Bioequivalence and Bioavailability Forum • Naproxen ER FDA guidance

lechia
☆

C of U,
2014-04-15 00:57
(4446 d 03:34 ago)

Posting: # 12839
Views: 5,229

Naproxen ER FDA guidance [Regulatives / Guidelines]

Hi all,

I was looking at the FDA guidance for Naproxen ER tablet:
Naproxen ER FDA guidance

It says: "Additional Comments: This drug product is designed to provide both a quick onset and prolonged action. Please ensure that the Tmax (time to peak plasma naproxen concentrations) is comparable between the test and reference products."

What does "comparable" mean? Is this a qualitative comparison or an important criterium that needs to be statistically analysed? If so, what would be the best way to do this?

One way would be to do partial AUCs, for example AUC0-Tmax and AUCTmax-t and have those pass the 80-125 criterium. Is this necessary?

Thanks,
Mac

Helmut
★★★

Vienna, Austria,
2014-04-15 15:09
(4445 d 13:22 ago)

@ lechia
Posting: # 12840
Views: 4,611

Naproxen ER FDA guidance

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Hi Mac,

❝ "Additional Comments: This drug product is designed to provide both a quick onset and prolonged action. Please ensure that the Tmax (time to peak plasma naproxen concentrations) is comparable between the test and reference products."

❝

❝ What does "comparable" mean? Is this a qualitative comparison or an important criterium that needs to be statistically analysed?

These are interesting questions! On different occasions the FDA pointed out that sometimes reviewers “look” at t_max – though not mentioned the [image]

general BE guidance (and in the recent draft as well). No idea what looking means. :cool:

Maybe something similar to the ambiguous statement in EMA’s GL?

[…] if rapid release is claimed to be clinically relevant and of importance for onset of action or is related to adverse events, there should be no apparent difference in median t_max and its variability between test and reference product.

What’s “no apparent difference” and how to compare “its variability”? Box plots?

❝ […] what would be the best way to do this?

If you want to perform a formal test, nonparametric statistics^1,2 (of untransformed data) are mandatory, since t_max is sampled from a discrete distribution.*

❝ One way would be to do partial AUCs, for example AUC0-Tmax and AUCTmax-t and have those pass the 80-125 criterium. Is this necessary?

I don’t think so, since the FDA specifically asks for t_max and not for partial AUCs. The truncation time-points (early onset and prolonged action) for other ER drugs (methylphendiate and zolpidem) are based on pharmacodynamics (not the reference’s median t_max used for early exposure). I’m not aware whether such data exists for ER naproxen.

Koch GG. The Use of Non-Parametric Methods in the Statistical Analysis of the Two-Period Change-Over Design. Biometrics. 1972;28(2): 578–85.
Steinijans VW, D Hauschke D. Update on the statistical analysis of bioequivalence studies. Int J Clin Pharm Ther Toxicol. 1992;30 Suppl 1:S45–50.

Nonparametric testing of t_max (if clinically relevant) was mandatory in the EU before 2010 – and still is in other regulations. Since nonparametrics gave EMA the creeps, testing was replaced in the current GL by the vague statement given above.

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jag009 ★★★ NJ, 2014-04-15 17:36 (4445 d 10:55 ago) @ Helmut Posting: # 12842 Views: 4,506	Naproxen ER FDA guidance Post reply
	Hi Helmut and Mac, Probably use the same approach as in assessing lagtime similarity between T and R. We did that before for a product with specific lagtime, Covera HS (for FDA). Yes nonparametric test will do (Wilcoxon signed rank test was what we submitted with and no issue came back. John Edit: This is your post #500. Congratulations! [Helmut]

lechia
☆

C of U,
2014-04-15 18:10
(4445 d 10:21 ago)

@ Helmut
Posting: # 12843
Views: 4,469

Naproxen ER FDA guidance

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Thank you for your input, Helmut and John.

❝ I don’t think so, since the FDA specifically asks for t_max and not for partial AUCs. The truncation time-points (early onset and prolonged action) for other ER drugs (methylphendiate and zolpidem) are based on pharmacodynamics (not the reference’s median t_max used for early exposure). I’m not aware whether such data exists for ER naproxen.

No, you're right. In fact, according to the label, these ER tablets are supposed to work over 24h. They are made up of an immediate acting (30%) portion and a delayed release portion that's supposed to be released over a whole day.

❝ Probably use the same approach as in assessing lagtime similarity between T and R. We did that before for a product with specific lagtime, Covera HS (for FDA). Yes nonparametric test will do (Wilcoxon signed rank test was what we submitted with and no issue came back.

What significance level did you use, John? Given that there is no guidance on this, it seems like anything reasonable (as long as it's in the protocol prior to the start) would be fine?!? z_0.05,N?

Thank you for your help.

lechia
☆

C of U,
2014-04-24 18:49
(4436 d 09:42 ago)

@ lechia
Posting: # 12891
Views: 4,399

Naproxen ER FDA guidance

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❝ Coincidentally, I found a pending citizen petition related to BE criteria for Naprelan (extended release Naproxen). The petitioner did ask FDA to request partial AUCs. In checking the package insert, EC-Naprosyn (enteric coated Naproxen for delayed release) was not approved for acute pain as the release is delayed. I would like to know your opinion on this citizen petition.

For some reason I can't reply to sonny's post and had to reply to my own.

It's funny that they call it a citizen petition, because it's a petition of an interested party (the patent holder trying to protect their product from generic competition). The goal here is to make it harder for others to get bioequivalence with their product by requiring partial AUCs.

I guess anyone running a BE study for this product is advised in case the FDA is convinced by Almatica.

sunny
☆

2014-04-25 04:43
(4435 d 23:48 ago)

(edited on 2014-04-25 10:10)
@ lechia
Posting: # 12893
Views: 4,267

Naproxen ER FDA guidance

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I think the issue here is how critical the early exposure is. If early exposure is not so important based ER product's approved indications, the partial AUC may not be justified. In the case of methylphenidate and ambien, early exposure is extremely important for the onset of effect (inducing focusing and inducing sleep, respectively). In my view, the early exposure of naproxen is a little difficult to be justified. I would like to hear my thoughts from you all.

Thanks,
Sunny

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! [Dr_Dan]

sunny
☆

2014-04-17 02:07
(4444 d 02:24 ago)

(edited on 2014-04-25 10:10)
@ Helmut
Posting: # 12845
Views: 4,485

Naproxen ER FDA guidance

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Hi Helmut,

Thank you for sharing your thoughts on this topic. Coincidentally, I found a pending citizen petition related to BE criteria for Naprelan (extended release Naproxen). The petitioner did ask FDA to request partial AUCs. In checking the package insert, EC-Naprosyn (enteric coated Naproxen for delayed release) was not approved for acute pain as the release is delayed. I would like to know your opinion on this citizen petition.

http://www.regulations.gov/#!documentDetail;D=FDA-2014-P-0407-0001

Thanks,
Sunny

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! [Dr_Dan]