1. 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. 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. 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. 4 DRUG X: PK/PD scatter plot with loess fits

5. 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. 6 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

7. 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. 8 DRUG X: 95% CIs for ratios 1 / 0 for concentrations: 0, 20,50,70,90 via model-based method

9. 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