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Anand ☆ India, 2017-10-30 07:38 (2695 d 09:11 ago) Posting: # 17945 Views: 10,205 |
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Dear All, Request to clarify, In our Pivotal BE Study ULOQ was observed, whether we should exclude from PK? After Dilution also it found ULOQ. Method should be redeveloped or revalidated? If included,What justification we should provide to Regulatory Agency? Thanks in advance. Regards, A.A Edit: Category changed; see also this post #1. [Helmut] |
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Helmut ★★★   Vienna, Austria, 2017-10-30 11:30 (2695 d 05:20 ago) @ Anand Posting: # 17947 Views: 8,716 |
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Hi Anand, ❝ In our Pivotal BE Study ULOQ was observed, whether we should exclude from PK? ❝ After Dilution also it found ULOQ. ❝ Method should be redeveloped or revalidated? Perform a partial validation with a higher dilution. If passing the usual criteria for A&P, re-analyse the sample(s) with high concentrations. ❝ If included,What justification we should provide to Regulatory Agency? IMHO, that’s not possible. — 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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Ohlbe ★★★ France, 2017-10-30 11:35 (2695 d 05:14 ago) @ Anand Posting: # 17948 Views: 8,751 |
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Dear Anand, ❝ After Dilution also it found ULOQ. ❝ ❝ Method should be redeveloped or revalidated? You should dilute further, till you get a result below your ULOQ. If this requires a dilution factor greater than what you tested during validation, then you need to do a partial validation with a greater dilution factor. If you have many results above the ULOQ you may wish to consider to expand your calibration range with a partial validation. You can't exclude subjects or data points because they are ULOQ: the ULOQ result would be the Cmax for that subject. If you exclude the data, you will bias the outcome of the study. — Regards Ohlbe |
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Helmut ★★★ Vienna, Austria, 2017-10-30 11:59 (2695 d 04:50 ago) @ Ohlbe Posting: # 17950 Views: 8,680 |
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Hi Ohlbe, ❝ You can't exclude subjects or data points because they are ULOQ: the ULOQ result would be the Cmax for that subject. If you exclude the data, you will bias the outcome of the study. Really? Let’s assume that the subject with concentrations >ULOQ is observed in the last batch and we are already close to the validated long-term stability. Even if we revalidate with a higher dilution, we may exhaust the storage interval – resulting in unacceptable results as well. In such a case we have to exclude the subject. — 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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Ohlbe ★★★ France, 2017-10-30 16:10 (2695 d 00:39 ago) @ Helmut Posting: # 17953 Views: 8,701 |
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Hi Helmut, ❝ Let’s assume that the subject with concentrations >ULOQ is observed in the last batch and we are already close to the validated long-term stability. Even if we revalidate with a higher dilution, we may exhaust the storage interval – resulting in unacceptable results as well. In such a case we have to exclude the subject. If the storage interval is limited by the duration studied during validation (e.g. stability demonstrated for 30 days, still fine at the end): I would extend the validated period (always keep some extra stability samples in the freezer, just in case !). If the stab failed at the last time point: indeed in trouble. But I think that regulators would not see with a very positive eye the exclusion of the one subject with the highest Cmax in the whole study. Particularly if his Cmax was within range in the other period. — Regards Ohlbe |
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Helmut ★★★ Vienna, Austria, 2017-10-30 18:34 (2694 d 22:16 ago) @ Ohlbe Posting: # 17954 Views: 8,605 |
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Hi Ohlbe, ❝ […] I think that regulators would not see with a very positive eye the exclusion of the one subject with the highest Cmax in the whole study. Particularly if his Cmax was within range in the other period. Let me play the devil’s advocate. I think there are two worst case scenarios. (1) Further dilution fails A&P or (2) the storage cannot be extended (fails as well). Now what? All reanalysed concentrations (>ULOQ is mentioned as a reason in the BMV-GL) are not valid. Given the high variability generally observed for Cmax, the value in the other period is not relevant. Even with true F=1, Cmax might be ≤ULOQ in one period and >ULOQ in the other. What do you think a regulator would prefer?
 ) but (a) would not bias the treatment comparison. Only the producer’s risk increases. IMHO, (b) contradicts all rules about using valid data only and the treatment comparison might be biased.— 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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Ohlbe ★★★ France, 2017-10-30 19:03 (2694 d 21:46 ago) @ Helmut Posting: # 17956 Views: 8,647 |
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Hi Helmut, ❝ What do you think a regulator would prefer?
Please don't misunderstand what I mean. I'm certainly not pleading to use data which were not demonstrated to be valid during method validation. I would not extrapolate above the ULOQ and I would not analyse a sample beyond its stability period. But let me play the devil's advocate too. Let's imagine your subject had a Cmax at midrange of the calibration curve in Period 1 and is at least 5 x ULOQ in Period 2 (still ULOQ after a 1/5 dilution). Regulators would not be happy with the exclusion of the subject. Which doesn't mean that they would like possibly unreliable data to be used instead: rather that they may reject the study as a whole  . Regulators don't wear Armani suits.OK, we're discussing rather extreme situations. Let's remain optimistic and hope that Anand still has enough plasma for re-analysis, that the analyte is stable, and that the validation of the higher dilution factor will pass  — Regards Ohlbe |
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ElMaestro ★★★ Denmark, 2017-10-30 14:18 (2695 d 02:31 ago) @ Anand Posting: # 17952 Views: 8,676 |
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Hi Anand, dilute the sample you already diluted; use the already validated dilution factor and inject. Continue doing that until you get a measurable concentration. It does require that you have started the dilution series with sufficient volume. — Pass or fail! ElMaestro |
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Helmut ★★★ Vienna, Austria, 2017-10-30 18:53 (2694 d 21:57 ago) @ ElMaestro Posting: # 17955 Views: 8,677 |
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Hi öberster größter Meister, ❝ dilute the sample you already diluted; use the already validated dilution factor and inject. Continue doing that until you get a measurable concentration. Really? Quoting the BMV-GL: 4.1.7. Dilution integrity If you want to dilute ×2, ×4, ×8 those are the dilution factors – not serial ones like 1×2, 2x2, 2x2x2. Imagine a propagation of error which results in an accuracy of 90% in each of the steps. If done properly (only one dilution), you pass the requirements (within ±15%). With serial dilutions you would fail already in the second step (81% outside ±15%) and even more in the third (73%). But: Since you didn’t validate it, you falsely assume that the accuracy is still 90%. You don’t want to go there. Of course, you could validate serial dilutions as well but I don’t see any rationale for doing so. — 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