Helmut
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Vienna, Austria,
2010-07-01 17:22
(5019 d 21:28 ago)

Posting: # 5582
Views: 6,261
 

 Cmin (double pulse MR formulation) [NCA / SHAM]

Dear all,

maybe you can help me getting answers to a tricky question.
The drug has a half-life of 2-3 hours; the formulation is a double pulse MR, consisting of an IR part and a MR part for OAD administration. The 20 mg strength was BE to a conventional 10 mg IR formulation administered twice a day with a dosage interval of 4 hours (AUCt, Cmax, AUC0-4, AUC4-24, Cmax,0-4, Cmax,4-24). Dose linearity was shown between 5/10/20/30/40 mg strengths. Since the profiles of MR OAD were superimposable to IR TAD after 8-12 hours and no accumulation is possible (0.7 % higher Cmax in steady state), it was agreed in a scientific advisory meeting at the German BfArM a couple of years ago not to perform a multiple dose study.
The MRP was a pain in the ass, since some member states missed the steady state study according to the MR-guideline. But finally the MA was granted. Same story in the DCP five years later. Now the sponsor is tired of answering deficiency letters from Saudia Arabia, China, etc. ;-)
In the course of a line extension (50/60 mg) we have already shown BE of the 60 mg formulation to 2×30 mg after a single dose. Now for the question:
According to the 1999 MR-NfG Cmin is one of the required PK metrics, which gives me a headache. Essentially no accumulation is expected, but the metric will be highly variable. The drug/formulation shows low variability (≈15 %) for Cmax and extremely low variability for AUC (≈7 %). We had already the 100 %-not-included-in-the-CI issue in the past… In a simulation I got a CV of ≈32 % for the global Cmin and ≈75 % for Clast (preferred by some regulators). Cmin was removed from the current IR-GL for exactly these reasons. The recently published concept paper states:

3.1 The necessity to combine the current guideline with existing documents touching different aspects of modified release products […] implies several aspects. The newly revised Note for Guidance on the Investigation of Bioequivalence (EWP/QWP/1401/98 rev1), the emergence of science as well as applications on new types of formulations require thorough discussions on:

  • requirements for steady-state studies,
  • primary pharmacokinetic parameters,
  • possibility of widening (and narrowing) of acceptance ranges,
  • requirements for specific formulations, e.g. “timed – released” dosage forms

What would you do? Treat the formulation according the IR-GL (following the arguments used in the original MA) and forget about Cmin, report it only, or what else? From a clinical point of view it does not matter, because the formulation is intended for chronic use and according to the SmPC patient’s are to be titrated for the effect.

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d_labes
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Berlin, Germany,
2010-07-01 18:10
(5019 d 20:41 ago)

@ Helmut
Posting: # 5583
Views: 5,071
 

 Cmin (double pulse MR formulation)

Dear Helmut,

❝ According to the 1999 MR-NfG Cmin is one of the required PK metrics, which gives me a headache.


Do you consider a multiple dose study? Although it was considered not necessary in EU? For answering Chinese, Saudis etc. ?

❝ Essentially no accumulation is expected, but the metric will be highly variable. …


Of course. And in most / many / all cases not reliable estimable.
With the common rule values reported as <LLOQ set to zero the ratios T/R for subjects are inf, 0 or not defined as you know.

❝ What would you do? Treat the formulation according the IR-GL (following the arguments used in the original MA) and forget about Cmin, report it only, or what else? From a clinical point of view it does not matter,❝ because the formulation is intended for chronic use and according to the SmPC patient's are to be titrated for the effect.


I would take all your arguments (including that from the scientific advice and from the new guidance) over to the study protocol to justify why Cmin and or Clast is considered not an useful PK metric for that product and is expected not estimable in most subjects ... And therefore can at the best only reported.

Eventually our "regulator" EM has a good EMphylistic text suggestion for you if he is debarked :cool:.

Regards,

Detlew
Helmut
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Vienna, Austria,
2010-07-01 18:27
(5019 d 20:23 ago)

@ d_labes
Posting: # 5584
Views: 5,084
 

 Cmin (double pulse MR formulation)

Dear D Labes,

thanks for the answer!

❝ Do you consider a multiple dose study? Although it was considered not necessary in EU? For answering Chinese, Saudis etc. ?


Yes – already decided. Even in the EU the five year DCP was painful. Summing up their internal costs answering deficiency letters, delayed approvals, and my honorary in the last years, the sponsor decided to be pragmatic. ;-)

❝ ❝ Essentially no accumulation is expected, but the metric will be highly variable. …


❝ Of course. And in most / many / all cases not reliable estimable. With the common rule values reported as <LLOQ set to zero the ratios T/R for subjects are inf, 0 or not defined as you know.


Yes. The compound is chiral, with different PK and PD. We expect to be able to measure Cmin in ≈80 % of cases, but no way to go further down due to limitations of the linear range of the MS (right now we already have a range of 1:200).

❝ I would take all your arguments (including that from the scientific advice and from the new guidance) over to the study protocol to justify why Cmin and or Clast is considered not an useful PK metric for that product and is expected not estimable in most subjects ...

❝ And therefore can at the best only reported.


Agree. That was exactly what I’m planning to do.

❝ Eventually our "regulator" EM has a good EMphylistic text suggestion for you if he is debarked.


Ahoy! :pirate:

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ElMaestro
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Denmark,
2010-07-04 20:24
(5016 d 18:26 ago)

@ Helmut
Posting: # 5588
Views: 4,984
 

 Cmin (double pulse MR formulation)

Ahoy :pirate:

❝ ❝ Eventually our "regulator" EM has a good EMphylistic text suggestion for you if he is debarked.


What a mess. Here’s a proposal for a practical money-saving solution:
  1. You seek central Scientific Advice at EMEA for this issue.
  2. You get a nice SA report stating black in white that these things are not considered necessary in the EU.
  3. When the regulators in Saudi Arabia etc ask for add'l stuff (which they do for historical reasons, having to do with what was once required in the EU) you show them the European SA report and tell them that you agree with the European regulators.
  4. You receive approval.
  5. You go celebrate.

Best regards
EM.

Pass or fail!
ElMaestro
Helmut
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Vienna, Austria,
2010-07-06 17:05
(5014 d 21:46 ago)

@ ElMaestro
Posting: # 5596
Views: 5,041
 

 EMA SAWP

¡Hola ElMaestro!

❝ What a mess.


Yes.

❝ Here’s a proposal for a practical money-saving solution:

❝ 1. You seek central Scientific Advice at EMEA for this issue.


Well; five months from the date of the letter of intend to the adoption by CHMP and a fee of 38,100 €:-D

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Helmut Schütz
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ElMaestro
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Denmark,
2010-07-08 12:44
(5013 d 02:07 ago)

@ Helmut
Posting: # 5602
Views: 4,919
 

 EMA SAWP

Dear HS,

❝ Well; five months from the date of the letter of intend to the adoption by CHMP and a fee of 38,100 €... :-D


Westferry Circus. One of the most exclusive addresses in the Docklands. Mexican, French, Indonesian etc. dishes for lunch. Employees with 50+ holidays per year, free regular plane tickets to their country of origin, subsidised housing, language classes during office hours.
Surely, things take a tiny bit of time and it is necessary to rake in some modest fees to finance it all. :-D

EM.

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ElMaestro
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