1. FDA Pediatric Oncology Subcommittee Meeting “Company Perspective”

2. Key Questions to Address (Company Perspective) Question #1-When in the development of a new oncolytic should pediatric studies be undertaken? Question #2-What factors influence the decision whether or not pediatric studies are undertaken? Question #3-Should pediatric studies be performed only by cooperative groups?

3. Key Questions to Address Question #1-When in the development of a new oncolytic should pediatric studies be undertaken? Question #2-What factors influence the decision whether or not pediatric studies are undertaken? Question #3-Should pediatric studies be performed only by cooperative groups?

4. Historically When Are Pediatric Studies Performed? DrugDate of Initial FDA Approval Date of 1 st Adult Study Date of 1 st Pediatric Study Difference in Years Between Studies Gemcitabine19961991Ongoing10+ Paclitaxel1992198619937 Cladribine1993198419917 Irinotecan19961993 (US)1999 (US)6 Temozolomide1999199219986 Docetaxel1996199219975 Tretinoin1995198819924 Topotecan1996199219931 Imatinib2001 Ongoing1+

5. ASPHO Survey 1 (Interim Results) 1 Survey of 91 ASPHO Members-October 2002

6. Key Questions to Address Question #1-When in the development of a new oncolytic should pediatric studies be undertaken? Question #2-What factors influence the decision whether or not pediatric studies are undertaken? Question #3-Should pediatric studies be performed only by cooperative groups?

7. ASPHO SURVEY 1 -INFLUENTIAL FACTORS 2 1.Pediatric preclinical data 2.Drug with new mechanism or target 3.Positive data from adult phase I or II 4.Availability of drug for pediatric studies 5.Other factors 1 Survey of 91 ASPHO Members-October 2002 2 Rate from 1-7; One being least influential

8. “Most Influential-#7” #Responders choosing “7”

9. Key Questions to Address Question #1-When in the development of a new oncolytic should pediatric studies be undertaken? Question #2-What factors influence the decision whether or not pediatric studies are undertaken? Question #3-Should pharmaceutical companies conduct pediatric studies outside of cooperative groups?

10. ASPHO Survey 1 1 Survey of 91 ASPHO Members-October 2002

11. Comments- “No” Patient numbers too small-direct competition with COG studies Definitely “no”; “That would be a terrible mistake” Concerned about “conflict of interest” Cooperative group(s) are cornerstone of our success against pediatric cancer More convincing if studies are done within Cooperative group setting Cooperative group mechanism in concert with industry and the NCI, when necessary, should meet all industry and FDA requirements

12. Comments-“Yes” The Cooperative groups have a problem with congestion; Speed! Cooperative group is a monolith Any route necessary if it means getting phase I studies in children Resources and infrastructure Opportunity for smaller institution

13. “Company Prospective” Early Pediatric Studies Late Pediatric Studies Medical/Scientific Similar disease process Similar target expression (Novel mechanism) Regulatory Pediatric Rule Business Development FDAMA/BPCA CMC Formulation-oral Stability (Drug supply) Toxicology “Unaccepted” toxicities Unusual target organs Unmet Need Each new agent needs to be considered separately (there is no standard approach) Data Management Cooperative group

14. Summary- “Company Perspective” Strong shift towards  not if, but when, should pediatric studies be undertaken Most pediatric oncologist believe studies should be done early versus late –Company involvement is OK-But! –Perception that conducting studies outside cooperative groups could speed up the process? Companies are showing increased interest in developing new agents in children –FDAMA and Pediatric Rule Many factors influence decision to conduct studies in children –Industry views are similar to those of pediatric oncologist, but there are obvious differences

15. Questions-Discussion?

16. “Other Influential Factors” A company that is not overtly hostile towards pediatric studies (7) Favorable side-effect or toxicity profile (6) Unmet need (5) Ease of study (5) Foreign experience (4)

17. Recent/Ongoing Pediatric Phase I Studies ABT-751 (ST)Arsenic Trioxide (L)BMS 247550 (ST) Clofarex (L)Carbo/Irinotecan (ST)DX-8951f (ST) Fenretinide (ST)Doxorubicin Liposome (ST)Flavopiridol (ST) Gadolinium TexaphyrinCisplat/VP16/Bleo/Amifostine (GC)IT-Busulfan (BT) Iodine I131 MIBG (NB)Melphalan/Buthionine SulfoximineIrinotecan Oxaliplatin (ST)R115777PS-341 SCH 66336 (BT)Squalamine/Carbo (ST)SU5416 (BT) Temozolomide/O 6 BGThiotepa/Carbo/Topotecan (ST)Irinotecan/VCR (ST) XR 9576 (ST)STI571 (ST)Holmium Ho 166 IL-2Expanded CD8 Cells (NB)Rituximab  -Glucan MoAb 3F8 (NB)hu14.18/IL-2 (NB) MoAb Ch14.18/IL2 (NB)