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I am currently involved in a quality assurance program for drug analysis and we are re-visiting the
issue of how to set allowable limits of performance for the samples analysed in the program. The QA
program is intended to support therapeutic drug monitoring for a range of drugs. Apart from "expert
opinion" there currently seems to be no sound scientific basis on which to set these criteria. Is
anyone aware of any relevant papers proposing objective approaches, as we have not been able to find
any?
Alternatively, is there anyone with an interest in looking at this issue as a modelling exercise?
Having objective criteria to support quality assurance programs has the potential to make a marked
improvement in therapeutic drug monitoring for a range of drugs.
Regards,
Ross Norris,
PhD, MAppSc, BAppSc.
Research Consultant, Australian Centre for Paediatric Pharmacokinetics, Mater Pathology Services,
Raymond Terrace, South Brisbane, Q 4101, Australia.
Senior Research Fellow, Mater Medical Research Institute,South Brisbane, Qld, Australia.
Associate Professor, School of Pharmacy, Griffith University, Gold Coast, Qld, Australia.
Senior Lecturer, School of Pharmacy, University of Queensland, St Lucia, Qld, Australia.
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Ross,
You wrote:
'I am currently involved in a quality assurance program for drug analysis and we are re-visiting the
issue of how to set allowable limits of performance for the samples analysed in the program. The QA
program is intended to support therapeutic drug monitoring for a range of drugs. Apart from "expert
opinion" there currently seems to be no sound scientific basis on which to set these criteria'
Performance criteria depend upon the objective. What objective do you have in mind?
Some suggestions:
1. The objective is to report the measured concentration rapidly enough so that those responsible
for interpreting the concentration and doing something helpful for the patient have access to the
measurement in time to be useful.
2. The accuracy and imprecision of the chemical analysis procedure are sufficient to make a useful
clinical decision based on the measurement.
Objective 1 requires the clinical staff to take responsibility for obtaining a blood sample at a
suitable time e.g. after the first dose of an aminoglycoside rather than 2 or 3 days later and also
for the laboratory staff to measure and report the result within a practical and useful time frame.
Objective 2 requires that the accuracy and precision are connected to the clinical decision making
process. However, this is not usually a problem unless the chemical analysts refuse to tell the
truth and report actual measurements as "below the limit of quantitation" which frustrates
pharmacokinetic analysts who are capable of dealing with the realities of measured concentrations.
If you are not aware of the extensive literature on this problems caused by chemical analysts who
refuse to divulge the truth then let me know.
If you would like to have scientific support rather than "expert opinion" then you need to specify
the scientific objective accurately and precisely.
Best wishes with my best "expert opinion",
Nick
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Good for you, Nick! You are absolutely correct! Use of CV% as a measure of assay precision has no
basis in science, statistics, or math. The correct measure of assay precision is the reciprocal of
the variance of the assay measurement. The laboratory community is totally behind reality in this
important case. The correct measure of precision is the reciprocal of the variance of the
measurement. This is easily obtained by exactly the same method by which CV% is obtained. See
Jelliffe RW, Schumitzky A, Van Guilder M, Liu M, Hu L, Maire P, Gomis P, Barbaut X, and Tahani B:
Individualizing Drug Dosage Regimens: Roles of Population Pharmacokinetic and Dynamic Models,
Bayesian Fitting, and Adaptive Control. Therapeutic Drug Monitoring, 15: 380-393, 1993.
All the best to all,
Roger
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Precision as CV, variance etc etc etc is half the story. Of what note is precision if your method
is inaccurate? The FDA has a guidance for industry bioanalytical method validation and the Eu has
a similar doc. Each describes components of validation for methods including accuracy, precision,
total error, linearity, stability, Etc. those are the documents to consider with others.
Speed accuracy and precision are elements of any analysis any one by itself is useless!
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