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ElMaestro ★★★ Denmark, 2011-10-09 15:44 (5377 d 00:55 ago) Posting: # 7454 Views: 6,000 |
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Hi all, I noticed via this link that regulators seemingly -at least this is how I read it- accepted widened acceptance range for Cmax in study 065-08 (page 5 of the pdf) in a study that followed the basic standard 2,2,2-design. The holy scripture reads: "For the acceptance interval to be widened the bioequivalence study must be of a replicate design", so ElMaestro's walnut-sized brain cannot comprehend. Is it a simple typo, a regulatory deviation from the guideline or do you read the PAR in a way that I don't? Have a great day. EM. |
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Helmut ★★★   Vienna, Austria, 2011-10-09 18:40 (5376 d 21:59 ago) @ ElMaestro Posting: # 7455 Views: 5,110 |
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Dear ElMaestro, guidelines are not laws.  Obviously the study design followed the 2001 NfG Section 3.6.2: Cmax-ratio A replicate design was first requested in the Q&A 2006 (A2 and especially A8). It’s not stated in the PAR when the studies were performed. If the fed study was designed before July 2006 the assessor shouldn’t have a problem accepting it (since according to the NfG). If the study was performed later, he was brave (see my first sentence). — 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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Dr_Dan ★★ Germany, 2011-10-10 14:01 (5376 d 02:38 ago) @ Helmut Posting: # 7457 Views: 5,087 |
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Dear both the procedure was finalized one year ago, October 6th 2010. Although at that time the new BE guideline was finalized it is very unlikely that this NfG was taken into considerations. I guess the study was conducted in 2009 according to the old guideline and the Q&A 2006 document. In contrast to immediate release oral formulations the applicant performed three studies for a modifies release formulation and based on the results of all three studies the assessor judged the product to be bioequivalent to the reference even if the tighter acceptance range in one study was not met. Fed studies are known to have a higher variability. I assume the applicant agreed with this decision. However, it will be hard for a competitor to claim the same. Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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Helmut ★★★ Vienna, Austria, 2011-10-10 14:57 (5376 d 01:42 ago) @ Dr_Dan Posting: # 7458 Views: 5,325 |
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Dear both, THX Dan for the hints. Although the MR GL (1999) was applicable … Assessment of bioequivalence will be based on AUCτ, Cmax and Cmin applying similar statistical procedures as for the immediate release formulations. The bioequivalence approach considering usual acceptance limits (80 – 125 %) is applicable for generic MR products. […]
Therefore for MR products a replicate design was requested in 2009. But the assessor was not blind. Most likely he/she was just fed [sic!] up from too many PPIs… Quod licet Iovi, non licet bovi — 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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Dr_Dan ★★ Germany, 2011-10-10 18:57 (5375 d 21:42 ago) @ Helmut Posting: # 7461 Views: 5,076 |
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Dear Helmut Esomeprazole is a proton pump inhibitor that suppresses gastric acid secretion by specific inhibition of H+/K+-ATPase in the gastric parietal cell. By acting specifically on the proton pump, esomeprazole blocks the final step in acid production, thus reducing gastric acidity. This effect is dose-related. Therefore the bioavalability in terms of total exposure (AUC) controls the effect and is consequently of much more interest than bioavailability in terms of peak exposure (tmax and Cmax). This is what the assessor had in mind (I guess). Therefore widening of acceptance range was clinically justified. But I agree, seen under formal aspects the widening of the acceptance range should have been not possible at that time. Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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Helmut ★★★ Vienna, Austria, 2011-10-10 20:23 (5375 d 20:16 ago) @ Dr_Dan Posting: # 7462 Views: 5,065 |
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Dear Dan! ❝ [Some very usefully clinical remarks…]. This is what the assessor had in mind (I guess). Therefore widening of acceptance range was clinically justified. ❝ But I agree, seen under formal aspects the widening of the acceptance range should have been not possible at that time. See a presentation given by C. Baumgärtel at a meeting entitled ‘Generika-Offensive’ organized by the Austrian agency AGES this March. From slide 30: BE → Akzeptanzgrenzen Sorry folks, it’s in German. Essentially it says: Don’t even try to submit a study if the CI is outside 80.00% – 125.00%. — 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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Dr_Dan ★★ Germany, 2011-10-11 11:54 (5375 d 04:45 ago) @ Helmut Posting: # 7467 Views: 5,027 |
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Dear Helmut ❝ ❝ ❝ ❝ Of course this deals with IR, but nice to know. To be honest, we submitted this year a bioequivalence study for an IR formulation of a well known uncomplicated drug with following results: upper confidence interval limit for Cmax slightly out of acceptance range Results for AUC and Cmax ratios opposit => complete different kinetic in comparison to the originator Point estimator shows a difference > 15% => narrow confidence interval due to high subject number and very low intra-subject variability. I was convinced that we would have been slaughtered by the regulatory authorities, but what a surprise we got the marketing authorisation. RMS = Germany (BfArM). In fact the assessor did not care about the acceptance criteria layed down in the guideline. He just judged the clinical impact. So we are far away from a consistent assessment. Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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Helmut ★★★ Vienna, Austria, 2011-10-11 18:27 (5374 d 22:12 ago) @ Dr_Dan Posting: # 7472 Views: 5,100 |
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Dear Dan! ❝ […] In fact the assessor did not care about the acceptance criteria layed down in the guideline. He just judged the clinical impact. So we are far away from a consistent assessment. Nice experience. Common sense obviously is still not dead. Or to quote our famous Capt’n: Recipe for success: Treat guidelines like variable constants. — 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 |
Ing. Helmut Schütz