1. Oncology Pediatric Initiatives Richard Pazdur, MD Director, Division of Oncology Drug Products

2. Food and Drug Modernization Act of 1997- An incentive Program Provision for 6 month extension to existing marketing exclusivity or patent protection can be granted to an entire product line of an active moiety for providing new pediatric information that will benefit the public health. Submissions must come in response to an FDA Written Request.

3. Pediatric Rule of 1998- A Mandate A product under review must provide pediatric information if the indication under review is a disease found in children. If the disease is not found in children, a waiver may be granted.

4. Comparison of FDAMA vs. 1998 Rule Voluntary Applies to entire product line No restriction on eligible pediatric diseases Only applies when there is underlying patent or exclusivity protection Biologicals and some products excluded Orphan products included Mandatory Only applies to the product and indication under review Only applies if the pediatric disease is similar to the adult disease Applies to biologicals Orphan products excluded

5. Pediatric Exclusivity Written Request From FDA Submission of Study Reports FDA Determination Proposed Pediatric Study Request

6. FDA experience with FDAMA incentive Overall Proposals received: 184 Written Requests issued: 153 Oncology Proposals received: 5 Written Requests issued: 3 Written Requests pending: 4

7. Pediatric Development Plan Overview Dosing and pharmacokinetics in Phase 1 Phase 2 or pilot studies in a range of potential indications Not a supplemental NDA since efficacy need not be demonstrated Applies to both new agents and approved agents that have not been adequately investigated in pediatric oncology

8. Pediatric Development Plan First Stage Phase 1 studies to determine dose, pharmacokinetics, and toxicities Planned for about 25 patients If unacceptable toxicity occurs, the development would stop and an exclusivity extension could be granted If toxicity is acceptable, proceed to second stage (anticipated general case)

9. Pediatric Development Plan Second Stage Phase 2 studies (single agent or add on comparative design) and/or pilot studies (combinations) to demonstrate an agent’s characteristics and contribution to –efficacy, perhaps using surrogate endpoints such as response rate –justification for further development to examine clinical benefit

10. Possible Outcomes At the completion of the second stage If efficacy is demonstrated, approval for the indication under subpart H or full approval If no beneficial effect is observed, development is stopped If results are promising but not sufficient to support approval, a commitment to further development ALL THREE CASES CAN RESULT IN GRANTING OF EXCLUSIVITY EXTENSION

11. Results of Completion of a Pediatric Development Plan The results are summarized in a study report and submitted to the FDA Upon review, if the conditions of the initial Written Request are met, REGARDLESS OF OUTCOME, a 6 month exclusivity extension may be granted Well designed, well executed studies with a negative result can qualify Intent is a prospective plan to produce new information of importance to pediatric oncology