Design and Analysis of Pharmacodynamic Crossover 药效学交叉的设计与分析.pptVIP

Bhargava Kandala Department of Pharmaceutics College of Pharmacy , UF Design and Analysis of Crossover Study Designs Crossover Study Treatments administered in a sequence to each experimental unit over a set of time periods. Comparison of treatments on a within-subject level. Increased precision of treatment comparisons. A treatment given in one period might influence the response in the following treatment period – residual/carryover effect Baseline values – Can be included as covariates to increase the precision Study Design Single center, double blind, randomized, 3 period, 3 treatment, 3 sequence crossover study Randomization Low Medium High Low Medium High Low Medium High Washout Washout Subjects = 10 Baseline 1 Period 1 (q.d.) ? ? Period 2 (q.d.) Period 3 (q.d.) Baseline 2 Baseline 3 PD Measurements PD Measurements PD Measurements 1 Week 1 Week 5 days 5 days 5 days Model for Crossover Design Period 1 2 3 4 5 6 I A B C A B C II B C A C A B III C A B B C A proc glm data = allperiodanaly; class sequence subject period trt; model fenoav = sequence subject(sequence) period trt/solution; random subject(sequence); run; proc mixed data = allperiodanaly; class sequence subject period trt; model fenoav = sequence period trt; random subject(sequence); lsmeans trt/ pdiff cl; run; Baseline Baseline - Covariate Average baseline values not significantly different Presence of significant carryover effects (p-value 0.05) No Covariate Analysis of Covariance (ANCOVA) Baseline – Treatment β = 0 β = Model Estimate β =1 Baseline is not used as a covariate Baseline values are treated as a quantitative variable By taking the simple difference the value of β is forced to be 1 Carryover Effect * Covariates tested for carryover; proc mixed data = allperiodanaly; class sequence subject period trt; model fenoav = sequence period fenob trt carry1 carry2; random subject(sequence); lsmeans trt/ pdiff cl e; run; Results β cannot be forced to be 1 Parameter No Covari