sarada06884 ☆ India, 2013-04-09 14:22 (4006 d 05:51 ago) Posting: # 10381 Views: 14,633 |
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Hi Helmut, Incurred sample reanalysis has been suggested by USFDA but I would like to debate on this topic. How are ISR samples different from subject samples? The answer would be they are in vivo samples and the QCs are in vitro samples. ISR samples are meant for demonstrating assay reproducibility. Based on this now my concern would be:
Regards Srinivas |
Ohlbe ★★★ France, 2013-04-09 16:09 (4006 d 04:04 ago) @ sarada06884 Posting: # 10382 Views: 14,021 |
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Dear Srinivas, ❝ Hi Helmut, Not interested in the opinion of other members of the forum ? ❝ Incurred sample reanalysis has been suggested by USFDA It is now also required for EMA submission. ❝ 1. When the whole validation has been done based on in vitro samples and when the results of these experiments have been accepted then why ISR again? Because in vitro samples are not fully representative of the subject samples. They usually do not contain metabolites, and I've never seen overfilled QC samples (two of the possible causes of ISR failure). ❝ 2. When Long Term Matrix Stability of the drug and metabolites are proven taking invitro samples is proven and when the stability of such experiment is accepted then why ISR again? The long-term stability is not the only issue anyway: back-conversion during sample processing can be of greater concern. And are you sure you know all metabolites ? EMA got trapped in their recommendations on clopidogrel.1 ❝ 3. Even though the ISR samples are reanalysed they are analysed along with CCs and QCs which are invitro again!!!! So what ? The idea with ISR is to test for the variability of the method when analysing subject samples. Some variability factors affect the subject samples more than the CCs and QCs, which are used as a reference. ❝ 4. What if ISR fails?? probably they have to ascertain the cause and go for the development of the method again????? First try and find the reason for failure, and see if and how it can be corrected.
M. Yadav, P. S. Shrivastav Incurred sample reanalysis (ISR): a decisive tool in bioanalytical research Bioanalysis (2011) 3(9), 1007–1024 A. Tan, S. Gagnon-Carignan, Sylvain Lachance et al. Beyond successful ISR: case-by-case investigations for unmatched reassay results when ISR passed Bioanalysis (2011) 3(9), 1031–1038 — Regards Ohlbe |
The Outlaw Torn ★ Europe, 2013-04-10 10:40 (4005 d 09:33 ago) @ Ohlbe Posting: # 10387 Views: 13,405 |
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Dear Ohlbe, ❝ The long-term stability is not the only issue anyway: back-conversion during sample processing can be of greater concern. And are you sure you know all metabolites ? EMA got trapped in their recommendations on clopidogrel1 I just happened to be cruising by this joint looking for anything new on ISR. Glad to see you tapping this subject. You answered a lot of my questions, except I'm not sure I understand what you mean by the EMA getting trapped. Do you mean that there are ways around justifying clopidogrel, or other drugs known for back-conversion, that EMA hadn't considered (the paper you quoted where the authors found a way of controlling back-conversion)? Is that it? If that's not the case, mind expanding on this while I sit back and have a drink? Thanks, Outlaw |
Ohlbe ★★★ France, 2013-04-10 12:34 (4005 d 07:39 ago) @ The Outlaw Torn Posting: # 10393 Views: 13,472 |
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Dear Outlaw, ❝ [...] I'm not sure I understand what you mean by the EMA getting trapped. Do you mean that there are ways around justifying clopidogrel, or other drugs known for back-conversion, that EMA hadn't considered Oh no... If the drug is know for back-conversion, I don't really see a way out. ❝ (the paper you quoted where the authors found a way of controlling back-conversion)? Which means there is a need to study back-conversion anyway... ❝ If that's not the case, mind expanding on this What I mean to say is that it may not be sufficient to test known metabolites for back-conversion, or to just say that the drug has no known metabolite which could be back-converted. What EMA recommended for clopidogrel was to demonstrate the lack of back-conversion of clopidogrel carboxyacid, the main metabolite, to clopidogrel. The simplest way to do it would be to spike blank plasma with clopidogrel carboxyacid, process it, and check that no clopidogrel is generated. It made sense: one could imagine that clopidogrel carboxyacid could be re-esterified with methanol, and that this could explain the back-conversion issues with clopidogrel which some people were talking about. Problem: the metabolite which is back-converted is not the carboxyacid, but the acylglucuronide* (not described in the literature when EMA published their recommendation, as far as I know), by a transesterification mechanism. Silvestro et al. clearly demonstrate in their paper that what was recommended by EMA just doesn't work. Only ISR allowed them to first identify the issue, then develop a method with no back-conversion issue.
— Regards Ohlbe |
The Outlaw Torn ★ Europe, 2013-04-10 13:31 (4005 d 06:42 ago) @ Ohlbe Posting: # 10399 Views: 13,232 |
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Very thorough and answers my query quite clearly, Ohlbe. Merci beaucoups. On a side note, does anyone have actual experience with the authorities concerning lack of ISR justifications? Whether they require it for products that have already been marketed for years now that are going through ruMRPs, etc? The only feedback we are getting for all ISR queries is a reference back to the Q&A document. Seems like they are hoping someone gets referred to CMDh so that whatever internal disagreement there is on ISR gets resolved by CHMP. |
Helmut ★★★ Vienna, Austria, 2013-04-22 19:01 (3993 d 01:11 ago) @ The Outlaw Torn Posting: # 10459 Views: 14,275 |
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Hi Outlaw & all! ❝ On a side note, does anyone have actual experience with the authorities concerning lack of ISR justifications? Last Friday (today is day 100): Line extension of an MR formulation (racemate), two studies (single & multiple dose), stable-isotope IS chiral GC/MS method (BE based on the active enantiomer d-█████).
But The Netherlands: PSRPH:
— 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 |
ElMaestro ★★★ Denmark, 2013-04-22 20:56 (3992 d 23:17 ago) @ Helmut Posting: # 10461 Views: 13,104 |
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Hi Hötzi, sad story. I'd love to see the faces of the CMD(h) members if or when they realise that they have yet another ISR case to deal with. The details are good: the ISR seemed to work well in June, but NL's fear is it didn't in April?!? I might be inclined to play the regulatory chicken game and go ahead full throttle. If any situation would merit a deviation from the guideline's requirement then this development would be a good candidate, wouldn't it. Anyways to mitigate any risk, if this was a compound like meth (very -very!- low CV intra) then you'd be looking at 12-16 subjects in a 222-BE trial. Would be a cheapo and could be done and dusted by any CRO way before the end of a clockstop. — Pass or fail! ElMaestro |
Helmut ★★★ Vienna, Austria, 2013-04-22 21:35 (3992 d 22:37 ago) @ ElMaestro Posting: # 10462 Views: 13,235 |
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Ahoy, my Capt’n, ahoy! ❝ sad story. I'd love to see the faces of the CMD(h) members if or when they realise that they have yet another ISR case to deal with. The details are good: the ISR seemed to work well in June, but NL's fear is it didn't in April?!? That’s not a fear, but PSRPH… ISR ‘worked’ nicely in 5% of samples (in June), but 10% are “required” (published in August). Ha! ❝ […] and go ahead full throttle. Do I look like James Dean? ❝ If any situation would merit a deviation from the guideline's requirement then this development would be a good candidate, wouldn't it. I’m in the right mood for it. ❝ Anyways to mitigate any risk, if this was a compound like meth (very -very!- low CV intra) … Good guess. Not exactly meth (that was the story at the end of this post), but close. Remember the recent Two-Stage thread? ❝ … then you'd be looking at 12-16 subjects in a 222-BE trial. Would be a cheapo and could be done and dusted by any CRO way before the end of a clockstop. Please no. BTW, at a meeting at the BfArM in 2010 they were surprised that we have done the MD study at all: “We expect that such a study will not be necessary any more according to the new MR GL.” Accumulation in the MD study was <1%… — 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 |
ElMaestro ★★★ Denmark, 2013-04-22 22:03 (3992 d 22:10 ago) @ Helmut Posting: # 10463 Views: 13,137 |
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Hi again, ❝ Good guess. Not exactly meth (that was the story at the end of this post), but close. Remember the recent Two-Stage thread? Jawohl; I apologise for that abbreviation - I actually meant meth█████ which I have seen have quite low intra-CVs in IR formulations. In the world of inhalation I also occasionally see meth used as acronym for methacholine. It is used to provoke artifical asthma attacks in volunteers. Wonderful stuff - crossover studies now and then have a lot of subjects who mysteriously don't feel like showing up for period 2 Edit: Your guess was exactly right. However, I blacked it out (not sure whether the sponsor wants to see it in public right now). Low CVs also for all MR formulations – unless you go for the first pAUC (not to speak about EMA’s invention pCmax,1). — Pass or fail! ElMaestro |
The Outlaw Torn ★ Europe, 2013-04-23 10:27 (3992 d 09:46 ago) @ ElMaestro Posting: # 10468 Views: 13,002 |
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Thanks for the example, Helmut. Nothing like a concensus! This is the kind of thing that makes you want to bang your head on your desk! NL have been rather difficult lately for us as well (and Spain). And some of the eastern block countries to, for some reason. Ummmm. El Maestro, you said "I'd love to see the faces of the CMD(h) members if or when they realise that they have yet another ISR case to deal with." Has anyone challenged ISR to the CMDh yet, as far as you know (I mean, has the committee had to make any decisions regarding ISR or the lack of it)? |
ElMaestro ★★★ Denmark, 2013-04-23 16:29 (3992 d 03:44 ago) @ The Outlaw Torn Posting: # 10472 Views: 12,964 |
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Hi Outlaw, ❝ El Maestro, you said "I'd love to see the faces of the CMD(h) members if or when they realise that they have yet another ISR case to deal with." Has anyone challenged ISR to the CMDh yet, as far as you know (I mean, has the committee had to make any decisions regarding ISR or the lack of it)? It is difficult to challenge the CMD(h) directly; in a DCP they will be on the receiving end of a PSRtPH if a national agency declares one. The CMD(h) doesn't really 'decide' much here, and the members are often relying on their experts since the core business of CMD(h) is regulatory rather than strictly scientific (but please don't ask me to draw the line between what's regulatory and what's science ). They can talk and they can invite experts for specific issues in a procedure and they can more generally send over issues to the PK work group as needed. Many companies have submitted study reports without ISR data and many times this has caused trouble at the CMD(h), and this in a sense one reason why the PK work group's statement re. ISR was born. In a case like Helmut's I believe the CMD(h) members would with very decent effort try to reach consensus for acceptance due to e.g. "ISR data obtained for the same analyte from other studies carried out in the same laboratory and with the same analytical method may be used as supportive data to justify the lack of ISR." I hope this answers your question. — Pass or fail! ElMaestro |
The Outlaw Torn ★ Europe, 2013-04-24 09:44 (3991 d 10:29 ago) @ ElMaestro Posting: # 10482 Views: 13,058 |
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❝ I hope this answers your question. Yes, that answers a lot of my concerns. What I was wondering, more precisely, is the same old question I have on ISR, and that is whether anyone has been referred to CMDh for not providing ISR in a ruMRP. I'd like to hear the committee's reasoning for denying an ruMRP based on lack of ISR, when an ruMRP is based solely on a previously accepted dossier and now back up by several years of the actual product being taken by patients, yada, yada, yada. We are being told to refer back to the Q&A document for our answer, which says nothing or tells me that they expect some kind of justification for lack of ISR or else the ruMRP will be denied, which as I've mentioned before makes no sense. It's so difficult to get go advice, because each country is unsure what another country's position on a given issue will be (see the NL in Helmut's case; everything seemed fine with the other CMSs and DE). Very frustrating. |
ElMaestro ★★★ Denmark, 2013-04-24 13:08 (3991 d 07:05 ago) @ The Outlaw Torn Posting: # 10485 Views: 12,823 |
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Hi Outlaw, I would certainly go ahead with the repeat use MRP dossier. If there is any concern it has probably been caught by the pharmacovigilance system. Hard to believe a repeat use MRP can be rejected, really. After all it is the same product - by nature equally efficient and safe as the previous/first MRP. — Pass or fail! ElMaestro |
Ohlbe ★★★ France, 2013-04-24 13:41 (3991 d 06:32 ago) @ ElMaestro Posting: # 10486 Views: 12,784 |
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Hi El Maestro, ❝ If there is any concern it has probably been caught by the pharmacovigilance system. I doubt it, unless it is really a big, big problem... The substitution of the reference product by the generic is made by the pharmacist selling the drug to the patient. The prescriber usually doesn't even know which generic was given to his patient. If, by some sort of a miracle, he decides to make a pharmacovigilance declaration, to which product will he assign the AE ? Sorry for being pessimistic, but I don't have much trust in the pharmacovigilance of generics — Regards Ohlbe |
ElMaestro ★★★ Denmark, 2013-04-24 15:45 (3991 d 04:27 ago) @ Ohlbe Posting: # 10488 Views: 12,816 |
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Hi Ohlbe, ❝ I doubt it (...) If, by some sort of a miracle, he decides to make a pharmacovigilance declaration, to which product will he assign the AE? ❝ ❝ Sorry for being pessimistic, but I don't have much trust in the pharmacovigilance of generics I agree in the sense that the PV systems -and here I do not mean any applicant's own system but the EU-wide and possibly ROW-wide systems- do not pick up issues with great sensitivity and they rely on active reporting reporting. Only the serious stuff gets reported. For a repeat use MRP the applicant will be able to refer to something like 1.000.000 patient years of treatment experience and garnish that with info about reported numbers of deaths or people who contracted syphilis while being treated with the drug etc etc. I think that counts for something although it is not formalised. In a nutshell I would rather take a product that has 1.000.000 or whatever patient years in the luggage and no ISR rather than taking a product with acceptable ISR for which the total human exposure is a 2,2,2-BE trial in Hevo's totalling 1 day of exposure with one unit dose for the Test. — Pass or fail! ElMaestro |
Helmut ★★★ Vienna, Austria, 2013-09-20 23:50 (3841 d 20:23 ago) @ The Outlaw Torn Posting: # 11537 Views: 11,930 |
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Hi all, 17 pages of justification – essentially following the Q&A (simulations, later studies with ISR, literature data, back-conversion neither under physiological nor sample treatment conditions chemically possible, ). Day 145 (NL) Clinical aspects Potential Serious Risks to Public Health Pharmacokinetics Study #1: The conclusion of the preliminary assessment report stands true as both prerequisites are met for waiving ISR: At the time point of the studies the Guideline on analytical validation was not in operation and back conversion is not an issue (re-esterfication is not an issue under physiological or sample preparation conditions; interconversion can be excluded, plasma concentrations are consistent with literature data). Moreover the applicant provided supportive data e.g. ISR results of studies #2 and #3 using the same analytical method and results of remeasurements confirming the robustness and reliability of the analytical method. Study #2: ISR has been performed and the results comply with the actual recommendations, however formal requirements for the sample size were not met. This is considered acceptable as the same considerations as for study #1 are applicable. Moreover the results demonstrated very high reproducibility as 100% of ISR in study #3 were within the acceptance criteria for deviation. Overall Summary and Conclusion Issues resolved. Edit: PAR from HMA as of 2014-01-27. DE (RMS), AT, DK, ES, FI, LU, NL, NO, PL, SE, UK (CMS). Both studies were performed in a Two-Stage Design (Potvin’s “Method C”) – already passing in the first stage (no α-adjustment = 90% CIs). The estimated Ĉmin was assessed in the MD study. — 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 |
Dr_Dan ★★ Germany, 2013-09-22 18:56 (3840 d 01:17 ago) @ Helmut Posting: # 11540 Views: 11,544 |
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Dear Helmut Congratulations! — Kind regards and have a nice day Dr_Dan |
ElMaestro ★★★ Denmark, 2013-04-24 01:31 (3991 d 18:42 ago) @ Helmut Posting: # 10480 Views: 12,848 |
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Cool code Helmut. Run your code, then do shapiro.test(data) and discuss if the high p-value proves that the data are Gaussian.Next do this:
data <- c(-1.05, -6.38, -5.30, -5.55, -2.99, -2.24, +10.75, +0.90, ...and argue that even when you do not make any assumption of ISR distribution you are still very clearly very far from any sort of trouble. — Pass or fail! ElMaestro |
Helmut ★★★ Vienna, Austria, 2013-04-24 04:08 (3991 d 16:05 ago) @ ElMaestro Posting: # 10481 Views: 12,981 |
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Hi ElMaestro, THX for your help over there. Now it looks even more nice (using the repeats’ % deviation): data <- c(-0.53, -3.19, -2.65, -2.77, -1.49, -1.12, +5.38, +0.45, ❝ Run your code, then do Yessir! Shapiro-Wilk normality test I was already amazed yesterday by: xfit <- seq(-max(abs(data))*1.25, max(abs(data))*1.25, length=50) Haven’t thought about a formal test for normality! Of course I can politely ask for the probability of getting a deviation of -20% or lower: pnorm(-20, mean=mean*100, sd=sd*100) Didn’t I fantasize about 6σ already? What about a wacky setup in the spirit of Anderson & Hauck to get the probability of a result outside of [-20%, +20%]? ❝ Next do this: […] I would rather bootstrap for 10% of the study’s samples based on the 5% I have … xboot <- sample(data, size=ISR.no, replace=T) … since I want to justify that based on the x/SD from 32 samples I will pass with the Dutch 66 as well. ❝ ...and argue that even when you do not make any assumption of ISR distribution you are still very clearly very far from any sort of trouble. Yep. — 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 |
nobody nothing 2014-10-23 12:06 (3444 d 08:07 ago) @ ElMaestro Posting: # 13775 Views: 9,396 |
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❝ Next do this: ❝ ❝ ❝ ❝ ❝ ❝ ❝ ❝ ❝ ❝ Wanted to perform some kind of sensitivity analysis to see at which criterion studies start to fail. With 1/8 of samples deviating more than 20% I get 200% study failure, due to simply multiplying number of failed studies by 100 in the output, but should be divided by number of studies simulated, I guess. The code above works only as long as 0 trials fail, i guess Οὐδείς 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] Of course, you are correct. The line should be: sprintf("%.2f%% %s", 100*failed/sims, "of studies.\n")) — Kindest regards, nobody |