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chris089
Junior

Munich, Germany,
2018-04-16 13:43

Posting: # 18687
Views: 1,312
 

 oral powder with water acceptable? [Regulatives / Guidelines]

Hello,

We have developed an oral powder for which we need to show BE to an existing tablet. I have inherited the results of a (narrowly) failed two-way BE study where the powder was administered without water and the reference with water. We have reasons to believe that the powder administered with water, would be bioequivalent to the tablet, and while it would not be as sexy marketing-wise as the intake without water, we are considering a second study where test and reference are taken with water.

Does anybody have experience, if the regulatory agencies (EU, free choice of RMS) would accept these results if only administration with water is claimed in the SmPC?

I know, that an oral powder is treated similarly to an ODT (PKWP Q&A). THE Guideline recommends a 3-period study (we would have 2x2, but should be OK), but there is no information on the consequence, if BE w/ water is demonstrated, but BE w/o water fails. Does this mean, that the whole product is considered not bioequvalent, or just that you cannot claim the application w/o water?
The famous last paragraph says "recommended use of the product", which I translate as "according to the SmPC".

Maybe it's a stupid question, but I'm new to the business. I have read the previous 1000 questions on water, but AFAIK this has not been discussed yet.

Best,
Christian
ElMaestro
Hero

Denmark,
2018-04-16 14:14

@ chris089
Posting: # 18688
Views: 1,145
 

 oral powder with water acceptable?

Hello Christian,

'narrowly failed' suggests that your product may indeed be BE but that you lacked sample size. This scenario if often a candidate for a repeat trial, but it comes down to the specifics and sometimes even national habits.
Can you show the numbers for the CIs?

Having said that, an oral powder is often given with something that isn't chewed. Can you shed a little more light on your previous trial: results, administration, food/water restriction post dose, and so forth?

If your product is approved only along with water, which is indeed a quite possible future outcome if you go down that route, then you may run into some substitution issues such as getting an approval but not the substitution in some countries. Do you aim for a 10.1/2 or a 505(j), or what country(ies)?

if (3) 4

Best regards,
ElMaestro

"(...) targeted cancer therapies will benefit fewer than 2 percent of the cancer patients they’re aimed at. That reality is often lost on consumers, who are being fed a steady diet of winning anecdotes about miracle cures." New York Times (ed.), June 9, 2018.
chris089
Junior

Munich, Germany,
2018-04-17 12:12

@ ElMaestro
Posting: # 18689
Views: 1,088
 

 oral powder with water acceptable?

Hello ElMaestro,

Thank you for your quick reply.

The kind of oral powder I meant is something like that (http://www.sanaplus.com/product/powder-shots/powder-shot-vitamin-c-500-mg/), not the kind that is meant to be mixed with food for toddlers or elderly. That's why a claim "without water" would have been preferred, but it's not a no-go to specify water in the SmPC.
We are targeting OTC only, reimbursement is not an issue for us.

Regulatory environment: EU only, decentralised procedure, definitely Germany and Austria, probably additional CMS, free choice of RMS, 10(1) generic application (or probably 10(3) hybrid)

Study results
Cmax: 82,70%, CI 77,08%-88,74%, CV 15,81%
AUC0-tlast: 98,22%, CI 95,26%-101,28%, CV 6,84%
tmax(test): 2,70h
tmax(ref): 1,85h

sample size: 29 (30-1 dropout)
power for 15% CV and 10% product difference: 90%
necessary sample size for observed difference (17%): 280 for 80%, which is a no-go

Study design
single centre, open-label, randomised order of treatments, balanced, 3-period, 6-sequence, single dose change-over trial, administration under fasting conditions, separated by washout period >= 2 days
(Two reference products were used, one for BE, the other for marketing reasons...)

Food/liquid intake:
(Fasted state is the recommended condition for this substance.)
standardized dinner on evening before treatment, >8h fasting (no food, no beverages) before administration
standardized meals at 4, 8 and 12h p.a.
no fluid intake for 1h p.a., standardized fluid intake at 1-10h p.a. (150ml non-carbonated water per hour)

Administration of oral powder: wet mouth by swallowing 20ml tap water before administration, oral cavity examined after swallowing
Administration of reference: tablet taken with 240ml water

Our conclusion: We missed Cmax due to slower absorption, most likely because of slower gastric passage (no resorption in the stomach). Administration with water would most likely solve the problem, i.e. result in a lower CI above 80.00%.

Therefore our main question is:
If BE is shown for administration with water, but not shown for administration without water, would the regulatory authorities accept a restriction "only with water" in the product information, or would they consider it a "potential serious risk to public health" and refuse the marketing authorisation, arguing that a patient might take the powder without water?

The situation is similar to the guideline for ODTs, where a comparative study ODT with water vs ODT without water vs reference with water is recommended, but the consequences of "failing BE without water" are not clear to me.

Thanks again,
Christian

P.S.: The statistics are all calculated by the CRO, not in-house.
ElMaestro
Hero

Denmark,
2018-04-17 12:57

@ chris089
Posting: # 18690
Views: 1,064
 

 oral powder with water acceptable?

Hi Christian,

» Study results
» Cmax: 82,70%, CI 77,08%-88,74%, CV 15,81%
» AUC0-tlast: 98,22%, CI 95,26%-101,28%, CV 6,84%

Damned!:-)

What potencies or assays were mentioned on the CoA's?

if (3) 4

Best regards,
ElMaestro

"(...) targeted cancer therapies will benefit fewer than 2 percent of the cancer patients they’re aimed at. That reality is often lost on consumers, who are being fed a steady diet of winning anecdotes about miracle cures." New York Times (ed.), June 9, 2018.
chris089
Junior

Munich, Germany,
2018-04-17 15:57

@ ElMaestro
Posting: # 18692
Views: 1,018
 

 oral powder with water acceptable?

Assays are:
test product: 101,2%
reference product: 99,1%
ElMaestro
Hero

Denmark,
2018-04-17 16:23

@ chris089
Posting: # 18693
Views: 1,026
 

 oral powder with water acceptable?

» Assays are:
» test product: 101,2%
» reference product: 99,1%

Alter Schwede, this one is difficult.
I think your own idea is viable and that your considerations sound ok, but the whole scenario kind of sucks. Big time.
Perhaps I would approach the friendly people in Sweden, mention SE as RMS and AT+DE as CMS and see if they (SE) are lenient on you.

One last thing: If the abs is "very fast", and I cannot quantitatively define it very well as it also has to do with your sampling regimen, then perhaps you want to try to look into partial AUCs up to around the time of Cmax.

I hope others will chime in with opinions here. This is a great case, actually.

if (3) 4

Best regards,
ElMaestro

"(...) targeted cancer therapies will benefit fewer than 2 percent of the cancer patients they’re aimed at. That reality is often lost on consumers, who are being fed a steady diet of winning anecdotes about miracle cures." New York Times (ed.), June 9, 2018.
chris089
Junior

Munich, Germany,
2018-04-19 16:18

@ ElMaestro
Posting: # 18700
Views: 799
 

 oral powder with water acceptable?

It does suck, doesn't it? Even more so as I see another company who has almost the same formulation and got lucky. But then, good and bad luck is part of statistics (they had fewer samples - broader CI, but slightly higher). Or they used water and it's not mentioned in the public AR...

Excuse me, but being a newbie, I need some translations:
» Perhaps I would approach the friendly people in Sweden, mention SE as RMS and AT+DE as CMS and see if they (SE) are lenient on you.
approach = "scientific advise"?
lenient = "accept our results as BE"? or "give us the marketing authorisation if we pass BE with water in an additional study"?

» One last thing: If the abs is "very fast", and I cannot quantitatively define it very well as it also has to do with your sampling regimen, then perhaps you want to try to look into partial AUCs up to around the time of Cmax.
What might be the outcome of that?
There seem to be sufficient samples around tmax (10, 20, 30min, every 15min til 2h, every 30min til 4h, ...)

» I hope others will chime in with opinions here. This is a great case, actually.
Glad to hear that. Initially, I was hesitant to ask.
ElMaestro
Hero

Denmark,
2018-04-19 18:30

@ chris089
Posting: # 18701
Views: 777
 

 oral powder with water acceptable?

Hi again,

» Excuse me, but being a newbie, I need some translations:

I apologise, sometimes I write stuff that isn't very clear.

» » Perhaps I would approach the friendly people in Sweden, mention SE as RMS and AT+DE as CMS and see if they (SE) are lenient on you.
» approach = "scientific advise"?
» lenient = "accept our results as BE"? or "give us the marketing authorisation if we pass BE with water in an additional study"?

Yes something along those lines. You can never know when regulators throw a curve ball, but sometimes they take an interest in the product and will help you forward. But they don't do that in all countries.

» What might be the outcome of that?
» There seem to be sufficient samples around tmax (10, 20, 30min, every 15min til 2h, every 30min til 4h, ...)

I don't know what the outcome is. But if the outcome is suggestive of equivalence then perhaps this is the kind of thing that will make regulators be gentle to you. We are way out of the book here, and that is why you need the advice.

if (3) 4

Best regards,
ElMaestro

"(...) targeted cancer therapies will benefit fewer than 2 percent of the cancer patients they’re aimed at. That reality is often lost on consumers, who are being fed a steady diet of winning anecdotes about miracle cures." New York Times (ed.), June 9, 2018.
chris089
Junior

Munich, Germany,
2018-04-19 18:36

@ ElMaestro
Posting: # 18702
Views: 779
 

 oral powder with water acceptable?

Thank you for the clarification!
Let's see if we find something, but there are many alternatives for this substance, just not as user-friendly, so I doubt regulators will take enough interest in it to bend guidelines.

Have a nice evening,
Christian
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