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Dear All,
Can anyone suggest and justify what are all the points to be
considered while preparing SOPs for Pharmacokinetic Re-assays
(Bioequivalence studies).
With regards
N.Ramesh
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The following message was posted to: PharmPK
Do you mean re-assaying the bioanalytical data then re-analysis of the
PK?
Or just re-analysis of the PK? With or without editing points?
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Hi Ramesh,
If I understand correctly you want to prepare an SOP for identifying
PK repeats in Bioequivalence studies.
Well nower days majority of companies are avoiding reanalysis based on
PK, as FDA inspectors have lot of queries on such repeats, they ask
for justification for such repeats and want to make sure that there is
no bias in selecting such repeat samples in BE studies.
Better way is to identify such repeats under analytical repeats (if
possible) or identify them as anomalous values and you should have a
pre-defined SOP for identifying such repeats.
Comments from other experts are welcomed.
Thanks
Tausif Ahmed, Ph.D.
Principal Scientist, DMPK,
Sai Advantium Pharma Ltd., Pune, India
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Hi N. Ramesh,
I wrote an SOP on identifying PK repeats some time ago.
Here are a few points I would consider:
-How to identify anomalous points. Who will identify them? Will it be
visually identified? Statistically? Grubb's test, r-studentized
residual, etc.?
-Is there a limit to the # of points to re-assay in one curve?
-What stage of the process (i.e. will you have a cut-off time where it
is too late to identify a PK repeat, like for instance, before the
statistical analysis is run?)
-What is your tolerance range for "confirming" or "refuting" the old
values?
-If the re-assayed values are within a tolerance range of the old
values, will you use the new ones or the old ones?
-Will a secondary analysis be run using the old data to explore
whether or not re-assay changes the conclusion of bioequivalence?
Best,
-Dave
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1) if the assay passes curve and QCs- there is little justification for
re-analysis. Given that, the first thing you should rule out is the
possibility of analytical errors-incorrect dilution, incorrect sample,
miscalculation due to internal standard, poor peak shape and or
resolution.
2)Next rule out pre-analytical errors- incorrect subject, incorrect
time,
incorrect cycle- including variances in handling as well as variances
from
the targeted dosing or sample time--I have had subjects sampled much to
early to the dose as well as much too late. The clinic or in-life
staff
should help resolve this. If you do not do this you may retest
infinitely.
3)Next rule out post analytical variables- were the correct values
assigned
to the correct samples, were the calculations correct?
4)After you have done this then begin the actual re-analysis,
including the
re-application of your outlier test.
5)Re-assay from a "split" of the original sample- and remember you
have one
suspect result, you will need to re analyze in duplicate-not just 2
aliquots
of the same extract but two independent extracts from the original
split.
6) Set up a tolerance for acceptance for the re-analysis results and
stick
with it. How will you calculate the tolerance?
7) describe how you will use the new values-take the mean or median?
8) if it still looks suspect and there is no indication of a sampling,
dosing or analytical error??? Present the data with and without the
supect
data.
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