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d_labes ★★★ Berlin, Germany, 2011-02-23 15:47 (5239 d 03:11 ago) Posting: # 6664 Views: 15,001 |
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Dear all, in Saranadasa, Krishnamoorthy the authors describe a test for the comparison of drug dissolution profiles which is - in the eyes of the authors - more powerful then others, like similarity factor f2, IUT test ... This test uses the variance-covariance matrix and therefore needs the individual values of %dissolved. But in the examples given in the paper I found only means and SD for the measurement time points. Thus I couldn't recalculate the authors values for their new delta statistic if I understand their formulas (many matrices in there  ) some days.My question: Has anybody examples of the application of this test with all necessary data? Is there any code (SAS, R or whatever) out there? — Regards, Detlew |
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yjlee168 ★★★   Kaohsiung, Taiwan, 2011-02-24 09:50 (5238 d 09:09 ago) @ d_labes Posting: # 6666 Views: 13,488 |
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Dear D. Labes, Have you checked with the book of Chow SC and Liu JP's Design and Analysis of Bioavailability and Bioequivalence Studies, 3r ed. (2009), CRC Press, pp.497-503? The method of the paper was discussed there. Hope it can help. ❝ My question: Has anybody examples of the application of this test with all necessary data? Is there any code (SAS, R or whatever) out there? Unfortunately, I don't have a clue for your question. — All the best, -- Yung-jin Lee bear v2.9.2:- created by Hsin-ya Lee & Yung-jin Lee Kaohsiung, Taiwan https://www.pkpd168.com/bear Download link (updated) -> here |
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d_labes ★★★ Berlin, Germany, 2011-02-24 16:04 (5238 d 02:55 ago) @ yjlee168 Posting: # 6668 Views: 13,410 |
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Dear Yung-jin, ❝ Have you checked with the book of Chow SC and Liu JP's I have. But they only excerpt the paper and the main formulas, funny enough with other symbols and some typing errors . Unfortunately without a numerical example.— Regards, Detlew |
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Aceto81 ★ Belgium, 2011-02-25 13:33 (5237 d 05:26 ago) @ d_labes Posting: # 6670 Views: 13,385 |
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Dear d_labes, maybe you can contact the authors to get the data? Or you can write out a simulation of the data, calculate your p-value and see if you can get the same value when running your simulation n-times? Ace |
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Helmut ★★★  Vienna, Austria, 2011-03-01 14:30 (5233 d 04:29 ago) @ d_labes Posting: # 6675 Views: 13,450 |
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Dear D. Labes, don’t want to interfer with your enthusiasm, but it seems that currently (anything?) except f2 is not acceptable (in the EU). See HMA (XLS; tab ‘Finalised in 2008’, row 76 on Pantoprazole 20mg gastro-resistant, UK/H/1163/001/DC). Grounds for referral to CMD(h) The procedure was referred to CMD(h) due to potential serious risk to public health concerns raised on the absence of a bioequivalence study for the 20 mg strength. Concerns were raised that the justification for a biowaiver for the 20 mg strength based on similarity to the 40 mg strength was not acceptable due to differences in dissolution profiles. Although the applicant used statistical methods to prove similarity, these methods were not universally accepted. Outcome At the CMD(h) meeting, the RMS and CMS presented their view on the outstanding issue. The applicant had provided dissolution data to support the biowaiver for the 20 mg strength product, along with statistical assessment of these data. In order to confirm that the possible differences seen in the dissolution profile did not impact on the in vivo performance of the 20 mg product, the applicant would perform an additional bioequivalence study for the 20 mg strength within an agreed time frame. RMS and CMS agreed on this confirmatory study and consensus was reached that the procedure could be positively concluded. CMD(h) also considered that the issue of statistical methods used to show similarity of dissolution studies, should be referred to the QWP for further discussion and advice. (my emphases) The Mahanalobis distance was used in the application; for details see MHRA’s Public Assessment Report (pages 33-35). — 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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d_labes ★★★ Berlin, Germany, 2011-03-01 17:07 (5233 d 01:52 ago) @ Helmut Posting: # 6676 Views: 13,386 |
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Dear Helmut, ❝ don’t want to interfer with your enthusiasm, but it seems that currently (anything?) except f2 is not acceptable (in the EU). Thanks for your viewpoint. I'm a bloody newbie on the field of dissolution. Usually I have nothing to do with the evaluation of dissolution profile. Therefore I'm not familiar with used and/or accepted methods. I simply was asked to implement Sarandanasa/Krishnamoorthy method (of course in SAS  ) for what end ever.Your reasoning about f2 (there can be only one?) is nevertheless astonishing for me. Let me cite Appendix I of the EMA guideline: "When the ƒ2 statistic is not suitable (however this has to be justified, remark by D.L.), then the similarity may be compared using model-dependent or model-independent methods e.g. by statistical multivariate comparison of the parameters of the Weibull function or the percentage dissolved at different time points. Alternative methods to the ƒ2 statistic to demonstrate dissolution similarity are considered acceptable, if statistically valid and satisfactorily justified." Ok, ok, I see: Acceptable, but if not satisfactorily justified (howsoever it should be done) ... As far as I noticed the 1997 FDA guidance "Dissolution testing for Immediate Release Solid Dose Forms" has also a recommendation of a multivariate measure of similarity (Tsong's Mahalanobis distance?) Tsong, Y., Hammerstrom, T, Sathe, P., Shah, V. P. Statistical assessment of mean differences between two dissolution data sets. Drug Information Journal 30:1105–1112 (1996). There is a free EXCEL Add-in out there (DDSolver and supplemental material) which implements Tsongs method. But seems the source code is not free. Its safeguarded by a password  . Anybody out there to guide me to the upper 90% CI of the Mahalanobis distance?— Regards, Detlew |
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ElMaestro ★★★ Denmark, 2011-03-01 21:02 (5232 d 21:57 ago) @ d_labes Posting: # 6677 Views: 13,520 |
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Dear d_labes, when new assessors start their career at the agencies around the EU, they are invited to a training session at the EMA in London. The SOPs the hopeful young scientists will receive training for include, without being limited to, the following: SOP TRVL-14: Making a qualified choice between the Thistle Marble Arch and Hilton Docklands when attending meetings at the EMA. SOP TRVL-15: Racking in a boatload of Hilton Honours Points when staying at the Hilton Docklands. SOP BRKFST-10: Predicting the impact on the assessor's intestinal flora when trying haggis for the first time at Hilton Docklands. SOP BRKFST-22: To muffin or not to muffin, that's the question at Starbucks on Canary Wharf when attending meetings at the EMA. SOP ASSSSMNT-76: Decision tree for complex issues arising during the evaluation of dossiers. The latter is of particular importance to the question you are raising here, as well as other questions raised in the forum in the past. While the SOP is not in the public domain, I can reveal an excerpt from page 12 of this document: ![[image]](img/uploaded/image23.jpg) — Pass or fail! ElMaestro |
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Helmut ★★★ Vienna, Austria, 2011-03-02 02:06 (5232 d 16:53 ago) @ ElMaestro Posting: # 6679 Views: 13,335 |
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My Capt'n! ❝ SOP TRVL-14: Making a qualified choice between the Thistle Marble Arch and Hilton Docklands when attending meetings at the EMA. ❝ SOP TRVL-15: Racking in a boatload of Hilton Honours Points when staying at the Hilton Docklands. ❝ SOP BRKFST-10: Predicting the impact on the assessor's intestinal flora when trying haggis for the first time at Hilton Docklands. ❝ SOP BRKFST-22: To muffin or not to muffin, that's the question at Starbucks on Canary Wharf when attending meetings at the EMA. ❝ SOP ASSSSMNT-76: Decision tree for complex issues arising during the evaluation of dossiers. Some minor comments. I guess concerning TRVL-14/15 you would opt for Hilton Docklands, just to enjoy the boatride? BRKFST-10: haggis is everywhere challenging. BRKFST-22: irresolvable! A catch question?  Though I haven’t seen the decision tree in such clarity yet, it looks quite familiar to me. The authenticity of the excerpt is proven by the typos. My clients regularly get lost in the right branches. My favourite: […] Method justified and statistically valid → Check if statistical endpoint is satisfactorily met → Met → Reject — 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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d_labes ★★★ Berlin, Germany, 2011-03-02 09:06 (5232 d 09:53 ago) @ ElMaestro Posting: # 6680 Views: 13,265 |
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— Regards, Detlew |
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Aceto81 ★ Belgium, 2011-03-02 13:28 (5232 d 05:31 ago) @ d_labes Posting: # 6683 Views: 13,295 |
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I will take a deeper look at the free solver, looks interesting. For the f2 calculation, there are some rules on %RSD. If your RSD is too high, you can bootstrap your results to calculate CI on your f2 value. I must have an R script for this bootstrap, if anyone is interested, I will digg into my harddisk to see if I can find it. Ace |
Ing. Helmut Schütz