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The following message was posted to: PharmPK
Dear Colleagues,
For comparing PK parameters between two cycles we
proposed to look at the 95% confidence intervals
associated with the least square geometric mean (LSGM)
for the Cl, AUC, MRT and Vss and if contained the
value of 1 then conclude no statistically significant
difference. Do we need to declare the width of the CI
first and if the CI falls within that declared
interval, then conclude that the two Cycles are
equivalent. What should be the width (80%-125% or
others)? Is it necessary to include 1.0 in the
interval? What about just looking at p-values?
Rostam
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The following message was posted to: PharmPK
Dear Rostam,
You asked the following:
For comparing PK parameters between two cycles we proposed to look at
the 95% confidence intervals associated with the least square geometric
mean (LSGM) for the Cl, AUC, MRT and Vss and if contained the value of
1 then conclude no statistically significant difference. Do we need to
declare the width of the CI first and if the CI falls within that
declared interval, then conclude that the two Cycles are equivalent.
What should be the width (80%-125% or others)? Is it necessary to
include 1.0 in the interval? What about just looking at p-values?
I would not look at p-values because these are meaningless. First,
they test the hypothesis that the means are different. This is a silly
null hypothesis because of course they will be different. The question
is, are they clinically or meaningfully different. For that you need a
confidence interval approach. That is the rationale for the whole CI
approach in bioequivalence. Looking only at whether the CI contains 1
is not very informative either and can be quite misleading. Suppose
your CI is 0.1 to 10. This interval does contain 1, but obviously the
standard error of the mean is so large that the estimate is very
imprecise. This might happen if the sample size is small. So, yes, I
would a priori define a acceptance interval that if my entire CI is
contained within I would declare the two means to be equivalent.
I would just use what some of the guidance's recommend: 90% CI
contained within 80 to 125% or 70 to 143%, depending on the therapeutic
window of the drug. If you don't know what the window is go with 80 to
125%.
Good luck,
Peter Bonate
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Dear Mr. Rostam Namdari,
If you are going for95% CI calculation then you need to write range(or
width)of your CI, means upper limit and lower limit of interval and if
interval include 1 mean there is no statistically significant
difference and if 1 comes in between your interval then definitely you
have to include that. I don’t have idea about what should be the width
of interval (it again depends upon regulatory agency) . If you look for
only "p" value means you will get only conclusion about, “Is there any
significant difference between two cycle or not?” But when you look for
CI means you will evaluate spread of your observation around your mean
value and can evaluate strength of significance also. From CI, you can
evaluate how much variation is there in your observation.
Regards
Priti
Biostatistician
Aurobindo Pharma, Hyderabad, India
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