1 • 16 Bioequivalence Studies in Russia: Pharmacokinetics, Statistics and Analytics Moscow, 24 April 2014 Outliers in BE Studies Outliers in BE Studies Helmut Schütz BEBAC Helmut Schütz BEBAC Biostatistics Outliers in BE Studies Biostatistics Biostatistics Outliers in BE Studies Outliers in BE Studies Wikimedia Wikimedia Commons Commons • • 2006 2006 Schwallex Schwallex • • Creative Commons Attribution Creative Commons Attribution - - ShareAlike ShareAlike 3.0 3.0 Unported Unported
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1 • 16Bioequivalence Studies in Russia: Pharmacokinetics, Statistics and Analytics
Moscow, 24 April 2014
Outliers in BE StudiesOutliers in BE Studies
Helmut Schütz
BEBAC
Helmut Schütz
BEBAC
BiostatisticsOutliers in BE Studies
BiostatisticsBiostatisticsOutliers in BE StudiesOutliers in BE Studies
Wikim
edia
Wikim
ediaCommons
Commons
••20
06
2006 Sch
wallex
Sch
wallex
••Creative Commons Attribution
Creative Commons Attribution-- ShareA
like
ShareA
like3.0
3.0 Unported
Unported
2 • 16Bioequivalence Studies in Russia: Pharmacokinetics, Statistics and Analytics
Moscow, 24 April 2014
Outliers in BE StudiesOutliers in BE Studies
OutliersOutliers
�Problems
�Parametric methods (ANOVA, GLM, LMEM) are very
sensitive to outliers
�A single outlier may underpower a properly sized study!
�Exclusion of outliers only possible if procedure stated in the
protocol, and reason can be justified, e.g.,
�Lacking compliance (subject did not take the medication),
�Vomiting (up to 2 × tmax for IR, at all times for MR),
�Analytical problems (e.g., interferences in chromatography);
�Not acceptable if only based on statistical grounds.
3 • 16Bioequivalence Studies in Russia: Pharmacokinetics, Statistics and Analytics
Moscow, 24 April 2014
Outliers in BE StudiesOutliers in BE Studies
OutliersOutliers
�TypesI. Concordant outlier
The PK response for both test and reference deviates from the
majority of the study sample.
� Poor metabolizers may lead to high concentrations in
5–10% of subjects.
� Does not effect the BE-assessment in a cross-over study,
but should be discussed (polymorphism known?)
II. Discordant outlierThe PK response of either test or reference deviates form the
majority of the study sample.
4 • 16Bioequivalence Studies in Russia: Pharmacokinetics, Statistics and Analytics
Moscow, 24 April 2014
Outliers in BE StudiesOutliers in BE Studies
Type I/IIType I/II
PK response (AUC)
0
1000
2000
3000
0 1000 2000 3000reference
test
sequence 1sequence 2identitytest/reference
PK response (AUC)
0
1000
2000
3000
0 1000 2000 3000reference
test
sequence 1sequence 2identitytest/reference
concordant outlier
PK response (AUC)
0
1000
2000
3000
0 1000 2000 3000reference
test
sequence 1sequence 2identitytest/reference
discordant outlier
5 • 16Bioequivalence Studies in Russia: Pharmacokinetics, Statistics and Analytics