lakshmiprasad
☆    

India,
2018-04-11 15:09

Posting: # 18666
Views: 2,108
 

 Levothyroxine Sample size and study design [Power / Sample Size]

Dear All,

I would like to Know that regarding the sample size for levothyroxine sodium, I had gone through the all available literature's for sample size the levothyroxine sodium ISCV was found the below 18%. But the sample size was taken 72 or more than 50. if CV is below the 18% THEN what is the reason behind to considered 70 subjects:confused:.

Even OGD also It was mentioned as design is fully replicate but all literature's it was mentioned 2 way cross over.

I am thinking due to base line correction, this molecule will show any more variability?

Please guide me levothyroxine is variable drug or not.

if it was not variable in literature why it was mentioned 72 subjects.


thanks & Regards

N. L. D. Prasad
jag009
★★★

NJ,
2018-04-12 22:47

@ lakshmiprasad
Posting: # 18673
Views: 1,743
 

 Levothyroxine Sample size and study design

Hi,
1) How old are the literatures? Crossover studies probably were done before drug was considered under the NTI assessment rules.
2) Are you filing FDA or elsewhere?
3) Are you going to run pilot studies?
J
bebac_fan
☆    

US,
2018-04-12 22:49

@ lakshmiprasad
Posting: # 18674
Views: 1,708
 

 Levothyroxine Sample size and study design

Dear Prasad,

OGD product specific guidance is for 2x2x4, following NTID rules (laid out in Warfarin guidance). Yes, this is a recent change, most levo generic drugs on market right now were approved with a CO study. Current OND guidance (for NDA) is 2x2x2 crossover.

Variability would be much smaller without baseline correction. For either test, baseline correction must be applied, which is subtracting the average of 3 predose measurements from all further PK samples.

Regarding the studies you found with a sample size of 50-72, that may be required if they were powering the study for the NTID test. OR, the large sample size may be used to pass a drug with a small (e.g. GMR of 1.05) bias. AFAIK the FDA doesn't get too upset over conservative sample sizes unless they are outrageous.

Hope that helps,
BF
balakotu
★    

India,
2018-04-13 07:15
(edited by Ohlbe on 2018-04-13 10:21)

@ lakshmiprasad
Posting: # 18676
Views: 1,715
 

 Levothyroxine Sample size and study design

Dear Prasag,
Levothyroxine is tricky product and FDA categorized it as NTI drug. As per the FDA guidance for Levothyroxine (as per Warfarin guidance), bioequivalence to be established as per reference scaled average bioequivalence (95% upper CI) and average bioequivalence (90% CI within 80-125).
Also need to show the upper limit of the 90% confidence interval for σWT/σWR is less than or equal to 2.5.
As per my understanding "σWT" will be more and it is difficult to show the 90% confidence interval for σWT/σWR. (which should be less than or equal to 2.5)
The proposed sample size may be due to "90% confidence interval for σWT/σWR" and not because of RSABE or ABE.
Considering all the above information also 48 to 52 subjects are sufficient to establish bioequivalence for Levothyroxine sodium tablets 0.3 mg (dose is 0.6 mg)


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! [Ohlbe]
lakshmiprasad
☆    

India,
2018-04-14 12:55
(edited by Ohlbe on 2018-04-16 10:31)

@ balakotu
Posting: # 18681
Views: 1,638
 

 Levothyroxine Sample size and study design

Dear All,

Good Evening,

Here I gone through the all Guidelines, I understood Now because NTI nature (https://www.fda.gov/downloads/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/abbreviatednewdrugapplicationandagenerics/ucm292676.pdf), We are going to do the Fully replicate.

Thank you very much for your guidence.


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! [Ohlbe]
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