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Dear all,
What could be possible reasons for Aberrant values in the Bioanalytical
samples in a Bioequivalence study.?
If the aberrant values are identified before or after breaking the
bioanalytical code, what steps need to be taken for Repeat assay.?
If the Repeat assay fails again, third analysis is allowed as per the
Regulatory Guidelines.?
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There are many possible reasons for (apparently) aberrant concentration
values for samples from a bioequivalent (or other type) of study
samples. Among these are:
1. Dosing error
2. Collection error. This could be switching of samples from two
subjects, or a more complicated mix-up (e.g., shifting a row of samples
in a rack by one position).
3. Contamination of the sample. This results in high values. Could
occur at the collection site or at the analyzing lab.
4. Analyst error
5. Instrument error
6. Analyte instability, poor method, etc (uncommon for validated
methods).
I'm sure others can think of more possibilities!
Sometimes the error is clear from the pattern of concentration-vs-time
plots (e.g., sample from placebo subject switched with sample from
dosed subject at the same timepoint). Only #4 and #5 (and some forms of
#3) can be detected and confirmed as aberrant by repeat analysis of the
same sample or frozen sample aliquot.
Also, one must also consider that the apparently aberrant value is
actually correct, and represents something going on with the drug in the
particular dosed subject.
Regulatory authorities are very skeptical of repeating analyses until
you get a value that you like. You or the clinical PK group should have
an SOP in place that outlines how samples with aberrant values are
handled and how results are used in subsequent calculations and data
analyses.
Tom
Thomas L. Tarnowski, Ph.D.
Bioanalytics and CMC
ttarnowski1.-at-.aol.com
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Dear Sir,
In most studies, some plasma samples will require re-assay. Criteria for
identifying these samples should be established ahead of time.
Certain aberrant values can be identified before breaking the analytical
code. These values may be attributed to such factors as:
a) processing errors;
b) equipment failure;
c) obviously poor chromatography; or
d) quality control samples outside pre-defined tolerances.
Other apparently aberrant values may become evident after the analytical
code is broken.
In some such cases, the original assay value would show poor
pharmacokinetic fit (but this should be applied with caution). In other
cases, there might be a need to confirm a double peak.
For aberrant values that have become evident after the analytical code
is broken, the submission should note the reason for the repeat assay.
When the results of a repeat assay differ from the original by more than
15 percent, a third analysis should be performed. When three replicate
analyses indicate that one is spurious, then the average of the other
two should be used. The criteria used in selecting among replicates for
inclusion in calculations should be stated.
Reference: Conduct and Analysis of Comparative Bioavailability Studies -
Health Canada , Jan 25, 2010.
Regards,
Dr.S.Gunasakaran, MD
Head - Clinical Research & Medical Affairs
www.clinicalresearchsociety.org
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The following message was posted to: PharmPK
The pre, post and analytical errors could all contribute. Before
jumping the gun and re-analyzing the sample (putting it at further
risk because of volume) exhaust investigations into dosing,
collection, processing and reporting. It is likely that nothing would
be found there but those channels must be exhausted. Also eliminate
the possibility that an additional medication was taken or given and
the possibility that an endogenous feature (antibody to drug,
circulating receptor) may be involved. Next insure that the
analytical processing and reporting was accurate. If all of this was
done, the study director/medical director or in-life PI may request a
re-analysis given there is sufficient volume. This does not restrict
re-analysis if a technical error is identified, e.g., absence of an
internal standard when one should be present, standard or QC failure,
etc. The analysis of the sample in question should be repeated at
least twice more, in separate batches.
--
Edward F. O'Connor
efoconnor.-at-.cox.net
efoconnor.-at-.gmail.com
www.aegisbioconsult.com
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I would echo Ed O'Connor's recommendation on performing a complete investigation, and
emphasize that you should clearly document each portion of the investigation (e.g., each
potential error source that was checked, what was found (even if nothing), and
conclusions/implications). This will help down the road, if the work is audited, if you
get regulatory questions, and for internal memory of what was done.
-Tom
Thomas L. Tarnowski, Ph.D.
Bioanalytics and CMC
ttarnowski1.aaa.aol.com
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