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jag009 ★★★ NJ, 2013-09-09 23:12 (3879 d 16:18 ago) Posting: # 11464 Views: 10,165 |
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Hi guys, If a blood draw has a time deviation which pushes it to overlap with the next blood draw time point, how do you deal with PK if you need to calculate partial AUC0-4? 3.5 hr blood draw has time deviation of +41 mins. 4 hr blood draw has time deviation of +2 mins. $&#%! Don't ask how and why. Thanks John |
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Ohlbe ★★★ France, 2013-09-09 23:26 (3879 d 16:04 ago) @ jag009 Posting: # 11465 Views: 8,653 |
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Hi John, ❝ 3.5 hr blood draw has time deviation of +41 mins. ❝ 4 hr blood draw has time deviation of +2 mins. How did they manage to collect the 3.5 hr sample after the 4 hr sample  ?❝ how do you deal with PK if you need to calculate partial AUC0-4 ? With PK, no idea. With the CRO, I have a pretty good idea  Unless the staff were kept busy by a serious adverse event and had more urgent things to do, I can't see how they managed to f... up that much. Even with a blocked canula they should be able to collect the sample via a fresh venipuncture. Or did they have no spare phlebotomist at hand ? OK, I know it doesn't help, sorry... — Regards Ohlbe |
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Helmut ★★★   Vienna, Austria, 2013-09-09 23:55 (3879 d 15:36 ago) @ Ohlbe Posting: # 11466 Views: 8,730 |
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Hi Ohlbe & John, Unbelievable snafu: 3:30 ⇒ 4:11 4:00 ⇒ 4:02 I hope they had no barcode-/CDMS in place. Such data might foul up the entire data base. At least in our validation we did not challenge the system with a later sample harvested earlier than the ‘previous’ one. Wacky. ❝ With the CRO, I have a pretty good idea  What was going on in their wetware? Lights on, nobody at home?❝ ❝ how do you deal with PK if you need to calculate partial AUC0-4 ? In Phoenix no need to worry. Like in this post. — 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, 2013-09-10 18:11 (3878 d 21:20 ago) @ Helmut Posting: # 11469 Views: 8,626 |
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Hi Ohlbe & Helmut, Not a joke. The reply from the project manager: Subject 143 – the 3.5 hour sample should not have been collected due to the delay in resticks of 41 minutes. Unfortunately, both were collected, shipped. I have reached out to PK group for input regarding this. Restick = Difficulty in drawing blood. WTF for 41 mins. How many holes did they poke? I don't know. The subject should've been dropped out since it is inhuman to poke so many holes (it hurts!). P.S. Helmut, From our previous discussion, you wrote: ❝ BTW, if you ask Phoenix/WinNonlin for partial AUCs (and sampling wasn’t performed exactly at the cut-off time point) an interpolation between two adjacent time points (before/after) is used; linear if C2 ≥ C1 and log/linear if C2 < C1. Makes sense, IMHO. I don't think you can make interpolation to obtain the concentration at the desire time right (example: interpolate 4 hr concentration from 3.5 hr and 4.25 hr concentration)? I thought you have to use the time point as is? Thanks John |
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Helmut ★★★ Vienna, Austria, 2013-09-11 23:01 (3877 d 16:29 ago) @ jag009 Posting: # 11482 Views: 8,899 |
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Hi John, ❝ ❝ BTW, if you ask Phoenix/WinNonlin for partial AUCs (and sampling wasn’t performed exactly at the cut-off time point) an interpolation between two adjacent time points (before/after) is used; linear if C2 ≥ C1 and log/linear if C2 < C1. Makes sense, IMHO. ❝ ❝ I don't think you can make interpolation to obtain the concentration at the desire time right Why not? As you know we work on the same drugs (pAUCs standard). Never had a problem. Of course I describe the procedure in the protocol and even give an example plot similar to that one …
… showing how pAUCs, t75%, and HVD are calculated. Samples denoted with an orange circle were not taken at scheduled time points – they were either interpolated (at t=0 and t=4) or extrapolated (t=24). ❝ (example: interpolate 4 hr concentration from 3.5 hr and 4.25 hr concentration)? I thought that you don’t have the 3.5 sample (delayed till 4:11)? But you have the one at 4:02. Interpolate between this one and the one before. If you feel that you are reaching too far “to the left”, drop the AUCs and keep the Cmax. ❝ I thought you have to use the time point as is? Who told you that?  Did you never have small time deviations close to the truncation time point and asked Phoenix/WinNonlin for partial AUCs? If yes, I’m surprised. If no, guess what was going on behind the veil (or look it up in the User’s Guide). — 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 |
![[image]](img/uploaded/image76.png)
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jag009 ★★★ NJ, 2013-09-12 22:48 (3876 d 16:43 ago) @ Helmut Posting: # 11489 Views: 8,422 |
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Hi Helmut, ❝ Why not? As you know we work on the same drugs (pAUCs standard). Never had a problem. Of course I describe the procedure in the protocol and even give an example plot similar to that one … That's the beauty of it. It's not described on the protocol and CRO's SOP doesn't have this. Of course I can do a supplmental analysis myself... ❝ I thought that you don’t have the 3.5 sample (delayed till 4:11)? But you have the one at 4:02. Interpolate between this one and the one before. If you feel that you are reaching to far “to the left”, drop the AUCs and keep the Cmax. Oh something NEW has popped up (I was looking at 50% of the subject, now I have 100%). They have the following: 3.5 hr with a time deviation of 45 mins; Reason - Restick 4 hr with a time deviation of 15 mins; Reason - Restick The concentration values are different. @$^% !!!!! How the hell do you tackle this??? Should I take the average of the two concentrations and use only the 4 hr time point? John |
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Helmut ★★★ Vienna, Austria, 2013-09-13 02:55 (3876 d 12:36 ago) @ jag009 Posting: # 11490 Views: 8,486 |
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Hi John, ❝ It's not described on the protocol and CRO's SOP doesn't have this. So in the protocol they simply copypasted from the guidance “AUC0-4, AUC4-t, AUC0-∞, and Cmax, where AUC0-4 is the area under the plasma-concentration vs. time curve from 0 to 4 hours, AUC4-t is area under the curve from 4 hours to the last measurable time point” without stating the algo? Brilliant. Which software are they using? ❝ They have the following: ❝ 3.5 hr with a time deviation of 45 mins; Reason - Restick ❝ 4 hr with a time deviation of 15 mins; Reason - Restick Splendid. As you posted before I thought I have seen everything – but this?! ❝ The concentration values are different. Sure. AP hits. ❝ How the hell do you tackle this??? Should I take the average of the two concentrations and use only the 4 hr time point? The latter (OK, the second one at 4:15). Set the first one to “missing”, “not reportable“, or “oops”. — 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, 2013-09-13 17:26 (3875 d 22:05 ago) @ Helmut Posting: # 11491 Views: 8,455 |
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❝ So in the protocol they simply copypasted from the guidance “AUC0-4, AUC4-t, AUC0-∞, and Cmax, where AUC0-4 is the area under the plasma-concentration vs. time curve from 0 to 4 hours, AUC4-t is area under the curve from 4 hours to the last measurable time point” without stating the algo? Brilliant. Which software are they using? Exactly... Software wise I think they use both WinNonlin and SAS. I think they can do the interpolation by doing a protocol amendment? I have seen this before and FDA accepted it (not for partial AUC but for other things). A lot of companies do this because they don't know whether their Kel elimination coding in SAS is "safe" so they need something that is officially validated. ❝ ❝ They have the following: ❝ ❝ 3.5 hr with a time deviation of 45 mins; Reason - Restick ❝ ❝ 4 hr with a time deviation of 15 mins; Reason - Restick ❝ ❝ Splendid. As you posted before I thought I have seen everything – but this?! YES! I told you I haven't seen EVERYTHING  ❝ The latter (OK, the second one at 4:15). Set the first one to “missing”, “not reportable“, or “oops”. Why the latter and not the first? If they have both samples and the numbers are different? I think they should take the average? Thanks John |
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Helmut ★★★ Vienna, Austria, 2013-09-13 18:00 (3875 d 21:30 ago) @ jag009 Posting: # 11493 Views: 8,442 |
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Hi John, ❝ Exactly... Software wise I think they use both WinNonlin and SAS. I think they can do the interpolation by doing a protocol amendment? I have seen this before and FDA accepted it (not for partial AUC but for other things). ❝ A lot of companies do this because they don't know whether their Kel elimination coding in SAS is "safe" so they need something that is officially validated. Again: If you ask Phoenix/WinNonlin for partial AUCs they will be calculated up to/from the requested truncation time point – irrespective of time deviations (like in the plot above). I don’t think that you need an amendment. ❝ ❝ The latter (OK, the second one at 4:15). Set the first one to “missing”, “not reportable“, or “oops”. ❝ ❝ Why the latter and not the first? Gut feeling. I prefer a 15 min deviation over 45. I’m asking myself how they got two samples at the same time point. Two nurses sticking needles in the left and right arms of the subject competing on who finishes first? ❝ If they have both samples and the numbers are different? Due to analytical variability the values are expected to be different. ❝ I think they should take the average? Yes and no. Although the average should be more close to the “true value” you might open a can of worms. Some nitpicking assessor might tell you this value carries undue weight (since all other values are single determinations). Duno. — 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, 2013-09-13 21:57 (3875 d 17:34 ago) @ Helmut Posting: # 11496 Views: 8,368 |
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Hi Helmut, ❝ ❝ Why the latter and not the first? ❝ ❝ Gut feeling. I prefer a 15 min deviation over 45. I’m asking myself how they got two samples at the same time point. Two nurses sticking needles in the left and right arms of the subject competing on who finishes first? Like Formula 1 GP. Photo finish... I don't know what they were thinking and I don't know why they persistent in collecting the 3.5 hr sample if they were unsuccessful after a few poke on the subject's arm... John |
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jag009 ★★★ NJ, 2013-09-10 18:13 (3878 d 21:18 ago) @ Ohlbe Posting: # 11470 Views: 8,664 |
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Hi Ohlbe, ❝ Unless the staff were kept busy by a serious adverse event and had more urgent things to do, I can't see how they managed to f... up that much. Even with a blocked canula they should be able to collect the sample via a fresh venipuncture. Or did they have no spare phlebotomist at hand ? ❝ ❝ OK, I know it doesn't help, sorry... For 41 mins??? I still want to know how many holes they punched the poor subject with! John |
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ElMaestro ★★★ Denmark, 2013-09-10 20:31 (3878 d 19:00 ago) @ jag009 Posting: # 11472 Views: 8,546 |
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Hi John, ❝ For 41 mins??? I still want to know how many holes they punched the poor subject with! Did the monitor have any remarks in the report? Did (s)he visit on the day this happened? — Pass or fail! ElMaestro |
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jag009 ★★★ NJ, 2013-09-11 00:48 (3878 d 14:43 ago) @ ElMaestro Posting: # 11473 Views: 8,536 |
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❝ ❝ For 41 mins??? I still want to know how many holes they punched the poor subject with! ❝ ❝ Did the monitor have any remarks in the report? Did (s)he visit on the day this happened? Waiting for their "explanation"... Study info to be released in upcoming weeks. So far the explanation is "restick". The clinic thought subjects were not hydrated adequately before dosing in Period 1 so they ask them to drink more the night before period 2. Problem solved? Sort of but nope, still had long time deivations... In my opinion the subject should've been dropped. Its not ethical to keep on poking for blood for so long... It occured at 3.5-4 hr so the P.I. should've made a decision (A DOCTOR!) John |
Ing. Helmut Schütz