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dear all,
greetings!
In BA/BE studies has any one of you come across a study in which there was a
significant period effect (particularly for two way crossover)? As per my
knowledge period effect is orthogonal to treatment effect i.e., the true
treatment effect is not affected if a statistically significant period effect is
encountered. But i am not able to find what is the regulatory take on this &
What could be the possible reasons for this effect.?
thanks
shikha
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The following message was posted to: PharmPK
Dear Shikha!
> In BA/BE studies has any one of you come across a study in which there was a
significant period effect (particularly for two way crossover)?
Yes  but only rarely.
> As per my knowledge period effect is orthogonal to treatment effect i.e., the
true treatment effect is not affected if a statistically significant period
effect is encountered.
Correct. Take any of your 2x2 studies and calculate the ANOVA and PE/CI
of the treatment effect. Now multiply all values of the second period by
1000 and run the analysis again. The PE and CI of the treatment effect
will be exactly the same as before though you will observe a highly
significant period effect.
> But i am not able to find what is the regulatory take on this
EMA's draft BE guideline from 2008
(http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/
09/WC500003011.pdf)
contained following statement:
[...] tests for difference and the respective confidence intervals for
the treatment effect, *the period effect*, and the sequence effect
should be reported for descriptive assessment. A test for carryover
should not be performed and no decisions regarding the analysis (e.g.
analysis of the first period, only) should be made on the basis of such
a test. The potential for carryover can be directly addressed by
examination of the pretreatment plasma concentrations in period 2 (and
beyond if applicable).
Based on stakeholder's comments
(http://www.ema.europa.eu/docs/en_GB/document_library/Other/2010/02/WC500073572.
pdf)
pp.141143 the suggested tests for period and sequence/unequal
carryover was removed. See the current guideline
(http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/
01/WC500070039.pdf).
> & What could be the possible reasons for this effect.?
Almost everything (wheater, lunar phases...). More serious: Especially
'novice' volunteers may show consistently different concentrations in
the second period because they adapt to the unfamiliar clinical setting.
However, since due to randomization both test and reference are affected
the treatment effect is not influenced.
Helmut

Ing. Helmut Schuetz
BEBAC  Consultancy Services for
Bioequivalence and Bioavailability Studies
Neubaugasse 36/11
1070 Vienna, Austria
email helmut.schuetz.at.bebac.at
web http://bebac.at/
forum http://forum.bebac.at/
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dear Helmut ,
thanks a lot for your reply..
"Take any of your 2x2 studies and calculate the ANOVA and PE/CI
of the treatment effect. Now multiply all values of the second period by
1000 and run the analysis again. The PE and CI of the treatment effect
will be exactly the same as before though you will observe a highly
significant period effect."
this is great way to prove that a period effect does'nt affect the treatment
effects significantly and also does'nt alter the CI's.
"Almost everything (wheater, lunar phases...). More serious: Especially
'novice' volunteers may show consistently different concentrations in
the second period because they adapt to the unfamiliar clinical setting.
However, since due to randomization both test and reference are affected
the treatment effect is not influenced."
can we say that if we increase the washout period the period effect will surely
be detected as insignificant? if the AUC's are higher in the 2nd period ,it
gives me a feeling that the drug was not metabolised completely... i am not sure
.. don't have core knowledge about ADME ... but just statistics
thanks.....
shikha rawat
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