Statistical Evaluation of Bioequivalence Studies - BEBAC ...

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Add-on Design• Reasonable,• if uncertain sample size estimate,• for ethical reasons. Canada If BE not shown, additional subjects are included;F-test (equality of variances), pooledanalysis. No α-adjustment. Japan 2 nd part with sample size ≥ 1 st part / 2 RSA max. sample size must be stated a-priori NZ Group sequential design (with α-adjustment)– USA No way± EU Evaluation of first part by an independentstatistician (CV only!). Not covered in NfG.Dissolution Testing, Bioavailability & Bioequivalence | Budapest, 24 May 2007 24
Group Sequential Design• Not mentioned in any Guideline, but• are standard in clincial research.• Although discussed at BioInternationals ’89to ’96, no concensus was reached.± EU• Personal Experience:‣ A proposed method *) was not accepted in theplanning phase (3 cases Germany).*)L.A. Gould;Group Sequential Extension of a Standard Bioequivalence TestingProcedure.J. Pharmacokin. Biopharm. 32(1), 57-86 (1995)Dissolution Testing, Bioavailability & Bioequivalence | Budapest, 24 May 2007 25
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 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 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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