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Compliance ★ India, 2012-07-09 09:13 (5101 d 02:11 ago) Posting: # 8906 Views: 6,405 |
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Dear All, Recently FDA has rejected one of the our Narrow Therapeutic study by stating following: "Fed study is not acceptable due to the substantial difference in Tmax between test product and the reference listed drug product. Recommendation of the medical reviewer of the division of clinical reviewer of the office of generic drug. The reviewer stated that “there is a large difference in the median Tmax between the test and reference (6 hrs for test treatment versus 8 hrs for the RLD treatmement or 25% difference) is accompanied by also relatively large difference in the Cmax (with the point estimate of 1.15 hrs) under fed condition. These differences are unacceptable as they may adversely impact the anticipated safety and efficacy of the product when interchanged with the reference listed drug product. Patient used to taking one ER formulation preparation would at risk of having a different safety profile from the standard of on set of adverse effects." In this case i could not get any kind of clarity in the present regulation (as per my understanding) about the consideration of median Tmax during the estimation of BE for narrow therapeutic drugs. Kindly help me to come out of this issue and our study get accepted by the agency. Awaiting for your answer which may guide me to prepare my justification. Regards, Compliance |
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hiren379 ★ India, 2012-07-11 08:17 (5099 d 03:07 ago) @ Compliance Posting: # 8921 Views: 5,268 |
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Hello, I think you can try below approaches 1) Go for Wilcoxon for Tmax----if results come in yr favour, u can further justify otherwise yr battle is lost 2) Next, if step 1 is in yr favour. You can clinically justify using literature that Tmax observed is clinically not significant (Strong justification will be required) 3) Can assess individual and population BE as per USFDA and give supportive evidance All the best... |
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Compliance ★ India, 2012-07-11 08:29 (5099 d 02:55 ago) @ hiren379 Posting: # 8922 Views: 5,223 |
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Dear Mr. Hiren, Thank you for your reply and guiding me. regards, Compliance |
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hiren379 ★ India, 2012-07-11 10:59 (5099 d 00:26 ago) @ Compliance Posting: # 8924 Views: 5,192 |
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Thanks dear, I suggest you Individual Bioequivalence will be the best to support you as FDA's statement looks like they are more worried about PK when brand substitution from Innovator to Generic is done. If the therapy is for chronic use, then you can simulate your data to staedy state levels and give further justification I would be more interested in knowing the name of molecule if possible!!! |
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Helmut ★★★   Vienna, Austria, 2012-07-11 17:59 (5098 d 17:26 ago) @ hiren379 Posting: # 8934 Views: 5,376 |
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Dear Hiren & Compliance! ❝ 1) Go for Wilcoxon for Tmax----if results come in yr favour, u can further justify otherwise yr battle is lost ❝ 2) Next, if step 1 is in yr favour. You can clinically justify using literature that Tmax observed is clinically not significant (Strong justification will be required) ❝ 3) Can assess individual and population BE as per USFDA and give supportive evidance It’s interesting that FDA’s reviewer looked directly at tmax – not the partial AUC truncated at the reference’s median tmax (aka ‘early exposure’). I would try this PK metric first. I’m not too optimistic about Wilcoxon with such a difference in tmax-values. #3 is of historical interest only, IMHO. Since tmax is sampled from a discrete distribution you could perform the analysis only on partial AUC. — 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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kumarnaidu ★ Mumbai, India, 2013-04-10 12:27 (4825 d 22:58 ago) @ Compliance Posting: # 10391 Views: 4,766 |
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Power calculation in sas for NTI drug Hello everybody, for calculating power in bio equivalence we use following code in SAS. Can anybody tell me what is 1.25 in 3rd line. Is it upper limit of ratio (0.8 to 1.25). If it is upper limit then in that case should I replace it by 1.11 for analysis of NTI drug. Please reply.....  pt=tinv(0.05,df,0); apt=abs(pt); pw=(log(1.25)/se-apt); Power=100*probt(pw,df); Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post! [Ohlbe] — Kumar Naidu |
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d_labes ★★★ Berlin, Germany, 2013-04-10 12:38 (4825 d 22:47 ago) @ kumarnaidu Posting: # 10394 Views: 4,592 |
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Dear Kumarnaidu! Could give some references for your code? I never have seen such formulas for power calculations! What most puzzles me is that nowhere in your formulas the number of subjects is present. And the power definitely depends on the number of subjects. Search the forum category power/sample size or refer to Helmuts lectures to find some more correct methods. — Regards, Detlew |
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kvgreddy06 ☆ India, 2014-09-01 19:13 (4316 d 16:12 ago) @ Compliance Posting: # 13449 Views: 3,963 |
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Dear Compliance, Can I know the your experience on above situation which one you have faced. I Have one doubt, in a scenario.. if Product monograph shows Tmax range 4-12 hours, (if we get Tmax 4.5 hours for Reference treatment and 10.5 hours for test Treatment) i.e as per Product monograph the obeseved values are with in range, however it is statistically more significant difference. Based on significant if FDA gives query on this scenario, how can we give justification.. Regards, kvgreddy Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post! [Helmut] |
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Compliance ★ India, 2014-09-10 14:07 (4307 d 21:18 ago) @ kvgreddy06 Posting: # 13473 Views: 3,789 |
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Dear kvgreddy, Here the window of Tmax wan't work as we argue on that basis also. FDA rejected data and now we are off from that filing . such difference in the Tmax is not acceptable in Narrow Therapeutic Statistics. Regards, Compliance |
Ing. Helmut Schütz