Pediatric Drug Development Overview of FDA Initiatives

1. Pediatric Drug DevelopmentOverview of FDA Initiatives Karen Weiss, M.D. Center for Biologics FDA

2. Chronology of initiatives • 1979 - Establish a “Pediatric Use” sub-section of product labels • 1994 - Extrapolation of efficacy • 1997 - FDAMA/exclusivity provisions • 1998 - Requirement for studies in pediatric populations • 2000 - ICH E-11, guidance re: studies in pediatric populations • 2001 - Subpart D - protection of pediatric research subjects

3. Pediatric labeling - 1979 • Encourage labeling that would regularly contain information about Rx drugs in pediatrics • Basis: substantial evidence from adequate and well controlled studies in the pediatric population, unless that requirement is waived • Codified at Sec. 201.57 (f) (9)

4. Problems with 1979 rule • Waiver intended when other data could suffice • Basis for requesting/granting waivers unclear • Most Rx drugs continued to lack information on pediatric use • default: “Safety and efficacy below age X have not been established”

5. The 1994 rule • Broader basis for inclusion of pediatric data in label • Evidence to support pediatric claims can include effectiveness data in adults + additional data in pediatrics • “agency concludes that the course of the disease and the drug’s effects are sufficiently similar to permit extrapolation”

6. 1994 rule • Called for a review of existing data, submission of pediatric labeling • No need to submit pediatric data if: • belief disease/drug effects not similar btw. adults and pediatric patients, or • if pediatric use not otherwise adequately supported • No requirement to conduct new pediatric studies

7. Impact of the ‘94 rule • Did not result in more pediatric labeling • Already marketed products • some pediatric data submitted on ~ 400 of the approved drugs and biologicals • ~ 25% (100) resulted in some pediatric labeling • New Products • ~ 1/3 of new approvals with potential utility in pediatrics contained relevant data in 1996, 1997 not different than 1991

8. 1998 rule • Requirement: new drugs and biologicals will be studied in pediatric patients for the indication in adults unless waived • Waiver if: • Not likely to be used in substantial numbers of pediatric patients • Does not represent a meaningful advance

9. Timing of pediatric studies • For many indications, pediatric studies will lag behind adult studies • Many factors influence timing of pediatric studies, e.g., • seriousness of the disease • safety, activity profile in adults • availability of other therapies • ability to develop pediatric formulations

10. What types of studies? • 1998 rule does not mandate any particular type of study • Retains language of ‘94 • Where appropriate, pediatric use can be based on extrapolation of adult efficacy data + other data

11. Impact of 1998 rule • Greater emphasis on need for, timing of pediatric studies • Pediatric drug development considerations are included in the overall drug development schemes for every new product, indication, formulation, etc.

12. FDAMA - Exclusivity Provisions • Applicable to certain drugs approved under Sect 505 of FD&C act • excludes biologics, old antibiotics • Manufacturer voluntarily conduct pediatric studies responsive to FDA’s Written Request • Eligible to receive 6 additional months marketing exclusivity or patent protection • Exclusivity attached to the active moiety

13. FDAMA vs Rule

14. Impact of FDAMA • As of April 1, 2001: • FDA issued 188 WR, 411 studies (each WR may include > 1 study) • 28 grants of exclusivity • 18 products with new labeling • 13 to extend age and safety profile • 5 to change dosing or risk

15. ICHE-11 • Considerations in determining the need for a pediatric program • Issues in pediatric formulations • Timing of pediatric studies • Types of studies: pK, pK/pD, safety, including long term follow up • Ethical considerations

16. Subpart D regulations • Children’s Health Act signed Oct. 2000 • Directs the Secretary of HHS to require all research involving children that is conducted, supported, or regulated by HHS to be in compliance with Subpart D within 6 months of enactment (by April 17, 2001) - thus, interim (vs proposed) rule 8fr/cd0030http://www.fda.gov/OHRMS/

17. Citations I • Specific Requirements on Content and Format of Labeling for Human Prescription Drugs: 44 FR 37434 June 26 1979 • Specific Requirements on Content and Format of Labeling for Human Prescription Drugs: Revision of Pediatric Use Subsection in the Labeling; Final Rule 59 FR 6420 Dec. 13, 1994 • Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biologicals in Pediatric Patients; Final Rule 63 FR 66632, Dec 2, 1998

18. Citations II • FDA Modernization Act, PL 105-111, Nov 21, 1997 • Guidance for Industry Qualifying for Pediatric Exclusivity Under Section 505A of the FD&C Act Sept 1999 • ICH E-11 Clinical Investigation of Medicinal Products in the Pediatric Population //www.ifpma.org/ich5.html • Additional Safeguards for Children in Clinical Investigations of FDA-Regulated Industry Products Interim Rule //www.fda.gov/OHRMS/DOCKETS/98fr/cd0030.pdf