Statistical Evaluation of Bioequivalence Studies - BEBAC ...

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Are we making progress?PubMed/MedLine: (bioequivalence) OR (comparative ANDbioavailability), Field: Title/Abstract, Limits: Humans, Publication Date200Publications on BE referred on PubMed/MedLine150number1005001972197419761978198019821984198619881990year19921994199619982000200220042006Dissolution Testing, Bioavailability & Bioequivalence | Budapest, 24 May 2007 68
Are we making progress?• About 3 000 – 10 000 BE studies / year are conductedworldwide; only ∼ 1 – 5% of them are published.• Although a standard for publishing data of BEstudies was already suggested in 1992, 1)• a review in 2002 found only 17 complete data sets on AUCand 12 on C max . 2)• Since no ‘real world’ data are available, proposed methods(e.g., reference-scaled ABE) rely entirely on simulations!• Studies seen by regulators are ‘selection biased’.1) Sauter, R., Steinijans, V.W., Diletti, E., Böhm, E. and H.-U. Schulz;Int. J. Clin. Pharm. Ther. Toxicol. 30/Suppl.1, S7-30 (1992)2) Nakai, K., Fujita, M. and M. Tomita;Int. J. Clin. Pharmacol. Ther. 40, 431-438 (2002)Dissolution Testing, Bioavailability & Bioequivalence | Budapest, 24 May 2007 69
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Statistical Evaluation ofBioequival
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Assumptions: StatisticsMultiplicati
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Nonparametrics5. In which cases may
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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 and 66: Nuisance: sequence effect• In a l
Page 67: Nuisance: sequence effect• Conclu
Page 71 and 72: ...to be rememberedWhenever a theor
Page 73 and 74: Statistical Evaluation ofBioequival
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