Alyssa ☆ Malaysia, 2020-05-04 06:35 (1682 d 07:50 ago) Posting: # 21389 Views: 13,488 |
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Hi, We have a product, conducted pilot study, 2x2x2 , 18 subjects. Geometric Lease square Mean Cmax (ng/mL) T = 15032.282 Geometric Lease square Mean Cmax (ng/mL) R = 15227.106 T/R ratio % = 98.70 90% CI = 84.41 – 115.46 ISCV (%) = 26.4 Power(%) = 76.6% However, based on published literature (Public assessment report, PAR) for the same product. 3 way crossover, reference replicate with 41 subjects completed, the results shows below:- Geometric Lease square Mean Cmax (ng/mL) T = 16530.654 Geometric Lease square Mean Cmax (ng/mL) R = 15064.108 T/R ratio % = 109.7 90% CI = 96.25-125.11% ISCV (%) = 42.6% Power(%) = NA Based on the CRO in house data for their past experience, Range of Intra-Subject Variability of Reference Formulation (CVWR): 26.8% – 50.3% (Pass studies) Question: 1. Usually ISCV result of the 3 way crossover or 4 way crossover, replicate study published in the PAR is CVwR or CVw? 2. Which ISCV should i consider to use for sample size calculation as our own pilot study shows promising result, however, published literature and CRO past experience shows the other way. CRO advised us to go for 4 way crossover, replicate design, with ratio 90-111%, ISCV = 35-40% 3. What would be the recommended ISCV and study design for product like this? I have to balance between passing the study and the company's budget. Hope the expert here can give me some recommendation. Appreciated. TQ |
Dr_Dan ★★ Germany, 2020-05-04 10:46 (1682 d 03:39 ago) @ Alyssa Posting: # 21391 Views: 11,350 |
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Dear Alyssa I guess you are talking about an oral IR formulation, right? ISCV are not carved in stone, there will always be a certain variability. However, big differences hint on differences in study performance and/or quality of formulations. It is reasonable to assume that the ISCV in the pivotal study will be similar to the pilot study if you use the same CRO (study procedure performance), the same test formulation vs. the same (batch of) reference product and the same bioanalytical method. If costs do not matter you can of course follow the suggestion of the CRO to go for 4 way crossover, replicate design, with ratio 90-111%, ISCV = 35-40%. I hope this helps — Kind regards and have a nice day Dr_Dan |
Alyssa ☆ Malaysia, 2020-05-04 11:26 (1682 d 02:59 ago) @ Dr_Dan Posting: # 21392 Views: 11,260 |
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Dear Dr. Dan, Thanks for your reply. ❝ I guess you are talking about an oral IR formulation, right? Is a oral MR formulation. ❝ It is reasonable to assume that the ISCV in the pivotal study will be similar to the pilot study if you use the same CRO (study procedure performance), the same test formulation vs. the same (batch of) reference product and the same bioanalytical method. The CRO we used for pilot study is the same as per the one used in the published literature (sponsor mentioned the CRO name in the PAR). Therefore, the study procedure performance and bioanalytical method variability is reduced. ❝ If costs do not matter you can of course follow the suggestion of the CRO to go for 4 way crossover, replicate design, with ratio 90-111%, ISCV = 35-40%. Cost is definitely a matter for us now, especially during this Covid-19 pandemic, have to spend wisely. Therefore i need some expert opinion here for my consideration. Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post #5! [Helmut] |
Helmut ★★★ Vienna, Austria, 2020-05-04 14:07 (1682 d 00:18 ago) @ Alyssa Posting: # 21393 Views: 11,196 |
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Hi Alyssa, ❝ Usually ISCV result of the 3 way crossover or 4 way crossover, replicate study published in the PAR is CVwR or CVw? There are no rules (it depends on what the assessor decides to include of the study report). However, since the study was a replicate design with reference-scaling, possibly it is CVwR (more important). We can estimate the CVw with the R-package PowerTOST :
[Nonsense, not a Williams’ design! See ElMaestro’s post and the correction.] If the expanded limits are given in the PAR, you can estimate the CVwR from the upper limit by the function CVwRfromU() to check. Example for 136.4%:
I agree with Dan but want to add one point. In my experience the variability across studies (with the same clinical setup, bioanalytical method, ) tends to be more “stable” than the T/R-ratio. Hence, don’t fall into the trap of believing the nice 98.7% you observed in the pilot study. It might well have been pure chance. For HVD(P)s assuming a T/R-ratio of better than 90–111% is not a good idea (recommended by the two Lászlós* and therefore, the default in functions sampleN.scABEL() and sampleN.RSABE() of PowerTOST ).PS: Avoid sample size “calculation” if you don’t mind. Use “estimation” instead. PPS: The partial replicate is a lousy design. If you want to have only three periods I suggest the 2×2×3 full replicate TRT|RTR instead. If you insist in the partial replicate (why?), use the function sampleN.scABEL.sdsims() . Slower than sampleN.scABEL() but more accurate. For a comparison see the vignette and scroll down to “Heterogenicity”.
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ElMaestro ★★★ Denmark, 2020-05-04 14:14 (1682 d 00:11 ago) @ Helmut Posting: # 21394 Views: 11,233 |
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Hi Hötzi, the powerTOST package is excellent and I am not myself a very experienced user (yet) as I tend to rely on much less reliable code of my own making So forgive me I am asking: I think the OP implied a partial replicate. TRR/RRT/RTR is not 3x6x3 but rather 2(trts)x3(seqs)x3(pers), is there a reason to plug in 3x6x3 in your code? — Pass or fail! ElMaestro |
Helmut ★★★ Vienna, Austria, 2020-05-04 14:40 (1681 d 23:46 ago) @ ElMaestro Posting: # 21395 Views: 11,405 |
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Hi ElMaestro, ❝ the powerTOST package is excellent … THX! ❝ … and I am not myself a very experienced user (yet) as I tend to rely on much less reliable code of my own making Sure. In line what Jaime once stated: Never trust in any piece of software you haven't written yourself ❝ So forgive me I am asking: I think the OP implied a partial replicate. TRR/RRT/RTR is not 3x6x3 but rather 2(trts)x3(seqs)x3(pers), … Oops! You are absolutely right. ❝ ❝ 3 way crossover, reference replicate ❝ … is there a reason to plug in 3x6x3 in your code? I screwed up! Of course, not a 3-period Williams’ design. Hence,
@Alyssa: Can you please check whether the expanded limits are also given in the PAR? Based on CVwR 42.6% they should be close to
— 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 |
ElMaestro ★★★ Denmark, 2020-05-04 15:46 (1681 d 22:40 ago) @ Helmut Posting: # 21396 Views: 11,250 |
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Hi again, I believe it must be this assessment report.: "the acceptance criteria for Cmax was widened to the acceptance range of 72.83-137.31%", — Pass or fail! ElMaestro |
Helmut ★★★ Vienna, Austria, 2020-05-04 16:07 (1681 d 22:19 ago) @ ElMaestro Posting: # 21397 Views: 11,147 |
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❝ I believe it must be this assessment report.: ❝ "the acceptance criteria for Cmax was widened to the acceptance range of 72.83-137.31%", Almost my dear Dr Watson! It’s the first study; results on page 7: “… within-reference intra-subject CV of ln-transformed Cmax > 30% (42.6%), hence Cmax limits were widen[ed] to 73.31–136.42% using scaled-average-bioequivalence.”
— 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 |
Alyssa ☆ Malaysia, 2020-05-05 07:00 (1681 d 07:26 ago) @ Helmut Posting: # 21400 Views: 11,328 |
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Wow! @Elmaestro nothing can hide from you. Opss I should'nt disclose it here. @Helmut thanks for the explanation i will try to digest the PowerTOST calculation mentioned above. I'm not a biostatistician.....so need some time. Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post #5! [Helmut] |
Helmut ★★★ Vienna, Austria, 2020-05-05 14:45 (1680 d 23:40 ago) @ Alyssa Posting: # 21401 Views: 11,401 |
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Hi Alyssa, ❝ i will try to digest the PowerTOST calculation mentioned above. Estimation, pleeze. ❝ I'm not a biostatistician.....so need some time. It’s not that difficult; short tutorial:
Sample sizes for the 3-period full replicate are higher than for the partial replicate. However, don’t think only about costs. The former is more informative, since you can estimate also CVwT. Not only that you learn something about your formulation, it is useful for designing other studies. Whereas expanding the limits is based on CVwR, the CI depends on the pooled variance of both treatments. In many cases CVwT < CVwR, which would give you an incentive of the sample size. Unfortunately CVwT is never given in PARs (not of regulatory concern). I recommend to perform pilot studies always in a full replicate design to obtain this information. Example:
But in your case we don’t have this information and have to assume that CVwT = CVwR. I recommend to perform a power analysis (see the vignette) to assess the impact of deviations from our assumptions on power. Try:
Sample size plan scABE (EMA/ABEL) Now:
Let’s explore the panels.
— 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 |
Alyssa ☆ Malaysia, 2020-05-08 08:48 (1678 d 05:38 ago) @ Helmut Posting: # 21406 Views: 10,729 |
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Dear Helmut, Thanks for the detailed tutorial! I was trying to follow your command and out in the powerTOST, however, i cant get the sample size estimation. May i know what has gone wrong? Thank you ~ # partial replicate, 3- and 4-period full replicate designs Edit: Code and results BBCoded; see also this post #10. [Helmut] |
d_labes ★★★ Berlin, Germany, 2020-05-08 13:16 (1678 d 01:10 ago) @ Alyssa Posting: # 21407 Views: 10,886 |
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Dear Alyssa, ❝ I was trying to follow your command and out in the powerTOST, however, i cant get the sample size estimation. May i know what has gone wrong? Thank you ~ Did you issue a library(PowerTOST) before executing the rest of the code? — Regards, Detlew |
Helmut ★★★ Vienna, Austria, 2020-05-08 15:08 (1677 d 23:17 ago) @ Alyssa Posting: # 21408 Views: 10,695 |
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Hi Alyssa, ❝ Thanks for the detailed tutorial! Welcome. ❝ I was trying to follow your command and out in the powerTOST, however, i cant get the sample size estimation. May i know what has gone wrong? Your results show that you did not attach the library (see Detlew’s post). However, this part of the code alone will still not work because the CV is not specified. You would get: Error in sampleN.scABEL(CV = CV, design = res$design[j], targetpower = res$target[j], : I assumed that you will execute the entire code of the tutorial step by step. If you want only this part and/or the power analysis at the end, start with:
PS: R-terminology.
— 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 |
Alyssa ☆ Malaysia, 2020-05-12 06:05 (1674 d 08:21 ago) @ Helmut Posting: # 21426 Views: 10,269 |
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Hi Helmut, Yeah, you are right, i din't install powerTOST. Once i installed and i follow from the the start, i managed to get up to :- Sample size search Then i continued with the following command but it appeared error:- > # partial replicate, 3- and 4-period full replicate designs May i know what is this error about? Thank you. Edit: Code and results BBCoded; see also this post #10. [Helmut] |
Helmut ★★★ Vienna, Austria, 2020-05-12 13:49 (1674 d 00:36 ago) @ Alyssa Posting: # 21427 Views: 10,305 |
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Hi Alyssa, ❝ Then i continued with the following command but it appeared error: […] Let’s try to figure it out. Execute this code: library(PowerTOST) If it works now, fine. If you get the same error, try: res[1, 3:4] <- sampleN.scABEL(CV = CV, design = "2x3x3", Expected: design target n power If you get an error (or something else), let’s see what you have installed. Try this: p <- c("PowerTOST", "mvtnorm", "stats", "utils", On my machine: name version status If you have <4.0.0, I suggest to update. Then copy the entire library -folder of the old installation over the new installation. When asked whether newer files should be overwritten, answer . Open the console of the new and execute: update.packages(checkBuilt = TRUE, ask = FALSE) Once done, it should look similar to mine. 1.4.9.9999 is the development version of PowerTOST ; on your machine it should be 1.4.9. If one is missing (<NA> in the column version ), download/install it.To get more information about you installation, execute: devtools::session_info() On my machine: - Session info --------------------------------------------------------------- Likely your list will be shorter; please post here what you got. PS: When you post code/output, please embed it within the respective BBCode. With active JavaScript highlight the text in the message-area and click on the Button . THX. — 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 |
d_labes ★★★ Berlin, Germany, 2020-05-13 13:34 (1673 d 00:51 ago) @ Helmut Posting: # 21431 Views: 10,109 |
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Dear Helmut, dear Alyssa! ❝ ❝ Then i continued with the following command but it appeared error: […] ❝ Let’s try to figure it out. Execute this code: ❝ ... ❝ res <- data.frame(design = rep(designs, each = length(target)), ❝ target = target, n = NA, power = NA) This line is the casus knacktus! The error Error in match.arg(design) : 'arg' must be NULL or a character vector means that the design argument in the call of sampleN.scABEL() is not character.Reason: Before R4.0.0 the optional argument stringsAsFactors in the call of data.frame() was TRUE. Changed in R4.0.0 to FALSE.Check this in your installation via default.stringsAsFactors() If you get TRUE as answer change res <- data.frame(design = rep(designs, each = length(target)), and than I'm sure that it works. All the best — Regards, Detlew |
Helmut ★★★ Vienna, Austria, 2020-05-13 14:07 (1673 d 00:18 ago) @ d_labes Posting: # 21432 Views: 10,141 |
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Dear Detlew, oh, f**k! I forgot that users may not have updated yet. Shall we add a line to PowerTOST ’s functions as a precaution? if (is.factor(design)) design <- as.character(design) — 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 |
ElMaestro ★★★ Denmark, 2020-05-13 16:18 (1672 d 22:08 ago) @ Helmut Posting: # 21433 Views: 9,979 |
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Doh! — Pass or fail! ElMaestro |
Helmut ★★★ Vienna, Austria, 2020-05-13 16:21 (1672 d 22:04 ago) @ ElMaestro Posting: # 21434 Views: 10,008 |
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— 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 |
d_labes ★★★ Berlin, Germany, 2020-05-13 20:50 (1672 d 17:35 ago) @ Helmut Posting: # 21435 Views: 10,010 |
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Dear Helmut, ❝ oh, f**k! I forgot that users may not have updated yet. Don't worry. Many R users are fallen or will fall into this trap I think, amongst others me. ❝ Shall we add a line to ❝ Not a bad idea. But don't really know if this is absolutely necessary and if it pays the effort. — Regards, Detlew |
Helmut ★★★ Vienna, Austria, 2020-05-13 20:55 (1672 d 17:30 ago) @ d_labes Posting: # 21436 Views: 9,952 |
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Dear Detlew, ❝ Don't worry. Many R users are fallen or will fall into this trap I think, amongst others me. Count me in. ❝ ❝ Shall we add a line to ❝ ❝ ❝ ❝ Not a bad idea. But don't really know if this is absolutely necessary and if it pays the effort. It’s easy for us. But you’re right: Duno how many times a user would set up a data.frame and call the design-argument in a loop. — 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 |
Alyssa ☆ Malaysia, 2020-05-15 07:08 (1671 d 07:17 ago) @ Helmut Posting: # 21438 Views: 10,032 |
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Hi Helmut and d_labes, Sorry for late reply because i din't receive email notification i thought no one has reply to my query yet until i login just now. I followed your instructions and yeah...finally i could get the sample size estimation !!!! so happy! I dint get to try the below command because i have updated the programme to R 4.0.0 res <- data.frame(design = rep(designs, each = length(target)), When i run devtools::session_info() , this is what i get:-- Session info --------------------------------------------------------------- Thank you and Cheers~~ |
Helmut ★★★ Vienna, Austria, 2020-05-15 12:52 (1671 d 01:33 ago) @ Alyssa Posting: # 21439 Views: 9,846 |
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Hi Alyssa, ❝ Sorry for late reply because i din't receive email notification … You didn’t tick the box ☐ E-mail notification if there has been a reply to this message See also there. However, that’s not ideal because you will miss other replies (i.e., not directly addressed to you). Consider to subscribe the thread. ❝ … i thought no one has reply to my query yet until i login just now. You don’t have to login to read posts in the forum. I suggest to bookmark the Latest Posts. ❝ I followed your instructions and yeah...finally i could get the sample size estimation !!!! so happy! ❝ When i run Perfect! ❝ Thank you and Cheers~~ You are welcome! — 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 |