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jagankm ☆ 2011-06-01 13:19 (5086 d 06:23 ago) Posting: # 7046 Views: 11,683 |
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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. |
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Ohlbe ★★★ France, 2011-06-01 13:31 (5086 d 06:11 ago) @ jagankm Posting: # 7047 Views: 10,299 |
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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 |
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drgunasakaran1 ★★  2011-06-02 06:24 (5085 d 13:18 ago) (edited on 2011-06-02 11:21) @ jagankm Posting: # 7054 Views: 10,227 |
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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 Gunasakaran Sambandan MD Disclaimer: The replies/posts are my personal opinions, and they do not represent my company's views on the same. LinkedIn |
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Ohlbe ★★★ France, 2011-06-02 10:56 (5085 d 08:45 ago) @ drgunasakaran1 Posting: # 7055 Views: 10,295 |
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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 |
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jagankm ☆ 2011-06-02 12:35 (5085 d 07:07 ago) @ drgunasakaran1 Posting: # 7056 Views: 10,304 |
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❝ 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] |
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Helmut ★★★   Vienna, Austria, 2011-06-03 16:58 (5084 d 02:44 ago) @ jagankm Posting: # 7062 Views: 10,646 |
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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:
— Dif-tor heh smusma 🖖🏼 Довге життя Україна! ![[image]](https://static.bebac.at/pics/Blue_and_yellow_ribbon_UA.png) Helmut Schütz ![[image]](https://static.bebac.at/img/CC by.png) The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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Ohlbe ★★★ France, 2011-06-06 12:46 (5081 d 06:56 ago) @ Helmut Posting: # 7072 Views: 9,997 |
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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 |
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Helmut ★★★ Vienna, Austria, 2011-06-06 15:05 (5081 d 04:37 ago) @ Ohlbe Posting: # 7073 Views: 10,401 |
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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. — Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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Ohlbe ★★★ France, 2011-06-06 15:54 (5081 d 03:48 ago) @ Helmut Posting: # 7075 Views: 10,071 |
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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 |
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Helmut ★★★ Vienna, Austria, 2011-06-06 16:06 (5081 d 03:36 ago) @ Ohlbe Posting: # 7076 Views: 10,132 |
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Dear Ohlbe! ❝ […] I forgot this part of the problem I agree with Hermann’s statement about guidelines quite a while ago.  I support keeping (t)his order:
— Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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ElMaestro ★★★ Denmark, 2011-06-07 00:35 (5080 d 19:07 ago) @ Helmut Posting: # 7079 Views: 9,915 |
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Dear Helmut, I am rather confused now. ❝ I agree with Hermann’s statement about guidelines quite a while ago.
"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. |
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Helmut ★★★ Vienna, Austria, 2011-06-07 01:25 (5080 d 18:17 ago) @ ElMaestro Posting: # 7080 Views: 9,981 |
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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. ❝ 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.  — Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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kvgreddy06 ☆ India, 2014-07-23 20:32 (3937 d 23:10 ago) @ jagankm Posting: # 13303 Views: 6,373 |
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❝ 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] |
Ing. Helmut Schütz