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Dear all,
can you give your thoughts on below point with refering the guideline
1. for ba/be study, normally subject withdrawn during any period
should be analyze or not? (statistical and analytical)
for EU submission, it is analyze in analytical but not in statistical
for usfda recomended that should not be analyze for both.
2. during last period if subject miss to give only few sample i.e 1
or 2 and withdrawn with personal ground than should be consider for
analysis and submitted data?
kindly give your thoughts on analyze the subject analysis who drop
out at any point.
regards,
paresh
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Dear paresh,
In first point you are right.
In second point if samples in elimination phase are able to represent
the half life and Lamda Z by a softtware like WinNonlin or Kinetica
then it will work, generally 3-4 points after C max are more than
sufficient to get the Pk profile.
regards..
Hiren Mehta
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Paresh:
You wrote;
1. for ba/be study, normally subject withdrawn during any period
should be analyze or not? (statistical and analytical) for EU
submission, it is analyze in analytical but not in statistical for
usfda recomended that should not be analyze for both.
2. during last period if subject miss to give only few sample i.e 1
or 2 and withdrawn with personal ground than should be consider for
analysis and submitted data?
You have to decide this in your protocol upfront what would be your
action plan on withdrawn subjects (whatever the reason, missed blood
draws, personal reasons, AEs etc), my best suggestion is not to
analyze samples from withdrawn or not completing complete blood draws
and exit exam. this way you will collect the samples send the
samples to analytical lab but do not analyze them, thus you are not
introducing any bias into your BE calculations. In simple words.
analyze and calculate BE stats from subjects completing all periods
of the BE study.
Hope this clarification helps.
Prasad
Prasad NV Tata, Ph.D., FCP
Manager-Pharmacokinetics
Mallinckrodt, Inc.
675 McDonnell Blvd.
Saint Louis, MO 63134
Tel: (314) 654-5325
Fax: (314) 654-9325
e-mail: prasad.tata.aaa.tycohealthcare.com
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The following message was posted to: PharmPK
Hi Paresh,
The analysis of dropouts can also depend on the country of
submission. The
TPD interpretation of the ICH guidelines state: "plasma concentration
data
for subjects withdrawn due to adverse drug reaction(s) should be
provided
in Appendix 16.2.5."
Source:
http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/
draft_ebauche_ctdbe_e.pdf
In ICH E3 there are several references to the handling of dropouts
and/or
missing data, one of which is:
11.4.2.2: "The results of a clinical trial should be assessed not
only for
the subset of patients who completed the study, but also for the entire
patient population as randomized or at least for all those with any
on-study measurements."
In my opinion, it is good form to analyze the PK samples from subjects
withdrawn due to AEs. What if the reason for the AE was dose dumping
in the
case of a modified release product? If you don't measure the samples,
you'll never know. This is what section 16.2.5 is for in the ICH report.
For EMEA studies they typically would like to see the analysis performed
with and without these subjects to show that the reason for exclusion
wasn't that they changed the final conclusion of the study.
There may also be statistical reasons why you wouldn't want to exclude a
subject from the analysis if they do not complete the study in its
entirety. If there were many dropouts and power is a concern, you can
still
analyze the subject's samples and include them in the PK analysis for
Cmax.
It is far more often that a study fails on Cmax than on AUC. Whatever
procedure or method you decide on, make sure you detail it in the
protocol
before hand. Typically I would only consider including an incompleted
subject in the analysis provided there were no alternates to replace
them,
they at least started the second period, and they covered at least
what the
expected Cmax would be.
Hope this helps,
-Dave
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