Statistical modelling issues arising from PK/PD bridging in paediatrics The Trileptal Example Jerry R. Nedelman, Modeling and Simulation, Novartis Workshop on Modelling in Paediatric Drug Development and Use 14 April 2008
Outline � Background � Pediatric Decision Tree � The problem: “observational data”, potential confounding � The solution: diagnostics for confounding � Lessons learned 2 | Statistical Modelling Issues Arising from PK/PD Bridging in Paediatrics | Jerry R. Nedelman | 14 April 2008
Outline � Background � Pediatric Decision Tree � The problem: “observational data”, potential confounding � The solution: diagnostics for confounding � Lessons learned 3 | Statistical Modelling Issues Arising from PK/PD Bridging in Paediatrics | Jerry R. Nedelman | 14 April 2008
Background: Trileptal � Oxcarbazepine � Anti-epileptic � Activity primarily through active metabolite MHD � “PK” refers to MHD concentrations � “PD” refers to seizure rates 4 | Statistical Modelling Issues Arising from PK/PD Bridging in Paediatrics | Jerry R. Nedelman | 14 April 2008
Background: Initial approval status in the U.S. Adjunctive Monotherapy therapy ☑ ☑ Adults ☑ Children Goal 5 | Statistical Modelling Issues Arising from PK/PD Bridging in Paediatrics | Jerry R. Nedelman | 14 April 2008
Background: Available data Adjunctive Monotherapy therapy ☑ ☑ PK/PD PK/PD Adults ☑ PK/PD PK Children Goal 6 | Statistical Modelling Issues Arising from PK/PD Bridging in Paediatrics | Jerry R. Nedelman | 14 April 2008
Background: Bridging strategy Adjunctive Monotherapy therapy ☑ ☑ PK/PD PK/PD Adults ☑ PK/PD PK Children Goal 7 | Statistical Modelling Issues Arising from PK/PD Bridging in Paediatrics | Jerry R. Nedelman | 14 April 2008
Outline � Background � Pediatric Decision Tree � The problem: “observational data”, potential confounding � The solution: diagnostics for confounding � Lessons learned 8 | Statistical Modelling Issues Arising from PK/PD Bridging in Paediatrics | Jerry R. Nedelman | 14 April 2008
Pediatric Decision Tree Pediatric Study Decision Tree Reasonable to assume (pediatrics vs adults) � similar disease progression? � similar response to intervention? YES TO BOTH NO Reasonable to assume similar • Conduct PK studies concentration-response (C-R) • Conduct safety/efficacy trials* in pediatrics and adults? NO NO YES • Conduct PK studies to Is there a PD measurement** achieve levels similar to adults that can be used to predict • Conduct safety trials efficacy? YES • Conduct PK/PD studies to get • Conduct safety trials C-R for PD measurement • Conduct PK studies to achieve http://www.fda.gov/cder/guidance/5341fnl.htm target concentrations based on C-R 9 | Statistical Modelling Issues Arising from PK/PD Bridging in Paediatrics | Jerry R. Nedelman | 14 April 2008
Pediatric Decision Tree Pediatric Study Decision Tree Reasonable to assume (pediatrics vs adults) � similar disease progression? � similar response to intervention? YES TO BOTH NO Reasonable to assume similar • Conduct PK studies concentration-response (C-R) • Conduct safety/efficacy trials* in pediatrics and adults? NO NO YES • Conduct PK studies to Is there a PD measurement** achieve levels similar to adults that can be used to predict • Conduct safety trials efficacy? YES • Conduct PK/PD studies to get • Conduct safety trials C-R for PD measurement • Conduct PK studies to achieve target concentrations based on C-R 10 | Statistical Modelling Issues Arising from PK/PD Bridging in Paediatrics | Jerry R. Nedelman | 14 April 2008
Pediatric Decision Tree: Bridging (1) Pediatric Study Decision Tree Reasonable to assume (pediatrics vs adults) � similar disease progression? � similar response to intervention? YES TO BOTH Reasonable to assume similar Adjunctive Adjunctive Monotherapy Monotherapy concentration-response (C-R) therapy therapy ☑ ☑ ☑ ☑ in pediatrics and adults? Adults Adults YES PK/PD PK/PD • Conduct PK studies to ☑ ☑ achieve levels similar to adults Children Children • Conduct safety trials PK/PD PK Goal Goal 11 | Statistical Modelling Issues Arising from PK/PD Bridging in Paediatrics | Jerry R. Nedelman | 14 April 2008
Pediatric Decision Tree: Bridging (2) Pediatric Study Decision Tree Reasonable to assume (pediatrics vs adults) � similar disease progression? � similar response to intervention? YES TO BOTH Reasonable to assume similar Adjunctive Adjunctive Monotherapy Monotherapy concentration-response (C-R) therapy therapy ☑ ☑ ☑ ☑ in pediatrics and adults? Adults Adults YES PK/PD PK/PD • Conduct PK studies to ☑ ☑ achieve levels similar to adults Children Children • Conduct safety trials PK/PD PK Goal Goal 12 | Statistical Modelling Issues Arising from PK/PD Bridging in Paediatrics | Jerry R. Nedelman | 14 April 2008
Pediatric Decision Tree: Burden of proof Reasonable to assume similar Adjunctive Adjunctive Monotherapy Monotherapy concentration-response (C-R) therapy therapy ☑ ☑ ☑ ☑ in pediatrics and adults? Adults Adults PK/PD PK/PD ☑ ☑ Children Children PK/PD PK Goal Goal 13 | Statistical Modelling Issues Arising from PK/PD Bridging in Paediatrics | Jerry R. Nedelman | 14 April 2008
Pediatric Decision Tree: But first … Reasonable to assume similar concentration-response (C-R) in pediatrics and adults? Are the estimated PK/PD (C-R) relationships acceptable in the first place? 14 | Statistical Modelling Issues Arising from PK/PD Bridging in Paediatrics | Jerry R. Nedelman | 14 April 2008
Outline � Background � Pediatric Decision Tree � The problem: “observational data”, potential confounding � The solution: diagnostics for confounding � Lessons learned 15 | Statistical Modelling Issues Arising from PK/PD Bridging in Paediatrics | Jerry R. Nedelman | 14 April 2008
Observational vs Experimental � “Relationship”: Input � Output � Experimental study: Input controlled by investigator • Usually assigned randomly to experimental units • E.g., dose-controlled trial, concentration-controlled trial � Observational study: Input not controlled by investigator • E.g., PK � PD in a dose-controlled trial • PK is an output as well as an input • For PK/PD purposes, a dose-controlled trial is an observational study � What can go wrong with observational PK/PD? …. 16 | Statistical Modelling Issues Arising from PK/PD Bridging in Paediatrics | Jerry R. Nedelman | 14 April 2008
Concentration-controlled PK/PD Efficacy vs Concentration 35 30 25 Efficacy 20 15 10 5 1 2 3 Concentration PK/PD data and least-squares model fit, assuming concentration controlled trial , with 3 concentrations, at each of which patients divide evenly into two groups of high and low responders 17 | Statistical Modelling Issues Arising from PK/PD Bridging in Paediatrics | Jerry R. Nedelman | 14 April 2008
Dose-controlled PK/PD, scenario 1 Efficacy vs Concentration Concentration vs Dose 35 30 D 3 25 Concentration Efficacy 20 B C 2 15 10 A 1 5 1 2 3 50 100 150 200 250 Concentration Dose Suppose that in a dose-controlled trial, patients who have higher concentrations at a given dose also have higher efficacy at a given concentration , and lower goes with lower 18 | Statistical Modelling Issues Arising from PK/PD Bridging in Paediatrics | Jerry R. Nedelman | 14 April 2008
Dose-controlled PK/PD, scenario 1 Efficacy vs Concentration Concentration vs Dose 35 30 D 3 25 Concentration B Efficacy 20 B C 2 15 10 A 1 5 1 2 3 50 100 150 200 250 Concentration Dose Suppose that in a dose-controlled trial, patients who have higher concentrations at a given dose also have higher efficacy at a given concentration , and lower goes with lower 19 | Statistical Modelling Issues Arising from PK/PD Bridging in Paediatrics | Jerry R. Nedelman | 14 April 2008
Dose-controlled PK/PD, scenario 1 Efficacy vs Concentration Concentration vs Dose 35 30 D 3 25 Concentration B Efficacy 20 B C 2 15 C 10 A 1 5 1 2 3 50 100 150 200 250 Concentration Dose Suppose that in a dose-controlled trial, patients who have higher concentrations at a given dose also have higher efficacy at a given concentration , and lower goes with lower 20 | Statistical Modelling Issues Arising from PK/PD Bridging in Paediatrics | Jerry R. Nedelman | 14 April 2008
Dose-controlled PK/PD, scenario 1 Efficacy vs Concentration Concentration vs Dose 35 30 D D 3 25 Concentration B Efficacy 20 B C 2 15 C 10 A A 1 5 1 2 3 50 100 150 200 250 Concentration Dose Suppose that in a dose-controlled trial, patients who have higher concentrations at a given dose also have higher efficacy at a given concentration , and lower goes with lower 21 | Statistical Modelling Issues Arising from PK/PD Bridging in Paediatrics | Jerry R. Nedelman | 14 April 2008
Dose-controlled PK/PD, scenario 1 Efficacy vs Concentration Concentration vs Dose 35 30 D D 3 25 Concentration B Efficacy 20 B C 2 15 C 10 A A 1 5 1 2 3 50 100 150 200 250 Concentration Dose Suppose that in a dose-controlled trial, patients who have higher concentrations at a given dose also have higher efficacy at a given concentration , and lower goes with lower 22 | Statistical Modelling Issues Arising from PK/PD Bridging in Paediatrics | Jerry R. Nedelman | 14 April 2008
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