Joga\'s talk at ASCPT 2010, Atlanta.

1. How to Double Success
Rate of Pediatric Trials?
Simulate2Design
Joga Gobburu
Model4Approval
Division of Pharmacometrics
Office of Clinical Pharmacology
Office of Translational Sciences,
CDER/FDA
1
jogarao.gobburu@fda.hhs.gov

2. Model4Approval
How to Double Success
Rate of Pediatric Trials?
Joga Gobburu
Simulate2Design
Division of Pharmacometrics
Office of Clinical Pharmacology
Office of Translational Sciences,
CDER/FDA
2
jogarao.gobburu@fda.hhs.gov

3. Learn-Apply Approach to
Pediatric Drug Development
Power PK Study (20% SE)
Sample size, Sampling
Simulate2Design Power Registration study
Dose range selection,
Endpoints, Analyses
Exposure-response to
Model4Approval Support
Approval & Dosing
3
Gobburu, Pediatric advisory committee meeting, 2009
Liu, Oncology advisory committee meeting, 2010

4. Pediatric Exclusivity Program
400
350
360 Statistics
WR
Labeling
300
250 Good improvement in pediatric
200
159 information available after 2002. Next
150
100
phase is to ‘learn-apply’ this experience
50 to further improve quality of ped trials
0
Pediatric Submissions (N) Age range
100
No S/E
New Safety
80
Dosing
Ped Formulation
60 Extemporaneous
Safety reporting
40
20
0 4
Labeling Changes (N of 159)

5. 50% of Late Trials Fail
5
Source: N Singh, McKinsey

6. 50% Trials Fail –
Even for Pediatrics
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7. FDA Pharmacometrics 2020: Strategic Goals
Train 20 Pharmacometricians International Harmonization
-Technical track
-Share expertise between global
-Disease track
regulatory bodies
-Drug development track
Implement 15 Standard Templates Integrated Quantitative CP Summary
-Develop disease specific data, -All NDAs should have exposure-
analysis standards response analyses
-Expect industry to follow
Design by Simulation: 100% Pediatric Studies
Develop 5 Disease Models
-Create public disease model library -Leverage prior knowledge to design
Pediatrics Written Request trials
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8. Learn-Apply
• ‘Learning’ is the process of transforming information
(here clinical trial data) into generalizable knowledge.
• ‘Applying’ is the process of utilizing the knowledge to
make a decision.
– Confirmation of effectiveness is one of such
decisions, not the sole.
– Others include dose selection, understanding time-
course of drug effects, biomarker-outcome
relationships, etc.
– According to this principle, at the end of each trial
scientists must learn what worked and what did not.
• Learn-apply paradigm must become part of the critical
path process. 8
Gobburu, ASCPT, Meet the Experts, 2008

9. Learn-Apply Approach to
Model4Approval
Pediatric Drug Development
Protocol
Simulate2Design
Trial
Quantitative
Data
drug-disease-trial
model
Adults, peds
9

10. Quantitative Clinical
Pharmacology can Lead the
Improvement of Pediatric
Programs
10

11. Learn-Apply Approach to
Pediatric Drug Development
Power PK Study (20% SE)
Sample size, Sampling
Simulate2Design Power Registration study
Dose range selection,
Endpoints, Analyses
Exposure-response to
Model4Approval Support
Approval & Dosing
11
Gobburu, Pediatric advisory committee meeting, 2009
Liu, Oncology advisory committee meeting, 2010

12. Model4Approval
References
• Bhattaram VA, Bonapace C, Chilukuri DM, Duan JZ, Garnett C, Gobburu JV, Jang SH,
Kenna L, Lesko LJ, Madabushi R, Men Y, Powell JR, Qiu W, Ramchandani RP, Tornoe CW,
Wang Y and Zheng JJ (2007) Impact of pharmacometric reviews on new drug approval and
labeling decisions--a survey of 31 new drug applications submitted between 2005 and 2006.
Clin Pharmacol Ther 81:213-221.
• Booth BP, Rahman A, Dagher R, Griebel D, Lennon S, Fuller D, Sahajwalla C, Mehta M and
Gobburu JV (2007) Population pharmacokinetic-based dosing of intravenous busulfan in
pediatric patients. J Clin Pharmacol 47:101-111.
• Gobburu JV and Lesko LJ (2009) Quantitative disease, drug, and trial models. Annu Rev
Pharmacol Toxicol 49:291-301.
• Jadhav PR, Burckart G.J., Lesko LJ and Gobburu JV (2010b) Paediatric Drug Development
and Clinical Pharmacology. Drug Development In press.
• Jadhav PR, Zhang J and Gobburu JV (2009) Leveraging prior quantitative knowledge in
Simulate2Design
guiding pediatric drug development: a case study. Pharm Stat 8:216-224.
• Li F, Nandy P, Chien S, Noel GJ, and Tornoe CW (2009) Pharmacometrics-based dose
selection of levofloxacin as a treatment for post-exposure inhalational anthrax in children
Antimicrobial Agents and Chemotherapy doi:10.1128/ACC.00667-09:1-21.
• Madabushi R, Cox D, Hossain M, Boyle DA, Patel BR, Young G and Choi YM (2010)
Pharmacokinetic and pharmacodynamic basis for effective argatroban dosing in pediatrics.
Journal of pediatrics In press.
• Tornoe CW, Tworzyanski JJ, Imoisili MA, Alexander JJ, Korth-Bradley JM and Gobburu JV
(2007) Optimising piperacillin/tazobactam dosing in paediatrics. Int J Antimicrob Agents
30:320-324.
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13. Acknowledgements
• Pediatric Working Group – OCP
• Pravin Jadhav, Gil Burckart, Raj
Madabushi
• Division of Pharmacometrics
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jogarao.gobburu@fda.hhs.gov

14. Interested in Fellowship?
• If you are interested in a fellowship with
the Division of Pharmacometrics,
OCP/OTS/CDER/FDA please send your
resume to:
• Jeffrey J. Tworzyanski, Pharm.D.
CDR, U.S. Public Health Service
OTS/OCP/Pharmacometrics
U.S. Food and Drug Administration
Center for Drug Evaluation and Research
E-mail: jeffrey.tworzyanski@fda.hhs.gov
Telephone: (301) 796-1617
FAX: (301) 847-8720
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