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Hello Forum,
Could anyone tell me why and how the limit of 80% to 125% is fixed for
Bioequivalence studies.
Nisha. K.R.
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I'm sure you will hear many different explanations for how these
standards were developed. I've been involved in various aspects of
Comparative Bioavailability testing since 1978, and have worked with
some pretty bright experts in this field over the years (hi Mike,
Yu-Chung, Laszlo, Radu). Here's one explanation.
Manufacturing standards for individual dose concentrations (Content
Uniformity and/or Uniformity of Dosage Unit Limits per USP/BP)
typically allow for limits between 75 to 125% of label claim.
The bioequivalence limit was established, at least in part, based on
the CU Limits, and the sense that a standard that is more stringent
than the limits on the permissible concentration of the drug in an
individual dose would be unnecessary, and perhaps illogical.
Peter Gingras
Apotex Inc
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This was derived from the FDA guidance for BE and in their judgment a
20% change will not affect the clinical outcome.
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Vuong:
Actually, 80 - 120% (125%, 130%) limits were in use long before there
were any written regulatory guidelines, American, Canadian or other.
Those limits where incorporated into the guidance documents after many
years of data collection.
An interesting side note, well into the 1980's, many generic drugs were
approved (and continue to be used interchangeably with brand drugs)
based on comparative dissolution rate data alone. It is interesting
that the FDA has recently contemplated this approach again. There is
certainly plenty of historical precedent for this approach, for drugs
with certain properties.
Peter Gingras
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Peter, Vuong,
Thank you.
But I am still puzzled. It seems pretty arbitrary for something that
companies spend a lot on to establish.
Also, 80 is -20%, but 125 is... ?
Can someone clarify?
Nisha. K. R.
[But 80/100 = 100/125 i.e. 0.8 - db]
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Nisha,
When the lower limit, teta1=0.8, the upper limit
teta2, after log transformation is ln(teta2) -ln(teta1),i.e. teta2 =
teta1^(-1). Hence, for teta1 0.8, teta2 results in 1.25.
Greetings,
D.Terziivanov
Dimiter Terziivanov, MD,PhD,DSc, Professor
Head, Clinic for Clinical Pharmacology and
Pharmacokinetics, Univ Hosp "St. I.Rilsky",
15 Acad. I. Geshov st, 1431 Sofia, Bulgaria
Tel:(+ 359 2)8510639;(+ 359 2)5812 828.
Fax:(+ 359 2)8519309. e-mal: terziiv.aaa.yahoo.com
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Dear Nisha K.R.,
the reason is that you must consider a NORMAL distribution to compare
data and it's well known that to obtain AUC and Cmax NORMAL
distributions you have to apply a log-transformation!! This implies
that you confidence limits 0.8-1.2 are log-transformed as well and
become 0.8-1.25.
I report exactly what it's written in Bioavailability and
Bioequivalence section of "Applied Biopharmaceutics and
Pharmacokinetics" L.Shargel and A.B.C. Yu :
"The lower 90% confidence interval for the ratio of means cannot be
less than 0.8, and the upper 90% confidence interval for the ratio of
the means cannot be greater than 1.20. When log-transformed data is
used, the 90% confidence interval is set at 80 to 125%, since the log
of 0.8 (except for sign) is 1.25 or 125%...................for AUC and
Cmax values of the test drug product should not be less than 0.8 (80%)
nor greater than 1.25 (125%) of the reference product based on
log-transformed data."
Best regards
Dr. Stefano Porzio
Pharmacokinetic and Tox. Dept.
Inpharzam Ricerche SA - ZAMBON-GROUP
Taverne - Switzerland
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Nisha,
The 20% maximum difference between a test (T) and a reference (R)
formulation can be expressed in 4 different ways
(do not forget we are considering a multiplicative model, e.g. T being
20%
higher than are is not equivalent to are being 20% lower than T):
1) Test 20% lower than Reference <=> T/R = 80%
(=0.8/1.0)
2) Test 20% higher than Reference <=> T/R = 120%
(=1.2/1.0)
3) Reference is 20% lower than Test <=> T/R = 125%
(=1.0/0.8)
4) Reference is 20% higher than Rest <=> T/R = 83.3%
(=1.0/1.2)
As you see, T/R within 80-125% covers all cases consistent with a
maximum
20% difference between both formulations.
Hope this helps,
Fabrice
Fabrice Nollevaux,
Senior Pharmacocineticist
SGS Life Science Services, www.sgs.com/life_sciences
SGS Biopharma - Wavre, Belgium, www.sgsbiopharma.com
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Dear Nisha,
80% to 125% comes from the statistical analysis of natural log
transformed of Pharmacokinetic parameters. The 90% CI of the estimate
of the difference of treatment should between -0.223 (ln(0.8)) and
0.223 (ln(1.25)). The difference in the PK parameters due to treatment
is of transformed data. To show the ratio on original scale we have to
exponentiate the point estimate and the CI. Hence exp(-0.223)=0.8 and
exp(0.223)=1.25. I think this is the reason why we have 80 to 125%
rather than 80 to 120%.
Hope it clarifies.
Thanks,
Shilpi
Shilpi Khan, M.S.
Staff Scientist/Biostatistician
CEDRA Corporation
Austin, TX 78754
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Hi Nisha,
Once upon the time, the clinicians and pharmacologists were asked what
kind of fluctuation in the blood/plasma/serum concentration levels of a
drug can be tolerated. Meaning, what kind of changes in the
concentration
levels should not trigger significant/observable changes in the
clinical/pharmacological end point. The agreement was that a 20% change
can be considered tolerable.
Based on this, the 80-120% (0.8-1.2 in ratio terms) range was
established
as a regulatory standard. It corresponds to a symmetrical interval of
+-20% around 100%.
Later, based on observation of the pharmacokinetic data, it was decided
that the PK parameters (AUC, Cmax, Cmin) follow a normal distribution
only
after log-transformation. The assumption of normal distribution is
important because all the formulas used in the statistical analysis were
derived based on this distribution.
Consequently, it was recommended that statistical analysis should be
applied to log-transformed PK parameters. On the logarithmic scale the
80-120% range does not correspond to a symmetrical interval: equal
"distances" on both sides of the central tendency.
The central tendency of 100% (1.0) from the raw scale correspond to the
value 0.0 on the logarithmic scale.
The lower limit of 80% (0.8) corresponds to approximately -0.223:
ln(0.8)=-0.223143551...
The location of the upper limit at equal distance, but on the opposite
direction from 0.0 on the logarithmic scale is +0.223 that corresponds
on
the raw data scale to 1.25 (125%): exp(0.223...)=1.25.
I hope this help.
radu
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Nishra:
It is pretty arbitrary; however, most or all ANDAs approved has only 10%
variation. So in practice, you do try to be as close to the innovator
as possible.
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