Design and Analysis of Pharmacodynamic Crossover Studies.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 Covariate Analysis of