1. Overview of Pediatric Drug Development Dianne Murphy, MD Director Office of Counterterrorism and Pediatric Drug Development Center for Drug Evaluation and Research February 2, 2004 Dianne Murphy, MD Director Office of Counterterrorism and Pediatric Drug Development Center for Drug Evaluation and Research February 2, 2004

2. 2 Goals Provide condensed historical background to better understand how we arrived at the present place in pediatric drug development Provide condensed historical background to better understand how we arrived at the present place in pediatric drug development Review FDA’s Pediatric Drug Development responsibilities Review FDA’s Pediatric Drug Development responsibilities

3. 3 Acronyms FDAMA – Food and Drug Administration Modernization Act FDAMA – Food and Drug Administration Modernization Act BPCA – Best Pharmaceuticals for Children Act BPCA – Best Pharmaceuticals for Children Act PREA – Pediatric Research Equity Act PREA – Pediatric Research Equity Act WR – Written Request (FDA issues) WR – Written Request (FDA issues) PPSR – Proposed Pediatric Study Request (sponsor submits) PPSR – Proposed Pediatric Study Request (sponsor submits)

4. 4 Historical Perspective Tragedies in children lead to new laws Tragedies in children lead to new laws 1902 - Biologics Control Act 1902 - Biologics Control Act –diphtheria antitoxin contaminated with live tetanus bacilli 1938 - Food, Drug and Cosmetic Act 1938 - Food, Drug and Cosmetic Act –sulfanilamide 1962 - Amendments 1962 - Amendments –thalidomide

5. 5 BENCHMARKS Pediatric Drug Development 1977 – AAP statement concerning the need to conduct trials in children 1977 – AAP statement concerning the need to conduct trials in children 1979 – FDA requires trials in children parallel to adult process 1979 – FDA requires trials in children parallel to adult process 1994 – FDA requires sponsors to update label; introduces “extrapolations” 1994 – FDA requires sponsors to update label; introduces “extrapolations” 1997 – Congress passes FDAMA/Exclusivity Provision – “Incentives” (voluntary) 1997 – Congress passes FDAMA/Exclusivity Provision – “Incentives” (voluntary) 1998 – FDA publishes Pediatric Rule (mandatory) 1998 – FDA publishes Pediatric Rule (mandatory)

6. 6 BENCHMARKS Pediatric Drug Development (cont.) 2002 – Congress passes Best Pharmaceuticals for Children Act (BPCA) 2002 – Congress passes Best Pharmaceuticals for Children Act (BPCA) – renewed Exclusivity – provides process for “off-patent” drug development – public posting of results – reporting of all AE’s for 1 year after Exclusivity granted 2003 – Congress passes Pediatric Research Equity Act (PREA) 2003 – Congress passes Pediatric Research Equity Act (PREA) –Requires the study of drugs and biologics for pediatric population except in defined situations –Creates Pediatric Advisory Committee

7. 7 Impact of Legislation Proposals from Industry336 Proposals from Industry336 FDA-issued Written Requests283 FDA-issued Written Requests283 Exclusivity Determinations101 Exclusivity Determinations101 Exclusivity Granted91 Exclusivity Granted91 New Labels63 New Labels63

8. 8 1-Year Post-Exclusivity Reporting of Adverse Events Tamoxifen Tamoxifen Quinapril Quinapril Paroxetine Paroxetine Nefazodone Nefazodone Citalopram Citalopram Pravastatin Pravastatin Vinorelbine Vinorelbine Sertraline Sertraline Oxybutynin Oxybutynin Atorvastatin Atorvastatin Simvastatin Simvastatin Busulfan Busulfan Cetirizine Cetirizine Losartan Losartan Products

9. 9 Ethical Issues Pediatric Advisory Subcommittee Meetings have addressed: Pediatric Advisory Subcommittee Meetings have addressed: –Patients vs. subjects in pediatric trials (11/15/99) –Placebo controlled trials (9/11/00) –Vulnerable pediatric populations (4/24/01)

10. 10 Prior Peds Advisory Subcommittee Discussion 1999 November: Issues regarding a Pediatric Drug Development Program for the Treatment of Insomnia November: Issues regarding a Pediatric Drug Development Program for the Treatment of Insomnia2000 September: Pediatric Psychotropic Drug Use Issues September: Pediatric Psychotropic Drug Use Issues2001 April: Treatment of Chronic Hepatitis C in Children April: Treatment of Chronic Hepatitis C in Children2002 June: Reflux disease; GERD-Template June: Reflux disease; GERD-Template

11. 11 Prior Peds Advisory Subcommittee Discussion (cont.) 2003 March: Development of Antiretroviral Drugs in HIV-Infected and HIV-Exposed Neonates Younger than four weeks of age March: Development of Antiretroviral Drugs in HIV-Infected and HIV-Exposed Neonates Younger than four weeks of age June: Current Epidemiology and Therapeutic Interventions Relevant to Hyperbilirubinemia in the Term and Near-Term Newborn June: Current Epidemiology and Therapeutic Interventions Relevant to Hyperbilirubinemia in the Term and Near-Term Newborn October: Clinical Risk Management of HPA Axis Suppression in Children with Atopic Dermatitis being treated with Topical Corticosteroids October: Clinical Risk Management of HPA Axis Suppression in Children with Atopic Dermatitis being treated with Topical Corticosteroids Tracking Cancer Risk among Children with Atopic Dermatitis who are treated with Topical Calcineurin Inhibitors

12. 12 ONGOING LESSONS LEARNED 1-Pharmacokinetics are more variable than anticipated 2-Adverse reactions that are pediatric specific are being defined 3-Trial designs are being modified as we learn from submitted studies 4-Ethical issues have to be reassessed from the pediatric perspective

13. 13 General Principles* Pediatric patients should be given medicines that have been properly evaluated for their use in the intended population Pediatric patients should be given medicines that have been properly evaluated for their use in the intended population Product development programs should include pediatric studies when pediatric use is anticipated Product development programs should include pediatric studies when pediatric use is anticipated Pediatric development should not delay adult studies nor adult availability Pediatric development should not delay adult studies nor adult availability Shared responsibility among companies, regulatory authorities, health professionals, and society as a whole Shared responsibility among companies, regulatory authorities, health professionals, and society as a whole * from ICH E-11

14. 14 To Find out More Internet: Internet: http://www.fda.gov/cder/pediatric http://www.fda.gov/cder/pediatric Peds Line: Peds Line: (301) 594-7337 (301) 594-7337