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Past method
– tested null hypothesis- no difference between means
Not adequate in 1980s
Current method
– proves similarity between two products
– BE- diff <20%
Avg rate & extent of BA of T within ±20% that of R
– Log transformed scale- limits of ratio b/n 0.8 and 1.25
The statistical procedure ..
‘two one-sided test’
– introduced by Hauck
Method – defines error α- probability of concluding
BE when in reality it is not true
– Usually fixed to a min- 5%
– BE concluded if 90% CI of the ratio is within 80-125
– Power of study (regulatory)=80%
– 20% probability of not demonstrating BE even if they are
truly BE
– No of sub: based on variability of metric that study must
pass on
Cmax: most variable metrics
Sample size
Analysis of Variance
ANOVA
– Most common technique of analysis and estimation
Lognormal distribution
– Raw data must be log transformed
– Comparison of means & variances of transformed data
– Geometric mean (GM)
– Results reported in original scale
Confidence Intervals (CI)
Average BE
Conventional method
Compares only population averages
Does not compare products variances
Does not assess subject x formulation
interaction
Statistical Approaches for BE
Sequence effect
Subject (SEQ) effect
Formulation effect
Period effect
Carryover effect
Residual
Statistical Analysis
Bioequivalence criteria
– Two one-sided tests procedure
Test(T) is not significantly less than reference
Reference (R) is not significantly less than test
Issues
100s or 1000s of vols to operate with net post-dose
values
– Not acceptable from ethical or financial point of view
Lesser no of vols- post dose values without baseline
subtraction
Steady state studies
– preferred design when possible
Assay sensitivity issues
Predominating active metabolite
Three classes
Administered topically for absorption into sys
circulation e.g. patches
– can use usual BE
Designed to exert topical activity only – absorption is
negligible e.g. ointments, creams
– PD study or clinical efficacy study
Designed to exert local activity – absorbed to a
certain extent only e.g. vaginal prep etc.
– Considered individually
BE vs. Clinical Trial: Differences
• Labeling
• Chemistry/Microbiology
• Bioequivalence
• Legal
Labeling
Welage LS, Kirking DM, Ascione FJ, Gaither CA.J Am Pharm Assoc (Wash). 2001 Nov-
Dec;41(6):856-67
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