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Back to the forum  Query: 2018-05-21 13:13 CEST (UTC+2h)
 
Elena777
Junior

Belarus,
2018-01-20 12:31
(edited by Elena777 on 2018-01-20 20:44)

Posting: # 18231
Views: 1,845
 

 CV values in BE studies: intra, or inter, or total? [Study As­sess­ment]

Hello to all.

There is data about CV values (often these values are placed into brackets) in many published reports of BE studies.

I`ll provide two examples in order to make my BIG question clear:

1. In a single dose, randomised 3-way cross-over bioequivalence study, comparing the proposed 160 mg product with two reference 160mg tablets from France (Sotalex, Bristol Myers Squibb, France) and Australia (Sotacor, Bristol Myers Squibb, Australia) in healthy adult male volunteers under fasting conditions such results were obtained:

Ln Cmax(ng/ml) for Sotalex-French Reference tablets 160 mg: Mean (CV) = 1212.09 (28.7)

The link to the source: http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con2031163.pdf

2. In a another randomized two-dose two-period crossover study on the bioequivalence of oral and intravenous sotalol CV for Cmax (oral route of administration) was 0.41. This value was performed in a separate cell of a table (that table contained data about individual levels of PK parameters of participants, min, max, mean, median as well; you can check it here: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022306s000ClinPharmR.pdf)

The question:

Which kind of CV is performed in my examples? And in general which kind of CV is usually performed in reports of BE studies? Is it CVintra, or CVinter, or CVtotal?


Edit: Please don’t shout! [Helmut]
jag009
Hero

NJ,
2018-01-20 19:18

@ Elena777
Posting: # 18232
Views: 1,601
 

 CV values in BE studies: intra, or inter, or total?

Hi

» Ln Cmax(ng/ml) […]: Mean (CV) = 1212.09 (28.7)

I checked the table... That's not the intrasubject CV. That's just the CV from (SD/Mean)*100.
Same answer from your 2nd question (I didn't look but I assume you were referring to a result that has similar output format as in Mean(CV)).

» Which kind of CV is performed in my examples? And in general which kind of CV is usually performed in reports of BE studies? Is it CVintra, or CVinter, or CVtotal?

In the world of BE we deal with CVintra because that's what we are interested in since that's one of the driving force in computing the 90% CI goal post for BE. We do care about inter and CVtotal as well depending on the type of BE study design we are going after (crossover or parallel).

J
Elena777
Junior

Belarus,
2018-01-20 21:10

@ jag009
Posting: # 18233
Views: 1,540
 

 CV values in BE studies: intra, or inter, or total?

jag009, thank you for your answer and for revision of my link. But what does it mean "simple CV"? Why can't we say that this is CVinter?
I understood that CVintra is a value important in planning and realization of BE studies. But I need your consultation once more: after all which kind of CV we usually observe in reports of BE studies (when CV is performed in the way like in my examples)?


Edit: Please don’t shout! [Helmut]
jag009
Hero

NJ,
2018-01-21 03:17

@ Elena777
Posting: # 18235
Views: 1,509
 

 CV values in BE studies: intra, or inter, or total?

What is simple CV? :confused:
IntraCV is called within subject CV. To keep it simple yes this is the one we usually focus on (and yes observe mostly) on in the BE report.
J
Elena777
Junior

Belarus,
2018-01-21 08:21

@ jag009
Posting: # 18237
Views: 1,510
 

 CV values in BE studies: intra, or inter, or total?

jag009, sorry, I was wrong with my text input. Sometimes it is quite uncomfortable to input text on my tablet, I used a wrong word. I wanted to ask which CV did you mean in the following sentence of you previous message:

» That's just the CV from (SD/Mean)*100."

So I wanted to write: what is "just the CV..."? Not "simple CV". Sorry once more.


Edit: Standard quotes restored; see also this post #8. [Helmut]
Helmut
Hero
Homepage
Vienna, Austria,
2018-01-21 17:33

@ Elena777
Posting: # 18240
Views: 1,486
 

 CV values in BE studies: intra, or inter, or total?

Hi Elena,

» […] in general which kind of CV is usually performed in reports of BE studies? Is it CVintra, or CVinter, or CVtotal?

It depends on the design of the study. See this presentation (slides 17–18).

[image]Cheers,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
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ElMaestro
Hero

Denmark,
2018-01-21 18:17

@ Elena777
Posting: # 18242
Views: 1,504
 

 CV values in BE studies: intra, or inter, or total?

Hi Elena

perhaps not a direct answer to your actual question but a general comment to the general question you aired:
  1. For a crossover trial with 2 treatments, 2 sequences and 2 periods we use the "within subject variance" to construct the confidence interval. The CV is derived from this variance. We can call it a within-subject CV but it is not treatment-specific; you can say it is an estimate of a common intra-subject variance or CV. CV = sqrt(exp(Variance)-1). We get that variance as the residual error from a linear model with various factors.
  2. For a crossover trial with replication of the reference treatment the important CV, but not the only one, is the CV associated with the reference treatment.
  3. For a parallel trial we derive a total variance and total CV for the construction of a confidence interval. If the trial is done in batches, then the CV is somehow a kind of total CV excluding the component of the influence of batch, if calculated correctly. Yes, cosmic mindf%cker but BE often is.
When you read study reports or assessment reports you often come across descriptive statistics. Here the CV is simply the (sample) sd divided by (sample) mean.

If you want to use a CV for sample size calculation, then you need to know which model you applied in the dataset where the CV came from and what the model is the design you want to apply - the model is dependent on the study design itself. If you have a CV from a 222BE trial, then obviously this could be directly used for sample size calculation in another 222BE trial assuming your assay and other factors are as good as in the other trial. If you want to apply the CV from a 222BE trial to a replicated trial then that is still a decent guess in my opinion and vice versa. What you should not do is to apply the CV from descriptive stats to any sample size calculation, or to confuse CV's from parallel trial with CV's from crossovers.

Intra-subject CVs are generally (=most often) lower than between-subject CVs which are lower than total CVs.

“A ten-year, double-blind study from the Mayo Clinic concluded that even in late stages of dementia, the last to go is the lobe of the brain in charge of cafeteria layout.” (Serge Storms/Tim Dorsey).


Best regards,
ElMaestro

- Bootstrapping is a relatively new hobby of mine. I am only 30 years late to the party.
Elena777
Junior

Belarus,
2018-01-27 09:57

@ ElMaestro
Posting: # 18294
Views: 1,308
 

 CV values in BE studies: intra, or inter, or total?

jag009, Helmut and ElMaestro, thank you so much for the information, you`ve provided here. It is really useful for me.
Louis52
Junior

2018-02-07 20:22

@ Elena777
Posting: # 18372
Views: 980
 

 CV values in BE studies: intra, or inter, or total?

Just to follow up with a question regarding the total CV...as in the case of the sampleN.TOST function for "parallel" design. We supposed to use the total CV in that case, right? That means we should have prior knowledge of both MSEw and MSEb.
Helmut
Hero
Homepage
Vienna, Austria,
2018-02-07 20:31

@ Louis52
Posting: # 18373
Views: 981
 

 CV values in BE studies: intra, or inter, or total?

HI Louis,

» […] the sampleN.TOST function for "parallel" design. We supposed to use the total CV in that case, right?

Correct.

» That means we should have prior knowledge of both MSEw and MSEb.

Again correct (you get them from crossover designs). If the previous study had a parallel design the CV (calculated from the ANOVA’s residual error) is already CVtotal (aka CVpooled) anyway and you can plug it in directly.

[image]Cheers,
Helmut Schütz 
[image]

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