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Hi All,
Can anyone please help with a reference to FDA or EMEA guidance on the
acceptable percentage AUC extrapolation in BE, food effect or drug-
interaction studies, if guidance exists? Or any other publication of
use in this context? I have been using 15% as the upper limit, but is
this too strict? What would you normally set as limit, if there is no
formal guidance? Thanks in advance, any help is greatly appreciated.
Frieda Ebes,
ebes.frieda.-at-.kendle.com
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The following message was posted to: PharmPK
Hi Frieda!
> Can anyone please help with a reference to FDA or EMEA guidance on
the
> acceptable percentage AUC extrapolation in BE, food effect or drug-
> interaction studies, if guidance exists? Or any other publication of
> use in this context?
Maybe this collection of guidelines helps:
http://bebac.at/Guidelines.htm
> I have been using 15% as the upper limit, but is
> this too strict? What would you normally set as limit, if there is no
> formal guidance?
Commonly 20% are applied.
Best regards,
Helmut
Ing. Helmut Schuetz
BEBAC - Consultancy Services for
Bioequivalence and Bioavailability Studies
Neubaugasse 36/11
1070 Vienna, Austria
e-mail helmut.schuetz.-a-.bebac.at
web http://bebac.at/
contact http://bebac.at/Contact.htm
forum http://forum.bebac.at
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Dear Ebes:
I don't recall any guidance in this regard, but routinely we would
like to keep % Extrapolated AUC under 10%, this way you can
demonstrate that you made every effort to capture more than 90% of
drug exposure in the body and your extrapolation is reasonably under
control. Agencies do allow ignoring (not calculating the terminal
phase) Kel determination when it poses a problem by yielding unusual
extrapolation due to analytical outliers in the terminal phase, but
again these exceptions should be to the minimum extent.
In brief my ground rules of computing terminal phase is that R2 > 0.90
(desirable 0.9999) and % Extrp <10%, these values played the magic
trick of keeping the confidence intervals tight.
Hope this helps,
Prasad
Prasad NV Tata, MS, Ph.D., FCP
Manager-Pharmacokinetics
Mallinckrodt, Inc.
675 McDonnell Blvd.
Saint Louis, MO 63134
e-mail: prasad.tata.-at-.covidien.com
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The following message was posted to: PharmPK
Hello Frieda,
The EMEA guidance states "This is generally achieved if the AUC derived
from measurements is at least 80% of the AUC extrapolated to infinity."
Page 6 of 18 in the 2001 doc CPMP/EWP/QWP/1401/98
Susan
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There is an obscure reference in the FDA relating to percent AUC
covered. It is cited in the Federal Register / Vol. 67, No. 244 /
Thursday, December 19, 2002 / Rules and Regulations:
"The agency recognizes that for a drug with a long half-life, a drug
elimination period of five half-lives may be impractically long. FDA
has concluded that a drug elimination period of three half-lives,
which characterizes approximately 88 percent of the AUC[inf], is
sufficent. Therefore, the final rule leaves S 320.26(b)(2)(i)
unchanged. "
A link to the original document is here:
http://edocket.access.gpo.gov/2002/pdf/02-31996.pdf
Some people have chosen to interpret the 88% very literally; depending
on the elimination characteristics of the drug (e.g. bi-exponential,
etc.) 88% may or may not be obtained by three half-lives. I believe
the wording was intended to emphasize the importance of three half-
lives, rather than the %AUC coverage. I have seen a few places use 80%
as a cutoff for FDA and EMEA submissions. What ever you decide, make
sure it goes in your SOPs. Hope this helps,
-Dave
--
David Dubins, Ph.D., B.A.Sc.
Global Bioequivalence Consulting
Assistant Professor, Leslie Dan Faculty of Pharmacy
University of Toronto
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The following message was posted to: PharmPK
THE SAME ANVISA, BRAZIL.
Atenciosamente,
Bernardino Silva
[ANVISA
Agencia Nacional de Vigil=E2ncia Sanit=E1ria (National Health =
Surveillance
Agency Brazil) - db]
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The following message was posted to: PharmPK
THE SAME ANVISA, BRAZIL.
Atenciosamente,
Bernardino Silva
[ANVISA
Agencia Nacional de Vigil=E2ncia Sanit=E1ria (National Health
Surveillance
Agency Brazil) - db]=
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The following message was posted to: PharmPK
Dear Frieda,
There is no clear cut reference on AUC extrapolation from regulatory
agencies. But it is common world wide to use 20% as a cut off. I would
also be interested to know from the group, if there is any publication
for the same.
Moreover, the same should be mentioned in your SOP's and the regulatory
agencies would accept your data.
Comments from the experts are welcomed.
Thanks and regards
Dr. Tausif Ahmed
Ranbaxy Research Laboratories, India
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Dear Frieda,
In veterinary medicine, the EMEA guidelines state that extrapolation
should be less than 20%:
Guidelines for the Conduct of Bioequivalence studies for veterinary
medicinal products. EMEA/CVMP/016/00-corr-Final
Regards Bert
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The following message was posted to: PharmPK
Dear Prasad,
you wrote:
> In brief my ground rules of computing terminal phase is that R2 >
0.90
> (desirable 0.9999) and % Extrp <10%, these values played the magic
> trick of keeping the confidence intervals tight.
Not again... ;-)
R2 is a useless metric, I almost can 'see' Roger Jelliffe grabbing
his keyboard starting to type...
Please use the search feature of the PharmPK-list
http://www.boomer.org/pkin/simple.html
Why is 0.9999 more desirable than 0.9 (for how many data points,
etc., etc.)?
How does 0.9999 do the 'magic trick' of 'keeping the confidence
intervals tight'?
See also this thread:
http://forum.bebac.at/mix_entry.php?id=1572
Best regards,
Helmut
Ing. Helmut Schuetz
BEBAC - Consultancy Services for
Bioequivalence and Bioavailability Studies
Neubaugasse 36/11
1070 Vienna, Austria
e-mail helmut.schuetz.at.bebac.at
web http://bebac.at/
contact http://bebac.at/Contact.htm
forum http://forum.bebac.at
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The following message was posted to: PharmPK
Dear Prasad,
you wrote:
> In brief my ground rules of computing terminal phase is that R2 >
0.90
> (desirable 0.9999) and % Extrp <10%, these values played the magic
> trick of keeping the confidence intervals tight.
Not again... ;-)
R2 is a useless metric, I almost can 'see' Roger Jelliffe grabbing
his keyboard starting to type...
Please use the search feature of the PharmPK-list
http://www.boomer.org/cgi-bin/htsearch
Why is 0.9999 more desirable than 0.9 (for how many data points,
etc., etc.)?
How does 0.9999 do the 'magic trick' of 'keeping the confidence
intervals tight'?
See also this thread:
http://forum.bebac.at/mix_entry.php?id=1572
Best regards,
Helmut
Ing. Helmut Schuetz
BEBAC - Consultancy Services for
Bioequivalence and Bioavailability Studies
Neubaugasse 36/11
1070 Vienna, Austria
e-mail helmut.schuetz.aaa.bebac.at
web http://bebac.at/
contact http://bebac.at/Contact.htm
forum http://forum.bebac.at
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