11/29/2011 JadhavP 2011- EMA Workshop 1

Impact of Pharmacometric Analysis on Drug Approvals and Therapeutics

Pravin R JadhavTeam Leader, Division of PharmacometricsOffice of Clinical PharmacologyCDER, FDA

The opinions expressed in this presentation do not represent official FDA policy

11/29/2011 JadhavP 2011- EMA Workshop 2

Today’s ObjectivesToday’s Objectives

1. Highlight Growth of Pharmacometricsat FDA

1. Highlight Growth of Pharmacometricsat FDA

2. Describe Scope of Pharmacometricsat FDA

2. Describe Scope of Pharmacometricsat FDA

3. Discuss Impact on Drug Developmentand Therapeutics

3. Discuss Impact on Drug Developmentand Therapeutics

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What is Pharmacometrics?What is Pharmacometrics?Decisions• Go/No-go, trial design• Approval, Label, Policy • Personalized medicine

DecisionsDecisions•• Go/NoGo/No--go, trial designgo, trial design•• Approval, Label, Approval, Label, PolicyPolicy•• Personalized Personalized medicinemedicine

Analysis• Quantitative disease- drug-trial modeling • Simulations

AnalysisAnalysis•• Quantitative diseaseQuantitative disease-- drugdrug--trial modelingtrial modeling•• SimulationsSimulations

InformationInformation•• Data collected in trials Data collected in trials and studies.and studies.•• Domain expertiseDomain expertise

Pharmacometrics is the science of quantifying disease, drug and trial characteristics with the goal to influence drug development, regulatory and h i d i i

P’Metrics

Boceprevir

Topiramate

Scope

Guidance

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10- fold Increase in Demand10- fold Increase in Demand

<2000 2001-022003-04

2005-06

2007-08

2008-09

2009-10

0

20

40

60

80

100

120

140

160To

tal #

IND

/ND

A/B

LAP’Metrics

Boceprevir

Topiramate

Scope

Guidance

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FDA Pharmacometrics: Return on Investment FDA Pharmacometrics: Return on Investment

P’Metrics

Boceprevir

Topiramate

Scope

Guidance

http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm167032.htmBased on 2007-08 reviews

<1 Month30%

1-6 Months45%

>6 Months25%

Approved DoseApproved Dose

SafetySafety

18%

64%

18%

40%45%

15%

Evidence of Evidence of EffectivenessEffectiveness

30%55%

15%

<1 Month

<1 Month

<100 patients100-400 patients

>400 patients

1-6 Months

>6 Months

1-6 Months

>6 Months

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Several Guidance Documents Illustrate Application of Modeling and Simulation Several Guidance Documents Illustrate Application of Modeling and Simulation

P’Metrics

Guidance

Boceprevir

Topiramate

Scope

Population PharmacokineticsExposure-Response

Evidence of EffectivenessCombination Drugs

Hepatitis C Drug DevDrug-Drug Interaction

Diabetes Drug Dev

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Pharmacometrics ScopePharmacometrics Scope

Scope

Boceprevir

Topiramate

P'Metrics

Guidance

Review Research

IND/NDA/BLAIRT-QT

Knowledge ManagementPolicy

Operations

Disease Model Guidance

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Pivotal Role in Pediatric Applications

Case Study: Topiramate

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Model Based Extrapolation for All Monotherapy Approvals for Treatment of Epilepsy Model Based Extrapolation for All Monotherapy Approvals for Treatment of Epilepsy

Topiramate

Boceprevir

P'Metrics

Guidance

Scope

Empirical Empirical

? Empirical

Adults

Peds

Monotherapy Adjunct

Is Exposure-Response Similar in Adults?

Extrapolate Adjunct Therapy to Monotherapy

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Topiramate Dosing Regimen was Derived by Matching Steady State Trough Concentrations (CMIN) for Different Age Groups Topiramate Dosing Regimen was Derived by Matching Steady State Trough Concentrations (CMIN) for Different Age Groups

Topiramate

Boceprevir

P'Metrics

Guidance

Scope

4

6

8

10

12

14

16

18

20

6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Median Adult Cmin

Median Pediatric (6-9 years) Cmin

Dose(mg/kg/day)

Cm

in (

mcg

/ml)

BWT - 2 yearsBWT - 4 yearsBWT - 6 yearsBWT - 8 yearsBWT - 10 years

Pharmacokinetic Modeling and Simulation Based Approval

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Pivotal Role in Dosing Recommendations After Pivotal Trials Are Completed

Case Study: Boceprevir

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Null Responders were Excluded from Pivotal Trials but Pharmacometrics Bridging Approach Filled the Gap Null Responders were Excluded from Pivotal Trials but Pharmacometrics Bridging Approach Filled the Gap

SPRINT-2(Untreated)

P/R

P/R

B32+P/R (RGT)

P/R – PegInterferon/Ribavirin

B44+P/R

B24+P/R (RGT)

B44+P/R

RESPOND-2(Treated)

ALLPreviously P/R

TreatedInformed from

SPRINT-2

Evidence of EffectivenessAnd Dosing

Dosing InformationDosing

For subgroupsInformed from

RESPOND-2

Pivotal Trials Approval

http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/ucm254073.htm

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Null Responders can be identified based on Week 4 P/R response (<0.5 or <1 log decline) in untreated subjects Null Responders can be identified based on Week 4 P/R response (<0.5 or <1 log decline) in untreated subjects

Guidance

Scope

Boceprevir

`Topiramate

P'Metrics

Responders38%

Relapsers11%

Partial Responders

20%

Null20%

d/c12%

Responder

Relapser

Partial

Null

SOC outcome in untreated subjects

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Higher SVR in Subjects with <0.5 or <1 log Week 4 P/R response with Boceprevir Compared to P/R Treatment Higher SVR in Subjects with <0.5 or <1 log Week 4 P/R response with Boceprevir Compared to P/R Treatment

Guidance

Scope

Boceprevir

`Topiramate

P'Metrics

• <1.0 log10 decline includes subjects who are not null responders and may over estimate SVR

• <0.5 log10 decline includes predominantly null responders and provides a more conservative estimate for SVR

(Untreated Subjects)(Untreated Subjects)

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Business and Public Health ImpactBusiness and Public Health Impact

Guidance

Scope

Boceprevir

`Topiramate

P'Metrics • Evidence of Effectiveness for Prior Null Responders– Estimated Sample Size for New Study

200-300 patients studied over 72 weeks

• Dosing Recommendations for Untreated Late Responders– Impact on Healthcare Cost

12 weeks of less therapy that costs $1100/week

These estimates are derived after regulatory review and were not considered during the review. The review focus was to scientifically justify the regulatory decision.

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Summary Impact on Drug Development and Therapeutics Summary Impact on Drug Development and Therapeutics

Identified an exploratory subgroup potentially lacking benefit Asked for new study

Treatment of SEGA Pivotal Exposure-Response for evidence of effectiveness and TDM justification

Concentration-QT analysis predicted QT effects at 40 mg/day to limit the dose

http://www.fda.gov/Drugs/DrugSafety/ucm269086.htm

Derived and recommended Pediatric Dosing Recommendations without any empirical data

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Summary Impact on Drug Development and Therapeutics Summary Impact on Drug Development and Therapeutics• Increased Demand for Pharmacometrics at

FDA• Several Pharmacometrics Applications in

Review, Research, Official Guidance and Policy

• Pharmacometrics at FDA Plays Pivotal Role in Approval and Labeling

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BACK UP

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Return on Investment – Drug Approval and Labeling Return on Investment – Drug Approval and Labeling

0

10

20

30

40

50

60

70

80

<2000 2001-02 2003-04 2005-06 2007-08

Num

ber o

f Rev

iew

s

Approval

Labeling

Impact on Approval-ER analysis provided supportive or pivotal evidence of effectiveness.Impact on labeling-ER analysis supported D&A, Warnings, Intrinsic/Extrinsic factors sections

P’Metrics

Boceprevir

Topiramate

Scope

Guidance