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ABE1580 ☆ India, 2012-09-13 11:55 (5029 d 17:01 ago) Posting: # 9199 Views: 8,082 |
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Dear Sir, Will it be acceptable to the FDA; if we keep option of excluding the volunteer based on the residence time of dosage form in GIT in case of Osmotic drug delivery system (ODDS)? Let me explain the problem properly: In case of ODDS the tablets stay for more time in GIT and that leads to variability. Say in case of Test product tablets, it was there in GIT till 33 hrs and after that it was expelled in feces. But in same volunteer; the reference product expelled after 46 hrs. So, will it be acceptable to FDA, if we predefine the exclusion criteria "The subjects will be excluded from the bioequivalence evaluation; who do not expel the tablets within 42 hrs" Any such type of observation any one came accross? Regards, |
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Helmut ★★★   Vienna, Austria, 2012-09-13 16:28 (5029 d 12:29 ago) @ ABE1580 Posting: # 9200 Views: 7,234 |
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Hi ABE1580! ❝ Dear Sir,
❝ Will it be acceptable to the FDA; if we keep option of excluding the volunteer based on the residence time of dosage form in GIT in case of Osmotic drug delivery system (ODDS)? No way. ❝ […] In case of ODDS the tablets stay for more time in GIT and that leads to variability. Say in case of Test product tablets, it was there in GIT till 33 hrs and after that it was expelled in feces. But in same volunteer; the reference product expelled after 46 hrs. BE is a surrogate of clinical efficacy. You can’t ignore variability caused by the formulation itself or the motility of the GIT. Does the label of OROS state “check your feces daily – if you don’t find a tablet there, see your physician”? ❝ So, will it be acceptable to FDA, if we predefine the exclusion criteria "The subjects will be excluded from the bioequivalence evaluation; who do not expel the tablets within 42 hrs" No. ❝ Any such type of observation any one came accross? I stopped peeking into my feces a long time ago. GIT in non-vegetarians is ≤72 hours (BTW, this is the rationale behind AUC72 for IR formulations). Gastric motility in vegetarians might be decreased;* I would suggest to include non-vegetarians in the study.
— 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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jag009 ★★★ NJ, 2012-09-13 19:34 (5029 d 09:23 ago) @ ABE1580 Posting: # 9203 Views: 7,343 |
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Hi ABE, No. You can't do that. I worked with OROS BE studies before and we never drop subjects due to long residence time of the tablet in the guts. But due the nature of the OROS system, you might be able to exclude subjects who went to the bathroom at earlier time (or subjects who use laxative regularly). Helmut, What do you think? Thanks John |
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Helmut ★★★ Vienna, Austria, 2012-09-13 19:45 (5029 d 09:12 ago) @ jag009 Posting: # 9205 Views: 7,122 |
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Hi John! ❝ […] But due the nature of the OROS system, you might be able to exclude subjects who went to the bathroom at earlier time (or subjects who use laxative regularly). If you define “earlier time” in the protocol.* I haven’t done so in my studies, though I state cases of diarrhea within the first 24 hours as an exclusion criterion. Haven’t thought about regular users of laxatives yet; good idea! ❝ Helmut, What do you think? About the blanks? SCNR; forget it. 
— 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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jag009 ★★★ NJ, 2012-09-13 21:45 (5029 d 07:11 ago) @ Helmut Posting: # 9207 Views: 7,155 |
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I hate OROS  ... Especially Nifedipine OROS... In one pilot study we collected feces from subjects who had bowel movement before 24 hours (and noted the time) to determine if the GITS was excreted.Speaking of Nifedpine OROS(might be applicable to all OROS?), I ran a food effect study High Fibre vs Low Fibre on the reference itself and the PK was different. John |
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ABE1580 ☆ India, 2012-09-14 09:56 (5028 d 19:01 ago) @ jag009 Posting: # 9211 Views: 7,073 |
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Dear John and Helmut, Thank you for your inputs.....thanks |
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ABE1580 ☆ India, 2012-09-14 13:14 (5028 d 15:43 ago) @ ABE1580 Posting: # 9216 Views: 7,040 |
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Dear Sir(s) and Madam(s), Will it be possible to keep an option: "If the subject does not have at least one bowel movement a day, the plasma samples will not be analysed and the subject will be excluded from the study" Regards, |
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Helmut ★★★ Vienna, Austria, 2012-09-14 15:58 (5028 d 12:59 ago) @ ABE1580 Posting: # 9220 Views: 7,061 |
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Hi ABE1580! ❝ Will it be possible to keep an option: "If the subject does not have at least one bowel movement a day, the plasma samples will not be analysed and the subject will be excluded from the study" Again this does not make sense. Three defecations per day to one per three days are normal physical conditions. Keep in mind that BE should reflect what is stated in the label. Does the label state “If you defecate less frequently than once a day, see your physician”? — 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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jag009 ★★★ NJ, 2012-09-17 18:47 (5025 d 10:09 ago) @ Helmut Posting: # 9227 Views: 6,999 |
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Hi Helmut. You heard about someone who accumulated a bunch of GITS shells in their colon due to diverticulosis? He/she was having severe constipation and upon x-ray the doctor found the cause. John |
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Helmut ★★★ Vienna, Austria, 2012-09-17 18:56 (5025 d 10:01 ago) @ jag009 Posting: # 9229 Views: 7,021 |
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Hi John! ❝ […] He/she was having severe constipation and upon x-ray the doctor found the cause. Yes; I have seen these X-rays at a couple of conferences.  At last years MR conference in Barcelona there was a poll amongst participants whether monolithic formulations should be replaced by multiparticulate formulations. The outcome was clear – I didn’t count, but would guess >90%…— 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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jag009 ★★★ NJ, 2012-09-18 19:11 (5024 d 09:46 ago) @ Helmut Posting: # 9236 Views: 6,946 |
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Hi Helmut, ❝ “Earlier” is a comparative degree; so earlier compared to? With reference to GI Transit time? Or do a fecal inspection if subject has a bowel movement in less than 24 hours? Dissolution for OROS tablets usually achieve 90% release by 12-16 hours? John |
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drsinghs ☆ India, 2012-10-05 08:04 (5007 d 20:53 ago) @ Helmut Posting: # 9311 Views: 6,834 |
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Dear All, I have some questions as below to add to this debate. Assuming that the Tmax of the drug is 24 hours and both test and reference are OROS tablets.
Thanks & Regards, drsinghs |
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Ohlbe ★★★ France, 2012-10-05 12:40 (5007 d 16:17 ago) @ drsinghs Posting: # 9313 Views: 6,737 |
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Dear drsinghs, What if your drug has an effect on intestinal motility (either slowing it, or speeding it up) ? Let's say one of the two formulations is released faster in some subjects, leading to a higher Cmax, and a higher effect on motility. If you exclude those subjects who expel the tablet faster or slower, you will selectively exclude those subjects who will show a difference between test and reference ! Even if an effect on motility is not described as an effect or adverse event of your drug, I really doubt any regulator would accept such an exclusion. Regards Ohlbe — Regards Ohlbe |
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drsinghs ☆ India, 2012-10-05 14:14 (5007 d 14:42 ago) @ Ohlbe Posting: # 9314 Views: 6,759 |
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❝ Even if an effect on motility is not described as an effect or adverse event of your drug, I really doubt any regulator would accept such an exclusion. Dear Ohlbe, Before I ask anything Can I request you to have a look on below link and request your comment? http://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/075289.PDF Thanks & regards, drsinghs |
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Helmut ★★★ Vienna, Austria, 2012-10-05 15:34 (5007 d 13:23 ago) @ drsinghs Posting: # 9315 Views: 6,816 |
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Dear drsinghs, it would be helpful to state where to look. I guess only a few people have the stamina to read a 298 page document. — 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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drsinghs ☆ India, 2012-10-05 16:16 (5007 d 12:41 ago) @ Helmut Posting: # 9316 Views: 6,761 |
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Sorry Ohlbe, Please see page no 56. Note that applicant has excluded the subjects who have expelled GITS in < 16hrs. As the test formulation was matrix tablet, this criteria was not applicable to test product. Regards, drsinghs 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! [Ohlbe] |
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Ohlbe ★★★ France, 2012-10-05 18:00 (5007 d 10:56 ago) @ drsinghs Posting: # 9318 Views: 6,698 |
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Dear drsinghs, OK, it was accepted by FDA in 2000. I don't know whether they would still accept it now, and I'm not sure it would be acceptable in other parts of the world. The exclusion of subjects who expel the tablet within 16 hours could be justified in the same way as subjects who vomit. But I'm still concerned about the possible influence of the product on motility. Regards Ohlbe — Regards Ohlbe |
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jag009 ★★★ NJ, 2012-10-13 01:05 (5000 d 03:51 ago) @ Ohlbe Posting: # 9409 Views: 6,662 |
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This is great!  Why not collect the GITS (if found in the feces) from those subjects who have bowl movement at earlier time, analyze for the drug content and use that as an argument? Clinic people will hate you for that. John |
Ing. Helmut Schütz