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Case Studies in Modeling and Simulation Discussion Stella G. Machado, Ph.D. Office of Biostatistics/OTS/CDER/FDA FDA/Industry Workshop, September 2006 1 Regulatory issue • Approval was sought for monotherapy for pediatric population, without another clinical trial • Clinical trial data for Drug X: – Adults: adjunct and monotherapy – Pediatric population: adjunct • PK/PD modeling used for bridging the adjunct therapy data (data masked) 2 Bridging PK/PD Studies • General method comparing PK/PD response curves in: Pediatric versus Adult populations Different Regions • Exposure: dose, AUC, Cmin, etc • Response: biomarkers, clinical endpoints • Goal is to evaluate similarity in PK/PD relationships between 2 populations Conclude: similarity, similarity with some dose regimen modification; lack of similarity 3 DRUG X: PK/PD scatter plot with loess fits 5 0 N e w O r i g i n a l 4 0 Respon 3 0 2 0 1 0 0 0 2 0 4 0 6 0 8 0 1 0 01 2 0 C o n c . 4 STEPS IN THE STATISTICAL APPROACH • assess similarity between responses at all concentrations likely to be encountered • account for variability of the response • need “Equivalence” type approach, not hypothesis tests showing that the responses are not significantly different • analysis is more “exploratory” than “confirmatory” 5 Steps • Usual equivalence-type analysis: – “similarity” defined as requirement that average responses in the 2 populations, at the same C, are closely similar: – choose reference “goalposts” L and U, eg 80% to 125% – calculate 95% confidence interval for ratio of average responses (1 / 0) for “all” C 6 EXAMPLE: Drug X • Response transformed by square root to stabilize the variance • Linear models fitted separately for the two populations: • sqrt(response) = a + b * Conc + • For each C, 5000 pairs of studies generated 5000 estimates of 1/0, and percentiles 7 DRUG X: 95% CI’s for ratios 1/0 for concentrations: 0, 20,50,70,90 via model-based method 1 . 8 95%confidebusforimlaty 1 . 4 1 . 0 0 . 6 0 4 0 8 0 1 2 0 C o n c 8 Remarks for example • Response higher for pediatric population for concentrations above 50mg =>Shows lack of similarity, but dose adjustment would be possible if high concentrations are called for • Limits of (80, 125) might not be medically most sensible for interpretation in each situation 9