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  1. 1. Pediatric Oncology and the BestPediatric Oncology and the Best Pharmaceuticals for Children ActPharmaceuticals for Children Act Lisa L. Mathis, M.D.Lisa L. Mathis, M.D. OND Associate DirectorOND Associate Director Pediatric and Maternal Health StaffPediatric and Maternal Health Staff Office of New DrugsOffice of New Drugs 27 June 200727 June 2007
  2. 2. ODAC Peds Subcommittee 2007 2 ObjectivesObjectives • Review Pediatric Legislation with aReview Pediatric Legislation with a focus on the Best Pharmaceuticals forfocus on the Best Pharmaceuticals for Children ActChildren Act • Describe BPCA On Patent ProcessDescribe BPCA On Patent Process • Discuss ResultsDiscuss Results
  3. 3. ODAC Peds Subcommittee 2007 3 Pediatric LegislationPediatric Legislation • VoluntaryVoluntary – Best Pharmaceuticals for Children Act (BPCA)Best Pharmaceuticals for Children Act (BPCA) • Signed into law January 4, 2002Signed into law January 4, 2002 • Renewed pediatric exclusivity incentive originally inRenewed pediatric exclusivity incentive originally in FDAMAFDAMA • MandatoryMandatory – Pediatric Research Equity Act (PREA)Pediatric Research Equity Act (PREA) • Signed December 3, 2003Signed December 3, 2003 • Restored some important aspects from the PediatricRestored some important aspects from the Pediatric Rule, enjoined in 2002Rule, enjoined in 2002
  4. 4. ODAC Peds Subcommittee 2007 4 BPCABPCA • Renewed Pediatric Exclusivity provision in FDARenewed Pediatric Exclusivity provision in FDA Modernization Act (FDAMA)Modernization Act (FDAMA) – Provides 6 months of market exclusivity inProvides 6 months of market exclusivity in return for voluntarily conducting FDA-return for voluntarily conducting FDA- requested pediatric studies contained in arequested pediatric studies contained in a Written Request (WR) within a specificWritten Request (WR) within a specific period. (Written request includes studiesperiod. (Written request includes studies needed to label drug in kids)needed to label drug in kids)
  5. 5. ODAC Peds Subcommittee 2007 5 BPCABPCA • If a drug is on-patent, or has existing exclusivityIf a drug is on-patent, or has existing exclusivity (e.g., new molecular entity, orphan), the FDA(e.g., new molecular entity, orphan), the FDA may issue a Written Request (WR) for clinicalmay issue a Written Request (WR) for clinical studiesstudies – If the requested studies are conducted and fullIf the requested studies are conducted and full reports submitted in a manner consistent withreports submitted in a manner consistent with WR, they may get 6 months of additionalWR, they may get 6 months of additional exclusivityexclusivity • Within 90 days of submission, Exclusivity BoardWithin 90 days of submission, Exclusivity Board determines if Sponsor met terms of WRdetermines if Sponsor met terms of WR
  6. 6. ODAC Peds Subcommittee 2007 6 BPCABPCA • Provides mechanism to work withProvides mechanism to work with National Institutes of Health to awardNational Institutes of Health to award contracts to study drugs not currentlycontracts to study drugs not currently protected by patent or exclusivity (“off-protected by patent or exclusivity (“off- patent process)patent process) • Provided mechanism for WRs declined byProvided mechanism for WRs declined by sponsors (for drugs currently protected bysponsors (for drugs currently protected by patent or exclusivity) to be referred topatent or exclusivity) to be referred to NIH if the sponsor declines to conduct theNIH if the sponsor declines to conduct the studies included in the WRstudies included in the WR
  7. 7. ODAC Peds Subcommittee 2007 7 What is in a Written Request?What is in a Written Request? • IndicationIndication • Study typeStudy type • Statistical information appropriate to the type ofStatistical information appropriate to the type of studystudy • 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. 8. ODAC Peds Subcommittee 2007 8 What is Different in an OncologyWhat is Different in an Oncology Written Request?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. 9. ODAC Peds Subcommittee 2007 9 Process for the Study ofProcess for the Study of On-Patent DrugsOn-Patent Drugs FDA issues (WR)FDA issues (WR) Written RequestWritten Request Industry agreesIndustry agrees to conduct studiesto conduct studies Industry declinesIndustry declines to conduct studiesto conduct studies Referral to FoundationReferral to Foundation for NIHfor NIH Industry has 180Industry has 180 days to responddays to respond Industry submitsIndustry submits a Proposeda Proposed Pediatric StudyPediatric Study Request (PPSR)Request (PPSR) FDA determinesFDA determines public health benefitpublic health benefit to support pediatric studiesto support pediatric studies yes yes no
  10. 10. ODAC Peds Subcommittee 2007 10 Success of BPCASuccess of BPCA • PPSRs submitted 492PPSRs submitted 492 • Written Requests Issued 340Written Requests Issued 340 • Studies requestedStudies requested 793793 • Exclusivity DeterminationsExclusivity Determinations 150150 • Exclusivity GrantedExclusivity Granted 136136 • New LabelsNew Labels 131131
  11. 11. ODAC Peds Subcommittee 2007 11 Pediatric Research Equity ActPediatric Research Equity Act PREAPREA • Became law December 3, 2003Became law December 3, 2003 • Legislation mimics Pediatric RuleLegislation mimics Pediatric Rule • Requires pediatric studies if condition inRequires pediatric studies if condition in adults occurs in childrenadults occurs in children • Retroactive for all applications back toRetroactive for all applications back to April 1, 1999April 1, 1999
  12. 12. ODAC Peds Subcommittee 2007 12 Pediatric Research Equity ActPediatric Research Equity Act PREAPREA • Most pediatric cancers different fromMost pediatric cancers different from adult cancers, thus most oncology drugsadult cancers, thus most oncology drugs receive waiversreceive waivers • Supportive therapies (pain, prevention ofSupportive therapies (pain, prevention of nausea and vomiting) usually studied ornausea and vomiting) usually studied or deferreddeferred
  13. 13. ODAC Peds Subcommittee 2007 13 Success of PREASuccess of PREA • New LabelsNew Labels 5555 – Only 15 of the 40 have new clinicalOnly 15 of the 40 have new clinical informationinformation • Post Marketing Commitments 191Post Marketing Commitments 191
  14. 14. ODAC Peds Subcommittee 2007 14 Post Marketing CommitmentsPost Marketing Commitments • Avastin, Bevacizumab - Safety andAvastin, Bevacizumab - Safety and activity data and to characterize theactivity data and to characterize the pharmacokinetics in pediatric patientspharmacokinetics in pediatric patients with relapsed or refractory solid tumorswith relapsed or refractory solid tumors • Erbitux, Cetuximab - Dose finding studyErbitux, Cetuximab - Dose finding study in children and adolescents who havein children and adolescents who have EGFR-expressing, treatment refractory,EGFR-expressing, treatment refractory, pediatric solid tumors.pediatric solid tumors. • Neulasta, Pegfilgrastim - ChemotherapyNeulasta, Pegfilgrastim - Chemotherapy in Pediatric Sarcoma Patientsin Pediatric Sarcoma Patients
  15. 15. ODAC Peds Subcommittee 2007 15 Post Marketing CommitmentsPost Marketing Commitments Supportive CareSupportive Care • Mycamine, Micafungin Sodium – StudyMycamine, Micafungin Sodium – Study prophylaxis of Candida infections in patientsprophylaxis of Candida infections in patients ages 0 to 16 years old undergoingages 0 to 16 years old undergoing hematopoietic stem cell transplantationhematopoietic stem cell transplantation • Cancidas, Caspofungin – Study treatment ofCancidas, Caspofungin – Study treatment of presumed fungal infections in febrile,presumed fungal infections in febrile, neutropenic patientsneutropenic patients • Vfend, Voriconazole – Study treatment ofVfend, Voriconazole – Study treatment of candidemia and invasive candidiasiscandidemia and invasive candidiasis infectionsinfections
  16. 16. ODAC Peds Subcommittee 2007 16 Post Marketing CommitmentsPost Marketing Commitments Supportive CareSupportive Care • Kepivance, Palifermin - Study decreases theStudy decreases the incidence and duration of severe oralincidence and duration of severe oral mucositis and related sequelae experiencedmucositis and related sequelae experienced by patients age 3-16 with hematologicby patients age 3-16 with hematologic malignancies who are receiving myelotoxicmalignancies who are receiving myelotoxic therapy.therapy.
  17. 17. ODAC Peds Subcommittee 2007 17 Post Marketing CommitmentsPost Marketing Commitments Supportive CareSupportive Care • Aloxi, Palonosetron HCl – Study prevention ofAloxi, Palonosetron HCl – Study prevention of acute nausea and vomiting associated with initialacute nausea and vomiting associated with initial and repeat courses of moderately and highlyand repeat courses of moderately and highly emetogenic cancer chemotherapy (CINV)emetogenic cancer chemotherapy (CINV) • Emend, Aprepitant – Study prevention of acuteEmend, Aprepitant – Study prevention of acute and delayed nausea and vomiting associated withand delayed nausea and vomiting associated with initial and repeat courses of highly emetogenicinitial and repeat courses of highly emetogenic cancer chemotherapycancer chemotherapy • Kytril, Granisetron HCl - Stduy treatment of postKytril, Granisetron HCl - Stduy treatment of post operative nausea and vomiting in pediatric patientsoperative nausea and vomiting in pediatric patients 2 to 16 years of age2 to 16 years of age
  18. 18. ODAC Peds Subcommittee 2007 18 Post Marketing CommitmentsPost Marketing Commitments Supportive CareSupportive Care • Aranesp, Darbepoetin alfa - StudyAranesp, Darbepoetin alfa - Study treatment of anemia in pediatrictreatment of anemia in pediatric patientswith non-myeloid malignanciespatientswith non-myeloid malignancies receiving multi-cycle chemotherapyreceiving multi-cycle chemotherapy
  19. 19. ODAC Peds Subcommittee 2007 19 BPCA vs. PREABPCA vs. PREA PREAPREA • Studies areStudies are requiredrequired • Orphan drugs exemptOrphan drugs exempt • Studies limited to indication forStudies limited to indication for which sponsor seeks approval inwhich sponsor seeks approval in adultsadults • applies toapplies to §§ 505 (FD&C Act)505 (FD&C Act) (NDA) and(NDA) and §§ 351 (PHS Act)351 (PHS Act) (BLA) products(BLA) products • 10-1-07 Sunset10-1-07 Sunset BPCABPCA • Studies areStudies are voluntaryvoluntary • Includes orphan drugsIncludes orphan drugs • Studies on whole moietyStudies on whole moiety • FDA Issues WRFDA Issues WR • Mechanism for funding studies ofMechanism for funding studies of off-patent moietiesoff-patent moieties • Required safety reviewsRequired safety reviews • Transparency: SummariesTransparency: Summaries • applies toapplies to §§ 505 products only505 products only • 10-1-07 Sunset10-1-07 Sunset
  20. 20. ODAC Peds Subcommittee 2007 20 ConclusionConclusion • BPCA and PREA have had a powerful impactBPCA and PREA have had a powerful impact on providing important safety, efficacy, andon providing important safety, efficacy, and dosing information for drugs used in children.dosing information for drugs used in children. • Oncology products have been studied andOncology products have been studied and information has been learnedinformation has been learned • Scientific advancements must be reflected in theScientific advancements must be reflected in the studies for oncology drugsstudies for oncology drugs • New legislation being crafted with support fromNew legislation being crafted with support from Oncology groups and may expand types ofOncology groups and may expand types of studies we are able to ask for in pediatricsstudies we are able to ask for in pediatrics

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