase my first question [...] You guessed right: individual = patient/person/subject/volunteer/animal/borg...  ❝ How can there be a geometric mean for a BE measure of a subject? ❝ One subject has only one value for a BE measure for one product. I told you before that WinNonlin's manual only quoted FDA's guideline. The wording there is nonsense. Forget about the 'geometric mean' - what FDA means is a table of individual PK metrics (AUC, Cmax,...) and ratios like this one ... subject test reference T/R... which is provided by WinNonlin. — Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
Ing. Helmut Schütz