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Obinoscopy
Junior

Nigeria,
2018-08-19 16:22

Posting: # 19173
Views: 488
 

 Blinding in Bioanalysis [Bioanalytics]

Hi guys,

I have been thinking....please help me out lest I drown in my thoughts.

What's the relevance of treatment blinding of the bioanalyst if he analyses all the samples of each subject in one single run. I feel it's irrelevant that he is blinded cos he knows that all samples for a subject (for both treatments in period 1 and 2) will be analyzed in a single run.

I think the best form of blinding would be blinding of the sampling time points within each period. This way, the analyst wouldn't be biased into ensuring the results follow the single compartment PK model. The concern of carryover effect if detected during the bioanalytical method validation can be taken care of by the injection of blank samples.

Please let me know where I'm missing it...cos I feel I'm missing something.

Regards,

Scopy
ElMaestro
Hero

Denmark,
2018-08-19 18:46

@ Obinoscopy
Posting: # 19174
Views: 440
 

 Blinding in Bioanalysis

Hi Obi,

» Please let me know where I'm missing it...cos I feel I'm missing something.

Those are very valid thoughts.
In BE the tradition is to have analysts blinded wrt treatment, so they know subject and period and time point but not randomisation and therefore they can't say if subject 3 in period 1 got treatment T or R. They will not be able to tell the T/R for any subject. And therefore they cannot easily manipulate it.

Blinding wrt time point would be interesting. It may be the solution to a non-existing problem, though? You mean they could use that info to create smooth profiles that more or less correspond to the expectation in terms of e.g. t half etc? I'd say that is theoretically correct, they could do that.

History has shown that if you really keep the randomisation code under lock and key then the chance to manipulate a trial is lower than if you don't. Conversely the PI in a BE trial needs not be blinded because she/he cannot easily manipulate the trial result. If the PI were scoring e.g. wound healing visually in a PD trial then she/he would often need to be blinded.

if (3) 4

Best regards,
ElMaestro

"(...) targeted cancer therapies will benefit fewer than 2 percent of the cancer patients they’re aimed at. That reality is often lost on consumers, who are being fed a steady diet of winning anecdotes about miracle cures." New York Times (ed.), June 9, 2018.
Helmut
Hero
avatar
Homepage
Vienna, Austria,
2018-08-19 19:06

@ ElMaestro
Posting: # 19175
Views: 434
 

 Not blinding sampling times

Hi ElMaestro and Scopy,

» Blinding wrt time point would be interesting. It may be the solution to a non-existing problem, though? You mean they could use that info to create smooth profiles that more or less correspond to the expectation in terms of e.g. t half etc? I'd say that is theoretically correct, they could do that.

Even if substantial carry-over is not apparent in method validation (which would call for injecting mobile phase between samples), it exists. The EMA’s GL tells us:

If it appears that carry-over is unavoidable, study samples should not be randomised. Specific measures should be considered, tested during the validation and applied during the anal­ysis of the study samples, so that it does not affect accuracy and precision. This could include the injection of blank samples after samples with an expected high concentration, before the anal­ysis of the next study sample.

For decades the Canadian GL called for completely randomized samples but HC abandoned this requirement for good reasons. If one doesn’t want to give the scheduled time points, that’s fine. But still give an index of sample / subject / period. Then the analyst can minimize carry-over by alternating periods and increasing indices, e.g.,

Sub1Per1Spl1 – Sub1Per2Spl1 –
Sub1Per1Spl2 – Sub1Per2Spl2 –
… –
Sub1Per1Spln – Sub1Per2Spln.


Of course, this is best only for BE (where one can expect similar profiles). In BA (say EV vs. IV) inject all samples of one period followed by the other.

Cheers,
Helmut Schütz
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Obinoscopy
Junior

Nigeria,
2018-08-19 22:20

@ Helmut
Posting: # 19177
Views: 412
 

 Not blinding sampling times

Hi Helmut,

» Even if substantial carry-over is not apparent in method validation (which would call for injecting mobile phase between samples), it exists. The EMA’s GL tells us [...]

Going by that guideline, will it be safe to say that the converse it also true. That is:

If it appears there is no carry-over, study samples should be randomised


Well, just as you said, carryover is always very likely. Thus complete randomisation will not be the reasonable path to follow.

Thanks guys, at least I am glad I let my thoughts out and not get drowned in them.

Scopy
Obinoscopy
Junior

Nigeria,
2018-08-19 21:37
(edited by Obinoscopy on 2018-08-19 22:23)

@ ElMaestro
Posting: # 19176
Views: 412
 

 Blinding in Bioanalysis

Dear ElMaestro,

» In BE the tradition is to have analysts blinded wrt treatment, so they know subject and period and time point but not randomisation and therefore they can't say if subject 3 in period 1 got treatment T or R. They will not be able to tell the T/R for any subject. And therefore they cannot easily manipulate it.

Yes they won't be able to tell the T/R ratio. But don't you think blinding wrt treatment will not change the bias of ensuring that the results of Period 1 and Period 2 are similar irrespective of whether it's T before R or vice versa?

For instance, if response for time point 2.0hr at Period 1 is 6.3 and response for same time point at Period 2 is 2.3, the bioanalyst might want to review the chromatogram once more (or the analysis methodology proper) to find out why the discrepancy....and he just might see something to justify a reanalysis ;-).

But then again I think the statistical analysis for the Period and Sequence effect might further reveal some anomaly. So you are right.

» You mean they could use that info to create smooth profiles that more or less correspond to the expectation in terms of e.g. t half etc?

Yes. They have an idea of the expected absorption and elimination phase of the curve. So they already have an idea of the expected response of the respective timepoints.

» History has shown that if you really keep the randomisation code under lock and key then the chance to manipulate a trial is lower than if you don't.

I agree. I'm just saying if one could go beyond that and further blind the time points as well. But perhaps it's something that is not reasonable logistic wise.

» Conversely the PI in a BE trial needs not be blinded because she/he cannot easily manipulate the trial result. If the PI were scoring e.g. wound healing visually in a PD trial then she/he would often need to be blinded.

I totally understand the irrelevance of blinding the subjects or the PI since this is a BE study and the efficacy is measured purely via bioanalysis and not via a physician or a subject's assessment. I'm simply making a case for further blinding the bioanalyst from the sampling timepoints. But perhaps it's just me being overly paranoid over the likelihood of bias. Perhaps it's not likely that bias might result but it's the likelihood of reanalysis due to pharmacokinetic reasons which the guidelines have spoken against.

Scopy
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