jag009
★★★

NJ,
2019-12-06 15:19

Posting: # 20943
Views: 756
 

 NDA study for Mexico [Regulatives / Guidelines]

Hi,

Does anyone have experience conducting NDA studies for ER products in Mexico? I mean running a study comparing ER once a day vs IR given multi-times a days, e.g, ER vs IR given every 4 hours. When conducting such studies, the success criteria is based on equivalent AUC (90% CI), and not Cmax due to the nature of the ER drug release kinetic.

I received a comment from the mexico regulatory when they reviewed the protocol. They wanted Cmax as an equivalent criteria as well but that is not my intention (I ran studies like this in US and usually this is not a problem at the protocol review stage).


Thx
J
Helmut
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Vienna, Austria,
2019-12-06 15:41

@ jag009
Posting: # 20945
Views: 474
 

 Cmax ER = Cmax IR ?

Hi John,

» […] a study comparing ER once a day vs IR given multi-times a days, e.g, ER vs IR given every 4 hours. When conducting such studies, the success criteria is based on equivalent AUC (90% CI), and not Cmax due to the nature of the ER drug release kinetic.
»
» I received a comment from the mexico regulatory when they reviewed the protocol. They wanted Cmax as an equivalent criteria as well …

What‽ If you would succeed in demonstrating BE of Cmax you would have proven that your product is not an ER. Bizarre idea.

Cheers,
Helmut Schütz
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The quality of responses received is directly proportional to the quality of the question asked. 🚮
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mittyri
★★  

Russia,
2019-12-06 16:08

@ Helmut
Posting: # 20946
Views: 462
 

 Cmax ER = Cmax IR - the only option

Hi All,

» What‽ If you would succeed in demonstrating BE of Cmax you would have proven that your product is not an ER. Bizarre idea.

Hmmm
the only option I see is something like this
t <- c(seq(0,24,0.1))
ka <- .5
ke <- 0.1
D = 100
V = 2
C <- D/V*(ka/(ka-ke))*(exp(-ke*t) - exp(-ka*t))
C[50] <- C[50]*10
ggplot2::qplot(t,C, geom = "line")

[image]
Could it be Mexico's reviewers ER vision?

Kind regards,
Mittyri
Helmut
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Homepage
Vienna, Austria,
2019-12-06 16:36

@ mittyri
Posting: # 20947
Views: 449
 

 Cmax ER = Cmax IR - the only option

Hi Mittyri,

lovely plot!

» Could it be Mexico's reviewers ER vision?

Helmut Schmidt once said: “Anyone who has visions should go to the physician!”

Cheers,
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
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jag009
★★★

NJ,
2019-12-06 16:38

@ Helmut
Posting: # 20948
Views: 449
 

 Cmax ER = Cmax IR ?

» » […] a study comparing ER once a day vs IR given multi-times a days, e.g, ER vs IR given every 4 hours. When conducting such studies, the success criteria is based on equivalent AUC (90% CI), and not Cmax due to the nature of the ER drug release kinetic.
» »
» » I received a comment from the mexico regulatory when they reviewed the protocol. They wanted Cmax as an equivalent criteria as well …
»
» What‽ If you would succeed in demonstrating BE of Cmax you would have proven that your product is not an ER. Bizarre idea.

Exactly. I am at a lost. I am not sure if the reviewer misread the protocol or he doesn't understand the concept. Having said that (dont laugh), FDA once asked us to show BE for a 505b2 for an once day ER vs IR @ 4 hrs with respect to Cmax and AUC. It was v strange unless they are suspecting that Cmax is associated with efficacy (somehow).

John
Helmut
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Vienna, Austria,
2019-12-06 16:45

@ jag009
Posting: # 20949
Views: 448
 

 Cmax ER = Cmax IR ?

Hi John,

» » If you would succeed in demonstrating BE of Cmax you would have proven that your product is not an ER. Bizarre idea.
»
» Exactly. I am at a lost. I am not sure if the reviewer misread the protocol …

Might well be.

» … or he doesn't understand the concept.

Well,…

» Having said that (dont laugh), FDA once asked us to show BE for a 505b2 for an once day ER vs IR @ 4 hrs with respect to Cmax and AUC. It was v strange unless they are suspecting that Cmax is associated with efficacy (somehow).

Had that on this side of the pond as well (called a “hybrid application”); multiphasic product. Cmax was doable but only with expanded limits.

Cheers,
Helmut Schütz
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The quality of responses received is directly proportional to the quality of the question asked. 🚮
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jag009
★★★

NJ,
2019-12-06 20:21

@ Helmut
Posting: # 20950
Views: 420
 

 Cmax ER = Cmax IR ?

Hi Helmut (and guys and girls)

» Had that on this side of the pond as well (called a “hybrid application”); multiphasic product. Cmax was doable but only with expanded limits.

Do you know of any articles which say that Cmax is not a primary parameter (for equivalence) for ER product, when compared to IR?

Thx
john
Yura
★    

Belarus,
2019-12-06 21:40

@ jag009
Posting: # 20952
Views: 413
 

 Cmax ER = Cmax IR ?

Hi John

We have: four maximums and four minimums for IR and one maximum and one minimum for ER

We substantiate: Long-acting opioids will help to avoid the ups and downs of pain that a patient may experience when taking short-acting drugs.
Also compare the time for Cmin ER and the time for fourth Cmin4 IR - is it correct to compare the time of the general action?

Kind regards
jag009
★★★

NJ,
2019-12-09 17:15

@ Yura
Posting: # 20967
Views: 354
 

 Cmax ER = Cmax IR ?

Hi,

» We have: four maximums and four minimums for IR and one maximum and one minimum for ER

If I understand your question correctly... In general, your trough (Cmin) for ER should be similar (or above) your Cmin of the IR in terms of level (is your a 24hr once daily? If so, then the Cmin of ER at 24 should be similar to Cmin of IR at 24). Your ER should also show less fluctuation than IR (you should).

J
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