1. Pediatric Oncology and the Best Pharmaceuticals for Children Act Lisa L. Mathis, M.D. OND Associate Director Pediatric and Maternal Health Staff Office of New Drugs 27 June 2007

2. ODAC Peds Subcommittee 20072 Objectives Review Pediatric Legislation with a focus on the Best Pharmaceuticals for Children ActReview Pediatric Legislation with a focus on the Best Pharmaceuticals for Children Act Describe BPCA On Patent ProcessDescribe BPCA On Patent Process Discuss ResultsDiscuss Results

3. ODAC Peds Subcommittee 20073 Pediatric Legislation VoluntaryVoluntary –Best Pharmaceuticals for Children Act (BPCA) Signed into law January 4, 2002Signed into law January 4, 2002 Renewed pediatric exclusivity incentive originally in FDAMARenewed pediatric exclusivity incentive originally in FDAMA MandatoryMandatory –Pediatric Research Equity Act (PREA) Signed December 3, 2003Signed December 3, 2003 Restored some important aspects from the Pediatric Rule, enjoined in 2002Restored some important aspects from the Pediatric Rule, enjoined in 2002

4. ODAC Peds Subcommittee 20074 BPCA Renewed Pediatric Exclusivity provision in FDA Modernization Act (FDAMA)Renewed Pediatric Exclusivity provision in FDA Modernization Act (FDAMA) –Provides 6 months of market exclusivity in return for voluntarily conducting FDA- requested pediatric studies contained in a Written Request (WR) within a specific period. (Written request includes studies needed to label drug in kids)

5. ODAC Peds Subcommittee 20075 BPCA If a drug is on-patent, or has existing exclusivity (e.g., new molecular entity, orphan), the FDA may issue a Written Request (WR) for clinical studiesIf a drug is on-patent, or has existing exclusivity (e.g., new molecular entity, orphan), the FDA may issue a Written Request (WR) for clinical studies –If the requested studies are conducted and full reports submitted in a manner consistent with WR, they may get 6 months of additional exclusivity Within 90 days of submission, Exclusivity Board determines if Sponsor met terms of WRWithin 90 days of submission, Exclusivity Board determines if Sponsor met terms of WR

6. ODAC Peds Subcommittee 20076 BPCA Provides mechanism to work with National Institutes of Health to award contracts to study drugs not currently protected by patent or exclusivity (“off- patent process)Provides mechanism to work with National Institutes of Health to award contracts to study drugs not currently protected by patent or exclusivity (“off- patent process) Provided mechanism for WRs declined by sponsors (for drugs currently protected by patent or exclusivity) to be referred to NIH if the sponsor declines to conduct the studies included in the WRProvided mechanism for WRs declined by sponsors (for drugs currently protected by patent or exclusivity) to be referred to NIH if the sponsor declines to conduct the studies included in the WR

7. ODAC Peds Subcommittee 20077 What is in a Written Request? IndicationIndication Study typeStudy type Statistical information appropriate to the type of studyStatistical information appropriate to the type of study Drug information (formulation, dosing)Drug information (formulation, dosing) Drug specific safety concerns (what to monitor)Drug specific safety concerns (what to monitor) Labeling that may resultLabeling that may result Formats of study reports (full study reports)Formats of study reports (full study reports) Timeframe for submitting reportsTimeframe for submitting reports

8. ODAC Peds Subcommittee 20078 What is Different in an Oncology Written Request? Types of studies to be performed:  Phase I dose finding, including pharmacokinetics with doses determined for all appropriate age groups. Number of patients sufficient to achieve the objectives; typically 18-25 patients.  Phase II or pilot: enrollment of at least 14 patients with the tumor type.

9. ODAC Peds Subcommittee 20079 Process for the Study of On-Patent Drugs FDA issues (WR) Written Request Industry agrees to conduct studies Industry declines to conduct studies Referral to Foundation for NIH for NIH Industry has 180 days to respond Industry submits a Proposed Pediatric Study Request (PPSR) FDA determines public health benefit to support pediatric studies yes no

10. ODAC Peds Subcommittee 200710 Success of BPCA PPSRs submitted 492PPSRs submitted 492 Written Requests Issued 340Written Requests Issued 340 Studies requested 793Studies requested 793 Exclusivity Determinations 150Exclusivity Determinations 150 Exclusivity Granted 136Exclusivity Granted 136 New Labels 131New Labels 131

11. ODAC Peds Subcommittee 200711 Pediatric Research Equity Act PREA Became law December 3, 2003Became law December 3, 2003 Legislation mimics Pediatric RuleLegislation mimics Pediatric Rule Requires pediatric studies if condition in adults occurs in childrenRequires pediatric studies if condition in adults occurs in children Retroactive for all applications back to April 1, 1999Retroactive for all applications back to April 1, 1999

12. ODAC Peds Subcommittee 200712 Pediatric Research Equity Act PREA Most pediatric cancers different from adult cancers, thus most oncology drugs receive waiversMost pediatric cancers different from adult cancers, thus most oncology drugs receive waivers Supportive therapies (pain, prevention of nausea and vomiting) usually studied or deferredSupportive therapies (pain, prevention of nausea and vomiting) usually studied or deferred

13. ODAC Peds Subcommittee 200713 Success of PREA New Labels 55New Labels 55 –Only 15 of the 40 have new clinical information Post Marketing Commitments 191Post Marketing Commitments 191

14. ODAC Peds Subcommittee 200714 Post Marketing Commitments Avastin, Bevacizumab - Safety and activity data and to characterize the pharmacokinetics in pediatric patients with relapsed or refractory solid tumorsAvastin, Bevacizumab - Safety and activity data and to characterize the pharmacokinetics in pediatric patients with relapsed or refractory solid tumors Erbitux, Cetuximab - Dose finding study in children and adolescents who have EGFR-expressing, treatment refractory, pediatric solid tumors.Erbitux, Cetuximab - Dose finding study in children and adolescents who have EGFR-expressing, treatment refractory, pediatric solid tumors. Neulasta, Pegfilgrastim - Chemotherapy in Pediatric Sarcoma PatientsNeulasta, Pegfilgrastim - Chemotherapy in Pediatric Sarcoma Patients

15. ODAC Peds Subcommittee 200715 Post Marketing Commitments Supportive Care Mycamine, Micafungin Sodium – Study prophylaxis of Candida infections in patients ages 0 to 16 years old undergoing hematopoietic stem cell transplantationMycamine, Micafungin Sodium – Study prophylaxis of Candida infections in patients ages 0 to 16 years old undergoing hematopoietic stem cell transplantation Cancidas, Caspofungin – Study treatment of presumed fungal infections in febrile, neutropenic patientsCancidas, Caspofungin – Study treatment of presumed fungal infections in febrile, neutropenic patients Vfend, Voriconazole – Study treatment of candidemia and invasive candidiasis infectionsVfend, Voriconazole – Study treatment of candidemia and invasive candidiasis infections

16. ODAC Peds Subcommittee 200716 Post Marketing Commitments Supportive Care Study decreases the incidence and duration of severe oral mucositis and related sequelae experienced by patients age 3-16 with hematologic malignancies who are receiving myelotoxic therapy.Kepivance, Palifermin - Study decreases the incidence and duration of severe oral mucositis and related sequelae experienced by patients age 3-16 with hematologic malignancies who are receiving myelotoxic therapy.

17. ODAC Peds Subcommittee 200717 Post Marketing Commitments Supportive Care Aloxi, Palonosetron HCl – Study prevention of acute nausea and vomiting associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy (CINV)Aloxi, Palonosetron HCl – Study prevention of acute nausea and vomiting associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy (CINV) Emend, Aprepitant – Study prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapyEmend, Aprepitant – Study prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy Kytril, Granisetron HCl - Stduy treatment of post operative nausea and vomiting in pediatric patients 2 to 16 years of ageKytril, Granisetron HCl - Stduy treatment of post operative nausea and vomiting in pediatric patients 2 to 16 years of age

18. ODAC Peds Subcommittee 200718 Post Marketing Commitments Supportive Care Aranesp, Darbepoetin alfa - Study treatment of anemia in pediatric patientswith non-myeloid malignancies receiving multi-cycle chemotherapyAranesp, Darbepoetin alfa - Study treatment of anemia in pediatric patientswith non-myeloid malignancies receiving multi-cycle chemotherapy

19. ODAC Peds Subcommittee 200719 BPCA vs. PREA PREA Studies are requiredStudies are required Orphan drugs exemptOrphan drugs exempt Studies limited to indication for which sponsor seeks approval in adultsStudies limited to indication for which sponsor seeks approval in adults applies to § 505 (FD&C Act) (NDA) and § 351 (PHS Act) (BLA) productsapplies to § 505 (FD&C Act) (NDA) and § 351 (PHS Act) (BLA) products 10-1-07 Sunset10-1-07 SunsetBPCA Studies are voluntaryStudies are voluntary Includes orphan drugsIncludes orphan drugs Studies on whole moietyStudies on whole moiety FDA Issues WRFDA Issues WR Mechanism for funding studies of off-patent moietiesMechanism for funding studies of off-patent moieties Required safety reviewsRequired safety reviews Transparency: SummariesTransparency: Summaries applies to § 505 products onlyapplies to § 505 products only 10-1-07 Sunset10-1-07 Sunset

20. ODAC Peds Subcommittee 200720 Conclusion BPCA and PREA have had a powerful impact on providing important safety, efficacy, and dosing information for drugs used in children.BPCA and PREA have had a powerful impact on providing important safety, efficacy, and dosing information for drugs used in children. Oncology products have been studied and information has been learnedOncology products have been studied and information has been learned Scientific advancements must be reflected in the studies for oncology drugsScientific advancements must be reflected in the studies for oncology drugs New legislation being crafted with support from Oncology groups and may expand types of studies we are able to ask for in pediatricsNew legislation being crafted with support from Oncology groups and may expand types of studies we are able to ask for in pediatrics