History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Leveraging Prior Knowledge inGuiding Pediatric Drug Development

Pravin R JadhavPharmacometrics, Office of Clinical Pharmacology

Office of Translational SciencesCDER,FDA

Workshop on Modeling in Pediatric MedicinesLondon, UK

April 14, 2008The views expressed in this presentation do not necessarily reflect the agency position

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 1/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Agenda

1 History of Legislation

2 Retrospective Analysis

3 Impetus

4 CTS Framework

5 Results

6 Conclusions

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 2/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Legislation HistoryActive history to obtain good quality pediatric data

1979 Labeling Requirement1994 Pediatric Labeling Rule1997 FDA Modernization Act (FDAMA)1998 Pediatric Rule2002 Best Pharmaceuticals for Children Act (BPCA)2002 Pediatric Rule Enjoined2003 Pediatric Research Equity Act (PREA)2007 FDA Amendments Act of 2007

Pediatric Medical Device Safety and Improvement ActPediatric Research Equity Act (PREA)Best Pharmaceuticals for Children Act (BPCA)

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 3/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Legislation HistoryActive history to obtain good quality pediatric data

1979 Labeling Requirement1994 Pediatric Labeling Rule1997 FDA Modernization Act (FDAMA)1998 Pediatric Rule2002 Best Pharmaceuticals for Children Act (BPCA)2002 Pediatric Rule Enjoined2003 Pediatric Research Equity Act (PREA)2007 FDA Amendments Act of 2007

Pediatric Medical Device Safety and Improvement ActPediatric Research Equity Act (PREA)Best Pharmaceuticals for Children Act (BPCA)

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 3/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Legislation HistoryActive history to obtain good quality pediatric data

1979 Labeling Requirement1994 Pediatric Labeling Rule1997 FDA Modernization Act (FDAMA)1998 Pediatric Rule2002 Best Pharmaceuticals for Children Act (BPCA)2002 Pediatric Rule Enjoined2003 Pediatric Research Equity Act (PREA)2007 FDA Amendments Act of 2007

Pediatric Medical Device Safety and Improvement ActPediatric Research Equity Act (PREA)Best Pharmaceuticals for Children Act (BPCA)

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 3/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Improved Labeling Information for PediatricsA central goal of pediatric exclusivity program

General principles a

Pediatric patients should be given medicines that havebeen appropriately evaluated for their use in thosepopulations

Product development programs should includepediatric studies when pediatric use is anticipated

Shared responsibility among companies, regulatoryauthorities, health professionals, and society as awhole

aICH E-11:http://www.fda.gov/cber/gdlns/ichclinped.htm#id

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 4/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Improved Labeling Information for PediatricsA central goal of pediatric exclusivity program

General principles a

Pediatric patients should be given medicines that havebeen appropriately evaluated for their use in thosepopulations

Product development programs should includepediatric studies when pediatric use is anticipated

Shared responsibility among companies, regulatoryauthorities, health professionals, and society as awhole

aICH E-11:http://www.fda.gov/cber/gdlns/ichclinped.htm#id

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 4/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Improved Labeling Information for PediatricsA central goal of pediatric exclusivity program

General principles a

Pediatric patients should be given medicines that havebeen appropriately evaluated for their use in thosepopulations

Product development programs should includepediatric studies when pediatric use is anticipated

Shared responsibility among companies, regulatoryauthorities, health professionals, and society as awhole

aICH E-11:http://www.fda.gov/cber/gdlns/ichclinped.htm#id

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 4/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Improving Pediatric Dosing through PediatricInitiativesWhat we have learned

Substantive differences in dosing, safety, or efficacy inchildren 1 compared with adults for at least half of theproducts studied

Twenty nine of 131 drugs were concluded to be ineffective

Several oral antihypertensive products that were approvedin adults did not seem to work in children

With rising obesity in children and adolescents, failed trialsfor antihypertensive products have significant public healthimplications

1Rodriguez W, Selen A, Avant D et. al. Improving pediatric dosing through pediatric initiatives: What we have

learned, Pediatrics, 2008; 121(3): 530-9

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 5/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Improving Pediatric Dosing through PediatricInitiativesWhat we have learned

Substantive differences in dosing, safety, or efficacy inchildren 1 compared with adults for at least half of theproducts studied

Twenty nine of 131 drugs were concluded to be ineffective

Several oral antihypertensive products that were approvedin adults did not seem to work in children

With rising obesity in children and adolescents, failed trialsfor antihypertensive products have significant public healthimplications

1Rodriguez W, Selen A, Avant D et. al. Improving pediatric dosing through pediatric initiatives: What we have

learned, Pediatrics, 2008; 121(3): 530-9

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 5/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Improving Pediatric Dosing through PediatricInitiativesWhat we have learned

Substantive differences in dosing, safety, or efficacy inchildren 1 compared with adults for at least half of theproducts studied

Twenty nine of 131 drugs were concluded to be ineffective

Several oral antihypertensive products that were approvedin adults did not seem to work in children

With rising obesity in children and adolescents, failed trialsfor antihypertensive products have significant public healthimplications

1Rodriguez W, Selen A, Avant D et. al. Improving pediatric dosing through pediatric initiatives: What we have

learned, Pediatrics, 2008; 121(3): 530-9

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 5/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Improving Pediatric Dosing through PediatricInitiativesWhat we have learned

Substantive differences in dosing, safety, or efficacy inchildren 1 compared with adults for at least half of theproducts studied

Twenty nine of 131 drugs were concluded to be ineffective

Several oral antihypertensive products that were approvedin adults did not seem to work in children

With rising obesity in children and adolescents, failed trialsfor antihypertensive products have significant public healthimplications

1Rodriguez W, Selen A, Avant D et. al. Improving pediatric dosing through pediatric initiatives: What we have

learned, Pediatrics, 2008; 121(3): 530-9

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 5/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Antihypertensive Trial FailuresAnalysis of 6 type C study designs

Six dose-ranging antihypertensive efficacy trials completed forpediatric exclusivity from 1998 to 2005 were reviewed a

Three failed and Three succeeded to demonstrate doseresponse as a primary endpoint

Failed trials included 2-9 fold and Successful trials included20-32 fold dose rangeTwo failed drugs were significantly different compared toplacebo in the 2nd part of the study

Poor dose selection, lack of acknowledgment of differencesbetween adults and pediatrics and lack of suitable pediatricformulations as potential failure reasons

aBenjamin DK, Smith PB, Jadhav PR et. al. Pediatric Antihypertensive Trial Failures: Analysis of End Points and Dose

Range, Hypertension, 2008; 51: 834-840

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 6/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Antihypertensive Trial FailuresAnalysis of 6 type C study designs

Six dose-ranging antihypertensive efficacy trials completed forpediatric exclusivity from 1998 to 2005 were reviewed a

Three failed and Three succeeded to demonstrate doseresponse as a primary endpoint

Failed trials included 2-9 fold and Successful trials included20-32 fold dose rangeTwo failed drugs were significantly different compared toplacebo in the 2nd part of the study

Poor dose selection, lack of acknowledgment of differencesbetween adults and pediatrics and lack of suitable pediatricformulations as potential failure reasons

aBenjamin DK, Smith PB, Jadhav PR et. al. Pediatric Antihypertensive Trial Failures: Analysis of End Points and Dose

Range, Hypertension, 2008; 51: 834-840

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 6/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Antihypertensive Trial FailuresAnalysis of 6 type C study designs

Six dose-ranging antihypertensive efficacy trials completed forpediatric exclusivity from 1998 to 2005 were reviewed a

Three failed and Three succeeded to demonstrate doseresponse as a primary endpoint

Failed trials included 2-9 fold and Successful trials included20-32 fold dose rangeTwo failed drugs were significantly different compared toplacebo in the 2nd part of the study

Poor dose selection, lack of acknowledgment of differencesbetween adults and pediatrics and lack of suitable pediatricformulations as potential failure reasons

aBenjamin DK, Smith PB, Jadhav PR et. al. Pediatric Antihypertensive Trial Failures: Analysis of End Points and Dose

Range, Hypertension, 2008; 51: 834-840

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 6/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Antihypertensive Trial FailuresAnalysis of 6 type C study designs

Six dose-ranging antihypertensive efficacy trials completed forpediatric exclusivity from 1998 to 2005 were reviewed a

Three failed and Three succeeded to demonstrate doseresponse as a primary endpoint

Failed trials included 2-9 fold and Successful trials included20-32 fold dose rangeTwo failed drugs were significantly different compared toplacebo in the 2nd part of the study

Poor dose selection, lack of acknowledgment of differencesbetween adults and pediatrics and lack of suitable pediatricformulations as potential failure reasons

aBenjamin DK, Smith PB, Jadhav PR et. al. Pediatric Antihypertensive Trial Failures: Analysis of End Points and Dose

Range, Hypertension, 2008; 51: 834-840

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 6/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Antihypertensive Trial FailuresAnalysis of 6 type C study designs

Six dose-ranging antihypertensive efficacy trials completed forpediatric exclusivity from 1998 to 2005 were reviewed a

Three failed and Three succeeded to demonstrate doseresponse as a primary endpoint

Failed trials included 2-9 fold and Successful trials included20-32 fold dose rangeTwo failed drugs were significantly different compared toplacebo in the 2nd part of the study

Poor dose selection, lack of acknowledgment of differencesbetween adults and pediatrics and lack of suitable pediatricformulations as potential failure reasons

aBenjamin DK, Smith PB, Jadhav PR et. al. Pediatric Antihypertensive Trial Failures: Analysis of End Points and Dose

Range, Hypertension, 2008; 51: 834-840

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 6/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Leveraging Prior Quantitative KnowledgeA case study

Drug X to be used for immediate blood pressure (BP) control

The initial study design to obtain exclusivity was fraught withuncertainties

Dose/exposure rangePlacebo durationSample size and primary endpoint

Leveraging prior quantitative knowledge to design a studywith adequate power and improve data quality to deriverational dosing recommendations

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 7/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Leveraging Prior Quantitative KnowledgeA case study

Drug X to be used for immediate blood pressure (BP) control

The initial study design to obtain exclusivity was fraught withuncertainties

Dose/exposure rangePlacebo durationSample size and primary endpoint

Leveraging prior quantitative knowledge to design a studywith adequate power and improve data quality to deriverational dosing recommendations

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 7/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Leveraging Prior Quantitative KnowledgeA case study

Drug X to be used for immediate blood pressure (BP) control

The initial study design to obtain exclusivity was fraught withuncertainties

Dose/exposure rangePlacebo durationSample size and primary endpoint

Leveraging prior quantitative knowledge to design a studywith adequate power and improve data quality to deriverational dosing recommendations

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 7/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Leveraging Prior Quantitative KnowledgeSponsor and FDA conducted clinical trial simulations (CTS) to substantiate thechoice of trial design, dosing regimens and sample size

Information available toSponsor and FDA

Patient level exposure-response data on drug X in adultsMean exposure-response data on fenoldopam a

FDAPatient level exposure-response data on fenoldopam in adultsand pediatrics

Inputs for CTSExposure response modelPlacebo response modelDrop-out modelTrial design

ahttp://www.fda.gov/cder/foi/label/2004/19922se5-005 colopam lbl.pdf

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 8/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Leveraging Prior Quantitative KnowledgeSponsor and FDA conducted clinical trial simulations (CTS) to substantiate thechoice of trial design, dosing regimens and sample size

Information available toSponsor and FDA

Patient level exposure-response data on drug X in adultsMean exposure-response data on fenoldopam a

FDAPatient level exposure-response data on fenoldopam in adultsand pediatrics

Inputs for CTSExposure response modelPlacebo response modelDrop-out modelTrial design

ahttp://www.fda.gov/cder/foi/label/2004/19922se5-005 colopam lbl.pdf

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 8/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Inputs for CTS

Exposure response modelPatient level adult data for Drug X

Placebo response modelPatient level pediatric data for fenoldopam

Drop-out modelPatient level pediatric data for fenoldopamClinical experience: Subjects with >25% decrease in DBPdiscontinue

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 9/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Trial Design and Statistical Tests

Screening

Baseline/Run-in Constant dose Infusion

(Randomized phase)30 min

Placebo

0.5X of Lowest dose approved in adults

Lowest dose approved in adults

2X highest dose approved in adults

Highest dose approved in adults

5 10 15 20 25 30

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 10/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Trial Design and Statistical Tests

Screening

Baseline/Run-in

Placebo

0.5X of Lowest dose approved in adults

Lowest dose approved in adults

2X highest dose approved in adults

Highest dose approved in adults

5 10 15 20 25 30Longitudinal analysis (Mixed model

repeated measures)

Single point analysis with LOCF

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 10/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Simulation ExperimentExposure-response, placebo model, trial design and drop-out assumptions

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 11/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Simulation ExperimentExposure-response, placebo model, trial design and drop-out assumptions

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 11/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Simulation ExperimentExposure-response, placebo model, trial design and drop-out assumptions

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 11/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Longitudinal Analysis More Powerful than SinglePoint AnalysisSample size of 40 should be adequate

20

40

60

80

100

10 20 30 40 50

Pediatrics NE Adults (Emax 0.5x : EC50 2x)

'Longitudinal'

'Single point'

Number of subjects per arm

Prob

abili

ty o

f rej

ectin

g nu

ll hy

poth

esis

, %

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 12/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Longitudinal Analysis More Powerful than SinglePoint AnalysisSample size of 40 should be adequate

20

40

60

80

100

10 20 30 40 50

Pediatrics NE Adults (Emax 0.5x : EC50 2x)

'Longitudinal'

'Single point'

Number of subjects per arm

Prob

abili

ty o

f rej

ectin

g nu

ll hy

poth

esis

, %

20

40

60

80

100

10 20 30 40 50

Pediatrics = Adults (Base design)

Pediatrics ≠ Adults (Emax 0.5x : EC50 2x)Pediatrics ≠ Adults (Emax 0.75x : EC50 1.5x)

Number of subjects per armPr

obab

ility

of r

ejec

ting

null

hypo

thes

is, %

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 12/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Key FindingsLeveraging prior knowledge allowed us to

effectively use prior knowledge to develop a pediatricwritten request

make informed decisions on dose range, number ofsubjects, sampling scheme and statistical tests

design a study with adequate power and improve dataquality to derive rational dosing recommendations

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 13/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Key FindingsLeveraging prior knowledge allowed us to

effectively use prior knowledge to develop a pediatricwritten request

make informed decisions on dose range, number ofsubjects, sampling scheme and statistical tests

design a study with adequate power and improve dataquality to derive rational dosing recommendations

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 13/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

Key FindingsLeveraging prior knowledge allowed us to

effectively use prior knowledge to develop a pediatricwritten request

make informed decisions on dose range, number ofsubjects, sampling scheme and statistical tests

design a study with adequate power and improve dataquality to derive rational dosing recommendations

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 13/14

History of Legislation Retrospective Analysis Impetus CTS Framework Results Conclusions

AcknowledgmentsInternal and External Experts

Clinical PharmacologyJoga Gobburu PhD, Pharmacometrics, Office of Clinical PharmacologyPatrick Marroum PhD, Office of Clinical PharmacologyMehul Mehta PhD, Office of Clinical Pharmacology

ClinicalNorman Stockbridge MD, Division of CardioRenal Drug ProductsLisa Mathis MD, Pediatric and Maternal Health StaffAbraham Karkowsky MD, Division of CardioRenal Drug Products

StatisticsJialu Zhang PhD, Office of BiostatisticsJim Huang PhD, Office of Biostatistics

OthersCDR Denise Hinton, Project ManagerScientists with the Anonymous Sponsor, Pharmaceutical Industry

Pravin.Jadhav@fda.hhs.gov Pediatric Drug Development 14/14