marianna.macera
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Brazil,
2021-06-30 15:04
(78 d 06:09 ago)

(edited by marianna.macera on 2021-06-30 16:48)
Posting: # 22443
Views: 475
 

 Intrauterine Device – Levo­nor­gestrel 52 mg [Design Issues]

Dear All,

Could anyone make a suggetion about number of subjects to a Bioequivalence / Bioavailability studie of a intrauterine system contening Levonorgestrel? We are following FDA- "Draft Guidance on Levonorgestrel" and was used CV 35.5%, from a clinical study phase II, it is that possible?
Relaxation
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Germany,
2021-06-30 17:22
(78 d 03:51 ago)

@ marianna.macera
Posting: # 22445
Views: 393
 

 Intrauterine Device – Levo­nor­gestrel 52 mg

Dear Marianna.

Interesting question. Although I'd say its possible in principle (but have no experience myself with this specific approach for a long-term contraceptive), I would say that some more information is required.

Like is the CV you mentioned taken from a clinical trial at least similar to the intended investigation? And from a similar evaluation (point estimates and CI available, ANOVA on logarithmized values)? Or from a descriptive statistic and calculated as mean/standard deviation?
I think a link to the report of the phase II would be the best approach here, if something like that is available.

I may also say, that, given that the trial will take at least 12 months and likely hundreds of subjects in each arm will be required, it may be wise to get a biostatistician involved into the trial who can thoroughly check the available data, whether these fit.

Best regards,
Relaxation.
marianna.macera
☆    

Brazil,
2021-07-02 16:55
(76 d 04:18 ago)

@ Relaxation
Posting: # 22453
Views: 349
 

 Intrauterine Device – Levo­nor­gestrel 52 mg

Dear Relaxation,

I appreciated your answer, thank you.
There is Besides " FDA Draft Guidance on Levonorgestrel", We used data from the article: "Comparative pharmacokinetic analysis of levonorgestrel-releasing intrauterine systems and levonorgestrel-containing contraceptives with oral or subdermal administration route" Hofmann et. al, 2020.
But the point still the number of subjects in this BE/BA study, because in this case, parallel design needs an intra+inter CV%. But in a scientific literature review, we don't find something like that. A suggestion about mitigating the error in subject number determination?

Best regards,
Helmut
★★★
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Vienna, Austria,
2021-07-02 17:18
(76 d 03:54 ago)

@ marianna.macera
Posting: # 22454
Views: 349
 

 Intrauterine Device – Levo­nor­gestrel 52 mg

Hi Marianna,

» We used data from the article: "Comparative pharmacokinetic analysis of levonorgestrel-releasing intrauterine systems and » levonorgestrel-containing contraceptives with oral or subdermal administration route" Hofmann et. al, 2020.
» But the point still the number of subjects in this BE/BA study, because in this case, parallel design needs an intra+inter CV%.

Actually you need CVtotal. That’s not the sum (or average) of both. You need to average the variances and back-convert them to a CV. In [image]:

pooling <- function(CV.inter, CV.intra) {
  CV2var <- function(CV)  return(log(CV^2 + 1))
  var2CV <- function(var) return(sqrt(exp(var) - 1))
  return(var2CV(mean(c(CV2var(CV.inter), CV2var(CV.intra)))))
}
CV.inter <- 0.80
CV.intra <- 0.40
CV.total <- pooling(CV.inter, CV.intra)
cat("CV.inter =", sprintf("%.2f%%", 100 * CV.inter),
    "\nCV.inter =", sprintf("%.2f%%", 100 * CV.intra),
    "\nCV.total =", sprintf("%.2f%%", 100 * CV.total), "\n")

Gives

CV.inter = 80.00%
CV.inter = 40.00%
CV.total = 61.59%


» But in a scientific literature review, we don't find something like that.

I don’t have this article. If the study was performed in a parallel design, you have already CVtotal. If it was not reported, you can calculate it from the confidence interval and the sample size by the function CVfromCI() in PowerTOST. If it was a crossover (very, very unlikely), use the code above.

» A suggestion about mitigating the error in subject number determination?

Not sure what you mean by that. Perhaps this article helps.

Dif-tor heh smusma 🖖
Helmut Schütz
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