Transforming Translation-Harnessing Discovery for Patient and Public Benefit

Report of the Translational Research Working Group of the National Cancer Advisory Board

June 2007

Transforming Translation—Harnessing Discovery for Patient and Public BenefitN

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U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health

ii Transforming Translation—Harnessing Discovery for Patient and Public Benefit

Report of the NCAB Translational Research Working Group

Proposed TRWG Initiatives

Coordinated Management

A1 EstablishacoordinatedNCI-wideorganizationalapproachtomanagethediverseearlytranslationalresearchportfolio,reducefragmentationandredundancy,andensurethatresourcesarefocusedonthemostimportantandpromisingopportunities.

A2 DesignateaspecificportionoftheNCIbudgetforearlytranslationalresearchtofacilitatecoordinatedmanagement,long-termplanning,andprioritizationamongopportunitiesandapproachesaswellastodemonstrateNCI’scommitmenttotranslationalresearch.

A3 Developasetofawardcodesthataccuratelycapturesthenatureandscopeoftheearlytranslationalresearchportfoliotoenableacomplete,sharedunderstandingofNCI’stotalinvestment,helpidentifygapsandopportunities,anddemonstratetheextentoftranslationalactivitytothepublic.

A4 Createatransparent,inclusiveprioritizationprocesstoidentifythemostpromisingearlytranslationalresearchopportunitiesbasedonscientificquality,technicalfeasibility,andexpectedclinicalorpublichealthimpact.

Tailored Funding Programs

B1 Modifyguidelinesformultiprojectcollaborativeearlytranslationalresearchawardstofocusresearchonadvancingspecificopportunitiesalongadevelopmentalpathwaytowardpatientbenefit,andtorewardcollaborativeteamscience.

B2 Improveprocessesandmechanismsforreviewandfundingofinvestigator-initiatedearlytranslationalresearchtoincentivizeresearcherstoproposesuchstudies.

B3 Establishaspecialfundingprogramtoadvanceaselectnumberofespeciallypromisingearlytranslationalresearchopportunitiesidentifiedthroughthenewlycreatedprioritizationprocess.

B4 EstablishaprogramforjointNCI/industryfundingofcollaborativeearlytranslationalresearchprojectsthatintegratethecomplementarystrengthsofbothpartiestopursueopportunitiesthataremoreattractiveasacombinedeffort.

B5 IntegrateaccesstoGMP/GLPmanufacturingandotherpreclinicaldevelopmentservicesmoreeffectivelywithhigh-priority,milestone-drivenearlytranslationalresearchprojectstobetteraddressthisoftenrate-limitingstepinmovingaproductforwardtoearlyhumantesting.

Operational Effectiveness

C1BuildaprojectmanagementsysteminvolvingstaffbothatNCIandatextramuralinstitutionstofacilitatecoordination,communication,resourceidentificationandaccess,andmanagementofmilestone-basedprogressformultidisciplinary,earlytranslationalresearchprojects.

C2Coordinatecoreservicesessentialforearlytranslationalresearchtoreduceduplicationandensurethathigh-qualityservicesarereadilyaccessibletoallprojectsandinvestigators.

C3 Improvestandardization,qualitycontrolandaccessibilityofannotatedbiospecimenrepositoriesandtheirassociatedanalyticmethodstostrengthenthiskeytranslationalresource.

C4Developenhancedapproachesfornegotiationofintellectualpropertyagreementsandagentaccesstopromotecollaborationsamongindustry,academia,NCI,andfoundations.

C5 IncreaseNCIinteractionandcollaborationwithfoundationsandadvocacygroupstocapitalizeupontheircomplementaryskillsandresourcesforadvancingearlytranslationalresearch.

C6Enhancetrainingprogramsandcareerincentivestodevelopandmaintainacommittedearlytranslationalresearchworkforce.

Transforming Translation—Harnessing Discovery for Patient and Public Benefit iii


Initiatives FY08 FY09 FY10 FY11 FY12

A1: Integrated NCI Management

A2: Budget Designation

A3: Translational Research Coding

A4: Prioritization Process

B1: Modify Translational Research Award Guidelines

B2: Improve Investigator-Initiated Translational Research Awards

B3: STRAP Awards

B4: Academia/Industry Collaboration Awards

B5: Develop Integrated Services

C1: Project Management

C2: Core Services Coordination

C3: Enhance Biorepositories

C4: Improve Intellectual Property Negotiations

C5: Enhance Foundation/Advisory Group Collaborations

C6: Enhance Training Programs and Career Incentives

Evaluation


A1: Integrated NCI Management $800K $800K $850K $850K $850K

A2: Budget Designation — — — — —

A3: Translational Research Coding $150K $150K $150K $150K

A4: Prioritization Process $950K $750K $750K $750K $750K

B1: Modify Translational Research Award Guidelines — — — — —


— — — — —

B3: Special Translational Research Acceleration Project (STRAP) Awards

— — $10M $20M $30M

B4: Academia/Industry Collaboration Awards $5M $10M

B5: Develop Integrated Services — — — — —

C1: Project Management $1.35M $1.3M $1.55M $1.75M $2M

C2: Core Services Coordination $200K $370K — — —

C3: Enhance Biorepositories — — — — —

C4: Improve Intellectual Property Negotiations $100K $530K

C5: Enhance Foundation/Advisory Group Collaborations

— — — — —

C6: Enhance Training Programs and Career Incentives $300K $100K — — —

Evaluation $350K — $350K — $350K

TOTAL $4.05M $3.99M $13.65M $28.5M $44.1M

TRWG Initiatives Summary Timeline

TRWG Initiatives Summary Budget

iv Transforming Translation—Harnessing Discovery for Patient and Public Benefit


AcknowledgmentsInadditiontoallofthededicatedmembersoftheTranslationalResearchWorkingGroup,severalotherindividualshaveplayedimportantrolesfacilitatingtheeffortsoftheTRWG,fromitsinceptionthroughthedevelopmentofthisreport.

Lisa Stevens,Ph.D.,Chief,SciencePlanningBranch,andJennifer Kwok,PublicHealthAnalyst,OfficeofScience,PlanningandAssessment,NCI,providedguidanceandsupporttotheTRWGleadershipandwerecriticaltotheoperationandorganizationofTRWGactivities.

Jaye Viner,M.D.,M.P.H.,DeputyDirector,OfficeofCenters,Training,andResources,NCI,providedguidanceanddirectiontotheTRWGleadership.

NOVAResearchCompany:NOVAprovidedoverallsupportfortheTRWGmeetings,Website,materialsproduction,andwriting/notetaking.Dana Young,J.D.,monitoredNOVAsupportactivitiesandcoordinatedsciencewritingforplenaryandworkgroupsessions.Janet BraunprovidedexceptionalplanningandlogisticalsupportforthemanyTRWGmeetings.Ray ButlerandVictor Linprovidedfirst-rateaudiovisualsupportandkeptthingsrunningsmoothlyduringnumerousTRWGmeetings.Michelle Murrayprovidedbackupandonsitemeetingsupport.Erin Milliken,Ph.D.,andKerri Lowrey,J.D.,M.P.H.,providedmanyexcellentpagesofmeetingsummariesandactionitemsthatkeptusontrack.Sue Bentleyprovidedproofreadingandcopyediting.Ed Rorie,M.S.L.S.,providedconsultationontheformattingandfinalprintingofthereport.Dan Eckstein,M.A.,providedprofessionalfacilitation,andAllyson Harkey;ErinMilliken,Ph.D.;Olivia Propst,M.Ed.;Kathy Sedgwick;Melanie Simpson,Ph.D.;Ann Welch,Ph.D.;Dana Young,J.D.;andAllison Zambon,M.H.S.,providedexcellentsciencewritingsupport.

ScienceApplicationsInternationalCorporation(SAIC):Jeffrey Zalatoris,Ph.D.,providedcoordinationofSAIC’sPortfolioAnalysiswork,withassistancefromGregory Cole,Ph.D.,Karen Rulli,Ph.D.,Adeyinka Smith,M.S.,Quentin Scott,Ph.D.,Allart Kok,M.S.,andJoshua Wolfe,Ph.D.Kathy Sorrow,M.S.,Deborah Berlyne,Ph.D.,Julie Ter Borg,M.P.H.,andAdam Book,Ph.D.providedinvaluablesciencewritingsupport.

Gary Dorfman,M.D.,SpecialAssistanttotheAssociateDirectorforImageGuidedInterventionsintheDivisionofCancerTreatmentandDiagnosis,NCI,ablyrepresentedtheCancerImagingProgram,providingcriticalinputandmanyhourstotheInterventiveDeviceandImaging-relatedRiskAssessmentDevicepathways.

Henry Rodriguez,Ph.D.,M.B.A.,ablyrepresentedtheOfficeofTechnologyandIndustrialRelationsoftheNCIintheTRWGdeliberations.

Jane Reese-Coulbourne,M.S.,M.B.A.,providedvaluableinputfromtheadvocateperspectiveintothepenultimateTRWGreport.

David Dilts,Ph.D.,M.B.A.,ProfessorofEngineeringManagementandManagementatVanderbiltUniversity,passedoninsightsfromthebusinessworldintohowthebarrierstotranslationalresearchmightbeaddressed.

Vanessa Hill,DepartmentofCancerBiologyatVanderbiltUniversity,providedcriticalsupportinassistingtheco-chairinmanagingTRWGactivities.

ScienceandTechnologyPolicyInstitute(STPI)oftheInstituteforDefenseAnalyses:ThecontributionsoftheSTPIteamtothedevelopmentandexecutionoftheTRWGreportcannotbeoverestimated.EachmemberoftheSTPIteam,Oren Grad,M.D.,Ph.D.,Brian Zuckerman,Ph.D.,Maureen McArthur,andAlexis WilsonplayedanessentialroleinmovingallphasesofTRWGactivitiesforwardinaneffectiveandinclusivemanner,andinparticularweacknowledgethecontributionsofDr.GradtothePathwaydiagramsandDr.ZuckermantotheProcessAnalysis.Judith Hautala,Ph.D.,servedasLeadCoordinatoroftheSTPIteamandwasexemplaryinherservicetotheTRWGeffort.Shespentcountlesshoursorganizingandcoordinatingtheteam’sinteractions,andmovingustowardthedevelopmentoffinalrecommendationsandimplementationstrategies.WearedeeplygratefulfortheSTPIteam’smanycontributions.

Transforming Translation—Harnessing Discovery for Patient and Public Benefit v

Report of the NCAB Translational Research Working Group—Members of the TRWG

Chair

Ernest T. Hawk, M.D., M.P.H.Director,OfficeofCenters,Training,andResourcesOfficeoftheDirectorNationalCancerInstituteBethesda,MD

Co-Chairs

Lynn M. Matrisian, Ph.D.ProfessorandChair,DepartmentofCancerBiologyVanderbiltUniversityNashville,TN

William G. Nelson, M.D., Ph.D.Professor,Oncology,Urology,Pharmacology,Medicine,andPathologySidneyKimmelComprehensiveCancerCenteratJohnsHopkinsBaltimore,MD

Members

James L. Abbruzzese, M.D., F.A.C.P.Professor/Chairman,DivisionofCancerMedicineTheUniversityofTexasM.D.AndersonCancerCenterHouston,TX

David S. Alberts, M.D.Director,ArizonaCancerCenterUniversityofArizonaTucson,AZ

Kenneth C. Anderson, M.D.KraftFamilyProfessorofMedicineDivisionofHematologicNeoplasiaHarvardMedicalSchoolBoston,MA

Robert C. Bast, M.D.VicePresident,TranslationalResearchTheUniversityofTexasM.D.AndersonCancerCenterHouston,TX

Darell D. Bigner, M.D., Ph.D.JonesCancerResearchProfessorDeputyDirector,DukeComprehensiveCancerCenterDurham,NC

Kenneth H. Buetow, Ph.D.AssociateDirector,BioinformaticsandInformationTechnologyNationalCancerInstituteBethesda,MD

Translational Research Working Group

vi Transforming Translation—Harnessing Discovery for Patient and Public Benefit


Michael A. Caligiuri, M.D.Director,ComprehensiveCancerCenterTheOhioStateUniversityColumbus,OH

Mac Cheever, M.D.DirectorofSolidTumorResearchFredHutchinsonCancerResearchCenterSeattle,WA

Jerry M. Collins, Ph.D.AssociateDirector,DevelopmentalTherapeuticsDivisionofCancerTreatmentandDiagnosisNationalCancerInstituteRockville,MD

Richard J. Cote, M.D.ProfessorofPathologyandUrology,KeckSchoolofMedicineNorrisComprehensiveCancerCenterUniversityofSouthernCaliforniaLosAngeles,CA

Sara A. Courtneidge, Ph.D.Professor/ProgramDirector,CellAdhesionandExtracellularMatrixProgramBurnhamInstituteforMedicalResearchLaJolla,CA

Kenneth H. Cowan, M.D., Ph.D.Director,EppleyCancerCenterUniversityofNebraskaMedicalCenterOmaha,NE

Phillip A. Dennis, M.D., Ph.D.SeniorInvestigator,MedicalOncologyBranchCenterforCancerResearchNationalCancerInstituteBethesda,MD

Adrian M. Di Bisceglie, M.D., F.A.C.P.ProfessorofInternalMedicine/ChiefofHepatology,DivisionofGastroenterologyandHepatologySt.LouisUniversitySchoolofMedicineSt.Louis,MO

James H. Doroshow, M.D.Director,DivisionofCancerTreatmentandDiagnosisNationalCancerInstituteBethesda,MD

Gregory J. Downing, D.O., Ph.D.Director,OfficeofTechnologyandIndustrialRelationsNationalCancerInstituteBethesda,MD

Transforming Translation—Harnessing Discovery for Patient and Public Benefit vii


Steven M. Dubinett, M.D.ProfessorofMedicineandPathologyDirector,LungCancerResearchProgramJonssonComprehensiveCancerCenterDavidGeffenSchoolofMedicineatUCLALosAngeles,CA

Raymond N. DuBois, M.D., Ph.D.Director,TheVanderbilt-IngramCancerCenterNashville,TN

Peter D. Emanuel, M.D.Professor,DivisionofHematology-OncologyUniversityofAlabamaatBirminghamBirmingham,AL

Laura Esserman, M.D., M.B.A.Director,CarolFrancBuckBreastCareCenterProfessorofSurgeryandRadiologyUniversityofCalifornia,SanFranciscoSanFrancisco,CA

Laurie FentonPresident,LungCancerAllianceWashington,DC

Tona M. Gilmer, Ph.D.Director,U.S.HumanBiomarkerLabsTranslationalMedicineandGeneticsGlaxoSmithKlineResearchTrianglePark,NC

Jorge Gomez, M.D., Ph.D.BranchChief,OrganSystemsBranchNationalCancerInstituteRockville,MD

Gary Gordon, M.D., Ph.D.DivisionalVicePresident,GlobalOncologyDevelopmentGlobalPharmaceuticalResearchandDevelopmentAbbottLaboratoriesAbbottPark,IL

Joe W. Gray, Ph.D.DivisionDirector,AssociateLaboratoryLifeSciencesDivisionLawrenceBerkeleyNationalLaboratoryBerkeley,CA

Ellen R. Gritz, Ph.D.ProfessorandChair,DepartmentofBehavioralScienceTheUniversityofTexasM.D.AndersonCancerCenterHouston,TX

viii Transforming Translation—Harnessing Discovery for Patient and Public Benefit


William N. Hait, M.D., Ph.D.Director,MedicalOncologyTheCancerInstituteofNewJerseyNewBrunswick,NJ

Waun Ki Hong, M.D.Head/Professor,CancerMedicineTheUniversityofTexasM.D.AndersonCancerCenterHouston,TX

David Kerr, C.B.E., M.D., D.Sc., M.A., F.R.C.P., FMedSciRhodesProfessor,CancerTherapeuticsandClinicalPharmacologyHead,DepartmentofClinicalPharmacologyDirector,NationalTranslationalCancerResearchNetworkOxford,UnitedKingdom

Theodore S. Lawrence, M.D., Ph.D.ProfessorandChair,DepartmentofRadiationOncologyUniversityofMichiganAnnArbor,MI

Paul J. Limburg, M.D., M.P.H.AssociateProfessorofMedicineDivisionofGastroenterologyandHepatologyMayoClinicCollegeofMedicineRochester,MN

A. Thomas Look, M.D.ViceChairforResearchDepartmentofPediatricOncologyDana-FarberCancerInstituteBoston,MA

Anne E. Lubenow, M.P.H.Chief,CommunicationsProgramandStrategyBranchOfficeofCommunicationsNationalCancerInstituteBethesda,MD

H. Kim Lyerly, M.D.Director,ComprehensiveCancerCenterDukeUniversityDurham,NC

David E. Maslow, Ph.D.Chief,ResourcesandTrainingReviewBranchDivisionofExtramuralActivitiesNationalCancerInstituteRockville,MD

Gail P. McGrathPresident,NationalDirectorofGovernmentAffairsNationalPatientAdvocateFoundationWashington,DC

Transforming Translation—Harnessing Discovery for Patient and Public Benefit ix


Howard McLeod, Pharm.D.FredN.EshelmanDistinguishedProfessorDirector,UNCInstituteforPharmacogenomicsandIndividualizedTherapy,OncologyDivisionUniversityofNorthCarolina,ChapelHillChapelHill,NC

Anne McTiernan, M.D., Ph.D.CancerPreventionFredHutchinsonCancerResearchCenterSeattle,WA

Suresh Mohla, Ph.D.Chief,TumorBiologyandMetastasisBranchDivisionofCancerBiologyNationalCancerInstituteRockville,MD

Ida M. Moore, D.N.Sc., R.N., F.A.A.N.Professor,NursingPracticeDivisionUniversityofArizonaCollegeofNursingTucson,AZ

Cherie Nichols, M.B.A.Director,OfficeofSciencePlanningandAssessmentOfficeoftheDirectorNationalCancerInstituteBethesda,MD

J. Carl Oberholtzer, M.D., Ph.D.AssociateDirectorforTrainingOfficeofCenters,Training,andResourcesOfficeoftheDirectorNationalCancerInstituteBethesda,MD

Funmi Olopade, M.B.B.S., F.A.C.P.Director,FellowshipTrainingProgramDepartmentofHematology/OncologyUniversityofChicagoChicago,IL

Roman Perez-Soler, M.D.Chairman,DepartmentofOncologyMontefioreMedicalCenterAlbertEinsteinCollegeofMedicineBronx,NY

Charles S. Rabkin, M.D.MedicalEpidemiologistViralEpidemiologyBranchDivisionofCancerEpidemiologyandGeneticsNationalCancerInstituteRockville,MD

x Transforming Translation—Harnessing Discovery for Patient and Public Benefit


Brian J. Reid, M.D., Ph.D.Member,HumanBiologyandPublicHealthSciencesFredHutchinsonCancerResearchCenterSeattle,WA

David Scheinberg, M.D., Ph.D.Chair,MolecularPharmacologyandChemistryProgramChair,ExperimentalTherapeuticsCenterMemorialSloan-KetteringCancerCenterNewYork,NY

Richard L. Schilsky, M.D.ProfessorofMedicine/AssociateDeanforClinicalResearchBiologicalSciencesDivisionUniversityofChicagoChicago,IL

Jeffrey Schlom, Ph.D.LabChief,LaboratoryofTumorImmunologyandBiologyCenterforCancerResearchNationalCancerInstituteBethesda,MD

Mitchell D. Schnall, M.D., Ph.D.AssociateChairforResearch,DepartmentofRadiologyUniversityofPennsylvaniaPhiladelphia,PA

Thomas A. Sellers, Ph.D., M.P.H.AssociateCenterDirector,CancerPreventionandControlDivisionH.LeeMoffittCancerCenterandResearchInstituteTampa,FL

David Sidransky, M.D., Ph.D.Director/Professor,HeadandNeckCancerResearchJohnsHopkinsMedicalInstitutionsBaltimore,MD

Ellen V. Sigal, Ph.D.Chairperson,FriendsofCancerResearchArlington,VA

Richard M. Simon, D.Sc.Chief,BiometricResearchBranchDivisionofCancerTreatmentandDiagnosisNationalCancerInstituteRockville,MD

Sudhir Srivastava, Ph.D., M.P.H.Chief,CancerBiomarkersResearchGroupDivisionofCancerPreventionNationalCancerInstituteRockville,MD

Transforming Translation—Harnessing Discovery for Patient and Public Benefit xi


Daniel C. Sullivan, M.D.AssociateDirector,CancerImagingProgramDivisionofCancerTreatmentandDiagnosisNationalCancerInstituteRockville,MD

Thea D. Tlsty, Ph.D.Professor,DepartmentofPathologyUniversityofCalifornia,SanFranciscoSanFrancisco,CA

Louis M. Weiner, M.D.VicePresident,TranslationalResearchMedicalScienceDivisionFoxChaseCancerCenterPhiladelphia,PA

Janet Woodcock, M.D.DeputyCommissionerandChiefMedicalOfficerOfficeoftheCommissionerFoodandDrugAdministrationRockville,MD

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Transforming Translation—Harnessing Discovery for Patient and Public Benefit xiii

Report of the NCAB Translational Research Working Group—Table of Contents

Table of Contents

Executive Summary ............................................................................................................................ 1

Summary Vision .................................................................................................................................. 5

Introduction ......................................................................................................................................... 9

Coordinated Management ................................................................................................................ 13

Initiative A1: Establishaflexible,integratedorganizationalapproachthatcoordinatesearlytranslationalresearchacrosstheNationalCancerInstitute...............................................................14

Initiative A2: DesignateaspecificportionoftheNationalCancerInstitutebudgetforearlytranslationalresearch.......................................................................................................23

Initiative A3: Developasetofawardcodesthataccuratelycapturethenatureandscopeoftheearlytranslationalresearchportfolio...............................................................................25

Initiative A4: Establishadistinctiveprioritizationprocessforearlytranslationalresearch..................................................................................................................................28

Tailored Funding Programs .............................................................................................................. 33

Initiative B1: Modifymultiprojectcollaborativeawardguidelines,asappropriate,tofacilitateearlytranslationalresearch......................................................................................................34

Initiative B2: Improveprocessesandmechanismsforfundinginvestigator-initiatedearlytranslationalresearch......................................................................................38

Initiative B3: Establishaspecialtranslationalresearchfundingprogramtoadvanceprioritizedearlytranslationalresearchopportunities................................................40

Initiative B4: Establishafundingprogramforearlytranslationalresearchthatrequiresacademic/industrycollaborationinvolvingresourcesharingand/orco-funding.......................................45

Initiative B5: IntegrateaccesstoGMP/GLPmanufacturingandotherpreclinicaldevelopmentservicesmoreeffectivelywithmilestone-drivenearlytranslationalresearchprojects..............................50

Operational Effectiveness ................................................................................................................. 53

Initiative C1: Establishaformalprojectmanagementsystemforearlytranslationalresearch.......................................54

Initiative C2: Establishasystemtocoordinatecoreservicesessentialforearlytranslationalresearch..........................59

Initiative C3: Enhancequalityandaccessibilityofannotatedbiospecimenrepositoriesandassociatedanalyticmethods.......................................................................................................................64

Initiative C4: Developenhancedapproachesfornegotiationofintellectualpropertyagreementsandagentaccess.........................................................................................................................................68

Initiative C5: Enhanceinteractionsandcollaborationswithfoundationsandadvocacygroupstoadvanceearlytranslationalresearch......................................................................................................72

Initiative C6: Enhancetrainingandcareerincentivesforearlytranslationalresearch....................................................75

xiv Transforming Translation—Harnessing Discovery for Patient and Public Benefit

Report of the NCAB Translational Research Working Group—Table of Contents

Timeline and Budget ......................................................................................................................... 79

Evaluation and Outcome Measures ................................................................................................. 91

Appendices ......................................................................................................................................... 95

Appendix A: FoundationalDocuments...........................................................................................................................97

Appendix B: TRWGTranslationalResearchDefinitionandScopeofActivity..............................................................99

Appendix C: TRWGDevelopmentalPathwaystoClinicalGoals................................................................................101

Appendix D: TranslationalResearchPortfoliofortheNCITranslationalResearchWorkingGroup........................... 111

Appendix E: ProcessAnalysisfortheNCITranslationalResearchWorkingGroup....................................................125

Appendix F: TRWGMeetingDates..............................................................................................................................151

Transforming Translation—Harnessing Discovery for Patient and Public Benefit 1

Report of the NCAB Translational Research Working Group—Executive Summary

Executive Summary

InJune2005,theTranslationalResearchWorkingGroup(TRWG)wasestablishedundertheauspicesoftheNationalCancerAdvisoryBoard(NCAB)toadvisetheNationalCancerInstitute(NCI)onthefuturecourseofNCI-supportedtranslationalresearch,acriticallinkinrealizingthepromiseofmolecularoncologyforpatientandpublicbenefit.TheTRWGwasconstitutedasabroadandinclusivepaneloftranslationalresearchexperts,includingacademicscientistsandclinicians,representativesfromindustryandfoundations,patientadvocates,andNCIstaff.

TheTRWGfirstreachedconsensusonanoperationaldefinitionoftranslationalresearchas“researchthattransformsscientificdiscoveriesarisinginthelab,clinic,orpopulationintonewclinicaltoolsandapplicationsthatreducecancerincidence,morbidity,andmortality.”Forthefocusofitsdeliberations,theTRWGfurtherselectedthe“earlytranslationalresearch”portionofthePresident’sCancerPanelTranslationalContinuum,whichissituatedbetweenfundamentaldiscoveryresearchandPhaseIIIclinicaltrials(seeFigure1).TheTRWGthusintentionallydidnotseektochangeanyaspectofdiscoveryresearch—thelargestcomponentoftheNCIextramuralresearchfundingportfolio—andalsofocusedoncomplementingandextending,butnotduplicating,theinitiativesoftheClinicalTrialsWorkingGroup,whichconcentrateditsattentiononclinicaltrials.TheTRWGalsoviewedtheareasofdisseminationandadoption,whilecriticallyimportanttotheoverallsuccessofthecontinuum,tobeoutsidethescopeofitsdeliberations.

TheTRWGnextdraftedsixdevelopmentalpathwaystoclinicalgoals,definingtheoverallcourseofearlytranslationforeachofsixkeydomains—biospecimen-basedriskassessmentdevices,image-basedriskassessmentagents/techniques,agents,immuneresponsemodifiers,interventivedevices,andlifestylealterations.TheTRWGalsoconductedananalysisofNCI’scurrentportfoliointranslationalresearch,whichrevealedawiderangeofactivitiessupportedthroughmanydifferentmechanismsincludingbothinvestigator-initiatedandsolicitedprograms.Inaddition,aprocessanalysisinvolving20recenttranslational“successes”wasconductedtoidentifytheNCIprograms,individuals,organizations,etc.,involvedinachievingtranslationalprogresswithinthecurrentsystem.Finally,inanattempttolearnfromothers’experiencesandrecommendations,theTRWGreviewed11priorreportsandplanningdocumentsrelevanttotranslationalresearchthathadbeengeneratedoverthepreviousseveralyears.

Figure 1. TRWG Scope of Activity: The Translational Continuum*

Basic Science Discovery

Early Translation Late Translation Dissemination Adoption

• Promising molecule or gene target

• Candidate protein biomarker

• Basic epidemiologic finding

• Partnerships and collaboration (academia, government, industry)

• Intervention development

• Phase I/II trials

• Phase III trials• Regulatory approval• Partnerships• Production and

commercialization• Phase IV trials

– approval for additional uses

• Payment mechanism(s) established to support adoption

• Health services research to support dissemination and adoption

(newdrug,assay,device,behavioralintervention,educationalmaterial,training)• To community

health providers• To patients and

public

• Adoption of advance by providers, patients, public

• Payment mechanism(s) in place to enable adoption

TRWG Activity

*FromthePresident’sCancerPanel’s2004-2005reportTranslatingResearchIntoCancerCare:DeliveringonthePromise.

2 Transforming Translation—Harnessing Discovery for Patient and Public Benefit


Inassessingtherationaleforchange,theTRWGrecognizedfromtheoutsetthattheNCI-supportedtranslationalresearchenterpriseisnotkeepingpacewiththeenormousopportunitiespresentedbyadvancesinknowledgeandtechnologyoverthepast40yearsofcancerresearch.Basedontheseopportunities,publicexpectationsforsignificantadvancesincancerprevention,treatment,andcarearerising,yetresourcesdevotedtocancerresearchhavereachedaplateau.Giventhisclimate,theTRWGaskedhowNCIcouldbestensurethatthemostpromisingbasicresearchconceptsenterthedevelopmentalpathwaysandareadvancedrapidlyandefficientlyeithertotranslationalsuccessortoaproductivefailurethatusefullyinformsfurthertranslationalordiscoveryresearch.

Tomeetthischallenge,theTRWGidentifiedfourcriticalobjectivesforanationalearlytranslationalresearchenterprisethatcanadvancediscoveriesmoreeffectivelytowardearlyhumantestingofanewdrug,biologic,diagnostic/screeningtest,orothertherapeutic,diagnostic,orpreventativeintervention.Thefirstobjectivewastoimprovecoordinationandcollaborationandinstillacultureofactive,goal-orientedmanagementforbothindividualprojectsandtheenterpriseasawhole.Thesecondobjectivewastoimproveidentificationofthemostpromisingearlytranslationalresearchopportunitiesacrossalldiseasesites,populations,andpathwaystoclinicalgoalsthroughatransparent,inclusiveprocessinvolvingallrelevantstakeholdersanddrivenby:a)thestrengthofthescientificrationale,b)thetechnicalfeasibilityofthedevelopmentapproach,c)theexpectedclinicalorpublichealthimpact,andd)theriskthattheopportunitywouldnotbetakenforwardbyindustry.Thethirdobjectivewastotailorbothnewandexistingfundingprogramstofacilitateearlytranslationalresearchprogressandincentivizeresearcherparticipation.Thefourthobjectivewastoenhancetheoperationalefficiencyandeffectivenessofearlytranslationalresearchprojectsandthemanysupportingactivitiesessentialtotheenterprise,includingtheparticipationofpatientsandadvocacygroups.

Inaddressingtheseobjectives,theTRWGproceededthroughaconsensus-buildingprocessinvolvingthreesequentialstages.First,theTRWGidentifiedthosespecificaspectsofthecurrentNCI-supportedearlytranslationalresearchenterpriseinneedofimprovement.Thesecondstagewastodeveloprecommendationsfortargetedenhancementsineachofthoseaspects,someofwhichwerepresentedtotheNCABonJune14,2006.Inthethirdstage,theTRWGdefinedspecificinitiativesbasedonthoserecommendationsanddesignedimplementationplansfortheirpracticalrealization.Ineachofthesestages,theTRWGobtainedsubstantiveandvaluableinputfromthebroadercancerresearchcommunitythroughbothInternet-basedpublicforumsandinvitedRoundtableMeetings.

Thistransparent,inclusive,andstrategicallydrivenprocess,involvingallthecriticalstakeholdergroupsinthecancerearlytranslationalresearchcommunity,resultedinthe15initiativesdetailedinthisreporton“TransformingTranslation—HarnessingDiscoveryforPatientandPublicBenefit.”Theproposedinitiativescoverthefullbreadthofthecurrentandfutureearlytranslationalresearchenterprise,andeachaddressesoneofthecommonthemesderivedfromtheTRWGgoals:CoordinatedManagement,TailoredFundingPrograms,orOperationalEffectiveness.Takentogether,theseinitiativeswillstrengthenandtransformtheNCI-supportedearlytranslationalresearchenterpriseintoanationaleffortthatintegratestheindividuallystrongcomponentsofthecurrentsystemintoacoordinatedandcollaborativeendeavorfocusedonthedistinctiveneedsandcharacteristicsofearlytranslationalresearchandoptimizedforitssuccess.

Theinitiatives,whicharedescribedindetailinthereport,aresummarizedbelow.


• EstablishacoordinatedNCI-wideorganizationalapproachtomanagethediverseearlytranslationalresearchportfolio,reducefragmentationandredundancy,andensurethatresourcesarefocusedonthemostimportantandpromisingopportunities.

• DesignateaspecificportionoftheNCIbudgetforearlytranslationalresearchtofacilitatecoordinatedmanagement,long-termplanning,andprioritizationamongopportunitiesandapproachesaswellastodemonstrateNCI’scommitmenttotranslationalresearch.



• Developasetofawardcodesthataccuratelycapturesthenatureandscopeoftheearlytranslationalresearchportfoliotoenableacomplete,sharedunderstandingofNCI’stotalinvestment,helpidentifygapsandopportunities,anddemonstratetheextentoftranslationalactivitytothepublic.

• Createatransparent,inclusiveprioritizationprocesstoidentifythemostpromisingearlytranslationalresearchopportunitiesbasedonscientificquality,technicalfeasibility,andexpectedclinicalorpublichealthimpact.


• Modifyguidelinesformultiproject,collaborativeearlytranslationalresearchawardstofocusresearchonadvancingspecificopportunitiesalongadevelopmentalpathwaytowardpatientbenefit,andtorewardcollaborativeteamscience.

• Improveprocessesandmechanismsforreviewandfundingofinvestigator-initiatedearlytranslationalresearchtoincentivizeresearcherstoproposesuchstudies.

• Establishaspecialfundingprogramtoadvanceaselectnumberofespeciallypromisingearlytranslationalresearchopportunitiesidentifiedthroughthenewlycreatedprioritizationprocess.

• EstablishaprogramforjointNCI/industryfundingofcollaborativeearlytranslationalresearchprojectsthatintegratethecomplementarystrengthsofbothpartiestopursueopportunitiesthataremoreattractiveasacombinedeffort.

• IntegrateaccesstoGMP/GLPmanufacturingandotherpreclinicaldevelopmentservicesmoreeffectivelywithhigh-priority,milestone-drivenearlytranslationalresearchprojectstobetteraddressthisoftenrate-limitingstepinmovingaproductforwardtoearlyhumantesting.


• BuildaprojectmanagementsysteminvolvingstaffbothatNCIandatextramuralinstitutionstofacilitatecoordination,communication,resourceidentificationandaccess,andmanagementofmilestone-basedprogressformultidisciplinaryearlytranslationalresearchprojects.

• Coordinatecoreservicesessentialforearlytranslationalresearchtoreduceduplicationandensurethathigh-qualityservicesarereadilyaccessibletoallprojectsandinvestigators.

• Improvestandardization,qualitycontrol,andaccessibilityofannotatedbiospecimenrepositoriesandtheirassociatedanalyticmethodstostrengthenthiskeytranslationalresource.

• Developenhancedapproachesfornegotiationofintellectualpropertyagreementsandagentaccesstopromotecollaborationsamongindustry,academia,NCI,andfoundations.

• IncreaseNCIinteractionandcollaborationwithfoundationsandadvocacygroupstocapitalizeupontheircomplementaryskillsandresourcesforadvancingearlytranslationalresearch.

• Enhancetrainingprogramsandcareerincentivestodevelopandmaintainacommittedearlytranslationalresearchworkforce.

Foreachoftheseinitiatives,theTRWGdevelopedanimplementationplantorealizeitsgoals.TheindividualplansweredevelopedthroughmanyhoursofiterativediscussionanddeliberationbytheTRWG,firstwithinthesubcommitteethatgeneratedtheinitiativeandtheninplenarysession.Whilecompleteconsensuswasnotachievedonallspecificpoints,therewaswidespreadsupportforalloftheproposedplans.Theplanspresentedinthereportthusrepresentthecombinedwisdomofthe62TRWGmembersconcerninghoweachoftheinitiativesmightbeimplementedinaneffectiveandinnovative,yetfeasible,manner.ThegoalwastodevelopimplementationplansthatwouldbuildonthebestofthecurrentNCIearlytranslationalresearchsystemwhileproposingspecificnewactionstepsdesignedtoachievetheimprovements



envisionedbytheinitiatives.TheTRWGrecognizesthatactualimplementationmaywellproceedalongadifferentcourse.TheplansdetailedinthereportareofferedasanapproachwhichtheTRWGbelievescouldachievethegoalsoftheproposedinitiatives.

Theimplementationplanproposedforeachinitiativeincludesanassociatedtimelineandbudget.TheTRWGestimatesthatimplementationofalltheinitiatives,accordingtotheproposedplans,wouldrequire4to5yearstocomplete,withthefullimpactonroutineNCIoperationalpracticesexpectedtorequireatleast2to3additionalyears.Inthistimeline,allinitiativesaretargetedtobeginimplementationbytheendofyearthree.TheimplementationeffortasoutlinedisprojectedbytheTRWGtocost$94Mover5years.Estimatedexpensesincreasefromapproximately$4MeachinFY08andFY09to$13.5MinFY10,$28.5MinFY11,and$44MinFY12.TheincreasedexpendituresinFY10-12aredueentirelytodirectsupportfortheextramuralcommunityassociatedwiththenewtailoredearlytranslationalresearchfundingprograms.Oftheannual$4Minnonextramuralfunding,50%istooperatetheprojectmanagementsystem,25%istosupporttheprioritizationprocess,and25%isfortheNCImanagementandadministrativestructurenecessarytoimplementtheremaininginitiativesandeffectivelyguidethetransformedenterprise.

Majorchangesinanongoingenterprise,suchastheTRWGproposesforNCI-supportedearlytranslationalresearch,shouldbeundertakenonlyifthereisaplantoevaluatethesuccessofthosechanges.Therefore,iftheinitiativesareimplemented,theTRWGproposesthataformalevaluationsystembeestablishedtodeterminetheimpactoftheinitiatives.Theproposedevaluationsystemwouldincludemeasuresthataddressthreeimportantdimensionsofsuccess.Thefirstareprogrammanagementmeasurestoevaluatetheeffectivenesswithwhichtheinitiativesareimplemented.Thesecondaresystemperformancemeasurestodeterminewhetherthenewstructures,processes,andprogramsareachievingtheobjectivesofamorecoordinated,collaborative,transparent,efficient,andgoal-orientedearlytranslationalresearchenterprisethatisbettermanagedandprioritized.Thethirdaresystemoutcomemeasurestoassesswhetherthecombinedchangesresultinadvancinganincreasednumberofearlytranslationalresearchopportunitiestomiddle-andlate-stagehumanstudies.

ImplementationoftheTRWGinitiatives,whetherasoutlinedinthereportorbyothermeans,willrequireconsiderableadditionaleffortbythecancertranslationalresearchcommunity,aswellasafocused,butmodest,financialinvestmentbyNCI.TheTRWGbelievesthatthiscommitmentandinvestmentareessentialtoensurethatthemuchlargerongoingnationalinvestmentinearlytranslationalresearchisappropriatelymanagedandtargetedtohelprealizethepromiseofmolecularoncologybymovingimportantnewdiscoverieseffectivelytowardearlyhumantesting.Byembracingtheseinitiatives,NCIandthecancerresearchcommunitywilldemonstratetheirstrongcommitmenttoharnessingtheadvancesincancerbiologyachievedthroughthelast40yearsofprogressforpatientandpublicbenefit.


Report of the NCAB Translational Research Working Group—Summary Vision

Summary Vision

Build a focused, collaborative, multidisciplinary enterprise, tailored to the distinctive requirements of early translational research, which transforms and

strengthens this essential link from discovery to patient and public benefit.

Advancesinunderstandingthemolecularandcellulareventsunderlyingcancerofferanunprecedentedopportunitytotranslatediscoveriesintotangiblebenefitsforpatientsandthepublic.However,developmentoftargeted,molecularapproachestotherapy,prevention,prediction,detection,diagnosis,andprognosisrequiresnotonlyaneffectiveclinicaltrialssystembutalsoadynamicearlytranslationalresearchenterprisethatcantransformfundamentaldiscoveriesfromthelab,clinic,orpopulationintospecificproducts,interventions,orlifestylealterationsreadyforhumantesting.

Inparticular,earlytranslationalresearchhasenormouspotentialtoimprovetheoutcomeofclinicaltrialsdirectedatnewtherapiesbybothestablishingreliablemolecularmarkersoftherapeuticresponseandclearlyidentifyingthepatientsmostlikelytorespondbasedonthemolecularcharacteristicsoftheirdisease.Clinicaltrialsinformedbysuchmolecularunderstandingwillbemoreefficientandputfewerpatientsatriskthantheempiricapproachesusedinthepast.

Earlytranslationalresearchposesthreeprimarychallenges.Thefirstistoensurethatthemostpromisingandimportantdiscoveriesareidentifiedandmovedforwardintodevelopment.Thesecondistoensurethatthesediscoveriesadvancethroughthecomplex,multidisciplinary,goal-orienteddevelopmentprocessasefficientlyandeffectivelyaspossible.Thethirdistoensureasmooth,timelytransitionbetweenearlytranslationalresearchandlate-stagehumantrials,productcommercialization,andcommunitydissemination.

Meetingthesechallengeswillrequireacoordinatedandcollaborativenationalenterprisefocusedonthedistinctiveneedsandcharacteristicsofearlytranslationalresearchandoptimizedforitsconduct.Suchanenterpriseisneededbecausetranslationalresearchhasonlyrecentlyemergedasafocusedendeavor,distinctfromdiscoveryorclinicalresearch,dueatleastinparttotheenormousarrayofdiscoveriesonwhichscientificallydrivendevelopmentofabroadrangeofnewcancerinterventionscanbebased.ThisenterprisewillalsoimprovetheNationalCancerInstitute’s(NCI)abilitytoensurethatallAmericansbenefitfromtheNation’sinvestmentincancerresearch.Thisincludespatientsafflictedwithrarecancers,whichmaynotbeattractivetargetsforindustry-supportedearly-stagedevelopment,andpopulationsthataredisproportionatelyaffectedbycertaincancersorunderservedbycurrentapproachestoresearch,prevention,andtreatment.

BuildingamoreeffectiveandcoordinatedNCIearlytranslationalresearchenterprisewillrequireashareddefinitionofwhatconstitutesearlytranslationalresearch,anaccurateandcomprehensiveunderstandingofthescopeofongoingactivity,andacommitmenttoadequatefunding.GiventhatearlytranslationalresearchisdistributedacrossvirtuallyallNCIDivisions,Centers,andOffices,anintegrated,cross-NCIapproachisneededtoadequatelyanalyzetheportfolioofcurrentawardsandaddressanyidentifiedgaps,overlaps,orinefficienciesinallocationofresources.Acomprehensive,coordinatedapproachisalsorequiredtoensurethatscarceresourcesareequitablybalancedacrossdiseasesites,affectedpopulations,andthedevelopmentalpathwaystoclinicalgoals,andarefocusedonprojectswiththegreatestpotentialforbothtranslationalsuccessandimpactonpatientsandthepublic.

Theaccumulatingnumberofearlytranslationalresearchopportunities,coupledwithfiniteresources,requiresatransparent,inclusive,andfact-basedprocessforidentifyingthoseopportunitiesthataremostpromisingfordevelopment.Scientificquality,thegoldstandardfordiscoveryresearch,isanessentialcriterionforsuchaprocess.However,earlytranslationalresearchmustalsobejudgedbythetechnicalfeasibilityofafocuseddevelopmenteffort,thepotentialimpactonacriticalunmetclinicalorpublichealthneed,andthelikelihoodthattheopportunitywillnotbetakenforwardbyprivateindustrywithoutNCIinvolvement.Onceacomprehensiveandinclusiveprocesstoidentifythemostimportantopportunitiesisinplace,thetranslationalresearcheffortcanbeenhancedintwocomplementaryways.Thefirstisto



establishaproactive,highlyfacilitatedfundingprogramtoadvanceaselectnumberofthehighestpriorityopportunitiesthroughthedevelopmentprocessasefficientlyandeffectivelyaspossible.ThesecondistousetheidentifiedprioritiestoinformfundingdecisionsandthedevelopmentofnewinitiativeswithinthebroadertranslationalresearchportfolioacrosstheInstitute.

Forenhancedearlytranslationalresearchcoordinationandprioritizationtobeoptimallyeffective,fundingprogramsmustbestructuredtoadvanceprojectsdownadevelopmentalpathwayinafocused,milestone-driven,andgoal-orientedfashion.Suchprogramsmusthaveguidelines,incentives,andawardstructuresdesignedtofacilitatetimelydevelopmentalprogresstowardaspecificclinicalgoalratherthantoadvancescientificknowledgeoridentifynewresearchopportunities.Theselattergoalsarecentraltodiscoveryresearch,andremainimportantancillarygoalsfortranslationalresearch,buttheprimarypurposeoftranslationalprogressispatientandpublichealthbenefit.Moreover,becauseoftheircomplex,multidisciplinarynature,earlytranslationalresearchprojectsneedmoreactivemanagementtoensurethatneededresourcesareavailableandthatdiverseparticipantsandactivitiesarecoordinatedacrossthevariousstagesofdevelopment.Efficienttranslationalprogresswillalsorequireintegrationbetweenawardprogramsthatfunddifferentportionsofthedevelopmentalpathwaysandtimelyhandofftolate-stageclinicaltrials.

Enhancingearlytranslationalresearchproductivitywillalsorequireimprovementsinseveralaspectsofoperatingefficiency.High-quality,cost-effectivecoreservices,frommolecularanalysistomanufacturing,mustbereadilyaccessibletoallprojectsandinvestigators.Thisisespeciallytrueforstandardized,annotatedbiospecimens,whichareanessentialfoundationforkeyelementsoftranslationalprogress.Improvedtrainingandcareerincentiveswillbeessentialtoensureaworkforcecommittedtoearlytranslationalresearchthatiscontinuallyrefreshedbynewgenerationsofclinicalandlaboratoryresearchers.Collaboration,notonlyamongNCI-fundedresearchersbutwithotherkeyplayerssuchasindustry,researchfoundations,healthcarepractitionersandotherhealthcareprofessionals,patients,andpatientadvocates,iscentraltothesuccessoftheearlytranslationalresearchendeavor,particularlyinthetransitiontolater-stagedevelopment.Successfulcollaborationamongallpartieswilldependonenhancedcommunicationandoutreach,broadparticipationinNCImanagementandprioritizationprocesses,morejointfundingopportunities,andstreamlinedprocessesforestablishingrelationships.

Toachievetheseobjectives,theTranslationalResearchWorkingGroup(TRWG)oftheNationalCancerAdvisoryBoard(NCAB)hasdevelopedadetailedblueprintfor“TransformingTranslation—HarnessingDiscoveryforPatientandPublicBenefit.”TheTRWGstrategyistobuildonthestrengthsofexistingearlytranslationalresearchendeavorsbyenhancingcoordination,prioritization,andoperationaleffectivenesswhiletailoringfundingprogramstofacilitatetranslationalprogress.Thestrategyrecognizesthekeyroleofcancercentersinprovidingastabletranslationalresearchinfrastructure,thestrongearlytranslationalresearchconductedthroughtheSpecializedCenters(P50)andvariouscooperativeagreementandcontract-basedprograms,andthemanyexcellentearlytranslationalresearchprojectssupportedthroughinvestigator-initiatedProgramProject(P01),R01,andZ01awards.TheproposedTRWGinitiativespreserveandstrengtheneachoftheseexistingcomponentswhilecreatingneworganizationalstructuresandprocessesthatwillenablethemtoworktogetherinamoreintegratedandcooperativeway.TheproposedinitiativesarealsointendedtocomplementandextendtheworkoftheClinicalTrialsWorkingGroup,whichfocuseditsinitiativesontheclinicaltrialsenterprise,especiallylate-stagetrials,andtheenablinginformaticsinfrastructureandapplicationscurrentlybeingdevelopedbytheNCICenterforBioinformaticsaspartofthecancerBiomedicalInformaticsGrid(caBIG™).

ExtramuralinvestigatorsandNCIstafffromthroughouttheInstitutewillbeaskedtocollaborateinensuringthattheNCIearlytranslationalresearchportfolioisappropriatelybalancedacrossdiseasesites,affectedpopulations,anddevelopmentalpathwaystoclinicalgoalswithappropriateattentiontoprojectstargetedatrarecancersandminority/underservedpopulations.Theywillalsobeaskedtoparticipateinidentifyingespeciallypromisingearlytranslationalresearchopportunitiesandtoincorporateidentifiedprioritiesintotheirresearchprograms.Milestone-based,goal-orientedprogresswillbecomethestandardforrewardingearlytranslationalresearch,andinvestigatorswillbeexpectedtocollaborateopenly,sharingresources,handingoffprojectstonewteamsofexpertsasdevelopmentwarrants,andmakingteamscienceareality.



Implementingthesechangeswillrequireastrong,committedeffortbyallstakeholdersaswellasamodest,focusedfinancialinvestment.Butthisinvestmentofbothtimeandmoneyiswelljustifiedtoensurethatthemuchlargerongoingnationalinvestmentinearlytranslationalresearchachievesthegoalofmovingimportantdiscoveriesmoreeffectivelytowardsuccessfulhumantesting.Byembracingtheseinitiatives,NCIandthecancerearlytranslationalresearchcommunitywillenhancetheNation’seffectivenessandcompetitivenessinmeetingtheneedsandopportunitiesofcancerresearchasitevolvesintoaglobalpriority.Perhapsmoreimportantly,theNCI’scommitmenttotheseinitiativeswillalsodemonstrateastrongdedicationtoharnessingtheadvancesincancerbiologyachievedthroughthelast40yearsofresearchprogressforpatientandpublicbenefit.


Report of the NCAB Translational Research Working Group—Introduction

Introduction

InJune2005,theTranslationalResearchWorkingGroup(TRWG)wasestablishedundertheauspicesoftheNationalCancerAdvisoryBoard(NCAB)toadvisetheNationalCancerInstitute(NCI)onthefuturecourseofthiskeycomponentofNCI’sresearchportfolio.ThechargetotheTRWGwastoevaluatethecurrentstatusofNCI’sinvestmentintranslationalresearch,envisionitsfuture,anddeveloprecommendationsandimplementationplanstorealizethatvision.Thiseffortfollowed—andwasintendedtocomplementandextend—theworkoftheClinicalTrialsWorkingGroup,whichhadjustcompletedasimilarprocessrelatedtoclinicaltrials.TheTRWGisabroadlyconstitutedpanelofacademictranslationalresearchers,representativesfromindustryandfoundations,patientadvocates,andNCIstaff.ThemembershipoftheTRWGisprovidedatthefrontofthisreport.

Inordertofullyunderstandthecontextforitscharge,theTRWGbeganitsworkwithadetailedreviewof11prioranalysesandrecommendationsforimprovingtranslationalresearch.ThisincludedthePresident’sCancerPanel2004-2005AnnualReport;theNCAB1994CancerataCrossroadsReport;theNCABP30/P50AdHocWorkingGroupReport;theNCABClinicalTrialsWorkingGroupReport;severalNCIProgressReviewReports;theNIHRoadmapforMedicalResearch;andtheFoodandDrugAdministrationCriticalPathInitiativeReport(seeAppendixAforcitations).TheTRWGalsoreviewedseveralpublishedarticlesonthepromiseandchallengesoftranslationalresearch.

Tofurtherguideandinformitsdeliberations,theTRWGdevelopedanoperationaldefinitionoftranslationalresearchandselectedthe“earlytranslationalresearch”portionofthePresident’sCancerPanelTranslationalContinuumasthefocusforitsdeliberations(seeAppendixB).Basedonthedefinitionofearlytranslationalresearchasextendingfromacredentialeddiscoveryinthelab,clinic,orpopulationtothepointofearlyhumantesting,theTRWGdraftedsixdevelopmentalpathwaystoclinicalgoals:biospecimen-basedriskassessmentdevices,image-basedriskassessmentagents/techniques,agents,immuneresponsemodifiers,interventivedevices,andlifestylealterations(seeAppendixC).Byclearlydefiningthestepsinvolvedinearlytranslationalresearchanddistinguishingitfromdiscoveryresearch,thesepathwaysservedasavaluabletoolforunderstandingbarriersandchallengesinthecurrentsystemandforidentifyingareasinneedofimprovement.

TounderstandthenatureandscopeofNCI’scurrenttranslationalresearchactivity,theTRWGcommissionedacomprehensiveanalysisoftheFY04awardportfolio,includinginvestigator-initiated,solicited,andinfrastructureawards(seeAppendixD).ThisportfolioanalysisrevealedthattranslationalresearchawardsarecurrentlydistributedovermostDivisions,Centers,andOfficesandfundedbyarangeofprograms.However,theanalysisalsorevealedthatawardsarenotcurrentlycategorizedinamannerthatprovidesanaccurateassessmentoftranslationalcontent.TheTRWGalsocommissionedananalysisof20NCI-supportedtranslationalresearchsuccessestodeterminewhethertherewerecommonelementsorthemesthatcontributedtothosesuccesses(seeAppendixE).Theseanalysesdemonstratedthatsuccessfultranslationoccursthroughadiverserangeoffundingprogramsandstakeholderinteractions.

TheTRWGconductedsevenface-to-facemeetingsfromDecember2005throughJanuary2007.Toaccomplishitswork,theTRWGorganizeditselfintosubcommitteesresponsiblefordifferentaspectsoftranslationalresearch.Duringtheplenarymeetings,eachsubcommitteereportedontheprogressofitsworkandsolicitedcommentsfromtheTRWGasawhole.Betweenplenarymeetings,thesubcommitteesconductedasubstantialnumberofconferencecallsamongthemselvesandwithnon-TRWGexpertstodevelopandrefinetheirproposals.Furthermore,duringthisprocess,theexternalcommunityprovidedsubstantive,real-timeinputintothedevelopmentoftheTRWGrecommendationsthroughtwoimportantvenues—Internet-basedpublicforumsandinvitedRoundtableMeetings.

DuringthefirstInternetforum,conductedDecember2005throughJanuary2006,1theTRWGsoughtpublicinputonvarioustranslationalresearchissuesincludingbarriers,incentives,prioritization,funding,systemorganization,facilities/technologies,andmanpower/training.AttheinitialRoundtableMeeting,heldinFebruary2006,theTRWGsolicitedinputfromabroadarrayofcancercommunitystakeholdersonissuesintranslationalresearchandrecommendationsfor

1 MeetingdatesarelistedinAppendixF.



improvementfromthreedifferentperspectives:a)theTRWGpathwaystoclinicalgoals;b)populationsserved;andc)cross-cuttingthemessuchasfunding,organization,coordination,facilities/technologies,workforce/training,andindustryinteractions.AnIndustry/Society/FoundationRoundtable,heldinApril2006,providedanopportunityfortheTRWGtogatherinputfrompharmaceutical,biotechnology,anddevicecompaniesaswellascancersocietiesandfoundations.ThediscussionsatthisRoundtablefocusedonissuesofresources,collaboration,andmanagementintranslationalresearchaswellastheutilityoftheTRWGpathwaysastoolsfordevelopingandguidingresearchplans.DuringthesecondInternetforuminOctober2006,theTRWGrequestedpubliccommentonthedraftinitiativesandimplementationconcepts.DuringthefinalRoundtableMeeting,alsoheldinOctober2006,theTRWGrequestedcommentsanddiscussionconcerningthedraftinitiativesandtheirassociatedimplementationconcepts,againfromtheperspectiveofthedifferentTRWGdevelopmentalpathwaysandpopulationsserved.

InadditiontotheInternetforumsandRoundtableMeetings,theTRWGalsoreceivedvaluableinputfromtheAmericanAssociationforCancerResearch,theAmericanSocietyofClinicalOncologyTranslationalResearchTaskForce,theOncologyNursingSociety,theCancerBiologyTrainingConsortium,theUKMedicalResearchCouncil,theNationalInstituteofNeurologicalDiseasesandStroke,andtheDirectorsoftheSpecializedProgramsinResearchExcellence,theEarlyDetectionResearchNetwork,andthecancercenters.

Initsdeliberations,theTRWGreachedconsensusthroughfoursequentialstages.Thefirststagewastodefinethefollowinglistofcurrentchallengestothesuccessofearlytranslationalresearch:

1. Insufficientcoordinationandintegrationresultsinafragmentedtranslationalresearcheffortthatrisksduplicationandmaymissimportantopportunities.

2. AbsenceofclearlydesignatedfundingandadequateincentivesforresearchersthreatenstheperceivedimportanceoftranslationalresearchwithintheNCIenterprise.

3. Absenceofastructured,consistentreviewandprioritizationprocesstailoredtothecharacteristicsandgoalsoftranslationalresearchmakesitdifficulttodirectresourcestocriticalneedsandopportunities.

4. Themultidisciplinarynatureoftranslationalresearchandtheneedtointegratesequentialstepsincomplexdevelopmentalpathwayswarrantdedicatedprojectmanagementresources.

5. Translationalresearchcoreservicescanbeduplicativeandinconsistentlystandardized,withcapacitypoorlymatchedtoneed.

6. Inadequatecollaborationwithindustrydelaysappropriatedevelopmentalhandoffs.

7. Extendednegotiationonintellectualpropertyissuesdelaysorpreventspotentiallyproductivecollaborations.

8. Inadequatecollaborationwithfoundations/advocacygroupsrisksmissingimportantopportunitiesforpatientoutreachandintegrationoftranslationalresearchefforts.

9. Insufficientcollaborationandcommunicationbetweenbasicandclinicalscientistsandthepaucityofeffectivetrainingopportunitieslimitsthesupplyofexperiencedtranslationalresearchers.

TheTRWGthendefinedspecificimprovementsinthecurrentNCI-supportedearlytranslationalresearchenterprisetoaddresstheseobstacles.

Thesecondstagewastodeveloprecommendationsaddressingthemostimportantimprovements.Aninitialgroupofrecommendationsconcerningorganizationandfunding,prioritization,coreservices,andprojectmanagementwerepresentedtotheNCABonJune14,2006.Duringthethirdstage,additionalrecommendationsweredeveloped,focusingonexternalintegrationandworkforce/training.Finally,duringthefourthstage,specificinitiativesandimplementation



plansweredevelopedaddressingthevariousrecommendations.Thegoalwastodevelopproposedimplementationplansthatwouldbeinnovative,yetpractical,andwouldbuildonthebestofthecurrentNCIearlytranslationalresearchsystem.

Thisconsensus-buildingprocessresultedinthe15initiativesdetailedinthisreport,“TransformingTranslation—HarnessingDiscoveryforPatientandPublicBenefit.”TheseinitiativesarenotintendedtoaddressNCIeffortsinotherareasoftheTranslationalResearchContinuumasdefinedbythePresident’sCancerPanel,includingbasicsciencediscovery,latetranslation(PhaseIIItrials),dissemination,andadoption.

Theproposedinitiativesareorganizedintothreecategories:CoordinatedManagement,TailoredFundingPrograms,andOperationalEffectiveness.TheCoordinatedManagementInitiativesestablishanintegratedorganizationalapproachacrossNCItocoordinateandprioritizeearlytranslationalresearch,designateaspecificportionoftheNCIbudgetforearlytranslationalresearch,andimprovethecodingofearlytranslationalresearchawards.TheTailoredFundingProgramsInitiativesestablishnewfundingprogramstailoredtothedistinctivecharacteristicsofearlytranslationalresearchandmodifyexistingprogramstoenhancetranslationalproductivity.TheOperationalEffectivenessInitiativesimprovetheconductofearlytranslationalresearchbyestablishingaformalprojectmanagementsystem,coordinatingcoreservices,improvingbiospecimenresources,facilitatingindustryandfoundationcollaborations,andenhancingworkforcedevelopment.EachinitiativealsohasaproposedimplementationtimelineandbudgetpresentedinaconsolidatedTimelineandBudgetsection.

EachoftheinitiativespresentedinthisreportwascreatedtoaddressacriticalissuefortranslationalprogressandrepresentsanessentialgoalaboutwhichthereisstrongconsensusamongtheTRWGmembership.Foreachinitiative,theTRWGdevelopedarationalethatsupportsthegoaloftheinitiativeandservedasapremisefortheimplementationstrategy.TheTRWGthengavecarefulconsiderationtodevelopingconstructiveideasforimplementationstepsthatcouldmosteffectivelyachievethestatedgoals.Theseproposedimplementationplansattempttobalancetherequirementsoftheinitiativesagainsttherealitiesandconstraintsofcurrentstructural,functional,economic,andpoliticalenvironments.TheTRWGhopestheseideaswillbegivencarefulconsideration;theyarenotintendedtoconstrainNCI’soptionsforachievingthegoalsbut,rather,toenhanceitssuccessindoingso.

Nomajormodificationtoanongoingenterprise,suchasthatrecommendedbytheTRWG,shouldbeundertakenwithoutestablishingamechanismforevaluatingitssuccess.Accordingly,thisreportincludesasectiononEvaluationandOutcomesthatoutlinestheprocessrecommendedbytheTRWGforevaluatingtheimplementationandimpactoftheproposedinitiatives.


Report of the NCAB Translational Research Working Group—Coordinated Management


Introduction

TheTRWGportfolioanalysisrevealedthatearlytranslationalresearchissupportedbyawidevarietyofprogramsmanagedthroughvirtuallyallNCIDivisions,Centers,andOffices.Coordinationoftranslationalresearchactivitiesacrosstheseprogramsandorganizationalstructuresiscurrentlyinformalandprojectorissuespecific,whichcanresultinduplication,missedopportunities,andlackofsynergy.Amoreintegratedmanagementapproachhasthepotentialtodevelopasharedvisionforthegoalsoftheoverallenterpriseandincreasetheefficiency,productivity,andtransparencyofNCI-supportedearlytranslationalresearch.

AmorecoordinatedNCIorganizationalstructureforearlytranslationalresearchwilltakebetteradvantageoftherespectivescientificandmanagerialstrengthsoftheexistingDivisions,Centers,andOfficesandfacilitatecomprehensiveextramuraladviceandoversight.Akeymanagementtoolwillbeasharedunderstandingofthenatureandscopeoftheearlytranslationalresearchportfolioatboththeprogramandawardlevel.Suchanunderstandingisessentialtoidentifypotentialgaps,redundancies,andsynergiesacrossprojectsandprograms.Coupledwithabudgettargetforearlytranslationalresearch,italsowillfacilitatelong-termplanningandthebalancingofinvestmentsacrossdiseasesites,populations,andthesixTRWGdevelopmentalpathways.

AnotherkeymanagementtoolwillbeasystematicprioritizationprocessdrawingoninputfromallNCIDivisions,Centers,andOfficesandthebroadextramuralcommunity,includingawiderangeofhealthcareprofessionals,patientadvocates,andtheothergovernmentagenciesandfoundationsactiveincancerresearch.Theprocesswillbedesignedtoidentifytranslationalopportunitiesmostpromisingfordevelopmentbaseduponscientificquality,technicalfeasibility,andexpectedclinicalorpublichealthimportance,includingtheneedsofthosewithrarecancersandmedicallyunderservedpopulations.

Tobuildacoordinatedmanagementapproachthatincorporatestheseelements,theTRWGproposesfourinitiatives.

A1. Establish a flexible, integrated organizational approach that coordinates early translational research across the National Cancer Institute.

A2. Designate a specific portion of the National Cancer Institute budget for early translational research.

A3. Develop a set of award codes that accurately capture the nature and scope of the early translational research portfolio.

A4. Establish a distinctive prioritization process for early translational research.



Initiative A1: Establish a flexible, integrated organizational approach that coordinates early translational research across the National Cancer Institute.

Rationale

Translationalresearchisintendedtomoveadiscoveryorsetofdiscoveriesthroughafocuseddevelopmentprocesstothepointofearlyhumantesting(seethesixTRWGdevelopmentalpathwaysinAppendixC).Becauseofthecomplex,multidisciplinary,goal-oriented,fast-paced,andtime-sensitivenatureofthisdevelopmentprocess,translationalresearchrequiresamoreintegratedandcoordinatedmanagementapproachthanwouldbeappropriatefordiscoveryresearch.

Currently,NCI-fundedtranslationalresearchprojectsaremanagedbyindividualprogramsdistributedacrossvirtuallyallDivisions,Centers,andOffices.Coordinationacrossprogramsandorganizationalstructuresisgenerallyinformalandsituational,whichresultsinthepotentialforoverlap,duplication,missedopportunities,andotherinefficiencies.Thisdistributedapproachcanmakeitchallengingtoidentifypotentialsynergiesandtoredirectenergiesandresourcestoemergingopportunitiesinatimelymanner,andcanleadtoalackoffocusintranslationalresearchgoalsandprograms.Whilethescientificqualityoftheindividualresearchprojectsandprogramsisveryhigh,integratingtheprogramsmoreformallyandsubstantivelywouldenhancetheefficiencyandproductivityoftheenterpriseasawhole.

ManyoftheTRWGinitiativesaredesignedtoimprovecoordinationandintegrationoftranslationalresearchacrossprojectsandprograms,bothamonginvestigators,institutions,andNCI,andwithexternalstakeholderssuchasindustry,foundations,andadvocacygroups.However,tofullyrealizetheirpotential,theseinitiativesmustbeguidedbyacohesiveandcoordinatedNCIorganizationalstructurethatisfocusedspecificallyontheneedsoftranslationalresearchanddedicatedtoitsvitality.Suchacoordinatedstructureisnecessarytoeffectivelymanagetheoveralltranslationalresearchportfolio;reducefragmentationandredundancy;ensurethatrarecancers,medicallyunderservedpopulations,andhistoricallylower-resourcedpathwaystoclinicalgoalsareappropriatelyaddressed;andallocateresourcesacrosstheenterpriseformaximumoverallbenefit.Thiscomprehensivecoordinationisespeciallyimportanttodaygiventheanticipatedrapidpaceofcancerdiscoveriesandtheresultingneedforadaptivestructuresandfunctionstomanageandguidetheoverallenterprise.

Torealizethegoalsofthisinitiative,theTRWGproposestheimplementationplandescribedbelow.

Implementation Plan

Overall Approach

InordertoestablishamoreintegratedandcoordinatedmanagementapproachfortranslationalresearchacrossNCI,threecriticalorganizationalelementswillbeestablished.Thefirstisformalextramuraladviceandoversightspecificallyfortranslationalresearch,whichtheTRWGrecommendsbevestedinthenewClinicalTrialsAdvisoryCommitteeestablishedasaresultoftheClinicalTrialsWorkingGroupReport.ThesecondelementisaTranslationalResearchOperationsCommitteeinvolvingtheDirectors(ordesignees)ofallNCIDivisions,Centers,andOfficeswithresponsibilityfortranslationalresearchprogramsinamatrixmanagementstructureresponsibleforcoordinatingandintegratingtranslationalresearchactivitiesacrosstheInstitute.ThethirdelementisaTranslationalResearchSupportOfficewithinthenewCoordinatingCenterforClinicalTrialsestablishedasaresultoftheClinicalTrialsWorkingGroupReport.ThisSupportOfficewillberesponsibleforsupportingtheTranslationalResearchOperationsCommitteeandfacilitatingandcoordinatingimplementationofalloftheTRWGinitiatives.ThiscoordinatedmanagementstructureisdepictedinFigure2,page15.

Leadership Focus

AstrongfocusfortranslationalresearchwithintheOfficeoftheDirectorisessentialtoprovidecleardirectionforthefutureofNCI-fundedtranslationalresearchandensurethatissuesrelatedtotranslationalresearchhaveadedicated,coordinatedvoicewithintheNCIseniorleadershipteam.Thisleadershiprolefortranslationalresearchwillbeeither



assumedbytheNCIDirectorordelegatedbytheDirectortoaseniortranslationalresearcherwhoisatthelevelofaDivisionDirectorandservesontheExecutiveCommittee.ToensurecommitmenttothebroadtranslationalmissionoftheInstituteratherthananysinglecomponent,thisindividualideallywouldnotbeastandingDirectorofaDivision,Center,orOffice.IftheNCIDirectorelectstodelegatethisresponsibility,thedesigneeshouldhaveanationallyrecognizedscientificreputationintranslationalresearchandexperiencemanagingorganizationscarryingouttranslationalresearch.TheindividualshouldalsohaveexperiencewithNCIoperations,possiblythroughservingonNCIadvisorycommittees(e.g.,NationalCancerAdvisoryBoard(NCAB),AdvisoryCommitteeoftheDirector(ACD),BoardofScientificAdvisors(BSA),BoardofScientificCounselorsforBasicSciences,BoardofScientificCounselorsforClinicalSciencesandEpidemiology).

TheNCIDirectorordesigneewillserveasChairoftheTranslationalResearchOperationsCommittee(discussedbelow).TheChairwillberesponsibleforensuringthattheCommitteefunctionsasacohesiveteamtoadvancetranslationalresearchinacoordinatedandbalancedmanneracrossNCI.AparticularlyimportantresponsibilitywillbetoguidetheCommitteethroughanannualreviewoftheNCItranslationalresearchportfolioinordertoachieveaconsensusrecommendationonanintegratedprogramandbudgetacrossallDivisions,Centers,andOffices.

Translational Research External Advisory Oversight

AsaresultoftheinitiativesrecommendedbytheClinicalTrialsWorkingGroup,anewexternaladvisorycommittee,theClinicalTrialsAdvisoryCommittee,hasrecentlybeenestablishedtoadvisetheNCIDirectorontheconductofclinicalresearchacrosstheInstitute.TheTRWGiskeenlyawarethatthebenefitsofasimilarlyfocusedandinformedoversightgroupfortranslationalresearchmustbebalancedagainstthepotentialcostsandcomplexitiesofsuchanundertaking.Therefore,theTRWGrecommendsthattheresponsibilitiesofthenewClinicalTrialsAdvisoryCommitteebeextendedtoincludeoversightoftranslationalresearchandthatNCIconsiderchangingthenameofthiscommitteetotheClinicalandTranslationalAdvisoryCommittee.(Hereafterinthisreport,theCommitteewillbereferredtosimplyasthe“AdvisoryCommittee”whendiscussingitstranslationalresearchresponsibilities.)AlthoughseveralnewlyappointedmembersoftheAdvisoryCommitteeareexperiencedtranslationalresearchers,theTRWGrecommendsthatthemembershipbereviewedandexpandedasnecessarytoensurethatatleast50%ofthemembershavetranslationalresearchexpertise.

Therationaleforthisapproachisfourfold.First,thenewAdvisoryCommitteealreadyhasoversightresponsibilitynotonlyforlate-stageclinicaltrials,butalsoforearly-stagetrials,whichareanintegralpartofearlytranslationalresearch.Second,theAdvisoryCommitteehasresponsibilityforcertaincorrelativesciencestudies,whichmayinformnonclinicaldiscoveryandtranslationalresearchactivities.Third,integratedoversightwillfacilitatecoordinationoftheprioritizationprocessesforearlytranslationalresearchandlater-stageclinicaltrials.

Thefourth,andmostimportant,rationaleisthatrapidadvancesincancerbiology,whichenhanceourunderstandingofthegeneticandcellularmechanismsunderlyingspecificcancers,aremakingpossiblethescientificallydrivendevelopmentandclinicaltestingofnovelinterventionstargetedatthespecificcharacteristicsofapatient’stumororunderlyinggeneticprofile.Capitalizingontheseadvanceswillrequireclosecollaborationamongtranslationalscientistsandtheclinicalresearchersresponsibleforbothearly-andlate-stagetrials.Thededicatedhigh-levelattentionprovidedbyacoordinated

Figure 2. Coordinated NCI Organizational Structure



extramuraloversightbodyisneededtoensurethattheseadvancesinmolecularmedicinemoveforwardthroughdevelopmentandclinicaltrialsinacoordinatedandefficientfashion.

InvestingoversightresponsibilityfortranslationalresearchintheAdvisoryCommitteeratherthanNCI’sotheradvisorycommittees(e.g.,NCAB,ACD,BSA,theBoardsofScientificCounselors)isrecommendedbecausetheseothercommitteesarechargedwithadvisingtheDirectoronallaspectsofcancerresearch,ratherthanfocusingspecificallyonindividualcomponentsoftheenterprise.Incontrast,mergingoversightresponsibilityforearlytranslationalresearchwiththatforclinicaltrialswillprovideefficient,focusedoversightforbothcriticalcomponentsoftheoveralltranslationalresearchcontinuumacrossboththeintra-andextramuralcommunities.

TheAdvisoryCommitteewillhavethefollowingresponsibilitieswithregardtoearlytranslationalresearch:

1. AdvisetheDirectorontheeffectivenessofNCI’stranslationalresearchmanagementandadministrationacrossallDivisions/Centers/Officesinmeetingdemandsandopportunitiesacrossdiseasesites,patientpopulations,thesixTRWGdevelopmentalpathways,andtherangeofmolecularmechanismsresponsibleforcancerdevelopment,andmakerecommendationsforneededimprovementsandfuturedirections.

2. AdvisetheDirectorontheoperationsandactivitiesoftheTranslationalResearchOperationsCommittee(describedbelow).

3. AdvisetheDirectorandExecutiveCommitteeontheappropriatemagnitudeforthededicatedtranslationalresearchbudgettarget(seeCoordinatedManagementInitiativeA2)andrecommendallocationoftranslationalresearchfundingacrossorganizationalunits,programs,diseasesites,populations,developmentalpathways,andmolecularmechanisms.

4. Ensurethatappropriateemphasisisplacedonidentifyingresearchneedsandprioritiesforrarecancers,medicallyunderservedpopulations,andhistoricallylower-resourcedpathwaystoclinicalgoals(e.g.,immunotherapy,interventivedevices,lifestyleinterventions).

5. RecommendtotheDirectortranslationalresearchprioritiesbasedonthenew,system-widetranslationalresearchprioritizationprocess(seeCoordinatedManagementInitiativeA4).

Translational Research Operations Committee

Giventhenumber,breadth,andpaceofearlytranslationalresearchactivitiesunderwayacrossNCIDivisions,Centers,andOffices,itisessentialtocreateaninternalmanagementstructurethatcancoordinateandintegratetheseactivitiesandrespondtoemergingopportunities.Tothatend,aTranslationalResearchOperationsCommitteewillbeestablishedthatincludestheDirectors(ordesignees)ofallNCIDivisions,Centers,andOfficeswithresponsibilityforsubstantialearlytranslationalresearchprograms.TheCommitteewillbechairedbytheNCIDirectorortheindividualdesignatedbytheDirectortoleadtranslationalresearchacrossNCI(seeabove).

Aswiththeexternaladvisoryrole,theTRWGconsideredtheadvantagesanddisadvantagesoftaskinganexistingbody,suchastheExecutiveCommittee,withtheresponsibilitiesenvisionedforthisnewcommittee.Inthiscase,however,anew,dedicatedcommitteeseemedthemosteffectiveapproachgiventherequirementforactivemanagementandtheoperationalchallengestobeaddressed.SuchanewOperationsCommitteewillconstituteanefficientmanagementtoolandforumtoensurethattranslationalresearchissuesareaddressedwithadedicatedtimeandagendathatcannotbedivertedtootherpressingmatters.

Membership. GivenNCI’scurrenttranslationalresearchportfolio,initialmembershipoftheTranslationalResearchOperationsCommitteewillbetheDirectors(ordesignees)fromthefollowingNCIorganizationalunits:

• DivisionofCancerPrevention

• DivisionofCancerTreatmentandDiagnosis



• DivisionofCancerBiology

• DivisionofCancerControlandPopulationSciences

• DivisionofCancerEpidemiologyandGenetics

• OfficeofCenters,Training,andResources

• CenterforCancerResearch

• OfficeofTechnologyandIndustrialRelations

• CenterforBioinformatics

• DivisionofExtramuralActivities.

OtherNCIentities—suchastheOfficeofSciencePlanningandAssessment,theOfficeofLegislativeAffairs,andtheTechnologyTransferBranch—willberepresentedontheOperationsCommitteeonanadhoc,nonvotingbasis.

Coordination of Translational Research Portfolio. TheTranslationalResearchOperationsCommitteewill,onanannualbasis,reviewandprioritizethetranslationalresearchportfolioproposedbyeachDivision,Center,andOfficewiththegoalofbalancing,coordinating,andintegratingtranslationalresearchacrossNCI.PrioritizationofnewinitiativesandguidancetoprogramstaffconcerningR01andP01prioritieswillbebasedontheprioritiesresultingfromthenewprioritizationprocess(seeCoordinatedManagementInitiativeA4),aswellasequitablebalanceacrossdiseasesites,populations,andtheTRWGdevelopmentalpathways,alongwithspecialattentiontotheneedsofrarecancersandminorityorunderservedpopulations.TheCommitteewillreviewandapprovealltranslationalresearchProgramAnnouncements(PAs)andRequestsforApplications(RFAs)priortosubmissiontotheExecutiveCommittee.

Development of an Integrated Translational Research Program Budget. TheOperationsCommitteewilldevelopanintegratedtranslationalresearchprogrambudgetthatwillberecommendedtotheExecutiveCommitteeandtheNCIDirectorforuseinNCI-widebudgetdeliberations.This“translationalresearchbudget”willrepresentamatrixoftheportionofeachDivision,Center,andOfficebudgetdevotedtotranslationalresearch.

ThematrixtranslationalresearchbudgetwillinitiallyinvolveallRFA-andPA-directedprogramsidentifiedbytheOperationsCommitteeasfocusedonearlytranslationalresearch.ThesewilllikelyincludetheSpecializedProgramsofResearchExcellence(SPORE),EarlyDetectionResearchNetwork(EDRN),In VivoCancerMolecularImagingCenters(ICMIC),NationalCooperativeDrugDiscoveryGroups(NCDDGs),RapidAccesstoInterventionDevelopment(RAID)/RapidAccesstoPreventiveInterventionDevelopment(RAPID)/DevelopmentofClinicalImagingDrugsandEnhancers(DCIDE)programs,andprojectsfundedthroughPAsandRFAsidentifiedas“translational.”ThePhaseIandPhaseIIclinicaltrialcontractswilleitherbeincludedinthisbudgetoraspartoftheclinicaltrialsbudgetmanagedbytheClinicalTrialsOperationsCommitteeformedinresponsetotheClinicalTrialsWorkingGroupReport.

Whilethisinitialgroupofprojectswillnotdefinethecompletetranslationalresearchbudget,itwillrepresentacoresetoftranslationalresearchactivities.ThiswillallowtheOperationsCommitteetomakeaninitialevaluationofthetranslationalresearchbudgetwithregardtothefollowing:

• OverallsizerelativetothetotalNCIresearchbudget

• AllocationacrossDivisions,Centers,andOffices

• PercentageoffundingfromeachDivision,Center,andOfficedesignatedfortranslationalresearch

• Allocationacrossfundingprograms

• Allocationacrossdiseasesites



• Allocationacrosspopulations

• Allocationacrossprevention,therapy,riskassessment,etc.

• AllocationacrossthesixTRWGdevelopmentalpathways

• Allocationacrosstopicsofinterest(e.g.,explorationofspecificmechanismsofcancerdevelopment,specifictechnologies,corefacilities).

Asthecodingsystemandportfolioanalysistechniquesimprove(seeCoordinatedManagementInitiativeA3),theintegratedbudgetwillbeexpandedtoincludeR01andP01andZ01awardsthatarecodedastranslational,trainingawardsfromprogramsidentifiedasapplicabletotranslationalresearchers(e.g.,K12,K23,K24),andawardsfromothermechanismsidentifiedbytheTRWGportfolioanalysisasbeingmorethan50%translational(e.g.,SmallBusinessInnovationResearchProgram[SBIR]/SmallBusinessTechnologyTransferProgram[STTR]).ThiswillallowtheOperationsCommitteetofurtherrefineitsmanagementoftranslationalresearchfundingacrossNCI.

Oncetheintegratedtranslationalbudgetanditsassociatedportfolioanalysisareavailableinacomprehensivefashion,theOperationsCommitteewillbeabletoidentifygaps,overlaps,andopportunities.Thesecanthenbeusedasthebasisfordevelopingandsustaininga5-yearrollingplanandbudgettoguidethefutureoftranslationalresearch.SuchaplanwillallowNCItochartfutureobligationsassociatedwithalready-fundedtranslationalresearchawardsaswellasanalyzetradeoffsthatmayberequiredamongfundingexistingprograms,fundingnewTRWG-recommendedprograms(seeTailoredFundingProgramsInitiativesB3andB4),andfundingothernewprograms.

Additional Responsibilities. Inadditiontothemajorresponsibilitiesdescribedabove,theTranslationalResearchOperationsCommitteewillberesponsibleforthefollowingtasksinconsultationwiththeAdvisoryCommittee:

1. EvaluateorganizationalinfrastructuresandoperatingbudgetsfortranslationalresearchprogramsupportacrossallDivisions,Centers,andOffices,andmakerecommendationsasnecessarytoimprovecost-effectivenessandreduceduplicationandoverlap.

2. RefinetheTRWGoperationaldefinitionof“translationalresearch,”asdistinguishedfromdiscoveryorclinicalresearch,andapproveanewcodingsystemthatwillallowtheNCItranslationalresearchportfoliotobeidentifiedandtrackedaccurately.

3. Identifyfutureopportunitiesforprogrammaticimprovement,whetherthroughnewpartnerships(industry,foundations,trans-NIH),newcollaborationsacrossNCIgrantees,newintramural-extramuralpartnershipsandcollaborativeactivities,oridentificationofemergingbarriers/roadblockstotranslationalsuccess.

4. OverseeandcoordinateimplementationoftheTRWGinitiatives.

Translational Research Support Office

TomanageimplementationoftheTRWGinitiativesandsupporttheTranslationalResearchOperationsCommitteeandtheAdvisoryCommittee,aTranslationalResearchSupportOffice(TRSO)willbecreatedwithintheCoordinatingCenterforClinicalTrials(CCCT)recentlyestablishedintheOfficeoftheDirectorasaresultoftheClinicalTrialsWorkingGroupprocess.SuchanexpansionoftheCCCT’sresponsibilitieswillrequirecreatingtwodistinctbutintegratedofficesundermanagementofacenterdirector.Oneofficewillhaveprimaryresponsibilityforclinicaltrialsissuesandtheotherwillhaveprimaryresponsibilityfortranslationalresearchissues.

Thisorganizationalstructurewillhaveseveralbenefits.First,itwillensurethatactivitiesattheintersectionoftranslationalandclinicalresearch(e.g.,early-stagetrials)arewellintegrated.Second,itwillfacilitatecreationofacadreofprofessionalswhoarecross-trainedandabletocontributebothoperationallyandstrategicallytoactivitiesthatimpact



eithertranslationalorclinicalresearch,regardlessoftheirprimaryfocusofresponsibility.Finally,itwillallowmoreefficientuseofadministrativesupportandorganizationalservices.

Staffing. TheSupportOfficestaff,whichwillbephased-inovertimetosupportimplementationoftheTRWGinitiatives,willbeprimarilyprofessionalstaff.TheheadoftheOfficewillbeatranslationalresearcherandmanager,preferablywithexperienceinboththeextramuralcommunityandatNCI.HeorshewillberesponsibleformanagementoftheOfficeanditsintegrationwithoverallactivitiesoftheexpandedCoordinatingCenter.TheprofessionalstaffwillhavetranslationalresearchexperienceineitheracademiaorindustryaswellasexperienceinNCIextramuralprogrammanagementorreview.TheSupportOfficewillalsoincludeindividualswithtranslationalresearchprojectmanagementexperienceineitherindustryoracademia(seeOperationalEffectivenessInitiativeC1).ManySupportOfficeresponsibilitieswillbeimplementedwiththeassistanceofcontractorsandotherNCIstaff;however,thoseactivitieswillbedirectedandcoordinatedbySupportOfficestaff.

Responsibilities. TheTRSOwillhavethefollowingresponsibilities:

1. Manageoperationofthenewtranslationalresearchprioritizationsystem(seeCoordinatedManagementInitiativeA4),includinggatheringandanalyzinginputfromthebroadcancerresearchcommunityandoverseeingtheportfolioanalysisofongoingNCI-fundedactivities.

2. ProvidesupportfortheTranslationalResearchOperationsCommittee,especiallyinoverseeingportfolioanalysesanddevelopingtheintegratedtranslationalresearchbudget.

3. ServeasprogramofficersandprojectmanagersfortheSpecialTranslationalResearchAccelerationProject(STRAP)programandtheacademic/industrycollaborationprogram(seeTailoredFundingProgramsInitiativesB3andB4).2

4. ProvideprojectmanagementsupportandcoordinationtoprojectmanagersandprogramofficersintheDivisions/Centers/Officesinexecutingtheirprojectmanagementresponsibilitiesformultiprojectcollaborativeawards,includingP50andU-seriesawards.

5. ManageimplementationoftheremainingTRWGinitiativesinconsultationwithNCIleadershipandprogramstaff:

Newcodingsystemfortranslationalresearchawards

Modificationsofguidelinesformultiprojectcollaborativetranslationalresearchawards

CollaborationacrossNIHtocreatenewR-seriesandP-seriesmechanismstailoredtotranslationalresearch

Integrationoffundingprogramsforpharmacology,toxicology,andmanufacturingserviceswithfundingprogramsforotherstepsintranslationalresearch

Coreservicescoordinationandcreationofregionalcentersofexcellence

CollaborationwiththeOfficeofBiorepositoriesandBiospecimenResearchonenhancedqualityandaccessibilityofbiospecimenrepositories

Improvedpracticesfornegotiationofintellectualpropertymattersintranslationalresearch

Enhancedintegrationandcollaborationwithfoundationsandadvocacygroups

Improvedtrainingandcareerincentivesforthetranslationalresearchworkforce.

2 Foreachaward,TRSOstaffwillworkcloselywithadesignatedDivisionalprogramstaffmemberwhohastherelevantscientificexpertiseandexperience.Astheprogramsexpand,programofficer/projectmanagerresponsibilitiesmaybeshiftedtotherelevantDivisionalstaffattimeofaward.

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Minority and Underserved Populations Working Group

Tofacilitatethefocusingoftranslationalresearchresourcesonunmetcancerresearchneedsassociatedwithminorityandunderservedpopulations,theTRWGrecommendsthattheAdvisoryCommitteeestablishaTranslationalResearchMinorityandUnderservedPopulationsWorkingGroupchargedwithmakingrecommendationswithregardtothefollowingareas:

1. Identifyinitialtargetsoftranslationalresearchneedandopportunitywithregardtothesespecialpopulations,usingprioritizationapproachessimilartothosedescribedinCoordinatedManagementInitiativeA4.

2. Developaprogrammaticstrategyforaddressingtheidentifiedtargets,includingtheappropriatemixofintramuralandextramuralactivities,thefundingvehiclesbestsuitedtofacilitatingtheextramuralcomponent,andapproachesforobtainingnewfundsorreprogrammingexistingfundsovertimetosupportthiseffort.

3. Designresearch-linkedtrainingopportunitiesthatwillengageyoungresearchersfromunderrepresentedpopulationsaswellasresearchersinterestedinaddressingtheunmetneedsofminorityandunderservedpopulations.

4. Developastrategyfornetworkingandcollaborationwithindustry,foundations,advocacygroups,communityorganizations,etc.,insupportoftheobjectivesofthiseffort,andfordisseminationofitspriorities,strategies,andresults.

TheTRWGrecommendsthattheWorkingGroupincludethefollowingmembers:

• AdvisoryCommitteememberswithtranslationalresearchexpertiserelevanttominorityandunderservedpopulations

• RepresentativesfromtheDirector’sConsumerLiaisonGroup

• Directors(ordesignees)ofallintramuralandextramuralDivisions,Centers,andOfficeswithprogramsrelevanttominorityandunderservedpopulations

• DirectoroftheNCICentertoReduceCancerHealthDisparities

• ChiefoftheComprehensiveMinorityBiomedicalBranchintheNCIOfficeofCenters,Training,andResources

• Cancerdisparitiesexperts

• Intramuraltranslationalresearchersfocusedontheneedsofminorityandunderservedpopulations

• Extramuraltranslationalresearchersfocusedontheneedsofminorityandunderservedpopulations

• Leadersofexistingcancerresearchinitiatives,networks,andconsortiaintheareasofminoritiesandunderservedpopulations

• Advocatesrepresentingpatientsfromminorityandunderservedpopulations

• Communityleadersrepresentingminorityandunderservedpopulations.

Rare and Pediatric Cancers Working Group

Tofacilitatethefocusingoftranslationalresearchresourcesonunmetneedsassociatedwithrarecancersandpediatriccancers,theTRWGrecommendsthattheAdvisoryCommitteeestablishaTranslationalResearchRareandPediatricCancersWorkingGroupchargedwithmakingrecommendationswithregardtothefollowingareas:

1. Identifyinitialtargetsoftranslationalresearchneedandopportunitywithregardtothesecancers,usingprioritizationapproachessimilartothosedescribedinCoordinatedManagementInitiativeA4.



2. Developaprogrammaticstrategyforaddressingtheidentifiedtargets,includingtheappropriatemixofintramuralandextramuralactivities,thefundingvehiclesbestsuitedtofacilitatingtheextramuralcomponent,andapproachesforobtainingnewfundsorreprogrammingexistingfundsovertimetosupportthiseffort.

3. Designresearch-linkedtrainingopportunitiesthatwillengageyoungresearchersinterestedinaddressingtheunmetneedsofrareandpediatriccancers.

4. Developastrategyfornetworkingandcollaborationwithindustry,foundations,advocacygroups,etc.,insupportoftheobjectivesofthiseffort,andfordisseminationofitspriorities,strategies,andresults.

TheTRWGrecommendsthattheWorkingGroupincludethefollowingmembers:

• AdvisoryCommitteememberswithtranslationalresearchexpertiserelevanttorarecancersandpediatriccancers

• RepresentativesfromtheDirector’sConsumerLiaisonGroup

• Directors(ordesignees)ofallintramuralandextramuralDivisions,Centers,andOfficeswithprogramsrelevanttorarecancersandpediatriccancers

• Intramuraltranslationalresearchersfocusedontheneedsofpatientswithrarecancersandpediatriccancers

• Extramuraltranslationalresearchersfocusedontheneedsofpatientswithrarecancersandpediatriccancers

• Leadersofexistingcancerresearchinitiatives,networks,andconsortiaintheareasofrarecancersandpediatriccancers

• Advocatesrepresentingpediatriccancerpatientsandpatientswithrarecancers.

Potential Translational Research Consortia

Asthetranslationalresearchprocessevolves,anadditionallevelofcoordinationaroundorgan-specificdiseasesitesmaybebeneficialinenhancingsynergyandreducingredundancies.TheTRWGthereforerecommendsthattheAdvisoryCommitteeevaluatethebenefitsofestablishingorgan-specific,multi-institutional,multidisciplinary,multiprojectconsortiaintegratingallaspectsofearlytranslationalresearchacrosstheTRWGdevelopmentalpathways.Theseconsortiaareenvisionedtoincludethefollowingelements:

• Significanttranslationalandclinicalresearchexperienceintherelevantorgansystem

• Linkagetorelevantdiscoverylaboratoriesforidentificationofnewapproaches

• ExpertiseinthetechnologiesrequiredfortherelevantTRWGdevelopmentalpathways

• Accesstocross-cuttingtechnologiessuchasimaging,animalmodels,high-throughputscreening,andassayvalidation

• Experiencewithmolecularmechanismsknowntoberelevanttotheorgansystem

• Accesstosignificantnumbersoftissuesamplesandexpertiseinthestandardizedcollection,storage,andannotationofrelevantbiospecimens

• Accesstotoxicology,pharmacology,andmanufacturingfacilitiesandexpertise

• Experienceintheconductofearly-stage,tissue-drivenPhaseIandPhaseIItrialsinrelevantpatientpopulationsandaccesstothosepatientpopulations

• Integrationwiththelate-stageclinicaltrialsinfrastructureforrelevantpatientpopulations.



Indeterminingwhethersuchconsortiawouldbevaluableandfeasible,theTRWGrecommendsthattheAdvisoryCommitteeconsideravarietyofmodels.Forexample,onemodelwouldbetoestablishspecificrequirementsandsupplementalfundinginordertointegrateexistingfundingprogramsandprojectsintoconsortia.Anothermodelwouldinvolvecreatinganewmulti-institutional,multidisciplinaryconsortiumfundingmechanismbyconsolidatingseveralcurrentfundingmechanisms,atleastinpart.

TheTRWGrecommendsthattheAdvisoryCommitteeaddressthebenefitsofcreatingforthecommoncancers(e.g.,breast,prostate,lung,colorectal)twoormoreconsortiafocusedonspecificaspectsofthedisease(e.g.,therapyversusprevention)andalsoidentifyorgansystemsthatmightbeespeciallyappropriateforpilotingofsuchanapproach(e.g.,rarecancers).Inaddition,theTRWGsuggeststhattherewouldbesubstantialbenefitinconfiguringtheseconsortiainamatrixedmanner,notjustfororgansbutalsoforcross-cuttingthemes,suchasmolecularmechanismsorspecifictechnologies(e.g.,imaging,biospecimens,mousemodels,moleculardiagnostics)thatwouldinteractwiththeorgan-specificconsortia.Finally,theCommitteeshoulddeterminewhetherseedgrantswouldbebeneficialinencouragingtheextramuralcommunitytodevelopapproachesforbuildingsuchconsortia.



Initiative A2: Designate a specific portion of the National Cancer Institute budget for early translational research.

Rationale

Currently,theNCI“translationalresearchbudget”isnotwelldefined.Anintegratedbudgetcomprisingidentifiabletranslationalresearchcomponents(i.e.,intra-andextramuralresearchinfrastructures,projects,personnel,etc.)andtheirmissionsdoesnotexist.AlthoughcertainNCIprogramsareclearlytranslational,identifyingall“translationalresearchawards”andunderstandingtheircontributiontothetranslationalresearchbudgetcurrentlyrequiresthedevelopmentofadhocinclusion/exclusioncriteriaandlabor-intensiveportfolioanalysesofindividualtranslationalresearchawards.Moreover,notargethasbeenestablishedfortheportionoftheNCIbudgetthatshouldbedevotedtotranslationalresearch.Thus,evenifthetotaltranslationalresearchbudgetwereknownwithaccuracy,itwouldstillbetheresultofalargenumberofindividualdecisionsasopposedtoacoordinatedprocesstoachieveanagreed-uponbudgetallocation.

TheportfolioanalysiscommissionedbytheTRWG(seeAppendixD)revealedthathalfoftheresearchidentifiedastranslationalwasfundedthroughinvestigator-initiatedR01andP01awards($662Mof$1.33B,or49.8%).3Giventhisprominenceofunsolicitedinvestigator-initiatedresearchwithinNCI’stranslationalresearchportfolio,withoutabudgettargettheactualamountoftranslationalresearchfundingcouldvarywidelyovertimedependinguponthefortunesofindividualproposalswithintheNIH-widepeerreviewsystem.

DesignatingaspecificportionoftheNCIbudgetfortranslationalresearchwillhavetwocriticalbenefits.ThefirstisthatNCIwillbeabletomanageitsinvestmentintranslationalresearchinacoordinatedfashion,facilitatinglong-termplanningandallowingprioritizationamongprogramsandapproaches.ThesecondbenefitisthatadesignatedbudgettargetwilldemonstrateNCI’srecognitionofandcommitmenttotheimportanceoftranslationalresearchthatisessentialtoachieveitscoremissionofimprovingthehealthofpatientsandthepublic.Moreover,achievingconsensusonadesignatedbudgettargetisavitalcomplementtothecreationofacoordinatedmanagementstructurefortranslationalresearchacrossNCI.ItisalsoinkeepingwiththeNIHDirector’scommitmenttodevoteapproximately35%oftheoverallNIHbudgettotranslationalresearch.4


Implementation Plan

TheAdvisoryCommittee(seeCoordinatedManagementInitiativeA1)willberesponsibleforrecommendingthedesiredpercentagetargetforNCI’sannualspendingontranslationalresearch.BasedontheTRWGtranslationalresearchportfolioanalysis(seeAppendixD),itappearsthatapproximately30%ofthetotalNCIbudget($1.33Brelativetoatotalof$4.4B)wasdevotedtotranslationalresearchinFY04.Althoughamoredetailedassessmentofasubsetoftheawardsindicatedthatthisnumbermaybehighbyasmuchas20-40%,itisreasonabletoassumethatcurrenttranslationalresearchfundingisintherangeof20-30%ofthetotalNCIbudget.Therefore,theTRWGrecommendsthattheinitialtargetbeinthe25%-35%range,whichisinlinewithDr.Zerhouni’srecommendation.TheTranslationalResearchOperationsCommitteeandtheAdvisoryCommitteewillusethisbudgettargettomanagetranslationalresearchacrossNCI,whiletheOfficeoftheDirectorwillusethebudgettargetasacomponentinmanagingNCI-wideresearchfunding.

Thetranslationalresearchbudgettargetwillbeexpectedtoencompassfourcomponents.Thefirstisthesolicited(i.e.,RFA/PA-directed)programsalreadyidentifiedastranslationalintheportfolioanalysis.Theseprogramsprovidecriticalinfrastructures,projects,andpersonneltoadvancetranslationalresearch.Thesecondistheunsolicited,investigator-

3 AlthoughtheportfolioanalysisdidnotassessfundingbyindividualProgramAnnouncementsorRequestsforApplication,itislikelythatthevastmajorityoftheR01andP01awardsidentifiedastranslationalareinvestigator-initiated.WhenfundingmechanismssuchasK-seriescareerdevelopmentawards,R37MethodtoExtendResearchinTime(MERIT)awards,andSmallBusinessInnovationResearch/SmallBusinessTechnologyTransferResearchawardsareaddedtotheR01andP01awards,nearly60%oftheidentifiedtranslationalresearchoccursthroughinvestigator-initiatedmechanismsnotnecessarilyspecificallydesignedbyNCItofostertranslation.

4 NIH at the Crossroads: Myths, Realities and Strategies for the Future.



initiatedawardsidentifiedastranslationalbythenewcodingsystem(seeCoordinatedManagementInitiativeA3).ThethirdistheawardsresultingfromthenewsolicitedfundingprogramsproposedbytheTRWG(seeTailoredFundingProgramsInitiativesB3andB4).ThefourthistheoperationalexpensesassociatedwithimplementingandsustainingtheTRWGinitiatives.

Onceacompletepictureoftranslationalresearchfundingisobtainedbasedonthenewcodingsystem,theTranslationalResearchOperationsCommitteewillcomparethebudgettarget,onanannualbasis,withtheactualtranslationalresearchfundingactivitythroughbothsolicitedandinvestigator-initiatedawards.Ifthetargetfundinglevelisnotbeingachieved,fundingprioritieswillbeadjustedand/ornewdirectedprogramscreatedtobringactualfundinginlinewiththetarget.



Initiative A3: Develop a set of award codes that accurately capture the nature and scope of the early translational research portfolio.

Rationale

Currently,thereisnosetofNCI-specificawardcodesthataccuratelyandexplicitlycharacterizestranslationalresearch,makingitnearlyimpossibletodeterminethenatureandscopeofNCItranslationalresearchfunding.Translationalresearchisnotspecificallyidentifiedbyanyofthecodesappliedtogrants,suchastheCommonScientificOutline(CSO),5SpecialInterestCategory,orNIHClinicalAspect(NIHCA)6codes,althoughtranslationalactivitieswouldclearlybeincluded,alongwithothertypesofresearch,incertaincategories.Therefore,inorderfortheTRWGtocharacterizetheNCItranslationalresearchportfolio,anadhoccodingsystemhadtobeemployed(seeAppendixD).Thiswasnotonlylabor-intensive,butitproducedresultsthatareopentocriticismbecauseoftheirdependenceonadhocinclusion/exclusioncriteriaregardingthetranslationalnatureofvariousprojectsandinfrastructurecomponents.

Managingtranslationalresearchmoreeffectivelyinthefuturewillrequirealogisticallystraightforwardandpreciselydefinedmethodforcodingawardsastranslational.Aunifiedsetofcodeswillhaveanumberofadvantages.ItwillenhanceunderstandingofNCI’soverallinvestmentintranslationalresearchandhelptoidentifygapsandopportunitiesinamoretimelyandeffectivemanner.ItwillalsoenableNCIstaff,leadership,andadvisorycommitteestobettermonitorthenatureandscopeofNCI’stranslationalresearchportfolioovertime.Andfinally,theestablishmentofmeaningfulawardcodeswillallowNCItobettercommunicatetranslationalresearchactivities,opportunities,andprogresstothepublic.Thisisessentialtobuildandsustainthepublic’scommitmenttoandparticipationintranslationalresearch.


Implementation Plan

Overall Approach

TheTranslationalResearchSupportOffice,underguidancefromtheTranslationalResearchOperationsCommittee,andinassociationwiththeResearchAnalysisandEvaluationBranch(RAEB),willdevelopanewsetofcodes,basedonthesixTRWGdevelopmentalpathways,thatoperationalizetheTRWGfunctionaldefinitionofearlytranslationalresearch.ThesenewcodeswillbeincorporatedintotheexistingNCIcodingsystemoperatedbyRAEB.

Integration with Current NCI Coding System

Currently,codingofallNCIawardsisperformedbyRAEBintheDivisionofExtramuralActivities,whichhasalargecodinggroupofprofessionalindexers.Thenewtranslationalresearchcodeswillbeincorporatedintothisestablishedsysteminthefollowingmanner.First,anawardwillbeclassifiedas“translational,”basedonitsrelevancetooneormoreoftheTRWGdevelopmentalpathways.Thedegreeoftranslationalrelevance(e.g.,25%,50%,75%,or100%)willalsobecoded.Onceatranslationalresearchcodehasbeenapplied,anadditionalgroupofcodeswillbeconsideredtofurthercharacterizetheexactnatureofthetranslationalresearchactivity(seebelow).Asimilarapproachtodetailedcodingisbeingemployedfortrans-NIHAIDS-relatedandnanotechnology-relatedresearch,whichmayserveasusefulmodels.Theimplementationofthenewtranslationalresearchcodeswillalsobecoordinated,asappropriate,withthenewportfolioanalysistoolsbeinginvestigatedbytheNIHOfficeofPortfolioAnalysisandStrategicInitiatives.

5 TheCommonScientificOutlineisaclassificationsystemthatdividescancerresearchintosevencategories:Biology;Etiology;Prevention;EarlyDetection,DiagnosisandPrognosis;Treatment;CancerControl,SurvivorshipandOutcomesResearch;andScientificModelSystems.Fullinfor-mationisavailableat:http://researchportfolio.cancer.gov/crp/cso.jsp.

6 NIHCAcodesarequartile-basedmeasures,assignedbyNCI’sResearchAnalysisandEvaluationBranch,oftherelevanceofprojectstotheNIHdefinitionofclinicalresearch.NIHdefineshumanclinicalresearchasfollows:1)Patient-orientedresearch—researchconductedwithhumansubjects(oronmaterialofhumanoriginsuchastissues,specimens,andcognitivephenomena)forwhichaninvestigator(orcolleague)directlyinteractswithhumansubjects.Excludedfromthisdefinitionarein vitrostudiesthatutilizehumantissuesthatcannotbelinkedtoalivingindi-vidual.Patient-orientedresearchincludes:a)mechanismsofhumandisease,b)therapeuticinterventions,c)clinicaltrials,ord)developmentofnewtechnologies.2)Epidemiologicandbehavioralstudies.3)Outcomesresearchandhealthservicesresearch.



Coordination with Other Organizations

Indevelopingthenewcodes,theTranslationalResearchSupportOfficewillseekinputfromotherFederalagenciesthathavedevelopedtheirowncodingandtrackingsystems.Forexample,theDepartmentofDefense(DOD)hasworkedtogenerateataxonomysystemtocodeandtrackallfundedresearchfromtheinitialstagesuptopublicdelivery.Thesystemisnowbeingusedforportfolioanalysisandmonitoring,reportingof“success,”andongoingtrackingofprojects.AlthoughasystemofthistypemightbetoocomprehensivetobeimplementedthroughoutNCI,theDODhasdevelopedsomebestpracticesthatcouldproveuseful.TheSupportOfficewillalsoworkwiththeFoodandDrugAdministrationtoensureconsistencybetweentheeffortsofthesetwoagenciesandtoadoptcommonlanguageandclassificationsystems.

Coding Categories

Thenewcodeswillincorporatearangeofcategoriesrelatedtotranslationalresearch.TheRAEBalreadycodesgrantsbasedonorgansiteandtargetpopulations(rarecancers,pediatrics,minorities,underservedpopulations,etc.).Additionalcategoriesspecificallyrelevanttotranslationalresearchmightincludethefollowing:

• Mechanismofcancerdevelopment

Tissue/cellularlevel(e.g.,apoptosis,proliferation,angiogenesis)

Molecularlevel(e.g.,p53alterations,APCalterations,Her-2alterations)

PrimaryTRWGdevelopmentalpathway

Agent(drugorbiologic)

Immuneresponsemodifier

Biomarkerriskassessmentdevice

Imagingriskassessmentdevice

Interventivedevice

Lifestyleintervention

• RegionoftherelevantTRWGdevelopmentalpathway

Earlydevelopment/testing(targetvalidation,assaydevelopment,prototypedevelopment,etc.)

Optimization/validation

Preclinicaldevelopment(process/devicedevelopment,pharmacology,toxicology,manufacturing,etc.)

Early-stagehumanstudies

• Population

Averagerisk/unscreened

Elevatedrisk

Localdisease

Regionaldisease

Advanceddisease

Palliative.

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TRWGrepresentatives,NCIprogramstaff,TranslationalResearchSupportOfficestaff,andrepresentativesfromtheNCICenterforBioinformatics(NCICB),RAEB,andOfficeofSciencePlanningandAssessmentwillbeconvenedtodefinethecodesanddeterminehowtheycanbemostefficientlyandrapidlyincorporatedintothecodingsystem.ThenewcodeswillbeexpressedusingenterprisevocabulariesandCommonDataElementsdevelopedbyNCICB.

Coding of Awards

Oncethenewtranslationalresearchcodesareincorporatedintothecodingsystem,RAEBstaffwillcodeallnewlyfundedawardsbasedonthosecodes.Thiswillensurethatcodingisconsistentlyandobjectivelyappliedacrossalltranslationalresearchprojects.Itcurrentlyisnotpossibletocodeindividualsubprojectsforgrantswithmultiplecomponents(e.g.,SpecializedProgramsofResearchExcellence,P01s),althoughNCIandNIHareactivelyworkingtoincorporatesuchcapability.Ascodingofsubprojectsisessentialforaccurateportfolioanalysis,incorporatingsuchcapabilityshouldbeahighpriorityforbothNCIandNIH.Untilcodingofsubprojectsisimplementedcodingwillbeappliedtotheparentgrantonly,althoughallrelevantcodeswillbeincludedfromthesubprojects.OncecodinghasbeenassignedbyRAEB,itwillbeforwardedtotherelevantprogramofficerforconcurrencethatthecodeshavebeenappliedcorrectly.InordertogainacompletepictureoftheNCItranslationalresearchportfolioinatimelymanner,RAEBwillbeaskedtoassigntranslationalresearchcodesretrospectivelytoallactiveawardssoonafterthecodeshavebeenimplementedfornewawards.

Oncethenewcodingsystemisinplace,theTranslationalResearchOperationsCommitteewillevaluatetheoptionofinvestigator-assignedcodesthatarethenconfirmedduringpeerreviewandbyprogramandRAEBstaff.Iffeasible,theTRWGconsidersthislatteroptiontobehighlypreferable,asitwouldencourageamorecomprehensiveunderstandingonthepartofinvestigatorsoftheroleoftheirindividualresearchprojectstotheoveralltranslationalresearchprocess.



Initiative A4: Establish a distinctive prioritization process for early translational research.

Rationale

Infundingdiscoveryresearch,NCI’sprimaryobjectiveistoenablequalifiedresearcherstofreelyexplorenewideasinfundamentalcancerscienceandpursuenewlinesofinquiryinwhateverdirectionsseemmostpromising.Infundingtranslationalresearch,ontheotherhand,NCI’sobligationistodeployitsscarceresourcessoastomaximizetheeffectiveness,speed,andefficiencywithwhichpromisingnewinsightsfromdiscoveryresearcharetransformedintotangibleproducts,7interventions,orlifestylealterationsthatcanimpactpatientcareorpublichealth.

Mechanismsforallocatingresourcesshouldbetailoredtotherespectivecharacteristicsofthesedifferenttypesofresearch.Fordiscoveryresearch,selectionmechanismsfocusonidentifyingthebestscientificideasproposedbyinvestigatorsqualifiedtopursuethem.Fortranslationalresearch,selectionmechanismsneedtoconsidernotonlythestrengthofthescientifichypothesis,butalsoidentifyconceptsespeciallyripefordevelopmentandtargetedatimportantunmetclinicalorpublichealthneedsunlikelytobeadvancedbyindustry.

Existingapproachestoselectionofresearchprojectsforfundingevolvedprimarilytosupportdiscoveryresearch.AstranslationalresearchisappreciatedasadistinctpartofNCI’sresearchportfolio,itisimportantthatappropriateselectionmechanismsbedevelopedtooptimizethatportionofourNation’sinvestmentincancerresearchaswell.Bycreatingaprioritizationprocessdistinctivetotranslationalresearch,itwillbepossibletoidentifyandprioritizeemergingtranslationalresearchconceptsandopportunitiesandensurethattheyareadvancedviaappropriateNCItranslationalresearchsupportmechanisms,withoutcompromisingthefunctionofexistingselectionprocessesandfundingtailoredtothedifferentneedsofdiscoveryresearch.


Implementation Plan

Theintentoftheprioritizationprocesswillbetoidentify,onanannualbasis,asmallnumberofspecificclinicalorproductdevelopmentgoalstobedesignatedasprioritiesbasedontheirripenessfordevelopmentandtheirpotentialclinicalsignificancefordefinedpatientsorpopulations.ThisnewprioritizationprocesswillbemanagedbyaPrioritizationWorkingGroupoftheAdvisoryCommittee(seeCoordinatedManagementInitiativeA1,page14,andFigure3).

Prioritization Working Group

Membership. ThePrioritizationWorkingGroupwillinclude15-20members,drawninpartfrommembersoftheparentAdvisoryCommitteeandinpartfromthelargercancerresearchcommunity.Membershipwillencompassarangeofkeystakeholders,including:

• Extramuraltranslationalresearchers,aswellasdiscovery,clinical,andpopulationresearchersexperiencedintheconductoftranslationalresearch

� “Products”includesneworrepurposeddrugs,biologics,devices,andothertangibleproductsthatcanbeusedfortherapeutic,diagnostic,prog-nostic,preventive,orpopulationriskassessmentpurposes.

Figure 3. Relationship of Prioritization Working Group to Coordinated NCI Organizational Structure



• NCIprogramandintramuralresearchstaffexperiencedintheconductorcoordinationoftranslationalresearch

• Patientadvocates

• Nonacademichealthprofessionals

• Representativesfromafoundationactiveintranslationalresearchfunding

• Representativesfromindustry.

Inadditiontorepresentingthesestakeholdergroups,thePrioritizationWorkingGroupwillincludeexpertiseacrossthefollowingdomains:

• Diseasesites

• Mechanismsofcancerdevelopment

• TRWGdevelopmentalpathwaystoclinicalgoals

• Prevention

• Therapy

• Populationsciences

• Rarecancers

• Minority/underservedpopulations.

TopromotedynamismandadaptabilityoftheprioritizationprocessandensurethattheWorkingGroupiscontinuallyrefreshedwithnewperspectives,anewWorkingGroupwillbeformedeachyearwith30-50%newmembers.NoindividualwillserveonmorethanthreesuccessiveWorkingGroups.

Responsibilities. EachyearthePrioritizationWorkingGroupwillhavethefollowingresponsibilities,whichareexplainedingreaterdetailbelow.

1. Identifytranslationalresearchopportunitiesthatwarrantthehighestpriorityforadvancement.

2. IdentifygapsintheNCItranslationalresearchportfolio(i.e.,infrastructures,projects,personnel,resources)relativetotheseopportunities.

3. Recommendasubsetofthesehigh-priorityopportunitiesforSpecialTranslationalResearchAccelerationProjectfundingsolicitations(seeTailoredFundingProgramsInitiativeB3).

4. Issueareporttothecommunityontheidentifiedpriorities.

Prioritization of Opportunities

EachyearthePrioritizationWorkingGroupwillusethesix-stepprocessoutlinedbelowtoidentifythemostimportanttranslationalresearchopportunitiesforthatyear.Allofthesestepswillbesupported,facilitated,andimplementedthroughtheTranslationalResearchSupportOfficewiththeassistanceofotherNCIstaffand/orcontractors.

Information Gathering. ThePrioritizationWorkingGroup,withtheassistanceoftheSupportOffice,willsystematicallygather,review,andanalyzeinformationfromthepublishedliterature,includingreviewsandstate-of-the-sciencereports.ThegoalwillbetoidentifyconceptsthatpotentiallywarrantafocusedefforttoadvancethemdowntherelevantTRWGdevelopmentalpathway.



ThePrioritizationWorkingGroupwillalsoconvene,asneeded,“TranslationalNeedsandOpportunities”symposiatoobtainexpertinputfromdiscovery,translational,andclinicalresearchers;manufacturingandregulatoryspecialists;managementexperts;industryrepresentatives;patientadvocates;andNCIprogramandintramuralresearchstaff.ThesesymposiawillbeorganizedbytheSupportOfficeandconductedasfocusedsessionsduringexistingprofessionalsociety,foundation,oradvocacygroupmeetings,and/oraspartofexistingprogrammeetings(e.g.,SpecializedProgramsofResearchExcellence,EarlyDetectionResearchNetwork)or“state-of-the-science”meetingsconductedbythedisease-specificScientificSteeringCommitteesformedaspartoftheClinicalTrialsWorkingGroupReportimplementation.

IfdeemedappropriatebythePrioritizationWorkingGroup(ortheparentAdvisoryCommittee),theSupportOfficewillconvenetargetedsubgroupsofkeyinvestigatorsandNCIprogramstafftoprovideneededinput.Thefocusofsuchsubgroupsmaybeorgan/diseasesystems(e.g.,breastcancer,leukemia/lymphoma),TRWGdevelopmentalpathways(e.g.,immuneresponsemodifiers,imaging),mechanismsofcancerdevelopmentorprogression(e.g.,proteinkinases,angiogenesis),orotherorganizingprinciples.Inparticular,theTRWGrecommendsthatsuchsubgroupsbeconvenedtoprovideinputonprioritiesforrarecancers,minority/underservedpopulations,andlifestyleinterventions.

Solicitation of Ideas. ThePrioritizationWorkingGroupwill,throughtheSupportOffice,issueaRequestforInformation(RFI)solicitingideasforimportanttranslationalresearchopportunitiesthatareripefordevelopment.TheRFIwillincludeasubmissiontemplatespecifyingthefollowingkeyelementsthatmustbeaddressedinorderforasubmittedconcepttobeevaluatedbythePrioritizationWorkingGroup:

• Keyresultsofdiscoveryresearchthatsupporttheopportunityproposed

• Keyfactorssupportingthetechnicalfeasibilityofafocuseddevelopmenteffort

• Importanceofclinicalorpublichealthneed

• Likelihoodthattheneedwillbemet,ortheopportunityadvanced,byprivateindustrywithoutNCIinvolvement.

Conceptsmaybesubmittedbytheresearchandadvocacycommunitiesatlarge,byadhocgroupsfocusedontranslationalresearch,orbyanyotherintra-orextramuralsource.Allconceptssubmittedwillbesubjecttoacommonreviewprocess.

Analysis of Input. Basedontheinformationgatheredfromtheliterature,theoutputoftheTranslationalNeedsandOpportunitiessymposia,andtheconceptsproposedinresponsetotheRFI,theSupportOfficewillpreparebriefconceptpackagesforthoseopportunitiesthathavethefollowingattributes:

• Astrongandvalidatedbodyofknowledgesupportingthepotentialofthediscoverytoleadtomeaningfulimpactoncancerprevention,detection,diagnosis,ortherapy

• Afeasibleseriesofstepsforadvancingthediscoveryintoearlyhumantesting

• Ademonstratedclinicalorpopulationhealthneedthatisnotadequatelyaddressedbyeitherexistingapproachesorthosealreadyindevelopment.

ConceptpackagessummarizingtheinformationsupportingeachoftheseattributeswillbepresentedtothePrioritizationWorkingGroupforreviewandprioritizationofupto10ofthemostpromisingtranslationalresearchopportunities.Inselectingpriorities,thePrioritizationWorkingGroupwillensurethatappropriateemphasisisplacedontheneedsofpatientswithrarecancersandmedicallyunderservedpopulations.

Portfolio Analysis. Foreachselectedopportunity,theSupportOfficewillanalyzethecurrentNCIgrantportfoliotodeterminethescopeofongoingtranslationalactivityrelevanttothatopportunity.Thisanalysiswillidentifywhatadditionalresearchactivitiesarerequiredtocompleteafocused,coordinated,andfacilitatedtranslationalresearchefforttomovetheidentifiedconceptintoearlyhumantesting.Theportfolioanalysiswillalsoattempttoidentifyrelevantresearchunderwaywithfoundation,industry,orotherGovernmentagencysupport.ThiswillallowNCItoavoid



duplicationofongoingeffortsandidentifyopportunitiesforsynergy.Basedonthisanalysis,thePrioritizationWorkingGroupwillselectthefivehighestpriorityopportunities.

Public Comment. ThePrioritizationWorkingGroupwillpublishtheconceptpackagesforthefivemostpromisingopportunities,presentthemfordiscussionataspecialannualTranslationalResearchNeedsandOpportunitiessymposiumreservedespeciallyforthispurpose,andsolicitpubliccommentmoregenerally.Allcommentsreceivedwillbeanalyzedandusedtorefineandfurtherprioritizetheselectedopportunities.

Selection of Prioritized Opportunities. Takingintoaccountalloftheinputreceivedandtheanalysisconductedaswellasitsowncollectiveknowledgeandexpertjudgment,thePrioritizationWorkingGroupwillrankordertheidentifiedopportunities.Inpreparingtheranking,thePrioritizationWorkingGroupwillensurethatappropriateemphasisisplacedontheneedsofpatientswithrarecancersandmedicallyunderservedpopulations.ThePrioritizationWorkingGroupagainwillselecttwoorthreeoftheopportunitiesassubjectsforSTRAPsolicitations(seeTailoredFundingProgramsInitiativeB3).TheprioritizedopportunitiesplustherecommendationsforSTRAPsolicitationswillbeforwardedtotheAdvisoryCommitteeforreviewandapproval.TheAdvisoryCommitteewillthenforwardtheprioritiesandSTRAPrecommendationsthattheyapprovetotheExecutiveCommitteeandtheBoardofScientificAdvisorsforfinalreviewandapproval.Uponfinalapproval,theprioritieswillbepublishedandusedtoformthebasisforSTRAPsolicitationsandtoguidetranslationalresearchacrossNCI.

Application of Priorities Across NCI

TheTranslationalResearchOperationsCommitteewilldeveloppoliciesandproceduresforintegratingthedesignatedpriorities,asappropriate,intoSpecialEmphasisPanelreviewcriteriaandintofundingdecisionsbyprogramstafffortheoverallNCItranslationalresearchportfolio,includingP50,U-series,P01,andR01awards,aswellasforstimulatingthecreationofnewinitiativesbyprogramstaffonspecificpriorities.TheOperationsCommitteewillalsoinformotherstandingcommittees,suchastheInvestigationalDrugSteeringCommitteeandthedisease-specificScientificSteeringCommittees,abouttheidentifiedpriorities,sothattheycanbeincorporated,asappropriate,intotheirrespectiveactivities.

Annual Report

Followingcompletionofitsdeliberationsforthatyear,thePrioritizationWorkingGroupwillissueareportcoveringthefollowingtopics:

• DescriptionoftheWorkingGroup’sactivities

• Listofprioritizedopportunities,includingrationaleforselection

• Summaryofotheropportunitiesproposedbutnotselectedforprioritization

• SummaryofSTRAPsolicitationsproposed.


Report of the NCAB Translational Research Working Group—Tailored Funding Programs


Introduction

Fundingprogramstailoredtothedistinctiveneedsandcharacteristicsoftranslationalresearchareessentialtoadvancepromisingconceptstothepointofinitialtestingofaspecificdrug,biologic,device,procedure,orotherinterventionintheclinicorcommunity.However,themajorNCIfundingmechanisms,especiallyR01sandP01s,aredesignedprimarilytoenableresearcherstoexplorenewideasinfundamentalscienceandpursuenewlinesofinquiryinresponsetotheirresults.Whileidealfordiscoveryresearch,thesemechanismsarenotwellmatchedtothegoalsoftranslation.

Asaresult,severaltargetedfundingprogramshavebeendevelopedoverthelastseveralyears,especiallytheP50andvariousU-seriesprograms,toaddressthetranslationalresearchopportunitiesemergingfromrecentadvancesincancerbiology.Thefuturevitalityoftranslationalresearchdependsatleastinpartoncontinuedrefinementofthesecurrentprogramstoreflectevolvingbestpracticesinthemanagementoftranslationalresearch.Managementbestpracticesofparticularimportanceincludeaprojectplancoveringalltheactivitiesuptoandincludingearly-stageclinicaltrials,projectmilestoneswithassociateddatesandfundingrequirements,anddevelopment/commercializationstrategiesdescribinglikelyapproachesforlate-stagehumantestingandeventualcommercialization.

Inadditiontorefiningexistingprograms,NCI’stranslationalresearchportfolioshouldbeaugmentedbytwonewprogramsthatexemplifythesebestpracticesandaddressimportanttranslationalopportunitiesnotcapturedbyexistingefforts.Forsupportingemergingopportunitiesselectedbythenewprioritizationprocess(seeCoordinatedManagementInitiativeA4),anewtypeoffundingprogramisneededthatcanassembleanoptimalmixofresources,investigators,andinstitutionstoconductalarge,integrated,multidisciplinaryefforttoaccomplishaprioritizedtranslationalgoal.Inaddition,althoughNCIhasseveralprogramsthatencourageindustryinvolvement,itwouldbeadvantageoustodevelopanewprogramthatrequiresindustryresourceandcostsharing.Suchaprogramwouldincentivizeindustryinvolvementinprojectstheywouldnottakeforwardindependently.Andfinally,itisimportanttointegratesuccessful,milestone-drivenearlytranslationalresearchprojectsseamlesslywithNCI-fundeddevelopmentresourcesinordertopreventunnecessarydelaysinmovingprojectstowardhumantesting.

Toachievethedesiredimprovementsinfundingprogramstofacilitateandpromotetranslationalresearch,theTRWGproposesfiveinitiatives.

B1. Modify multiproject collaborative award guidelines, as appropriate, to facilitate early translational research.

B2. Improve processes and mechanisms for funding investigator-initiated early translational research.

B3. Establish a special translational research funding program to advance prioritized early translational research opportunities.

B4. Establish a funding program for early translational research that requires academic/industry collaboration involving resource sharing and/or co-funding.

B5. Integrate access to GMP/GLP manufacturing and other preclinical development services more effectively with milestone-driven early translational research projects.



Initiative B1: Modify multiproject collaborative award guidelines, as appropriate, to facilitate early translational research.

Rationale

NCIhascreatedadiverseportfolioofProgramAnnouncement/RequestforApplication-directedtranslationalresearchfundingprogramsthatsupportmultiproject,collaborativeawards.Theseincludecenter/multiprojectawards(P50programs)andavarietyofcooperative-agreementbasedprograms(U01,U19,U24,andU54).Inaddition,usinganRFAapproach,NCIcanestablishP01programsspecificallyfocusedontranslationalresearch.Becauseofthedifferingcircumstancesunderwhichtheywerecreatedandthedifferentmodelsonwhichtheyarebased,theseprogramsutilizearangeofmanagementpractices,programguidelines,andreviewapproaches.

Throughitsdeliberations,theTRWGidentifiedanumberofmanagementbestpracticesthatifuniformlyincorporatedintoprogramguidelinesformultiprojectcollaborativeawardswouldfacilitatetranslationalprogress.Thepurposeoftheseproposedmodificationsisnottohomogenizealltranslationalresearchprogramsorforcethemintoacommonmodel.Rather,thegoalistoenhanceproductivityacrosstheenterprisebyconsistentlyimplementingbestpracticesformanagementelementssharedbyalltranslationalresearchprograms,whilemaintainingthevariationinresearchdesignandscientificapproachthatisessentialtoinnovationandproblemsolving.

Thesecommonmanagementelementsinclude:

• FocusresearchprojectsonaccomplishingspecificmilestonesalongtheTRWGdevelopmentalpathwaysinordertomovediscoveriesefficientlyforwardintohumantesting.

• Rewardprojectsthathaveadefineddevelopmentandcommercializationstrategy.

• Rewardinter-institutionalcollaborationandnetworkformation,includingwithindustry.

• Incentivizeparticipationbyincreasingbudgetaryauthorityandresponsibilityandrewardingsuccesswithgreaterfundingstability.


Implementation Plan

GuidelinesfortheSpecializedCentersP50programs(e.g.,SPORE,ICMIC)8andcooperativeagreement-basedprograms(e.g.,EarlyDetectionResearchNetwork[EDRN],NetworkforTranslationalResearch:OpticalImaging[NTROI],NationalCooperativeDrugDiscoveryGroups[NCDDGs])9willbereviewedandmodifiedasdescribedbelow.SincetheseareNCI-specificprogramsreviewedbyNCI-charteredSpecialEmphasisPanels,theycanbeflexibleinincorporatingtranslationalresearchprinciplesintothedesignoftheirRFAsorPAsandtheirprogramguidelines.10Anynewtranslationalresearch-oriented,multiproject/collaborativeprograms,includingRFA-directedP01programs,willalsoincorporatetheseprinciples.

8 TheP50center/multiprojectawardsfundseveralindependentresearchprojectsandsupportingcores,organizedaroundacommonthemesuchasanorgansite.Thecenterprincipalinvestigatorcoordinatestheoveralleffortandhasdiscretiontoreallocatefundsamongprojectsandtoter-minateprojectsasnecessary.Unlikecooperativeagreement-fundednetworks,thereisnoformalprogram-widegovernancestructureorSteeringCommittee.DiscretionaryfundsheldattheprogramlevelaredisbursedbytheNCIprogramofficerthroughasupplementprocess.

9 CooperativeagreementprogramssuchasEDRNandNTROIarestructuredsuchthateachawardactsasacomponentofacommonresearchnetwork.ThenetworkhasaSteeringCommitteeconsistingofawardprincipalinvestigatorsandNCIprogramofficersthatdirectsnetwork-wideresearchactivitiesanddisbursesfundsheldatthenetworklevel.Othercooperativeagreementprograms,suchasNCDDG,fundmultipleinter-relatedprojectswithineachawardbutdonotcoordinatetheawards.

10 AllguidelinechangeswillbesubjecttoNIH-widereview.P01guidelinechanges,especially,mayrequireNIH-wideinputtoensurethatmodifi-cationsremainwithintheboundariesoftheP01programprojectconcept.



TheTranslationalResearchOperationsCommittee,withsupportfromtheTranslationalResearchSupportOffice,willreviewtheguidelinesofotherU-seriesprogramsidentifiedas“translational”butwhichcontributemodelsystems(e.g.,MouseModelsConsortium),coreresources(e.g.,CooperativeHumanTissueNetwork),orspecificservices(e.g.,PhaseI/IIconsortia)todeterminewhich,ifany,ofthetranslationalresearchprinciplesdelineatedbelowshouldbeincorporatedintotheirprogramguidelines.11

Incorporation of Milestones

TheguidelinesforP50andtranslationalU-seriesprograms,aswellasRFA-directedtranslationalP01programs,willbemodifiedtorequiretheinclusionofmilestonesinproposedprojectplans.Milestoneswillbedevelopedbytheinvestigatoronaproject-specificbasis,butwillbebasedonthestepsintheTRWGdevelopmentalpathways(seeAppendixCforpathways).

ForP50programs,eachindividualresearchprojectwillberequiredtoproposeasetofmilestonestobeachievedoverthe5-yeargrantperiod.Themilestoneswouldsetoutthestartingpointoftheproject,theprojectedpathwaystepsthatwouldbecompletedbytheendofthe5-yearfundingperiod,andspecificmilestonesthatwouldbereachedduringtheawardperiod,includingdatesbywhichsuchmilestonesareexpectedtobeachieved.Thereasonablenessoftheproposedmilestonesintermsofchartingefficient,timely,andyetrealisticprogresswillbeanimportantelementininitialreviewoftheapplication.Eachresearchprojectproposedshouldhaveearlyhumantestingasthefinalmilestone.However,notallprojectswillbeabletomeetthatmilestonein5years.Therefore,proposingareasonablesetofinterimmilestoneswiththegoalofenteringhumantestinginasubsequentgrantperiodwillbeacceptableforcertainprojects.

Eachprojectwillbesubjecttorigorousformalreviewatthetimeofeachprojectedmilestone.Inprogramsthataregovernedbyaprogram-wideSteeringCommittee(e.g.,EDRN,CentersofCancerNanotechnologyExcellence[CCNE]),themilestonereviewwillbeperformedbytheSteeringCommittee.Inprogramswhereawardshaveexternaladvisorygroups(e.g.,manySPOREawards,someP01awards),theseadvisorybodieswillparticipateinmilestonereview.Resultsofthemilestonereviewwillbeusedbytheprincipalinvestigatortomakeadecisiononcontinuation,modification,orterminationofthespecificproject.Whenappropriate,milestonereviewwillbeintegratedwithreviewbytheRAID,RAPID,orDCIDEprograms(seeTailoredFundingProgramsInitiativeB5).Inaddition,wheneverprojectsreachthestageofPhaseIIclinicaltrialdesign,milestonereviewsanddesignactivitieswillbecoordinatedwiththeongoingclinicaltrialprioritizationeffortsofanyrelevantdisease-specificScientificSteeringCommitteesestablishedasaresultoftheClinicalTrialsWorkingGroupReportimplementation.

Annualprogressreportswillrequireanaccountofthestatusofproposedmilestones.Ifforagivenprojectamilestonehasnotbeenachievedbytheprojecteddate,thereportwillincludeananalysisoftheproblemsencounteredandarecommendationastowhetherthereshouldbecontinuedeffortstoreachthemilestoneorwhethertheprojectshouldbeterminated.

Successinachievingtheproposedmilestonesandeffectiveactiontoterminateormodifyprojectsthatarenotachievingtheirmilestoneswillbekeyreviewcriteriaatthetimeofcompetitiverenewal.Movingexistingprojectsforwardaccordingtoamilestone-basedplanwillbemoreimportantincompetitiverenewalthangenerationofdataonwhichtobasenew,futureprojects.Fornetworkprograms,progressinachievingmilestoneswillbetakenintoaccountinevaluatingindividualawardswithinthenetworkforrenewal.ForP50andP01awards,successinachievingmilestonesthroughoutthevariousresearchprojectsandactingtomodifyorterminateunsuccessfulprojectswillbeacriticalelementatthetimeofcompetitiverenewaloftheentireaward.

Development/Commercialization Strategies

Becausetranslationalresearchprojectsareintendedtoresultindrugs,biologics,devices,procedures,orotherinterventionsthatultimatelybenefitpatients,guidelinesfortranslationalresearchP50,U-series,andRFA-directed

11 CertainclinicalresearchU-seriesprograms(e.g.,PhaseIU01trialists,AmericanCollegeofRadiologyImagingNetwork[ACRIN],thecoopera-tivegroups,andCommunityClinicalOncologyPrograms[CCOPs])arenotintendedtobecoveredbythisinitiative.



P01programswillbemodified,asnecessary,toincludearequirementtopresentaproposeddevelopmentandcommercializationstrategyforeachprojectproposed.12ThestrategywilldescribenotonlytheenvisionedapproachforproceedingalongtherelevantTRWGdevelopmentalpathwayintoearlyhumantestingbutalsoananalysisoftherequirementsandpotentialoptionsforlater-stagehumanstudiesandeventualproductcommercializationand/ordisseminationtothelargercommunity.

Iftheultimategoalisacommercialproduct,whetherfortesting,therapy,orprevention,thestrategywillincludeadescriptionoftheoptimalstageforindustryhandoffandpotentialcommercializationpartners.Thestrategywillalsoincludeaplanforprotectingandlicensinginventionsanddescribeanylicenseormaterialtransferagreementsalreadyinplace.Thestrengthandfeasibilityofthedevelopmentstrategywillbeanimportantcriterionininitialreview,andprogresstowardestablishingtherelationshipsnecessarytoimplementthestrategywillbeanimportantcriterioninrecompetingreview.TheNCDDGprogramalreadyincludesguidelinesandreviewcriteriafordevelopmentplansthatmayserveasastartingpoint.

Promotion of Collaborations

SPOREguidelinescurrentlyencourageinterinstitutionalcollaborationsbothwithotherSPOREsandwithotherNCI/NIHprograms.Thiswillbestrengthenedbymakingevidenceofmeaningfulinterinstitutionalcollaborationanimportantelementinbothinitialandrecompetingreview.ComparablerequirementsforcollaborationwillbeincorporatedintoallnewandexistingP50andtranslationalRFA-directedP01programs.Becauseindustrycollaborationscanbecriticalfortheultimatevalueoftranslationalresearchforpatients,guidelineswillbemodifiedtoencourageindustrycollaborationsandrewardtheminreview.Suchcollaborationsmayincludeco-fundingofprojects,in-kindprovisionofmaterialsortechnicalassistance,industryadvisoryroles,orhandoffofprojectsreachingmaturity.Industrycollaborationswillnot,however,serveasapreconditionforawardorrenewal.

NetworkssupportedbycooperativeagreementssuchasEDRNandNTROIcurrentlyincentivizeandrewardcollaborationswithotheracademicinstitutionsandindustrybyprovidingcollaboratorswithassociatemembershipsandallocatingnetworkfundstofacilitatecollaborations.CollaborationswithindustryareexplicitlyincorporatedintoEDRNreviewcriteriaandencouragedbytheNCDDGprogram.SimilarincentivesandrewardsforinterinstitutionalandindustrycollaborationwillbeincorporatedintotheguidelinesofallothernewandexistingU-seriestranslationalresearchprograms.

NCItermsandconditionsofawardrequiresharingofresearchresources(e.g.,researchtools,celllines,modelsystems),andplanstoshareresourcesarerequiredandusedinreviewforallP50,U-series,andRFA/PA-directedprograms.However,giventheimportanceofcollaborationintranslationalresearch,guidelineswillbemodifiedtospecifynotonlythatplansarerequired,butalsothatsharingofresourcesduringtheawardperiodwillbeanimportantcriterionduringrecompetingreview.

Budgetary Flexibility

Maximizingthebenefitofmilestone-drivenprojectreviewswillrequirethatprincipalinvestigatorsand/orsteeringcommitteeshavetheabilitytoreallocateorredirectfundswhenprojectsarecompletedorterminatedearly.Thiscouldinvolveprovidingadditionalfundstoaccelerateexistingprojectsorprovidingfundsforthestartupofnewprojects.Suchbudgetaryflexibility,whichisalreadyincorporatedintoSPOREawardsandcertainU-seriesnetworkawards,willbeexpandedtoallP50,RFA-directedP01,andU-seriestranslationalresearchprograms.Effectiveuseofthisbudgetaryflexibilitytokeeptheoverallprogramontrackdespiteeventsinindividualprojectswillbeanimportantreviewcriterionforcompetingrenewals.Ifongoingpeerreviewofthesedecisionsiswarranted,externaladvisoryboardsassociatedwiththeprogramshouldbechargedwithprovidingthisservice.

12 Commercializationplanswillbetailoredtotheneedsoftheindividualapplication.Forexample,ifasetofprojectscombinetoproduceasingletranslationalproduct,orifanindividualprojectwithinatranslationalmechanismisnotintendedtoproduceaspecifictranslationalproduct,ap-plicantswillnotberequiredtoproposeadevelopmentplanforeachproject.



Review Panels

P50,U-series,andRFA-directedP01applicationsarereviewedbySpecialEmphasisPanelsconvenedbyNCIratherthanthroughtheNIH-wideCenterforScientificReview.Forawardprogramsfocusedontranslationalresearch,andinlightoftheproposedguidelinechangesdiscussedabove,involvementbyindustryscientists,nonacademichealthprofessionals,programmanagersatfoundationsfundingcancerresearch,andpatientadvocates,inadditiontoacademictranslationalresearchersisespeciallyimportant.Asguidelinechangesareimplemented,therostersofthesepanels,includingtheP01DiscoveryandDevelopmentSpecialEmphasisPanel,willbeexaminedbytheDivisionofExtramuralActivitiesResearchProgramsReviewBranchtodeterminewhetheradditionalreviewersmaybeneeded.Shouldtheevaluationidentifypotentialgapsorlimitationsinrostermembership,theResearchProgramsReviewBranchwillcoordinatewiththeTranslationalResearchSupportOfficeandrelevantprogramstaffinidentifyingandrecruitingadditionalmembers.Astranslationalresearchprogramsbecomemorecollaborative—bothamongacademicresearchersandbetweenacademicandindustryresearchers—recruitingqualifiedreviewersfreeofconflictofinterestmayrequireafocusedandproactiveeffortonthepartofNCI.

Rolling Review

Oncemilestoneshavebeenincorporatedintoprojectplansasobjectivecriteriaforevaluatingthesuccessorproductivefailureoftranslationalresearchprograms,theTranslationalResearchOperationsCommitteewill,inconsultationwiththeDivisionofExtramuralActivities(DEA),considerwhethera3+3rollingreviewsystemforselectedawardsisfeasibleand,ifso,howitmightbestructured.13Suchareviewsystemwouldinvolveconductingafullprogramreview(comparabletoacompetitivereview)after3yearsofa5-yearaward,withoneoftworesults.Iftheawardisgoingwellandmeetingmostifnotallofitsprojectmilestones,theawardwouldberenewedforanother5yearswith,again,afullprogramreviewafter3years.Iftheawardhasexperienceddifficultyinmeetingmilestonesandredirectingprojectfunds,itwouldbesubjecttoterminationattheendoftheremaining2-yearperiodunlesssignificantpositiveprogressweremade.

13 AnysuchchangeswouldbesubjecttoNIH-widereview.



Initiative B2: Improve processes and mechanisms for funding investigator-initiated early translational research.

Rationale

TheTRWGportfolioanalysisfoundthatmorethanhalfoftheidentifiedearlytranslationalresearchawardswerefundedthroughmechanismsdesignatedforunsolicited,investigator-initiatedresearch,predominantlyR01sandP01s(seeAppendixD).TheprogrammaticguidelinesforthesemechanismsaresetNIH-wide,andtheyweredevelopedprimarilyforthesupportofdiscoveryresearch.Asaresult,theydonotincorporateimportanttranslationalresearchconcepts,includingmilestones,collaboration,developmentplans,etc.Moreover,althoughseveraloncologystudysectionshavebeenrecentlyestablishedthatarefocusedontranslationalresearch,thereisstillaperceptionthattranslationallyorientedR01sandP01sfareworseinpeerreviewthandodiscovery-orientedproposals.

ImprovementsintheprocessforreviewandfundingoftranslationallyorientedR01andP01applications,asdistinctfromdiscovery-orientedapplications,arethusnecessarytoincentivizeinvestigatorstoproposesuchprojectsbyassuringthattheirapplicationswillbejudgedbyreviewcriteriatailoredtotranslationalresearch.SuchimprovementswillassistNIHinachievingthesecondcomponentofitsmission—“...applicationof(that)knowledgetoextendhealthylifeandreducetheburdensofillnessanddisability”14andareespeciallyimportantgiventheprominenceoftheResearchProjectGrant(RPG)poolintheoverallNCI,andNIH,fundingportfolio.


Implementation Plan

Translational Research Study Section Analysis

RecenteffortsbytheNIHCenterforScientificReview(CSR)andNCIresultedincreationoftheOncologicalSciencesIntegratedReviewGroup,whichincludessixstudysectionsspecificallyorientedtowardtranslationalresearch.Todeterminewhetherthesenewstudysectionsareprovidingadequateandequitablereviewoftranslationalresearchapplications,theTranslationalResearchSupportOfficewillcoordinatewiththeNCIDEAandCSRtoconductananalysisofcurrentstudysections.Theanalysiswillhavethreecomponents.Thefirstistoexaminewhetherthereareanygapsinstudysectioncoverageforspecificareasoftranslationalresearch(e.g.,immunotherapy,imaging,lifestyle).Thesecondistoevaluatereferralguidelinesforthestudysectionsandperceptionsofstudysectionmembersconcerningwhethertheyreceiveanappropriateportfolioofgrantstoreview.Thethirdistoexaminemembershiponthestudysectionstoidentifyanygapsinthetranslationalresearchexpertiserepresented.

Ifanygapsinstudysectioncoverageareidentified,theSupportOfficewillworkwithDEAandCSRstafftoexpandthemandateofexistingstudysectionsorsuggestthecreationofnewstudysectionstofillthosegaps.Ifdeficienciesinstudysectionoperationsareidentified,theSupportOfficewillcoordinatewithDEAandCSRtorefineproceduresandreferralguidelines.Wherethereappeartobegapsinreviewerexpertise,theSupportOfficewillidentifyadditionaltranslationalresearchersqualifiedforserviceonstudysections.Ascollaborationintranslationalresearchincreases,SupportOfficestaffwillcoordinatewithCSRtodevelopstrategiesforidentifyingandrecruitingqualifiedreviewerswhoarefreeofconflictsofinterest.TheSupportOfficewillalsoworkwithCSRtoencouragetheinvolvementofpatientadvocatesinstudysectionsorientedtowardtranslationalresearch.

ArelatedactivitywillbetoworkwiththeDEAResearchProgramsReviewBranchtoassessthereviewoftranslationalP01sthroughNCI-charteredSpecialEmphasisPanels.Thisassessmentwillinclude:a)determiningtheeffectivenessofthepilotsingle-tierP01structureasappliedtotranslationalP01applications;b)assessingthetreatmentofP01applicationsidentifiedas“translational”astheyareassignedtothefivestandingpanels(MolecularBiology;Cellularand

14 NationalInstitutesofHealth:http://www.nih.gov/about/index.html#mission.htm.



TissueBiology;Prevention,Control,andPopulationSciences;DiscoveryandDevelopment;andClinicalStudies);andc)identifyingpotentialimprovementstotheP01reviewprocesswithintheboundariesoftheNCI-wideP01guidelines.

Exploration of Translational R-Series and P-Series Mechanisms

NIHhasadualmissionofscientificdiscoveryandtranslationaldevelopmenttobenefithumanhealth.R01andP01mechanisms,whichserveasthefoundationofNIH’sgrant-basedeffortstoachievethesegoals,aregovernedbyNIH-wideguidelinesthatarenotspecifictothetranslationalmission,nortotheneedsofanyindividualInstituteorCenter.However,becausethechallengesoftranslationalresearcharecriticallyimportanttoallNIHInstitutesandCenters,NIHshouldevaluatewhetheritsoverallgrantprogramproperlyincentivizesandsupportstranslationalresearch.

BecauseNCI’sperspectivesontranslationalresearchneedsandopportunitiesmaybesharedbyandusefultootherInstitutesandCenters,NCIwillpursueanNIH-wideinitiativetoexaminethevalueofcreatingdistinctiveR-seriesandP-seriesmechanismsforsupportingunsolicited,investigator-initiatedtranslationalresearch.Thesemechanismswouldincorporatecharacteristicsdesirablefortranslationalresearch(e.g.,milestone-basedreview,team-basedscience,projectmanagement,device/interventiondevelopment)andensurethatreviewoftranslationalresearchproposalsreflectsthesecriteria.

MembersoftheTranslationalResearchOperationsCommittee,withsupportoftheTranslationalResearchSupportOffice,willbeginadialoguewithotherNIHInstitutesandCentersconcerningthepotentialvalueofnewR-seriesandP-seriesmechanismsfocusedontheneedsoftranslationalasopposedtodiscoveryresearch.OneopportunitywouldbetoworkwiththeNIHOfficeoftheDirector/OfficeofPortfolioAnalysisandStrategicInitiativestodevelopaRoadmapinitiative.



Initiative B3: Establish a special translational research funding program to advance prioritized early translational research opportunities.

Rationale

Theprimaryobjectiveofearlytranslationalresearchistoadvancepromisingconceptseithertoinitialtestingintheclinicorpopulationortothepointwhereresultsindicatethatanalternateapproachshouldbepursued.Inmanysituations,existingfundingprograms,whichadvanceknowledgeincrementallybysupportingportionsofadevelopmentalpathway,likelyconstituteanoptimaluseofresources.However,incertaininstances,opportunitiesarisethatareespeciallypromising,bothbecauseoftheirapparentreadinessfordevelopmentfromascientificandtechnicalperspectiveandbecauseoftheirpotentialclinicaland/orpublichealthimpact.ThenewtranslationalresearchprioritizationprocessproposedbytheTRWG(seeCoordinatedManagementInitiativeA4)isintendedtoidentifyjustsuchopportunities,especiallythosethatareunlikelytobepursuedbyprivateindustrybecausetheymaynotbejustifiableonbusinessgrounds.Thisisespeciallylikelytobetrueofopportunitiesrelatedtorarecancers,minority/underservedpopulations,immunotherapies,andlifestylealterations.

Whileitmightbepossibletoadvancetheseprioritizedopportunitiesthroughexistingprograms,progressalongaspecificdevelopmentalpathwayislikelytobeslowifdifferentstepsaresupportedviamultiple,uncoordinatedfundingvehiclessubjecttoseparatepeerreview.Evenunderidealcircumstances,suchfragmentedfundingwillimposeburdensoftime,logisticalcomplexity,andcostthatcanimpedeprogress.Accordingly,NCIshoulddevelopaninnovativefundingprogramthatisdesignedtoadvancecertainprioritizedearlytranslationalresearchopportunitiesefficientlyalongtheappropriateTRWGdevelopmentalpathwayinacoordinatedandhighlyfacilitatedfashion.


Implementation Plan

Overall Approach

NCIwillestablishanewfundingprogramentitledtheSpecialTranslationalResearchAccelerationProject(STRAP)program.Thisprogramwillbedesignedtofundtheadvancementofspecificopportunities,identifiedbythenewtranslationalresearchprioritizationprocess,alongoneoftheTRWGdevelopmentalpathwaysthroughearlyhumantestingofaspecificdrug,biologic,diagnostic/screeningtest,orothertherapeutic,diagnostic,orpreventiveintervention.Thisprogramisnotintendedtodevelopnewscientificknowledge,researchmethodologies,orinfrastructureexceptwhennecessaryforandlinkedtothedevelopmentofspecificproductsorinterventions.

STRAPawardswillsupportanintegratedresearchanddevelopmentprogramdesignedtoachieveaspecificclinicalorproductdevelopmentgoal.TheinitiationofaSTRAPcanoccuratavarietyofpointsatthebeginningof,orearlyin,aTRWGdevelopmentalpathway.However,theprojectplanandproposedbudgetwillextendthroughtheendofthedevelopmentpathway(i.e.,tothepointofearlyhumantesting)andencompassasubstantialportionofthepathway.STRAPawardsareintendedtosupportalargerscopeofintegratedactivityandhaveahigherdegreeofNCI-facilitationthanwouldbefeasibleunderanyofthefundingprogramscurrentlyinexistence.

ThesizeanddurationofaSTRAPawardwillbedeterminedonaproject-specificbasis,vianegotiationbetweenNCIandtheprincipalinvestigators,inlightoftheneedsoftheparticularresearchanddevelopmentplan.Itisunderstoodthatincertaincases,thegoalsofaSTRAPmayentailaneffortlastingmorethan5years.

Structure

Bydefinition,aSTRAPawardisintendedtosupportatranslationalresearchopportunitythathasbeenprioritizedbecauseofacombinationofscientificcredibility,technicalfeasibility,clinicalorpublichealthimpact,andthelikelihoodthattheopportunitywillnotbepursuedbyanotherfundingagency(i.e.,privateindustry,foundation,othergovernmentalagency).



Inmanycases,thescientificcredibilityandtechnicalfeasibilityofaconceptwillbebasedontheresultsofoneormoreexistingresearcheffortsalongtherelevantTRWGdevelopmentalpathway.Insuchsituations,itmaybeappropriateforNCItoimplementaSTRAPbyintegratingexistingawardsandmakingnewawardstocoverthemissingcomponentsofthedevelopmentalpathway.

Inothersituations,asubstantiallynewscopeofworkmaybeoptimalforachievingtheobjectivesofaSTRAP.Accordingly,theSTRAPprogramwillalsoprovideforentirelynewawardscoveringtheentiredevelopmentalpathwayforaconceptjustemergingfromdiscoveryresearchthatisdeemedsufficientlycompellinganditsdevelopmentpathconceptualizedwithsufficientclaritytojustifyafocused,prioritizeddevelopmenteffort.

Becauseofthediverserequirementsandmultidisciplinarycharacterofthedevelopmentalpathways,STRAPawardsmayuseanyorallofthefollowingstrategieswhenevertheywillfacilitatetimelyandefficientachievementofthegoalsoftheSTRAP:

• Participationofmultiple,collaboratingprincipalinvestigators,includinginvestigatorsfromtheNCIintramuralresearchprogram

• Collaborationofmultipleacademicinstitutions

• Collaborationwithindustrytoaccesscomplementaryhuman,infrastructure,and/orfinancialresources

• Contractswiththeprivatesectorforappropriateactivities(standardanalyses,manufacturing,etc.)

• Collaborationandcoordinationwithexistingfoundation-supportedeffortsrelevanttothegoalsoftheSTRAP.

Funding

Approximately$10millionwillbeallocatedtonewSTRAPawardseachyear,uptoasteadystateofapproximately$50millioninannualfundingafter5years.IfSTRAPfundingforcertainprojectscanbeassembledbyintegratingexistingawards,thislevelofannualfundingcouldbereducedoradditionalprojectscouldbepursued.ItisanticipatedthatfundingforacompleteSTRAPwouldtypicallyrequire$5-10millionoveramultiyearperiodaveragingabout$2millionperyear.However,fundingforeachSTRAPwillbedeterminedbythespecificneedsoftheapproveddevelopmentprogram,andfundingforanyparticularSTRAPmayvaryconsiderablyfromprogramaverages.

Projectswillgenerallybefundedinannualincrementsbasedontheproposedbudget,subjecttosuccessfulachievementofagreed-uponmilestones(seebelow).UponarecognizedneedtoterminateaSTRAPduetotheinabilitytoreachthetranslationalgoalasdeterminedbythemilestonereviewgroup,investigatorswillbepermitted,dependingonthereasonformilestonefailure,tonegotiateupto75%ofthecurrentbudgetfor1moreyear.15Thiswillassistinpromotingthestabilityofestablishedtranslationalresearchteams.

Industryorfoundationco-fundingwillnotbearequirementforaSTRAPproposal.However,industryfinancialorin-kindsupportorfoundationfinancialsupportthatacceleratesachievementofSTRAPgoalswillbeviewedfavorably.Whereappropriate,NCIwillengagetheassistanceoftheFoundationforNIHinidentifyingpotentialexternalcollaboratingfundersforSTRAPawards,andwillassistSTRAPprincipalinvestigatorsinnegotiationofsuchsupport.

Solicitation and Award Process

Topicsforeachyear’sSTRAPsolicitationwillbedeterminedthroughthenewprioritizationprocess(seeCoordinatedManagementInitiativeA4).Asinglesolicitationwillbeissued,identifyingtheprioritizedconceptsfortheyear.ThesolicitationwillbepreparedbytheTranslationalResearchSupportOfficewiththeactiveinvolvementofDivisionalprogramstaffwhohavescientificexpertiserelevanttotheprioritizedconcepts.

15 TheTRWGrecognizesthatimplementationofsuchafundingstrategymaybecomplexandwillrequireNIH-levelreview.



Awardswillbemadefromasinglepooloffunds,ratherthanreservingspecificfundingforeachprioritizedconcept.However,awardswillnotnecessarilybelimitedtooneperprioritizedconcept.Guidelineswillallowforthefundingoftwoormoreawardsforprojectspursuingalternateapproachestothesameearlytranslationalresearchgoalifthecompetingproposalsareequallymeritorious.Conversely,issuanceofthesolicitationwillnotimplyacommitmenttofundproposalsforeveryprioritizedconcept.Fundingmightnotbegrantedifproposalsresponsivetoaparticularconceptarejudgednottobecompetitivewiththoseforotherconceptsoriftherequiredbudgetsaretoolargetofundprojectsforallsolicitedconcepts.

ForSTRAPsthatinvolveacomplete,de novoprogramofactivity,acooperativeagreementmechanismislikelytobemostappropriate,althoughacontractmechanismcouldbeusedaswell.ForSTRAPsthatareconstructedviaintegrationofexistingawards,asupplementalfundingmechanismwillberequiredtofillinthemissingcomponentsofthedevelopmentalpathway,andprocedureswillbeneededtointegrateexistinggrantsintoacoordinatedendeavorsubjecttotherequiredmilestone-basedreviewandotherappropriaterequirements(seebelow).

STRAPproposalswillbereviewedbyaSpecialEmphasisPanelconvenedforreviewofproposalsinresponsetoagivensolicitation.Toensureappropriateexpertiseforevaluationoftheproposals,thepanelswillincludememberswhoareexperiencedinpreclinicaldevelopmentandmanufacturing,projectmanagement,andacademic-industrialcollaboration,inadditiontoencompassingscientificdomainsrelevanttotheprioritizedconceptstargetedbythesolicitation.Therewillalsobeanextramuralstandingoversightcommitteetoprovidecontinuityandabroaderperspectiveonoverallprogramobjectives.Oncethereviewsarecomplete,theTranslationalResearchOperationsCommitteewillrecommendasetofawardstotheExecutiveCommitteeforfunding.

Management

EachSTRAPproposalwillincludeacompleteprojectplan,addressingactivitiesthroughearly-stageclinicalorpopulationtrials.Inadditiontoaddressingtheresearchanddevelopmentactivitiestobeconductedandtheresourcesrequired,eachprojectplanmustincludeawell-developedmanagementplanaddressingthefollowing:a)governance,organizationalstructure,andprojectmanagement;b)approachestocommunicationandcoordination;c)theprocessformakingdecisionsonscientificdirection,allocationofresources,publications,andintellectualpropertyissues;andd)proceduresforresolvingconflicts.AsdescribedinOperationalEffectivenessInitiativeC1,NCIprojectmanagementresourceswillalsobeavailableforSTRAPawardsandtheprojectswillbehighlyfacilitatedbyNCIstaff.

EachSTRAPawardwillbegovernedbyaSteeringCommitteecomprisingtheseniorinvestigatorfromeachcomponentoftheawardandtheTranslationalResearchSupportOfficestaffmemberservingastheSTRAPprogramofficerandprojectmanager.16ThisSteeringCommitteewillhaveoversightresponsibilityfortheentireprojectincludingallocationofresources,participationinreviewofprogressagainstmilestones,andoverallcoordinationoftheproject.EachSTRAPprojectwillalsohaveanexternaladvisorycommittee,composedofscientific,clinical,andproductdevelopmentexpertsrelevanttothespecificproject,aswellasapatientadvocatewithprioradvisoryexperiencewithintheNCIsystem.Theadvisorycommitteewillparticipateinmilestonereviews(seebelow)andideallywillincludeatleastsomemembersofthereviewpanelthatrecommendedtheparticularSTRAPaward.

Milestones

EachSTRAPproposalwillincludeaspecificsetofdevelopmentmilestones,definedbyreferencetotherelevantTRWGdevelopmentalpathway(s),includingdatesbywhichsuchmilestonesareexpectedtobeachieved.Thereasonablenessoftheproposedmilestonesforchartingefficient,timely,yetrealisticprogresswillbeanimportantelementininitialreviewoftheapplication.DefinitivemilestonesanddateswillbeestablishedatthetimeofawardthroughnegotiationbetweenNCIandtheprincipalinvestigators.

16 Initially,TranslationalResearchSupportOfficestaffwillserveastheofficialSTRAPprogramofficerandprojectmanager,butwithactivein-volvementofadesignatedDivisionalprogramstaffmemberwhohastherelevantscientificexpertiseandexperiencetoguidethespecificprojectinquestion.AstheSTRAPprogramexpands,itmaybepreferabletotransfertheprogramofficer/projectmanagerresponsibilitiestorelevantDivisionalstaffatthetimeofaward.



AsecondaryobjectiveoftheSTRAPprogramistoimprovethelikelihoodthatanyfailureofadevelopmenteffortwillbe“productive”or“informative”;i.e.,thatknowledgegainedwillbeofsubstantialvalueinfocusingfutureresearch.Inevaluatingprojectproposals,NCIwilltakeintoaccountthedegreetowhichsuchknowledgeacquisitionisbuiltintothedesignofmilestones.

EachSTRAPawardwillbesubjecttoongoinginformalmonitoringbytheSteeringCommittee,aswellasarigorousformalreviewbytheSteeringCommitteeandtheexternaladvisorycommitteeatthetimeofeachprojectedmilestone.Ongoinginformalmonitoringwillhaveseveralpurposes,includingto:

• Ensurethattheperceptionofprojectprogressonthepartofboththeprincipalinvestigator(s)andtheresponsibleNCIprojectmanagerisconsistent,accurate,andup-to-date.

• Ensurethatproblemsareidentifiedandaddressedinatimelymannerandthatnomajorproblemfirstbecomesapparentatthetimeofaformalmilestonereview.

• Anticipateforthcomingformalmilestonereviewsandfacilitatetimelygenerationofneededdocumentarysupport.

• Enableformalmilestonereviewstobemovedforwardwheneverprogresswarrants.

• Anticipateforeseeablefailurestoreachmilestonesanddevelopcontingencyplans.

FormalmilestonereviewsinvolvingtheprojectSteeringCommitteeandtheexternaladvisorycommitteewillbeusedtomakearecommendationtoNCIoncontinuation,modification,orterminationoftheproject.Whenappropriate,STRAPmilestonereviewwillbeintegratedwithreviewbytheRAID,RAPID,orDCIDEprograms(seeTailoredFundingProgramsInitiativeB5).Inaddition,wheneverprojectsreachthepointofPhaseIIclinicaltrialdesign,theSTRAPSteeringCommitteewillcoordinatemilestonereviewsanddesignactivitieswiththeongoingclinicaltrialprioritizationeffortsofanyrelevantdisease-specificScientificSteeringCommitteeestablishedasaresultoftheClinicalTrialsWorkingGroupReportimplementation.

AnnualSTRAPreportswillincludeadescriptionofprogresstowardappropriatemilestones.Ifprogresstowardamilestoneisbehindschedule,thereportwillincludeananalysisoftheproblemsencounteredandarecommendationastowhetherthereshouldbecontinuedeffortstoreachthemilestoneorwhethertheprojectshouldbemodifiedorterminated.SuchrecommendationswouldbetheresultofSteeringCommitteeandexternaladvisorycommitteedeliberations.

Development/Commercialization Strategy

EachSTRAPproposalwillincludeaproposedlate-stagedevelopmentandcommercializationstrategy.Thestrategywilldescribetherequirementsandpotentialoptionsforbothlater-stagehumantestingandeventualproductcommercializationand/ordisseminationtothelargercommunity.Iftheultimategoalisacommercialproduct,whetherfortesting,therapy,orprevention,thestrategywillincludeadescriptionoftheoptimalstageforindustryhandoffandpotentialcommercializationpartners.Thestrategywillalsoincludeanintellectualpropertyplanforprotectingandlicensingpotentialinventionsandwilldescribeanylicenseormaterialtransferagreementsalreadyinplace.Thestrengthandfeasibilityofthislate-stagedevelopmentandcommercializationstrategywillbeanimportantcriterionininitialreviewofSTRAPproposals.

Investigator Credit for Participation

InvestigatorswhoparticipateinSTRAPswillbecreditednotonlyforsuccessfulhandoffofanewproductorinterventiontolate-stagetrials,butalsoforconductofSTRAPactivitiesinawaythatmaximizesthedevelopmentofscientificinsightandthetimelyrecognitionofdevelopmentfailureforprojectsthatarenotabletoachievetheintendedgoal.



Program Evaluation

TheTranslationalResearchSupportOfficewilldevelopaplanforevaluationoftheSTRAPprogram,includingtheidentificationofbothprocessandoutcomemeasures.Continuationoftheprogramafterthefirst5yearswillbesubjecttoanevaluationoftheeffectivenessofitsimplementationandofpreliminaryevidenceconcerningtranslationalimpact.Continuationorexpansionoftheprogramafter10yearswillbesubjecttoanevaluationthataddressestheimpactandproductivityoftheprogram.AswithallNCIprograms,long-termcontinuationwillbesubjecttoexternalpeerreviewandtoweighingofprioritiesinlightofneeds,opportunities,andbudgetconditions.



Initiative B4: Establish a funding program for early translational research that requires academic/industry collaboration involving resource sharing and/or co-funding.

Rationale

AdvancingmostNCI-fundedcancerdiscoveriesintoproductsofbroadutilityforpatientsorthecommunityrequirestheeventualparticipationofindustry.Therefore,NCIhasdevelopedseveralprogramsthatencourageindustrycollaborationinthedevelopmentofnewagents,devices,andotherinterventions.However,NCIdoesnothaveaprogramspecificallyfocusedonjointindustry/NCIfundingofcollaborativeearlytranslationalresearchprojectsthatintegratethecomplementaryskillsandexpertiseofacademicinstitutionsandpharmaceuticalandbiotechnologycompaniestopursuespecificearly-stageproductdevelopmentopportunities.

TheAcademicPublic-PrivatePartnershipProgram(AP4),whichwasrecentlyeliminatedduetobudgetconstraints,focusedonassemblingmultidisciplinaryteamsinvolvingacademicresearchcenters,pharmaceuticalandbiotechnologycompanies,nonprofitagencies,andgovernmentorganizations.EachAP4centerwastodevelopabroadscopeofresearchprojectsratherthanpursueasingle,focusedprojecttoachieveaspecificproductdevelopmentgoal.Similarly,althoughtheNetworkforTranslationalResearch:OpticalImaging(NTROI)programrequiresindustrycollaboration,itsupportsbroadresearchprogramsratherthanatargeteddevelopmenteffort.TheDivisionofCancerTreatmentandDiagnosisfundsinvestigator-initiatedgrantsthatsupportdrugdiscovery,butthisprogramdoesnotfocusonearly-stageproductdevelopmentorhandofftoindustry.TheMolecularTargetedDrugDiscovery(MTDD)programprovidesfundingtoanacademicresearchcenterorasmallbusinessforidentificationofnewtherapies,andtheNationalCooperativeDrugDiscoveryGroups(NCDDGs)programfundsresearchfordiscoveryofnewanticancerdrugs.However,neitherprogramrequirescollaborationbetweenacademicandindustrialresearchers.Finally,althoughthegoaloftheCentersofCancerNanotechnologyExcellence(CCNE)programisthedevelopmentofnewtherapiesandindustrycollaborationisrequired,thisprogramonlyfundsnanotechnologyresearch.

Anewfundingprogramthatspecificallyrequiresacademic/industrycollaborationhasthepotentialtospeedthepaceandproductivityofearlytranslationalresearchinseveralways.First,itwillcapitalizeonthecomplementarystrengthsofindustryandacademia.Second,itwillfacilitatethetransferofacademicearlytranslationalresearchsuccessestolater-stagedevelopmentbyindustry.Third,itwillencourageindustrytopursuepromisingopportunitiesthattheywouldnotundertakeontheirown,includingprojectsfocusedonpediatricandrarecancersorminority/underservedpopulations.Finally,itwillallowNCItoleverageindustryfundingtopursueopportunitiesthathaveahigherpotentialtobetakenforwardbyindustry.

Bothindustryandacademiahavedemonstratedinterestinthetypesofcollaborativerelationshipsenvisionedbysuchanewprogram.ThisisevidencedbythesuccessparticipantsintheAP4PlanningGrantprogramexperiencedinstructuringrelationshipswithindustrialpartnersandtheestablishmentofsimilarstateprograms,suchastheUniversityofCaliforniaDiscoveryGrantprogram,whichfundscollaborativerelationshipsbetweenUniversityresearchersandCalifornia-basedcompanies.


Implementation Plan

Overall Approach

NCIwillestablishanewprogramdesignedtofundinvestigator-initiatedacademic/industrycollaborativeearlytranslationalresearchprojectsviaaU-seriesmechanism.TheprogramwillfundprojectsthatadvanceadiscoveryorsetofdiscoveriesalongoneoftheTRWGdevelopmentalpathwaysthroughearlyhumantestingofaspecificdrug,biologic,diagnostic/screeningtest,orothertherapeuticdiagnosticorpreventativeintervention.Theprogramwillbedesignedtoencourageprojectsthatfocusonrarecancers,pediatriccancers,orissuesinvolvingminority/underservedpopulationsthat



arelesslikelytoattracttheinterestandinvestmentofindustrywithoutNCIinvolvement.ThisprogramisfundamentallydifferentfromtheSTRAPprogram(seeTailoredFundingProgramsInitiativeB3)inthatindustryparticipationandco-fundingarerequired,notoptional,andbecausetheprojectsareproposedbyinvestigatorsratherthanbeingdrivenbysystem-widepriorities,asisthecaseforSTRAPawards.

Theprogramwillrequireactiveparticipationandco-fundingbyatleastoneindustrypartner.TheTranslationalResearchSupportOfficewillworkwithNIH’sProgramonPublic-PrivatePartnershipswithintheOfficeoftheDirector,asappropriate,indevelopingthisinitiativeandwillalsoworkwiththeOfficeofLiaisonActivitiesandtheFoundationforNIHtoinvestigateopportunitiesforjointfundingbyfoundationsforspecificprojects.Thesizeanddurationoftheawardswillbedeterminedonaproject-specificbasis,vianegotiationbetweenNCIandtheprincipalinvestigator(s),inlightoftherequirementsofthespecificprojectplan.Thus,aprojectcouldbefundedfor6monthstopursueaveryspecificshort-termgoalorfor5ormoreyearstopursueamorecomplex,involveddevelopmentplan.

Industry Relations Working Group

Inordertolaythegroundworkfornegotiationofthejointfundingarrangementsunderlyingthesenewacademic/industrycollaborationawards,NCIwillestablishanIndustryRelationsWorkingGroupundertheauspicesoftheAdvisoryCommitteeandwithlogisticalsupportfromtheTranslationalResearchSupportOffice.Themembershipwillbecomposedof8-10individualsfromindustryandNCIrepresenting:

• Alargebiotechnology/pharmaceuticalcompany

• Asmallbiotechnology/pharmaceuticalcompany

• Devicedevelopment

• Imagingagentdevelopment

• Drugdevelopment

• Biologicsdevelopment.

TheWorkingGroupwillreviewpastexamplesofinteractionsbetweenNCIandindustry,drawingfromseveralusecases,suchasintellectualpropertylicensing,accesstoagents,andCooperativeResearchandDevelopmentAgreements.TheWorkingGroupwillbeaskedtoreportwithin1yearonthefindingsandrecommendationsderivedfromitsinvestigation,consultation,andconsensus-buildinginthefollowingareas:

• ActionsNCIcantaketoimproveNCI-industryinteractions

• NewapproachesNCIcanimplementforNCI-industryinteractions

• ActionsNCIcantaketoeliminatebarrierstoeffectiveNCI-industryinteractions.

ThefindingsoftheWorkingGroupwillbeshared,asappropriate,withNIH’sProgramonPublic-PrivatePartnershipswithintheOfficeoftheDirectorfordisseminationinsupportofeffortstofosterindustryrelationshipsacrossNIH.

Funding

Approximately$5millionwillbeallocatedtonewacademic/industrycollaborationseachyear,uptoasteadystateofapproximately$25millioninannualfundingafter5years.Itisanticipatedthatfundingforacompleteproject(includingbothNCIandindustrycomponents)wouldrequire$5-10millionoveramultiyearperiod,averaging$1-2millionperyear.However,fundingwillvarywiththenatureandsizeoftheproject.Forexample,smaller,morenarrowlyfocusedprojectscouldbefundedfor$500,000orless,whilelarger,morecomplexprojectscouldbefundedformorethan$10million.



Projectfundingwillbedistributedinaccordancewiththemilestonesprovidedinthedevelopmentplan(seebelow).Uponaward,theresearchteamwillbeprovidedwiththefundingrequiredtomeetthefirstmilestone,plusadditionalfundingtosupport6monthsofworkfollowingthemilestoneduedate.Thiswillensurecontinuedfundingfortheresearchwhilethemilestonereviewiscompleted.Ifthemilestonereviewispositive,fundingwillbeprovidedforreachingthenextmilestone(plusthe6-monthextension).17

Solicitation and Award Process

NCIwillissueaRequestforApplicationswithmultipleannualsubmissiondates,solicitingproposalsforjointlyfundedacademic/industrycollaborativeprojects.ProposalswillbereviewedbyaSpecialEmphasisPanelcomposedoftranslationalexpertsdrawnapproximatelyequallyfromindustryandacademia,18withadditionalinputfromtheadvocacycommunity.Toensureappropriateexpertiseforreviewandevaluationoftheseprojects,thereviewpanelwillincludememberswithexpertiseinprojectmanagement,drugdevelopment,andintellectualpropertyinadditiontoappropriatescientificexpertiseandacademicorindustrialexperience.

Management

Eachproposalwillincludeacompleteprojectplan,coveringallactivitiesthroughtheprojectedhandoffoftheproduct,device,orinterventiontofurtherdevelopmentbytheindustrypartner.Inadditiontoaddressingtheresearchanddevelopmentactivitiestobeconductedandtheresourcesrequired,eachprojectplanmustalsoincludeawell-developedmanagementplanaddressingthefollowing:a)governance,organizationalstructure,andprojectmanagement;b)approachestocommunicationandcoordination;c)theprocessformakingdecisionsonscientificdirectionandallocationofresources;andd)proceduresforresolvingconflicts.AsdescribedinOperationalEffectivenessInitiativeC1,NCIprojectmanagementresourceswillbeavailablefortheseprojects.Aprojectmanagermaybeoneoftheresourcesthattheindustrialpartnercontributestotheproject.

EachprojectwillbegovernedbyaSteeringCommitteecomposedoftheseniorinvestigatorfromeachcomponentoftheproject(includingindustryinvestigator(s))andtheTranslationalResearchSupportOfficestaffmemberservingastheProgramOfficerandprojectmanager.19TheSteeringCommitteewillhaveoversightresponsibilityfortheentireproject,includingallocationofresources,reviewofprogressagainstmilestones,andoverallcoordinationoftheproject.Eachprojectwillalsohaveanexternaladvisorycommittee,composedofscientific,clinical,andproductdevelopmentexpertsrelevanttothespecificproject,drawnequallyfromindustryandacademia,aswellasapatientadvocatewithprioradvisoryexperiencewithintheNCIsystem.Theadvisorycommitteewillparticipateinmilestonereviews(seebelow)andideallywillincludeatleastsomemembersofthereviewpanelthatrecommendedtheaward.

Industry Participation

Participationandcost-sharingintheresearchprojectbyatleastonecompanywillberequired.Multipleindustrialpartnerswillbepermittedifthereisastrongscientificortechnicalrationale.Industrialpartnerswillgenerallybeexpectedtofund50%ofthetotaldirectprojectcostsplusapplicableindirectcosts.Someorallofthatfundingcanbein-kindprovisionofmaterials,services,orresearchwork.Aco-investigatorfromindustrywillberequired,andtheproposalwilldescribethenatureoftheinteractionbetweentheacademicinstitutionandtheindustrialpartner,thetimecommitmentoftheindustrialresearcher(s),thenatureoftheworktobeperformedbyindustry,andthecost-orresource-sharingplan.Collaborationsinvolvingmorethanoneacademicpartnerwillalsobepermittedbutnotrequired.

17 TheTRWGrecognizesthatimplementingsuchafundingstrategymaybecomplexandwillrequireNIH-levelreview.18 TheTRWGrecognizesthatitmaybechallengingtorecruitindividualsfromindustryforthesereviewpanelsduetopotentialconflictsofinterest.19 Initially,TranslationalResearchSupportOfficestaffwillserveastheofficialprogramofficerandprojectmanager,butwithactiveinvolvement

ofadesignatedDivisionalprogramstaffmemberwhohastherelevantscientificexpertiseandexperiencetoguidethespecificprojectinquestion.Astheprogramexpands,itmaybepreferabletotransfertheprogramofficer/projectmanagerresponsibilitiestorelevantDivisionalstaffatthetimeofaward.



Intellectual Property

Aspartoftheproposaldevelopmentprocess,theindustrialandacademiccollaboratorswillnegotiateanintellectualpropertyagreement,includingpublicationandpatentrights,thatwillbeincludedwiththeproposal.Adraftagreementwillberequiredatthetimeofproposalsubmission,withthesignedagreementrequiredatthetimeofaward.

Aspartoftheintellectualpropertyagreement,theindustrialpartner(s)willhavea“rightoffirstrefusal”foranyintellectualpropertydevelopedundertheproject.However,iftheindustrialpartnerdeclinestofurtherdevelopthetechnologyorproduct,theacademicinvestigatorsandNCIwillhavetherighttopursuefurtherdevelopmentandnegotiatelicenseswithotherindustrialpartners.Theintellectualpropertyagreementwilladdresscompensationtotheoriginalindustrypartnerifaproductissuccessfullycommercializedbysuchafollow-onpartner.

Milestones

EachproposalmustincludeadetailedtimelineanddevelopmentplanwithappropriatemilestonesdefinedbyreferencetotherelevantTRWGdevelopmentalpathway.Thereasonablenessoftheproposedmilestonesforchartingefficient,timely,andrealisticprogresswillbeanimportantelementininitialreviewoftheapplication.DefinitivemilestonesanddateswillbeestablishedatthetimeofawardthroughnegotiationbetweenNCIandtheprincipalinvestigator(s).

EachprojectwillbesubjecttoongoinginformalmonitoringbytheSteeringCommittee,aswellasarigorousformalreviewbytheSteeringCommitteeandtheexternaladvisorycommitteeatthetimeofeachprojectedmilestone.Ongoinginformalmonitoringwill:

• Ensurethattheperceptionofprojectprogressonthepartofboththeprincipalinvestigator(s)andtheresponsibleNCIprojectmanagerisconsistent,accurate,anduptodate.

• Ensurethatproblemsareidentifiedandaddressedinatimelymannerandthatnomajorproblemfirstbecomesapparentatthetimeofaformalmilestonereview.

• Anticipateforthcomingformalmilestonereviewsandfacilitatetimelygenerationofneededdocumentarysupport.

• Enableformalmilestonereviewstobemovedforwardwheneverprogresswarrants.

• Anticipateexpectedfailurestoreachmilestonesanddevelopcontingencyplans.

Annualreportswilladdressprogresstowardappropriatemilestones.Ifprogresstowardamilestoneisbehindschedule,thereportwillincludeananalysisoftheproblemsencounteredandarecommendationastowhetherthereshouldbecontinuedeffortstoreachthemilestoneorwhethertheprojectshouldbemodifiedorterminated.SuchrecommendationswouldbetheresultofSteeringCommitteeandexternaladvisorycommitteedeliberations.

Milestone Review

FormalmilestonereviewsinvolvingtheprojectSteeringCommitteeandtheexternaladvisorycommitteewillbeusedtomakeafinalrecommendationtoNCIoncontinuation,modification,orterminationoftheproject.Ifamilestoneisachievedaheadofschedule,thereviewwilloccurwhenthemilestoneisachievedandfundingcanbeaccelerated.

UpondeterminationoftheSteeringCommitteeandtheexternaladvisorycommitteethatamilestonehasbeenmetsuccessfully,thenextroundoffunding,sufficienttocompletethenextmilestoneplus6monthsofwork,willbereleasedtotheresearchteam.Thisfundingprocesswillcontinueuntileitheramilestonehasnotbeenmetortheprojectiscompleted.IftheSteeringCommitteeandtheexternaladvisorycommitteedeterminethatthemilestonehasnotbeenmet,noadditionalfundingwillbereleasedandtheawardwillbeterminated.Theongoinginformalmonitoringprocessshouldanticipatethissituationandallowtheinvestigatorstoplanforterminationoftheproject.



Program Evaluation

TheTranslationalResearchSupportOfficewilldevelopaplanforevaluationoftheacademic/industrycollaborationfundingprogram,includingtheidentificationofbothprocessandoutcomemeasures.Continuationoftheprogramafterthefirst5yearswillbesubjecttoanevaluationoftheeffectivenessofitsimplementationandpreliminaryevidenceconcerningtranslationalimpact.Continuationorexpansionoftheprogramafter10yearswillbesubjecttoanevaluationthataddressestheimpactandproductivityoftheprogram.AswithallNCIprograms,long-termcontinuationwillbesubjecttoexternalpeerreviewandweighingofprioritiesinlightofneeds,opportunities,andbudgetconditions.



Initiative B5: Integrate access to GMP/GLP manufacturing and other preclinical development services more effectively with milestone-driven early translational research projects.

Rationale

Availabilityofpreclinicaldevelopmentservices,especiallymanufacturingofclinical-gradematerials,isperceivedtobeamongthebiggestbottlenecksinbringingdiscoveriesfromthelaboratorytotheclinic.DespitethesuccessofNCI-fundedmanufacturingandpreclinicaldevelopmentresourceprogramssuchasRAID,RAPID,andDCIDE,accesstothesedevelopmentcapabilitiesisstillarate-limitingstepfortranslationalresearchingeneral.IntegratingaccesstotheseserviceswiththenewtailoredtranslationalresearchfundingprogramsproposedbytheTRWGwillenhancetheproductivityofNCIinvestmentsintranslationalresearchandthedevelopmentservicesrequiredtobringproductstotheclinic.Itwillalsoensurethatdevelopmentresourcesarereadilyavailableforhigh-priority,milestone-drivenearlytranslationalresearchprojects.


Implementation Plan

Overall Approach

Currently,thereviewoftranslationalresearchprojectsisnotcoordinatedwiththereviewsconductedbyNCI-supportedpreclinicaldevelopmentresourceprograms.Anapplicationfordevelopmentresourcesrequiresaseparateinvestigator-initiatedapplicationandreviewprocessthatisindependentofthereviewandapprovalofprojectscoveringearlierstepsinthetranslationalpathway.Thislackofintegrationisperceivedbyinvestigatorstocauseasignificantadditionaldelayforprojectsthathavereachedthestagewheredevelopmentservicesareneeded.

UnderthemodifiedP50/U-seriesguidelinesandthenewSTRAPfundingprogramforprioritizedprojects(seeTailoredFundingProgramsInitiativesB1andB3),allmajortranslationalresearchprojectswillbesubjecttoobjective,formal,milestone-basedreview.Fortheseprojects,accesstothedevelopmentcapabilitiesrepresentedbyRAID,RAPID,andDCIDEwillnotoccurviathestandardapplicationandreviewprocesses,althoughtheseprocesseswillcontinuetoberequiredforinvestigator-initiatedprojectsnotsubjecttomilestone-basedreview.Rather,thereviewprocessesestablishedbyRAID,RAPID,andDCIDEwillbeintegratedwiththenewtranslationalresearchmilestone-basedreviewprocesses.Suchanintegratedreviewwillensurethatwhenaprojecthasachievedalloftherequiredmilestonesandisreadyfortoxicology/pharmacologytestingandclinicalgrademanufacturing,itwillneedtoundergoonlyonecoordinatedreviewtomoveforward.Thisintegratedreviewisnotintendedtoaffectorcompetewiththereviewandfundingoftraditional,investigator-initiatedRAID,RAPID,andDCIDEapplications.

Integrated Review

Theintegratedreviewprocesswillbeimplementedasfollows.Whenasuccessfultranslationalresearchprojectisnearingthestagewherepreclinicaldevelopmentresourcesareneeded,therelevantprogramofficerwillcontactstafffromeitherRAID,RAPID,orDCIDE,asappropriate,toorganizeacoordinatedreview.Thiscoordinatedreviewwillinvolvetheindividualsandcommitteesinvolvedinthestandarddevelopmentresourcesreviewprocessaswellastheexternaladvisorycommittees,steeringcommittees,principalinvestigators,projectmanagers,programstaff,etc.,thatwereinvolvedwithpreviousmilestonereviewsforthetranslationalresearchprojectinquestion.

Forexample,RAIDnowusesatwo-tieredreviewprocess—anoversightcommitteeandaninitialreviewcommitteethatisasubcommitteeoftheoversightcommittee.Theinitialreviewcommitteeiscomposedofmembersoftheoversightcommitteeplus,ifnecessary,additionalexpertsinthescienceandproductiontechnologyrelevanttotheapplicationinquestion.TheoversightcommitteeiscomposedofindividualsfromNCI,academia,andindustrywhohaveexperience



indevelopingnewanticanceragents.20Theoversightcommitteerecommendsfundingbasedonreviewoftheapplicationsgivenasufficientlyhighpriorityscorebytheinitialreviewcommittee.Theserecommendationsarebasedonscientificmerit,feasibility,practicaldevelopmentconsiderations,andNCIpriorities.Theoversightcommitteealsoconductsperiodicreviewsoffundedprojectstoevaluateachievementofmilestonesandadherencetotimelinesaswellastodecideoncontinuation.

Formilestone-basedtranslationalresearchprojectsrelevanttoRAID,aRAIDinitialreviewcommitteewillbeinvolvedinthecoordinatedreview,andtheRAIDoversightcommitteewillprioritizetherecommendedprojectsforfunding.Thus,thenewNCAB-approvedRAIDreviewprocesswillconstitutetheintegrated“back-end”ofthenewmilestone-based“front-end”reviewprocessforthesetranslationalresearchprojects.

Theintegratedreviewprocesswillevaluatethefollowingcriteria:

• Scientificquality

• Importanceofclinicalneed

• FitwithNCI-widetranslationalresearchpriorities

• Strengthandfeasibilityofthepreclinicaldevelopmentplan,includingappropriatenessofmilestones

• Strengthandfeasibilityoftheenvisionedclinicaldevelopmentplan

• Projectedcostofthedevelopmentprogram

• Experienceoftheprincipalinvestigatorandtheinstitutionindrugdevelopment,includingInvestigationalNewDrugApplication(IND)submissions

• Strengthofintellectualpropertyprotectionandresolutionofanyintellectualpropertyissues.

Project Management

Asatranslationalresearchprojectproceedsthroughpreclinicaldevelopment,itwillbeoverseenbytheprogramandprojectmanagementstaffinvolvedinearlierstagesoftheproject(seeOperationalEffectivenessInitiativeC1)andbyprojectmanagementand/orprogramstafffromtherelevantdevelopmentresourcesprogram.Theprojectwillbereviewedatpredeterminedmilestonesbythesameintegratedprocessdescribedabove,withfundingforeachstagecontingentonsuccessfulcompletionofthemilestone.

Funding

Becausethecostofmanufacturingandotherpreclinicaldevelopmentservicesissubstantial,fundsfortheseserviceswillnotbeincludedinspecifictranslationalresearchawards.Rather,eachyear,theTranslationalResearchOperationsCommitteewillrecommendreservingaportionofthededicatedtranslationalresearchbudgetinaset-asidepoolofcontractfundsforpreclinicaldevelopment.ThesefundswillbeallocatedbytheExecutiveCommitteebasedonrecommendationsfromtheOperationsCommitteeconcerningwhichprojects,approvedthroughtheintegratedreviewprocessdescribedabove,arethehighestpriorityforuseofthesepreclinicalcontractdevelopmentfunds.Theserecommendationswillbebasedonavailablefunds,fitwithNCI-widetranslationalresearchpriorities,estimatedcostsofcompletingdevelopment,andcompetingneedsandopportunitiesacrossdiseasesites,TRWGpathways,patientpopulations,etc.Asmanyprojectswillrequiremorethan1yeartocompleteallpreclinicalwork,someportionoftheset-asideeachyearlikelywillberequiredtofulfillongoingcommitments.ThiscontractfundingwillbeinadditiontocurrentRAID,RAPID,andDCIDEfundingforindependentinvestigator-initiatedprojects.TRWGmembersbelievethisisacriticallyunderresourcedareaoftranslationalservices.Thenewportfoliocodingandcoordinatedtranslational

20 ReportoftheWorkshoptoReviewtheNationalCancerInstitute’sRapidAccesstoInterventionDevelopment(RAID)Program,November2005.Availableat:http://dtp.nci.nih.gov/docs/RAID/RAIDFinalReport061406.pdf.



researchmanagementsystemisenvisionedtomakethismoreapparentandprovidethesystem-widecredibilitynecessarytowarrantincreasedinvestment.

Involvement of Development Experts in Translational Research Review

DevelopmentexpertsinvolvedintheRAID,RAPID,andDCIDEreviewprocesseswillbeincorporated,asappropriate,inearlierstagesofreviewingmilestone-basedtranslationalresearchprojectsfundedthroughthemodifiedP50andU-seriesprogramsandthenewSTRAPfundingprogram.Involvementofdrug,biologics,orimagingagentdevelopmentexpertsearlierintheprocesswillhelpensurethatprojectsarenotadvancedthathaveahighprobabilityofencounteringseriousroadblocksintoxicology,pharmacology,ormanufacturing.Moreover,theseexpertscansharelessonslearnedandbestpracticeswithinvestigatorsattheinitialphasesofaprojecttobetterinformtheapproachtaken.ThistypeofearlyinvolvementandcollaborationwillensurethatRAID,RAPID,andDCIDEprogramstaffandexternalreviewersbecomemoreintegratedwiththeoveralltranslationalresearcheffort.

Molecular Analysis Assay/Device Preclinical Development Resource Program

TheTranslationalResearchSupportOfficewillworkwiththeDivisionofCancerTreatmentandDiagnosisandtheDivisionofCancerPreventiontoevaluatetheneedforandpotentialbenefitsofanNCIdevelopmentresourcesprogramtodevelopandvalidatebiomarkermolecularanalysisassaysanddevicesforuseinNCI-supportedprojects.Theevaluationwillalsoaddressthetechnicalandfinancialrequirementsofsuchaprogramandthepotentialthatindustrymightlicensecertainofthedevelopeddevices.

Use of Industry Excess Capacity

ItmaybepossibletotakeadvantageofexcesscapacityatpharmaceuticalandbiotechnologycompaniesiftheservicesarenotavailablethroughNCIdevelopmentprograms.TheTranslationalResearchSupportOfficewillinvestigatewhethersuchexcesscapacityexists,forwhatservicesitexists,andtheinterestofindustryinmakingtheseservicesavailableatareasonablecosttoNCI-fundedacademicresearchers.


Report of the NCAB Translational Research Working Group—Operational Effectiveness


Introduction

InadditiontoimprovingmanagementcoordinationacrossNCIandstrengtheningfundingprograms,theTRWGidentifiedanumberofspecificopportunitiestoenhancetheoveralloperationaleffectivenessoftranslationalresearch.

Onekeyimprovementwouldbetheavailabilityofcriticalprojectmanagementresourcestoassistlarge,multiproject,collaborativetranslationalresearchprogramsinachievingtheirgoals.Industryhaslongusedformalprojectmanagementapproachestofacilitatetheirdevelopmentprogramsbyensuringcommunicationacrossprojectteams,efficientlyidentifyingresources,coordinatingtransitionsbetweendevelopmentalstages,andsolvingproblems.ManyofthemorecomplexNCI-supportedtranslationalresearchprogramswouldbenefitfromsuchfacilitation.

Asecondcriticalareaforimprovementisincoreservices.Enhancedcoordinationacrossinstitutionsandprogramsisneededtoensurethatresourcesarenotinvestedinduplicativeinfrastructuresandthatservicesoperateinacost-effectivemanner.Inparticular,increasingdemandforhigh-quality,annotatedbiospecimensrequiresenhancedstandardization,dedicatedfunding,andapproachesforefficientandequitablesharingofavailablespecimens.

CollaborationsamongNCI,academicinstitutions,industry,andfoundationsarefundamentaltothesuccessoftranslationalresearch.Suchcollaborationsshouldbepromotedbystreamlininglegalnegotiationsandbuildingpartnershipsthatleveragecomplementaryskillsandresources.Finally,theneedforacontinuingflowofqualifiedtranslationalresearcherschallengesthecurrentsystem,whichisdesignedprimarilytotraineitherlaboratoryscientistsorclinicians.Acriticalevaluationoftrainingprogramsandcareerincentivesisneededtochartacleareducationandcareerdevelopmentpathfortranslationalresearchprofessionalsandothersengagedinmultidisciplinarytranslationalresearchteams.

ToachievethisdiversesetofobjectivesforimprovingtheoperationaleffectivenessofNCI-supportedtranslationalresearch,theTRWGproposessixinitiatives.

C1. Establish a formal project management system for early translational research.

C2. Establish a system to coordinate core services essential for early translational research.

C3. Enhance quality and accessibility of annotated biospecimen repositories and associated analytic methods.

C4. Develop enhanced approaches for negotiation of intellectual property agreements and agent access.

C5. Enhance interactions and collaborations with foundations and advocacy groups to advance early translational research.

C6. Enhance training and career incentives for early translational research.



Initiative C1: Establish a formal project management system for early translational research.

Rationale

Themultidisciplinarynatureoftranslationalresearchandtheneedtointegratesequentialstepsalongcomplexdevelopmentalpathwayswarrantstheprovisionofdedicatedprojectmanagementresources.CreationofaformalprojectmanagementsystematNCI,incorporatingspecificmanagementcompetenciesandclarifyingresponsibilityforkeyfunctionalroles,wouldspeedthetranslationalresearchprocessbyaddressingseveralimportantmanagementtasksthatarenotconsistentlyrealizedundercurrent,informalarrangements.

Thesetasksinclude:

• Identifyingandaccessingspecializedresourcesandexpertisesuchasmanufacturingcapabilitiesandregulatorysupport

• Coordinatingandcommunicatingbetweentheprojectscientificleadsandthemultidisciplinaryprojectteamtoensurethatprojectplanmodificationsareimplementedsmoothlyandthatproblemsareidentifiedandaddressedinatimelyfashion

• Coordinatingthetransitionofprojectsacrossdevelopmentstages,disciplines,andprograms

• Ensuringefficientprogressandadheringtoamilestone-basedprojectplan.

Projectmanagementhaslongbeenusedbyvariousindustries,includingpharmaceuticalandbiotechnologycompanies,toefficientlymoveresearchanddevelopmentprojectstowardtangibleproducts.Inaddition,severalacademicinstitutionshaveestablishedprojectmanagementpositionstoassistwiththeirlocaltranslationalresearchprograms.ImplementationofanNCIprojectmanagementsystemwouldbringthesebenefitsconsistentlytoallmajorNCI-fundedtranslationalresearchprograms.


Implementation Plan

Scope of Projects Covered

Projectmanagementresourceswillbeprovidedforthefollowingcategoriesoftranslationalresearchprojects:

• Multiprojectcollaborativetranslationalresearchawards(i.e.,P50,U-series,andRFA-directedP01awards)21

• ProjectsfundedviathenewSTRAPprogram(seeTailoredFundingProgramsInitiativeB3)

• Researchprojectsfundedviathenewprogramthatrequiresacademic/industrycollaboration(seeTailoredFundingProgramsInitiativeB4)

• PhaseIandIIclinicaltrialcontracts.

TheprojectmanagementsystemwillbeimplementedbyincludingprojectmanagementintheguidelinesforP50,U-series,andP01awardsaswellasPhaseIandPhaseIIclinicaltrialcontractsandthenewSTRAPandacademic/industrycollaborationprograms.Theseprojectsmayalsorequestandallocatefundstosupporttheservicesofaninstitutionallybasedprojectmanager.

21 NotethattheprojectmanagementsystemwillonlyberequiredforP50andRFA-directedP01awardsifguidelinescanbemodifiedtorequiretheuseofNCIprojectmanagementresources.Ifmodifyingtheguidelinestoincludethisrequirementisnotpossible,investigatorsfortheseawardswillbestronglyencouragedtoutilizeNCIprojectmanagementresourcesfortheirprojects.



Overall Approach

TheTranslationalResearchSupportOfficewillberesponsibleforensuringthattheprojectmanagementfunctionsdescribedbelowareprovidedforalldesignatedprojects.ForP50,P01,andU-seriesawardsandPhaseIandIIclinicaltrialcontracts,theproposedprojectmanagementfunctionswillbeperformedprimarilybycurrentprogramstaffinconjunctionwithanewprojectmanagementpositionwithineachappropriateDivision,Center,orOffice.Theseprojectmanagerswillserveasaresourceforprogramstaffrequiringguidanceorassistanceinfulfillingprojectmanagementfunctions.TheprojectmanagerswillalsoworkcloselywiththeTranslationalResearchSupportOfficeprojectmanagementstaffinimplementingandcoordinatingprojectmanagementfunctions.

ProjectmanagementwillbeimplementedinitiallyforP50,U-series,andRFA-directedP01awardsandPhaseIandIIclinicaltrialcontractsasthoseguidelineswillberevisedbeforetheinitialSTRAPandacademic/industrycollaborationawardsaremade.ForthenewSTRAPandacademic/industrycollaborationawards,SupportOfficestaffwillserveasbothprogramofficersandprojectmanagers.TheSupportOfficewillalsoprovidecertainprojectmanagementfunctions(e.g.,overviewandinventoryofresources)forallapplicableprojects.Mostimportantly,SupportOfficestaffwillserveasthecoordinatingfocusofresponsibilityforensuringthatthedistributedprojectmanagementsystemdescribedabovefunctionseffectively.ThiswillincludecoordinatingtheactivitiesofprojectmanagementstaffintheDivisions,Centers,andOffices;communicatingwiththeextramuralcommunityconcerningthevalueprovidedbytheNCIprojectmanagementsystem;andcommunicatingwithNCIleadershipconcerningprogressandanyissuesthatmayarise.

Following2yearsofimplementation,theprojectmanagementsystemwillbeevaluated.Oneaspectoftheevaluationwillbetodetermineifthedistributedmodel,withmostprojectmanagementfunctionsvestedintheDivisions,Centers,andOffices,hasbeeneffective,orwhetheramorecentralizedmodelshouldbeconsidered.Iftheconclusionisthatprojectmanagementhasprovidedsignificantvalue,adecisionwillbemadewhethertoexpandtheavailabilityofNCIprojectmanagementresourcestoincludeinvestigator-initiatedR01sandP01sthatprimarilyinvolvetranslationalresearchasidentifiedbythenewlyestablishedtranslationalresearchawardcodes(seeCoordinatedManagementInitiativeA3).

Project Management Staffing

Translational Research Support Office. TheTranslationalResearchSupportOfficeprofessionalstaffwillincludeindividualswithskillsandexperiencerelevanttoprojectmanagement(e.g.,industryinteraction,regulatorycompliance,interactionwithacademicinstitutions).AtleastoneSupportOfficeseniorprofessionalwillhaveadoctoraldegreeinarelevantscientificfield,orequivalentexperience,aswellasdirectprojectmanagementexperience,preferablywithinanindustryenvironment.Additionalstaffwithprojectmanagementexpertisewillbeaddedasprojectdemandsgrow.Cross-trainingwillbeprovidedsothatotherSupportOfficestaffmembershaveskillsincertainaspectsofprojectmanagement.

Divisions/Centers/Offices. AtleastoneprojectmanagementpositionwillbeestablishedwithineachDivision,Center,andOfficetoassistprogramstaffinprovidingprojectmanagementservices.Theseprojectmanagerswillhavedirectprojectmanagementexperience,preferablywithinanindustryenvironment,andwillworkcloselywithTranslationalResearchSupportOfficestafftoensuredevelopmentandoperationofacoordinated,well-functioningprojectmanagementsystem.Todrivesuccessfulimplementationofprojectmanagementresponsibilitiesbyprogramstaff,suchresponsibilities,includingcoordinationwiththeTranslationalResearchSupportOffice,willbeincludedintheirperformanceplans.

Project Management Roles and Responsibilities

System-Wide Roles and Responsibilities. TranslationalResearchSupportOfficestaffwillberesponsibleforcoordinatingtheformalprojectmanagementsystemanddirectlyprovidingthefollowingprojectmanagementfunctionsforallapplicabletranslationalresearchprojects.

1.Cross-NCICoordinationandCommunication.TheSupportOfficewillmaintainanoverviewandinventoryoftranslationalresearchprojectsacrossallNCIorganizationalunitsandprogramsandfacilitatecoordinationbetweenprogramswhereincreasedsynergyand/ordecreasedredundancycouldberealized.Inaddition,theSupportOffice



willarrangeregularforumswithprojectmanagementandprogramstafffromtherelevantDivisions,Centers,andOfficestodiscussprogrammaticprojectmanagementneeds.SupportOfficestaffwillalsointeractwithextramuralinvestigatorsandinstitutionallybasedprojectmanagerstodiscussprojectmanagementneeds.

2.ResourceInventoryandDatabase.TheSupportOfficewillmaintainaninventoryanddatabaseofthefollowingresources,oftenneededbytranslationalresearchprojects,whicharecurrentlyavailableacrossNCI,academicinstitutions,andindustry:

High-throughputscreening

Biospecimenrepositories

Researchtools(e.g.,celllines,animalmodels)

Biomarkerassaysystems

Imagingcapabilities

Agents,devices,orothermaterials/informationfromindustry

Developmentcapabilities,includingmanufacturing,toxicology,andpharmacology

Biostatisticalanalysisservices

Patientpopulations.

SupportOfficestaffwillcoordinateassemblyoftheinventoryandworkwiththeNCICenterforBioinformatics(NCICB)todesignandbuildthedatabase.ThisdatabasewillbeanexpansionoftheNCI-supportedcoreservicesdatabasedevelopedaspartofOperationalEffectivenessInitiativeC2.Programstaffandprojectmanagerswillusethisinventorytodirectinvestigatorstoneededresources.Thisinventoryalsowillbeavailabletoinvestigatorspreparingproposalsinresponsetotranslationalresearchsolicitationstoassistthemwithdevelopingfullyresponsiveproposals.

3. OversightRole.SupportOfficestaffwillbeavailableforconsultationwithprincipalinvestigatorswhohaveconcernsregardingprojectmanagementfunctionsprovidedbyprogramstaff.

Project-Specific Roles and Responsibilities. Programstaffwillberesponsibleforprovidingproject-specificprojectmanagementfunctionsfortheapplicableP50,P01,andU-seriesawardsandPhaseIandIIclinicaltrialcontractsinconsultationwiththeirunitprojectmanagementstaff.FortheSTRAPandacademic/industrycollaborationawards,thesefunctionswillbeprovidedbyTranslationalResearchSupportOfficestaff,whowillserveasprogramofficersandprojectmanagersforthoseawards.

1. ResourceIdentification.Programofficerswillworkproactivelywithprincipalinvestigatorstoidentifyresourcesneededateachstageofatranslationalresearchproject.ThisincludesfacilitatingcontactsandcollaborationsthroughwhichprincipalinvestigatorscanobtainaccesstoresourcessuchasthoselistedintheTranslationalResearchSupportOfficedatabase.

2. RegulatoryFilings.Programofficerswillassistwithregulatoryfilings,asnecessary,workingwithprincipalinvestigatorsandotherNCIprogramstaff.AnyInvestigationalNewDrug(IND)applicationswillbepreparedincooperationwiththeRegulatoryAffairsLiaisonfromtheCancerTherapyEvaluationProgramandotherrelevantintramuralorextramuralparties.

3. CoordinationandCommunication.Programofficerswillassistprincipalinvestigatorsinensuringconsistentandmeaningfulcommunicationamongallmembersofamultidisciplinary,multiprojecttranslationalresearchteam.Thiswillincludeorganizingregularmeetingsfordiscussionandplanning,identifyingpointsofcommunicationbreakdown,andcoordinatingthetransferofprojecttasksbetweengroupsthatmaybefromdifferentinstitutions.

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4. MonitoringProgressandProblemSolving.Programofficerswillworkwithprincipalinvestigatorstomonitorcontinuedprogressoftranslationalresearchprojectsaccordingtoestablishedprojectmilestones(seethesectionsonmilestoneswithintheTailoredFundingProgramsInitiativesB1,B3,andB4)andtoassistwithsolvinganyproblemsthatarise.Theywillorganizeappropriatemilestone-basedreviewsandprovideinputtothesteeringorexternaladvisorycommitteesthatarechargedwithdecidingwhetheraprojectshouldbecontinued,modified,orterminated.

5.CollaborationwithInstitutionallyBasedProjectManagers.Programofficerswillcollaboratewithinstitutionallybasedprojectmanagers(seebelow),asneeded,tofacilitatetheresearchprogram.Thismayincludecoordinationconcerningwhichprojectmanagementfunctionswillbefulfilledbyeachprojectmanagerandassistinginsolvingday-to-daymanagementissuesfortheproject.

Institutionally Based Project Managers

AlthoughtheNCIprojectmanagementsystemwillprovidevaluableassistanceformajorlong-termmanagementissues,large,complexprojectsoftenencounterday-to-dayissuesthatrequiremorelocalprojectmanagementsupport.TranslationalResearchSupportOfficestaffandprogramofficerswillfocusonbroader,globalissuesrelatedtoaproject,whileinstitutionallybasedprojectmanagerswillfocusonnarrower,localissues.

TheguidelinesforSTRAPandacademic/industrycollaborationawardswillrequireaninstitutionallybasedprojectmanagementplanandallowawardeestorequestfundingforprojectmanagementsupport.TheguidelinesformultiprojectcollaborativeP50,P01,andU-seriestranslationalresearchawardsaswellasPhaseIandIIclinicaltrialcontractswillbemodifiedtoencourageonsiteprojectmanagementandallowforfundingofinstitutionallybasedprojectmanagers.

Itisnotanticipatedthateachtranslationalresearchprojectorawardwillhaveadedicatedinternalprojectmanager.Rather,individualinstitutionallybasedprojectmanagersmightprovidesupportforseveraldifferentprojects,witheachawardcontributingfundstosupporttheposition.Oneoptionwouldbeforcancercenterstoestablishaprojectmanagementcoreresourcethatwouldserveandbeadditionallysupportedthroughcharge-backsfromthecenters’variousSTRAP,academic/industrycollaboration,P50,P01,andU-seriestranslationalawardsaswellasPhaseIandIIclinicaltrialcontracts.

Theexactrolesandresponsibilitiesofaninstitutionallybasedprojectmanagerwillbedeterminedbytheprincipalinvestigatorandspecifiedinthefundingapplication.However,thefollowingprovidesageneraloverviewofthetypesoffunctionsthatinstitutionallybasedprojectmanagersmaybeassigned:

• Prioritizeteamactivitiesandmakerecommendationsonappropriatecoursesofactioninresponsetoprojectresults.

• CoordinatewiththeprincipalinvestigatorandNCIstaffontheallocationofresourcesinthemosteffectivefashion,givencurrentprioritiesandtimelines.

• Facilitateaccesstoinstitutionaland/orregionalcoreservicestomeetprojectneeds.

• Developimplementationplans,timelines,andbudgets.

• Ensuretimelycontributionsbyallteammembers.

• Conductregularteammeetingsandensurethatactionitemsareexecuted.

• Identifypotentialbottlenecksandworkwithallteammembers,theprincipalinvestigator,andNCIstafftoresolveimpediments.

• Preparenon-INDregulatoryfilings.

• Prepareprogressreportsasneeded.



Project Management Training

Formaltraininginprojectmanagementiscrucialtoensurethatprojectmanagershavetherequisiteskills.Therefore,SupportOfficestaffandanyNCIprogramofficerswithprojectmanagementresponsibilitieswillbeprovidedwithformaltraining.Projectmanagementtrainingforinstitutionallybasedprojectmanagerswillbeanallowablecostfortheaward.

Severalprojectmanagementtrainingprogramsexist,includingwithinbusinessschools,professionalassociations,andprivateorganizations.TheTranslationalResearchSupportOfficewillconductananalysisofcurrentlyavailableprojectmanagementtrainingprogramstodetermineiftheywillprovidetheskillsandtrainingneededformanagementofacademictranslationalresearchprojects.Ifexistingprogramsaredeterminedtobeinadequate,SupportOfficestaffwillworkwithproviderstotailorprogramstomeetNCItranslationalresearchneeds.



Initiative C2: Establish a system to coordinate core services essential for early translational research.

Rationale

NCIhaslongrecognizedthevalueofconsolidatedcentersthatprovidecriticalinfrastructuresupport,includingcoreservices,asdemonstratedbytheestablishmentofcancercentersbeginningin1961.TheClinicalandTranslationalScienceAwards(CTSA)programrecentlyestablishedaspartoftheNIHRoadmaphassimilarobjectives.ThenewCTSAprogram,togetherwiththedevelopmentoverthepastseveralyearsofseveralotherNCIprogramsthatsupportcoreservices,providethepotentialofcreatingindependent,perhapsredundant,coreservicesinfrastructures.Thishasledtoconcernamongthecancerresearchcommunitythatcoreservicessupportingtranslationalresearchneedtobemoreeffectivelycoordinated,withcapacitywellmatchedtoneed.

Developingamoreefficientandcoordinatedcoreservicesnetworkwillfacilitateandaccelerateaccesstoabroadrangeofservicesandensurethatservicesareavailableinacoordinatedandcooperativemanneracrossfundingprograms.Itmayalsominimizeredundancies,ensureefficiencyandeconomyofscalebyoperatingservicesatoptimalcapacity,andincreasestandardization,qualityassurance,andcross-corereliability.


Implementation Plan

Analysis of Existing Core Services

TheTranslationalResearchSupportOffice,withassistancefromotherNCIandcontractorstaffasnecessary,willanalyzeNCI-fundedintramuralandextramuralcoreserviceswiththegoalofidentifyingpossiblefunctionalredundancies.Thisanalysiswillrequireaninvestigationoffundedcoreawards(i.e.,facilities,equipment,infrastructure,stafftime,supplies)todistinguishbetweentotallyindependentcoresforthesameserviceatasingleinstitutionversuscoresthatutilizethesamecorefacilityandequipmentandsimplyprovideincrementalfundingforstafftime,supplies,specificservices,etc.

Identification of Existing Core Services. DuringtheTRWGportfolioanalysis,apreliminarylistof1,364coreawardswasgeneratedthatincludesCancerCenters(P30s),SpecializedProgramsofResearchExcellence,andP01sbyinstitution.Asnodatabasecurrentlyexiststhatmaintainstheinformationforallextramuralcores,thislistwasassembledfromdataprovideddirectlybytheCancerCentersprogram,theidentificationofcoresontheComputerRetrievalofInformationonScientificProjects(CRISP)database,andbysearchingtheSPOREWebsiteorindividualabstractsontheCRISPdatabase.AllP30coresareincludedonthislist,butthecoreslistedforSPOREandP01awardshavenotbeenverifiedandmightnotbecomplete.Inaddition,coresfundedthroughU-seriesprograms,R24awards,etc.,arenotincluded.ThispreliminarylistofP30,P50,andP01coreserviceawardsincludes93U.S.institutionswiththemajority(55%)fundedthroughCancerCentergrants,followedbySPORE(27%)andP01(18%)grants.

Inordertodevelopacomprehensivelistofalltranslationalresearchcoreservices,thisinitiallistwillbeexpandedtoincludeallSPOREandP01cores,coreslocatedattheintramuralCenterforCancerResearch,andanycoresassociatedwithU-seriesawards,CTSAawards,etc.GrantapplicationsandprogressreportsforallSPOREandtranslational22P01awardsnotincludedinthecurrentlistandalltranslationalU-seriesawardswillbeanalyzedtoidentifyfundedcoresanddeterminewhetherthecorefundssupportself-containedservicesorareusedtoprocureservicesfromanalreadyexistingcorefacility.ThisinformationwillbeusedtoassembleacomprehensivelistofallNCI-fundedtranslationalresearchcoreservices.

Analysis for Redundancies. Thecomprehensivelistoffundedcoreswillbereviewedtoidentifypotentialredundanciesatindividualinstitutions.BasedonthelistofcorespreparedaspartoftheTRWGportfolioanalysis,itappearsthat“redundanciesbytitle”(i.e.,morethanonecoreofasingletypeataninstitution)existprimarilyforbiostatistics/bioinformatics,clinicaltrials,andtissuecores.However,because“redundancybytitle”doesnotnecessarilyequateto

22 P01awardscategorizedastranslationalforthisanalysiswillbethoseidentifiedintheoriginalTRWGportfolioanalysis.



actualredundancy,afunctionalassessmentisrequiredtodeterminethenatureoftheoverlap.Forexample,althoughbiospecimencoresmayhavecertainaspectsthatareuniquetotheorgansiteorstudy,otheraspectssuchasadministration,ITsupport,equipment,etc.,mightbeappropriatelyconsolidated.

Thefunctionalassessmentwillinvolveanalyzinggrantapplicationsandthemostrecentprogressreportsforthosecoresataninstitutionthatappeartoberedundantaccordingtotitle.Basedontheexistinglistof1,364cores,thereare733(54%)thatareredundantbytitle.Thegoaloftheanalysisistodetermineifthesecoresarefunctionallyredundantorwhethertheyutilizeacommoncoreinfrastructure.Ifpossible,thisanalysiswillalsoincludecoreservicesfundedinwholeorinpartbythehostinstitution.

Consolidation of Core Services

Iftheredundancyanalysisidentifiesinstitutionswherethereistrueduplicationofoneormoresignificantcoreserviceinfrastructures,aplanforconsolidationwillbedeveloped,includingananalysisofanyfinancialimpactfromtheproposedconsolidation.Forinstitutionswithcancercenters,consolidationwillbeachievedbystrengtheningtheroleofcancercentersastheprimaryprovidersofcoreservices.Forinstitutionswithoutcancercenters,individualawardeeswillbeexpectedprimarilytouseexistinginstitutionalservicesorthoseofneighboringinstitutions.Consolidationwillbepromotedbyadjustingreviewcriteriatorewardcollaborationandresourcesharingincoreservices.Asgrantscomeupforrenewal,consolidationwillbeimplementedaccordingtotheplandevelopedforthatinstitution.

GuidelinesforCancerCenterandP50,U-series,andRFA-directedP01awardswillberevisedasnecessarytoincorporatethefollowingprinciplesforcoreservicesresourcesharing.

1. Cancercenterswillprovidethecoreservicesinfrastructureforkeytranslationalresearchresourcesatinstitutionswithcancercenters.

2. IndividualP50,U-series,P01,andotherrelevantawardswillrequestfundseithertoaccesscancercenterorotherinstitutionalcoreservicesorformaterials/salarysupportforprojectstafftousethoseservices.

3. NewtranslationalresearchRequestsforApplicationsandProgramAnnouncementswillspecifyuseofcancercenterorotherinstitutionalcoreservices.

4. Ifapplicantsconsiderrequiredcoreservicesnonexistentorunavailableattheircancercenterorinstitution,theymustpresentalistoftherelevantcoreservicesthatdoexistandaspecificrationaleforcreationoftheproposednewcores.

5. Ifaserviceisnotavailableataninvestigator’shomeinstitution,apreferredoptionwillbetoprovidefundstousetheservicesofaneighboringinstitution.

6. Noawardwillmandatethecreationofaseparatecoreserviceifanappropriatecoreserviceislocallyavailableatcancercenters,thehomeinstitution,ortheNCIintramuralprogram.

Guidelineswillbechangedtoformallyrewardsharingofcoreservicesandfacilities.WhilecancercenterandSPOREguidelinesalreadyspecifythatcoreresourcesandfacilitiesshouldbeshared,additionalincentivesinthereviewprocessareneededtoencourageefficiency.Cancercenterguidelineswillbemodifiedtoprovideformalrecognitionduringthegrantrenewalprocessforcorefacilitiesthatprovideservicestoinvestigatorsorprojectsfundedbyotherprogramsorinstitutions.

Comprehensive, Publicly Accessible Core Services Database

AdatabasewillbecreatedcontainingregularlyupdatedinformationonallNCI-fundedcoreservices.ThedatabasewillinitiallyfocusonkeyNCI-fundedtranslationalresearchcoreservices,butcouldbeexpandedtoincludecoreservicesfundedbyCTSAs,otherNIHInstitutes,academicinstitutions,andindustry.Twocomponentsofthedatabasewillbenecessary:1)arestrictedportionthatwillbeusedbyNCIreviewersandprogramofficers,and2)apublicportionthat



willbeopentotheresearchcommunity.SuchadatabasewillserveasausefultoolforNCIprogramstaffwhentheyaredeterminingwhetherornottofundanewcoreserviceataninstitution.

DatabasedevelopmentwillbetheresponsibilityoftheNCICenterforBioinformatics,workingincoordinationwithTranslationalResearchSupportOfficestaff,NCIprogramstaff,andextramuralinvestigatorsandwillbeimplementedinaccordancewiththecaBIG™designprinciplesandstandards.Thisdatabasewillserveasafoundationfortheexpandedresourcedatabasedevelopedinsupportoftheprojectmanagementsystem(seeOperationalEffectivenessInitiativeC1).

Potential Data Fields. NCICBandTranslationalResearchSupportOfficestaffwillworkwithNCIprogramofficersandrepresentativesfromboththeintramuralandextramuralresearchcommunitiestodefinetheimportantdatafieldstocollect.Potentialfieldsinclude:

• Typeofservice

• Specificcapabilities

• Availableequipment

• Numberofusers

• Numberofprojectssupported

• Numberofstudies,analyses,etc.,performed

• Numberofsamplesprocessed

• Percentofcapacitycurrentlyinuse

• Coreservicecosts

• Averageturnaroundtime

• Otherfundingsourcesforthefacility.

Thedatabaseisultimatelyintendedtoraisestandardsandencouragebestpractices.Therefore,incorporationofauserratingfeature(e.g.,aratingscaleandcommentssection)willbeconsidered.

Reporting System and Data Submission. ReportingandupdatinginformationinthedatabasewillbecomearoutineobligationofallNCIawardsthatsupportanindependentcoreservicesfacility,regardlessoffundingprogram.Datawillbecollectedandmanagedonacore-by-corebasisandthedatabasewillretainacumulativerecordofactivity.Atinstitutionswherecancercentersexist,informationonallcoreserviceswillbeheldandmaintainedcentrallyandreportedbythecancercenter.

Design Principles. Coreserviceprincipalinvestigatorswillsubmitastandardizedelectronicfilecontainingspecificdataontheircoreservicesthatwillserveasthebuildingblocksforanonlinedatabase.ThisonlinedatabasewillthenbeavailabletoNCIstaffandinvestigatorsthroughaunified,Web-basedinterfaceorportalthatshieldstheuserfromthemechanicsoftheunderlyingsystem.Thesystemwillbedesignedsuchthatinvestigatorscanupdatetheircoreservicesdataonanas-neededbasis.Controlledaccesswillbegrantedthroughappropriatespecializedinterfacestoallotherusersforauthorizedpurposes.

Database Functionality. Thedatabasewillprovidethefollowingstandardfunctions.

1. Searches.Thedatabasewillbeequippedwithsoftwaretoolsthatallowsearchesonanyfieldorcombinationoffields,usingkeywordsorcombinationsofkeywords.Searchingwillbefacilitatedwithpredefinedmenusofkeywordoptions(e.g.,typeofservice,geographiclocationofparticipatingcenters).



2. Reporting.Bothinteractiveandbatch-modereportingwillbesupported,andpredefinedreporttemplateswillbeavailableforcommonsearchrequests.

3. AccessControls.Accessprivilegeswillbedefinedtoaddressthediverseneedsofdatabaseusers.Twousercategoriesareenvisioned:

• Extramuralinvestigatorsfrombothacademiaandindustrywillhaveaccesstofundamentalinformationsuchaslocationofcores,servicesoffered,capacity,costofservice,contactinformation,etc.

• NCIprogramstaffwillhaveaccesstoalldatainthesystem,includingrawdatathatmightbeusefulforreview(e.g.,numberofusersofthecore,otherfundingfortheservice),aswelldataaccessibletoextramuralinvestigators

Regional Centers of Excellence

Overall Approach. Ascoreservicesarestreamlinedandconsolidated,regionalcenterswillbeestablishedforhighlytechnical,service-based,equipment-orexpertise-intensivecoreservicesthatcannotbeasefficientlyoperatediflocatedateverycancercenterorotherresearchinstitution.Theresearchworldisalreadyevolvingtowardstheconceptofregionalornationalcentersofexcellence.TheHumanGenomeSequencingCentersareanexampleofnationalcores,whichareselectedbyanadvisorycommittee.

TheAdvisoryCommitteewillconveneaWorkingGroupofNCIprogramstaffandextramuralinvestigatorstoidentifyalistofcoreservicesthatarecandidatesforregionalization.Coreservicesthatwouldpotentiallybenefitfromcreationofregionalcentersornetworksinclude:

• GMP/GLPmanufacturing

• Massspectrometry

• State-of-the-artproteomics

• High-throughputgenomics/SNPanalysis

• Imagearchivingand/oranalysis.

Identifying and Selecting Regional Centers. Oncethecoreservicesappropriateforregionalizationhavebeenidentified,NCIwilldetermineifappropriateregionalcentersalreadyexistfortheidentifiedservicesorwhetherneworexpandedcentersarerequired.Ifneworexpandedcentersarerequired,NCIwillissueanRFAsolicitingproposalsforestablishmentofsuchcenters.TheRFAwillstipulatethescopeandqualityofservicetobeprovided,theprojectedusage,etc.Successfulapplicantswillreceivefundingforthecoreinfrastructureandabaselinelevelofserviceactivity.Thecoreswillbedesignedtoexpandinresponsetoincrementalfundingfromusers.Regionalcenterslikelywillbebasedatcancercenters,thoughthisshouldnotbealimitingrequirementintheRFA.

Thetransitiontoregionalcentersneednotbeadrasticchangefromthestatusquoandshouldnotrequirethecreationofnewfacilities.Rather,oncecentersareestablished,grantsrequiringtheservicewillbefundedforusingtheservice.Ingeneral,individualinstitutionswillnotbefundedforprovidingacoreserviceavailablefromaregionalcenter.

Oversight and Management. Regionalcoreservicecentersmusthaveamanagementplantoensureadequateaccessbyinvestigatorsfromotherinstitutionsandappropriatestandardizationandqualitycontrol.Inordertoensurequality,efficiency,andaccessibility,TranslationalResearchSupportOfficestaffwillbeinvolvedwithoversightoftheregionalcenters.

Standardization and Quality Assurance. Regionalcoreservicecenterswillestablishstandardizedprocesses,qualitycontrol,etc.,toensurecomparabilityofdataandhigh-qualityoutputs.TranslationalResearchSupportOfficestaffwillworkwithextramuralresearcherstodeterminewhichservicesneedtobestandardizedorcertifiedtoensurecomparability



betweeninstitutions.OversightandcertificationprocesseswillbeestablishedbytheSupportOfficeincoordinationwiththeregionalcenterprincipalinvestigatorstoensurethatcoreservicesandfacilitiesmaintainstate-of-the-artequipment,procedures,etc.



Initiative C3: Enhance quality and accessibility of annotated biospecimen repositories and associated analytic methods.

Rationale

Continuingadvancesingenomicandproteomictechnologiesaredrivinganincreaseddemandbythetranslationalresearchcommunityforstandardized,high-quality,clinicallyannotatedhumanbiospecimens.However,biospecimenresourcesofsufficientqualitytomeetthetechnicalrequirementsofthesenewanalytictoolsfallfarshortofthedemand.Thisshortageofannotatedbiospecimens—collected,processed,transported,stored,andanalyzedusingstandardoperatingprocedures—isakeybarriertotranslationalresearch.Threeothertranslationalresearchbarriersassociatedwithbiospecimenshavealsobeenidentified.Thefirstbarrieristheabsenceofstandardizedanalyticmethodsthatcanobtainconsistent,standardizeddatafrombiospecimensregardlessofthecollectiontechnique.Thesecondbarrieristhelow-levelrepresentationincurrentrepositoriesofspecimensfromminoritypopulations.Thethirdbarrieristhelow-levelrepresentationofprecancerousspecimenswhichareessentialforeffectivetranslationalresearchfocusedonprevention.Anenhancedsystemofbiospecimenrepositoriesandanalyticmethodswouldimprovestandardization,qualityassurance,andreliability,whileminimizingaccessbarriersandstrengtheningthecomprehensivenatureofthiskeytranslationalresearchresource.


Implementation Plan

Enhancingthequalityandaccessibilityofannotatedbiospecimensforuseintranslationalresearchwillrequireatwo-prongedapproach.Thefirstistoexpandthenumberoffullyannotatedbiospecimenscollected,processed,transported,andstoredusingstandardizedoperatingprocedures.However,sincesuchprocedureswillonlybeappropriateforuseinmajoracademicmedicalcenters,thiswilllimitthetotalnumberofspecimensavailableforresearch.Therefore,aparallelapproachwillbetoincreasetheoverallnumberofbiospecimens,especiallythosefromminoritypopulations,byencouragingsmallercentersandnonacademichospitals—especiallythosethatarepartoftheNewCommunityCancerCentersProgram(NCCCP)—tocollectandfullyannotatebiospecimensundercarefullycontrolled,butnotuniformlystandardized,procedures.Thesespecimenscanthenbeusedforstudiesexaminingresearchquestionsthatdonotnecessitateahighdegreeofstandardizationandwithstandardizedanalytictoolsthatgiveconsistentresultswithtissuesobtainedundervariableconditions.

Reinforce Ongoing Standardization Efforts

TheNCIOfficeofBiorepositoriesandBiospecimenResearch(OBBR)wasestablishedin2005toaddressthekeybarriersinbiospecimencollection,standardization,andstorage.OBBRiscurrentlyworkingtodevelopandimplementstandardsthatwillenableanationalcancerbiospecimenresourceinfrastructureandpromotespecimenanddatasharingtofacilitatemulti-institutional,high-throughputgenomicandproteomicstudies.Tothisend,OBBRhasproposedFirstGenerationBiorepositoryGuidelines(FGGs)toharmonizepoliciesandproceduresforNCI-supportedbiospecimenresources,includingclinicalandepidemiologicalannotationandpatientprivacyaspects.23TheTRWGstronglyendorsestheseOBBRactivitiesandproposesthefollowingadditionalapproachestofurtherenhancetheirmission.

Modification of Guidelines

Guidelinesforcancercenters,SPOREs,cooperativegroups,andotherlargeNCI-specificprogramsthatinvolvebiospecimencollectionwillberevisedasnecessarytoincorporateuseoftheFGGsastheyarefinalized.Prospectively,recipientsoftheseawardswillberequiredtoadheretostandardizedcollection,storage,retrieval,anddisseminationprocedurestopromoteconsistencyandcomparabilityofderiveddatabetweeninstitutions.Standardizationwillnotpertainsolelytotumortissue,butalsotonormalandpremalignanttissues,aswellasancillaryspecimens.Reviewcriteriafor

23 FirstGenerationGuidelinesforNCI-SupportedBiorepositories,April2006.Availableat:http://biospecimens.cancer.gov/biorepositories/guide-lines_full_formatted.asp.



cancercenters,SPOREs,andotherNCI-specificprogramswillbemodifiedtoformallyrewardstandardizedcollectionofbiospecimens.

Suchmodificationswilldictateaculturalshiftfromaninvestigator-centrictoacollaborativeapproachtobiospecimens.Cooperationandbuy-inwillberequiredfromInstitutionalReviewBoards(IRBs)andinformaticsgroups.SelectedNCIprograms(e.g.,theCancerGenomeAtlasBiospecimenCoreResource,theClinicalProteomicTechnologyAssessmentforCancerInitiative,theNCCCP)havealreadyincorporatedtheFGGsintorecentRFAsandRFPsandcanbeusedasmodelsforguidelinerevision.

Funding for Biospecimen Collection

Untiltherealexpenseofstandardizedbiospecimencollectionandstorageisfundedasaseparatecost,suchstandardizedcollectionwillneverbecomewidespread.Inthepast,pathologydepartmentscollectedtissueswithoutbeingpaidtodoso,butmanyinstitutionswillnolongerallowthispractice.Furthermore,evenwhenaninstitutionisreimbursedforspecimencollection,thefundsarenotalwaysallocatedtothepathologistsresponsibleforthetissues,resultinginanunwillingnesstocooperate.

Fundingforbiospecimencollectionrelatedtoclinicaltrialsshouldbeprovidedupfrontasaportionofthetrialcostwhentissueprocurementisaspecificcomponentoftheprotocol.Guidelineswillbemodifiedtoformallyrecognizetheimportanceoffundingstandardizedspecimencollectionandstorage.Thisfundingwillbeseparablefromthelumpsumofthegrantsothatthepathologygroupreceivesthesupportdirectly.Onepossibilityistoconsidera“tethered”fundingmodelthatgivescredittomultipleprincipalinvestigatorsandallowsfundstobedividedasneeded.FundingwillbecontingentonbiospecimencollectionandstoragebeingconductedinaccordancewiththeFGGs.

Informed Consent

Inordertofacilitatecollectionofawidevarietyofsamples,enablecontinuedcollectionofdataforsampleannotation(e.g.,epidemiologicandoutcomesdata)beyondthedateofthesamplecollection,andauthorizebiospecimentestingnotanticipatedattimeofcollection,astandard,nationalinformedconsenttemplateisneeded.ThetemplatemustbecompliantwiththeHealthInformationPortabilityandAccountabilityActandtheOfficeofHumanResearchProtectionsregulations.Additionally,becauseIRBstendtomodifymostconsentformstoaccommodatelocalissues,itwillbeadvantageoustodevelopacommontemplatethatcanbepluggedintotheconsentformsusedbyanyinstitution.

Severalinformedconsenttemplatesforthefutureuseoftissueshavebeendevelopedandarecurrentlyusedincooperativegroupsandcancercenters.AnewinformedconsenttemplatehasalsobeenproposedundertheFGGs.TheBiorepositoryCoordinatingCommittee(BCC)iscurrentlyworkingtoharmonizetheseformstoestablishastandardizedtemplate.Guidelinesforcancercenters,SPOREs,cooperativegroups,etc.,willberevisedtorequireuseofthestandardizedtemplate,oncedeveloped.TheTranslationalResearchSupportOfficestaffwillassistOBBRandtheBCCwiththeseefforts.Obtainingwidespreadacceptancemayrequireorganizingexpertworkshopsincludingbioethicists,patientadvocates,patients,governmentrepresentatives,academicandnonacademichealthprofessionals,industryrepresentatives,andotherleadersinthecancerresearchcommunity.

National Biospecimen Repository Network

Therehavebeeneffortsinthepasttodevelopanintegratednetworkofbiospecimenrepositoriesservedbyacommoninformaticsinfrastructureandacommonaccessportal.Forexample,OBBRdevelopedandpilotedaNationalBiospecimenNetworkBlueprint(NBN)concept24whichoutlinesanapproachforcreatingapublic-privatepartnershiptoestablishanationalresourceofstandardized,privacy-protected,high-qualitybiospecimensforgenomic-andproteomic-basedresearch.UseofthestandardizedproceduresrequiredfortheNBNconceptwaspilotedinaseriesofProstateCancerSPOREs.However,thepilotproveddifficulttoimplementduetothechallengesofmulti-institutionalstandardizationandbiospecimensharing.TheNBNconceptmaynowbepursuedinthecontextoftheNCCCP.

24 http://biospecimens.cancer.gov/nbn/blueprint.asp.



AdditionaleffortstoimplementtheNBNconceptarewarranted.TheTranslationalResearchSupportOfficewillworkwithOBBRtodevelopnewapproachesforimplementingsuchanationalvirtualnetworkpotentiallyincludingspecimenscollectedunderbothstandardizedandinstitution-specificproceduresandwithanincreasedfocusontheinclusionofspecimensfromminoritypopulationsandspecimensfromprecanceroustissues.Thegoalisforthenetworktolinknumerousrepositoriescontainingproperlyannotatedbiospecimens,includinglifestyleandepidemiologicinformationwherepossible.Ifsuchanetworkisrealized,programguidelineswillbemodifiedtorequirethatbiospecimenscollectedinconjunctionwithNCI-fundedclinicaltrialsbeproperlyannotatedandmadeavailableaspartofthenetwork.

Comprehensive Database. Adatabaseofallrelevantrepositorieswillbecriticaltothesuccessofabiospecimennetwork.PreviousanalysesoftheNCIbiospecimenresourceportfolioindicatedthatNCIsupportshundredsofbiospecimen-relatedactivities.BuildingontheexistingSpecimenResourceLocator,25OBBRisalreadyexploringthepossibilityofcreatingaWeb-basedcataloguetoprovidetheextramuralcommunitywithinformationonexistingbiospecimencollections.Thiscataloguecouldbeastartingpointforthedatabase.

Specimen Access. Oncethedatabaseiscreated,individualsseekingaccesstothespecimenswillsubmitanapplicationthatclearlyexplainsthenumberofspecimensneeded,theamountrequired,andthepurposeofthestudy.Applicationswillbereviewedandaccessgrantedbasedonmerit.OBBRwillberesponsiblefordevelopingandmanagingatransparent,fair,andscientificallybasedprocessforprioritizingaccesstothebiospecimens.

Industry Collaboration. Becauseanationalbiospecimenrepositorynetworkwillbeexpensivetobuildandmaintain,agovernment-industryconsortiummodelwillbeexplored.TheTranslationalResearchSupportOfficeandOBBRwillexplorewiththeFoundationforNIHthepotentialofestablishingaconsortiumofindustrypartnerswhowouldsupportthenetworkthroughcharitabledonations.TheSupportOfficewilldrawontheresourcesofNIH’sProgramonPublic-PrivatePartnershipswithintheOfficeoftheDirectorinsupportofestablishingsuchaconsortium.

Theindustrypartnersintheconsortiumwouldhavetheabilitytoapplyforaccesstothespecimens.Theywouldnotreceiveprioritizedaccess,butwouldhavethesameabilityasanyacademicresearchertoapplyandcompetebasedonimportanceoftheresearchprojectproposed.Companiesthatarenotmembersoftheconsortiumcouldalsoapplyforaccesstothespecimens,butwouldbechargedmoreforthosespecimensthanwouldconsortiummembers.

Inordertosuccessfullydevelopsuchaconsortium,aconvincingcasemustbepresentedtopotentialpartnersestablishingtheadvantagestheywouldreceivefromparticipation.Tosupportsuchacase,allspecimenswillneedtohaveaminimumannotationdatasetthatisattractivetoindustryandafairprioritizationprocessmustbedevelopedtoregulateaccesstothelimitedtissueresources.

Therearesomepublic/privatepartnershipsalreadyinexistencethatmightserveasmodelsforsuchaconsortium.Forexample,theInternationalGenomicsConsortium(IGC)hasaprojectcalledtheExpressionProjectforOncology(expO)thataimstobuildonthetechnologiesandoutcomesoftheHumanGenomeProjecttoaccelerateimprovedclinicalmanagementofcancerpatients.Thisconsortiumfacilitatespartnershipsbetweenacademicinstitutionsandpharmaceuticalcompaniesandhasledtothedevelopmentofastandardizedmethodoftumortissuecollectionthatisbeingusedforexpressionprofiling.26

Standardized Analytic Methods

Whilethestandardizationofbiospecimencollectionandprocessingisoneapproachtoobtaininghigh-qualitygenomicandproteomicdatafromhumanbiospecimens,itdoesnotaddressallfacetsoftheproblem.Forexample,newstandardprocedureswillnotaffecttissuesthatwerecollectedinthepastandsomeaspectsoftissuecollectionarelikelytoremainbeyondthereachofstandardization(e.g.,temperatureattimeofcollection,timeperiodoftissuedevascularization).Furthermore,improvedcollectionandprocessingtechniqueswillcontinuetobedeveloped.Therefore,specimenscollectedovertimemaynotnecessarilybeuniform.

25 http://pluto3.nci.nih.gov/tissue/default.htm.26 InternationalGenomicsConsortium:http://www.intgen.org/expo.cfm.



Moreover,becauseuniformcollectionoftissuesunderstandardconditionsisextremelyexpensive,suchmethodswillprobablybeimplementedonlyforspecificstudiesortissues.Manyinstitutions,particularlynonacademichospitals—whichareanextremelyimportantpotentialsourceoftissue—areunlikelytoimplementthesemethodsasstandardoperatingprocedures.Therefore,inadditiontostandardcollectionandprocessingmethods,standardanalyticmethodsmustbedevelopedforusewithtissuesobtainedunderroutine,andthusvariable,conditions.

Developmentofstandardanalytictechniquesisanemergingareathatwarrantsadditionalattentionandfunding.Sucheffortsarefocusedonthedevelopmentofmethodologiesthatcanyieldconsistent,comparable,quantitative,andreproducibleanalyticresultsnomatterhoworwhenthetissuewascollected.TheNCIInnovativeMolecularAnalysisTechnologiesprogramintheOfficeofTechnologyandIndustrialRelations(OTIR),aswellasotherNCIprograms,isbeginningtosupporttheseefforts.TheTranslationalResearchSupportOfficewillworkwithOTIR,OBBR,theBCC,andrelevantprogramstafftodeterminehowthesecurrenteffortscanbeenhancedandincorporatedintofutureendeavors.



Initiative C4: Develop enhanced approaches for negotiation of intellectual property agreements and agent access.

Rationale

Translationalresearchrequireseffectivecollaborationamongindustry,academia,NCI,andfoundations.Developingapproaches,procedures,andtoolsthatpromoterapidnegotiationofintellectualpropertyagreementsandfacilitateresearchersgainingaccesstoimportantagentswillimprovethetranslationalresearchprocessbyminimizingbarriersthatoftendelayorpreventpotentiallyproductivecollaborations.

ThreegeneralsituationscanbeidentifiedwithinNCI-fundedtranslationalresearchwhereintellectualpropertyissuesarefrequentlyproblematic:

• Industryprovidingmaterialstoacademicinstitutionsforresearchpurposes

• Exchangeofmaterialsbetweenacademicinstitutions

• LicensingofNCI-fundedintellectualpropertybyacademicinstitutionstoindustry.

Theapproachesdescribedbelowaretargetedatpromotingrapidnegotiationofintellectualpropertyagreementsinthesesituations.

Inaddition,havingavailableNCI-supportedagentrepositorieswouldreducesearchandnegotiationcostsforresearchersneedingspecificagentsfortheirresearch.Throughtheserepositories,researcherswouldbeabletoreadilyaccessagentsusingaprenegotiatedmaterialstransferagreement.Ifresearchresultswerepromising,theinvestigatorcouldthennegotiatefurtherwiththepatentowneroftheagent.Suchrepositoriescouldalsoserveasacentralizedsourceforcompoundsthatdonothavepatentprotection.


Implementation Plan

Model Agreements and Best Practices

Someofthedifficultiesinresolvingintellectualpropertyissuesresultfrombeginningnegotiationswithoutanyclearguidelines.Theavailabilityofmodelagreementsandbestpracticesshouldfacilitatenegotiations,therebyspeedingtheprocessofsharingintellectualproperty.

TheTranslationalResearchSupportOfficewillworkwiththeNCITechnologyTransferBranch(TTB)tocoordinatedevelopmentofmodelagreementsandbestpractices.Thefirststepwillbetoconductananalysisofexistingagreementsandpractices.Theanalysiswillincludebutnotnecessarilybelimitedtothefollowing:

• StandardizedlanguageforclinicaltrialandmaterialtransferagreementsdevelopedbytheCancerTherapyEvaluationProgram

• ModelagreementsandlicensingbestpracticesdevelopedbytheNIHNationalHumanGenomeResearchInstitute

• Modelagreementsdevelopedbyfoundationsandadvocacygroups

• ModellicensinglanguagedevelopedbytheAssociationofUniversityTechnologyManagers

• IntellectualpropertyagreementsdevelopedbytheplanninggrantparticipantsoftheAcademicPublic-PrivatePartnershipProgram

• MasterMaterialTransferAgreementsdevelopedbyNCIanduniversities.



Basedontheanalysisofexistingmodels,theSupportOffice,inconsultationwithTTBandrelevantNCIprogramstaff,willdevelopmodelagreementsandbestpracticesforuseinthefollowingsituations:

• NCI-fundedacademicresearchersobtainingmaterialsfromindustry

• NCI-fundedacademicresearchersobtainingmaterialsand/orlicensingintellectualpropertyfromanotheracademicresearcher

• IndustrylicensingintellectualpropertyfromNCI-fundedacademicresearchers.

Dependingontheresultsoftheanalysis,onemodelandsetofbestpracticesapplicabletoeachsituationmaybedeveloped.Alternatively,severalmodelsandsetsofbestpracticesmaybedevelopedforeachsituation.Examplesofconditionsthatmayrequirespeciallytailoredagreementsandbestpracticesincludethefollowing:

• Early-stagedevelopmentversuslater-stagedevelopment

• Combinationstudiesversussingle-agentstudies

• Significantpotentialapplicationsversusunknownpotentialapplications

• Co-exclusivityversusasingle,exclusivelicense.

NCIwillconveneaseriesofmeetingswithkeystakeholders,includingindustrysponsors,foundationandadvocacygrouprepresentatives,andacademictechnologytransferrepresentatives,toreviewtheassembledsetofmodelagreementsandbestpractices.Thegoalofthisseriesofmeetingswillbetodevelop,withinputfromawideaudienceofstakeholders,asetofharmonizedagreementsandpractices.Activeparticipationbyindustry,academia,foundationsandadvocacygroups,andNCItoaddresstheirindividualneedswillenhancethelikelihoodthatthefinalsetofmodelagreementsandbestpracticeswillbewidelyadoptedbyboththeprivate-andpublic-sectorresearchcommunities.ThesemeetingswillbecoordinatedwithsimilarmeetingsconcerningclinicaltrialcontractsorganizedaspartoftheClinicalTrialsWorkingGroupReportimplementation.

ThemodelagreementsandbestpracticeswillbemadeavailableonapublicWebsitemaintainedbyTTBforanyresearchertoaccessanduse.UseoftheseagreementsandbestpracticesbytranslationalresearchersfundedbyNCIwillbepromotedbyarticlesincancercenterpublicationsandreferencetothepublicWebsiteinNCIgrantandprogramannouncements.Followingdevelopmentofthemodelagreementsandbestpractices,NCI,incollaborationwithindustryanduniversitytechnologytransferrepresentatives,willconductanannualreviewtodeterminewhetherchangesareneededandwhetheradditionalmodelagreementsandbestpracticesshouldbeestablished.

Alternative Approaches

Moreefficientnegotiationofindividualagreementsisnottheonlyapproachthathasbeendevelopedforaddressingintellectualpropertyissues.Otherapproachesthathavebeendevelopedandappliedinvariousfieldsincludepatentpoolsandindustry-governmentconsortia.

Patent Pools. PatentpoolshavebeenusedinseveralfieldswithintheUnitedStatesduringthelast150years,includingsewingmachinemanufacturing,aircraftmanufacturing,radioandtelevisiontransmissions,anddigitalaudiovisualtechnology.27Apatentpooliscomposedoftwoormorepatentownerswhoagreetolicensetheirpatentstoothermembersofthepatentpooloranoutsideparty.Thelicensingcanbeconductedbyeitherthemembersofthepatentpoolorbyaspecificmechanism,suchasajointventure,developedtooverseethepatentpool.Whenthepatentpoolisadministeredbyajointventure,potentiallicenseesonlyhavetonegotiatewithoneentityforpatentswithinthepoolratherthanwithseveraldifferentpatentowners,therebyreducingnegotiationcostsandtime.

27 ThishistoryanddescriptionofpatentpoolsistakenfromClarkJ,PiccoloJ,StantonB,TysonK.Patentpools:asolutiontotheproblemofaccessinbiotechnologypatents?UnitedStatesPatentandTrademarkOffice,2000.Availableat:http://www.uspto.gov/web/offices/pac/dapp/opla/pat-entpool.pdf.



Althoughusedinseveralfields,patentpoolshavenotbeendevelopedforthebiotechnologyorpharmaceuticalindustries.AwhitepaperproducedbytheU.S.PatentandTrademarkOfficearguedforthefollowingbenefitsforbiotechnologypatentpools:28

• Eliminationofdifficultiesduetoblockingpatentsorstackinglicensesaslicenseeswillobtainaccesstoallpatentswithinthepatentpool

• Reductionoflegalcostsasdisputescanbesettledthroughthepatentpool

• Poolingoftherisksofresearchanddevelopment

• Facilitationofexchangeofinformationthatisnotprotectedbypatents.

Suchapatentpoolcouldpotentiallybepursuedforagentsdevelopedbyindustrythattheindustryhasnoplanstoexploit.Accesstotheseagentsbyacademicresearcherscouldbegovernedbyacommonsetofintellectualpropertytermsnegotiatedthroughthepool.

Government-Industry Consortia. Themostfamousexampleofagovernment-industryconsortiumisSEMATECH(SEmiconductorMAnufacturingTECHnology).SEMATECHwasformedin1987by14U.S.-basedsemiconductormanufacturersandtheU.S.Governmentwiththegoalofsolvingwidespreadmanufacturingproblemsthroughcommonlysupportedresearchanddevelopment.29Federalfundingforthisconsortiumendedin1996,buttheindustrialpartnershavemaintainedtheconsortium.Subsequently,internationalmembersandanacademicpartnerhavebeenincluded.SEMATECHholdsintellectualpropertyrightstotechnologydevelopedundertheconsortium.MembercompaniesareallowedtousetechnologiesdevelopedwithinSEMATECHwithoutanyadditionallicensing,and,afteraspecifiedtimeperiod,thetechnologiesaremadeavailabletononmembersthroughlicensingagreements.30Suchaconsortiummightbeappropriatefordevelopingalarge,comprehensive,annotatedcancerbiospecimenrepository(seeOperationalEffectivenessInitiativeC3),acomprehensiveagentrepository(seebelow),and/orcomprehensivemolecularanalysistechnologiesforcancerbiospecimens.

InconjunctionwithTTB,theTranslationalResearchSupportOfficewillevaluatethesealternativemodelstodeterminewhethertheycanbeadaptedtoNCI-fundedtranslationalresearchprojects.Ifeitheroftheseapproachesseemsfeasible,SupportOfficestaffwillbegindiscussionswithpotentialindustrypartners,inconjunctionwithTTB,todetermineinterestinformingsuchrelationships.

NCI Agent Repositories

Becauseofthepotentialbenefitsassociatedwithdecreasedsearchandnegotiationcosts,theTranslationalResearchSupportOfficewillevaluatethefeasibilityofdevelopingorenhancingthesize,quality,andaccessibilityofthefollowingtypesofagentrepositories.

Compounds without Patent Protection. Thisrepositorywouldincludecompoundsthathavelostorcannotreceivepatentprotection.Asurveyofcompoundsthathavelostpatentprotectionaswellasasurveyofnaturalproductsorotheragentsthatcannotbepatentedwillbeconductedandtheiravailabilityforinclusionintherepositoryassessed.

NCI-Developed Compounds. Thisrepositorywouldincludecompoundsdevelopedand/orcharacterizedbyNCIresearchers.AsurveyofNCIintramuralresearcherswillbeconductedtodevelopalistofcompoundsappropriateforsuchaninventory.Therequirementsnecessarytoprotecttheresearchinterestsoftheintramuralresearcherswillalsobeevaluated.

28 ClarkJ,PiccoloJ,StantonB,TysonK.Patentpools:asolutiontotheproblemofaccessinbiotechnologypatents?UnitedStatesPatentandTrademarkOffice,2000.Availableat:http://www.uspto.gov/web/offices/pac/dapp/opla/patentpool.pdf.

29 See“SEMATECHHistory”athttp://www.sematech.org/corporate/history.htm.30 U.S.CongressionalBudgetOffice,198�.TheBenefitsandRisksofFederalFundingforSematech.Availableat:http://www.cbo.gov/showdoc.

cfm?index=6205&sequence=0.



Compounds from NCI-Funded Extramural Researchers. ThisrepositorywouldincludecompoundsresultingfromresearchconductedunderNCIawards.AsurveyofNCItranslationalresearchgranteeswillbeconductedtoidentifycompoundsappropriateforthisrepositoryanddetermineunderwhattermssuchcompoundsmightbemadeavailabletootherresearchers.

Industrial Compounds. Thisrepositorywouldincludecompoundsprovidedbypharmaceuticalandbiotechnologycompanies.Asurveyofpharmaceuticalandbiotechnologycompanieswillbeconductedtodeterminetheirinterestinparticipatinginthisrepository.Ifinterestissufficient,aninventoryofcompoundsthatindustryiswillingtocontributewillbeassembled.

Ifdevelopingorimprovingsuchrepositoriesisfeasible,theSupportOfficewilldeveloppoliciesandprocedurestoensurethatappropriateannotatedinformationisavailableoneachsampleinanelectronic,searchableformatandthattherepositoriesaremaintainedandupdatedonaregularperiodicbasis.TheSupportOfficewillalsoworkwithNCIstaffandmanagementtoidentifyfacilitiesandfundingfortherepositoriesandworkwiththeTTBtodevelopstandardlanguagecoveringintellectualpropertyissues.



Initiative C5: Enhance interactions and collaborations with foundations and advocacy groups to advance early translational research.

Rationale

PartnershipsthatbringtogetherfoundationsandadvocacygroupswithNCIandacademicmedicalcentersarebecomingincreasinglyimportantinbiomedicalresearch.Suchpartnershipshaveallowedfoundationsandadvocacygroupstocontributevaluableenthusiasm,patient-centeredexpertise,and,attimes,fundingformanytranslationalresearchinitiativesandtrainingprograms.Forexample,withencouragementfromtheNIHDirector’sPanelReportin1997,severalfoundations,suchastheDorisDukeCharitableTrust,theBurroughsWellcomeFoundation,andtheHowardHughesMedicalInstitute,providedprojectfundingforclinicalresearchersanddevelopedtranslationalresearchtrainingprogramsatacademicmedicalcenters.31ItisvitaltothetranslationalresearchenterprisethatNCIfosterandstrengthentheserelationships.

Theenhancedinteractionsandcollaborationsproposedbelowaredesignedtocapitalizeonthecomplementaryskillsandresourcesoffoundationsandadvocacygroupstoadvanceearlytranslationalresearch.Theyalsoprovideanopportunitytobenefitfromthestrengthsoffoundationsandadvocacygroupsinfacilitatingintegrationofacademia,industry,NCI,andphilanthropicorganizations.


Implementation Plan

Overall Approach

TostrengthentherelationshipofNCIwithfoundationsandadvocacygroupsintheareaoftranslationalresearch,NCIshouldestablishaleadershippositionresponsiblefordevelopingandsustainingsuchrelationshipsandaddressingpotentialcollaborativeeffortsintranslationalresearchamongfoundations,includingtheFoundationforNIH,advocacygroups,andallNCIDivisions,Centers,andOffices.Thispositionwillberesponsibleforleading,developing,andmaintainingtheeffortsdescribedbelowandcoordinatingactivitieswiththeOfficeofLiaisonActivities(OLA)andtheDirector’sConsumerLiaisonGroup(DCLG)toensuremaximalimpactandauthoritiesfortheseendeavors.Thispositionwillalsointerface,asappropriate,withNIH’sProgramonPublic-PrivatePartnershipswithintheOfficeoftheDirectorforassistanceindevelopingtheseefforts.

Inaddition,theDCLGwilltakealeadershiproleincoordinatingtheparticipationofadvocacygroupsandindividualadvocatesinimplementationnotonlyofthisinitiativebutalloftheTRWGinitiatives.Thiswillincludegatheringinputonfundingprioritiesandprogramoperations,recommendingrepresentativesforthevariouscommitteesandworkinggroups,disseminatinginformationonimplementationtothelargerpatientcommunity,andpromotingabetterunderstandingoftheproductiverolesadvocatescanplayintheresearchprocess.

Structured Interactions

OLAwillorganizeregularperiodicmeetingsinvolvingprogramstaffresponsiblefortranslationalresearchfromallNCIDivisions,Centers,andOfficesandrepresentativesfromappropriatefoundationsandadvocacygroupsforthepurposeofaddressingthefullspectrumoftranslationalresearchactivities.Thegoalistoincreaseoverallawarenessandunderstandingofthefullbreadthanddepthoftranslationalresearchinfrastructuresandactivitiesbeingplanned,prioritized,andconductedbybothNCIandfoundationsandadvocacygroups.Thisincludesoutreachandcommunicationprogramsaswellasscientificinfrastructureandresearchprograms,includingSPOREs,theEarlyDetectionResearchNetwork,PhaseI/IIclinicaltrialcontracts,DevelopmentofClinicalImagingDrugEnhancers,RAID,RAPID,cancercenters,etc.Oneadditionalmechanismforenhancinginteractionswillbetoconduct“TranslationalNeedsand

31 NathanDG.Careersintranslationalclinicalresearch—historicalperspectives,futurechallenges.JAMA,2002;287:2424-87.Availableat:http://jama.ama-assn.org/cgi/content/full/287/18/2424#REF-JCO20035-18.



Opportunities”meetingsconvenedaspartofthenewtranslationalresearchprioritizationprocess(seeCoordinatedManagementInitiativeA4)inassociationwithfoundationoradvocacygroupmeetings.

Participation in NCI Prioritization Process

Advocacygroupsandfoundationshavebuiltstrengthsinscientificreviewandplanning,includingconductingscientificreviewstoinformtheirfundingdecisions.Moreover,aboutone-thirdoftheproposalssubmittedtofoundationsandadvocacygroupsaretranslational.Consequently,representativesfromthesecommunitiescanprovidevaluableinputasNCIprioritizestranslationalresearchprogramsandprojectsacrossthetranslationalresearchenterprise.

Atleastonerepresentativefromafoundationoradvocacygroupactiveintranslationalresearchfundingwillbenamedtoeachyear’sPrioritizationWorkingGroup(seeCoordinatedManagementInitiativeA4).TheadvocacyrepresentativewillbenamedincoordinationwithOLAstaffanddrawnfromthebroadcanceradvocacyandfoundationcommunity.TheselectionprocesswillensurethattheparticipanthasappropriateexpertiseandthattheadvocacycommunityiswellrepresentedinNCI’sprocessesforprioritizingtranslationalresearchopportunities.

Avoidance of Duplicative Review

RepresentativesfromfoundationsandadvocacygroupsindicatethatmanyofthetranslationalresearchproposalssubmittedtotheseorganizationsareeithersimultaneouslysubmittedtoNCIorhavebeenpreviouslyrejectedbyNCI.Consequently,foundations,advocacygroups,andNCIperformduplicativereviewsinmanyinstances.

NCIcannotcoordinatereviewwithanyoutsideagencyorfoundation.However,thereisoneadvocacygroupthatsolicitssummarystatementsfromapplicantswhoarejustoutsidetheNCIpaylineandthenmakesitsfundingdecisionsbasedonthosesummarystatementswithoutconductingaseparatescientificreview.NCIstaffassistinthisprocessbymakingapplicantsawareofthisadditionalfundingopportunity,buttheapplicantmustindependentlypursuethefoundationoradvocacygroupapplicationprocess.ThefeasibilityofextendingthisprocesstoadditionalfoundationsoradvocacygroupswillbeexploredduringtheregularmeetingsbetweenNCIprogramstaffandtheadvocacyorganizations.Ifinterestinthisprocessishigh,OLAwillworkwiththeTranslationalResearchSupportOfficetodevelopanapproachforcommunicatingwithNCIgrantapplicants,foundations,andadvocacygroupsaboutthisoption.

Funding Partnership Development

IncollaborationwiththeTranslationalResearchSupportOfficeanddrawingontheresourcesofNIH’sProgramonPublic-PrivatePartnershipswithintheOfficeoftheDirector,OLAwillinvestigatethefeasibilityofcreating,throughtheFoundationforNIH,jointfundingopportunities.Thesecouldincludethefollowing:

• Foundation/advocacygroupfundingofacomponentofaSTRAPaward(seeTailoredFundingProgramsInitiativeB3)

• Foundation/advocacygroupfundingofafellowshipforworkinassociationwithaspecifictranslationalresearchprojectembeddedwithinaSTRAP,P01,SPORE,orotheraward

• JointNCIandfoundation/advocacygroupfundingoffellowshipsandothertrainingawards

• Foundation/advocacygroupfundingofaresearchprojectorprogramviatheFoundationforNIH,modeledonprevioussuccessfulexamplessuchastheAVONPartnersforProgressprogram.

Enhanced Outreach Concerning Tissue Donation and Image Collection

Enhancedpublic,patient,andphysicianoutreachemphasizingthecriticalroleoftissuedonationandimagecollectiontocancerresearchprogressisparticularlyimportantastherearegenerallynodirectbenefitstopatientsandnoincentivesforcommunityoncologistswhoreferpatients.Thisisavastlyunderappreciatedaspectofcancerresearch.

StafffromtheTranslationalResearchSupportOfficewillworkwiththeOfficeofEducationandSpecialInitiatives(OESI),theOfficeofCommunications(OC),theOfficeofBiorepositoriesandBiospecimenResearch,andOLAto



developaproactiveprogramthatinvolvesfoundationsandadvocacygroupsinincreasingoverallpublic,patient,andcommunityoncologistawarenessandunderstandingofthevalueoftissuesampledonationandimagecollectionduringparticipationinclinicaltrialsaswellasduringclinicalfollow-up.OESI,OC,andOLAstaffwilltaketheleadindevelopingthisprogram.AsasimilarinitiativeisbeingpursuedaspartoftheClinicalTrialsWorkingGroupReportimplementation,thisprogramwouldbeoptimallyexecutedintandemwithpublicandpatientoutreachforclinicaltrialparticipation.Asincreasedpublicoutreacheffortsshouldresultinbothincreasedcollectionoftissuesamplesandimagesaswellasincreasedawarenessamongresearchersoftheavailabilityoftheseresources,issuesrelatedtotheownershipandsharingoftheseresourcesmaybecomeincreasinglyprominentandwillneedtobeaddressed.

Thefeasibilityandpotentialeffectivenessofseveralapproachesforoutreachwillbeexplored,includingthefollowing.

1. Assemblecasestudiesthatdemonstratetheimportanceoftissuedonationinadvancingcancerresearchandtreatmentanddistributethroughcancercenters,cooperativegroups,communitycancercenters,andadvocacygroups.

2. DevelopcooperativecommunicationprogramswithsisterFederalagencies,suchastheCentersforDiseaseControlandPreventionandtheOfficeoftheSurgeonGeneral.

3. DevelopinformationalmaterialwithNCI’sCancerInformationServicethatcanbedistributedtopatients,cancercenters,cooperativegroups,communitycancercenters,andadvocacygroups.

4. Compilebestcommunicationpracticesfromcancercentersregardingtissuedonationandimagecollectionanddistributetocancercenters,cooperativegroups,communitycancercenters,andadvocacygroups.

5. FundcommunityresearchprojectsthroughtheClinicalandTranslationalScienceAwardsprogramtodeterminewhyindividualsdoordonotdonatetissuesorimagesforresearchpurposes.

Initialmeetingswillbeconductedwithindividualfoundationandadvocacygroupstoidentifyopportunitiesforeffectivepublicandpatientoutreach.Iftheexploratorymeetingwithanindividualorganizationindicatesthereispotentialforcollaboration,specificactionplanswillbedevelopedforimplementingtheactivitiesandprogramsidentified.NCIwillalsocontactbroad-basedadvocacygroups,suchastheAmericanCancerSociety,theNationalCoalitionforCancerSurvivorship,andtheLanceArmstrongFoundationtoconsiderdevelopingageneralpublicawarenesscampaignonthevalueoftissuesampledonationandimagecollection.Thiscampaignwillutilizemanyofthesamecommunicationtactics,butbeaimedatalargerandmorediverseaudience.



Initiative C6: Enhance training and career incentives for early translational research.

Rationale

Integrationofawiderangeofdisciplinesfrombothlaboratoryandclinicalresearchinawell-coordinatedteameffortisessentialtoearlytranslation.Thefuturevitalityofthetranslationalresearchenterprisewillthereforedependonanewgenerationofresearcherswhohavemasteredrelevantscientificandclinicaldisciplines,understandboththelaboratoryandclinicalperspective,andareskilledingoal-orientedmanagementofcross-disciplinaryteams.

Initsrecentreportonobstaclestothedevelopmentofnewdrugs,theGovernmentAccountabilityOfficenotedseveralconceptsforimprovingtheproductivityofdrugdevelopmentthatwerehighlightedbyexpertsconsultedforthereport.Amongthesesuggestionswerethefollowingpointsrelevanttoworkforcedevelopment:

Academia could place a greater emphasis on developing research scientists with knowledge of translational medicine by providing financial incentives such as scholarships for students to pursue this discipline. Private and public partnerships could also create these incentives to develop such scientists. One of the panelists suggested that academia, industry, and the FDA (Food and Drug Administration) formally develop a paper that describes the skills most needed by this new type of translational scientist and develop funding and training mechanisms that would specifically support these individuals.32

Currentapproachestofundingandadministrationofbiomedicalresearchandtraininginacademiaoftenpromotethemaintenanceofindependentsilos.Theserelativelyrigidorganizationalelementsnotonlystandinthewayofteamscienceandcross-disciplinaryresearchandtrainingtodaybuttheyalsoretardadaptationtochangesintranslationalscienceforthefuture.ChangesinacademicorganizationalstrategiesandstructurescomplementedwithmoreeffectiveuseofNCIfundingmechanismsfortrainingandincreasedavailabilityofNCIawardprogramsfocusedontranslationalresearchwillbeessentialtodevelopacommittedtranslationalresearchworkforcetomeettherecognizedneedsoftodayandtheemergingneedsoftomorrow.


Implementation Plan

Translational Research Training Program Announcement

TheCancerTrainingBranchoftheOfficeofCenters,TrainingandResources(OCTR)willdevelopaProgramAnnouncementaddressingtrainingforearlytranslationalresearch.ThePAwilldrawattentiontoopportunitiesfortheuseofexistinginstitutionalfundingmechanisms,suchastheK12,R25T,andT32awards,ascomplementaryelementsinthedevelopmentofintegratedtrainingprogramsfortranslationalresearchersandteams.

Early Translational Research Training Working Group

NCIwillestablishaTranslationalResearchTrainingWorkingGroupundertheauspicesoftheAdvisoryCommitteeandwiththelogisticalsupportoftheTranslationalResearchSupportOffice.TheWorkingGroupwillinclude8-10membersencompassingarangeofkeystakeholders,including:

• TwomembersoftheAdvisoryCommittee

• TheAssociateDirectorforTraining,OCTR

32 NEWDRUGDEVELOPMENT:Science,Business,Regulatory,andIntellectualPropertyIssuesCitedasHamperingDrugDevelopmentEfforts,GAO-0�-49.Washington,DC:GovernmentAccountabilityOffice,November2006,p.36



• Extramuraltranslationalresearcherswithexperiencerunningformaltranslationalandclinicalresearchtrainingprograms

• Industryrepresentative(s).

TheWorkingGroupwillbeaskedtoreportwithin1yearonthefindingsandrecommendationsderivedfromitsinvestigation,consultation,andconsensus-buildingintheareasdescribedbelow.

Training of Clinician-Scientists for Translational Research. Tomeetthechallengeofensuringacontinualflowofwell-qualifiedresearcherswhocanleadandparticipateinthecomplex,multidisciplinaryresearchactivitiesthatarethefoundationoftranslationalresearch,itisnecessarytodefinetherequiredmixofskillsmoreclearlyandensurethatclinician-scientisttrainingprogramsprovidethoseskillsinamannerthatfacilitatescareerdevelopment.

Toaddressthisissue,theWorkingGroupwillundertakethefollowingtasks:

1. Defineacommonsetofskillsthatqualifyclinician-scientistsforleadershipofandparticipationintranslationalresearchteams;thesearelikelytoincludefoundationalskillsinbasicscience,statisticsandstudydesign,regulatoryaffairs,andmanagementoflarge,complex,multidisciplinaryprojectteams.

2. Reviewexistingclinician-scientisttrainingprogramsandawardstoassesstheextenttowhichtheyprovidetheseskillsandtoidentifygapsandbestpractices.

3. Designamodelcurriculumwithassociatedtrainingstandards,incentives,andbestpracticesthatcanbeusedforcreationofnewtrainingprogramsand/oradaptationofexistingones.

4. Identifyspecificclinicalspecialtiesthatareinadequatelyrepresentedintranslationalresearch.

5. Reviewexistingindustryfellowshipprogramstoassessthescopeofcurrentactivityandidentifybestpractices.

6. Disseminatetheinformationgatheredtothescientificcommunitythroughappropriatepresentationsorpublications.

TheWorkingGroupwillconsultwidelywiththeleadersofexistingclinician-scientisttrainingprograms,NCIstaff,leadersofprofessionalorganizationssuchastheAssociationofAmericanMedicalColleges(AAMC),FDAstaff,andtranslationalresearchleadersfromindustry.

Training of Ph.D. Scientists for Translational Research. ToprovidePh.D.scientistswiththerequisitetrainingtoleadandparticipatemosteffectivelyintranslationalresearch,Ph.D.programsinlaboratorybioscience,publichealth,andbehavioralscienceshouldbeenhancedwithopportunitiestogainafoundationofclinicalknowledge,includingclinicaltrials.

Toaddressthisissue,theWorkingGroupwillundertakethefollowingtasks.

1. DefineacommonsetofskillsthatqualifyPh.D.scientistsforleadershipofandparticipationintranslationalresearchteams;thesearelikelytoincludefoundationalskillsinclinicalmedicineandclinicaltrials,statisticsandstudydesign,regulatoryaffairs,andmanagementoflarge,complex,multidisciplinaryprojectteams.

2. ReviewexistingPh.D.trainingprogramsinlaboratorybioscience,publichealth,andbehavioralsciencetoassessthedegreetowhichtheyprovidetheopportunityforlearningaboutclinicaltopics,regulatoryaffairs,andteammanagement.

3. Identifyapproachesforincorporatingclinicaltopicsintolaboratorybioscience,publichealth,andbehavioralsciencePh.D.programs,includingtakingmedicalschoolcourses.



4. Identifyspecificscientific,non-M.D.,specialties(includingbiostatistics)thatareinshortsupplyforearlytranslationalresearch.

5. Disseminatetheinformationgatheredtothescientificcommunitythroughappropriatepresentationsorpublications.

TheWorkingGroupwillconsultwidelywiththeleadersofexistingPh.D.programsinlaboratorybioscience,publichealth,andbehavioralscience;NCIstaff;andleadersofrelevantprofessionalorganizations.

Training of Ph.D. Nurses for Translational Research. Translationalresearchwouldbenefitfromtheparticipationofnursingresearcherswhocanlinkdiscoveryresearchonbiologicalmechanismswithnursingresearchinthepatientcareenvironment.Thisparticipationwouldfacilitatetranslationalresearchinitiativesaddressingnewinterventionsforsupportivecareandqualityoflife,aswellastheincorporationofsupportivecareandquality-of-lifedimensionsintotranslationalresearchontherapeuticinterventions.TheWorkingGroupwillconsultwiththeNationalInstituteofNursingResearchtodeterminehowthetwoInstitutescanbestcollaboratetofacilitateappropriatetranslationalresearchtrainingactivities.

Cross-Disciplinary Sharing of Best Practices and Implications of the Clinical and Translational Science Awards (CTSA) Program for Translational Research Training. TheWorkingGroupwillconsultwithrepresentativesofotherbiomedicalresearchdisciplinesandotherNIHInstitutestoidentifyissuesandbestpracticesintranslationalresearchtrainingthatarecommonacrossdisciplines.Inaddition,theWorkingGroupwillconsultwiththeCTSAprogramleadershiponthepotentialimplicationsofCTSAsfortrainingincancer-relatedtranslationalresearch.

Regulatory Affairs Training

TheTRWGidentifiedanacuteneedforgreaterunderstandingoftheFDAregulatoryprocessonthepartofthosewholeadtranslationalresearch.IncollaborationwithFDAandindustry,NCIwillseektoexpandthenumberofshortcourses,intensiveworkshops,sabbaticalfellowshipsinindustry,andothertrainingactivitiesthatcanfitintothecalendarsofactiveclinician-scientistsandprovidetheknowledgeandskillsneededtointeracteffectivelywiththeFDAindruganddevicedevelopment.

Enhancement of Career Support and Incentives

Akeyelementindevelopingarobusttranslationalresearchworkforceistoprovideadequatesupportandincentivestoattractyoungresearcherstoacareerintranslationalscience.Threeapproachesforaddressingthischallengewillbepursued.Thefirstisoptimizingfundingprogramstoencourageandrewardtranslationalresearch.Thesecondaddressesexpandingtheuseofthelegislativesalarycaptoincludetrainingawards.Thethirdistoengageacademicinstitutionsinanactivedialogueconcerningappropriatemodificationstoinstitutionalpracticesthatwillfacilitateacademiccareersintranslationalscience.

Funding Programs and Award Guidelines. TheTRWGhasproposedseveralinitiativesthatwillstrengthentranslationalresearchfundingprograms(seeTailoredFundingProgramsInitiativesB1,B3,andB4).Theguidelinechangesproposedintheseinitiativeswillrewardandencourageprojectsthattakeconceptsthroughdevelopmenttoearlyhumantesting.Theenhancedemphasisintheseprogramsontranslationalresearchasopposedtodiscoverywillprovidegreaterfundingopportunitiesforresearchersprimarilyinterestedinmovingconceptsforwardtoearlyhumantestingratherthansolelyworkingattheinterfaceofdiscoveryandtranslation.TheseprogramscanalsoprovideappropriaterecognitionforinvestigatorsparticipatinginlargecollaborativestudiesbyutilizingtheNIH-widemultipleprincipalinvestigatorand“tetheredawards”conceptsinfundingtheseprograms.Inaddition,guidelinesforcancercenterswillbemodifiedtorewardtheconductoffocusedtranslationalresearchprojectsaswellashigh-quality,investigator-initiated,industry-sponsoredstudies.



Legislative Salary Cap for Training Awards. NCIleadershipwillworkwithoverallNIHleadershiptomodifyK08,K23,andK24trainingawardstoallowsalarysupportuptothelegislativecap.ThisisinaccordwithRecommendation7oftheAAMC’sTaskForceIIonClinicalResearch(CRTFII)2006reportentitled,“PromotingTranslationalandClinicalScience:TheCriticalRoleofMedicalSchoolsandTeachingHospitals.”33

Academic Reward Practices. NCIandNIHleadershipwillworkproactivelywiththeAAMC,theInstituteofMedicine,andotherorganizationstopersuademedicalschoolandacademicdeansoftheneedtoadjusttheirinstitutions’incentivestructurestorewardcollaborative,multidisciplinarytranslationalresearch.TheNCIwillalsoexaminetheintramuralprogram’sincentivestructurestobesurethatcollaborativetranslationalresearchisproperlyrecognizedandrewarded.TheClinicalTrialsWorkingGroupReportincludedaninitiativetopursuerealignmentofacademicrecognitionpolicies,includingpromotionandtenureguidelines,torewardcollaborativeclinicalresearch.ThiseffortwillbecombinedwiththisnewTRWGproposedefforttorealignthosesamepoliciestorewardcollaborativetranslationalresearchthatmovesdiscoveriestowardearlyhumantesting.Suchchangeswouldrewardacademicsnotonlyforindividualdiscoveryscholarshipbutalsoforadvancingdiscoveriestopatientbenefit.ThisinitiativeparallelsRecommendation6oftheAAMCCRTFIIReport.34

33 ReportoftheAAMC’sTaskForceIIonClinicalResearch.Washington,DC:AssociationofAmericanMedicalColleges,200634 ReportoftheAAMC’sTaskForceIIonClinicalResearch.Washington,DC:AssociationofAmericanMedicalColleges,2006.


Report of the NCAB Translational Research Working Group—Timeline and Budget

Timeline and Budget

Timeline

ImplementationoftheTRWGinitiativesaccordingtotheplansoutlinedinthisreportareprojectedtorequire4to5yearstocomplete,withthefullimpactonroutineNCIoperationalpracticesexpectedtorequireatleast2to3additionalyears.Allinitiativesaretargetedtobeginimplementationbytheendofyearthree.AsummarytimelineispresentedinFigure4andasummarybudgetinFigure5(page80).AscheduleofkeyactivitiesandmilestonesassociatedwitheachinitiativeispresentedinTable1(page83).

Majoritemsforeachyearincludethefollowing:

Year 1

Coordinated Management Initiatives

• EstablishTranslationalResearchSupportOffice.

• ExpandClinicalTrialsAdvisoryCommitteeoversighttoincludetranslationalresearch.

• EstablishTranslationalResearchOperationsCommittee.

• Setinitialtranslationalresearchbudgettarget.

• Establishtranslationalresearchawardcodes.

• EstablishPrioritizationWorkingGroup.

• Initiatefirstannualprioritizationprocess.

• EstablishIndustryRelationsWorkingGroup.

Tailored Funding Program Initiatives

• Modifymultiproject,collaborativeawardguidelines(P50,U-series,etc.).

• DevelopSTRAPawardstructures.

• Establishintegratedreviewproceduresfortranslationalresearchawardsanddevelopmentresourceprograms.

• EstablishIndustryRelationsWorkingGroup.

Operational Effectiveness Initiatives

• Hireprojectmanagementstaff.

• Begintodevelopinventoryofearlytranslationalresearchresources.

• Developprojectmanagementtrainingplan.

• Analyzecoreservicesredundancies.

• BegininteractionswithOfficeofBiorepositoriesandBiospecimenResearchconcerningbiospecimenrepositories.

• Analyzecurrentintellectualpropertyagreements/practices.

• Initiateregularfoundationandadvocacygroupmeetings.

• EstablishTrainingWorkingGroup.




A1: Integrated NCI Management $800K $800K $850K $850K $850K

A2: Budget Designation — — — — —

A3: Translational Research Coding $150K $150K $150K $150K

A4: Prioritization Process $950K $750K $750K $750K $750K

B1: Modify Translational Research Award Guidelines — — — — —


— — — — —

B3: Special Translational Research Acceleration Project (STRAP) Awards

— — $10M $20M $30M

B4: Academia/Industry Collaboration Awards $5M $10M

B5: Integrated Development Services — — — — —

C1: Project Management $1.35M $1.3M $1.55M $1.75M $2M

C2: Core Services Coordination $200K $370K — — —

C3: Enhance Biorepositories — — — — —

C4: Improve Intellectual Property Negotiations $100K $530K

C5: Enhance Foundation/Advisory Group Collaborations — — — — —

C6: Enhance Training Programs and Career Incentives $300K $100K — — —

Evaluation $350K — $350K — $350K

TOTAL $4.05M $3.99M $13.65M $28.5M $44.1M

Figure 5. TRWG Initiatives Summary Budget

Figure 4. TRWG Initiatives Summary Timeline

Initiatives FY08 FY09 FY10 FY11 FY12A1: Integrated NCI ManagementA2: Budget DesignationA3: Translational Research CodingA4: Prioritization ProcessB1: Modify Translational Research Award Guidelines


B3: STRAP AwardsB4: Academia/Industry Collaboration AwardsB5: Integrated Development ServicesC1: Project ManagementC2: Core Services CoordinationC3: Enhance BiorepositoriesC4: Improve Intellectual Property NegotiationsC5: Enhance Foundation/Advisory Group CollaborationsC6: Enhance Training Programs and Career IncentivesEvaluation



Year 2


• Begincodingofnewtranslationalresearchawards.

• Completeretrospectivecodingoftranslationalresearchawards.

• Selectinitialsetoftranslationalresearchpriorities.


• Implementrevisedguidelinesformultiprojectcollaborativeawards.

• IssueinitialSTRAPawardsolicitation.

• Beginintegratedreviewsoftranslationalresearchawardsanddevelopmentofresourceprograms.


• Completeinventoryoftranslationalresearchresources.

• Initiateprojectmanagementtrainingprogram.

• Developcoreservicesdatabase.

• Identifycoreservicesforregionalization.

• Conveneconsensusmeetingsonintellectualpropertyagreements/bestpractices.

• Begininteractionwithacademicandmedicalschooldeansregardingacademicincentives.

• BegintoimplementTrainingWorkingGrouprecommendations.

Year 3


• Analyzenewlycodedtranslationalresearchportfolio.

• Selectsecondsetoftranslationalresearchpriorities.


• FundinitialSTRAPawards.

• Issueinitialacademic/industrycollaborationawardsolicitation.


• Begintranslationalresearchresourcedatabasedevelopment.

• Conduct2-yearevaluationofprojectmanagementsystem.

• Implementcoreservicesconsolidation,ifappropriate.

• Developharmonizedintellectualpropertyagreements/practices.

• Developagentrepositories/databases,ifappropriate.



Years 4-5


• Beginmanagingtranslationalresearchportfoliotobudgettarget.

• Continuetoselectannualtranslationalresearchpriorities.


• FundsecondandthirdroundofSTRAPawards.

• Fundfirstandsecondroundofacademic/industrycollaborationawards.


• Completetranslationalresearchresourcedatabasedevelopment.

• Conduct4-yearevaluationofprojectmanagementsystem.

• EstablishcoreservicesRegionalCenters.

Budget

TheestimatedcostsforimplementingtheTRWGinitiativesaccordingtotheplansoutlinedinthisreportarepresentedinTables2and3.Table2presentsthecostsbycategory—Extramural,Analysis/DevelopmentProjects,NCIOperationalActivities,andMeetingSupport.Table3presentsthecostsbyyear.TheestimatedincrementalcostforYear1(FY08)andYear2(FY09)is$4Mannually.TheestimatedcostincreasesinYear3(FY10)to$13.5M,inYear4(FY11)to$28.5M,andinYear5(FY12)to$44Mareentirelyduetoimplementationofnewextramuralfundingprograms.Thus,thesecostincreasesarenottrulyincremental,butrepresentshiftingofasmallfractionofongoingNCItranslationalresearchextramuralfundingintothenewSTRAPandacademic/industrycollaborationawards.

Oftheannual$4Minnonextramuralfundingthroughoutthe5-yearperiod,50%istooperatetheprojectmanagementsystem,25%istosupporttheprioritizationprocess,and25%isfortheNCImanagementandadministrativestructurenecessarytoimplementtheremaininginitiativesandeffectivelyguidethetransformedenterprise.IftheTRWGinitiativesarefullyimplemented,theremaybeadditionalincrementalexpensesthatcannotbeestimatedatthistime.Examplesincludeexpansionoftheprojectmanagementsystemifitissuccessfulanddemandgrows(seeOperationalEffectivenessInitiativeC1)andcreationofagentrepositoriesandassociateddatabasesifthesearedeemedworthwhileandfeasible(seeOperationalEffectivenessInitiativeC4).



Init

iati

veK

ey M

ilest

on

es a

nd

Act

ivit

ies

Co

ord

inat

ed

Man

agem

ent

Year

1(O

ct. 2

007–

Sep

t. 2

008)

Year

2(O

ct. 2

008–

Sep

t. 2

009)

Year

3(O

ct. 2

009–

Sep

t. 2

010)

Year

s 4–

5(O

ct. 2

010–

Sep

t. 2

012)

A1

Inte

gra

ted

NC

I M

anag

emen

t•

Est

ablis

h T

RS

O (

Oct

. 200

7)•

Exp

and

CTA

C o

vers

igh

t (J

an. 2

008)

• E

stab

lish

TR

OC

(Ja

n. 2

008)

• E

stab

lish

Sp

ecia

l P

op

ula

tio

ns

Wo

rkin

g G

rou

p

• Im

ple

men

t re

com

men

dat

ion

s o

f S

pec

ial P

op

ula

tio

ns

Wo

rkin

g G

rou

p

• A

nal

yze

new

ly c

od

ed

po

rtfo

lio (

Oct

. 200

9–M

ar.

2010

)•

Eva

luat

e va

lue

of

con

sort

ia

con

cep

t

• B

egin

man

agin

g p

ort

folio

to

b

ud

get

tar

get

(O

ct. 2

010)

A2:

B

ud

get

D

esig

nat

ion

• S

et in

itia

l bu

dg

et t

arg

et

(Sep

t. 2

008)

• R

evie

w a

nd

co

nfi

rm o

r ch

ang

e b

ud

get

tar

get

• R

evie

w a

nd

co

nfi

rm o

r ch

ang

e b

ud

get

tar

get

• R

evie

w a

nd

co

nfi

rm o

r ch

ang

e b

ud

get

tar

get

A3:

Tr

ansl

atio

nal

R

esea

rch

C

od

ing

• E

stab

lish

co

des

(O

ct.

2007

– M

ar. 2

008)

• A

nal

yze

feas

ibili

ty o

f in

vest

igat

or-

assi

gn

ed c

od

es

• B

egin

co

din

g o

f n

ew

awar

ds

(Oct

. 200

8)•

Co

mp

lete

ret

rosp

ecti

ve

cod

ing

• C

on

tin

ue

anal

ysis

of

feas

ibili

ty o

f in

vest

igat

or-

assi

gn

ed c

od

es

• C

on

tin

ue

cod

ing

of

new

aw

ard

s•

Co

nti

nu

e co

din

g o

f n

ew

awar

ds

A4:

P

rio

riti

zati

on

P

roce

ss•

Est

ablis

h P

rio

riti

zati

on

W

ork

ing

Gro

up

(Ja

n. 2

008)

• D

evel

op

pri

ori

tiza

tio

n

pro

cess

(O

ct. 2

007–

Jan

. 20

08)

• S

olic

it id

eas

(Jan

. 200

8)•

Per

form

lite

ratu

re r

evie

w

(Jan

. –M

ar. 2

008)

• D

evel

op

co

nce

pt

pac

kag

e (A

pr.

–Ju

n. 2

008)

• E

valu

ate

con

cep

ts (

Jul.

2008

)•

Per

form

po

rtfo

lio a

nal

ysis

o

f m

ost

pro

mis

ing

co

nce

pts

(A

ug

.–S

ept.

200

8)

• P

ub

lish

/pre

sen

t p

rio

riti

zed

o

pp

ort

un

itie

s fo

r co

mm

ent

(Oct

. 200

8)•

Sel

ect

init

ial p

rio

riti

es (

Jan

. 20

09)

• In

itia

te F

Y10

pri

ori

tiza

tio

n

pro

cess

(Ja

n. 2

009)

• C

om

ple

te F

Y10

p

rio

riti

zati

on

pro

cess

• S

elec

t an

nu

al p

rio

riti

es

(Jan

. 201

0)•

Init

iate

FY

11 p

rio

riti

zati

on

p

roce

ss (

Jan

. 201

0)

• C

on

tin

ue

ann

ual

p

rio

riti

zati

on

pro

cess

• S

elec

t an

nu

al p

rio

riti

es

(Jan

. 201

1 an

d J

an. 2

012)

Tab

le 1

. Im

ple

men

tati

on

Tim

elin

e



Init

iati

veK

ey M

ilest

on

es a

nd

Act

ivit

ies

Tailo

red

Fu

nd

ing

P

rog

ram

sYe

ar 1

(Oct

. 200

7–S

ept.

200

8)Ye

ar 2

(Oct

. 200

8–S

ept.

200

9)Ye

ar 3

(Oct

. 200

9–S

ept.

201

0)Ye

ars

4–5

(Oct

. 201

0–S

ept.

201

2)

B1:

M

od

ify

Tran

slat

ion

al

Res

earc

h A

war

d

Gu

idel

ines

• R

evis

e g

uid

elin

es•

Exa

min

e re

view

pan

els

• Im

ple

men

t re

vise

d

gu

idel

ines

• C

on

tin

ue

gu

idel

ine

revi

sio

n

if n

eces

sary

• C

on

tin

ue

to im

ple

men

t re

vise

d g

uid

elin

es•

Per

form

ro

llin

g r

evie

w

eval

uat

ion

• C

on

tin

ue

to im

ple

men

t re

vise

d g

uid

elin

es•

Imp

lem

ent

rolli

ng

rev

iew

if

app

rop

riat

e

B2:

Im

pro

ve

Inve

stig

ato

r-In

itia

ted

Tr

ansl

atio

nal

R

esea

rch

A

war

ds

• E

xam

ine

stu

dy

sect

ion

s•

Beg

in N

IH-w

ide

dia

log

ue

• C

on

tin

ue

NIH

-wid

e d

ialo

gu

e•

Co

nti

nu

e N

IH-w

ide

dia

log

ue

B3:

S

pec

ial

Tran

slat

ion

al

Res

earc

h

Acc

eler

atio

n

Pro

ject

(S

TR

AP

) A

war

ds

• D

evel

op

ST

RA

P a

war

d

stru

ctu

res

(Jan

.–S

ept.

200

8)•

Co

nti

nu

e to

dev

elo

p S

TR

AP

aw

ard

str

uct

ure

s (O

ct.–

Dec

. 20

08)

• P

rep

are

init

ial S

TR

AP

so

licit

atio

n (

Jan

.–M

ar. 2

009)

• Is

sue

ST

RA

P s

olic

itat

ion

(A

pr.

2009

)•

Rev

iew

ST

RA

P a

pp

licat

ion

s (J

ul.–

Sep

t. 2

009)

• Is

sue

firs

t S

TR

AP

aw

ard

s (J

an. 2

010)

• Is

sue

seco

nd

an

d t

hir

d

rou

nd

of

ST

RA

P a

war

ds

(Jan

. 201

1 an

d 2

012)

B4:

A

cad

emia

/In

du

stry

C

olla

bo

rati

on

A

war

ds

• E

stab

lish

Ind

ust

ry R

elat

ion

s W

ork

ing

Gro

up

• P

rep

are

acad

emic

/ind

ust

ry

colla

bo

rati

on

so

licit

atio

n

(Oct

. –D

ec. 2

009)

• Is

sue

solic

itat

ion

(Ja

n. 2

010)

• R

evie

w a

pp

licat

ion

s (A

pr.–

Jun

. 201

0)

• Is

sue

firs

t aw

ard

s (O

ct.

2010

)•

Issu

e se

con

d r

ou

nd

of

awar

ds

(Oct

. 201

1)

B5:

In

teg

rate

d

Dev

elo

pm

ent

Ser

vice

s

• E

stab

lish

inte

gra

ted

rev

iew

p

roce

du

res

• B

egin

inte

gra

ted

rev

iew

s•

Eva

luat

e p

ote

nti

al f

or

assa

y/m

ole

cula

r an

alys

is d

evic

e d

evel

op

men

t p

rog

ram

• C

on

tin

ue

inte

gra

ted

rev

iew

s•

Co

nti

nu

e in

teg

rate

d r

evie

ws

Tab

le 1

. Im

ple

men

tati

on

Tim

elin

e (c

on

tin

ued

)



Init

iati

veK

ey M

ilest

on

es a

nd

Act

ivit

ies

Op

erat

ion

al

Eff

ecti

ven

ess

Year

1(O

ct. 2

007–

Sep

t. 2

008)

Year

2(O

ct. 2

008–

Sep

t. 2

009)

Year

3(O

ct. 2

009–

Sep

t. 2

010)

Year

s 4–

5(O

ct. 2

010–

Sep

t. 2

012)

C1:

P

roje

ct

Man

agem

ent

• H

ire

pro

ject

man

agem

ent

TR

SO

sta

ff

mem

ber

(O

ct. 2

007)

• B

egin

to

dev

elo

p in

ven

tory

of

reso

urc

es•

Rev

ise

gu

idel

ines

• D

evel

op

tra

inin

g p

lan

• B

egin

liai

son

wit

h P

50/U

-ser

ies

pro

gra

m

staf

f (A

pr.

2008

)•

Hir

e D

ivis

ion

al p

roje

ct m

anag

emen

t st

aff

• C

on

tin

ue

to e

stab

lish

in

ven

tory

of

reso

urc

es•

Imp

lem

ent

revi

sed

g

uid

elin

es•

Init

iate

tra

inin

g p

rog

ram

• B

egin

res

ou

rce

DB

d

evel

op

men

t*•

Co

nti

nu

e to

im

ple

men

t re

vise

d

gu

idel

ines

• C

on

tin

ue

trai

nin

g

pro

gra

m•

Co

nd

uct

2-y

ear

eval

uat

ion

• C

on

tin

ue

reso

urc

e D

B

dev

elo

pm

ent

• C

on

tin

ue

to

imp

lem

ent

revi

sed

g

uid

elin

es•

Co

nti

nu

e tr

ain

ing

p

rog

ram

• C

on

du

ct 4

-yea

r ev

alu

atio

n

C2:

C

ore

Ser

vice

s C

oo

rdin

atio

n•

An

alyz

e co

re s

ervi

ces

red

un

dan

cies

• R

evis

e g

uid

elin

es•

Beg

in t

o d

evel

op

co

re s

ervi

ces

dat

abas

e

• C

on

tin

ue

to d

evel

op

co

re

serv

ices

dat

abas

e•

Iden

tify

ser

vice

s fo

r re

gio

nal

izat

ion

• D

evel

op

co

nso

lidat

ion

p

lan

s, a

s ap

pro

pri

ate

• Im

ple

men

t co

nso

lidat

ion

• Im

ple

men

t re

gio

nal

izat

ion

, as

app

rop

riat

e

• C

on

tin

ue

to

imp

lem

ent

con

solid

atio

n•

Co

nti

nu

e to

im

ple

men

t re

gio

nal

izat

ion

C3:

E

nh

ance

B

iore

po

sito

ries

• R

evis

e g

uid

elin

es•

Beg

in in

tera

ctio

ns

wit

h O

BB

R/B

CC

•

Co

nti

nu

e in

tera

ctio

ns

wit

h O

BB

R/B

CC

• C

on

tin

ue

inte

ract

ion

s w

ith

OB

BR

/BC

C•

Co

nti

nu

e in

tera

ctio

ns

wit

h O

BB

R/B

CC

C4:

Im

pro

ve

Inte

llect

ual

P

rop

erty

N

ego

tiat

ion

s

• A

nal

yze

curr

ent

agre

emen

ts/p

ract

ices

• C

on

ven

e co

nse

nsu

s m

eeti

ng

s•

An

alyz

e al

tern

ate

IP

mo

del

s•

An

alyz

e re

po

sito

ry

op

tio

ns

• D

evel

op

har

mo

niz

ed

agre

emen

ts/p

ract

ices

• D

evel

op

ag

ent

rep

osi

tori

es/

dat

abas

es, i

f ap

pro

pri

ate

• C

on

tin

ue

to d

evel

op

ag

ent

rep

osi

tori

es/

dat

abas

es, i

f ap

pro

pri

ate

C5:

E

nh

ance

Fo

un

dat

ion

/A

dvi

sory

Gro

up

C

olla

bo

rati

on

s

• In

itia

te r

egu

lar

fou

nd

atio

n a

nd

ad

voca

cy

gro

up

mee

tin

gs

o A

void

du

plic

ativ

e re

view

o E

xplo

re f

un

din

g p

artn

ersh

ips

o B

egin

ou

trea

ch f

or

tiss

ue

do

nat

ion

• C

on

tin

ue

and

exp

and

in

tera

ctio

ns

• Im

ple

men

t id

enti

fied

in

itia

tive

s

• C

on

tin

ue

and

exp

and

in

tera

ctio

ns

• Im

ple

men

t id

enti

fied

in

itia

tive

s

• C

on

tin

ue

and

exp

and

in

tera

ctio

ns

• Im

ple

men

t id

enti

fied

in

itia

tive

s

C6:

E

nh

ance

Tr

ain

ing

P

rog

ram

s an

d C

aree

r In

cen

tive

s

• D

evel

op

tra

inin

g P

A (

Oct

. 200

7 –M

ar. 2

008)

• E

stab

lish

Wo

rkin

g G

rou

p (

Jan

. 200

8)•

Co

nd

uct

Wo

rkin

g G

rou

p d

elib

erat

ion

s (J

an.–

Sep

t. 2

008)

• A

nal

yze

reg

ula

tory

tra

inin

g o

pti

on

s (A

pr.–

Sep

t. 2

008)

• W

ork

wit

h N

IH le

ader

ship

co

nce

rnin

g

leg

isla

tive

cap

in t

rain

ing

aw

ard

s

• C

om

ple

te W

ork

ing

Gro

up

d

elib

erat

ion

s (D

ec. 2

008)

• B

egin

to

imp

lem

ent

WG

re

com

men

dat

ion

s•

Beg

in in

tera

ctio

n w

ith

ac

adem

ic d

ean

s/A

AM

C/

IOM

reg

ard

ing

aca

dem

ic

ince

nti

ves

• C

on

tin

ue

to

imp

lem

ent

Wo

rkin

g G

rou

p

reco

mm

end

atio

ns

• C

on

tin

ue

inte

ract

ion

w

ith

aca

dem

ic d

ean

s/A

AM

C/IO

M r

egar

din

g

acad

emic

ince

nti

ves

• C

on

tin

ue

to

imp

lem

ent

Wo

rkin

g G

rou

p

reco

mm

end

atio

ns

• C

on

tin

ue

inte

ract

ion

w

ith

aca

dem

ic d

ean

s/A

AM

C/IO

M r

egar

din

g

acad

emic

ince

nti

ves

Eva

luat

ion

Imp

lem

enta

tio

n o

f T

RW

G in

itia

tive

s•

Dev

elo

p e

valu

atio

n s

yste

m•

Co

nd

uct

bas

elin

e ev

alu

atio

n•

Co

nd

uct

2-y

ear

eval

uat

ion

• C

on

du

ct 4

-yea

r ev

alu

atio

n

*Fu

rthe

rde

velo

pmen

tof

core

ser

vice

sda

taba

se(

Initi

ativ

eC

2).

Tab

le 1

. Im

ple

men

tati

on

Tim

elin

e (c

on

tin

ued

)



Init

iati

veE

xpen

ses

Co

ord

inat

ed

Man

agem

ent

Ext

ram

ura

lA

nal

ysis

/Dev

elo

pm

ent

Pro

ject

sN

CI O

per

atio

nal

A

ctiv

itie

sM

eeti

ng

Su

pp

ort

Tota

l

A1

Inte

gra

ted

NC

I M

anag

emen

t

N/A

Po

rtfo

lio A

nal

ysis

Yr

3–5

......

......

.....

$50K

/yr

Tran

slat

ion

al R

esea

rch

S

up

po

rt O

ffice

*

Yr

1–5

.....

......

...$7

00K

/yr

Wo

rkin

g G

rou

p

Mee

tin

gs

Yr

1–5

......

......

...$1

00/y

r

Yr

1 ...

......

......

....$

800K

Yr

2 ...

......

......

....$

800K

Yr

3 ...

......

......

....$

850K

Yr

4 ...

......

......

....$

850K

Yr

5 ...

......

......

....$

850K

A2:

B

ud

get

D

esig

nat

ion

N/A

N/A

See

No

te 1

N/A

See

No

te 1

A3:

Tr

ansl

atio

nal

R

esea

rch

C

od

ing

N/A

N/A

RA

EB

Sta

ff

Yr

2-5 .

......

......

.. $

150K

/yr

N/A

Yr

1 ...

......

......

......

..$0

Yr

2 ...

......

......

....$

150K

Yr

3 ...

......

......

....$

150K

Yr

4 ...

......

......

....$

150K

Yr

5 ...

......

......

....$

150K

A4:

P

rio

riti

zati

on

P

roce

ss

N/A

Pri

ori

tiza

tio

n W

ork

ing

G

rou

p S

up

po

rt

(Lit

erat

ure

rev

iew

, p

ort

folio

an

alys

is, e

tc.)

Yr

1 ...

......

......

....$

400K

Yr

2-–5

.....

......

...$2

00K

/yr

Tran

slat

ion

al R

esea

rch

S

up

po

rt O

ffice

Yr

1–5

......

......

...$3

50K

/yr

Pri

ori

tiza

tio

n W

ork

ing

G

rou

p M

eeti

ng

s

Yr

1–5

......

......

...$2

00K

/yr

Yr

1 ...

......

......

....$

950K

Yr

2 ...

......

......

....$

750K

Yr

3 ...

......

......

....$

750K

Yr

4 ...

......

......

....$

750K

Yr

5 ...

......

......

....$

750K

No

te 1

: In

clu

ded

in T

ran

slat

ion

al R

esea

rch

Su

pp

ort

Off

ice

exp

ense

s fo

r In

itia

tive

A1

(see

ab

ove

).

*Expandedmanagem

entandprofessionalstafffortheTranslationalR

esearchSupportO

fficeoftheCoordinatingCenterforClinicalTrials,includingclerical,officeexpenses,

travel,etc.TheproratedTranslationalR

esearchSupportO

fficestaffandoperatingexpensesformanagingtheprioritizationandprojectm

anagem

entsystemsarenotincluded

inth

eto

tals

how

n;th

ese

expe

nses

are

incl

uded

inth

eex

pens

esf

orI

nitia

tive

A4

and

Initi

ativ

eC

1,r

espe

ctiv

ely.

Tab

le 2

. Est

imat

ed Im

ple

men

tati

on

Bu

dg

et b

y C

ateg

ory



Tab

le 2

. Est

imat

ed Im

ple

men

tati

on

Bu

dg

et b

y C

ateg

ory

(co

nti

nu

ed)

Init

iati

veE

xpen

ses

Tailo

red

Fu

nd

ing

P

rog

ram

sE

xtra

mu

ral

An

alys

is/D

evel

op

men

t P

roje

cts

NC

I Op

erat

ion

al

Act

ivit

ies

Mee

tin

g S

up

po

rtTo

tal

B1:

M

od

ify

Tran

slat

ion

al

Res

earc

h A

war

d

Gu

idel

ines

N/A

N/A

See

No

te 1

N/A

See

No

te 1

B2:

Im

pro

ve

Inve

stig

ato

r-In

itia

ted

Tr

ansl

atio

nal

R

esea

rch

A

war

ds

N/A

N/A

See

No

te 1

N/A

See

No

te 1

B3:

S

pec

ial

Tran

slat

ion

al

Res

earc

h

Acc

eler

atio

n

Pro

ject

(S

TR

AP

) A

war

ds

Yr

3 ...

......

......

......

$10M

Yr

4 ...

......

......

......

$20M

Yr

5 ...

......

......

......

$30M

N/A

See

No

te 2

N/A

Yr

1 ...

......

......

......

.$ 0

Yr

2 ...

......

......

......

.$ 0

Yr

3 ...

......

......

......

$10M

Yr

4 ...

......

......

......

$20M

Yr

5 ...

......

......

......

$30M

B4:

A

cad

emia

/In

du

stry

C

olla

bo

rati

on

A

war

ds

Yr

4 ...

......

......

......

.$ 5

M

Yr

5 ...

......

......

......

$10M

N/A

See

No

te 1

N/A

Yr

1 ...

......

......

......

.$ 0

Yr

2 ...

......

......

......

.$ 0

Yr

3 ...

......

......

......

.$ 0

Yr

4 ...

......

......

......

.$ 5

M

Yr

5 ...

......

......

......

$10M

B5:

In

teg

rate

d

Dev

elo

pm

ent

Ser

vice

sN

/AN

/AS

ee N

ote

1N

/AS

ee N

ote

1

No

te 1

: In

clu

ded

in T

ran

slat

ion

al R

esea

rch

Su

pp

ort

Off

ice

exp

ense

s fo

r In

itia

tive

A1

(see

pag

e 86

).

No

te 2

: In

clu

ded

in p

rio

riti

zati

on

pro

cess

exp

ense

s (I

nit

iati

ve A

4, s

ee p

age

86).



Init

iati

veE

xpen

ses

Op

erat

ion

al

Eff

ecti

ven

ess

Ext

ram

ura

lA

nal

ysis

/Dev

elo

pm

ent

Pro

ject

sN

CI O

per

atio

nal

A

ctiv

itie

sM

eeti

ng

Su

pp

ort

Tota

l

C1:

P

roje

ct

Man

agem

ent

N/A

Trai

nin

g A

nal

ysis

Yr

1 ...

......

......

......

......

..$5

0K

Res

ou

rce

Inve

nto

ry

Yr

1–2

......

......

......

..$2

00K

/yr

Res

ou

rce

Dat

abas

e D

evel

op

men

t*

Yr

3–5

......

......

......

..$2

00K

/yr

Eva

luat

ion

Yr

3 ...

......

......

......

......

$250

K

Yr

5 ...

......

......

......

......

$250

K

Tran

slat

ion

al R

esea

rch

S

up

po

rt O

ffice

Yr

1–5

......

......

......

..$3

50K

/yr

Div

isio

nal

Pro

ject

M

anag

ers

Yr

1–3

......

......

......

.$75

0K/y

r

Yr

4–5

......

......

......

.$1.

2M/y

r

N/A

Yr

1 ...

......

......

......

...$1

.35M

Yr

2 ...

......

......

......

...$1

.30M

Yr

3 ...

......

......

......

...$1

.55M

Yr

4 ...

......

......

......

...$1

.75M

Yr

5 ...

......

......

......

...$2

.00M

C2:

C

ore

Ser

vice

s C

oo

rdin

atio

n

N/A

Co

re S

ervi

ces

An

alys

is

Yr

1 ...

......

......

......

......

$200

K

Co

re S

ervi

ces

Init

ial

Dat

abas

e D

evel

op

men

t

Yr

2 ...

......

......

......

......

$250

K

See

No

te 1

Reg

ion

aliz

atio

n W

ork

ing

G

rou

p M

eeti

ng

Yr

2 ...

......

......

......

......

$120

K

Yr

1 ...

......

......

......

......

$200

K

Yr

2 ...

......

......

......

......

$370

K

Yr

3 ...

......

......

......

......

...$

0K

Yr

4 ...

......

......

......

......

...$

0K

Yr

5 ...

......

......

......

......

...$

0K

C3:

E

nh

ance

B

iore

po

sito

ries

N/A

N/A

See

No

te 1

N/A

See

No

te 1

C4:

Im

pro

ve

Inte

llect

ual

P

rop

erty

N

ego

tiat

ion

s

N/A

IP A

gre

emen

t A

nal

ysis

Yr

1 ...

......

......

......

......

$100

K

Alt

ern

ate

IP M

od

els

An

alys

is

Yr

2 ...

......

......

......

......

$200

K

An

alys

is o

f R

epo

sito

ry

Op

tio

ns

Yr

2 ...

......

......

......

......

$200

K

See

No

te 1

Co

nse

nsu

s M

eeti

ng

s

Yr

2 ...

......

......

......

......

$120

K

Yr

1 ...

......

......

......

......

$100

K

Yr

2 ...

......

......

......

......

$520

K

Yr

3 ...

......

......

......

......

...$

0K

Yr

4 ...

......

......

......

......

...$

0K

Yr

5 ...

......

......

......

......

...$

0K

No

te 1

: In

clu

ded

in T

ran

slat

ion

al R

esea

rch

Su

pp

ort

Off

ice

exp

ense

s fo

r In

itia

tive

A1

(see

pag

e 86

).

*Fu

rthe

rde

velo

pmen

tof

core

ser

vice

sda

taba

se(

Initi

ativ

eC

2).

Tab

le 2

. Est

imat

ed Im

ple

men

tati

on

Bu

dg

et b

y C

ateg

ory

(co

nti

nu

ed)



Init

iati

veE

xpen

ses

Op

erat

ion

al

Eff

ecti

ven

ess

Ext

ram

ura

lA

nal

ysis

/Dev

elo

pm

ent

Pro

ject

sN

CI O

per

atio

nal

A

ctiv

itie

sM

eeti

ng

Su

pp

ort

Tota

l

C5:

E

nh

ance

Fo

un

dat

ion

/A

dvi

sory

Gro

up

C

olla

bo

rati

on

s

N/A

N/A

See

No

te 1

N/A

See

No

te 1

C6:

E

nh

ance

Tr

ain

ing

P

rog

ram

s an

d C

aree

r In

cen

tive

sN

/A

Wo

rkin

g G

rou

p S

up

po

rt

Yr

1 ...

......

......

......

......

$150

K

Yr

2 ...

......

......

......

......

.$ 5

0KS

ee N

ote

1

Wo

rkin

g G

rou

p M

eeti

ng

s

Yr

1 ...

......

......

......

......

$150

K

Yr

2 ...

......

......

......

......

.$ 5

0K

Yr

1 ...

......

......

......

......

$300

K

Yr

2 ...

......

......

......

......

$100

K

Yr

3 ...

......

......

......

......

...$

0K

Yr

4 ...

......

......

......

......

...$

0K

Yr

5 ...

......

......

......

......

...$

0K

Eva

luat

ion

Imp

lem

enta

tio

n o

f T

RW

G In

itia

tive

sN

/A

Yr

1 ...

......

......

......

......

$350

K

Yr

3 ...

......

......

......

......

$350

K

Yr

5 ...

......

......

......

......

$350

K

N/A

N/A

N/A

No

te 1

: In

clu

ded

in T

ran

slat

ion

al R

esea

rch

Su

pp

ort

Off

ice

exp

ense

s fo

r In

itia

tive

A1

(see

pag

e 86

).

Tab

le 2

. Est

imat

ed Im

ple

men

tati

on

Bu

dg

et b

y C

ateg

ory

(co

nti

nu

ed)



Init

iati

veE

xpen

ses

Co

ord

inat

ed M

anag

emen

tYe

ar 1

—FY

08Ye

ar 2

—FY

09Ye

ar 3

—FY

10Ye

ar 4

—FY

11Ye

ar 5

—FY

12

A1

Inte

gra

ted

NC

I Man

agem

ent

$800

K$8

00K

$850

K$8

50K

$850

K

A2:

B

ud

get

Des

ign

atio

nS

ee N

ote

1S

ee N

ote

1S

ee N

ote

1S

ee N

ote

1S

ee N

ote

1

A3:

Tr

ansl

atio

nal

Res

earc

h C

od

ing

N/A

$150

K$1

50K

$150

K$1

50K

A4:

P

rio

riti

zati

on

Pro

cess

$950

K$7

50K

$750

K$7

50K

$750

K

Tailo

red

Fu

nd

ing

Pro

gra

ms

B1:

M

od

ify

Tran

slat

ion

al R

esea

rch

Aw

ard

Gu

idel

ines

See

No

te 1

See

No

te 1

See

No

te 1

See

No

te 1

See

No

te 1

B2:

Im

pro

ve In

vest

igat

or-

Init

iate

d T

ran

slat

ion

al R

esea

rch

A

war

ds

See

No

te 1

See

No

te 1

See

No

te 1

See

No

te 1

See

No

te 1

B3:

S

pec

ial T

ran

slat

ion

al R

esea

rch

Acc

eler

atio

n P

roje

ct

(ST

RA

P)

Aw

ard

sN

/AN

/A$1

0M$2

0M$3

0M

B4:

A

cad

emia

/Ind

ust

ry C

olla

bo

rati

on

Aw

ard

sN

/AN

/AN

/A$5

M$1

0M

B5:

In

teg

rate

d D

evel

op

men

t S

ervi

ces

See

No

te 1

See

No

te 1

See

No

te 1

See

No

te 1

See

No

te 1

Op

erat

ion

al E

ffec

tive

nes

s

C1:

P

roje

ct M

anag

emen

t$1

.35M

$1.3

0M$1

.55M

$1.7

5M$2

.0M

C2:

C

ore

Ser

vice

s C

oo

rdin

atio

n$2

00K

$370

KN

/AN

/AN

/A

C3:

E

nh

ance

Bio

rep

osi

tori

esS

ee N

ote

1S

ee N

ote

1S

ee N

ote

1S

ee N

ote

1S

ee N

ote

1

C4:

Im

pro

ve In

telle

ctu

al P

rop

erty

Neg

oti

atio

ns

$100

K$5

20K

N/A

N/A

N/A

C5:

E

nh

ance

Fo

un

dat

ion

/Ad

viso

ry G

rou

p C

olla

bo

rati

on

sS

ee N

ote

1S

ee N

ote

1S

ee N

ote

1S

ee N

ote

1S

ee N

ote

1

C6:

E

nh

ance

Tra

inin

g P

rog

ram

s an

d C

aree

r In

cen

tive

s$3

00K

$100

KN

/AN

/AN

/A

Eva

luat

ion

Imp

lem

enta

tio

n o

f T

RW

G In

itia

tive

s$3

50K

N/A

$350

KN

/A$3

50K

TO

TALS

$4.0

5M$3

.99M

$13.

65M

$28.

5M$4

4.1M

5-Y

EA

R T

OTA

L$9

4.29

M

No

te 1

: In

clu

ded

in T

ran

slat

ion

al R

esea

rch

Su

pp

ort

Off

ice

exp

ense

s fo

r In

itia

tive

A1

(see

pag

e 86

).

Tab

le 3

. Est

imat

ed Im

ple

men

tati

on

Bu

dg

et b

y Ye

ar


Report of the NCAB Translational Research Working Group—Evaluation and Outcome Measures

Evaluation and Outcome Measures

Introduction

Formalevaluationisanintegralpartofeffectiveprogramorenterprisemanagement.Itprovidesarationalbasisforassessingtherelationshipbetweenthestrategiesandtacticsimplementedinaprogramandtheirefficacyinachievingthedesiredgoalsandforidentifyingappropriatecorrectiveactionifneeded.

TheinitiativesproposedbytheTRWGrecognizetheimportanceofevaluationinthecontextofactivities,suchasearlytranslationalresearch,thatarestronglygoaloriented.Theintroductionofmilestone-basedprojectmanagementforcomplexprojectssuchasthosesupportedbytheproposedSTRAPawardsbringsevaluationdowntotheprojectlevelanddeploysitasatooltoincreaseproductivity.AcomparableevaluativedisciplinemustbeappliedtomeasuringtheeffectoftheTRWGinitiativesonthetranslationalresearchenterpriseasawholeinordertoensureeffectiveuseofthescarceresourcesentrustedtoit.

Evaluationattheprogramorenterpriselevelshouldaddressbothprocessandoutcomes.Processassessmentisimportantinordertohaveconfidencethattheeffortisproceedingappropriatelyduringitsinitialphase,aswellastocreateabasisforchartingarevisedcourseofactionifneeded.Outcomesassessmentisessentialtoconfirmthattheeffortisachievingitsgoals.

Evaluationoftranslationalresearchprogramspresentsseveralchallenges.First,importantdimensionsofperformancecannotbefullycapturedusingpurelyobjectiveandquantitativemeasures.Themeasuresmustincludeajudiciousblendofqualitativeandquantitative,objectiveandsubjectivemeasures.Second,althoughtranslationalresearchisstronglygoaloriented,itsresultsneverthelessremainsomewhatunpredictable,andcandependtoasignificantdegreeonfactorsbeyondthecontroloftheparticipants.Andthird,translationalresearchisacomplexsysteminwhichmultipleinternalandexternalfactorsinteractinmanydifferentways—someobservable,andsomenot—toaffectoutcomes.Thus,attributionofobservedoutcomestoparticularpolicies,organizationalstructures,ormanagementdecisionscanbedifficult.

Use of Measures

Anevidence-basedapproachisessential.Thedeterminationofsuccessorfailureanddecisionsonanyneededcoursecorrectionswillnotbeautomaticormechanical,butamatterofjudgmentbyexpertsinthefield.However,thisexpertjudgmentmustbeinformedbysystematic,structuredempiricaldatasothattherewillbeasharedbasisfordiscussionanddecision-making.Themeasuresuseddonotserveasthesumtotaloftheevaluation,butasessential“rawmaterial”foralargerprocessofexpertjudgmentinwhichthebroadoncologyresearchcommunitymustparticipate.

Theneededmeasuresfallintothreecategories:

• ProgrammanagementprocessmeasuresthatevaluateimplementationoftheinitiativesrecommendedbytheTRWG

• Systemprocessmeasuresthatevaluatetheeffectofthechangesinoperationalprocessesoncoordination,prioritization,management,funding,andconductoftranslationalresearch

• Systemoutcomemeasuresthatassesstheintendedresult—anincreasednumberofnewtreatments,diagnosticmethods,etc.,thatare“handedoff”tomiddleandlate-stagetrialsfordefinitiveevaluation.

Toevaluatetheimpactoftheproposedinitiatives,itisessentialtoconductabaselineevaluationofselectedmeasurespriortoimplementation.Onlythencantheeffectofchangeberecognized.Itisalsoessentialtosetrealistictimelinesforachievementoftheobjectivessothatevaluationisnotattemptedeithertooearlyortoolateintheprocess.Forexample,certainprocessmeasuresmayberelevantonlyafterotherprocessesonwhichtheydependhavebeencompleted.Similarly,itmaybeamatterofyearsbeforeitisreasonabletoexpectcertainoutcomestobeapparent.Nevertheless,manyprocessmeasurescanbefruitfullyassessedatintervalstodocumenttheprogressoftheinitiatives.



Aswell-definedmeasuresdonotcurrentlyexistformanyelementsoftheNCItranslationalresearchenterprise,establishingspecificmeasureswillbeanongoinganditerativeprocess.NCIwillengageexperiencedevaluationspecialiststoassistindevelopmentofthesemeasuresaswellasthesurveyinstruments,statisticaladjustments,andothertoolsrequiredtoconducttheevaluationsandrendertheevaluationmeasurespracticalandvalid.ThesespecialistswillalsoworkwithNCItodeterminetheappropriatetimingforexaminingthevariousmeasuresbasedonimplementationtimelinesandtheimpactsenvisioned.Abaselineevaluationofrelevantelementsofthecurrentsystemwillbeconductedassoonaspossibletoprovideareliablebasisforascertainingthevalueoftheinitiatives.Theresultsofthisbaselineevaluationwillbeanalyzedtodeterminewhetherthechosenmeasuresarevalidorshouldbeeliminatedorrevised.

Categories of Measures

Program Management Process Measures

ThesemeasureswillbetrackedbyNCIonacontinuingbasisaspartofitsmanagementofinitiativeimplementationandwillbeassessedinlightoftheproposedimplementationplanandtimeline.Questionstobeaddressedinclude:

• Werethetasksinitiatedontime?

• Didtheyfollowtheimplementationplanasoutlined?

• Ifobstacleswereencountered,werealternateplansimplementedquicklyandeffectively?

• Werethetasksaccomplishedontimeorweretimelinesrevisedinatimelyandrealisticfashion?

System Process Measures

Theproposedinitiativeshavethreekeyprocessobjectives:

• Improvedcoordinationandmoreactive,goal-oriented,andtransparentmanagementofthetranslationalresearchenterprise

• Moreeffectivetailoringoffundingprogramstothespecificcharacteristicsandneedsoftranslationalresearch

• Enhancedoperationalefficiencyandeffectivenessoftranslationalresearchprojectsandthemanysupportingactivitiesthatareessentialtotheenterprise.

Inaddition,theseimprovementsareexpectedtoencouragegreaterinterestandinvolvementintranslationalresearchbyinvestigators.Thus,afourthprocessobjectivecanbeadded:

• Increasedtranslationalresearchactivity.

Toaccomplishtheseobjectives,theproposedinitiativesenvisionimplementingnewstructures,processes,andbehaviorsonthepartofparticipantsintheenterprise.Thesystemprocessmeasuresmustthereforeprovideempiricalevidenceofwhetherthenewstructuresandprocessesareeffective,whetherthetargetedbehaviorsarechangingintheintendedways,whetherthelevelofactivityisincreasing,andwhethertheimpactedcomponentsandthesystemasawholeareinfactbecomingmorecoordinated,morecollaborative,moretransparent,moregoaloriented,moreefficient,andmoreproductive,aswellasbettermanagedandbetterprioritized.Measuresshouldalsobeincludedtoverifythatthenewobjectivesarenotachievedattheexpenseofothervaluedcharacteristicsofthetranslationalresearchenterpriseasitexiststoday.

Someofthesystemcharacteristicscanbeassessedviaobjectivemeasures,whileothersmustbeassessedsubjectively,throughasystematicandtransparentprocessofsolicitingexpertopinion.Itisimportanttorememberthatnosinglemeasurewillprovideaconclusiveindicatorofsuccess,norabasisforattributionofcauseandeffect.Rather,each



measuremustbecombinedwiththeothersandincludedinalarger,comprehensiveevaluationbyabroadrangeofcriticalstakeholders.

System Outcome Measures

ThemostimportantandmeaningfuloutcomemeasuresforevaluatingthesuccessoftheTRWGinitiativeswillbethosethatassesstheextenttowhichthereisanincreasednumberofnewcancertreatments,diagnosticmethods,andotherinterventionsadvancedtomiddle-andlate-stagetrials.

Inpractice,however,developmentoftenoccursonverylongtimescale—aslongasadecadeormore.Inevaluatingprogramsthatarecharacterizedbysuchlongtimescales,itiscommontoincludeproxyoutcomemeasuresaswell.Suchproxymeasurescapturecertaincriticalaspectsofsystemactivity,andassuchcouldalsobeviewedasprocessmeasures.However,iftheproxymeasuresaresufficientlytightlylinkedtotheultimatedesiredoutcome,theycanconstituteausefulinterimguidetoprogress.

Proposedsystemoutcomemeasureswillthereforeincludethefollowing:

• Numberofnewtherapies,diagnostic/screeningtests,lifestylealternations,preventiveagents,etc.,thatsuccessfullycompleteNCI-supportedearly(PhaseIorII)humantestingandarejudgedsuitableforlate-stagetesting

• Numberofnewtherapies,diagnostic/screeningtests,etc.,handedofftoindustryforfurtherdevelopmentfromanypointinthedevelopmentalpathway

• Numberofnewtherapies,diagnostic/screeningtests,lifestylealternations,preventiveagents,etc.,underNCI-supporteddevelopmentaccordingtooneoftheTRWGdevelopmentalpathways(proxymeasure).


Report of the NCAB Translational Research Working Group—Appendices

Appendices

Appendix A: Foundational Documents

Appendix B: TRWG Translational Research Definition and Scope of Activity

Appendix C: TRWG Developmental Pathways to Clinical Goals

Appendix D: Translational Research Portfolio for the NCI Translational Research Working Group

Appendix E: Process Analysis for the NCI Translational Research Working Group

Appendix F: TRWG Meeting Dates


Report of the NCAB Translational Research Working Group—Appendix A

Appendix A: Foundational Documents

FoodandDrugAdministration.InnovationorStagnation:ChallengeandOpportunityontheCriticalPathtoNewMedical

Products,March2004.

http://www.cancer.gov/pdf/trwg/Critical-Path-whitepaper.pdf

NationalCancerAdvisoryBoard.AdvancingTranslationalCancerResearch:AVisionoftheCancerCenterandSPORE

ProgramsoftheFuture,ReportoftheP30/P50AdHocWorkingGroup,February2003.

http://deainfo.nci.nih.gov/advisory/ncab/p30-p50/P30-P50final12feb03.pdf

NationalCancerAdvisoryBoard.CancerataCrossroads:AReporttoCongressfortheNation,Reportofthe

SubcommitteetoEvaluatetheNationalCancerProgram,September1994.

http://www.cancer.gov/pdf/trwg/Cancer-at-a-Crossroads.pdf

NationalCancerAdvisoryBoard.RestructuringtheNationalCancerClinicalTrialsEnterprise,ReportoftheClinical

TrialsWorkingGroup,June2005.

http://integratedtrials.nci.nih.gov/ict/CTWG_report_June2005.pdf

NationalCancerInstitute.ReportoftheKidney/BladderCancersProgressReviewGroup,August2002.

http://planning.cancer.gov/pdfprgreports/2002kidneyreport.pdf

NationalCancerInstitute.ReportoftheLeukemia,Lymphoma,andMyelomaProgressReviewGroup,May2001.

http://planning.cancer.gov/pdfprgreports/2001llm.pdf

NationalCancerInstitute.ReportoftheLungCancerProgressReviewGroup,August2001.

http://planning.cancer.gov/pdfprgreports/2001lung.pdf

NationalCancerInstitute.ReportoftheSarcomaProgressReviewGroup:ARoadmapforSarcomaResearch,January

2004.

http://planning.cancer.gov/pdfprgreports/2004sarcoma.pdf

NationalCancerInstitute.ReportoftheStomach/EsophagealCancersProgressReviewGroup,December2002.

http://planning.cancer.gov/stomach/stomach_esophageal.pdf

NationalInstitutesofHealth.NIHRoadmapforMedicalResearch,Re-engineeringtheClinicalResearchEnterprise,

October2006.

http://nihroadmap.nih.gov/clinicalresearch/overview-translational.asp

ThePresident’sCancerPanel.TranslatingResearchintoCancerCare:DeliveringonthePromise,2004-2005Annual

Report,NationalInstitutesofHealth,NationalCancerInstitute,June2005.

http://deainfo.nci.nih.gov/ADVISORY/pcp/pcp04-05rpt/ReportTrans.pdf


Report of the NCAB Translational Research Working Group—Appendix B

Appendix B: TRWG Translational Research Definition and Scope of Activity

“Translational research transforms scientific discoveries arising from laboratory, clinical, or population studies into clinical applications to reduce cancer incidence,

morbidity, and mortality.”

The Translational Continuum*

Basic Science Discovery

Early Translation Late Translation Dissemination Adoption

• Promising molecule or gene target

• Candidate protein biomarker

• Basic epidemiologic finding

• Partnerships and collaboration (academia, government, industry)

• Intervention development

• Phase I/II trials

• Phase III trials• Regulatory approval• Partnerships• Production and

commercialization• Phase IV trials

– approval for additional uses

• Payment mechanism(s) established to support adoption

• Health services research to support dissemination and adoption

(newdrug,assay,device,behavioralintervention,educationalmaterial,training)• To community

health providers• To patients and

public

• Adoption of advance by providers, patients, public

• Payment mechanism(s) in place to enable adoption

TRWG Activity

*FromthePresident’sCancerPanel’s2004-2005reportTranslatingResearchIntoCancerCare:DeliveringonthePromise.

New Tools and New Applications

Lab

Clinic Population


Report of the NCAB Translational Research Working Group—Appendix C

Appendix C: TRWG Developmental Pathways to Clinical Goals

Introduction to the TRWG Developmental Pathways

TheTRWGhasconstructedsix“developmentalpathways”thatcharacterizethetransformationofscientificdiscoveriesintonewclinicalmodalitiesforoncology.Thesemodalitiesfallintotwofundamentalandcomplementarycategories:

Riskassessmentmodalities,intendedtocharacterizethecancer-relatedhealthstatusofanindividual:

• Biospecimen-basedriskassessmentdevices(protocols,reagents,instruments,etc.)

• Image-basedriskassessment(agentsortechniques).

Interventivemodalities,intendedtochangethecancer-relatedhealthstatusofanindividual,viapreventionortreatment:

• Agents(drugsorbiologics)

• Immuneresponsemodifiers(vaccines,cytokines,etc.)

• Interventivedevices

• Lifestylealterations.

Thedevelopmentalpathwaydiagramsoutlinetheprocessesthroughwhichfundamentalscientificdiscoveriesaretransformedintotheseclinicalmodalities.Thediagramsspecifykeyactivitiesanddecisionpointsalongthedevelopmentpath,clarifydependenciesamongdifferentstepsaswellaskeyeventsthatoccurinparallel,andshowimportantfeedbackloopsanditerativeprocessesthatareembeddedwithinthedevelopmentprocess.

TheprimarypurposeofthesepathwaysistofacilitateTRWGdiscussionsbyclarifyingcertainessentialcharacteristicsoftheearlytranslationprocess.TRWGmembershaveusedthemtohelpunderstandthechallengesfacedbytranslationalresearchersandtoidentifywaystohelpthetranslationalresearchprocessfunctionmoreeffectively.Forexample,thepathwaydiagramsstimulatedfruitfuldiscussionamongTRWGmembersandparticipantsinthefirstTRWGpublicroundtableaboutrelationshipsamongdifferentelementsofthetranslationalresearcheffort,resourcesneeded,andbarriersthatstandinthewayofmorerapidprogress.

Increatingthesepathways,theTRWGwasawarethatsuchidealizedrepresentationscannotcapturethefullcomplexityoftherealworld.Foreachactivity,decisionpoint,parallelpath,orfeedbackloop,itisunderstoodthattherearemanymorevariationsthatcanoccur—andindeedhaveoccurred—inpracticeandthatnotallstepsmayoccurineachinstance.Inaddition,thesediagramsdonotcapturethefullrangeofpossibleinteractionsbetweenthepathways,nordotheyaddressthewaysinwhichinsightsgainedfromlate-stageclinicaltrialscaninfluencethedevelopmentprocess.Finally,therehasbeennoattempttoaddresstheinfluenceofmarketconditions,projectedfinancialreturn,orreimbursementconsiderationsondevelopmentpathwaydecisionsmadeinthecommercialsector.

Tofacilitateunderstandingofthepathways,agenericpathwaytemplatewasalsocreatedwhichcapturesthecommonelementsofthepathwaysinsimplifiedform.Thegenericpathwayappliesequallytoboththeriskassessmentandtheinterventivemodalities.Notethat,forinterventions,someofthesupportingtoolsrequiredinthedevelopmentprocess(redboxintheright-handsequenceofthegenericpathway)arethemselvesriskassessmentmodalities.



Discovery with potential clinical application

Redirect researcheffort elsewhere

no

Fundamental research

no

yes

Does envisioned clinicalneed justify expenditure of resources?

yes

GenericDevelopmental

Pathway

ClinicalModalities

forOncology

NCI TRWGversion 060807

Box = ActionBox/Ellipse = Iterative Action

Diamond = Decision

noIs the empirical basis for

attributing clinical relevance convincing?("credentialed concept")

yes

Develop modality

Efficacy justifycontinued development?

Refine for safety /manufacturability /

deployability

no

yes

Early-stageclinical trials

Refine modalityfor efficacy

no

Applicablestandards

met?Can it

be fixed?

no

Is development processlikely to be feasible?

Decision to proceed

Supporting tools

Creation of modality

Preclinical development

Develop requiredsupporting tools

or systems

Clinical Trials

Dec

isio

nto

proc

eed

Supp

ortin

gto

ols

Cre

atio

nof

mod

ality

Prec

linic

alde

velo

pmen

tCl

inic

altri

als yes

Assesstarget

effects

Identify cohortthat would

benefit

Generic Developmental Pathway: Clinical Modalities for Oncology



Discovery of molecular biomarker with clinical potential


no


no

no

yes

Develop reproducibleassay and standard

reagent(s) forbiomarker or profile

Is it feasible to developthe protocol / reagent / device?

yes


DevelopmentalPathway

Biospecimen-BasedRisk Assessment

Devices(Protocols / Reagents /

Instruments)

Biomarkers forScreening,

Diagnosis, Staging,Response Assessment,Prognosis, Prediction


Box = ActionDiamond = Decision

no

yes

Validate assay and correlation of biomarker withoutcome retrospectively using a large number

of specimens in different labs

Develop /refineclinical grade

biomarker assayprotocol / reagent / device

Validate correlation ofbiomarker with outcome as

a primary or secondary endpointin a prospective human study

Human study of utility ofbiomarker to direct

therapy or chemopreventionor predict outcome / risk

Is correlationstatistically robust?

yes

no


yes

Can itbe fixed?

no

yes

no Outcome =Disease occurrenceDisease progressionResponse to therapy

Biomarker =Single gene / protein

Molecular profile

Sensitivity and specificityexpected to be sufficient for clinicalutility? ("credentialed biomarker")


yes

no

Define patient subset withbiomarker using assayon a limited number of

specimensin a single lab

Identify or developbiospecimenrepositorieslinked with

outcomes data

Biospecimen-Based Risk Assessment Devices (Protocols, Reagents, Instruments, etc.)




yes



Image-BasedRisk AssessmentAgent / Technique

Biomarkersfor Screening,

Diagnosis, Staging,Response Assessment,Prognosis, Prediction



yes

Fundamental / applied research

Discovery of imaing biomarker with clinical potential

yes

Does theagent requireradiolabeling?

Optimize acquisitionand analyticparameters

in preclinical orPhase 0 setting

Performradiolabeling,dosimetry, etc.

Preclinicalperformanceadequate?

Can itbe fixed?

no no

yes

agentyes

no

yes

Pre-IDE meeting forplatform if necessary

Clinicalperformanceadequate?

Can itbe fixed?

no

Establish GMP manufacturingif necessary

yes

yes

no

Clinical study requiredfor regulatory approval?

Optimized platform availablefor clinical testing,

file 510(k) if necessaryFile IDE if necessary,

perform study

Regulatoryapproval

yes

Phase II+ trialsfor specific

clinical utilities

no

Test / refine imagingperformance, PK/PD,

toxicology, etc. inpreclinical setting

Test / refine imagingperformance, PK/PD,

toxicology, etc. inPhase I/II setting

Does new or optimizedexisting system or platform need

regulatory approval?

Establish GMP productionfor agent if necessary

Submit INDif necessary

no

yes

Is it feasible to develop theagent or imaging technique?

Is there an existing imaging platformfor the agent or technique?

Develop necessary newimaging platform

(iterative with development ofagent / technique)

technique

Is the innovationan agent or

a technique?

no

Sensitivity and specificityexpected to be sufficient for clinical utility?

("credentialed biomarker")

no

no

no

yes

Image-Based Risk Assessment (Agents or Techniques)



Discovery of target with clinical potential


no


Develop and validateassay and standardreagents or imaging

biomarkers to measurebiological response*

no

yes

Implement experimentalsystem to assess impact

of perturbing target

Does influencingtarget decrease oncogenic

activity?

yes

no

Identify candidateagents and screen forbinding and influence

on activity

Toxicity acceptable?Can itbe fixed?

no

yes

Identify or developreproducible assay

for effect on oncogenicactivity

Identify marker(s)that define(s)patient subset

with target

Characterize statisticalcorrelation of markerswith outcomes, select

optimal marker orprofile

Is correlationclinicallyrelevant?

Validate assay orimaging biomarker

for identifyingpatient cohort

yes

no

Is the empirical basis forattributing clinical potential alone and/or

in combination convincing?("credentialed target")

Is it feasible to identify/develop an agent against the target?

yes


yes

Activity / PK justifycontinued development?

yes

no


Agent(Drug or Biologic)

for

Therapy or Prevention


Box = ActionBox/Ellipse = Iterative Action

Diamond = Decision

no

Identify or developclinically- or target-

relevant cellculture system

and/or animal model

Select most promisingcandidates... Refine structure

based on random modification /screening or structure-based design... Assesscombinations...Identify

lead candidate

Conduct initial toxicology screenDevelop and

validate assay andstandard reagents orimaging biomarkers

to measuremolecular endpoint

in humans*

Identify or developbiospecimen /

image repositorieslinked with

outcomes data


and standard reagentsor imaging biomarkers

for target*

no

Agents (Drugs or Biologics) page 1 of 2



Process development / Pilot manufacturing

Implement GLP / GMP manufacturing

Definitive toxicityacceptable?

Submit IND

Phase I / IIClinical Trials

Verify activity / PK

Verify activity / PK / stability / QC

Conduct definitive toxicology screen

yes

yes

yes

no

yes

Activity / PK preserved?Can itbe fixed?

yes

no

Can itbe fixed?

Activity / PK / stability/ QC OK?

no

yes

no

no

*see Biospecimen RADand Imaging Pathways

Agents (Drugs or Biologics) page 2 of 2



Redirectresearch

effort elsewhere

no


no

Measure response toimmune response modifier

yes

Process development / Pilot manufacturingand scale-up

yes


yes


ImmuneResponse Modifiers

(Vaccines,Cytokines, etc.)

for

Therapyor Prevention



no Is the empirical basis for attributingclinical potential convincing?

("credentialed immune modifier")

Measure response toimmune response modifier

Can itbe fixed?

nono

Lead immune response modifier candidate

Is it feasible to identify/develop an immune response modifier?

Identify ordevelop

delivery vehicle(vector, cell, etc.)

Characterizeand/or modify

antigen(s)

Develop immuneresponse modifier

Activity sufficient towarrant continued development?

Refinedeliveryvehicle

Refineantigen(s)

yes

yes

Refineimmunemodulator

Activity sufficient towarrant continued development?

Identify or developclinically-relevant

cell culture systemand/or animal model

no

Refine immuneresponse modifier

and / orimmunization strategy

Discovery of antigen or other immune modifierwith clinical potential in specific cancer(s)

Identify or developimmune modulator(adjuvant,cytokine,chemokine, etc.)

Identifypatient subsetwith immune

target

Characterize statisticalcorrelation of target

with outcomes


Identify ordevelop

reproducibleassay andstandard

reagents orimaging

biomarkersfor immune

target*

Identify ordevelop

biospecimen /image

repositorieslinked withoutcomes

data

Develop andvalidate assayand standardreagents or

imagingbiomarkers to

measuremolecularendpoint

in humans*

Develop/validateassay and standard

reagents orimaging biomarkers

to measureresponse

to immuneresponse modifier*

no

yes

Validateassay orimaging

biomarkers foridentifying

patient cohort

Immune Response Modifiers (Vaccines, Cytokines, etc.) page 1 of 2



Implement GLP / GMP manufacturing

Submit IND

Phase I / IIClinical Trials

Activity preserved?

Verify activity

Can itbe fixed?

nono

Verify activity

Activity preserved?Can itbe fixed?

nono

yes

yes

yes

Note: This pathway is designed to accommodate immuneresponse modifiers of two types: "simple" (such as a cytokine useddirectly as a therapeutic agent) and "composite" (such as a vaccinethat incorporates an antigen, a vector and an immune modulator).For simple agents, the extra boxes that are incorporated in thediagram to capture parallel development of the components of

a composite product may be ignored.

*see Biospecimen RAD and Imaging Pathways

Conduct toxicology screen

yes

Toxicityacceptable?

yes

no

Immune Response Modifiers (Vaccines, Cytokines, etc.) page 2 of 2



Technology innovation or innovativeapplication of existing technology


no

no

no

yes

Is it feasible to developthe technology?

yes



InterventiveDevice



yes

Test on phantomsand / or animals

Define usageprotocol for humans

Build / refine clinical-grade device

Phase I trials(proof of principle)

Does technologyfunction as intended?

yes

Analyze technologyutility in laboratory

Fundamental / applied research

Is the empirical basis forattributing clinical potential convincing?

("credentialed technology")

Build / refineprototype

device

Can itbe fixed?

no

yes

no

Regulatory submission

Test on phantomsand / or animals

Does technologyfunction as intended?

yes

Can itbe fixed?

no

yes

"Phase zero"tests on humans

Identify marker(s)that define(s)patient subset

with target

Characterize statisticalcorrelation of markerswith outcomes, select

optimal marker orprofile


Validate assay orimaging biomarker

for identifyingpatient cohort

no

Identify or developbiospecimen /

image repositorieslinked with

outcomes data

yes


and standard reagentsor imaging biomarkers

for target*

Develop and validateassay and standardreagents or imaging

biomarkers to measurebiological response*

Develop andvalidate assayand standardreagents or

imagingbiomarkersto measuremolecularendpoint

in humans*


no

Interventive Devices



Discovery of correlation between behavior or exposure and disease


no

yes

yes


LifestyleAlteration



Does lifestyle alterationhave intended effect?

yes

Laboratory / epidemiological research

Is empirical basis for attributingcausal effect consistent across diverse

populations and study designs?("credentialed discovery")

Can itbe fixed?

nono

Identify correspondinghuman

lifestyle alteration

Identify targetpopulation via

existing databasesor new studies

Pilot studyto assess

effectiveness oflifestyle alteration

Study of effectivenessin larger, more

diverse population

Refinelifestyle

alteration

yes

yes

no

Evaluateeffect in

animal model

Develop and validatebiochemical,

behavioral and/orimaging "assays"to measure effect

of lifestyle alteration*

This diagram is intended to characterize the identification ordevelopment of lifestyle alterations that address behaviors(e.g., tobacco use, dietary patterns, sun / UV exposure)

or environmental exposures (e.g., toxic chemicals)associated with cancer.


Is there arelevant animal model?


Can a specific lifestylealteration be identified that

would mitigate the risk factor?

yes

no

no

Lifestyle Alterations


Report of the NCAB Translational Research Working Group—Appendix D

Appendix D: Translational Research Portfolio for the NCI Translational Research Working Group

Introduction and Summary

TheNationalCancerInstitute(NCI)supportsresearchthatspansbasicthroughclinicalinvestigations.Specificresearchawardsmaypredominantlyaddressbasicresearch,translationalresearch,clinicalresearch,oracombination.TheNCI’sfiscalyear2004researchportfoliowasanalyzedtounderstandtheInstitute’soveralleffortintranslationalresearch,informthedeliberationsoftheNCITranslationalResearchWorkingGroup(TRWG),andserveasapilotforfutureeffortsatanalyzingtranslationalresearch.ThisdocumentpresentsthemethodsusedforidentifyingNCI’stranslationalresearchawardsandprogramsandthesummarizedresultsoftheanalysis.

Key Findings

1. Theportfolioanalysisidentifiedawardsvaluedat$1.3billion(relativetoatotalNCIresearchbudgetof$4.4billioninFY20041)thatfittheinclusioncriteriafor“translationalresearch”(seesubsequentdiscussionforspecificcriteria).Asthecriteriawereappliedexpansively—includingas“translational”allawardsthathadanytranslationalcomponent—theportfoliolikelyoverestimatesthevalueofNCI-sponsoredtranslationalresearch.Amoredetailedassessmentofasampleof65R01awardsforthedegreeoftheirtranslationalresearchrelevance(seepage114,ValidityofTranslationalResearchFundingEstimate)suggeststhatthisestimateofoverallfundingfortranslationalresearchmaybehighby20-40%.

2. Awardsidentifiedas“translational”aredistributedthroughouttheInstitute.AllNCIaward-sponsoringOffices,Centers,andDivisionsfundtranslationalresearch,tovaryingdegrees(Figures1A,1B,and1C).

3. Awardsidentifiedas“translational”aredistributedacrossmanydifferentfundingmechanismstovaryingdegrees(Figures2A,2B,and2CandTables1and2).Approximatelythesamedollarvalueof“translational”fundsisawardedthroughprogramandcooperativeawardmechanismsandthroughindividualresearchawards.

4. Themajorityof“translational”fundsareawardedtoinstitutionswithNCI-designatedcancercenters(Figures3Aand3B).ThepercentageofNCIfundingidentifiedas“translational”atbothinstitutionswithNCI-designatedcancercentersandthosewithoutthemissimilar(Figure3C).

Methodology

Criteria for Including Awards as “Translational Research”

ThescopeofactivityoftheTRWGcanbedefinedas“earlytranslation”basedonthecontinuumdevelopedbythePresident’sCancerPanel.2Withthisandtheinterestincapturingthebroadestpossiblelandscapeinmind,criteriaweredefinedtoidentifyawardstobeincludedintheanalysis.Anawardabstractthatmetatleastoneoftheinclusioncriteriaforasinglespecificaimwasconsidered“translational,”evenifasignificantportionoftheproposedworkdidnotmeetthecriteria.Generally,awardswereidentifiedas“translationalresearch”basedontheawardabstractproposingtoconductresearchthatwouldresultinmovingadiscoveryalongthepathwaytoadefinedclinicalgoalorproductaccordingtothebench-to-bedsidemodel,includingusingclinicalresearchresultstoguidebasiclaboratorystudies.Ifanawardabstractdidnotmeetanyoftheinclusioncriteria,theawardwasnotconsideredtranslational.

Thefollowingcriteriawereusedtoidentifyawardstobeincludedintheportfolio:

1 “FactBook,”NationalCancerInstitute,2004,pageB-2.Availableat:http://fmb.cancer.gov/financial/04Factbk.pdf.ThetotalNCIbudgetinFY2004was$4.�billion,fromwhichthe$329millionfor“ProgramManagementandSupport”wasexcluded.

2 http://deainfo.nci.nih.gov/advisory/pcp/pcp04-05rpt/ReportTrans.pdf.



• Studiesofagents,includingchemical,biological,immunologic,imaging,etc.,atanystagefromevaluatingtheagentinrelevantmodelsystemsthroughPhaseIIclinicaltrials

• Studiesofmarkersandassaystomeasuretheefficacyofanagentorinterventivedevice,atanystagefromdevelopmentofanassaytotestingforclinicalutilityinpreclinicalandclinicalstudies

• StudiesofinterventivedevicesanywherealongthecontinuumfrombuildingacompleteprototypedevicetotestingadeviceinPhaseIIclinicaltrialsinhumans

• Studiesofbiomarkersandassaysfordetection,diagnosis,prognosis,andpredictionanywherealongthepathfromepidemiologicfindingstoatrialoftheclinicalutilityofthemarkerinhumans

• Studiesofimagingdevicesanywherealongthecontinuumfrombuildingacompleteprototypedevicetotestingtheclinicalutilityofthedeviceinhumans

• Endogenous(e.g.,geneticandmolecular)andexogenous(e.g.,viral,dietary,environmental)epidemiologicstudiesinvolvingasamplepopulationofatleast150cases

• Awardsthatincludethecreationorexpansionofrepositoriesofcohortdataand/orspecimenbanks

• Lifestyle,dietary,orbehavioralstudiesthatdevelopandvalidateortestaninterventionforcancercontroland/orpreventionpurposes(e.g.,tobaccousecessation,changestodiet/exercise,increasedparticipationincancerscreening)

• “Bedside-to-bench”studiesinwhichresultsfrompreclinicalandclinicalstudiesofagentsanddevicesareusedtoenhancethecapacitiesoftheagentsordevices,includingtheevaluationofbasicmechanismsnewlyinspiredbythepreclinicalorclinicalstudies

• Awardsforcorefacilitiesandsharedresourcesinvolvedintranslationalresearch

• AwardsthatproposetoconductPhaseIand/orPhaseIIclinicaltrials

• PhaseIIIclinicaltrialawardsthatincludeacorrelativeresearchcomponent.

Thefollowingareexamplesoftypesofawardsthatwerenotconsidered“translational”—awardsthatfellonlyintothesecategorieswereexcludedfromthetranslationalresearchportfolio:

• Discoveryormechanisticstudies

• Studiesdesignedentirelytodevelopamodel,whetherbiologic,population,statistical,orothertype

• Small-scale,hypothesis-generatingepidemiologystudies

• Developmentoftoolstoenablebasicorclinicalresearch(e.g.,computersoftware,nonclinicalassays,enhancementstoproteomics/arrays)

• Late-phaseclinicaltrials,withnoindicationofcorrelativecomponents

• Surveillance,survivorship,andoutcomesresearch

• Studiestodevelopcomponentsofnewdevices/assaysbutnottodevelopacompleteprototypedeviceorassay

• Developmentofeducationalmaterialsforcareprovidersorgeneralcancereducationalmaterials—materialsnotdirectlyintendedtochangeabehaviortocontrolorpreventcancer

• Studiesthatreferencelong-termtranslationalgoalssubsequenttothecurrentgrantfundingperiod

• Awardsforwhichtheabstractisambiguousorunavailable.



Data Collection

TheanalysiswasbasedonallawardsactiveinFiscalYear2004ascontainedintheCancerResearchPortfoliodatabasesystem.3

Analyzingresearchprojectsrequireseitherusingdatafromanestablishedcodingsystemorevaluatingresearchprojectabstractstoclassifytheprojects.Translationalresearchisnotcapturedinanyofthecodesappliedtogrants,suchasSpecialInterestCategory(SIC)orNIHClinicalAspect(NIHCA)codes;therefore,individualprojectabstractswereevaluatedtoidentifythetranslationalgrants.Projectswerefilteredtolimittheanalysistothesubsetoftheportfoliomostlikelytoincludetranslationalresearchprojects.Asetoffundingmechanismsandinitiativeprogramswasentirelyincludedintheanalysisduetothefocusedtranslationalnatureoftheprograms(e.g.,SpecializedProgramsofResearchExcellence[SPOREs],SmallBusinessInnovationResearch[SBIR]/SmallBusinessTechnologyTransfer[STTRs],RapidAccesstoInterventionDevelopment[RAID]).Forotherfundingmechanisms,theNIHCA4codewasusedtofiltertheprojectstoanalyzeonlythosewith25%-100%clinicalaspect.Otherfundingmechanismswereentirelyexcludedduetoeithertheunavailabilityofabstracts(e.g.,contractawardssuchastheN01mechanism)ortheiremphasisonnonresearchgoals(e.g.,trainingandeducationawardssuchasT32andR25).

Thefollowingawardcategorieswereincludedwithoutreviewofabstractsorspecificapplicationoftheinclusioncriteriadueto(1)thelackofdetailinprojectabstractsandtheperceptionthatthesearetranslational,and(2)theinclusionofPhaseIandIIclinicaltrialsastranslationalresearch:

• AllClinicalandComprehensiveP30CancerCenters(butnoBasicCancerCenters)

• AllK12mechanismclinicaloncologyresearchcareerdevelopmentawards

• AllprojectsoftheRAIDandDrugDevelopmentGroup(DDG)programs,sponsoredbytheNCI’sDevelopmentalTherapeuticsProgram

• AllprojectsoftheRapidAccesstoPreventiveInterventionDevelopment(RAPID)program,sponsoredbytheNCI’sDivisionofCancerPrevention.

Inthefollowingawardcategories,abstractswerereviewedfortranslationalcomponentsaccordingtotheinclusionandexclusioncriteria:

• Allawardsfundedthroughthefollowinginitiatives:SpecializedProgramsofResearchExcellence,EarlyDetectionResearchNetwork(EDRN),MouseModelsofHumanCancersConsortium(MMHCC),NetworkforTranslationalResearch:OpticalImaging(NTROI),In VivoCancerMolecularImagingCenters(ICMICs),andIntegrativeCancerBiology(ICB)

• AllPhase1andPhase2SBIRandSTTRawards(mechanismsR41,R42,R43,andR44)

• Allintramuralresearchawards(CenterforCancerResearch[CCR]and“Parent”DivisionofCancerEpidemiologyandGenetics[DCEG])

• R24andU24Corefacilityawards.

3 TheCancerResearchPortfolio(CRP)isapublicWebsitewithinformationoncancerresearchandfundingopportunitiesgatheredfromtheNIH-wideInformationforManagement,Planning,Analysis,andCoordination(IMPACII).TheCRPismanagedthroughtheNCIOfficeofSciencePlanningandAssessment.

4 NIHCAcodesarequartile-basedmeasures,assignedbyNCI’sResearchAnalysisandEvaluationBranch(RAEB),oftherelevanceofprojectstotheNIHdefinitionofclinicalresearch.NIHdefineshumanclinicalresearchasfollows:(1)Patient-orientedresearch.Researchconductedwithhumansubjects(oronmaterialofhumanoriginsuchastissues,specimens,andcognitivephenomena)forwhichaninvestigator(orcolleague)directlyinteractswithhumansubjects.Excludedfromthisdefinitionarein vitrostudiesthatutilizehumantissuesthatcannotbelinkedtoalivingindividual.Patient-orientedresearchincludes:(a)mechanismsofhumandisease,(b)therapeuticinterventions,(c)clinicaltrials,or(d)develop-mentofnewtechnologies.(2)Epidemiologicandbehavioralstudies.(3)Outcomesresearchandhealthservicesresearch.



Inthefollowingawardcategories,onlyawardswith25%-100%NIHCAcodeswerereviewedfortranslationalcomponentsaccordingtotheinclusionandexclusioncriteria:

• K01,K05,K07,K08,K22,K23,andK24careerdevelopmentawards

• P01,P20,R01,R03,R21,R33,R37,U01,U19,U54,andU56awards.

AwardscodedastranslationalwerestratifiedusingthesponsoringDivision,thecommonscientificoutline(CSO)codes,andtheinstitutionswheretheresearchgrantsareheldtoidentifypatternsoftranslationalresearchprojects.Forexample,researchinstitutionswereaggregatedintothreecategoriesbasedontheavailableinstitutionaldata.Alltranslationalintramuralawardswerecollectedinonecategory,andthetranslationalextramuralawardsweredividedintotwocategories—thosewheretheresearchgrantswereheldatclinicalandcomprehensiveNCI-designatedcancercentersandthosewherethegrantswereheldatotherinstitutions(includingbasiccancercenters).

Assessment of Inclusion Criteria—P01/R01 Analysis

TogaininsightintothevalidityoftheclassificationsystemforP01andR01awards,twoanalyseswereundertaken.First,NCIprogramdirectorsidentifiedawardsintwogroups:translationalandnottranslational.TheyidentifiedatotalofsevenP01awardsastranslationaland11P01awardsasnottranslational.Foreachoftheseawards,theclassificationassignedbytheprogramdirectorswascomparedwiththeclassificationofthesesameawardsintheoriginalportfolioanalysisbasedonreviewoftheabstracts.Inthisexercise,sixofthesevenP01awardsidentifiedastranslationalbytheprogramdirectorshadalsobeencodedastranslationalduringtheoriginalportfolioanalysis.Moreover,9ofthe11P01awardsidentifiedasnottranslationalbytheprogramdirectorshadalsobeencodedasnottranslationalduringtheoriginalportfolioanalysis.

Second,asetof36R01awardsactiveinFY2004wereidentifiedbyTRWGmembersastranslationalawards.Theclassificationoftheseawardsbasedonabstractreviewduringtheoriginalportfolioanalysiswasasfollows:

• Thirtyawardshadbeenclassifiedastranslational.

• Twoawardshadbeenclassifiedasnottranslational.

• Fourawardswerenotincludedintheabstractreviewbecausetheyhada0%NIHCAcode.

TheseresultsindicatethattheinclusioncriteriawerereasonablyaccurateinidentifyingawardsthatwouldbeconsideredtranslationalbyNCIprogramdirectorsandTRWGmembers.

Validity of Translational Research Funding Estimate

Togaininsightintotheaccuracyofthetranslationalresearchfundingestimate(seeTable1),100randomlyselectedawardsfromthelistofR01awardsclassifiedastranslationalintheoriginalportfolioanalysiswereevaluatedfortheextenttowhichtheyweretrulytranslationalbasedonspecificaims.Ofthe100awards,65weredeterminedtohaveabstractsthatclearlyidentifiedspecificaims.Eachofthese65awardabstractswasreviewedasecondtimetoassesstheextentoftranslationalresearchrelevanceandassignedatranslationalscoreaccordingtothepercentofthespecificaimsthatwereconsideredtranslational.Ofthe65awardsreviewed,40receivedtranslationalscoresof76%-100%,eightreceivedscoresof51%-75%,13receivedscoresof26%-50%,andtworeceivedscoresof1%-25%.Theremainingtwoprojectspreviouslyidentifiedastranslationalbasedontheoriginalabstractreviewwereconsideredtohavenotranslationalcomponentsinthissecondreview.Applyingthesetranslationalscorestocalculateaweightedaverageoftranslationalcharacterforthissetofawardssuggeststhattheoverallestimateoffundsattributabletotranslationalactivitymaybeoverstatedbyapproximately20-40%.



Findings: Translational Research Awards by Award Category

Table1(page11�)summarizesbymechanismtheawardscodedas“translational.”Themechanismsarealsogroupedbyawardcategory.Thesecondcolumnidentifiesthenumberofactiveawardsidentifiedas“translational”accordingtothecriteriadiscussedearlier.ThethirdcolumnidentifiesthetotalnumberofactiveawardsinthatmechanisminFY2004.Thefourthcolumnistheresultofdividingcolumn2bycolumn3,toshowthepercentageofawardsinthatmechanismidentifiedastranslational.ThefifthcolumnshowsanestimateofthetotalfundinginFY2004fortheawardscodedastranslational.

“Awardsforcorefacilitiesandsharedresourcesinvolvedintranslationalresearch”wasoneoftheinclusioncriteriaemployed.Thatcriterionidentifiedasetofawardmechanismsthatfundresearchinfrastructure,includingtheCancerCenters(P30mechanism)andR24andU24awards.Astheseinfrastructureawardsmaybeusedforpurposesspanningbasic,translational,andclinicalresearch,theywereseparatedfromthosemechanismsintendedtofundtranslationalresearchprojects.TheseinfrastructureawardsaresummarizedinTable2(page118).Itwasalsonotedthatmanyofthecollaborativeresearchmechanisms(e.g.,P01,andP50)alsofundcorefacilitiesasonefacetoftheoverallaward.Therefore,thesecorefacilitieswereevaluatedforthedegreetowhichtheysupportedtranslationalresearch,andtheresultsareincludedinTable2.

Future Considerations for Translational Research Analysis: Recommended Improvements in Award Coding System to Facilitate More Accurate Analysis of Translational Research Portfolio

Whentheportfolioanalysisexercisewasprepared,itrevealedthattherewasnoexistingcodingsystemthatcapturedtranslationalresearch;theTRWGthereforedevelopedanadhocsystemtosupportitsdeliberations.Theadhocsystemwaslabor-intensivetoapplyandresultedinasetoffindingsthatsomeTRWGmembersfoundtobecounterintuitive(especiallytheoverallsizeoftheenterpriseandthesubstantialamountoftranslationalresearchconductedunderindividualinvestigatorawards).Managingtranslationalresearchmoreeffectivelyinthefuturerequiresamorelogisticallystraightforwardandpreciselydefinedmethodforcodingawardsastranslationalresearch.Tothatend,thefollowingrecommendationsaremade.

1. New coding methods need to be developed to identify, classify, and categorize “translational research.” AsshowninFigure4,awardsidentifiedas“translational”aredistributedacrossNCI’sCSOcodes.Figures5Aand5Bshowthatawardsidentifiedas“translational”aredistributedacrossNIHCAcodesaswell.Moreover,analysisoftheR01awardsdesignatedastranslationalbyTRWGmemberssuggeststhatthe0%NIHCAcodealsocontainssometranslationalprojects.Figure5BsuggeststhatNIHCAcodesareapartiallyeffectivefilter,however,asthelikelihoodofbeingidentifiedas“translational”increasedfromtheNIHCA25%quartiletothe�5%quartile.5Thedifficultyinusingstandardcodingmechanismsinclassifyingresearchas“translational”or“nottranslational”suggeststhatnewmechanismsneedtobedevelopedtoidentify,classify,andcategorize“translationalresearch.”Itwillbeimportanttocodeseveralspecificaspectsoftranslationalresearch(e.g.,studypopulationbyorgan,stageofcancerdevelopment,intendedclinicalgoal(s)—riskassessmentdevice,interventionagent,interventiondevice,immunologicintervention,lifestylemodification,andmechanisticpathwayunderinvestigation)inaconsistentmanner.

2. Precise definitions of translational research and subcomponents of translational research and specific examples of both translational and nontranslational awards will be required as part of developing any new coding process. OperationalizingtheTRWG’sinclusioncriteriafortranslationalresearchproveddifficultevenwhenindividualawardabstractswerereviewed.However,theexercisesperformedtoassesstheinclusioncriteriasuggestthatreviewofabstracts,thoughlaborious,resultedinjudgmentsconsistentwiththoseofscientistscloselyassociatedwiththeindividualprojects.

5 Figure5C,however,showsthatonly1%ofNCIawardsactiveinFY2004wereclassifiedasbeinginthe�5%NIHCAquartile.



3. A database needs to be created that completely and accurately collects the current status of core facilities and infrastructure, captures their total dollar value or number, and allocates their usage to basic, translational, and clinical research. Corefacilitiesandinfrastructurearefundedthroughmanymechanisms.ThedollaramountsforP30,R24,andU24awardscanbecaptured,buttheseawardsarenot100%infrastructure.ItisalsopossibletodeterminethenumberofP30,P50,andP01coresbutnotthedollarsassociatedwiththem.Moreover,anycoresassociatedwithR01,U-seriesmechanisms,etc.,arenotcapturedatanylevel.Forthereasonsdiscussedearlier,italsoproveddifficulttoclassifycorefacilitiesandinfrastructureaseither“translational”or“nottranslational.”

4. A database needs to be created that completely and accurately tracks and codes the individual components and projects of multiproject mechanisms (e.g., P01, EDRN, SPORE, and P30 awards).



Award Category Awards Coded as Translational

Total Active Awards*

% of Active Awards Coded as

Translational

Estimated Funds in FY04 for

Translational Awards ($M)

Program and Cooperative Awards

P01 107 207 51.7 215.0P20 8 34 23.5 3.0SPORE (P50) 58 58 100.0 131.7ICMIC (P50) 7 7 100.0 15.8EDRN (U01/U24) 28 28 100.0 21.8MMHCC (U01) 10 23 43.5 8.1Other U01 122 209 58.4 98.6U19 5 18 27.8 3.7NTROI (U54) 3 3 100.0 3.8Other U54 10 19 52.6 13.0U56 4 40 10.0 1.6DDG projects 18 18 100.0 11.1RAID projects 45 45 100.0 16.3RAPID projects 19 19 100.0 3.1

Career Development

K01 14 116 12.1 1.9K05 1 19 5.3 0.1K07 37 93 39.8 4.8K08 21 139 15.1 2.5K12 21 21 100.0 8.8K22 13 42 31.0 1.4K23 55 64 85.9 6.8K24 25 34 73.5 2.2

Individual Research

R01 1,161 4,450 26.1 447.0R03 150 320 46.9 8.1R21 288 599 48.1 43.8R33 62 121 51.2 24.2R37 11 74 14.9 6.6

Small Business

R41 (STTR Phase 1) 28 42 66.7 4.7R42 (STTR Phase 2) 12 19 63.2 3.8R43 (SBIR Phase 1) 87 246 35.4 13.3R44 (SBIR Phase 2) 102 176 58.0 39.4

Intramural

Z01 257 630 40.8 164.4

Total 2,789 7,933 35.2 1,330.4

Table 1. Awards Identified as Translational by Project Funding Mechanisms

* Totalawardsidentifiedasbeingactiveinfiscalyear2004fromtheCancerResearchPortfolio(intramuralawardsandinitiativeprogramslikeICMIC),theDevelopmentalTherapeuticsProgram(DDGandRAID),theDivisionofCancerPrevention(RAPID),andtheResearchAnalysisandEvaluationBranch(allothermechanisms).



Table 2. Awards Identified as Translational by Infrastructure Funding Mechanisms

Award Category Awards Coded as Translational

Total Active Awards*

% of Active Awards Coded as

Translational

Estimated Funds in FY04 for

Translational Awards ($M)

Infrastructure*

P30 Cancer Centers 54 61 88.5 212.5R24 8 43 18.6 1.5U24 (excluding EDRN) 8 14 57.1 6.0Total 70 118 61.0 220.0

Extramural Core Facilities

Core Facilities supported through SPORE, P30, and P01 awards† 1,165 1,364 85.4 N/A

* Itshouldberecognizedthatsomeindividualawardsof“projectfunding”mechanismsareinfactusedtofundinfrastructure(e.g.,14Z01andtwoU54awardswereidentifiedthatweresolelyforinfrastructuralpurposes)andsomeCancerCenterfundsareusedtosupportprojects.

† TheExtramuralCoreFacilitiessectionshowsnumbersforthecorefacilitiesidentifiedatSPOREs,comprehensiveandclinicalP30s,andtransla-tionalP01s(AwardsCodedasTranslational)andatallSPOREs;basic,comprehensive,andclinicalP30s;andtranslationalandnontranslationalP01s(TotalAwardsReviewed).ThenumberofcorefacilitiesisnotdirectlyrelatedtotheestimatedFY2004fundingoftheInfrastructureawardcategory,whichdoesnotincludefundsforSPOREsandP01s.

Appendix Figures: Cross-Tabulations of NCI Translational Research Portfolio

Figure 1A. Percentage of the total 2,789 project funding awards identified as translational in FY 2004 supported by each NCI Division, Center, and Office.

* OfficeoftheDeputyDirectorforExtramuralScience(DDES)includestheOfficeofCenters,TrainingandResources(CancerCentersandSPOREs),theOfficeofCancerComplementaryandAlternativeMedicine,andtheOfficeofGrantProgramCoordination.

DDES* 9%

CCR 8%

DCB 11%

DCCPS 22%

DCTD 39%

DCP 9% DCEG

2%



Figure 1B. Percentage of the total $1.33 billion in funding identified as translational in FY 2004 supported by each NCI Division, Center, and Office.

Figure 1C. Percentage of total FY 2004 funding in each NCI Division, Center, and Office identified as translational.*

* MostawardswithNIHCAcodesof0%wereexcludedfromthereview;however,thepercentagesshowninthefigurearebasedonthetotalnumberofactiveawardsinFY2004foreachDivision,Center,orOffice.Therefore,thepercentagesrepresentminimalpercentagevalues.TheextentthatprojectswithNIHCAquartileof0%aretranslationalwasbeyondthescopeofthisanalysis.

DDES 13%

CCR 7%

DCB 8%

DCCPS 19%

DCTD 39%

DCP 9%

DCEG 5%

DDES DCB DCEGCCR DCCPS DCP DCTD



Figure 2A. Percentage of the 2,705 awards identified as translational in FY 2004 that are funded through the major funding mechanisms.*

* Thenumberofawardsisdifferentfromthetotalnumberofawardsidentifiedastranslational(2,�89)duetoexclusionof82RAID,RAPID,andDDGprojectsactiveinFY2004thatwereprimarilyfundedthroughcontractsandnotthroughthemajorfundingmechanismcategoriesandtwoEDRNU24infrastructure-basedawardsthatalsodidnotmatchthemajorfundingmechanismcategories.

Individual Research Awards (R01, R03, R21, R33, and R37)

62%

Intramural Awards 10%

Career Development Awards (K-series)

7%

Program and Cooperative Awards (P01, P50, U01,

and other U-series) 13%

Small Business Awards (R41–R44)

8%

Included:CareerDevelopmentAwards(K-awards),ProgramandCooperativeAwards(P01,P20,P50,U01,U19,U54,andU56),SmallBusinessAwards(R41–R44),IndividualResearchAwards(R01,R03,R21,R33,andR37),andIntramuralAwards.Notincluded:RAID,RAPID,DDG,andU24EDRNawards.

Figure 2B. Percentage of the $1.30 billion in funding identified as translational in FY 2004 supported through the major funding mechanisms.


40%

Intramural Awards 13%

Program and Cooperative Awards (P01, P50, U01,

and other U-series) 40%

Career Development Awards (K-series)

2%

Small Business Awards (R41–R44) 5%

Included:CareerDevelopmentAwards(K-awards),ProgramandCooperativeAwards(P01,P20,P50,U01,U19,U54,andU56),SmallBusinessAwards(R41–R44),IndividualResearchAwards(R01,R03,R21,R33,andR37),andIntramuralAwards.Notincluded:RAID,RAPID,DDG,andU24EDRNawards.



Figure 2C. Percentage of total FY 2004 funding within each award mechanism that was identified as translational.*

* AmajorityofindividualresearchawardswerenotreviewedbecausetheyhadtheNIHCAquartileof0%,whileamajorityofawardsintheothermechanismcategorieswerereviewed.Thepercentagesinthisfiguremaybeconsideredminimalpercentages,asinFigure2A(seefootnote6onpage25).

Included:CareerDevelopmentAwards(K-awards),ProgramandCooperativeAwards(P01,P20,P50,U01,U19,U54,andU56),SmallBusinessAwards(R41-R44),IndividualResearchAwards(R01,R03,R21,R33,andR37),andIn-tramuralAwards.Notincluded:RAID,RAPID,DDG,andU24EDRNawards.

Career Development

Awards (K-series)


Intramural Awards

Program and Cooperative

Awards (P01, P50, U01, and other U-series)

Small Business Awards

(R41–R44)

Figure 3A. Percentage of the 2,707 project funding awards identified as translational in FY 2004 made to major categories of institution.*

Non-Cancer Center Institute 35%

NCI-Designated Cancer Center

56%

Intramural Research 9%

Included:Researchawardstoinstitutionsdesignatedascomprehensiveorclinicalcancercenters,researchawardstoinstitutionsnotdesig-natedascomprehensiveorclinicalNCIcancercenters,andNCIintramuralawards.Notincluded:RAID,RAPID,andDDGawards..

* Thenumberofawardsisdifferentfromthetotalnumberofawardsidentifiedastranslational(2,�89)duetoexclusionofthe82RAID,RAPID,andDDGprojects.



Figure 3B. Percentage of the $1.30 billion in funding identified as translational in FY2004 awarded to major categories of institution.

Non-Cancer Center Institute 31%


56%

Intramural Research 13%

Included:Researchawardstoinstitutionsdesignatedascomprehensiveorclinicalcancercenters,researchawardstoinstitutionsnotdesig-natedascomprehensiveorclinicalNCIcancercenters,andNCIintramuralawards.Notincluded:RAID,RAPID,andDDGawards..

Figure 3C. Percentage of total FY 2004 funding at major categories of institutions that was identified as translational.


Non-Cancer Center Institution

Intramural Research



Figure 4. Percentage of the total 2,789 project funding awards identified as translational in FY2004 cross-tabulated by the seven major CSO categories.*

* AwardsassignedtotwoormoreCSOcategoriesarecountedtowardallassignedcategories.

Prevention 13%

Early Detection, Diagnosis, and Prognosis

19%

Biology 8%

Model Systems

1%

Etiology 20%

Treatment 34%

Figure 5A. NIHCA quartile of the 2,296 project funding awards active in FY 2004 that had a 25%-100% NIHCA code and were identified as translational.*

Included:AllactiveextramuralawardswithNIHCAquartileassignmentsof25%-100%identifiedastranslational.Notincluded:AwardsandprojectsnotassignedNIHCAcodes,includingintramuralawards(CCRandDCEG),RAID,RAPID,andDDGprojects,andawardswith0%NIHCAquartile.

* ProjectswithNIHCAquartileof0%werenotincludedbecauseonly8%oftheseawardswerereviewedtoidentifytranslationalresearchprojectsandthesetofprojectsreviewedisnotarepresentativesamplingofthe0%NIHCAawards.Examiningallsuchprojectswasbeyondthescopeoftheportfolioanalysis.

NIHCA = 100 56%

NIHCA = 25 22%

NIHCA = 50 19%

NIHCA = 75 3%

Cancer Control, Outcomes, and

Survivorship 5%



Figure 5B. Percentage of awards in each NIHCA quartile identified as translational.*

* CertainclinicalresearchU-seriesprograms(e.g.,PhaseIU01trialists,AmericanCollegeofRadiologyImagingNetwork[ACRIN],thecooperativegroups,andCommunityClinicalOncologyPrograms[CCOPs])arenotintendedtobecoveredbythisinitiative.

Included:AllactiveextramuralawardswithNIHCAquartileassignmentsof25%-100%identifiedastranslational.Notincluded:AwardsandprojectsnotassignedNIHCAcodes,includingintramuralawards(CCRandDCEG),RAID,RAPID,andDDGprojects,andawardswith0%NIHCAquartile.

NIHCA = 100NIHCA = 25 NIHCA = 50 NIHCA = 75

Figure 5C. Percentage of all active FY 2004 extramural project funding awards by NIHCA quartile.

NIHCA = 50 9%

NIHCA = 25 14%

NIHCA = 100 25%

NIHCA = 75 1%

NIHCA = 0 51%

Notincluded:AwardsandprojectsnotassignedNIHCAcodes,includingintramuralawards(CCRandDCEG),RAID,RAPID,andDDGprojects.


Report of the NCAB Translational Research Working Group—Appendix E

Appendix E: Process Analysis for the NCI Translational Research Working Group

Introduction and Summary

Inordertoinformitsdeliberations,theNationalCancerInstitute(NCI)TranslationalResearchWorkingGroup(TRWG)initiallydevelopedfivedevelopmentalpathwaystoclinicalgoalsencompassingriskassessmentdevices,agents,immuneresponsemodifiers,interventivedevices,andlifestyleinterventions.AttheDecember2005planningmeeting,TRWGmembersdecidedtoexamineseveralcasestudiesoftranslational“successes”alongeachofthesedevelopmentalpathways.Thegoalwastogaininsightsintothefollowingquestions.

• Whatpathsdosuccessestake?Aretherecommonalitieswithin/acrossthecasesexamined,oriseachtranslationunique?

• Evenforsuccesses,aretherebottleneckswherediscoveriesareheldup?Ifso,where?

• Whatrolesdoacademia,industry,andNCIplayinsuccessfultranslation?

• Whatinsightsdothecasestudiessuggestregardingthedevelopmentalpathwaystoclinicalgoals?

Twentycasestudiesspanningthefivedevelopmentalpathwaystoclinicalgoalswerecompleted.ThisdocumentpresentsthemethodsusedforidentifyingtheNCI-sponsoredtranslationalsuccesses,thekeyfindingsfromtheanalysis,andrepresentativesummariesofthecasesexamined.

Methodology

Identification of Case Study Candidates

AftertheDecember2005planningmeeting,membersoftheTRWGnominatedcandidatecasestudiesrepresentingeachofthedevelopmentalpathways.TheTRWGco-chairsselectedcasestudiesfromamongthenominees,aimingforadiversesetofcaseswithineachdevelopmentalpathway.

Data Collection

DatacollectionoccurredduringJanuaryandFebruary2006.Datacollectionincludedidentificationandreviewofpeer-reviewedpublications,tradeliterature,patentfilings,clinicaltrialabstracts,andfundingdata(includingNationalInstitutesofHealth(NIH)andnon-NIHfundingwhereavailable)foreachofthetranslationalresearchsuccesses.Keyparticipantswereidentifiedforeachtranslationalresearchsuccessandinterviewedwherepossible.TwentycaseswerecompletedinadvanceoftheTRWGRoundtableinFebruary2006.

• Risk Assessment Devices

BladderCancerEarlyDetection:MicrosatelliteInstabilityAssayofUrinarySediment

BladderCancerEarlyDetection:FluorescenceIn-SituHybridizationAssayofUrine

ProstateCancerEarlyDetection:ProteinExpressioninSerum

FDG-PETforEarlyDetection

•

•

•

•



• Agents

Avastin

DNAMethyltransferaseInhibitor(e.g.,Vidaza)/HistoneDeacetylaseInhibitorCombinations

Bortezomib/Velcade

Anti-HER2/neuLiposomes

Celecoxib

TNFerade

• ImmuneResponseModifiers

HER2/neuBreastCancerVaccine

RNA-TransfectedDendriticCells

CombinationofMDX-010/anti-CTLA-4AntibodywithMelanoma(andProstateCancer)Vaccines

Cell-BasedVaccinesforPancreaticCancer

GloboHBreastCancerVaccines

• Interventive Devices

RadiofrequencyAblation

Three-DimensionalConformalRadiationTherapyforProstateCancer

FDG-PETDeviceDevelopment

• Lifestyle Alterations

Exercise,Diet,andBreastCancer

SmokingCessationandLungCancer

Key Findings

Becauseonlyasmallsamplesizewasconsidered,norobustgeneralconclusionscanbedrawnfromthecasestudies.Nevertheless,severalinterestingpatternsemerged.

1. ThecasesdrewuponawidevarietyofNCIandNIHfundingmechanisms.Casesincludedtranslationalactivitiesfundedthroughasinglelarge-scale,team-basedprogram(e.g.,SpecializedProgramsofResearchExcellence(SPORE),EarlyDetectionResearchNetwork(EDRN)),othersfundedthroughaseriesofindividual-investigatorawards(e.g.,R01,K-series,SmallBusinessInnovationResearchProgram(SBIR)/SmallBusinessTechnologyTransferProgram(STTR)),andstillothersthroughtheNCIintramuralresearchprogram.Severalcasesusedacombinationofindividual-investigatorawardsandteam-basedprojects,whilesomewerefundedthroughotherNIHInstitutes(e.g.,NationalInstituteofGeneralMedicalScience(NIGMS),NationalInstituteofDiabetesandDigestiveandKidneyDiseases(NIDDK),NationalInstituteofAllergyandInfectiousDiseases(NIAID))aswellasNCI.Inthecasesinvestigated,itwasfoundthatbothNCIandindustrycouldbeinvolvedatanystagealongthetranslationcontinuumfromearly-tolate-stage.

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•



2. Themajorityofthecasesencounteredbottlenecksorchallengesinachievingsuccess.Severalcasesrequiredthedevelopmentofnewassaysorscreeningtechniquestovalidatethediscovery;severalencounteredbottlenecksinpreclinicaldevelopment(e.g.,GMPmanufacturing);andothersencountereddifficultiesinearly-stageclinicaltrialsbecauseofFoodandDrugAdministration(FDA)approvalorpatientrecruitmentissues.

3. Arangeofinteractionsamongstakeholderswasobserved.Casesincluded“traditional”handoffsfromacademiatoindustry,translationthatoccurredprimarilyinacademiabutwithindustryfundingofspecificprocesssteps,fullpublic-privatepartnerships,andevenexampleswherefundamentaldiscoveriesmadebyprivateindustrybenefitedfromNCI-fundedtranslationalresources.

4. Thecasestudiessuggestedcertaininsightsintothedevelopmentalpathways.

Somecasesbydefinitionspannedmultiplepathways.FDG-PET,forexample,functionsasariskassessmentdevice,butitwasdevelopedasacombinationofimagingagent(FDG)andaninterventivedevice(PET).Inotherexamples,activityinonepathwayledtodiscoveriesrelevanttootherpathways(e.g.,celecoxibdevelopmentledtothediscoveryofanewcandidatebiomarkerofbiologicalresponse).

TheTRWGdevelopmentalpathwaysareidealizedrepresentationsofthetranslationalresearchprocess.Forexample,severalcasesintheinterventivedevicepathwayskippedstepsorevenwholesegmentsofthepathwayandseveralimmuneresponsemodifiercasesinvolvedmultipleiterationsofrefinementbeforereachingclinicaltrials.

Conclusions and Future Considerations for Translational Research Analysis

Theprocessanalysisexerciseshowedthatinnoneofthecasesexaminedwastheentiredevelopmentalpathwayfundedbyasingle,comprehensiveprogramormechanismorbyasystematicallycoordinatedseriesofprogramsormechanisms.Individualinvestigatorsorteamsassembledfundingforeachcase,withtheparticularcombinationsthatadvancedaconceptthroughthedevelopmentalpathwayoftendependingontheingenuityoftheinvestigators.

Thecasessuggestthattranslationalresearchwouldbefacilitatedbytheavailabilityofmoreunifiedandbetter-coordinatedfundingmechanisms.Theyalsodemonstratetheabsenceofcriticalsystem-leveltranslationalresearchmetrics(e.g.,thefractionofsuccessesthatareadvancedthroughspecificprogramsormechanismsorthefractionthatencounterbottlenecksatspecificpointsineachdevelopmentalpathway).Creationofdatasystemsthatcanprovidesuchinformationinalogisticallystraightforwardandpreciselydefinedwaywillbebeneficialforimprovingthemanagementoftranslationalresearch.

Case Study Summaries

Summariesof10representativecasestudies,tworepresentingeachofthefiveinitialdevelopmentalpathways,arepresentedbelow.Casestudiesarenotincludedforthesixthpathway,image-basedriskassessmentagents/techniques,becausethispathwayhadnotbeendevelopedatthetimetheprocessanalysiswasconducted.Thecasestudiessummarizedarelistedbelow.

• Risk Assessment Devices

BladderCancerEarlyDetection:MicrosatelliteInstabilityAssayofUrinarySediment

BladderCancerEarlyDetection:FluorescenceIn-SituHybridizationAssayofUrine

• Agents

Bortezomib/Velcade

Celecoxib

•

•

•

•

•

•



• ImmuneResponseModifiers

HER2/neuBreastCancerVaccine

Cell-BasedVaccineforPancreaticCancer

• Interventive Devices

RadiofrequencyAblation

Three-DimensionalConformalRadiationTherapyforProstateCancer

• Lifestyle Alterations

Exercise,Diet,andBreastCancer

SmokingCessationandLungCancer

•

•

•

•

•

•



Bladder Cancer Early Detection: Microsatellite Instability Assay of Urinary Sediment

Summary:Intheearlytomid-1990s,severalresearchgroupsreportedstudiesindicatingthatmicrosatelliteinstabilitycouldhavepotentialutilityasamarkerforearlydetectionofcancer.In1996,theSidranskyandSchoenberggroupsatJohnsHopkinsUniversityreportedthaturinemicrosatelliteinstabilityassaysdetectedbladdercancerinpatientswith95%sensitivitywhereasurinecytologyhadonly50%sensitivity.Asecondstudyreportedin1997demonstratedthattheurinemicrosatelliteassaycouldalsodetectbladdercancerrecurrencewithapproximately90%sensitivity.BothofthesestudieswerefundedbyOncorInc.andledtofilingofpatentapplicationsin199�whichthenledtotheissuanceoffourU.S.patents.

Thetechnologyandintellectualpropertywerelicensedin2000toCangenBiotechnologies,whodevelopedaninitialtestkit.TheCangentestkitwasvalidatedbytheEDRNbiomarkerreferencelaboratoriesusingretrospectivesamplesetscollectedatJohnsHopkins.In2004EDRNinitiatedamultisiteprospectiveBiomarkersPhaseIIIstudy(whichdiffersfromaPhaseIIIclinicaltrial)with300patientsand200controlstocomparemicrosatelliteanalysiswithcystoscopyandcytologyfordetectionofbladdercancerrecurrence.ThestudywasclosedtoaccrualinJanuary2007with270patients.TheresultsofthistrialwillbeusedbyCangentopursueFDAlicensureofitstestkit.

Relationship to TRWG Pathway

Developmentofthemicrosatelliteassaycloselyfollowedtheriskassessmentdevicepathway.

Bottlenecks

1. BankruptcybyOncor,theinitiallicenseeofthetechnology,ledtoa2-yeardelayindevelopmentwhiletheintellectualpropertyrightsweretiedupinlegalproceedings.RecoveryoftherightsrequiredthecombinedeffortofJohnsHopkinsandCangen,whichbecameinterestedinthetechnologybecauseaco-discovererwastheirChiefScientificOfficer.

2. Developmentofapractical,validatedtestkitrequiredmigrationfromtheradioactivity-basedassaydevelopedatJohnsHopkins,whichrequiredsubjectivereadingandinterpretationbyatrainedobserver,toafluorescence-basedassaywhichusedautomatedsequencing,reading,andinterpretation.Industryinvolvementwascriticaltodevelopandvalidatethisautomatedassay.

3. AccrualtotheBiomarkersPhaseIIItrialwasinitiallyasignificantbottleneck,butthiswasovercomebytheadditionofmoreclinicalcenters.

Key Observations

1. Tomovenew,broad-basedrisk-assessmenttechnologiesforward,itisimportanttoidentifyaninitialdiseasetargetwithastrongclinicalneedinordertoattractindustryattention.

2. Intellectualpropertylicensingisessentialbutsuchlicensingmayinadvertentlyencumberthetechnologyandimpedeitsdevelopment.

3. Developmentofpractical,validatedassaymethodologiescanbechallengingforacademiclabs.

4. Thestandardmodelofindustryfundingoflate-stageratherthanearly-stagedevelopmentisnotalwaysfollowedastheearlytranslationalworkwasfundedlargelybyindustrywhilethedefinitiveBiomarkersPhaseIIItrialwasfundedbyNCI.

5. SmalldevicecompaniesoftenrelyonNCItofundthelargeclinicalstudiesnecessarytosupportFDAapprovalofnewcancerclinicaltests.



Sources

• InterviewwithDr.DavidSidransky/Dr.SudhirSrivastava(January31,2006)

Literature

• MaoL,LeeDJ,TockmanMS,ErozanYS,AskinF,SidranskyD.Microsatellitealterationsasclonalmarkersforthedetectionofhumancancer.ProcNatlAcadSci.1994;91(21):9871-5.

• MaoL,SchoenbergMP,ScicchitanoM,ErozanYS,MerloA,SchwabD,SidranskyD.Moleculardetectionofprimarybladdercancerbymicrosatelliteanalysis.Science.1996;271(5249):659-62.

• SteinerG,SchoenbergMP,LinnJF,MaoL,SidranskyD.Detectionofbladdercancerrecurrencebymicrosatelliteanalysisofurine.NatMed.1997;3(6):621-4.

• PepeMS,EtzioniR,FengZ,PotterJD,ThompsonML,ThornquistM,WingetM,YasuiY.Phasesofbiomarkerdevelopmentforearlydetectionofcancer.JNCI.2001;93(14):1054-61.

Patent Search

• Sidransky.Nucleicacidmutationdetectionbyanalysisofsputum(#5,561,041).FiledNovember12,1993;receivedOctober1,1996.

• Sidransky.Detectionofhypermutablenucleicacidsequenceintissue(#5,935,�8�).FiledMay12,199�;receivedAugust10,1999.

• Sidransky.Methodfordetectingcellproliferativedisorders(#6,291,163).FiledAugust28,1997;receivedSeptember18,2001.

• Sidransky.Methodfordetectingcellproliferativedisorders(#6,780,592).FiledSeptember10,2001;receivedAugust24,2004.



Bladder Cancer Early Detection: Fluorescence In-Situ Hybridization Assay of Urine

Summary:Fluorescencein-situhybridization(FISH)wasoriginallydevelopedbytheGraygroupatLawrenceLivermoreNationalLaboratoryinthelate1980susingDepartmentofEnergy(DOE),NCI,andNationalInstituteofChildHealthandHumanDevelopment(NICHD)funding.Intheearlytomid-1990s,severalacademicresearchersbegantoworkonapplicationofFISHtechnologyforearlydetectionofbladdercancer.Atthesametime,VysisInc.wasfurtherdevelopingtheFISHtechnologyforuseinclinicaltestsanddemonstratedtoFDAthatassaysbasedonFISHweresufficientlyrobustandreproducibletobeusedforclinicalpurposes.

In1998,VysisidentifiedtheuseofFISHforearlydetectionofbladdercancerasacommercialtargetbaseduponthecombinationofclinicalneed(existingtestshadlimitedsensitivity/specificity)andtheassessmentthatVysis’sFISHtechnologycouldimproveuponthosetests.ThecompanycollaboratedwiththeUniversityofBaselandMayoClinictoobtainsamplesandclinicaldatasetsforvalidatingthetechnology(1999-2000)andtopursuelarge-scaleprospectivestudies(2000-2001).FDAapprovalfortheUroVysiontestwasgrantedinAugust2001.


DevelopmentoftheFISHassayfollowedtheriskassessmentdevicepathwayquiteclosely.

Bottlenecks

Nosignificantbottleneckswerereported.

Key Observations

1. TheTRWGpathwayeffectivelydescribesthestepsusedtotranslatetheFISHtechnologyintoapracticaltestforbladdercancer.AllthreedecisionpointsforentryintotranslationaldevelopmentwereaddressedinVysis’sassessment;namely,thatthetechnologywasmatureandthatbladdercancerwasanappropriateapplicationtopursue.

2. Successfultranslationinvolvedindustryperformingtwocriticalroles.ThefirstwasrefinementandvalidationoftheFISHtechnologydevelopedwithgovernmentfundingintoamethodologysufficientlyrobustandreliabletoserveasthebasisforclinicaltests.ThesecondinvolvedbuildingonreportsbyseveralacademicinvestigatorsofthepotentialutilityofFISHforthedetectionofbladdercancerinordertodevelopanFDA-approvedtest.

3. Collaborationwithacademicinvestigatorswasimportantinorderforindustrytoobtaintheclinicalspecimensnecessarytodevelopandvalidatethenewcancerclinicaltest.

Sources

• InterviewwithDr.SteveSeelig,Abbot(February7,2006)

• AdvancedTechnologyProgramfactsheet,“BarCodeDiagnosticsforDNAAnalysis”

Literature

• vanDekkenH,PinkelD,MullikinJ,GrayJW.Enzymaticproductionofsingle-strandedDNAasatargetforfluorescenceinsituhybridization.Chromosoma.1988;9�(1):1-5.

• SokolovaIA,HallingKC,JenkinsRB,BurkhardtHM,MeyerRG,SeeligSA,KingW.Thedevelopmentofamultitarget,multicolorfluorescenceinsituhybridizationassayforthedetectionofurothelialcarcinomainurine.JMolDiagn.2000;2(3):116-23.



• HallingKC.VysisUroVysionforthedetectionofurothelialcarcinoma.ExpertRevMolDiagn.2003;3(4):507-19.Erratumin:ExpertRevMolDiagn.2004;4(2):266.

Patent Search

• Hallingetal.Methodandprobesetfordetectingcancer(#6,174,681).FiledMarch5,1999;receivedJanuary16,2001.

• Hallingetal.Methodandprobesetfordetectingcancer(#6,376,188).FiledJuly21,2000;receivedApril23,2002.



Bortezomib/Velcade

Summary

Interestintheroleoftheproteasome(acomplexofenzymesinvolvedindegradationofmisfoldedproteins)incarcinogenesisgrewduringthemid-1990s.In1994researchersatProScriptInc.developedagroupofproteasomeinhibitorsthatappearedtobeeffectiveinpromotingapoptosisofcancercells.Aspartoftheirresearch,theProScriptgroupalsodevelopedanin vitroassayforproteasomeinhibition,whichservedasasurrogatemarkerfortheeffectivenessofthisclassofdrugs.Beginningin1995,theNCIDevelopmentalTherapeuticsProgram(DTP)assistedProscriptwithin vitroandanimalmodelstudiesthatidentifiedoneoftheseinhibitors(PS-341,latertrade-namedVelcade)asalikelycandidateagentfromamongthegroupofcompoundsProScriptprovidedfortesting.ProscriptperformedpreclinicaldevelopmentofPS-341internallyandDTPassistedwithformulationstudies.

PhaseIclinicaltrialsinprostatecancerwereperformedbyacademicinvestigatorsbeginninginOctober1998withCaPCure(ProstateCancerFoundation)funding.In1999,preclinicalstudiesandPhaseItrialsinmultiplemyelomawereperformedatDana-FarberCancerInstitute,fundedbyNCI.TheacquisitionofProScriptbyMillenniumPharmaceuticalsin1999providedadditionalresourcesfordevelopmentofthedrugandMillenniumconductedPhaseIIBtrialsinmultiplemyelomapatientsduring2001-2002.Theresultswerepresentedinlate2002andledtoFDAapprovalofthedrugin2003.Throughoutdevelopment,theFDAwasquitesupportiveofbringingthisnewclassofcompoundsintoclinicaltrials.


DevelopmentofVelcadelargelyfollowedtheTRWGagentdevelopmentpathway.Atthebottomofthepathway,thedrug’sdevelopmentbranchedintomultiplePhaseItrialsforprostatecancer,multiplemyeloma,andseveralotherdiseasesites.

Bottlenecks

SeveralbottlenecksinthedevelopmentofVelcadewereidentified.Thesebottlenecksincluded(a)developinganassayforproteasomeinhibitionthatallowedidentificationofasafeandeffectivedosagerange(overcomebyProScriptscientists),(b)formulationofthedrug(overcomebyDTP),and(c)interestingacademictrialistsinbringingthedrugintoearly-stageclinicaltrials(overcomethroughentrepreneurshipbyProScriptscientists).

Key Observations

1. DevelopmentofVelcadeinvolvedcollaborationamongindustry,NCI,academictrialists,andfoundations.ClosecoordinationamongthestakeholdersnotonlyfacilitatedvalidationofthediscoveryandpreclinicaldevelopmentofthedrugbutalsospedtheenrollmentofmultiplemyelomapatientsintothePhaseIItrialsthatprovidedthedatatosupportFDAapproval.

2. Small-to-midsizecompaniesoftendonothavesufficientin-housecapabilitytodevelopapromisingtherapeuticagent.Inthiscase,DTPprovidedassayandanimalmodelcapabilitiesthatassistedProScriptinidentifyingaleadagentcandidateaswellasformulationcapabilities.Thisdemonstratesthevalueofacademic-industry-NCIcollaborationintranslationalresearch.

3. Late-stagedevelopmentofthedrugwasfacilitatedbyinvolvementofalargepharmaceuticalcompany.WithouttheacquisitionofProScriptbyMillenniumPharmaceuticals,developmentmayhaveceasedbecauseProScriptdidnothavethefinancialresourcestocontinuewithlate-stageclinicaltrials.



Sources

• “MyelomaToday”(InternationalMyelomaFoundation)profileofDr.JulianAdams,June2003

• NationalCancerInstitute/DevelopmentalTherapeuticsProgram,“SuccessStory:Velcade(NSC681239),”http://dtp.nci.nih.gov/timeline/noflash/success_stories/S6_Velcade.htm

• NationalCancerInstitute/DevelopmentalTherapeuticsProgram,“Velcade(PS-341),”http://dtp.nci.nih.gov/timeline/posters/Velcade.pdf

• InterviewwithDr.ChristopherLogothetis,MDAnderson(February10,2006)

• InterviewwithDr.KennethAnderson,BethIsraelDeaconessMedicalCenter(February7,2006)

Literature

• AdamsJ,BehnkeM,ChenS,CruickshankAA,DickLR,GrenierL,KlunderJM,MaYT,PlamondonL,SteinRL.Potentandselectiveinhibitorsoftheproteasome:dipeptidylboronicacids.BioorgMedChemLett.1998;8(4):333-8.

• AdamsJ,PalombellaVJ,SausvilleEA,JohnsonJ,DestreeA,LazarusDD,MaasJ,PienCS,PrakashS,ElliottPJ.Proteasomeinhibitors:anovelclassofpotentandeffectiveantitumoragents.CancerRes.1999;59(11):2615-22.

• TeicherBA,AraG,HerbstR,PalombellaVJ,AdamsJ.Dana-FarberCancerInstituteandJointCenterforRadiationTherapy.ClinCancerRes.1999;5(9):2638-45.

• HideshimaT,RichardsonP,ChauhanD,PalombellaVJ,ElliottPJ,AdamsJ,AndersonKC.TheproteasomeinhibitorPS-341inhibitsgrowth,inducesapoptosis,andovercomesdrugresistanceinhumanmultiplemyelomacells.CancerRes.2001;61(7):3071-6.

• RichardsonP.Clinicalupdate:proteasomeinhibitorsinhematologicmalignancies.CancerTreatRev.2003;29(Suppl1):33-9.

• TwomblyR.Firstproteasomeinhibitorapprovedformultiplemyeloma.JNCI.2003;95(12):845.



Celecoxib

Summary

TheCOX-2inhibitorcelecoxibwasinitiallydevelopedasananti-inflammatoryagentbySearle(laterPharmaciaandthenPfizer).Epidemiologicdatapublishedduringthelate1980sshowingthataspirinusewasassociatedwithdeclinesincolorectalcancer(CRC)suggestedthataspirinorothernon-steroidalanti-inflammatorydrugs(NSAIDs)couldpotentiallybeusedasapreventativeortherapeuticagentincancer.Thishypothesiswasfurthersupportedbystudiesinanimalmodelsofcarcinogenesiswhichexaminedthepotentialroleofprostaglandinsincancerprogression.Intheearly1990s,thegenerationofprostaglandinsfromarachadonicacidwasdeterminedtoarisefromtwodistinctcyclooxygenase(COX)enzymes—COX-1,whichwasassociatedwithamorebasal,housekeepingrole,andaninducibleCOX-2,whichwasresponsivetoavarietyofstimuliassociatedwithinflammationandcancer.

Basedontheseobservations,theDuBoisgroupatVanderbilt,fundedbyR01grantsfromtheNationalInstituteofDiabetesandDigestiveandKidneyDiseasesandseveralothersources,demonstratedseveralimportantfindings.First,overexpressionofCOX-2increasedtheinvasivenessandprostaglandinproductionofcoloncancercellsinculturewhichcouldbereversedbygeneticorpharmacologicCOX-2inhibition.Second,tissuestudiesshowedCOX-2wasexpressedinhumanadenocarcinomas.Third,mousemodelstudiesdemonstratedthatCOX-2inhibitorscouldreducetumorformationbycoloncancercelllinesconstitutivelyexpressingCOX-2,buthadnoeffectoncancercelllineslackingCOX-2.Theseobservationsweresupportedbystudiesfromseveralotherepidemiologylaboratorieswhichconfirmedthesedata,demonstratedtherelevanceofCOX-2toearlystagesofcolorectalcarcinogenesis,andsuggestedthatNSAIDsand/orCOX-2inhibitorswereassociatedwithreductionsincolorectaladenomaincidence,colorectalcancerincidence,andCRC-associatedmortality.AllofthesefindingssuggestedthatcelecoxibandotherCOX-2inhibitorscouldhavepromiseaseffectivechemopreventiveagentswithfewerGIsideeffects(e.g.,gastroduodenalulceration)andthuswereparticularlyappealingagentsforclinicaltrialsincolorectalneoplasiaprevention.

AspreclinicaldevelopmentoncelecoxibhadbeendonepreviouslybySearle,itwasthoughtatthetimethattherewasnoneedforadditionaltoxicology/pharmacologybeforeintroducingtheagentintocancerchemopreventionclinicaltrials.NCI-fundedphaseIIpreventiontrialsbeganin1998inpatientsatveryhighriskforcolorectalcancerduetofamilialadenomatouspolyposis(FAP).SuccessinthistrialledtotheinitiationofseveraltrialsinpatientsatmoremoderateriskforCRCduetoprioradenomas.MerckinitiatedatrialofitsCOX-2inhibitor—rofecoxib(Vioxx)—in1999,andtheNCIandPfizerpartneredtoinitiateathree-armtrialofcelecoxib(attwodoses)versusplacebo(theAPCtrial).Pfizeralsoinitiatedasecond,multinationaltrialofsimilardesignwithcelecoxibversusplaceboin2000(thePreSAPtrial).Afterrofecoxibwasobservedin2004tocausecardiovasculartoxicity,bothPfizerandNCImonitoredtheirlarge-scalechemopreventivetrialscloselyandin2005,celecoxibwasfoundtobeassociatedwithanelevatedriskforseriouscardiovasculareventsintheAPCtrialaswell.

Althoughcelecoxibdidnotprovesufficientlysafeforwidespreadchemopreventiveuseinmoderate-riskindividuals,investigationoftheCOX-2pathway’srelevancetocancerhasledtocertainothertranslationalopportunities.Forexample,subsequentresearchintotheCOX-2pathwayhasuncoveredadownstreampathwaystep(thefinalstepinprostaglandinPGE2synthesis)whosedisruptionmayhavethesametherapeuticbenefitwithoutthetoxicityofCOX-2inhibition.Inaddition,theDuBoisgrouphasusedNCIfundingtoexploretheuseofCOX-2levelsasabiomarkerfordiagnosisofcoloncancerandEDRNhasalsofundedstudiesconcerningCOX-2’spotentialasabiomarkerofrisk.


Thepre-existingleadagentcandidateenteredthedevelopmentalpathwaybasedonobservational/epidemiologystudies,preclinicaldata,andapprovaloftheagentforuseinadifferentdiseasearea.Thisexamplealsoshowslinkagesbetweenpathways.Workintheagentpathwayhassuggestedconceptsfordevelopmentthroughthebiospecimen-basedriskassessmentdevicepathway.



Bottlenecks

Althoughtoxicologywasnotviewedasabottleneckatthetime,developingmethodsthatcanidentifytoxicityassociatedwithlong-termuseisanimportantpotentialbottleneckinbringingforwardchemopreventiveagentsforuseinlow-tomoderate-riskpopulations.

Key Observations

1. AcompounddevelopedbyindustryforadifferentdiseaseareawastranslatedforuseincancerthroughtheinvolvementofacademicresearchersfundedbyNCIandotherInstitutes.

2. ResearchfundedbyotherNIHInstitutescanleadtodiscoveriesrelevanttocancer.

3. TheremaybeimportantdifferencesbetweenagentdevelopmentfortreatmentandforpreventioneventhoughtheycanbedescribedusingthesameTRWGdevelopmentalpathway.Thecelecoxibexamplehighlightsthecriticalroleofbalancingrisksandbenefitsinprevention,andsuggeststheimportantrolethatnewapproachestopreclinicaltoxicologicassessmentsmayplayinassessingtherisksassociatedwithapreventivecompound.

4. ClosecollaborationbetweenindustryandNCIfacilitatedtheconductoflargechemopreventiontrials.

Sources

• InterviewwithDr.RaymondDuBois,VanderbiltUniversity(January26,2006)

• InterviewwithDr.ErnestHawk,NCI(February8,2006)

Literature

• ThunMJ,NamboodiriMM,HeathCWJr.Aspirinuseandreducedriskoffatalcoloncancer.NEnglJMed.1991;325(23):1593-6.

• RosenbergL,PalmerJR,ZauberAG,WarshauerME,StolleyPD,ShapiroS.Ahypothesis:nonsteroidalanti-inflammatorydrugsreducetheincidenceoflarge-bowelcancer.JNCI.1991;83(5):355-8.

• EberhartCE,CoffeyRJ,RadhikaA,GiardielloFM,FerrenbachS,DuBoisRN.Up-regulationofcyclooxygenase2geneexpressioninhumancolorectaladenomasandadenocarcinomas.Gastroenterology.1994;107(4):1183-8.

• ReddyBS,RaoCV,SeibertK.Evaluationofcyclooxygenase-2inhibitorforpotentialchemopreventivepropertiesincoloncarcinogenesis.CancerRes.1996;56(20):4566-9.

• SteinbachG,LynchPM,PhillipsRKS,WallaceMH,HawkE,GordonGB,WakabayashiN,SaundersB,ShenY,FujimuraT,SuL,LevinB,GodioL,PattersonS,Rodriguez-BigasMA,JesterSL,KingKL,SchumacherM,AbbruzzeseJ,DuBoisRN,HittelmanWN,ZimmermanS,ShermanJW,KelloffG.Theeffectofcelecoxib,acyclooxygenase-2inhibitor,infamilialadenomatouspolyposis.NewEngJMed.2000;342(26):1946-52.

• SolomonSD,McMurrayJJV,PfefferMA,WittesJ,FowlerR,FinnP,AndersonWF,ZauberA,HawkE,BertagnolliM,fortheAdenomaPreventionwithCelecoxib(APC)StudyInvestigators:Cardiovascularriskassociatedwithcelecoxibinaclinicaltrialforcolorectaladenomaprevention.NEnglJMed.2005;352:1071-80.

• BertagnolliMM,EagleCJ,ZauberAG,RedstonM,SolomonSD,KimK-M,TangJ,RosensteinRB,WittesJ,CorleD,HessTM,WolojGM,BoisserieF,AndersonWF,VinerJL,BagheriD,BurnJ,ChungDC,DewarT,FoleyTR,HoffmanN,MacraeF,PruittRE,SaltzmanJR,SalzbergB,SylwestrowiczT,GordonGB,HawkETfortheAPCStudyInvestigators.Celecoxibforthepreventionofsporadiccolorectaladenomas.NEnglJMed.2006;355:873-84.



• SolomonSD,PfefferMA,McMurrayJJV,FowlerR,FinnP,LevinB,EagleC,HawkE,LechugaM,ZauberAG,BertagnolliMM,ArberN,WittesJfortheAPCandPreSAPTrialInvestigators.Effectofcelecoxiboncardiovasculareventsandbloodpressureintwotrialsforthepreventionofcolorectaladenomas.Circulation.2006;114:1028-35.



HER-2/neu Breast Cancer Vaccine

Summary

PreviousworkshowedthatthetumorantigenHER-2/neuisoverexpressedincertaintypesofbreastcancerandthatsomebreastcancerpatientshadexistentimmuneresponsesagainsttheHER-2/neuproteinalthoughtheresponsesfellshortoftherapeuticlevels.ThesefindingssuggestedthepossibilitythatHER-2/neuvaccinescouldtargetHER-2/neupositivebreastcancer.TheCheevergroupattheUniversityofWashington(UW)showedin1996thatitwasfeasibletoelicitanimmuneresponseinmousemodelsusingportionsoftheHER-2/neuproteinasanimmunogen.ThisworkwasfundedthroughanNCIR01grantoriginallyfocusedontheevaluationofimmuneresponsesagainstmelanoma.Patentapplicationswerefiledin1995throughUWclaimingimmunereactivitytoHER-2/neuproteinasthebasisfordiagnosisandtreatmentofHER-2/neu-associatedmalignancies.UWscientistsco-foundedastart-upbiotechcompany,Corixa,whichlicensedthepatentandcommencedGMPmanufacturingofaseriesofHER-2/neupeptidevaccinesusinganNCISBIRgrantasonesourceoffunds.

TheinitialPhaseItrialin1998wasconductedunderaUWINDwithCorixafunding.ThisinitialtrialledtomultipleCorixa-fundedPhaseItrialsincollaborationwithUWtranslationalscientistsinordertorefinethevaccineconstructandoptimizetheimmuneresponse.OnekeyrefinementwasthetransitionfromusingsmallerportionsoftheHER-2/neuproteintousingthefullextracellulardomainfusedtomajorportionsoftheintracellulardomainoftheprotein.

Inordertocontinuedevelopmentofthevaccine,CorixapartneredwithGSK.GSKwasessentialforfinancingtheprojectandformanufacturingthevaccineunderconditionsthatmaintainedthenaturalfoldingoftheextracellulardomain.ThevaccinewasalsoformulatedwithuniquecombinationsofadjuvantsavailabletoGSKandnotavailabletoacademicinvestigators.PhaseI/IItestingofthisimprovedvaccineformulationwasinitiatedin2004byGSKandCorixaincollaborationwithmultipleacademictranslationalresearchersincludingthoseatUW.ThevaccineformulationwasabletoinducesubstantialantibodyandTcellimmuneresponsesinbreastcancerpatientsandcontinuesindevelopmentatGSK.WhileCorixaandGSKmovedforwardwithimprovingtheHER-2/neuprotein-basedvaccine,otherUWscientists(fundedthroughNCIR01andK08grants)havebeensuccessfullyworkingonDNA-basedHER-2/neuvaccineapproaches.


Developmentfollowedtheimmuneresponsemodifierpathwaythroughmultipleiterationsofvaccineconstructionandadjuvantformulation,deliveryschemes,andvaccineregimens,bothinanimalmodelsandearly-phasehumanclinicaltrials.ThemultipleiterationsledtorefinementsoftheHER-2/neuvaccineconstructtofinallyachieveanimmuneresponsethatwasdeemedadequatetojustifytestingofthevaccineinlarger-scaletrials.

Bottlenecks

Preclinicaldevelopment/manufacturingrequiredbiotechandlarge-companyfinancialandtechnologicalresources.Thefinalvaccineformulationusedaseriesofadjuvantsnotcommonlyavailabletomostacademicresearchersorbiotechcompanies.

Key Observations

1. Successfulhandoffoftechnologyfromacademiatoindustrywasfacilitatedbyastrongintellectualpropertyposition,whichledtotheco-foundingofasmallbiotechcompanybytheacademicinventors.

2. Testingofthevaccineinpatientsrequiredthattheconstructedvaccinebe“handedback”toacademicinvestigators.



3. Partnershipbetweenasmallbiotechcompanyandalargepharmaceuticalcompanywasnecessarytoovercomefinancial,manufacturingandadjuvantavailabilityhurdles.

4. PhaseItrialsofinitialvaccineconstructscanserveas“validationsteps”thatassistresearchersinrefiningapproachesanddevelopingimprovedvaccinesforsubsequentexpandedtrials.

Sources

• InterviewwithDr.MacCheever,FredHutchinsonCancerResearchCenter/UniversityofWashington(February6,2006)

Literature

• DisisML,GralowJR,BernhardH,HandSL,RubinWD,CheeverMA.Peptide-based,butnotwholeprotein,vaccineselicitimmunitytoHER-2/neu,oncogenicself-protein.JImmunol.1996;156(9):3151-8.

• DisisML,PupaSM,GralowJR,DittadiR,MenardS,CheeverMA.High-titerHER-2/neuprotein-specificantibodycanbedetectedinpatientswithearly-stagebreastcancer.JClinOncol.1997;15(11):3363-7.

• DisisML,GrabsteinKH,SleathPR,CheeverMA.GenerationofimmunitytotheHER-2/neuoncogenicproteininpatientswithbreastandovariancancerusingapeptide-basedvaccine.ClinCancerRes.1999;5(6):1289-97.

• DisisML,GooleyTA,RinnK,DavisD,PiepkornM,CheeverMA,KnutsonKL,SchiffmanK.GenerationofT-cellimmunitytotheHER-2/neuproteinafteractiveimmunizationwithHER-2/neupeptide-basedvaccines.JClinOncol.2002;20(11):2624-32.

• DisisML,SchiffmanK,GuthrieK,SalazarLG,KnutsonKL,GoodellV,delaRosaC,CheeverMA.EffectofdoseonimmuneresponseinpatientsvaccinatedwithanHER-2/neuintracellulardomainprotein-basedvaccine.JClinOncol.2004;22(10):1916-25.

• LimentaniS,DorvalT,WhiteS,CuriglianoG,CamponeM,DisisM,PiccartM,CheeverM,GérardC,BrichardV.PhaseIdose-escalationtrialofarecombinantHER2vaccineinpatientswithStageII/IIIHER2+breastcancer.JClinOncol.2005;23(165)PartIofII(June1Supplement):2520.

Patent Search

• Cheeveretal.ImmunereactivitytoHER-2/neuproteinfordiagnosisandtreatmentofmalignanciesinwhichtheHER-2/neuoncogeneisassociated(#5,876,712).FiledJune6,1995;receivedMarch2,1999.

• Cheeveretal.ImmunereactivitytoHER-2/neuproteinfordiagnosisandtreatmentofmalignanciesinwhichtheHER-2/neuoncogeneisassociated(#5,846,538).FiledJune�,1995;receivedDecember8,1998.Subsequentpatentsinclude#6,075,122—UniversityofWashingtonand#6,379,951—Corixa.



Cell-Based Vaccine for Pancreatic Cancer

Summary

Inthelate1980sandearly1990s,anumberofstudieswerereportedindicatingthatmurinetumorcellstransducedtoexpressawiderangeofcytokinescouldinduceanimmuneresponseagainstthetransducedcellsandincertaincasesagainstsubsequentchallengewithnontransducedcellsorapre-existingtumor.In1993agroupincludingresearchersfromJohnsHopkinsUniversityreportedthatcellstransducedwithgranulocyte-macrophagecolony-stimulatingfactor(GM-CSF)wereaparticularlypotentstimulatorofsystemicantitumorimmunity.Extendingthisfinding,severalearly-stageclinicaltrialswereconductedinthelate1990swithautologousGM-CSF-secretingtumorvaccineswhichshowedpromisingresultsinpatientswithprostateandrenalcellcarcinomaandmelanoma.Basedontheseresultsandtheinherenttechnicalandregulatorydifficultiesassociatedwithautologousvaccines,theJohnsHopkinsgroupbeganpursuingdevelopmentofanirradiated,allogeneicGM-CSF-transducedcellularvaccineagainstpancreaticcancer.PancreaticcancerwaschosenasthetargetbasedonbothclinicalneedandtheassociationoftheinvestigatorswiththeJohnsHopkinsGISPORE.

Developmentoftheallogeneicvaccinerequiredestablishingnewmethodsforgenerationofin vitrocelllinesfromprimarytumorsaswellasanimalmodelsandin vitroassays.FortheinitialPhaseItrialbegunin1997,thenewallogeneiclinesweregeneticallymodifiedtoexpressGM-CSFandclinicalgradevaccinewasproducedbyacontractmanufacturerusingfundsprovidedbyaprivatedonor.ThevaccinedevelopmentandclinicaltrialcostswerefundedbyacombinationofNCIR01,SPORE,andtrainingawards.APhaseIItrialwasinitiatedin1999undertheHopkinsGISPOREusingvaccinepreparedbytheNCIRapidAccesstoInterventionDevelopment(RAID)program.

Asdevelopmentprogressed,theJohnsHopkinsgroupappliedforandreceivedU.S.patentscoveringabroadmethodfortreatingpancreaticcancerusingallogeneicpancreatictumorcelllinesmodifiedtoproduceacytokinethatstimulatesanantitumorresponseaswellasspecificcelllinesandcelllineproductionmethods.Thesepatentsandtheunderlyingvaccinetechnologywerelicensedin2001toCellGenesys,whoprovidedadditionalfundingfortheinitialPhaseIItrial.CellGenesysthensupportedasecondPhaseIItrialinmetastaticpatientscomparingthevaccinealonewithvaccineplusimmunemodulatingdosesofcyclophosphamidetodepleteregulatoryTcells.TwoadditionalPhaseIItrialsarealsonowunderway—oneexaminingthevalueofboostervaccinationsandthesecondtestingthevaccineincombinationwithcyclophosphamideandcetuximab.

Basedonthesuccessofthiscell-basedvaccinedevelopmentprogram,in2001JohnsHopkinsbegantodevelopaGMPvaccinemanufacturingcapabilityasaCancerCenterP30-supportedcoreresource.Thisfacilitybecamefullyoperationalin2004andhasfacilitatedrefinementofseveralothervaccinedevelopmentconceptsandexpandedthepoolofJohnsHopkinsinvestigatorsdevelopingvaccinesforclinicaltrials.


DevelopmentofthevaccinefollowedtheimmuneresponsemodifierpathwaythroughmultipleiterationsstartingwithautologousvaccinestestedinPhaseItrialsforseveraldifferentcancersbeforefocusingonanallogeneicvaccineforpancreaticcancerastheprimarydevelopmentalfocus.

Bottlenecks

Theprimarybottleneckidentifiedbytheinvestigatorwasmanufacturing.FundsfromprivatesourceswereneededforinitialPhaseImanufacturingandwithoutinvolvementoftheNCIRAIDprogramthevaccinemayneverhaveproceededtoPhaseIItrials.ThisexperienceledtheCancerCenteratJohnsHopkinstodevelopaGMPvaccinemanufacturingfacilityasacoreresource.



Key Observations

1. Intheareaofimmuneresponsemodifiers,itcanbedifficulttoobtainR01fundingfor“credentialing”adiscoveryforentryintotheTRWGdevelopmentalpathway.Becausetheapproachescanbequitenovel,researchersoftenmustusetrainingawards,SPOREfunds,orotherfundingsourcestoconductthenecessarystudies.

2. Completingthelaterstagesofdevelopment(e.g.,manufacturingandearly-stagetrials)requiredtheinvestigatortoassemblefundsfromseveraldifferentgovernmentprogramsaswellasprivatesources.

3. MultiplePhaseItrialsofinitialvaccineconceptswerenecessarytoprovideproofofprincipleandidentifydevelopmentalbottleneckstobeovercome(i.e.,promisingresultswithautologousvaccinesleadtodevelopmentofamorepracticalallogeneicversion).

4. Successfulhandofftoindustryforfurtherdevelopmentwasfacilitatedbyastrongintellectualpropertyposition,RAIDfundingofvaccineproduction,andSPOREfundingofaninitialPhaseIItrial.

5. Anacademicmedicalcenter’sinvestmentinGMPmanufacturingcapabilitiescanleadtosubstantialexpansionofrelatedtranslationalresearchattheinstitution.

Sources

• InterviewwithDr.ElizabethJaffee,JohnsHopkinsUniversity(February1,2006)

Literature

• DranoffG,JaffeeE,LazenbyA,GolumbekP,LevitskyH,BroseK,JacksonV,HamadaH,PardollD,MulliganRC.Vaccinationwithirradiatedtumorcellsengineeredtosecretemurinegranulocyte-macrophagecolony-stimulatingfactorstimulatespotent,specific,andlong-lastinganti-tumorimmunity.ProcNatlAcadSci.1993;90(8):3539-43.

• JaffeeEM,SchutteM,GossettJ,MorsbergerLA,AdlerAJ,ThomasM,GretenTF,HrubanRH,YeoCJ,GriffinCA.Developmentandcharacterizationofacytokine-secretingpancreaticadenocarcinomavaccinefromprimarytumorsforuseinclinicaltrials.CancerJSciAm.1998;4(3):194-203.

• JaffeeEM,AbramsR,CameronJ,DonehowerR,DuerrM,GossettJ,GretenTF,GrochowL,HrubanR,KernS,LillemoeKD,O’ReillyS,PardollD,PittHA,SauterP,WeberC,YeoC.AphaseIclinicaltrialoflethallyirradiatedallogeneicpancreatictumorcellstransfectedwiththeGM-CSFgeneforthetreatmentofpancreaticadenocarcinoma.HumGeneTher.1998;9(13):1951-71.

• JaffeeEM,HrubanRH,BiedrzyckiB,LaheruD,SchepersK,SauterPR,GoemannM,ColemanJ,GrochowL,DonehowerRC,LillemoeKD,O’ReillyS,AbramsRA,PardollDM,CameronJL,YeoCJ.Novelallogeneicgranulocyte-macrophagecolony-stimulatingfactor-secretingtumorvaccineforpancreaticcancer:aphaseItrialofsafetyandimmuneactivation.JClinOncol.2001;19(1):145-56.

Patent Search

• Jaffeeetal.Methodoftreatingcancerwithatumorcelllinehavingmodifiedcytokine(#6,033,6�4).FiledDecember26,1996;receivedMarch7,2000.

• Jaffeeetal.Purifiedpancreatictumorcelllinesandrelatedcompositionsandmethod(#5,985,290).FiledMarch18,1998;receivedNovember16,1999.Subsequentpatentsinclude#6,193,9�0and#6,350,445.

• Jaffeeetal.Growthmediumforprimarypancreatictumorcellculture(#6,087,174).FiledMarch18,1998;receivedJuly11,2000.



Radiofrequency Ablation

Summary

Radiofrequency(RF)ablationuseselectromagneticenergytoheatanddestroytissue.Thetechniquewasinitiallydevelopedforuseincardiology,primarilyasatreatmentforarrhythmias,andtheFDAapprovedcardiacRFablationdevicesin1994.Inearly1995,ItalianclinicianspresentedaseriesofcasereportsonusingRFablationtotreatlivercancerandresearchersattheUniversityofCaliforniaDavisreportedresultsfromRFablationofprostatetissueindogs.Duringtheperiod1995-1997,investigatorsatmultipleinstitutionsintheUnitedStatesandEuropereportedanumberofanimal,phantom,andexploratoryhumanstudiesexaminingRFablationforuseincancerintervention.Themajorityofthisworkwassupportedbyadhoclocalfundingratherthanbyatraditionalgrantmechanism.

ThefirstformalPhaseItrial,performedbyresearchersatCaseWesternReserveUniversity,wasreportedin1998.EvenafterthisfirstPhaseItrial,multipleresearchgroupsworldwidecontinuedtoexamineRFablationinbothphantomandanimalstudiesinordertorefineprocedures.AlthoughsomeofthesestudieswereNCIfundedthroughR01andSBIRawardsaswellasoneSPOREproject,mostofthepreclinicalworkwasfundedbyindustry.MultipleNCI-fundedPhaseIItrials,primarilyinpatientswithliverorrenalcancerwhowerenotcandidatesforsurgicalresection,werecarriedoutbeginninginthelate1990s.APhaseIIItrialcomparingsurgerydirectlywithRFablationinrenalcarcinomawasinitiatedin2005inFranceandisstillaccruingpatients.


AsRFablationdeviceswereoriginallydevelopedandFDAapprovedforanononcologypurpose,translationintooncologyproceededwithclinicalstudiesbeingconductedinparallelwithstudiesonphantomsandanimalsratherthaninsequentialfashionasdescribedbythepathway.

Bottlenecks

Therewerenosignificantbottlenecksencountered.

Key Observations

1. Interventionaldevicedevelopmentoftenproceedsthoughalearn-by-doingapproachwherebyclinicaltrial-and-errorisusedtorefinethetechniqueratherthanproceedingthroughastructuredpreclinicalvalidationprocessleadingtodefinitiveclinicaltrials.

2. Becauseinterventionaldevicedevelopmentisstronglydrivenbyindustry,particularlysmallcompanies,devicesareoftenmovedforwardintoclinicaltrialsandclinicalpracticewithoutsubstantialoptimization.Onceadeviceisapproved,itisdifficulttoobtaineitherindustryorgovernmentfundingforoptimizingitsuse(e.g.,optimizingthetime,size,andprecisionofRFablationtherapy).

3. Developmentofastrongerpreclinicaltestinginfrastructureforinterventionaldevicesmaybebeneficialinthelongrunasmoreeffortwouldbepaidtooptimization(andtheutilityofthetechniquerelativetocompetingapproaches)beforethedeviceisbroughtintotheclinic.

4. Developmentofastrongerearlyclinicaltestinginfrastructureforinterventionaldevices(comparabletotheCooperativeGroups)andmechanismsformulticenterdatabasereportingwillbeimportanttoensureefficienttranslationofpreclinicalstudiesandrobustevaluationofsafetyandefficacy.

Sources

• FDACenterforDevicesandRadiologicalHealth,Devices@FDAdatabase



• InterviewwithDr.NahumGoldberg,BethIsraelDeaconessMedicalCenter(February7,2006)

Literature

• ManolisAS,WangPJ,EstesNAIII.Radiofrequencycatheterablationforcardiactachyarrhythmias.AnnInternMed.1994;121(6):452-61.

• BuscariniL,RossiS,FornariF,DiStasiM,BuscariniE.Laparoscopicablationofliveradenomabyradiofrequencyelectrocauthery.GastrointestEndosc.1995;41(1):68-70.

• McGahanJP,GriffeySM,BudenzRW,BrockJM.Percutaneousultrasound-guidedradiofrequencyelectrocauteryablationofprostatetissueindogs.AcadRadiol.1995;2(1):61-5.

• DjavanB,SusaniM,ShariatS,ZlottaAR,SilvermanDE,SchulmanCC,MarbergerM.Transperinealradiofrequencyinterstitialtumorablation(RITA)oftheprostate.TechUrol.1998;4(2):103-9.

• LewinJS,ConnellCF,DuerkJL,ChungYC,ClampittME,SpisakJ,GazelleGS,HaagaJR.InteractiveMRI-guidedradiofrequencyinterstitialthermalablationofabdominaltumors:clinicaltrialforevaluationofsafetyandfeasibility.JMagnResonImaging.1998;8(1):40-7.

• AhmedM,LiuZ,AfzalKS,WeeksD,LoboSM,KruskalJB,LenkinskiRE,GoldbergSN.Radiofrequencyablation:effectofsurroundingtissuecompositiononcoagulationnecrosisinacaninetumormodel.Radiology.2004;230(3):761-67.

• GoldbergSN,BonnJ,DoddG,DupuyD,GeschwindJ,HicksM,HumeKM,LeeFT,LewisCA,LencioniRA,OmaryRA,RundbackJH,SilvermanS,DorfmanGS,SocietyofInterventionalRadiologyInterventionalOncologyTaskForce.Interventionaloncologyresearchvisionstatementandcriticalassessmentofthestateofresearchaffairs.JVascIntervRadiol.2005;16:1287-94.



Three-Dimensional Conformal Radiation Therapy for Prostate Cancer

Summary

Radiationtherapyrequirescarefulplanningtodirecttheradiantenergytotumortissuewhilelargelysparingsurroundinghealthytissue.Inthe19�0s,thearrivalofCTscantechnologygaveclinicians,forthefirsttime,detailedanatomicalinformationaboutthelocationofatumoranditssurroundingtissue.Three-dimensional(3-D)visualizationwasperformedmanuallybyusingmultiple2-DCTimagestodeterminetheoptimalgeometryforradiationdelivery.Althoughcomputerswereappliedtoradiotherapytreatmentplanningasearlyas1955,thehugegrowthincomputerpowerthroughthe1970sand1980smadepossiblethedevelopmentofalgorithmsforaccuratethree-dimensionalvisualizationofatumorandcreationofmoreoptimalradiationtreatmentplans,offeringthepotentialfordecreasederrorratesandincreaseddosesofradiationtocanceroustissue.

Duringthelate1970sandearly1980s,developmentofcomputer-assistedthree-dimensionaltumorvisualizationandradiationtherapytreatmentplanningwasundertakensimultaneouslybymanygroupsofinvestigators.Thefirst3-DplanningdevelopmentswerereportedbyMcShanetal.atRhodeIslandHospital(laterrelocatedtotheUniversityofMichigan)andGoitein,etal.,atMassachusettsInstituteofTechnologyandMassachusettsGeneralHospital(MGH).By1987,manygroupsweredeveloping3-Dplanningsystems.

Theearliestuseof3-DsystemsoccurredintheparticletherapyeffortsatMGHandtheUniversityofCaliforniaatBerkeley,whileroutineclinicaluseofafullyintegrated3-Dplanningsystemstartedin1986attheUniversityofMichigan.Duringthemidandlate1980s,NCIusedtheN01contractmechanismtofunddevelopmentandcomparisonstudiesofbothphotonandelectron3-Dplanningatanumberofinstitutions.Thesestudiesfurtherdocumentedthepotentialvalueof3-Dplanningbytestingthemethodologyinparallelatmultipleinstitutionsinordertodemonstratereproducibilitywhenusedbydifferentmachinesandoperators.

ThefirstPhaseItrialofthethree-dimensionaltumorlocalizationandtreatmentplanningsystembeganin198�attheUniversityofMichiganwithdoseescalationtrialsinprostateandlivercancer,followedbyalargerdoseescalationprostatecancertrialin1991atMemorialSloan-KetteringCancerCenterusingNCIP01funding.Duringthelate1980sandearly1990s,investigatorsatseveralinstitutions,someusingN01orP01funding,continuedtomakeimprovementsinthealgorithmsandcapabilitiesofthesystemsandtoextendtheiruseinclinicalsettings.AnumberofPhaseI/IItrialswereperformedinsingleinstitutionsettingsthroughthelate1990s,somewithNCIfunding.


Developmentofthree-dimensionalconformalradiationtherapyfollowedtheinterventionaldevicepathwayclosely.However,becauseofthenatureofthetechnology,itwaspossibletointroduceuseofthree-dimensionalconformalradiationtherapyintoclinicalpracticeinadvanceofcontrolledPhaseIandIItestingofitsutilityinguidingenhancedtherapyregimenssuchasdoseescalation.

Bottlenecks

Nosignificantearlytranslationalbottleneckswerereported.

Key Observations

1. Developmentrequiredthatmultipleinstitutionsbeinvolvedinboththevalidationphaseandinclinicaltrialstoensurethatoperator/machinerycharacteristicsdidnotbiastheresults.

2. AcombinationofNCIcontractandgrantfundingwasusedtosupportboththevalidationandearlyclinicaltrialphases.



Sources

• InterviewwithDr.TedLawrence,UniversityofMichigan(December29,2005)

Literature

• DLMcShan,ASilverman,DLanza,LEReinstein,ASGlicksman:Acomputerizedthree-dimensionaltreatmentplanningsystemutilizinginteractivecolorgraphics.BritJRad.1979;52:478-81.

• GoiteinM,AbramsM,RowellD,PollariH,WilesJ.Multi-dimensionaltreatmentplanning:II:Beam’seye-view,backprojection,andprojectionthroughCTsections.IntJRadiatOncolBiolPhys.1983;9(6):780-97.

• GWSherouse,CEMosher,KNovine,JRosenman,EChaney:Virtualsimulation:conceptandimplementation.In:BruinvisIAD,vanderGiessenFH,vanKleffensHJ,WittkamperFW,eds.TheUseofComputersinRadiationTherapy.North-Holland:Elsevier;1987,pp.423-36.

• MohanR,BarestG,BrewsterLJ,ChuiCS,KutcherGJ,LaughlinJS,FuksZ.Acomprehensivethree-dimensionalradiationtreatmentplanningsystem.IntJRadiatOncolBiolPhys.1988;15(2):481-95.

• McShanDL,FraassBA,LichterAS.Fullintegrationofthebeam’seyeviewconceptintocomputerizedtreatmentplanning.IntJRadiatOncolBiolPhys.1990;18(6):1485-94.

• TSLawrence,RJTesser,RKTenHaken:Anapplicationofdosevolumehistogramstotreatmentofintrahepaticmalignancieswithradiationtherapy.IntJRadOncolBiolPhys.1990;19:1041-7.

• SimpsonJR,PurdyJA,ManolisJM,PilepichMV,BurmanC,FormanJ,FuksZ,ChengE,ChuJ,MatthewsJ,etal.Three-dimensionaltreatmentplanningconsiderationsforprostatecancer.IntJRadiatOncolBiolPhys.1991;21(1):243-52.

• SandlerHM,Perez-TamayoC,TenHakenRK,LichterAS.DoseescalationforstageC(T3)prostatecancer:Minimalrectaltoxicityobservedusingconformaltherapy.RadiotherOncol.1992;23:53-4.

• LeibelSA,ZelefskyMJ,KutcherGJ,BurmanCM,KelsonS,FuksZ.Three-dimensionalconformalradiationtherapyinlocalizedcarcinomaoftheprostate:interimreportofaphase1dose-escalationstudy.JUrol.1994;152(5Pt2):1792-8.



Exercise, Diet, and Breast Cancer

Summary

Intheearly1990s,severalobservationalstudieswerereportedindicatingthatexcessweightandobesityareassociatedwithpoorerprognosisandsurvivalforbreastcancerpatients.Additionally,aspartofanNCI-fundedcohortstudythathasfollowed1,185breastcancercasesfor10years,theMcTiernangroupattheFredHutchinsonCancerResearchCenterinterviewedstudyparticipantstodeterminephysicalactivitybothpre-andpostdiagnosis.Inpreliminaryanalyses,theynotedthatwomenwhowerephysicallyactivebothpre-andpostdiagnosishadlowerrecurrenceofbreastcancer,whichsuggestedthatincreasingactivitycouldpotentiallyimproveprognosis.

However,becauseweight,diet,andphysicalactivityarehighlycorrelated,itwasdifficulttoassesstheirindependentcontributionstobreastcancerprognosisfromsuchobservationalstudies.Therefore,theMcTiernangroupconductedapilotdiet-exerciseinterventionstudy(fundedbyaClinicalResearchCenterawardfromtheNationalCenterforResearchResources)innineoverweight,sedentarybreastcancerpatientstotestthefeasibilityofsuchatrial.Theresultsreportedin1998indicatedthatrecruitmentsuccessandcompliancewereveryhighandthatsignificantreductionsinweight,bodyfat,bloodpressure,andpulsewereachieved.

Basedonthefeasibilitydemonstratedbythispilotstudy,theMcTiernangroupobtainedanNCIR01grantin1997whichfundedrandomizedcontrolledstudiesexaminingtheeffectofa1-year,moderateintensityexerciseprogramonhormonelevels(asapotentialsurrogateforoutcome)ofapproximately170sedentary,overweightpostmenopausalwomen.Resultsshoweddecreasesinserumestrogen,testosterone,andinsulin,whichmayexplaintheassociationofexercisewithreducedcancerrecurrence.Largeobservationalstudiesontherelationshipofexercise,diet,andsexhormoneorinsulinlevelsonbreastcancerriskcontinuetobereported,butnofurtherlarge,controlledinterventionalstudieshavebeenpublished.


Assessingeffectivenessofexerciseanddietonbreastcancerriskfollowedthelifestyleinterventionpathwayclosely.

Bottlenecks

TheprimarybottleneckreportedwasaperceivedlowpriorityforlifestyleinterventionresearchatNCI.OtherInstitutessuchastheNationalInstituteofDiabetesandDigestiveandKidneyDiseasesandtheNationalHeart,Lung,andBloodInstitutewerecharacterizedasbeingmoreaccustomedtofundingthistypeofresearch.

Key Observations

1. Small,carefullycontrolledpilotstudiesoflifestyleinterventionsarecriticaltoestablishfeasibilityofpatientrecruitmentandcompliance.

2. ItisdifficulttofundpilotlifestyleinterventionstudieswithtraditionalNCIgrants.ItisoftenusefultouseCancerCenterorotherinfrastructureresourcestofundsuchpilotstudiesandbuildthepremiseformoredefinitivetrials.

Sources

• InterviewwithDr.AnneMcTiernan(February7,2006)

Literature

• McTiernanA,UlrichC,KumaiC,BeanD,SchwartzR,MahlochJ,HastingsR,GralowJ,PotterJD.Anthropometricandhormoneeffectsofaneight-weekexercise-dietinterventioninbreastcancerpatients:resultsofapilotstudy.CancerEpidemiolBiomarkersPrev.1998;7(6):477-81.



• ChlebowskiRT,AielloE,McTiernanA.Weightlossinbreastcancerpatientmanagement.JClinOncol.2002;20(4):1128-43.

• McTiernanA,TworogerSS,RajanKB,YasuiY,SorensonB,UlrichCM,ChubakJ,StanczykFZ,BowenD,IrwinML,RudolphRE,PotterJD,SchwartzRS.Effectofexerciseonserumandrogensinpostmenopausalwomen:a12-monthrandomizedclinicaltrial.CancerEpidemiolBiomarkersPrev.2004;13(7):1099-105.

• McTiernanA,TworogerSS,UlrichCM,YasuiY,IrwinML,RajanKB,SorensenB,RudolphRE,BowenD,StanczykFZ,PotterJD,SchwartzRS.Effectofexerciseonserumestrogensinpostmenopausalwomen:a12-monthrandomizedclinicaltrial.CancerRes.2004;64(8):2923-8.



Smoking Cessation and Lung Cancer

Summary

Becauseofthewell-documentedcausaleffectofsmokingonlungcancerandpreviousstudiesofsmokingcessationinterventioninothertypesofcancer,arandomizedtrialofasmokingcessationinterventionforearly-stagelungcancerpatientswasdesignedbyDrs.Gritz(M.D.AndersonCancerCenter)andAlbain(LoyolaUniversity)intheCancerControlResearchCommitteeoftheSouthwestOncologyGroup(SWOG).ThetrialwasimplementedinSWOGandotheraffiliatedcooperativeoncologygroups.Becausepreviousworkhadidentifiedinterventionsthatwouldfacilitatesmokingcessation,apilotstudywasnotconductedinadvanceofstartingthisPhaseIIItrialin2002.However,membersoftheSWOGLungCommitteeweresurveyedregardingtheirsupportofthistrialpriortoitsinceptionandtheresponsewasextremelypositive.Smokingstatusdatawerealsosampledfromapriorclinicaltrialinlungcancerpatientstoestimatesmokingprevalenceintherelevantpopulation.Theinvestigatorsobtainedsupportfromapharmaceuticalcompanytocarryoutthisstudy.

After2yearsofimplementation,activetrainingattwoSWOGmeetings/year,andsignificantoutreachtoothercooperativegroups,thetrialwasclosedduetolackofaccrual.Accrualbarriersincluded(a)difficultyinaccessingpatients,asstageIandIIlungcancerpatientsaregenerallytreatedbysurgeons,notbymedicaloncologists;(b)lackofincentivesforinvestigatorstoparticipate,duetolow-levelreimbursementperpatient;and(c)perceiveddifficultiesinconductingtheinterventionandfollow-up,asnursesandSWOGpatientcoordinatorsaremoreaccustomedtomedicalinterventionswhichrequirelesspatient-completedassessment.


Developmentofthesmokingcessationinterventiondidnotfollowthepathwayinthatapilotstudytoassessfeasibilitywasnotconducted.

Bottlenecks

Theprimarybottleneckwasextremedifficultyinaccruingpatientstothisinterventiontrial.SignificantdelaysinreceivingNCIapprovaltoconductthetrialandtheneedtoobtainexternalfundingwerealsobarriers.

Key Observations

1. Pilotstudiestoassessfeasibilityofpatientrecruitmentandcomplianceaswellasotherlogisticalaspectsofalargedefinitivetrialarecriticalelementsinsuccessfullifestyleinterventiondevelopment.

2. Lifestyleinterventionstudiesincancersurvivorsarenotahighpriorityforoncologycooperativegroupsandrequireintensiveeffortstodevelop,fund,accruepatients,andsuccessfullycomplete.Inthiscase,thelattertwoobjectiveswerenotachieved.

Sources

• InterviewwithDr.EllenGritz,TheUniversityofTexasM.D.AndersonCancerCenter(February7,2006).

Literature

• GritzER,NisenbaumR,ElashoffRE,HolmesEC.SmokingbehaviorfollowingdiagnosisinpatientswithstageInon-smallcelllungcancer.CancerCausesControl.1991;2(2):105-12.



• GritzER,CarrCR,RapkinD,AbemayorEA,ChangLJ,WongWK,BelinTR,CalcaterraT,RobbinsKT,ChonkichG,BeumerJ,WardPH.Predictorsoflong-termsmokingcessationinheadandneckcancerpatients.CancerEpidemiolBiomarkersPrev.1993;2(3):261-70.

• GritzER,SchachererC,KoehlyL,NielsenIR,AbemayorE.Smokingwithdrawalandrelapseinheadandneckcancerpatients.HeadNeck.1999;21(5):420-7.

• GritzER,DreslerC,SarnaL.Smoking,themissingdruginteractioninclinicaltrials:ignoringtheobvious.CancerEpidemiolBiomarkersPrev.2005;14(10):2287-93(andreferencescitedtherein).


Report of the NCAB Translational Research Working Group—Appendix F

Appendix F: TRWG Meeting Dates

2005

November15-21TRWGConferenceCalls

December4-5TRWGFace-to-FaceMeetingBaltimore,MD

December7PresentationtoNationalCancerAdvisoryBoardBethesda,MD

2006

February23-24TRWGFirstPublicRoundtablePhoenix,AZ

March23-24TRWGFace-to-FaceMeetingBethesda,MD

April24TRWGIndustry,Foundation,SocietyRoundtablePhiladelphia,PA

May30-31TRWGFace-to-FaceMeetingHouston,TX

June14InterimReporttoNationalCancerAdvisoryBoardBethesda,MD

June30InterimReporttoNCIBoardofScientificAdvisorsBethesda,MD

August16-17TRWGFace-to-FaceMeetingChicago,IL

September14-15TRWGFace-to-FaceMeetingHerndon,VA

October16-17TRWGSecondPublicRoundtableAtlanta,GA

November27-28TRWGFace-to-FaceMeetingBethesda,MD

2007

January17-18TRWGFace-to-FaceMeetingMillbrae,CA

Transforming Translation-Harnessing Discovery for Patient and Public Benefit

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