Statistical Evaluation of Bioequivalence Studies - BEBAC ...

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Outliers• Problems• Parametric methods (ANOVA, GLM) arevery sensitive to outliers• A single outlier may underpower a properly sizedstudy.• Exclusion of outliers only possible if procedurestated in the protocol, and reason is justfied, e.g.,‣ Lacking compliance (subject did not take the medication),‣ Vomiting (up to 2 × t maxfor IR, at all times for MR),‣ Analytical problems (e.g., interferences in chromatography);‣ Not acceptable if only based on statistical grounds.Dissolution Testing, Bioavailability & Bioequivalence | Budapest, 24 May 2007 18
Outliers• Solution I• Since assumptions are violated, you mayapply a statistical method which does not relyon those!• Drawback: Regulatory acceptance?Dissolution Testing, Bioavailability & Bioequivalence | Budapest, 24 May 2007 19
Page 1: Statistical Evaluation ofBioequival
Page 7: Assumptions: StatisticsMultiplicati
Page 12: Nonparametrics5. In which cases may
Page 16 and 17: Acceptance range for C max2. Assess
Page 20 and 21: Outliers• Solution II• Stay wit
Page 22 and 23: Re-testing of subjectsn=24: 83.3%-1
Page 24 and 25: Add-on Design• Reasonable,• if
Page 26 and 27: Group Sequential Design± EU• Per
Page 29 and 30: Studiesof >2 formulations• Disadv
Page 31 and 32: Studiesof >2 formulations• Often
Page 33: Parallel Groups• Design Issues•
Page 36 and 37: Parallel Groups: Example• Evaluat
Page 38 and 39: Parallel Groups: Example• Evaluat
Page 40 and 41: Sample Size• Minimum Number of Su
Page 42 and 43: Sample Size: Planning• NfG on the
Page 48 and 49: Sample Size: PlanningDoxicycline (3
Page 50 and 51: Sample Size: PowerPower to show BEw
Page 53: Sample Size: Sensitivity Analysis
Page 58: Low Variability• Drugs / Drug Pro
Page 63 and 64: Nuisance: sequence effect• In a
Page 65 and 66: Nuisance: sequence effect• In a l
Page 67 and 68: Nuisance: sequence effect• Conclu
Page 69 and 70:
Are we making progress?• About 3
Page 71 and 72:
...to be rememberedWhenever a theor
Page 73 and 74:
Statistical Evaluation ofBioequival
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