Dear All,Back to the Top
We are currently performing the PK analysis of a BE study.
Per protocol, the required sample size was estimated to 48, but 8
additional reserve subjects to account for eventual dropouts.
Four subjects dropped out, so 52 subjects are evaluable at the end of
the study.
The protocol planned that the samples of the reserve subjects not
required to replace a dropout should not be assayed and these subjects
therefore not included in the BE assessment.
By mistake, the samples of all subjects (including the four reserves
not needed for replacement) were finally assayed.
Should the BE evaluation be conducted on all available subjects (52) or
only on 48 as originally planned in the protocol (excluding the four
reserves, even if they have available PK profiles)?
Any regulatory reference or experience is welcome,
many thanks in advance for your help.
Fabrice Nollevaux
SGS Biopharma - Wavre - Belgium
www.sgsbiopharma.com
Dear Fabrice,Back to the Top
As per my view you can always do the analysis of all the analysed
subjects.
I hope this will help you
Thanks
Dr. Shahid Karim
Dear Forum,Back to the Top
To my mind the fact that someone is asking this question raises
another. In
essence it is what to do when there is a conflict between the letter of
a
protocol and what I regard as truly ethical and good clinical practice?
In this case it seems to me that the extra data really should be used
on two
obvious grounds. 1.) It is basic good science to have the most data
possible
in the analysis. 2.) It is questionable ethics to throw away data
obtained
from volunteers who expect their efforts to be used in the promised
fashion.
If it were a smaller number then I agree it would be a protocol
violation
and efforts must be made to reach the planned quota but in this case it
would be quite wrong not to use the extra data.
We had another issue recently where the so-called GCP dictat was, and I
quote " Under no circumstances will you give the volunteers a card with
emergency telephone numbers because it is not written in the protocol."
It
is hard for me to understand how that could be called Good Clinical
Practice
and I would hope the forum would agree.
I am wondering if we can evolve a form of words that becomes one of the
standard paragraphs saying that when there are sound or ethical reasons
for
extending the study beyond the letter of the protocol, then it is
everyone's
responsibility to do so.
Thanks for your anticipated responses
Andrew Sutton
Fabrice,Back to the Top
Your protocol is your regulatory guide: as you state, it says to
include reserves just to make up for any drop outs.
OK, so an error was made, and extra assays were done. It is therefore
necessary to document this error, and then continue with the
documentation to show that the four reserves that were included were
chosen without bias. In particular, that they were picked in accordance
with the protocol, if the protocol covers this. That is, document that
the four included were chosen without regard to whether their results
were "better" in some way.
Regards,
Frank
Frank Bales, Ph.D.
Senior Regulatory Consultant
Worldwide Regulatory Affairs
PAREXEL Intl.
2520 Meridian Pkwy, Suite 200
Durham, NC 27713
(919) 294-5297 Phone
Email: frankbales.aaa.msn.com
frank.bales.aaa.parexel.com
Fabrice.Back to the Top
Yes, but there is an "agreed-to" protocol, which should be followed.
Peoplesometimes want to deviate from a protocol, usually to improve
the results. This is often seen in clinical trials, where additional
secondary end points are proposed when the primary end point was not
achieved. The regulatory authorities almost always reject this
approach, and inform the sponsors that if they want to change the
protocol, then they should run the test over again.
Which brings us to the motivation for including these reserves.
Is it to attempt to remedy the error of assaying them in the first
place? The proper remedy for this is to simply document this error.
Is it to improve the statistical power of test? If so, then the
analysis of all of the subjects could be included as supplemental
information, in addition to the analysis without these four reserves.
That is, do the computations twice: once as the compliant analysis
without the four extra reserves, and then a second time, including
these reserves, as a "for information only" analysis.
Is it to change the interpretation of the test? If so, then be prepared
for resistance.
Regards,
Frank
Frank Bales, Ph.D.
Senior Regulatory Consultant
Worldwide Regulatory Affairs
PAREXEL Intl.
2520 Meridian Pkwy, Suite 200
Durham, NC 27713
(919) 294-5297 Phone
Email: frankbales.at.msn.com
frank.bales.aaa.parexel.com
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