Statistical Evaluation of Bioequivalence Studies - BEBAC ...

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Nuisance: sequence effect• These results could beconfirmed (20 publishedstudies, 143 studies fromBEBAC’s database; AUC):• Significant sequenceeffects in 22/163studies (13.5%)• Significant sequenceeffects in properly plannedstudies should be considereda statistical artefact(significant results areobtained in α of studies)p-values for carry-over effects10.80.60.40.20studies with significant p:22/163 (13.5%)0 0.2 0.4 0.6 0.8 1AUC from cross-over studies:Uniform [0,1] quantilesline of identityDissolution Testing, Bioavailability & Bioequivalence | Budapest, 24 May 2007 66
Nuisance: sequence effect• Conclusions• No valid procedure exists to correct for a truesequence/carry-over effect• A true sequence/carry-over is highly unlikely in aBE study if• the study is performed in healthy subjects,• the drug is not an endogenous entity, and• an adequate washout period (no predose concentrations)was maintained.• Testing for a sequence effect is futile…Dissolution Testing, Bioavailability & Bioequivalence | Budapest, 24 May 2007 67
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Statistical Evaluation ofBioequival
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Assumptions: StatisticsMultiplicati
Page 12:
Nonparametrics5. In which cases may
Page 16 and 17: Acceptance range for C max2. Assess
Page 18 and 19: Outliers• Problems• Parametric
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: Nuisance: sequence effect• In a l
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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