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Emrah Soner Özdeş ☆ Turkey, 2014-11-21 08:25 (3838 d 15:38 ago) Posting: # 13897 Views: 15,654 |
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Hi All; I have got a message from the analytical Lab I work with regarding a "not reportable" value as follows: "This was a repeat value where the duplicate repeats were more than 20 percent different from one another and also differed from the original. Therefore according to the SOP it becomes Not Reportable." Do you think is it safe to simply ignore that value during the PK analysis ? Regards Emrah Soner Özdeş Edit: Category changed. [Helmut] |
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ElMaestro ★★★ Denmark, 2014-11-21 08:34 (3838 d 15:28 ago) @ Emrah Soner Özdeş Posting: # 13899 Views: 14,590 |
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Hi Emrah, ❝ "This was a repeat value where the duplicate repeats were more than 20 percent different from one another and also differed from the original. Therefore according to the SOP it becomes Not Reportable." Why was it re-analysed ? ❝ Do you think is it safe to simply ignore that value during the PK analysis ? Yes; it is likely safest, I think, to report the original value unless there is some other reason to consider the original value wrong. — Pass or fail! ElMaestro |
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Emrah Soner Özdeş ☆ Turkey, 2014-11-21 08:54 (3838 d 15:08 ago) @ ElMaestro Posting: # 13900 Views: 14,414 |
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Thanks for the prompt reply ElMaestro Here is the situation: Conc: 418.78 Re-analysis 1: 8.76 Re-analysis 2: 7.24 Means of Reanalyses : 8.00 Reported Conc: NR NR = Not Reportable Reason for re-analysis is Fault in sample processing |
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nobody nothing 2014-11-21 09:07 (3838 d 14:55 ago) @ Emrah Soner Özdeş Posting: # 13901 Views: 14,495 |
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Educated guess, considering the values reported: The first concentration did not fit considering the PK of the compound  Maybe the lab staff screwed a little up with pipetting or there was something else leading to a contamination of the first analysis. What does the SOP of the CRO say for such a case? Completely ignore the plausible 2 repeats? — Kindest regards, nobody |
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Emrah Soner Özdeş ☆ Turkey, 2014-11-21 09:18 (3838 d 14:44 ago) @ nobody Posting: # 13902 Views: 14,527 |
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Thanks for reply nobody: It is apparent that there is a sample processing fault. Here is the related part in the study protocol: "Individual samples will be re-assayed if at least one of the following criteria is met:
I think neglecting that value in PK analysis will be the best practice as ElMaestro advised. |
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ElMaestro ★★★ Denmark, 2014-11-21 10:53 (3838 d 13:09 ago) @ Emrah Soner Özdeş Posting: # 13903 Views: 14,545 |
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Hi Emrah, ❝ I think neglecting that value in PK analysis will be the best practice as ElMaestro advised. Careful, please. If you are submitting in a territory where outlier detection is the norm then perhaps you can neglect the original value after some number crunching gymnastics. But if you are not submitting in a territory where outliers testing is popular then you would perhaps need to either report the value however wrong it sounds, or, audit and self-inspect the study to see if you can verify that something really went wrong (and you need more than just an unexpected value for that); a verification of a problem would then allow you to report the re-analysed value. — Pass or fail! ElMaestro |
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nobody nothing 2014-11-21 12:11 (3838 d 11:51 ago) @ Emrah Soner Özdeş Posting: # 13904 Views: 14,433 |
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Which of those (a to f) did apply in this case to justify re-analysis of the sample? — Kindest regards, nobody |
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Emrah Soner Özdeş ☆ Turkey, 2014-11-21 17:14 (3838 d 06:48 ago) @ nobody Posting: # 13908 Views: 14,341 |
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❝ Which of those (a to f) did apply in this case to justify re-analysis of the sample? It is reported as "Fault in the sample processing". |
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Helmut ★★★   Vienna, Austria, 2014-11-21 17:45 (3838 d 06:18 ago) @ Emrah Soner Özdeş Posting: # 13909 Views: 14,516 |
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Merhaba Emrah! ❝ It is reported as "Fault in the sample processing". OK, but how can you know that? Was anything documented in the lab journal like “I’m not sure whether I added the IS to this sample”? Can you give us:
❝ ❝ Conc: 418.78 ❝ ❝ Re-analysis 1: 8.76 ❝ ❝ Re-analysis 2: 7.24 ❝ ❝ Means of Reanalyses : 8.00 ❝ ❝ Reported Conc: NR NR because “duplicate repeats were more than 20 percent different from one another”. That’s a matter of perspective: Re-analysis 1: 8.76 (+21.0% of 7.24, –9.5% of x)  If ever possible (i.e., sufficient sample) run triplicates and use the median for assessment. In which country do you want to submit the study? Bad luck for the EU and seemingly for Turkey as well. However, I would explore potential impact of IS carry-over. Inject a sample spiked to a similar concentration like the sample in the batch before the doubtful value followed by a spiked sample without IS. — 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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nobody nothing 2014-11-21 18:19 (3838 d 05:43 ago) @ Helmut Posting: # 13910 Views: 14,366 |
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...but that should end up in category b, huh? — Kindest regards, nobody |
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Emrah Soner Özdeş ☆ Turkey, 2014-11-24 09:58 (3835 d 14:05 ago) @ Helmut Posting: # 13921 Views: 14,259 |
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Hi Helmut; I guess I will be able to answer your questions after I obtain the Analytical Report. Thanks for reply |
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Emrah Soner Özdeş ☆ Turkey, 2014-11-27 11:28 (3832 d 12:35 ago) @ Helmut Posting: # 13927 Views: 14,147 |
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Hi again Helmut. The previous values were from another study. Here are the values from the current study and the thing you ask for. Conc: 0.00 Re-analysis 1: 2.63 Re-analysis 2: 2.15 Means of Reanalyses: 2.39 Reported Conc: NR ❝ ❝ It is reported as "Fault in the sample processing". ❝ ❝ OK, but how can you know that? Was anything documented in the lab journal like “I’m not sure whether I added the IS to this sample”? I guess I wont be able to access lab journals. ❝ NR because “duplicate repeats were more than 20 percent different from one another”. That’s a matter of perspective: ❝ Re-analysis 1: 8.76 (+21.0% of 7.24, –9.5% of x) ❝ Re-analysis 2: 7.24 (–19.9% of 8.76, +9.5% of x) ❝ Obviously the decision to not report the value was based on the first replicate – why not on the second? Looks like an ambiguity in the SOP. In case of these values original value is 0.00 which makes the situation more interesting i guess. Flow Chart states that If duplicates differ from each other more than 20%, the next step is checking whether difference between each duplicate and original is more than 20%. According to Lab, the difference is more than %20 and hence the value is "NR". But in my opinion it is "Not Applicable" to find the percent difference from a value of "0.00" ❝ Can you give us: ❝ – The LLOQ and ULOQ of the method. 1.31 - 193.21 ng/mL ❝ – The concentration of samples analyzed in the batch before and after the doubtful value. ❝ – The concentration of samples of the subject’s profile before and after the doubtful value + their sampling time points. 0.0-0.00 0.8-2.52 1.5-10.79 3.0-32.81 4.5-61.07 5.0-69.93 5.5-76.10 6.0-76.64 6.5-83.04 7.0-89.39 7.5-84.73 8.0-88.83 10.0-89.91 12.0-64.55 24.0-17.11 48.0-4.74 72.0-NR ❝ – The ranges of Cmax-values in the study. 43.41 - 170.70 ng/mL Regards |
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Helmut ★★★ Vienna, Austria, 2014-11-27 15:21 (3832 d 08:42 ago) @ Emrah Soner Özdeş Posting: # 13934 Views: 14,054 |
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Hi Emrah, ❝ The previous values were from another study. Yes, but it would have been nice to understand what was going on there. ❝ Here are the values from the current study and the thing you ask for. ❝ Conc: 0.00 ❝ Re-analysis 1: 2.63 ❝ Re-analysis 2: 2.15 ❝ Means of Reanalyses: 2.39 ❝ Reported Conc: NR OK, another story. Conc = 0 post dose? I don’t believe it. Rather BLQ at 72 hours. Did the CRO report other concentrations as zero? ![[image]](img/uploaded/image280.png) Why was the sample at 72 hours re-analysed? Without the 72 h-value the estimate of the elimination is not perfect, but acceptable (or has the CRO another stupid rule like “R²adj ≥0.95” in place?). From it we could expect the concentration at 72 hours to be <LLOQ (~0.80). On the other hand it looks like the drug follows a two-compartment model. It would have been nice to have a sampling time at ~16 h. Based on the 24/48-concentrations the repeated values at 72 h seem to be reasonable. But actually it is not important. The extrapolated part is <5% of AUC∞. I don’t get why the CRO repeated the value at all. ❝ ❝ ❝ It is reported as "Fault in the sample processing". ❝ ❝ OK, but how can you know that? Was anything documented in the lab journal like “I’m not sure whether I added the IS to this sample”? ❝ I guess I wont be able to access lab journals. If you are the sponsor of the study perform an audit. If the CRO is not willing to show you the lab journals never do a study with them again. ❝ Flow Chart states that If duplicates differ from each other more than 20%, the next step is checking whether difference between each duplicate and original is more than 20%. According to Lab, the difference is more than %20 and hence the value is "NR". But in my opinion it is "Not Applicable" to find the percent difference from a value of "0.00" All these flow-charts are crap anyway, IMHO. — 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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Emrah Soner Özdeş ☆ Turkey, 2014-11-28 11:00 (3831 d 13:02 ago) @ Helmut Posting: # 13944 Views: 13,885 |
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Hi Helmut; I would like to thank you for all your help on the subject. My guess is that the lab decided to renalayse the sample because of the "0.00" post dosing concentration. All other values are expressed BLOQ instead of "0.00" which makes me think that they really did a mistake in sample processing. (blank injection maybe). So they reanalysed the sample. If this is the scenario, avarage of the reanalyses which was "2.39" should be the reported value, i guess. I will question the lab with regard to those points. Thanks again Regards |
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nobody nothing 2014-11-28 11:18 (3831 d 12:45 ago) @ Helmut Posting: # 13945 Views: 13,872 |
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...but from visible inspection the concentrations found with re-analysis make more sense as the third data point for linear regression than the point close to Cmax, whih is more likely not really in the terminal phase I still don't get why the concentration was reported as ZERO for the first analysis, makes absolutely no sense at all. Would torture the lab to hand out the chromatograms of the whole analytical run for inspection by the sponsor... — Kindest regards, nobody |
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AngusMcLean ★★ USA, 2014-11-28 20:09 (3831 d 03:53 ago) @ Emrah Soner Özdeş Posting: # 13954 Views: 13,808 |
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it seems to me that the value > 400 WAS discordant with respect to the pharmacoknetic trend of the values prior to it. As such it can be repeated as a pharmacokinetic outlier according to an appropriate SOP. If the two new values for the duplicate repeats carried out are within 20% of each other then according to appropriate SOP then they would be averaged and report this value. The >400 values is rejected as a pharmcokinetic outlier. You need an SOP policy in place to follow and in the analytical report all repeats are Tabulated together with the reason for repeats and final values. This report will reference the Lab. SOPs for repeats Angus |
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Helmut ★★★ Vienna, Austria, 2014-11-28 20:16 (3831 d 03:46 ago) @ AngusMcLean Posting: # 13955 Views: 13,938 |
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Hi Angus, agree with everything you wrote. On this side of the pond common sense is (no more) the driving force behind (some) regulations. Repeating samples for PK reasons is not acceptable over here. A single value can screw up an entire 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 |
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jag009 ★★★ NJ, 2014-12-01 20:54 (3828 d 03:08 ago) (edited on 2014-12-02 16:07) @ Helmut Posting: # 13962 Views: 13,731 |
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Hi Helmut, On a side note (sort of). What if you have data from a subject (1 treatment) that is all BLQs? I mean the entire profile... No, there is no clinical evidence of cheating, vomiting etc etc... Thanks John |
Ing. Helmut Schütz