Elena777
☆

Belarus,
2018-01-20 11:13
(edited by Elena777 on 2018-01-21 08:46)

Posting: # 18229
Views: 2,834

## Usage of function CVfromCI (package PowerTOST) [R for BE/BA]

Dear participants of forum, I am relatively new to R and RStudio. And I really need your advise to clear some questions up which are important for my self-education and professional skills.

1. A BE study of Sotalol HCl 160 mg tablets (Mylan) and Betapace 160 mg tablets (Berlex Laboratories) with standard 2x2 cross-over design was described in one of the applications on FDA (application number 75-725). They planned to enroll 24 subjects. But in fact that study was conducted with 23 subjects. I would like to calculate CV from CI using data of that study. What data should I write for arguments "n" and "design"? If I input such data:

CVfromCI(pe = 0.99, lower = 0.87, upper = 1.13, n = 23, design = "2x2", alpha = 0.05, robust=FALSE)

RStudio gives me a result but with the following note:

CVfromCI(pe = 0.99, lower = 0.87, upper = 1.13, n = 23, design = "2x2", alpha = 0.05, robust=FALSE) Unbalanced 2x2 design. n(i)= 12/11 assumed. [1] 0.2617363

Can I use this result for futher calculations of CVpooled by means of using PowerTOST or should I correct my data?

2. While calculating CV from CI with data from another study Ive got the following result:

CVfromCI(pe = 0.96, lower = 0.9075, upper = 1.0089, n = 24, design = "2x2", alpha = 0.05, robust=FALSE) [1] 0.1071475 Warning message: sigma based on pe & lower CL more than 10% different than sigma based on pe & upper CL. Check input.

My input is correct because numbers are taken from that application not from my head. Should I pay attention to this warning message and can I use this result for futher calculations of CVpooled by PowerTOST?

3. While calculating CV from CI is it prefered to use CI for log-transformed parameters (for example LCmax) or for non-transformed parameters(Cmax)?

Big thanks in advance.
Helmut
★★★

Vienna, Austria,
2018-01-21 17:56

@ Elena777
Posting: # 18241
Views: 2,258

## Usage of function CVfromCI (package PowerTOST)

Dear Elena,

» 1. A BE study […] planned to enroll 24 subjects. But in fact that study was conducted with 23 subjects. […] If I input such data:
»
» CVfromCI(pe=0.99, lower=0.87, upper=1.13, n=23, design="2x2", alpha=0.05, robust=FALSE)
»
» RStudio gives me a result but with the following note:
»
» CVfromCI(pe=0.99, lower=0.87, upper=1.13, n=23, design="2x2", alpha=0.05, robust=FALSE)» Unbalanced 2x2 design. n(i)= 12/11 assumed.» [1] 0.2617363
»
» Can I use this result for futher calculations of CVpooled by means of using PowerTOST or should I correct my data?

The function does not “know” how many subjects in each of the sequences were dosed. The function tries to keep a 2×2 study with an odd number of subjects as balanced as possible (here 12 subjects in one sequence and 11 in the other) and throws this message.
CVfromCI(pe=0.99, lower=0.87, upper=1.13, n=23, design="2x2") Unbalanced 2x2 design. n(i)= 12/11 assumed. [1] 0.2617363
If you know the subjects per sequence and specify them in the argument n, you get the same result but without a message.
CVfromCI(pe=0.99, lower=0.87, upper=1.13, n=c(12, 11), design="2x2") [1] 0.2617363
But the study might have been even more unbalanced. Let’s try 14 subjects in one sequence and 9 in the other:
CVfromCI(pe=0.99, lower=0.87, upper=1.13, n=c(14, 9), design="2x2") [1] 0.255524
Given that if you don’t know the subjects / sequence the code’s attempt to keep the sequences as balanced as possible gives you the highest (i.e., most conservative) estimate. For the background see this presentation (slides 25–29).

» 2. While calculating CV from CI with data from another study Ive got the following result:
»
» CVfromCI(pe=0.96, lower=0.9075, upper=1.0089, n=24, design="2x2", alpha=0.05, robust=FALSE)» [1] 0.1071475» Warning message:» sigma based on pe & lower CL more than 10% different than sigma based on pe & upper CL. Check input.
»
» My input is correct because numbers are taken from that application not from my head.

Please check it again. The PE is given by $$\sqrt{lower \times upper}$$. In your case that’s $$\sqrt{0.9075 \times 1.0089} = 0.9568577$$. The function checks the input for plausibility. Hence, the message is correct since your 0.96 is different to 0.9568577.

» Should I pay attention to this warning message

Yes. Check the PE.

» and can I use this result for futher calculations of CVpooled by PowerTOST?

I would (after checking the data for correctness) suggest the ones with the highest numeric precision.

» 3. While calculating CV from CI is it prefered to use CI for log-transformed parameters (for example LCmax) or for non-transformed parameters(Cmax)?

The former. According to all guidelines the analysis for Cmax (and AUC as well) is done on log-transformed data.

Cheers,
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
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Elena777
☆

Belarus,
2018-01-27 10:02

@ Helmut
Posting: # 18295
Views: 2,071

## Usage of function CVfromCI (package PowerTOST)

Dear Helmut, thanks, I really appreciate it.