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HI,
every one. we are using confidence interval 75 - 133% for
lamvudine in combination with stamvudine which is acceptable for
european countries, i wanted to know that anyone has earlier used
this CI approach, if so then how they justifed the use of CI. If any
used this approach for lamvudine then kindly share in the group it
will be highly useful.
Regards,
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The following message was posted to: PharmPK
Dear Yousuf
You can always give a limit of confidence interval 75 - 133% for Cmax,
in case of highly variable drugs.
To date, there is no regulatory definition for these drugs or drug
products. In the context of bioequivalence, however, drugs and drug
products exhibiting intra-subject variability greater than 30% C.V.
(coefficient of variation) in the pharmacokinetic measures, AUC and/or
Cmax are considered highly variable.
So with this justification you can widen the confidence interval limit
from 80-125% to 75 - 133%.
I hope this will resolve your problem.
With best regards
Abhay
NDDS
Glenmark Research Center
Plot No: A607, TTC Industrial area,
MIDC, Mahape,
Navi Mumbai: 400709.
India.
Ph: 91-22-55902491/92
Fax: 91-22-55902318
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The following message was posted to: PharmPK
Dear Yousuf,
don't mix two things up:
The *confidence interval* to be used in European regulations
is the 90%-one (patient's risk 5%).
The *acceptance range* (where your CI has to be included)
is generally 80%-125%, but may be widened prospectively
(e.g., to 75%-133%) if justified based on clinical grounds
(safety, efficacy).
Although according to the guideline
http://www.emea.eu.int/pdfs/human/ewp/140198en.pdf
widening of the acceptance range - besides for Cmax -
should also be possible for AUC, I do not know know a
single study where this was accepted.
European authorities have become more restrictive even
for Cmax in the last years.
Recapitulatory: you must justify any widening prospectifely
based on clinical evidence; statistical grounds *alone*
(high intra-subject variability) are not sufficient.
If you want to be sure that your justification will be accepted,
I would suggest to opt for a 'Scientific Advisory Meeting' with
the Authority of your choice before initiation of the study.
Good luck,
Helmut
--
Helmut Schuetz
BEBAC
Consultancy Services for Bioequivalence and Bioavailability Studies
Neubaugasse 36/11
1070 Vienna/Austria
tel/fax +43 1 2311746
http://BEBAC.at
Bioequivalence/Bioavailability Forum at http://forum.bebac.at http://
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The following message was posted to: PharmPK
Dear Abhay!
I'm afraid most of your statements are not correct.
>You can always give a limit of confidence interval 75 - 133% for Cmax,
>in case of highly variable drugs.
>
Yes you can, but any widening of the acceptance range
is simply not acceptable in some regulations (e.g., US-FDA,
Brazil-ANVISA, India-CDSCO,
)
>[
] In the context of bioequivalence, however, drugs and drug
>products exhibiting intra-subject variability greater than 30% C.V.
>(coefficient of variation) in the pharmacokinetic measures, AUC and/or
>Cmax are considered highly variable.
>So with this justification you can widen the confidence interval limit
>from 80-125% to 75 - 133%.
>
Again wrong, even in regulations where widening of the
acceptance range is possible, the justification must be
based on clinical grounds (safety, efficacy); statistical
grounds (high variability) *alone* are not sufficient.
According to my knowlege South Africa (MCC) is the
only country where widening is acceptable for
*all HVDs* without any clinical justification
best regards,
Helmut
P.S: You may find a collection of guidelines at
http://bebac.at/Guidelines.htm
--
Helmut Schuetz
BEBAC
Consultancy Services for Bioequivalence and Bioavailability Studies
Neubaugasse 36/11
1070 Vienna/Austria
tel/fax +43 1 2311746
Web http://BEBAC.at
BE/BA Forum http://forum.bebac.at
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Dear Chandak
Is there any guidance that I can use for this matter, even if the
guidance is not so specific about the highly variable drugs.
Thank you in advance.
Nabil Darwazeh
darwazn58.-at-.yahoo.com
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