1. Pediatric Trials Network

2. What Is The Pediatric Trials Network PTN? Sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) The primary objective of the Pediatric Trials Network: The primary objective of the Pediatric Trials Network: Create an infrastructure for investigators to conduct trials that improve pediatric labeling and child health. PTN is studying product formulation, drug dose, efficacy, safety, and device validation PTN is studying product formulation, drug dose, efficacy, safety, and device validation Evidence of success will be completed trials that improve dosing, safety information, labeling, and ultimately child health Evidence of success will be completed trials that improve dosing, safety information, labeling, and ultimately child health 2

3. Structure of PTN 3

4. Pediatric Trials Network (PTN) 2011 4

5. Protocol Title: Safety and Pharmacokinetics of Multiple Dose Metronidazole in Premature Infants Objective: Evaluate the safety, PK, and surrogate PD of intravenous metronidazole in premature infants with suspected serious infection Study Population:16 to 32 participants <32 weeks gestational age with suspected serious infection. Participants will be divided into 2 groups based on postnatal age. Study Duration: original target 18 months (finished in 12); each participant will participate in the study for up to 15 days: 2-5 days of study drug administration followed by 10 days of adverse events monitoring. Number of Sites: 3 October, 2011 Enrollment Complete Protocol: Metronidazole Protocol Chair: Cohen-Wolkowiez 5

6. Demographic Distribution: These data have not been peer-reviewed 6

7. Metronidazole Individual EBE PK Parameter Estimates by Post Natal Age Group: These data have not been peer-reviewed 7

8. Concentration vs. Time: These data have not been peer-reviewed 8

9. Clearance vs. Post Menstrual Age: These data have not been peer-reviewed 9

10. Protocol: Acyclovir Protocol Chair: Smith Protocol Title: An Open Label Study to Describe the Pharmacokinetics of Acyclovir in Premature Infants Protocol Title: An Open Label Study to Describe the Pharmacokinetics of Acyclovir in Premature Infants Objective: To evaluate the safety and PK of IV acyclovir in premature infants with suspected systemic infections. Objective: To evaluate the safety and PK of IV acyclovir in premature infants with suspected systemic infections. Study Population: 20 Infants < 45 days postnatal age, suspected to have a systemic infection divided into groups by gestational and postnatal age Study Population: 20 Infants < 45 days postnatal age, suspected to have a systemic infection divided into groups by gestational and postnatal age Study Duration: each infant will be in the study for up to 13 days; goal is to provide final component of PK data for subsequent efficacy trial Study Duration: each infant will be in the study for up to 13 days; goal is to provide final component of PK data for subsequent efficacy trial Number of Sites: 3 Number of Sites: 3 First Patient Enrolled: September 19, 2011; target March 2012 First Patient Enrolled: September 19, 2011; target March 2012 10

11. Protocol: Hydroxyurea Protocol Chair: Neville Protocol Title: PK & Relative Bioavailability of a Liquid Formulation of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia Protocol Title: PK & Relative Bioavailability of a Liquid Formulation of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia Objective: relative bioavailabilty study and bioequivalence study with new formulation Objective: relative bioavailabilty study and bioequivalence study with new formulation Study Population: 40 children ages 2-17 with sickle cell anemia or sickle beta-zero thalassemia; two-armed study with older children (bioequivalence) enrolled first Study Population: 40 children ages 2-17 with sickle cell anemia or sickle beta-zero thalassemia; two-armed study with older children (bioequivalence) enrolled first Study duration: a subset of patients in each age cohort will receive single dose and a subset will receive multiple doses Study duration: a subset of patients in each age cohort will receive single dose and a subset will receive multiple doses Number of Sites: Six Number of Sites: Six First Patient: December, 2011 First Patient: December, 2011 11

12. Protocol Title: Pharmacokinetics of Understudied Drugs Administered to Children per Standard of Care Protocol Title: Pharmacokinetics of Understudied Drugs Administered to Children per Standard of Care Objectives: Objectives: Evaluate the PK of understudied drugs currently being administered to children. Study Population: 500 children (birth-20 years) who are receiving understudied drugs of interest per standard of care as prescribed by their treating caregiver Study Population: 500 children (birth-20 years) who are receiving understudied drugs of interest per standard of care as prescribed by their treating caregiver Study Duration: each child will participate in the study for up to 90 days per drug; study conduct for 3 years Study Duration: each child will participate in the study for up to 90 days per drug; study conduct for 3 years Number of Sites: 15 Number of Sites: 15 First Patient Enrolled: November, 2011 First Patient Enrolled: November, 2011 Protocol: POPS Pediatric Opportunistic PK Study 12

13. Protocol: Lisinopril Protocol Chair: Trachtman Protocol Title: Safety and Pharmacokinetics of Lisinopril in Pediatric Kidney Transplant Recipients Protocol Title: Safety and Pharmacokinetics of Lisinopril in Pediatric Kidney Transplant Recipients Objective: initial description of the PK-PD and safety of lisinopril following transplantation Objective: initial description of the PK-PD and safety of lisinopril following transplantation Study population: 24 children ages 2-18 with kidney transplant and stable allograft function Study population: 24 children ages 2-18 with kidney transplant and stable allograft function Study participation: Up to 51 days; enrolled children will receive multiple doses with multiple assessments for potential endpoints for subsequent efficacy trial Study participation: Up to 51 days; enrolled children will receive multiple doses with multiple assessments for potential endpoints for subsequent efficacy trial Number of Sites: 8 Number of Sites: 8 Target to Enroll First Patient: January 2012 Target to Enroll First Patient: January 2012 13

14. Protocol: TAPE Protocol Chair: Rahman 14 Protocol Title: Taking the Guesswork out of Pediatric Weight Estimation (TAPE): Validation of the Mercy TAPE Protocol Title: Taking the Guesswork out of Pediatric Weight Estimation (TAPE): Validation of the Mercy TAPE Objective: device trial to provide more accurate, rapid estimation of weight in the acute care setting—e.g., use in emergency setting or resource poor countries for quick dosing calculations Objective: device trial to provide more accurate, rapid estimation of weight in the acute care setting—e.g., use in emergency setting or resource poor countries for quick dosing calculations Study population: 625 children 2months to 16 years old enrolled into 17 strata Study population: 625 children 2months to 16 years old enrolled into 17 strata Protocol Final and target first enrollment January 2012 Protocol Final and target first enrollment January 2012

15. Other Task Orders 15 Midazolam Midazolam Analysis of previously collected data Analysis of previously collected data Provide supplemental data to support of the current prescription labeling to include the treatment of seizures Provide supplemental data to support of the current prescription labeling to include the treatment of seizures Ampicillin Ampicillin Original written request, PK study and efficacy study in infants Original written request, PK study and efficacy study in infants PPRU (Pediatric Pharmacology Research Unit) collected samples PPRU (Pediatric Pharmacology Research Unit) collected samples Obesity Obesity Analysis to provide preliminary data and hand held application for dosing in obese children Analysis to provide preliminary data and hand held application for dosing in obese children

16. Lessons Learned Main Contract Timelines Meropenem RFP NIH-NICHD-2005-18 released August 2005, submitted October 2005 Meropenem RFP NIH-NICHD-2005-18 released August 2005, submitted October 2005 Signed September 2007 (24 months) Signed September 2007 (24 months) Protocol in written as part of application; IND granted March 2008 (31 months) Protocol in written as part of application; IND granted March 2008 (31 months) Site contracts, IRB, investigators meeting Site contracts, IRB, investigators meeting First patient June 2008 First patient June 2008 200 infants; last infant enrolled September 2009 200 infants; last infant enrolled September 2009 16

17. Lessons Learned Main Contract Timelines Meropenem RFP release to signature 24 months Meropenem RFP release to signature 24 months IND 31 months IND 31 months First patient 34 months First patient 34 months Last infant 48 months Last infant 48 months Clinical Study Report 60 months from RFP release Clinical Study Report 60 months from RFP release Pediatric Trials Network RFP 3/2010, signature 6 months Pediatric Trials Network RFP 3/2010, signature 6 months IND 7 months IND 7 months First patient 9 months First patient 9 months Last patient 18 months Last patient 18 months Clinical study report 22 months (anticipated) Clinical study report 22 months (anticipated) 17

18. Differences in timelines IRB vs. Contracts IRB vs. Contracts Single entity of PTN mitigates Single entity of PTN mitigates Risk to NIH Risk to NIH Risk to investigators Risk to investigators Contracts with sites Contracts with sites Opportunistic study Opportunistic study Contracts with vendors Contracts with vendors 18

19. Comparison of output and efficiency Legacy Trials vs PTN Legacy Trials Timeline 8 years Legacy Trials Timeline 8 years PTN 12–18 months PTN 12–18 months Similar number of patients Similar number of patients PTN more INDs PTN more INDs By 24 months: studies enrolling more patients, in more sites, under more INDs By 24 months: studies enrolling more patients, in more sites, under more INDs Detailed Comparison 19

20. Pricing differential Per patient pricing reduced 30–50% Per patient pricing reduced 30–50% Faculty (thought leadership) Faculty (thought leadership) Winning a grant, conduct of the grant Winning a grant, conduct of the grant Junior faculty Junior faculty K23 awardees and young investigators K23 awardees and young investigators Operations (staff) efficiency Operations (staff) efficiency 20

21. Pediatric Trials Network (PTN) 2012 tentative 21

22. How Do I Participate in the PTN? The POPS study: The POPS study: children interact with the health care system (e.g., admitted to the PICU or seen in the ER) children interact with the health care system (e.g., admitted to the PICU or seen in the ER) on a prioritized off-patent therapeutic that has insufficient dosing information in their clinical stratum on a prioritized off-patent therapeutic that has insufficient dosing information in their clinical stratum age-based: e.g., premature neonates acuity based: e.g., resuscitation meds clinical-based: e.g., ethnicity, obesity ask for consent to take blood at pre-specified times based on dosing interval (Q4 vs. Q24) ask for consent to take blood at pre-specified times based on dosing interval (Q4 vs. Q24) 22

23. PTN and POPS Continued 15 or more therapeutics bundled into one protocol 15 or more therapeutics bundled into one protocol Samples stored locally and sent in batch Samples stored locally and sent in batch Flexibility to add molecules Flexibility to add molecules Provide preliminary and supportive data for subsequent trials Provide preliminary and supportive data for subsequent trials Compare to epi-data Compare to epi-data Metronidazole example Metronidazole example Provide a testing ground for sites—enrollment Provide a testing ground for sites—enrollment Facilitate contracts and infrastructure—enrollment in between more traditional trials Facilitate contracts and infrastructure—enrollment in between more traditional trials 23

24. Contacting the PTN for the POPS trial POPS Protocol Chair: Micky Cohen-Wolkowiez michael.cohenwolkowiez@duke.edu POPS Protocol Chair: Micky Cohen-Wolkowiez michael.cohenwolkowiez@duke.edu michael.cohenwolkowiez@duke.edu POPS project lead: Barrie Harper barrie.harper@duke.edu POPS project lead: Barrie Harper barrie.harper@duke.edu barrie.harper@duke.edu www.pediatrictrials.org www.pediatrictrials.org www.pediatrictrials.org 24

25. Limits of the mechanism Opportunistic PK and PK-PD Safety Efficacy 25