prashantmohite
☆    

India,
2014-12-20 05:57
(3387 d 10:45 ago)

Posting: # 14123
Views: 5,454
 

 Different strenghts [Design Issues]

Hi All...

At present i am working on XYZ molecule at three different strengths 10 mg, 25 mg and 50 mg for EU submission.

Currently only RLD available is for 25 mg. A couple of years back we performed a pilot biostudy and proved that 10 mg tablets show linear PK and dose proportionality with 25 x 2 dose (two 25 mg tablets administered). But their linear PK data is not available in the public domain.

Now since only 25 mg RLD is available, can i opt the following options to perform biostudy for getting approval for all three strengths:
  1. 10 mg x 2 and half tablets vs 25 mg RLD
  2. 10 mg x 5 tablets vs 25 x 2 mg RLD
  3. 25 mg x 2 tablets vs 25 x 2 mg RLD
  4. 25 mg vs 25 mg RLD
Is is there any other option that i can market all the three strengths.

Regards,

Prashant


Edit: Subject line and category changed. [Helmut]
ElMaestro
★★★

Denmark,
2014-12-20 14:19
(3387 d 02:23 ago)

@ prashantmohite
Posting: # 14124
Views: 4,442
 

 Different strenghts

Hi Prashant,

❝ Currently only RLD available is for 25 mg. A couple of years back we performed a pilot biostudy and proved that 10 mg tablets show linear PK and dose proportionality with 25 x 2 dose (two 25 mg tablets administered). But their linear PK data is not available in the public domain.


RLD and EU are mutually exclusive. RLD would be the term you use for US submissions. Do you mean in EU there is no reference product available in the strenght you're wishing to develop?

❝ Now since only 25 mg RLD is available, can i opt the following options to perform biostudy for getting approval for all three strengths:


❝ a. 10 mg x 2 and half tablets vs 25 mg RLD

❝ b. 10 mg x 5 tablets vs 25 x 2 mg RLD

❝ c. 25 mg x 2 tablets vs 25 x 2 mg RLD

❝ d. 25 mg vs 25 mg RLD


❝ Is is there any other option that i can market all the three strengths.


This is not straightforward.
If you can prove to regulators that PK is linear or proportional or whatever the term is (Hötzi, in which direction do the terminological winds blow these days?) then that is perhaps a very good start but I could be a little afraid that it is not necessarily enough.
If there is no ref. in the strength you are developing then I see only art. 10.3. of dir. 2001/83 as your EU submission basis and then we are no longer discussing a true generic. The wording of art. 10.3. specifically mentions a change in strength.
It is an interesting question if you could then first get a 10.1/10.2 (generic) approval for the 25mg formulation and then subsequently introduce the other two strengths via the hybrid article. I am not sure I have a qualified opinion. It could easily require additional trials, I reckon. Otherwise, how could you know if the other strengths are therapeutically efficaceous and safe?
Would like to hear other people's opinion about the regulatory principle. If I were you I would definitely take a scientific advice even if it means some cost and time consumption.

Pass or fail!
ElMaestro
Helmut
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Vienna, Austria,
2014-12-20 15:24
(3387 d 01:18 ago)

@ ElMaestro
Posting: # 14125
Views: 4,471
 

 Different strenghts

Hi ElMaestro & Prashant,

❝ If you can prove to regulators that PK is linear or proportional or whatever the term is (Hötzi, in which direction do the terminological winds blow these days?) then that is perhaps a very good start…


EMA uses only the term “dose proportionality” in relation to linear PK. Pharmacokineticists will tell you that’s a power model E(Y|D) = α·D β, where α >0 and β ≠ 0. No departure from dose linearity if the 95% (!) confidence interval (L, U) of β is 0.75 < L < 1 < U < 1.25. For EMA it’s just dose-nor­ma­lized AUC within ±25%.

❝ …but I could be a little afraid that it is not necessarily enough.


Exactly.

❝ Would like to hear other people's opinion about the regulatory principle.


One of my cases: Only IR on the market. One product 5/10/20 mg, another one 10/20/40 mg. Maximum approved daily dose 60 mg.
  • 20 mg new MR vs. 2 × 10 mg IR, hybrid pathway (two clinical studies; individualized doses up to 60 mg). ⇒ Approval of 20 mg.
  • Dose proportionality of new MR 10/20/40 mg; BE of dose-adjusted PK-metrics compared to 20 mg strength, 95% (Bonferroni!) CIs. ⇒ Approval of 10 & 40 mg.
    The BfArM told us that nowadays they would want to see 4 × 10 mg & 1 × 40 mg vs. 2 × 20 mg…
  • Dose proportionality biowaiver for 5 mg strength.
  • Line extension for new 50/60 mg MR. BE 60 mg vs. 2 × 30 mg. Two clinical studies.
  • Dose proportionality biowaiver for 50 mg strength. ⇒ Approval of 50 & 60 mg.

❝ If I were you I would definitely take a scientific advice even if it means some cost and time consumption.


As we did…

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cher0424
☆    

China,
2014-12-22 03:30
(3385 d 13:12 ago)

@ Helmut
Posting: # 14131
Views: 4,224
 

 Different strenghts

Hi Helmut

❝ One of my cases: Only IR on the market. One product 5/10/20 mg, another one 10/20/40 mg. Maximum approved daily dose 60 mg.

20 mg new MR vs. 2 × 10 mg IR, hybrid pathway (two clinical studies; individualized doses up to 60 mg). ⇒ Approval of 20 mg.


Can you specify what are these two clinical studies? One BE, and one dose up study?
Helmut
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Vienna, Austria,
2014-12-22 03:58
(3385 d 12:44 ago)

@ cher0424
Posting: # 14133
Views: 4,278
 

 Different strenghts

Hi cher0424

❝ ❝ 20 mg new MR vs. 2 × 10 mg IR, hybrid pathway (two clinical studies; individualized doses up to 60 mg). ⇒ Approval of 20 mg.


❝ Can you specify what are these two clinical studies? One BE, and one dose up study?


No. The hybrid pathway in the EU means PK + some clinical stuff in patients (therapeutic equivalence or non-inferiority). In my case I had one comparative BA-study (that’s not BE!) and two TE studies. And yes: In both TE studies dose tritration.

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mittyri
★★  

Russia,
2014-12-22 21:30
(3384 d 19:12 ago)

@ Helmut
Posting: # 14139
Views: 4,204
 

 Different strenghts

Hi Helmut,

❝ In my case I had one comparative BA-study (that’s not BE!) and two TE studies.


Could you please specify, what's the difference between comparative BA-study and BE?
As I can remember "A bioequivalence study is basically a comparative bioavailability study"

Kind regards,
Mittyri
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