Clinical Pharmacology Subcommittee of the Advisory Committee for Pharmaceutical Science Meeting April 22, 2003 Pediatric Population Pharmacokinetics Study Design Template Peter Lee, PhD Associate Director, Pharmacometrics Office of Clinical Pharmacology and Biopharmaceutics

Objectives Provide a consistent approach to design and evaluate pediatric population PK (PPK) study. Develop a computer-aided pediatric "study design template”: user-input study design features automatic assessment of study power Select case studies from the FDA database to test and iteratively refine the template. Promote a wider use of population design in pediatric PK study.

Pediatric Study Decision Tree Reasonable to assume (pediatrics vs adults) similar disease progression? similar response to intervention? Conduct PK studies Conduct safety/efficacy trials* NO Reasonable to assume similar concentration-response (C-R) in pediatrics and adults? YES TO BOTH Is there a PD measurement** that can be used to predict efficacy? NO NO Conduct PK studies to achieve levels similar to adults Conduct safety trials YES Conduct PK/PD studies to get C-R for PD measurement Conduct PK studies to achieve target concentrations based on C-R YES Conduct safety trials

Dose Selection in Pediatrics: Decision Tree for Dose Adjustment (TBD) If the 90% CI of test/ref is within the default “no effect boundaries” y n No dose adjustment Is PK/PD available ? y n Whether the PK change is clinically significant based on E-R ? n Pediatric Study Decision Tree y Dosing adjustment, precaution, or warning

Objectives of Pediatrics Population PK Studies to Support Decisions on Dose Selection Identifying a difference in pharmacokinetics between adults and pediatrics, Accurately estimating pharmacokinetic parameters in pediatrics without bias.

Factors Influencing Study Performance Study Design number of subjects, demographics, number and timing of samples, … Study Conduct variability in dosing time, missing dose, drop-off, … Pharmacokinetics parameter values, variability

Pediatrics PPK Study Design Template Flow Chart

Points-To-Consider for PPK Study Design The study performance should be estimated in terms of the specific study objectives, which may include (1) identifying if there is a clinical significant difference in pharmacokinetics between adults and pediatrics, and (2) accurately estimating pharmacokinetic parameters in pediatrics without bias. Study simulation is recommended as a best practice to determine study performance (power, precision, and accuracy). All relevant study design factors should be considered in the simulation.

Points-To-Consider for PPK Study Design (cont.) Dosing time and sampling time Compliance Number of samples and subjects Intra- and inter-subject variabilities Distribution of sampling times vs fixed sampling times Unbalanced design

Features (Inputs/Outputs) of the Proposed Study Design Template User-supplied information study design pharmacokinetics in adults variability of demographic, PK, and design variables criteria for study performance Output from the template estimated study performance power to identify PK difference precision and bias of parameter estimation

Proposed Clinical Trial Simulation in the Study Design Template 1. Generating demographic variables and PK parameters based on user-defined values and variability 2. Simulating study design and study conduct 3. Generating population PK data 4. Simulating the data analysis process 5. Estimating power, precision, and accuracy.

Criteria for Study Performance: Identify a Difference in PK Option 1: 90% CI within a default boundary Option 2: Clinically significant difference (e.g.: x%) in PK defined with PK/PD information for example: Study power Ho: Cl=0 H1: Cl/ Cltypical = x%

Criteria for Study Performance: Precision and Bias of PK Parameter Estimation

Outputs Power to identify a clinically significant difference in PK between pediatrics and adults Precision and accuracy of PK parameter estimation pediatric populations

Questions to the Committee Are the proposed objectives for pediatrics PPK studies reasonable, considering the decision tree for dose adjustment? Two main objectives Criteria for study performance Is the proposed pediatrics PPK study design template reasonable? CTS approach Factors to be considered Features

Acknowledgements Larry Lesko He Sun Arzu Selen Gene Williams Pharmacometrics Staffs

Backup Slides

Points-To-Consider for PPK Study Design Dosing time and sampling time should be recorded during the study conduct and accounted for in the data analysis. Deviations from the nominal times might be non-ignorable, therefore, analysis plans to deal with this are particularly important. Compliance is an important factor that influences the study outcomes. It should be considered in the study design and simulation. If compliance is to be used in the analysis of the study, the simulation should include consideration of the possibility that compliance is a confounder.

Points-To-Consider for PPK Study Design (cont.) More samples per subject, and more importantly, more subjects usually provide better study performance if the study design remains otherwise the same. Studies with higher intra- or inter- subject variability require more samples per subject, or more subjects per age group to achieve similar study performance.

Points-To-Consider for PPK Study Design (cont.) Distribution of the sampling times among subjects should cover the full dosing interval as much as possible to describe the concentration-time profile. Fixing sampling time among subjects (ie, same sampling time for all subjects) may be inferior to randomizing sampling times, especially when the number of samples permitted per subject is insufficient to fully identify each subject's full structural model. Unbalanced design (ie, different numbers of samples per subject or different sampling times between sub-populations), if these design differences are not randomly assigned may bias study results.

Points-To-Consider for PPK Study Design (cont.) One-sample-per-subject design does not allow intra-subject variability and inter-subject variability to be distinguished, and may result in biased estimates of either. At least some subjects (but preferably most or all) should be studied with an intra-subject design adequate to fully identify their individual model. To obtain good estimations of Ka, Cl and their variability, samples in the absorption and elimination phases, respectively, should be collected. Concentration of sampling times in a particular region of the dosing interval (eg, troughs in all subjects) may result in poor study outcomes.