StatisticalConsiderations.pptVIP

Statistical Considerations Evaluation of Quality and Interchangeability of Medicinal Products 10 – 14 September 2007 Dar Es Salaam, Tanzania Dr. Henrike Potthast; Temporary Advisor to WHO Statistical Considerations Bioequivalence – equivalent bioavailability within pre-set acceptance ranges Bioequivalence ? therapeutic equivalence Statistical Considerations “The primary concern in bioequivalence assessment is to limit the risk of a false declaration of equivalence. Statistical analysis of the bioequivalence trial should demonstrate that the clinically significant difference in bioavailability is unlikely…..” [WHO Working Document Multisource (Generic) Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability November 2005] Statistical Considerations HOW SIMILAR IS SIMILAR? Statistical Considerations basic measures AUC area under the plasma concentration curve Statistical Considerations basic measures Cmax – observed peak concentration tmax – the time after administration at which Cmax is observed (highly dependent on the sampling schedule!) t1/2 – half-life …a.o. Statistical Considerations log transformation…. ….for all concentration dependent pharmacokinetic parameters (e.g. AUC and Cmax) analysis of log-transformed data by means of ANOVA (analysis of variances) Statistical Considerations ANOVA model includes…. ….usually formulation, period, sequence or carry-over, and subject factors Statistical Considerations Parametric (normal-theory)…. ….to construct a 90 % confidence interval for μT-μR ….which is equivalent to carrying out two-one sided tests of hypothesis at the 5 % level of significance. Statistical Considerations …the constructed 90% confidence interval has to meet the pre-set acceptance criteria AUC – 80 – 125 % Cmax – 80 – 125 % (75 – 133 % may be possible if prospectively justified in terms of safety and efficacy) tmax – therapeutic relevance of mean difference Statistical Considerations