joy_fm
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Indonesia,
2015-08-10 08:50

Posting: # 15203
Views: 7,296
 

 Acceptable deviation of blood sampling time [Study Per­for­mance]

Dear all,
how to justify acceptable deviation of blood sampling time in BE studies ?

Thank you
joy_fm
Helmut
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Vienna, Austria,
2015-08-11 00:44

@ joy_fm
Posting: # 15217
Views: 6,190
 

 Time allowance windows?

Hi Joy,

» how to justify acceptable deviation of blood sampling time in BE studies ?

I’m not sure what you mean by justification here. There are many possible reasons which could justify a deviation: Technical problems (blocked venflow, difficulties in repeated venipuncure), logistics (subject arrives late for ambulatory blood draw), whatsoever.
Or do you mean the “magic” time allowance window (TAW)? Most CROs state in the protocol & CRF that sampling within the TAW must not be commented in the CRF. TAWs depend on the sampling schedule (increasingly wide). Example according to Papst* with an “irrelevant” deviation of 5% below:

scheduled ∆1    ∆2     TAW
  (h)     (h)   (h)    (min)
 pd                    –30
         0.25
 0.25            0.25   +1
         0.25
 0.5             0.25   +1
         0.25
 0.75            0.25   +1
         0.25
 1               0.25   +1
         0.25
 1.25            0.25   +1
         0.25
 1.5             0.25   +1
         0.25
 1.75            0.25   +1
         0.25
 2               0.25   +1
         0.25
 2.25            0.25   +1
         0.25
 2.5             0.25   +1
         0.5
 3               0.5    +2
         0.5
 3.5             0.5    +2
         0.5
 4               0.5    +2
         1
 5               1      +3
         1
 6               1      +3
         2
 8               2      +6
         2
10               2      +6
         2
12               2      +6
         4
16               4     +12
         8
24                     +12


∆1 is the difference between sampling time points. ∆2 is the smallest of two neighbouring ∆1s. However, rarely I see only positive TAWs in CRFs. Most CROs state ±sumfink. I don’t get it & concur with Papst, who wrote:

Any sampling occuring too early is a deviation that should be reported even if pharmacokinetically irrelevant, since there are only a few plausible reasons why an activity should have been performed earlier than planned.



  • Papst G. Deviations in sampling times. In: Cawello W. (ed) Parameters for Compartment-free Pharmacokinetics. Aachen: Shaker Verlag; 2003. p. 78–79.

Cheers,
Helmut Schütz
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joy_fm
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Indonesia,
2015-08-11 04:07

@ Helmut
Posting: # 15220
Views: 6,150
 

 Time allowance windows?

Hi Helmut,
thank you for your reply.
We have removed “magic” time allowance window (TAW) from our protocol. So every blood sampling deviation, will be reported in CRF and statistical analysis.

But one of our customer, ask us, to put TAW in our protocol. Since we can't justify the deviation, we can't accept the request. What I know from training, TAW will be specific for any kind of drug molecules, it can't 5%, more or less, depend on the impact to pharmacokinetic analysis.

But we don't how to decide the percentage of blood sampling deviation which can't make an effect to pharmacokintetic analysis.
Would you mind to share how to decide the percentage of blood sampling which can't categorize as deviation, so TAW won't be "magic" again, but scientifically sound.

Thank you
joy_fm
Helmut
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Vienna, Austria,
2015-08-11 13:09

@ joy_fm
Posting: # 15227
Views: 6,191
 

 Actual vs. scheduled times

Hi Joy,

» We have removed “magic” time allowance window (TAW) from our protocol. So every blood sampling deviation, will be reported in CRF and statistical analysis.

I think we disagree in terminology. Samples with deviations within the TAW don’t have to be com­mented in the CRF. However, the actual time point will always be recorded and used in PK. If you mandate to comment every deviation (even if considered irrelevant) you put stress on the clinical staff. They should concentrate on handling samples – not on prose.

» But one of our customer, ask us, to put TAW in our protocol. Since we can't justify the deviation, we can't accept the request.

I don’t understand. Can you elaborate?

» What I know from training, TAW will be specific for any kind of drug molecules, it can't 5%, more or less, depend on the impact to pharmacokinetic analysis.

Maybe, maybe not. I’m not aware of any paper exploring it. Papst wrote:

[…] only those time deviations will be of pharmacokinetic relevance in which the time interval between the preceding and the affected sample or the interval between the affected and the following sample was prolonged or shortened by, for example, more than 5%. In practice it has been proven acceptable to consider only those time deviations out of this specified range when calculating the AUC.
This procedure for calculating pharmacokinetic parameters by ignoring any time deviations of less than 5% of the shorter of the two time intervals surrounding the sample affected has been shown by simulations to lead to estimates that differ at the most by 1.5% from the theo­re­tical value. In unfavourable circumstances (very few samples, all deviations in one direction) the relative error may increase to 3.6%). The simulation furthermore showed that a well-chosen design (e.g. with respect to sampling times) is more important than other factors (e.g. theo­re­tical profile, analytical accuracy).

But: He compared PK parameters calculated from scheduled times (i.e., ignoring deviations) with ones calculated from actual times. Only the latter method is recommended in current guidelines anyway. Therefore, this issue is history.

» But we don't how to decide the percentage of blood sampling deviation which can't make an effect to pharmacokintetic analysis.

Use the actual times.

» Would you mind to share how to decide the percentage of blood sampling which can't categorize as deviation, so TAW won't be "magic" again, but scientifically sound.

I would keep it at 5% (yes, arbitrarily!). The idea to comment on larger deviations is sumfink like this:

“Hhm, this concentration looks really weird. It is much lower than the ones before and after. Let’s have a look at the CRF. Ah, the venflow was blocked and it took the study nurse 10 minu­tes to rinse it with Ringer’s solution. Maybe she didn’t discard the first milliliters and the sample was diluted? I will go downstairs and ask her.”

BTW, things like this are pretty common. Train the staff not to reach for the stars. If a venflow cannot be opened quickly (say within two minutes), opt for venipuncure at this timepoint (make sure to mention it in the ICF). They can deal with the blockage later on.

Cheers,
Helmut Schütz
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joy_fm
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Indonesia,
2015-08-13 19:00

@ Helmut
Posting: # 15259
Views: 5,999
 

 Actual vs. scheduled times

Hi Helmut,
thank you for the explanation.
I will try to find another literature related to this topic.

Best regards
joy_fm
Ohlbe
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France,
2015-08-17 17:51

@ joy_fm
Posting: # 15286
Views: 5,854
 

 Time allowance windows?

Dear Joy,

What I often see in protocols is that any time deviation of more than a certain value will be considered as a protocol deviation and will be reported as such in the study report. But all time deviations are reported and are considered in the PK analysis.

I have seen strange interpretations of such protocol provisions: allowed deviation ± 2 min, actual deviation + 5 min, reported deviation + 3 min...

I agree with Helmut: there is no reason why any sample should be collected early. Meaning that any sample collected early should be considered as a protocol deviation. After all, if a subject arrives late for an ambulatory sample there is little you can do; but if he arrives early you can ask him to wait. He was informed of the protocol constraints and agreed to them when signing the consent form.

Regards
Ohlbe
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