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RE: Honest measurements

From: Grevel, Joachim <Joachim.Grevel>
Date: Mon, 24 Aug 2009 14:18:04 +0100

Dear all,

I am thinking back to early days of pharmacodynamics. The clinical =
people would report to us "early" modellers response data in the form of =
percent change from baseline. Very soon we asked for the raw data =
rejecting their "model" of generating response data as being subjective =
and biased (how was that "baseline" established?).

It was Nick among others who rejected any delivered baseline. He =
insisted that the model "will tell us the baseline and its error". I =
somehow hear Nick telling us something similar about bioanalytical data: =
Do not truncate the data by some criterion established months (years) =
before the actual measurement. Give us the raw data and let us find the =
error in it.

Perhaps it is indeed time to rethink the ideas of validated methods and =
standard curves. Couldn't the standard curve be part of our modelling, =
and couldn't the error in the standard curve be integrated into the =
error structure for our PK (PKPD) model?

I have a feeling that our current practice may have all the flaws we =
found years ago in the "two-stage" PK modelling approach. We gave up on =
the two-stage approach because it did not describe variability =
correctly. (Mats, there were "millions" of two-stage analyses published =
and in submissions... and in the end we gave it up for something we had =
learned was better).

It will take a lot of theoretical work to make the case for an =
integrated bioanalytical-pharmacokinetic analysis. Nick, are you already =
working along these lines?

Good luck to all,

Joachim


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-----Original Message-----
From: owner-nmusers
[mailto:owner-nmusers
Sent: 24 August 2009 13:36
To: 'Stephen Duffull'; 'Nick Holford'; 'nmusers'
Subject: RE: [NMusers] Honest measurements


Sense and nonsense.

Analysts are constrained certainly but good analytical science is good
analytical science. During the method development stage several =
parameters
are examined.

One parameter for example is recovery of analyte from a set of spiked
individual (matrices). Another exercise is the recovery of material =
from
spiked matrix after exposure to a number of stability challenging
conditions, e.g., freeze thaw. During these tests it is certainly =
possible
to "find less or, even "none" of the response(s) to the analyte(s).

Analysts would then "improve" the assay using a number of techniques
including the addition of preservatives or specifying the handling and
storage conditions. Too often however, the clinical collection =
parameters
may have been defined before the conclusion or event the start of =
analytical
method development and perhaps "if pushed too far and incessantly" the
analyst will release "nonsense data" or instrument responses free of
"interpretation".

For people at the next rung to use data this in any rational way =
suggests
that those people should perhaps be using a seer rather than an analyst.
When they are stung by the results of their data analysis, they will
immediately revert and "blame" the analyst (or if they do not, =
regulatory
agencies will) for releasing "bad" data.

PK/PD and Analytical scientists usually work together during the =
analytical
process. PK/PD driving with LLOQ, suggesting metabolites, Analytical
providing the best approach to meet that requirement including meeting =
all
current method validation and reporting guidelines.


Edward F. O'Connor, PhD
78 Marbern Drive
Suffield, CT 06078
 
Tel 860-668=6201
Cel 860-324-6780
efoconnor

Edward F. O'Connor, PhD
78 Marbern Drive
Suffield, CT 06078
 
Tel 860-668=6201
Cel 860-324-6780
efoconnor

-----Original Message-----
From: owner-nmusers
On
Behalf Of Stephen Duffull
Sent: Monday, August 24, 2009 4:18 AM
To: Nick Holford; nmusers
Subject: RE: [NMusers] Honest measurements

Mats

I agree with Nick. Negative "observed" concns do occur for assays, even =
in
my limited time working with HPLC I have seen them, however due to =
LOD/LOQ
they are never really looked for and certainly never reported...

Steve

> -----Original Message-----
> From: owner-nmusers
> nmusers
> Sent: Monday, 24 August 2009 6:25 p.m.
> To: nmusers
> Subject: [NMusers] Honest measurements
>
>
>
> Mats Karlsson wrote:
>
> << Chemists, however pushed, would never report negative
> concentrations, not
> for past studies, not for future studies. The methods they use don't
> even
> report them.>>
>
> I am working with a chemist using LC/MS who has been persuaded to look
> honestly at his data without preconceived ideas of limits of
> quantitation and detection. Indeed when he opened his eyes he found
> that his system was indeed giving negative concentration measurements
> (at times when concentrations were expected to be very low).
>
> Of course we must do other things when the data is censored by bad
> scientific practice in the chemist's lab but with honest measurments =
an
> additive residual error model is required.
>
> Nick
>
>
> --
> Nick Holford, Professor Clinical Pharmacology
> Dept Pharmacology & Clinical Pharmacology
> University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
> Zealand
> n.holford
> mobile: +64 21 46 23 53
> http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford

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Received on Mon Aug 24 2009 - 09:18:04 EDT

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