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The Outlaw Torn ★ Europe, 2012-11-29 16:58 (4563 d 06:52 ago) Posting: # 9636 Views: 10,775 |
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Dear all, I heard from a little birdie that the CMDh is looking into the whole incurred sample re-analysis fiasco. Has anyone heard anything new about it? Also, I don't beleive this was discussed previously, but here's the situation. We have a client who wishes to run a repeat use procedure. As the BE studies for the original procedure are no longer compliant with the new guideline regarding ISR, they are concerned that if they run this repeat use procedure their original MA might be in danger of being revoked because the BE studies in the original precedure are no longer compliant with the current guidelines (ie. they might have to withdraw the product). This makes absolutely no sense to me. To withdraw a product that has already been on the market for a length of time, wouldn't the authorities need some kind of safety concern to do this? BTW, has anyone heard anything new about the new Modified-release guideling? Thank you all. |
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Dr_Dan ★★ Germany, 2012-11-29 17:30 (4563 d 06:21 ago) @ The Outlaw Torn Posting: # 9638 Views: 9,455 |
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Dear all The EGA (European Generic Association) sent a letter to the CMDh asking for a clarified joint statement by the EMA PKWP and the CMDh regarding the retrospective application of the bioanalytical method validation guideline for all studies performed (and completed) before finalisation of the guideline and already part of approved dossiers. As a reply CMDh is saying ‘indeed, it is under discussion’. In other words, they do not want to involve anybody in the discussion at this stage. However, once you received a marketing authorisation for a product you will not have to withdraw the product if your study submitted with the dossier is not compliant with the current guideline. In my opinion if you run a repeat use procedure your original MA should not be in danger of being revoked. Otherwise in this sense all marketing authorisation for generic products would be affected by the new guideline on method validation and this can not be. As stated by the CMDh this is only applicable for applications submitted after February this year. I hope this helps. Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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The Outlaw Torn ★ Europe, 2012-11-30 08:53 (4562 d 14:58 ago) @ Dr_Dan Posting: # 9640 Views: 9,306 |
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Dr. Dan, your interpretation parallels mine on this matter. And thanks for providing some clarity to the issue as it's being taken up by the CMDh. |
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Ohlbe ★★★ France, 2012-12-17 23:53 (4544 d 23:58 ago) @ Dr_Dan Posting: # 9727 Views: 8,390 |
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Dear all, ❝ The EGA (European Generic Association) sent a letter to the CMDh asking for a clarified joint statement by the EMA PKWP and the CMDh regarding the retrospective application of the bioanalytical method validation guideline for all studies performed (and completed) before finalisation of the guideline and already part of approved dossiers. Update of the PKWP Q&A published. Regards Ohlbe — Regards Ohlbe |
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The Outlaw Torn ★ Europe, 2012-12-18 09:09 (4544 d 14:41 ago) @ Ohlbe Posting: # 9728 Views: 8,350 |
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Thank you, Ohlbe. I appreciate the feedback. It's nice to see the EMA weigh in on this issue, however, their decisions always seem to come down to the same tired "appropriate justification," which everyone always provides, or at least tries to provide, whenever their is a discrepancy in their study with official guidelines. This type of position, IMO, allows too much leeway for interpretation, both for the applicant and the assessors; both in a good and bad direction. At the end of the day, no one really knows what is appropriate until one submits and finds out, which, in a roundabout way, appears to bring us all the way back to the status quo. Oh well, at least they didn't say it couldn't be justified. |
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Helmut ★★★   Vienna, Austria, 2012-12-18 18:12 (4544 d 05:38 ago) @ Ohlbe Posting: # 9729 Views: 8,373 |
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Dear Ohlbe and all, ❝ Update of the PKWP Q&A published. Does anybody understand / can explain to me what is meant by the last bullet point?
— 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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The Outlaw Torn ★ Europe, 2012-12-19 08:49 (4543 d 15:02 ago) @ Helmut Posting: # 9731 Views: 8,413 |
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❝ Does anybody understand / can explain to me what is meant by the last bullet point?
Dear Helmut et al, Maybe it's one of those riddles, wrapped in a mystery, inside an enigma.  My take may come across as a platitude, but it's not meant to so I'll go ahead with it anyway. The way I see it, and I'm not sure this is correct, is that if you happen to have a product with a narrow 90% CI (say 95 - 105), then you could opine that even if you have not performed the required ISR, it is unlikely that if you did and you found differences in your measurements that these differences would have pushed your study results outside the 80 - 125% CI. You would then conclude that is is unlikely the results of your study were the result of a false positive (i.e. it's a true positive).  You could make a similar argumentation if your ratio was within 95 - 105%, I'd say. So, you are probable going to have better luck with studies with low intrasubject variability...unless the product has been shown to exhibit back conversion, which appears, in that case, everyone is screwed for those products.Outlaw |
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Dr_Dan ★★ Germany, 2012-12-20 10:45 (4542 d 13:06 ago) @ The Outlaw Torn Posting: # 9735 Views: 8,352 |
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Dear all Sorry but IMHO the Q&A document does not help with respect to ISR at all. If the CHMP really follows the spirit of ISR then all of the arguments given in the Q&A document will be rejected. Regarding the 90% CI riddle: So if you have an overpowered study with a low variable substance you are lucky, because your CI is narrow and if you have a study with a HVD and a low number of subjects then the chance that execution (i.e. switched samples, instrument issues, scientist performance of method), and/or the method (i.e. metabolite interferences, back conversion of metabolites, poor ruggedness, internal standard response) and/or the samples, i.e. matrix effects, mislabelling) handling were inadequate is higher? Ridiculous!  It has to be noted, that the Q&A document points out:"The need for incurred sample reanalysis is discussed already since 20062 and regulators supported the need for incurred sample reanalysis also considering significant bioanalytical deficiencies observed in studies. Therefore, although incurred sample reanalysis is a requirement introduced in Europe for the first time with the new EMA Guideline on bioanalytical method validation (EMEA/CHMP/EWP/192217/2009), which came into force in February 2012, it should be noted that the scientific need to perform ISR as an element of bioanalytical method validation was already identified much earlier."  Furthermore the Q&A document points out that "Abridged applications may exclusively rely on pharmacokinetic data, e.g. bioequivalence studies, making overall validity of these data paramount. Therefore, the validity of the data needs to be considered for the assessment of the application and the specific study considering whether the data are pivotal or supportive." By this every application for a generic with an "old" BE study can be rejected by retrospective application of the guideline regardless of the scientific justification for missing ISR. In conclusion I am not convinced that the situation changed to the better I am looking forward to your opinions Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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The Outlaw Torn ★ Europe, 2012-12-20 12:23 (4542 d 11:27 ago) @ Dr_Dan Posting: # 9736 Views: 8,307 |
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❝ By this every application for a generic with an "old" BE study can be rejected by retrospective application of the guideline regardless of the scientific justification for missing ISR. Dear Dan, I am in agreement with you, though I tried to tone down my feelings above.  It only takes one stubborn assessor to stick to the ISR requirement and you're screwed.Concerning your comment above, how about repeat use procedures? Is it possible for the authorities to reject such applications because the studies that were initially accepted will now be rejected because they no longer abide by the new guideline? and that's despite the fact that the drug has been on the market for years (and therefore has been shown to be safe and effective)? This Q&A document provides no re-assurances regarding, I would assume, this common concern. It does raise more questions than it lays to rest, I think. Outlaw |
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Dr_Dan ★★ Germany, 2012-12-20 13:58 (4542 d 09:52 ago) @ The Outlaw Torn Posting: # 9737 Views: 8,290 |
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Dear Outlaw we currently have the problem that a BE study was accepted in a DCP procedure a while ago and now in a repeat use procedure (=new application!) the study is rejected. As you said, it only takes one stubborn (French) assessor to stick to the ISR requirement and you're screwed. I agree with you, the Q&A document raises more questions than it lays to rest. Kind regards Dan — Kind regards and have a nice day Dr_Dan |
Ing. Helmut Schütz