Brus
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Spain,
2021-01-21 14:24
(238 d 06:16 ago)

Posting: # 22186
Views: 987
 

 RLD strength for BE study [Design Issues]

Dear Colleagues,

We are developing a generic of an RLD with two strengths (100 mg and 50 mg).

But viewing the dosage regimen of reference drug product, it would make sense to develop a 150 mg strength even though the reference product does not have it. So, our generic drug product will have 3 strengths (150, 100 and 50 mg).

What dose should the BE study be done with? (PK linearity has been demonstrated in the range of that doses).

Should RLD 100mg VS Generic 100mg be done or RLD 100mg + RLD 50mg VS generic 150mg?

Best regards,
Helmut
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Vienna, Austria,
2021-01-21 14:37
(238 d 06:04 ago)

@ Brus
Posting: # 22187
Views: 829
 

 505(j) = ANDA, 505(b)(2) NDA = ‘hybrid’

Hi Brus,

» We are developing a generic of an RLD with two strengths (100 mg and 50 mg).
»
» But viewing the dosage regimen of reference drug product, it would make sense to develop a 150 mg strength even though the reference product does not have it. So, our generic drug product will have 3 strengths (150, 100 and 50 mg).
»
» PK linearity has been demonstrated in the range of that doses.

So far so good. Since you are mentioning RLD you are targeting the FDA, right?
Is a single (not daily) 150 mg dose approved?

» Should RLD 100mg VS Generic 100mg be done …

Yes. If a proportionality biowaiver (in vitro similarity) of the 50 mg strength works, fine. Check the product-specific guidance for the recommended conditions. If that fails, you need to perform a biostudy of the 50 mg strength as well.

» … or RLD 100mg + RLD 50mg VS generic 150mg?

For the FDA that’s an 505(b)(2) NDA (the guidance is quite old and not very specific); you can’t get an approval of the 150 mg via an ANDA since it not a generic (no 150 mg RLD). The study 150 mg (T) vs. 100 mg (RLD) + 50 mg (RLD) is just part of the story.
In Europe that’s the hybrid pathway. Additionally to this study generally clinical studies are required as well.

Dif-tor heh smusma 🖖
Helmut Schütz
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Brus
☆    

Spain,
2021-01-25 16:56
(234 d 03:45 ago)

@ Helmut
Posting: # 22188
Views: 714
 

 505(j) = ANDA, 505(b)(2) NDA = ‘hybrid’

Hi Helmut,

» So far so good. Since you are mentioning RLD you are targeting the FDA, right?

I called reference product as RLD, but it is not for FDA, it is for EMA. Sorry for the misunderstanding


» Is a single (not daily) 150 mg dose approved?

Yes. According SmPC of reference product, it is possible to administer one single dose of 150 mg.

» In Europe that’s the hybrid pathway. Additionally to this study generally clinical studies are required as well.

Why? If efficacy has indeed been demonstrated with 150 mg and SmPC establishes a 150 mg dose regimen. What more can you ask for? To my understanding, you just have to show that your 150 mg provided in your tablet will behave in the same way as the 150 mg of the reference product provided by a 100 mg tablet and a 50 mg tablet. What am I missing?

Best regards,
Helmut
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Vienna, Austria,
2021-01-25 17:39
(234 d 03:02 ago)

@ Brus
Posting: # 22189
Views: 703
 

 Directive 2001/83/EC, Article 10(3) = hybrid

Hi Brus,

» » So far so good. Since you are mentioning RLD you are targeting the FDA, right?
»
» I called reference product as RLD, but it is not for FDA, it is for EMA. Sorry for the misunderstanding

OK, then it’s a hybrid (see Dr_Dan’s post).

In cases where the medicinal product does not fall within the definition of a generic medicinal product as provided in paragraph 2(b) or where the bioequivalence cannot be demonstrated through bioavailability studies or in case of changes in the active substance(s), therapeutic indications, strength, pharmaceutical form or route of administration, vis-à-vis the reference medicinal product, the results of the appropriate pre-clinical tests or clinical trials shall be provided.


» » Is a single (not daily) 150 mg dose approved?
»
» Yes. According SmPC of reference product, it is possible to administer one single dose of 150 mg.

Good.

» » In Europe that’s the hybrid pathway. Additionally to this study generally clinical studies are required as well.
»
» Why? If efficacy has indeed been demonstrated with 150 mg and SmPC establishes a 150 mg dose regimen. What more can you ask for? To my understanding, you just have to show that your 150 mg provided in your tablet will behave in the same way as the 150 mg of the reference product provided by a 100 mg tablet and a 50 mg tablet. What am I missing?

Since no 150 mg reference exists, you can’t go the generic pathway acc. to Article 10(2)(b).
I strongly suggest a scientific advice (at a “difficult” agency). That’s what I did in all of my hybrid applications. What you need additionally to the comparative BA study needs to be settled. If it’s a simple IR product (no excipients influencing gastric motility, no solubility problems) maybe clinical trials can be waived.

Dif-tor heh smusma 🖖
Helmut Schütz
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