Sample Size Calculations - bebac.at

1 1 57 Sample Sample Size CalculationsSize CalculationsIn vitro in vivoIn vitro in vivoCorrelation (IVIVC), Biowaivers & Statistical Aspects of BioequCorrelation (IVIVC), Biowaivers & Statistical Aspects of Bioequivalenceivalencein Drug Product Developmentin Drug Product Development| | MumbaiMumbai, , 27 27 January January 20122012 Pharma EdgeHelmut Sch tzBEBACH elmut Sch tzBEBACW ikimediaWikimediaCommons Commons 2007 2007 Sujit KumarSujit Kumar Creative Commons AttributionCreative Commons UnportedUnportedSample Size CalculationsSample Sample Size CalculationsSize CalculationsNamaste!

2 Namaste!2 57 Sample Sample Size CalculationsSize CalculationsIn vitro in vivoIn vitro in vivoCorrelation (IVIVC), Biowaivers & Statistical Aspects of BioequCorrelation (IVIVC), Biowaivers & Statistical Aspects of Bioequivalenceivalencein Drug Product Developmentin Drug Product Development| | MumbaiMumbai, , 27 27 January January 20122012 Pharma EdgeOverviewOverview Classical Sample size estimation in BE Patient s & producer s risk Power in study planning Uncertainties Variability Test/Reference-ratio Sensitivity analysis Recent developments Review of guidelines3 57 Sample Sample Size CalculationsSize CalculationsIn vitro in vivoIn vitro in vivoCorrelation (IVIVC), Biowaivers & Statistical Aspects of BioequCorrelation (IVIVC)

3 , Biowaivers & Statistical Aspects of Bioequivalenceivalencein Drug Product Developmentin Drug Product Development| | MumbaiMumbai, , 27 27 January January 20122012 Pharma Edge --ErrorError All formal decisions are subjected to two typesof error: Error Type I ( -Error, Risk Type I) Error Type II ( -Error, Risk Type II)Example from the justice system:Error type IICorrectPresumption of innocence accepted(not guilty)CorrectError type I Presumption of innocence not accepted(guilty)Defendant guiltyDefendant innocentVerdict4 57 Sample Sample Size CalculationsSize CalculationsIn vitro in vivoIn vitro in vivoCorrelation (IVIVC), Biowaivers & Statistical Aspects of BioequCorrelation (IVIVC)

4 , Biowaivers & Statistical Aspects of Bioequivalenceivalencein Drug Product Developmentin Drug Product Development| | MumbaiMumbai, , 27 27 January January 20122012 Pharma Edge --ErrorError Or in more statistical terms: In BE-testing the null hypothesis is bioinequivalence( 1 2)!Error type IICorrect (H0)Failed to reject null hypothesisCorrect (Ha)Error type I Null hypothesis rejectedNull hypothesis falseNull hypothesis trueDecisionProducer s riskCorrect (not BE)Failed to reject null hypothesisCorrect (BE)Patients riskNull hypothesis rejectedNull hypothesis falseNull hypothesis trueDecision5 57 Sample Sample Size CalculationsSize CalculationsIn vitro in vivoIn vitro in vivoCorrelation (IVIVC), Biowaivers & Statistical Aspects of BioequCorrelation (IVIVC)

5 , Biowaivers & Statistical Aspects of Bioequivalenceivalencein Drug Product Developmentin Drug Product Development| | MumbaiMumbai, , 27 27 January January 20122012 Pharma Edge95% one-sided CIparticular one-sided CIparticular two-sided CI= two 95% one-sidedpopulation of --ErrorError -Error: Patient s Riskto be treated with a bioinequivalentformulation (H0falsely rejected) BA of the test compared to reference in a particularpatient is risky eitherbelow 80% orabove 125%.

6 If we keep the risk of particular patientsat (5%), the risk of the entirepopulation of patients(<80% and>125%) is 2 (10%) expressed as:90% CI = 1 2 = 57 Sample Sample Size CalculationsSize CalculationsIn vitro in vivoIn vitro in vivoCorrelation (IVIVC), Biowaivers & Statistical Aspects of BioequCorrelation (IVIVC), Biowaivers & Statistical Aspects of Bioequivalenceivalencein Drug Product Developmentin Drug Product Development| | MumbaiMumbai, , 27 27 January January 20122012 Pharma Edge --ErrorError -Error.

7 Producer s Riskto get no approval fora bioequivalentformulation (H0falsely notrejected) Setin study planning to , wherepower = 1 = 80% If power is set to 80 %One out of five studies will fail just by chance! A posteriori(post hoc) power does not make sense!Eithera study has demonstrated BE ornot. BEBE 57 Sample Sample Size CalculationsSize CalculationsIn vitro in vivoIn vitro in vivoCorrelation (IVIVC), Biowaivers & Statistical Aspects of BioequCorrelation (IVIVC), Biowaivers & Statistical Aspects of Bioequivalenceivalencein Drug Product Developmentin Drug Product Development| | MumbaiMumbai, , 27 27 January January 20122012 Pharma EdgePower CurvesPower CurvesPower to show BE with 12 36 subjects forCVintra20%n24 16:power T/.

8 Power 2 Cross-over T/ RPower20% 57 Sample Sample Size CalculationsSize CalculationsIn vitro in vivoIn vitro in vivoCorrelation (IVIVC), Biowaivers & Statistical Aspects of BioequCorrelation (IVIVC), Biowaivers & Statistical Aspects of Bioequivalenceivalencein Drug Product Developmentin Drug Product Development| | MumbaiMumbai, , 27 27 January January 20122012 Pharma EdgePower Power SizeSample Size It is not possible to calculate the requiredsample size directly.

9 Power is calculated instead; the smallestsample size which fulfills the minimum target power is used. Example: , target power 80%( ), T/R , CVintra20% minimum Sample size 19 (power 81%),rounded upto the next even number ina 2 2 study (power 83%).n 57 Sample Sample Size CalculationsSize CalculationsIn vitro in vivoIn vitro in vivoCorrelation (IVIVC), Biowaivers & Statistical Aspects of BioequCorrelation (IVIVC), Biowaivers & Statistical Aspects of Bioequivalenceivalencein Drug Product Developmentin Drug Product Development| | MumbaiMumbai, , 27 27 January January 20122012 Pharma EdgePower Power SizeSample Size2 2 cross-over, T/R , AR 80 125%, target power 80%08162432405%10%15%20%25%30%CVintrasam ple size80%85%90%95%100%powersample sizepowerpower for n=1210 57 Sample Sample Size CalculationsSize CalculationsIn vitro in vivoIn vitro in vivoCorrelation (IVIVC)

10 , Biowaivers & Statistical Aspects of BioequCorrelation (IVIVC), Biowaivers & Statistical Aspects of Bioequivalenceivalencein Drug Product Developmentin Drug Product Development| | MumbaiMumbai, , 27 27 January January 20122012 Pharma EdgeToolsTools Sample Size Tables (Phillips, Diletti, Hauschke, Chow, Julious, ..) Approximations (Diletti, Chow, Julious, ..) General purpose (SAS, S+, R, StaTable, ..) Specialized Software (nQuery Advisor, PASS, FARTSSIE, StudySize, ..) Exact method (Owen implemented in R-package PowerTOST)** Thanks to Detlew Labes!