FDA什么是高度生物变异性药物.ppt

Product B (ABE4)Test-1 versus Test-2 Measure GMR% CV% 90%CI ln Cmax 97 26.0 84-111 ln AUClast 97 18.7 87-107 ANOVA-1: (GLM) * Product B (ABE4)Ref-1 versus Ref-2 Measure GMR% CV% 90%CI ln Cmax 87 49.9 66-113 ln AUClast 87 39.2 71-108 ANOVA-1: (GLM) * Product C (ABE4) 37 healthy volunteers 2-Formulation, 4-Period, 4-Sequence Cross-Over design Washout period, 1 week 15 plasma samples collected over 13.5 hr * Product C (Cmax) 37 Subjects in Numerical Order ln Cmax Test Reference * Product C (AUClast) 37 Subjects in Numerical Order ln Cmax Test Reference * Product C (ABE4)Test versus Ref Measure GMR% CV% 90%CI ln Cmax 104 41.7 92-117 ln AUClast 103 35.8 93-114 ANOVA-3: (MIXED) * Product C (ABE4)Test-1 versus Test-2 Measure GMR% CV% 90%CI ln Cmax 99 29.6 87-111 ln AUClast 92 32.5 81-106 ANOVA-1: (GLM) * Product C (ABE4)Ref-1 versus Ref-2 Measure GMR% CV% 90%CI ln Cmax 107 33.7 94-123 ln AUClast 109 27.1 97-122 ANOVA-1: (GLM) * Dealing with HVDs HVDs are generally safe drugs High WSV of Cmax is often the problem A 90%CI is not required for Cmax in the case of ‘uncomplicated drugs’... a potential solution for HVD/Ps? * Suggested Approaches* BE Study Multiple dose study BE on the basis of metabolite Area correction method to reduce intra-subject variability Application of stable isotope technique * From Published Literature * Suggested Approaches* Statistical Considerations Scaled ABE criteria GMR-dependent scale ABE limits Individual Bioequivalence (IBE) BE Study Design Replicate Design Group sequential design *From Published Literature * Different analytical methods different analysts CV% consistent between studies The drug is HVD No evidence of HVD/P This plot is the actual data from the study High lighted are som