1. PEDIATRIC TRIALS NETWORK March 27, 2014 A project of the Best Pharmaceuticals for Children Act

2. Why are studies in children difficult? Limited number of patients with the disease No “healthy child/baby volunteer” Low rates of parental informed consent Perceived study risks Limited blood volume and timed sampling Sick population – increases variability Lack of clinical pharmacology expertise Lack of pediatric PK/PD modeling expertise

3. How Did The PTN Start? “Create an infrastructure for investigators to conduct trials that improve pediatric labeling and child health.” –Sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) –Network for studying drug product formulation, age-appropriate drug dosing, efficacy, safety, and device validation –Success: Completed trials that improve dosing, safety information, labeling, and ultimately child health

4. Pediatric Trials Network PI: Benjamin Since 2010, ~25 ongoing projects, 12 clinical trials Phase 1 and 2 studies All therapeutic areas 5 CSRs submitted to FDA 4-6 potential label changes Training of fellows/junior faculty

5. PTN Structure

6. PTN Administrative Core NameRoleCenter Daniel Benjamin, MD, PhdNetwork PIDuke University, Durham, NC Gregory Kearns, Pharm D, PhDChair, Clin. Pharmacology CoreChildren's Mercy Hospital &Clinics, Kansas City, MO Edmund Capparelli, Pharm DChair, Pharmacometrics CoreUC San Diego, San Diego, CA Andrew Muelenaer, MDChair, Devices CoreVirginia Tech Carilion School of Medicine, Roanoke, VA John van den Anker, MD, PhDCo-Chair, Mentorship CoreGWU School of medicine & Health Science, Washington, DC Kelly Wade, MD, PhDCo-Chair, Safety & Ethics CoreChildren's Hospital of Philadelphia, Philadelphia, PA Michael O'Shea, MDCo-Chair Devices CoreWake Forest University Medical Center, Winston-Salem, NC P. Brian Smith, MDNetwork Co-InvestigatorDuke University, Durham, NC Michael Cohen-Wolkoweiz, MD, PhDNetwork Co-InvestigatorDuke University, Durham, NC Matthew Laughon, MDAdministrative CoreUNC Memorial Hospital, Chapel Hill, NC Ian Paul, MDAdministrative CorePenn State College of Medicine, Hershey, PA Anne Zajicek, MD, PharmDBranch ChiefNIH/NICHD, Bethesda, MD David Siegel, MDNICHD COTRNIH/NICHD, Bethesda, MD Perdita Taylor-Zapata, MDNICHD COTRNIH/NICHD, Bethesda, MD Ravinder Anand, PhDDCC PIThe Emmes Corporation, Rockville, MD Traci Clemons, PhDDCC Co-PIThe Emmes Corporation, Rockville, MD

7. PTN Fellows FellowSpecialtyTO#Skill (PK/operations) Daniela TestoniNeonatologyfluconazole, Pediatrix, POPSOperations/PK Julie AutmizguineIDSCAMP, staph-trio, POPSOperations/PK Daniel GonzalezPharmacologylorazepam, staph-trioOperations/PK Lawrence KuNeonatologybpd, SCAMPOperations/PK Susi HuppCritical CaremethadoneOperations Jessica EricksonIDclinda obesityOperations Yamini VirkudAllergysildenafilOperations Kanecia ZimmermanCritical Carepantoprazole, POPSOperations Christoph HornikCardiologyPediatrix, ampicillin, obesity databaseBiostatistics, Operations Mario SampsonPharmacologymetronidazole, acyclovirOperations/PK Margreet Van GinkelClinical Researchobesity databaseOperations Kristian BeckerClinical Researchobesity databaseOperations

8. Pediatric Trials Network

9. PTN Site Participation 255 investigators at 138 sites expressed interest in participating Anticipate ~60 sites actively enrolling in trials conducted in 2014 Growth of the “rapid start network”, a pediatric clinical trial consortium affiliated with PTN to a total of approximately 100 sites

10. PTN Update Metronidazole: 3 sites, 24 premature infants at risk for NEC. Protocol chair: Michael Cohen-Wolkowiez. Enrollment and analysis complete, CSR submitted to FDA, published in PIDJ Acyclovir: 3 sites, 32 preterm and term infants with suspected HSV. Protocol chair: Brian Smith. Enrollment and analysis complete, CSR submitted to FDA, published in PIDJ TAPE weight estimate device: 3 sites, 625 children. Protocol chair: Sue Rahman, Children’s Mercy Hospital, Kansas City, MO. Enrollment and analysis complete. CSR submitted to FDA, published Ann of Emer Med Hydroxyurea: 6 sites, 40 children. Protocol chair: Kathleen Neville, Children’s Mercy Hospital, Kansas City, MO. Enrollment and analysis complete. CSR submitted to FDA Opportunistic (POPS I and POPD II): 36sites, 1200 children. Protocol chair: Michael Cohen-Wolkowiez. Enrollment ongoing (>1000 enrolled to date) Lisinopril PK: 8 sites, 24 children with kidney transplants and HTN. Protocol chair: Howard Trachtman, NYU Langone Medical Center. Enrollment complete. Analysis ongoing

11. PTN Update Midazolam meta-analysis: Support change of current midazolam labeling to include the treatment of seizures in children ages 2 years and older using existing PK and safety data. Protocol chair: Brian Smith. Analysis in progress. Ampicillin meta-analysis: PK analysis in combination with 2 retrospective cohort studies of infants with sepsis and/or meningitis. 1 site, 64 infants. Protocol chair: Michael Cohen- Wolkowiez. Data collection and analysis complete, CSR submitted to FDA. PAS poster. Obesity informatics: Literature search to create a database with published PK studies for the NIH Priority Drug List relevant to pediatric obesity. Protocol chair: Kevin Watt. Literature review complete. PAS poster. Staph microtrials: 9 sites, 96 infants, 3 anti-staph drugs. Protocol chair: Matt Laughon, UNC. Enrollment ongoing. Sildenafil: 5 sites, up to 24 infants with pulmonary arterial hypertension or lung disease. Protocol chair: Matt Laughon, UNC. Enrollment ongoing. Clindamycin obesity: 6 sites, up to 32 children. Safety/PK study of multiple-dose IV and oral clindamycin in obese children. Protocol chair: Janice Sullivan, University of Louisville, KY. Enrollment ongoing. Federated IRB.

12. PTN Update Methadone PICU: 4 sites, up to 36 patients. Protocol chair: Kevin Watt. Enrollment ongoing. Diuretics in NICU: retrospective review: 2 sites, 700 pts. Protocol Chair: Matt Laughon, UNC. Data collection ongoing. Piperacillin-tazobactam, clindamycin, metronidazole, ampicillin safety in infants with complicated intraabdominal infections (SCAMP): 50 sites, 374 subjects, Protocol Chair: Michael Cohen-Wolkowiez. Site start up Pantoprazole obesity: 3 sites and 60 children. Study to determine effect of obesity on the PK/PD of pantoprazole in children. Protocol chair: Greg Kearns, Children’s Mercy Hospital, Kansas City, MO. Site start up. Pediatrix meta-analysis of safety of 11 drugs: Retrospective data analysis; database to include >300 sites and >800,000 infants and data from FDA. Protocol chair: Brian Smith. Data analysis. Fluconazole safety meta-analysis: 33 sites, 361 infants enrolled in an earlier RCT. Protocol chair: Brian Smith. Data analysis.

13. PTN Resources How to get involved: https://pediatrictrials.org/how-to-get-involved How to develop a concept sheet: https://pediatrictrials.org/how-to-get-involved/for- healthcare-professionals