1. February 2, 2004 Pediatric Drug Development: A Decade of Progress: 1994-2004 Susan K. Cummins, MD, MPH Medical Team Leader Division of Pediatric Drug Development Center for Drug Evaluation and Research

2. Today’s Talk Review legal milestones of the last decade Review legal milestones of the last decade · 1994 Pediatric Rule · 1997 FDAMA · 2002 BPCA · 2003 PREA Review Written Request Process Review Written Request Process Discuss statistics, goals & available resources Discuss statistics, goals & available resources

3. Acronyms FDAMA – Food & Drug Admin Modernization Act FDAMA – Food & Drug Admin 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 WR – Written Request PPSR – Proposed Pediatric Study Request PPSR – Proposed Pediatric Study Request

4. 1994 Pediatric Regulations Required sponsor review of available pediatric data to determine whether existing data was adequate to support pediatric labeling Required sponsor review of available pediatric data to determine whether existing data was adequate to support pediatric labeling No clinical studies required No clinical studies required Introduced concept of extrapolation of efficacy data from adults to children Introduced concept of extrapolation of efficacy data from adults to children

5. 1997 FDAMA Pediatric Provisions Created pediatric exclusivity incentives based on Written Request from FDA Created pediatric exclusivity incentives based on Written Request from FDA Sunset on January 1, 2002 Sunset on January 1, 2002

6. What is “Pediatric Exclusivity”? An additional 6-month period during which a sponsor retains exclusive marketing control of all forms of a drug product line An additional 6-month period during which a sponsor retains exclusive marketing control of all forms of a drug product line Requires either an existing patent or existing exclusivity Requires either an existing patent or existing exclusivity Confers to the entire moiety Confers to the entire moiety Substantial financial incentive Substantial financial incentive Delays introduction of generic products Delays introduction of generic products

7. FDAMA “Priority List” Issued by FDA Issued by FDA Being on the priority list did not require a WR to be issued Being on the priority list did not require a WR to be issued Sunset on January 1, 2002 Sunset on January 1, 2002

8. 2002 Best Pharmaceuticals for Children Act Became law January 4, 2002 Became law January 4, 2002 Re-authorizes exclusivity incentive program under FDAMA Re-authorizes exclusivity incentive program under FDAMA Includes an additional mechanism for obtaining information on safe and efficacious use of drugs in pediatric populations for off-patent drugs Includes an additional mechanism for obtaining information on safe and efficacious use of drugs in pediatric populations for off-patent drugs

9. Best Pharmaceuticals for Children Act Establishes a process for studying both “off- patent” and “on-patent” drugs Establishes a process for studying both “off- patent” and “on-patent” drugs Mandates that FDA and NIH collaborate in the study of “off-patent” and “on-patent” drugs that industry does not want to study Mandates that FDA and NIH collaborate in the study of “off-patent” and “on-patent” drugs that industry does not want to study

10. Two Paths to a Written Request FDA generates and issues a WR FDA generates and issues a WR PPSR sent to FDA by industry PPSR sent to FDA by industry · FDA accepts proposal and issues WR · FDA modifies proposal and issues WR · FDA does not accept proposal and issues inadequate letter

11. Written Request A (legal) document sent by the FDA to sponsors requesting studies in the pediatric population A (legal) document sent by the FDA to sponsors requesting studies in the pediatric population Specifies: Specifies: · indication · population · type of studies · safety parameters · longer term follow-up · timeframe for response

12. Process for the Study of On-Patent Drugs under BPCA FDA issues Written Request Industry submits Proposed Pediatric Study Request FDA determines if there is a public health benefit yes no FDA issues Inadequate Letter

13. Process for the Study of On-Patent Drugs under BPCA (cont.) FDA issues Written Request Industry agrees to conduct studies Industry declines to conduct studies Possible Referral to Foundation for NIH Industry has 180 days to respond yes no

14. Process for the Study of On-Patent Drugs under BPCA (cont.) Referral to Foundation for NIH Foundation conducts studies Foundation lacks funds to conduct studies WR referred to NIH for inclusion on List

15. FDA On-Patent Drug Exclusivity Process Background Research/Extensive Literature Review Sponsor Sponsor Proposed PediatricDevelopment of Written Request Study Request (PPSR)by Reviewing Division Proposed PediatricDevelopment of Written Request Study Request (PPSR)by Reviewing Division Reviewed by PdIT FDA WR Issued FDA WR Issued Sponsor Completes Studies Sponsor Completes Studies or FDAExclusivity Determined by or FDAExclusivity Determined by Exclusivity Board (60-90 days) Action on Application (6-10 months) – includes label negotiations with sponsor

16. Progress: Industry Response as of January 2004 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

17. 2003 Pediatric Research Equity Act Became law December 3, 2003 Became law December 3, 2003 Legislation mimics Pediatric Rule Legislation mimics Pediatric Rule Retroactive for all applications back to April 1, 1999 Retroactive for all applications back to April 1, 1999

18. Pediatric Research Equity Act Requires pediatric studies of certain drugs & biological products Requires pediatric studies of certain drugs & biological products · New indication · New dosage form · New route · New dosing regimen · New active ingredient FDA Guidance under development FDA Guidance under development Establishes Pediatric Advisory Committee Establishes Pediatric Advisory Committee

19. Goal On-Patent Exclusivity Process and and Off-Patent BPCA Process New Pediatric Information in Label

20. FDA Web Page Link to Peds page www.fda.gov

21. Pediatric Web Page