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The following message was posted to: PharmPK
Hello,
We have a 24 bed clinical trial clinic that is approved by Ministry of
Health a few weeks ago and we have not started to perform studies yet.
We
have a question that we would like to share with you and we will be very
glad if we get it answered.
In order to perform a bioequivalence study on healthy volunteers, you
have
to have a cross-over study design during which the reference and test
drugs
are both administered to volunteers and we think that we have to leave
at
least one week between the two drug administrations. Wash-out period
for the
drug may be shorter but we suppose that at least a one week period must
be
left for the healing of the veins and to be able to collect blood for an
additional 10-16 time points.
In our standard operating procedures, after having the informed consent
signed, we plan to perform a physical examination to the healthy
volunteers
and order a list of laboratory tests, ECG and a chest x-ray. Let's
assume
that the clinical trial lasted for 2 days and after this period we have
let
the volunteers leave the clinic wanting them to come back to take the
other
(test or reference) drug a week later.
One choice is to repeat the physical examination, laboratory tests, ECG
and
chest x-ray after the 2 day clinical trial (when only one-test or
reference-
drug is administered to the healthy volunteer) and to repeat them before
starting the second part of the cross-over study and at the completion
of
the study once more. In other words, we will repeat the laboratory
tests,
ECG and chest-x-ray for 4 times during one clinical trial. That means
both
money, collecting an additional 2 x 20 ml blood and 2 times more
exposure to
x-ray. On the other hand, if the drug causes any changes in laboratory
tests, ECG or chest x-ray, we will be able to see it before the second
part
of the cross-over study (before waiting at least for one more week).
The other choice is to repeat the same procedures only when the clinical
trial is completely over (When both drugs are administered to the
healthy
volunteers). In other words, we will repeat the laboratory tests, ECG
and
chest-x-ray for 2 times during one clinical trial. That means less
money,
less blood collection and less exposure to x-ray but we may miss a
possible
effect of the drug on any of the laboratory tests, ECG or chest x-ray
during
the first period of the study.
Would you please tell us your comments concerning the problem from an
ethical point of view. We also wonder if this decision has to be
changed or
not according to the half life and wash-out period of the drug . If so
how
can we put the criteria for it?
We'll be glad if you share your opinions. Thanks a lot beforehand.
Sebnem APAYDIN, M.D.
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The following message was posted to: PharmPK
Dr. Sabnem,
U r very much correct in a way that even the drug wash out period is
very less, we have to give at least one week to start second period so
as to heal the painful procedures.
Regarding the laboratory tests and other tests. I feel any how it is
better to perform all the laboratory test, ECG and X-ray chest along
with physical examination just 2 days prior to the period I and then
perform the some biochemical tests viz. pertaining to liver, kidney and
gastrointestinal system and also ECG in case of cardiovascular drugs
(which u will be monitoring during the study as when it is required).
Again it is better to start minimum urine test, hematology and the above
said biochemical tests before the day of second period dosing and if any
found abnormal, we can drop that volunteer and same is tested when the
period II is over live Period I.
I think in this way u r getting an idea about the health status of
volunteer before start of the each period and at the same time u r
getting the effect of drug on some functions at the end of the period.
Regards,
KANTHI KIRAN V.S. VARANASI
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Dear Sebnem
You wrote
> In other words, we will repeat the laboratory tests,
> ECG and chest-x-ray for 4 times during one clinical trial. That means
> both money, collecting an additional 2 x 20 ml blood and 2 times more
> exposure to x-ray.
Comments: At best it would be completely unethical and unnecessary
your second choice is what i would recommend.
If you have any Adverse event then it may be necessary to carry "out of
protocol" tests and examinations as per the health status of volunteer
and physicians attending him/ her.
with regards
Dr.Prashant
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The following message was posted to: PharmPK
Dear Dr. Sebnem,
Please refer to the FDA guidelines for the conduct of
Bioequivalence studies.
" Bioavailability and Bioequivalence Studies for
Orally Administered Drug Products — General
Considerations " at
http://www.fda.gov/cder/guidance/index.htm
As per the guidelines, adequate wash out period of
more than five times the half life of the drug would
be sufficient between the two periods. We normally
adopt ten half lifes as wash out period betwen the two
periods, which is more than enough. You may perform
laboratory estimations prior to each period and at the
end of the study ( you may collect additional blood
with the last Pk sample) to detect any effect of the
drug, if required.
As far as ECG and X-ray is concerned, you may go ahead
with ECG unless the drug has any effect on cardiac
rythms.
X - ray may be performed at the time of screening
(enrolling volunteers in the study) and is not
required upto 6 months. Since too much of exposure to
X-rays is not advisable & un ethical and since they
can hardly cause any changes, repeating X-rays is not
required.
For a typical study, perform all the lab test, ECG,
X-ray, physical and clinical examination at the time
of enrollment. If the drug causes significant changes
in ECG & lab parameters this can be repeated as
required in each period.
Hope this clarifies your doubts.
Regards
Ganesh
Research Scientist
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