2. Initiatives Drive Pediatric Drug Development January 30, 2002

3. “OFF-LABEL” USE There is inadequate information regarding pediatric use of about 3/4 of prescription medications. Gilman, Gal: Clinical Pharmacokinetics, 1992

4. Labeling Requirement[44FR, 6/26/79] Statements on pediatric use of a drug for an INDICATION approved for adults must be based on substantial evidence derived from adequate and well-controlled studies, unless the requirement is waived.

5. 1994 Pediatric Rule Applied to approved drugs and biologics A pediatric indication may be based on adequate and well-controlled trials in adults, with other information supporting pediatric use, e.g., pK and safety data When? If the course of the disease and the effects of the drug, both beneficial and adverse, are sufficiently similar in the pediatric and adult populations, it may be permissible to extrapolate the adult efficacy data to pediatric patients.

6. Major Initiatives FDAMA –signed 11/21/97 –sunset 1/01/02 Pediatric Rule –final published 12/02/98 Best Pharmaceutical Act for Children –signed 1/04/02 –renews pediatric exclusivity –addresses off patent drugs

7. FDAMA - Sec. 111 505A(c) Market Exclusivity for already marketed drugs “If the secretary makes a written request to the holder of an approved application under Section 505(b)(1) for pediatric studies…” 6 months of exclusivity is added to the existing patent or exclusivity period

8. Response to Pediatric Exclusivity As of 1/01/02 Proposals from sponsor 293 FDA issued written request for 237 Number of products with submitted pediatric studies56 Number of products granted pediatric exclusivity49 Number of products with new labeling28

9. Types of Studies Requested As of 1/1/02 (under FDAMA) WRITTEN REQUESTS ISSUED: 237 Efficacy/Safety: 194 (35%) PK/Safety: 165 (29%) PK/PD: 56 (10%) Safety: 97 (17%) Other: 49 (9%) TOTAL STUDIES: 561

10. Health Impact of New Labels (1/01/02) Number of products granted pediatric exclusivity49 Number of products with new labeling 28 –Number of significant changes for dosing or risk 9 –Extending age and safety profile 18 –Safety and effectiveness not established 1

11. Significant label changes Midazolam Propofol Sevoflurane Fluvoxamine Gabapentin Etodolac Bethamethasone Ribavirin/Intron A Pimecrolimus

12. Major Initiatives FDAMA –signed 11/21/97 –sunset 1/01/02 Pediatric Rule –final published 12/02/98 Best Pharmaceutical Act for Children –signed 1/04/02 –renews pediatric exclusivity –addresses off patent drugs

13. 1998 Final Rule Requires pediatric studies for certain new and marketed drugs and biological products Became effective April 1, 1999 Compliance date - December 2, 2000 –Earliest date the agency could require submission of the pediatric studies –Applications being submitted need to comply with the Rule, i.e., studies completed, deferred, and/or waived

14. Deferred Submission of Studies Approval of a new drug is ready for adult use before pediatric studies are completed Additional safety or effectiveness information is needed in adults

15. Pediatric Studies are Waived if Do not meet criteria for “meaningful therapeutic benefit” AND “substantial use” Applicant shows studies are impossible or impractical Product is unsafe or ineffective in pediatrics Reasonable efforts to develop a formulation (if one is needed) have failed

16. Important Points of the Rule Does not delay approval for adult indication(s) Limits requirement to indication(s) under review or in development Promotes early consideration of pediatric use and drug development plans

17. 1998 Final Rule 4/99-6/01+ Products Approved since 4/99 41 * –(with Pediatric Studies) Deferred 178 Waived 241 *12 of these also granted exclusivity + 288 submitted thus far

18. Final Rule vs. FDAMA Studies are required Evaluate the need for pediatric information on only the drug product and indication currently being reviewed or to be submitted Studies are voluntary Evaluate the need for pediatric information on the active moiety Incentive only exists when there is underlying exclusivity or patent protection

19. Best Pharmaceuticals for Children Act Signed into Law 1/04/02 Pediatric exclusivity renewed Pediatric supplements to be handled as a 6 month priority review Sponsor required to submit with IND a statement about intent to study pediatric population

20. Off Patent Drugs NIH in consultation with FDA and pediatric research experts, shall develop, prioritize and publish a list of off-patent drugs that need study in pediatrics population FDA issues WR to innovator and generics If innovator and holder of generic applications decline, the WR referred to NIH for development of RFP

21. Off Patent Drugs (continued) Report of study including all data generated from the study submitted to NIH and FDA Each report submitted will be in the public domain and assigned a docket number Review and action within 180 days and findings published in Federal Register

22. Labeling Labeling available for both approvable and approved applications at time of action. If labeling remains the only issue, referral to Pediatric Advisory Subcommittee Summary to be published on web at time of action. Results published even if non- approvable A dispute resolution process to effectuate labeling changes if no agreement with the approved drug holder

23. Best Pharmaceuticals for Children Act (BPCA) Establishment of: –Office of Pediatric Therapeutics (Commissioner’s Office) –Pediatric Oncology Subcommittee (restructured) –Pediatric Pharmacology Advisory Committee New requirement concerning tracking of ethnicity and race for written agreement

24. Best Pharmaceuticals for Children Act (continued) IOM to develop a review of federal regulations and reports on research relating to children, addressing certain issues such as assent, minimal risk, and compensation (2 years after enactment 2004) Foundation for the National Institute of Health is to receive WR for products with patent life whose sponsors decline to honor the WR

25. BPCA continued Adverse Events All AEs (for product, not just relative indications) will be reported for 1 year, after exclusivity granted, to the new Office of Pediatric Therapeutics The report will be reviewed by the Pediatric Advisory subcommittee and any recommendations for action obtained

26. To Find out More Internet: –www.fda.gov/cder/pediatric PEDS Line: –301-594-PEDS (7337)