Bioequivalence and Bioavailability Forum • NDA study for Mexico

jag009
★★★

NJ,
2019-12-06 17:19
(1269 d 04:24 ago)

Posting: # 20943
Views: 3,009

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
★★★

Vienna, Austria,
2019-12-06 17:41
(1269 d 04:01 ago)

@ jag009
Posting: # 20945
Views: 2,430

Cmax ER = Cmax IR ?

Post reply

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 C_max you would have proven that your product is not an ER. Bizarre idea.

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes

mittyri
★★

Russia,
2019-12-06 18:08
(1269 d 03:34 ago)

@ Helmut
Posting: # 20946
Views: 2,406

Cmax ER = Cmax IR - the only option

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Hi All,

❝ What‽ If you would succeed in demonstrating BE of C_max 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")

Could it be Mexico's reviewers ER vision?

—
Kind regards,
Mittyri

Helmut ★★★ Vienna, Austria, 2019-12-06 18:36 (1269 d 03:06 ago) @ mittyri Posting: # 20947 Views: 2,396	Cmax ER = Cmax IR - the only option Post reply
	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!” — Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes

jag009
★★★

NJ,
2019-12-06 18:38
(1269 d 03:04 ago)

@ Helmut
Posting: # 20948
Views: 2,427

Cmax ER = Cmax IR ?

Post reply

❝ ❝ […] 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 C_max 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
★★★

Vienna, Austria,
2019-12-06 18:45
(1269 d 02:58 ago)

@ jag009
Posting: # 20949
Views: 2,387

Cmax ER = Cmax IR ?

Post reply

Hi John,

❝ ❝ If you would succeed in demonstrating BE of C_max 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. C_max was doable but only with expanded limits.

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes

jag009 ★★★ NJ, 2019-12-06 22:21 (1268 d 23:22 ago) @ Helmut Posting: # 20950 Views: 2,375	Cmax ER = Cmax IR ? Post reply
	Hi Helmut (and guys and girls) ❝ Had that on this side of the pond as well (called a “hybrid application”); multiphasic product. C_max 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 23:40 (1268 d 22:02 ago) @ jag009 Posting: # 20952 Views: 2,334	Cmax ER = Cmax IR ? Post reply
	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 19:15
(1266 d 02:28 ago)

@ Yura
Posting: # 20967
Views: 2,302

Cmax ER = Cmax IR ?

Post reply

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