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Back to the forum  2018-06-19 01:25 CEST (UTC+2h)
jagankm
Junior

2011-06-01 11:19

Posting: # 7046
Views: 8,534
 

 metformin steady state study [Regulatives / Guidelines]

Dear sir,
We are planing to conduct the Steady State BE study of Metformin SR 500 mg tablets in healthy, adult, human volunteers. Just we want to know whether we need to conduct steady state or not, as per SPC and Literature there is No Accumulation is observed after repeated administration of up to 2000 mg of Metformin as prolonged release Tablets. As per Modified released guidelines we need to conduct Fast, Fed and Steady state, Please suggest in this regard.
Your kind help will be highly appreciable.
Ohlbe
Hero

France,
2011-06-01 11:31

@ jagankm
Posting: # 7047
Views: 7,504
 

 metformin steady state study

Dear jagankm,

» Dear sir,

We also have some Ladies on this forum ;-)

» Just we want to know whether we need to conduct steady state or not

For which market ? EU, US, other ?

» As per Modified released guidelines we need to conduct Fast, Fed and Steady state, Please suggest in this regard.

Well, if the guidelines say you have to do it, why do you ask the question ?

Regards
Ohlbe

Regards
Ohlbe
drgunasakaran1
Senior
avatar

2011-06-02 04:24
(edited by Jaime_R on 2011-06-02 11:21)

@ jagankm
Posting: # 7054
Views: 7,437
 

 metformin steady state study

Dear Mr.Jagan,

As per FDA's Bioequivalence recommendations for Metformin Extended release tablets, they recommended to conduct Single dose, two way cross over Fasting and Fed studies only, not Steady State study.

Reference


Edit: GL linked. [Jaime]

Dr.S.Gunasakaran, MD
Vice President-Clinical Research & Medical Affairs
AZIDUS Clinical Research Organization. Linkedin Profile
Global Moderator – ClinicalResearchForum
Ohlbe
Hero

France,
2011-06-02 08:56

@ drgunasakaran1
Posting: # 7055
Views: 7,441
 

 metformin steady state study

Dear Dr Gunasakaran,

» As per FDA's Bioequivalence recommendations for Metformin Extended release tablets, they recommended to conduct Single dose, two way cross over Fasting and Fed studies only, not Steady State study.

True for FDA. But a steady state study is needed for EU submission.

Regards
Ohlbe

Regards
Ohlbe
jagankm
Junior

2011-06-02 10:35
(edited by Jaime_R on 2011-06-02 11:18)

@ drgunasakaran1
Posting: # 7056
Views: 7,494
 

 metformin steady state study

» As per FDA's Bioequivalence recommendations…

Dear Dr,

Thank you for your response.

we are planning this study for EU submission.

on scientific basis when there is no accumulation of drug on repeated administration what is the use of conducting steady state study. SPC of innovator itself noticing there is no accumulation of metformin after repeated administration. in this regard is it necessary to for steady state study as per guidelines. is there any way to skip to conduct steady state study for metformin for EU submission.

please suggest…


Edit: Full quote removed. Please delete anything from the text of the original poster which is not necessary in understanding your answer; see also this post! [Jaime]
Helmut
Hero
avatar
Homepage
Vienna, Austria,
2011-06-03 14:58

@ jagankm
Posting: # 7062
Views: 7,728
 

 Steady state (no accumulation)

Dear Jagankm & Ohlbe!

» […] a steady state study is needed for EU submission.

Yes and no (see below).

» […] SPC of innovator itself noticing there is no accumulation of metformin after repeated administration. in this regard is it necessary to for steady state study as per guidelines. is there any way to skip to conduct steady state study for metformin for EU submission.

Maybe it’s worthwhile reading this story. In short: No steady state studies were performed since the drug did not accumulate; MA was granted in the EU – despite required by the old (and still current) GL.

According to current thinking of EMA1,2 (internal draft #8 of the MR-GL as of May 2011) steady state studies will not have to be performed any more – if no accumulation is demonstrated in the single dose study (AUCt/AUC > 80%). A justification IMHO will be acceptable only if referring to a pivotal single dose study (not the SPC of the innovator or literature data). It’s up to you to go either for a (nonbinding, of course) scientific advice, or simply go ahead with a justification in the application. I think that in the light of international harmonisation this section will ‘make it’ through the official draft to the final version, because:
  • FDA requires multiple dose studies only in exceptional cases (mainly studies in patients).
  • A similar POV about accumulation in Canada.


  1. Christoph Baumgärtel [AGES PharmMed, Raporteur of the CHMP Pharmacokinetics Working Party (PKWP)]
    Bioequivalence requirements for MR products: Current regulatory thinking and open issues
    EUFEPS BABP Network Open Discussion Forum. Revision of BE Requirements for Modified Release Products
    Barcelona, Spain, 24 February 2011
  2. Jan Neuhauser (AGES PharmMed)
    Understanding the proposed guideline for modified release
    7th Annual Bioavailability/Bioequivalence and Dissolution Testing Conference
    Budapest, Hungary, 18 May 2011

Cheers,
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
Ohlbe
Hero

France,
2011-06-06 10:46

@ Helmut
Posting: # 7072
Views: 7,226
 

 Steady state (no accumulation)

Dear Helmut and Jagankm,

» According to current thinking of EMA1,2 (internal draft #8 of the MR-GL as of May 2011) steady state studies will not have to be performed any more – if no accumulation is demonstrated in the single dose study (AUCt/AUC > 80%).

Maybe, but it will take another couple of years before the draft is published for 6-month consultation, comments are received, a final version gets adopted and it comes into force. Until then the current guidance remains applicable... I would say the attitude depends on how critical this project is for your company, how much time you are ready to spend in discussions with various Agencies, in which EU Member State you plan to submit your dossier and when. If you want to be on the safe side, running the steady state study is expensive and may not sound scientifically necessary, but it may in the end be faster and with a more certain result.

Regards
Ohlbe

Regards
Ohlbe
Helmut
Hero
avatar
Homepage
Vienna, Austria,
2011-06-06 13:05

@ Ohlbe
Posting: # 7073
Views: 7,422
 

 Steady state (no accumulation)

Dear Ohlbe and Jagankm!

» […] but it will take another couple of years before the draft is published for 6-month consultation, comments are received, a final version gets adopted and it comes into force. Until then the current guidance remains applicable...

The draft is expected to be published early 2012. Agree with your remaining points.

» I would say the attitude depends on how critical this project is for your company, how much time you are ready to spend in discussions with various Agencies, in which EU Member State you plan to submit your dossier and when.

True.

» If you want to be on the safe side, running the steady state study is expensive and may not sound scientifically necessary, but it may in the end be faster and with a more certain result.

Agree with the former, but not the latter. From my little story: CVs of AUCt ≈7 %, Cmax ≈15 %, Cmin* ≈75 %. According to the current NfG Cmin is required – no scaling (EMA is considering scaling for HVDs/HVDPs if accumulation occurs as an alternative to multiple dose studies). For the usual stuff (AR 80–125%, α≤0.05, power 80%, PE 0.95) that would require increasing the sample size from 12 to 194 (!) in a 2×2 cross-over. IMHO it is not ethical to perform such a study just to show BE for a PK metric which is not relevant from a clinical point of view.
BTW, we performed the multiple dose study following my little story – but will report Cmin only. Both the EC and BfArM followed our arguments and approved the protocol.


  • Following EMA's definition: Concentration at the end of the dosing interval (see Edit 2 in this post and the two references given above).

Cheers,
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
Ohlbe
Hero

France,
2011-06-06 13:54

@ Helmut
Posting: # 7075
Views: 7,246
 

 Steady state (no accumulation)

Dear Helmut,

» Agree with the former, but not the latter. From my little story: CVs for AUCt ≈7 %, Cmax ≈15 %, Cmin1 ≈75 %. According to the current NfG Cmin is required – no scaling (EMA is considering scaling for HVDs/HVDPs if accumulation occurs as an alternative to multiple dose studies). For the usual stuff (AR 80–125%, α≤0.05, power 80%, PE 0.95) that would require increasing the sample size from 12 to 194 (!) in a 2×2 cross-over.

True, I forgot this part of the problem :-(

Regards
Ohlbe

Regards
Ohlbe
Helmut
Hero
avatar
Homepage
Vienna, Austria,
2011-06-06 14:06

@ Ohlbe
Posting: # 7076
Views: 7,286
 

 Science ↔ Guidelines

Dear Ohlbe!

» […] I forgot this part of the problem :-(

I agree with Hermann’s statement about guidelines quite a while ago. :ok: I support keeping (t)his order:
  1. Science (+ a drip of common sense)
  2. Guidelines

Cheers,
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
ElMaestro
Hero

Denmark,
2011-06-06 22:35

@ Helmut
Posting: # 7079
Views: 7,134
 

 Science ↔ Guidelines

Dear Helmut,

I am rather confused now.

» I agree with Hermann’s statement about guidelines quite a while ago. :ok: I support keeping (t)his order:
  1. Science (+ a drip of common sense)
  2. Guidelines

"common sense" ?
It isn't defined in any EU guideline or any eudralex document. I don't know how to validate it if anyone can propose a way of measuring it. Of course it is extremely informative what this document tell us:
...Common sense and a clear focus on the needs of the regulatory authority assessor are the best guides...
It is crystal clear, isn't it? When they speak of needs, I am pretty sure they mean something with coffee. Or perhaps a forced parametric analysis when residuals are not normal. Or something like that.

Don't we all wish we could coerce or unduly influence?


Best regards,
EM.
Helmut
Hero
avatar
Homepage
Vienna, Austria,
2011-06-06 23:25

@ ElMaestro
Posting: # 7080
Views: 7,179
 

 Science ↔ Guidelines

My Capt’n!

» Of course it is extremely informative what this document tell us:
» ...Common sense and a clear focus on the needs of the regulatory authority assessor are the best guides...

Ha! You dropped the start of the sentence: »It should be emphasised that no guideline can cover all eventualities, and common sense …«

» It is crystal clear, isn't it? When they speak of needs, I am pretty sure they mean something with coffee.

Don’t forget the whipped sweet cream on top.

» Or perhaps a forced parametric analysis when residuals are not normal. Or something like that.

Why not? To quote yourself:

Garbage in, garbage out.
It’s very very simple.


» Don't we all wish we could coerce or unduly influence?

Well; I’m neither the investigator nor member of the trial staff – if you mean §4.8.3. :pirate:

Cheers,
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
kvgreddy06
Junior

India,
2014-07-23 18:32
(edited by kvgreddy06 on 2014-07-23 18:48)

@ jagankm
Posting: # 13303
Views: 3,584
 

 metformin steady state study

» we are planning steady state study for EU submission.

what are the primary PK parameters? What are the secondary PK parameters?

FDA guidlines saying about swing. but in EMA guidlines there is no word related to swing, kindly explain what was the effect of swing parameter in PK.

Thanks and Regards.
venugopal


we are planning to conduct a single dose study plus steady state study for EU submission.
On first day single dose profiling and will be dosed continually till 7 day OAD, again on 7 th day profiling (steady state).

In this study,
If in case single dose study 90% CI were with in BE limits, but steady state study 90 % CI were not with in BE limits, or vice versa.
then what will be final conclusion of the study.


Edit: Full quote removed. Please delete anything from the text of the original poster which is not necessary in understanding your answer; see also this post!
Don’t reply to your own post; you should edit the original one within 24 hours. I merged both and deleted the second one. [Helmut]
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