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Case Studies in Modeling and Simulation

Case Studies in Modeling and Simulation. Discussion Stella G. Machado, Ph.D. Office of Biostatistics/OTS/CDER/FDA FDA/Industry Workshop, September 2006. Regulatory issue. Approval was sought for monotherapy for pediatric population, without another clinical trial

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Case Studies in Modeling and Simulation

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  1. Case Studies in Modeling and Simulation Discussion Stella G. Machado, Ph.D. Office of Biostatistics/OTS/CDER/FDA FDA/Industry Workshop, September 2006

  2. 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)

  3. 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

  4. DRUG X: PK/PD scatter plot with loess fits

  5. 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”

  6. 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 Steps

  7. 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

  8. DRUG X: 95% CI’s for ratios 1/0 for concentrations: 0, 20,50,70,90 via model-based method

  9. 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

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