DATA777tk

UncorrectedAuthorProofJournalofParkinson'sDiseasexx(20xx)x–xxDOI10.
3233/JPD-150570IOSPress1PrecompetitiveDataSharingasaCatalysttoAddressUnmetNeedsinParkinson'sDisease1123DianeStephensona,,MicheleT.
Hub,KlausRomeroa,KieranBreend,DavidBurne,YoavBen-Shlomof,AtulBhattaramg,MariaIsaach,CharlesVenutoi,KenKubotaj,MaxA.
Littlek,StephenFriendl,SimonLovestonec,HuwR.
Morrism,DonaldGrossetn,MargaretSutherlando,JohnGallacherp,CarolineWilliams-Grayq,LisaJ.
Bainr,EnriqueAvilesa,KenMareks,ArthurW.
Togat,YatStarku,MarkForrestGordonvandSteveFordw45678aCriticalPathInstitute,CAMD,Tucson,AZ,USA9bNufeldDepartmentofClinicalNeurosciences,UniversityofOxford,NeurologyDepartment,Level3,WestWing,JohnRadcliffeHospital,HeadleyWay,Headington,Oxford,UK1011cDepartmentofPsychiatry,UniversityofOxford,WarnefordHospital,Oxford,UK12dScienticconsultant,London,UK13eHenryWellcomeBuilding,FacultyofMedicalSciences,NewcastleUniversity,NewcastleuponTyne,UK14fUniversityofBristol,CanyngeHall,Bristol,UK15gUSFoodandDrugAdministration(FDA),NewHampshireAvenue,SilverSpring,MD,USA16hEMA,30ChurchillPlace,CanaryWharf,London,UK17iUofRochesterMedicalCenter,CrittendenBlvd,Rochester,NY,USA18jMichaelJFoxFoundationforParkinson'sResearch,SeventhAvenue,NewYork,NY,USA19kAstonUniversityandMIT,AstonUniversity,AstonTriangle,Birmingham,MediaLab,MassachusettsInstituteofTechnology,Cambridge,MA,USA2021lSageBionetworks,Seattle,WA,USA22mDepartmentofClinicalNeuroscience,UCLInstituteofNeurology,London,UKDepartmentofNeurology,RoyalFreeHospital,London,UKNeurology,NationalHospitalforNeurology,London,UK2324nInstituteofNeuroscienceandPsychology,UniversityofGlasgow,Scotland,UK25oNationalInstituteofNeurologicalDisordersandStroke(NINDS),NeuroscienceCenter,Bethesda,MD,USA26pDepartmentofPsychiatry,UniversityofOxfordHospital,Warneford,Oxford,UK27qDepartmentofClinicalNeurosciences,JohnVanGeestCentreforBrainRepair,UniversityofCambridge,E.
D.
AdrianBuilding,ForvieSite,RobinsonWay,Cambridge,UK2829rIndependentScientic&MedicalWriter,SavitsDrive,Elverson,PA,USA30sInstituteofNeurodegenerativeDiseases,Parkinson'sProgressionMarkersInitiative,Suite8B,NewHaven,CT,USA3132tLaboratoryofNeuroImaging,KeckSchoolofMedicineofUSC,UniversityofSouthernCalifornia,CA,USA33uTevaPharmaceuticalIndustriesLtd.
,PetachTikva,Israel34vBoehringerIngelheimPharmaceuticals,Inc.
,Ridgeeld,CT,USA35wParkinson'sUK,London,UK361SummaryofParkinson'sUK,LondonWorkshop,co-organizedbytheCoalitionAgainstMajorDiseases(CAMD)Correspondenceto:DianeT.
Stephenson,CriticalPathInstitute,1730E.
RiverRd,Tucson,AZ85718,USA.
Tel.
:+15203821405;Fax:+15205473456;E-mail:dstephenson@c-path.
org.
ISSN1877-7171/15/$35.
002015–IOSPressandtheauthors.
AllrightsreservedUncorrectedAuthorProof2D.
Stephensonetal.
/PrecompetitiveDataSharinginParkinson'sDiseaseAbstract.
Parkinson'sdiseaseisacomplexheterogeneousdisorderwithurgentneedfordiseasemodifyingtherapies.
ProgressinsuccessfultherapeuticapproachesforPDwillrequireanunprecedentedlevelofcollaboration.
AtaworkshophostedbyParkinson'sUKandco-organizedbytheCoalitionAgainstMajorDiseases(CAMD),investigatorsfromindustry,academia,governmentandregulatoryagenciesagreedontheneedforsharingofdatatoenablefuturesuccess.
GovernmentagenciesincludedEMA,FDA,NINDS/NIHandIMI(InnovativeMedicinesInitiative).
EmergingdiscoveriesinnewbiomarkersandgeneticendophenotypesarecontributingtoourunderstandingoftheunderlyingpathophysiologyofPD.
Inparallelthereisgrowingrecognitionthatearlyinterventionwillbekeyforsuccessfultreatmentsaimedatdiseasemodication.
Atpresent,thereisalackofacomprehensiveunderstandingofdiseaseprogressionandthemanyfactorsthatcontributetodiseaseprogressionheterogeneity.
Noveltherapeutictargetsandtrialdesignsthatincorporateexistingandnewbiomarkerstoevaluatedrugeffectsindependentlyandincombinationarerequired.
Theintegrationoflargeclinicaldatasetsisviewedasapowerfulapproachtohastenmedicaldiscoveryandtherapies,asisbeingrealizedacrossdiversediseaseconditionsemployingbigdataanalyticsforhealthcare.
Theapplicationoflessonslearnedfromparalleleffortsiscriticaltoidentifybarriersandenableaviablepathforward.
Aroadmapispresentedforaregulatory,academic,industryandadvocacydrivenintegratedinitiativethataimstofacilitateandstreamlinenewdrugtrialsandregistrationsinParkinson'sdisease.
3738394041424344454647484950Keywords:Datastandards,privacy,dataintegration,collaboration,quantitativediseaseprogression,regulatoryscience51ABBREVIATIONS37CamPaIGNCambridgeshireParkinson'sIncidencefromGPtoNeurologistOxfordPDTheOxfordParkinson'sDiseaseCentre(OPDC)DiscoverycohortTrackingPDParkinson'sRepositoryofProBaNDBiosamplesandNetworkedDatasetsPPMIParkinson'sProgressionMarkerInitiativeADAGIOAttenuationofDiseaseprogressionwithAzilectGivenOnceDailyDATATOPDeprenylandtocopherolantioxidativetherapyofparkinsonism)PRECEPT(ParkinsonResearchExaminationofCEP-1347Trial)SWEDDScanswithoutevidenceofdopaminedeciencyGLOSSARYOFTERMS38PDParkinson'sdiseaseACE-RAddenbrooke'sCognitiveExaminationRevisedADAlzheimer'sdiseaseADAGIOAttenuationofDiseaseProgressionwithAzilectGivenOnce-dailyADNIAlzheimer'sDiseaseNeuroimagingInitiativeALSAmyotrophicLateralSclerosisCAMDCoalitionAgainstMajorDiseasesCamPaIGNCambridgeshireParkinson'sIncidencefromGPtoNeurologistCDECommonDataElementsCDISCClinicalDataInterchangeStandardsConsortiumCHETCenterforHumanExperimentalTherapeuticsCODRC-PathOnlineDataRepositoryC-PathCriticalPathInstituteCSFCerebrospinalFluidDESCRIPADevelopmentofScreeningGuidelinesandCriteriaforPredementiaAlzheimer'sdiseaseDMRDataManagementResourceDPUKDementiasPlatformUKDTI/RSMRIDiffusionTensorImaging/RestingStateMRIEMAEuropeanMedicinesAgencyEMIFEuropeanMedicalInformationFrameworkETEssentialTremorFDAUSFoodandDrugAdministrationGAAINGlobalAlzheimer'sAssociationInteractiveNetworkICICLE-PDIncidenceofCognitiveImpairmentinCohortswithLongitudinalEvaluationPDIDAImagingDataArchiveIMIInnovativeMedicinesInitiativeIRBInstitutionalReviewBoardLONILaboratoryofNeuroImagingMDS-UPDRSMovementDisordersSociety-UPDRSMMSEMini-MentalStateExaminationMRIMagneticResonanceImagingMSAMultisystemAtrophyMSOACMultipleSclerosisOutcomesAssessmentConsortiumUncorrectedAuthorProofD.
Stephensonetal.
/PrecompetitiveDataSharinginParkinson'sDisease3NET-PDNIHExploratoryTrialsinPDNIHNationalInstituteofHealthNINDSNationalInstituteonNeurologicDisordersandStrokeOPDCOxfordParkinson'sDiseaseCentreParkinson'sUKParkinson'sUnitedKingdomPDPBParkinson'sdiseaseBiomarkersProgramPICNICSParkinsonism:IncidenceandCognitiveHeterogeneityinCambridgeshirePPMIParkinsonProgressionMarkerInitiativePRECEPTParkinsonResearchExaminationofCEP-1347TrialPRO-ACTPooledResourceOpen-AccessALSClinicalTrialsDatabaseProBaNDParkinson'sRepositoryofBiosamplesandNetworkedDatasetsPSGParkinson'sStudyGroupPSPProgressiveSupranuclearPalsySPECTSingle-photonEmissionComputedTomographySWEDDScansWithoutEvidenceofDopaminergicDecitUPDRSUniedParkinson'sDiseaseRatingScaleTHINTheHealthImprovementNetworkINTRODUCTION39Parkinson'sdisease(PD)isthesecondmostcommon40neurodegenerativediseaseafterAlzheimer'sdisease41(AD)[1].
Primarilyadiseaseofadultsovertheageof4260whomayalsohaveothercomorbidities,about4%of43casesbeginpriortotheageof50[2].
44TherapeuticgoalsforPDarebasedonsymptomatic45relief,buthaltingorslowingtheneurodegenera-46tiveprocessandthepreventionoflong-termadverse47outcomesrepresenturgentunmetneeds.
Available48dopamine-basedtherapeuticstrategiesachievethe49reductionofmotorsymptoms,butdonotsignicantly50impactonthenumerousnon-motormanifestationsof51PD[3].
Fluctuationphenomenaanddyskinesiaremain52achallenge,particularlyinlong-termtreatment[4].
It53isnowrecognizedthattherstsignsofmotorimpair-54mentinPD(earlymotorPD)isprecededformany55yearsbypathologicchanges(reduceddopaminenerve56terminalfunction)andavarietyofotherbiomarker57changesincludingrapideyemovement(REM)sleep58behavioraldisturbances,GIdisturbancesandolfactory59decits.
60Amajorchallengeisourlackofunderstanding61ofdiseaseprogressionandheterogeneity.
Despitethe62manydiseasemodifyingtherapiestestedtodate,there63isalackofretrospectivelearningfromthesecostly64clinicaltrials.
Forexample,analysisofthefailedPRE-65CEPTstudy[5]illustratesthatmanysubjectswho66wereenrolleddidnothaveevidenceofdopaminergic67decitordiseaseprogressionandthuswereunlikely68tohavePD.
Atpresent,theeldlacksacomprehen-69sive,standardizedandintegrateddatabaseofrelevant70longitudinalstudiesandclinicaltrialsinPD.
71Bigdataanalyticsinhealthcarehasevolvedsigni-72cantlyasaninnovativeapproachforprovidinginsight73fromverylargedatasetswiththegoalofimprov-74ingpatientoutcomesinclinicalpracticeanddrug75development.
Otherdiseaseshaveundergoneefforts76tostandardizeandintegraterelevantdata,whichhave77advancedtherapeutictrialdesignsandenabledmodel-78baseddrugdevelopmentandpersonalizedmedicine79strategies.
Examplesinclude:fromtheoncologyeld,80DataSphere[6],fromAmyotrophicLateralScle-81rosis(ALS),thePRO-ACTdatabase[7,8],from82Alzheimer'sdisease,TheCriticalPathInstitute(C-83Path)OnlineDataRepository(CODR)[9];andfrom84MultipleSclerosis,theMultipleSclerosisOutcomes85AssessmentConsortium(MSOAC)database[10].
PD86standstobenetfromapplyingsuchlearnings,par-87ticularlygiventheadvancesinourunderstandingof88thesediseasesandvastamountsofdatanotpresently89availableforbroaduse.
90Thefutureofopenscienceiscatalyzedbythe91expandinglandscapeofprecompetitivecollaborative92consortia.
Theterm'precompetitive'referstocollab-93orationonprojectsofmutualbenetbetweendiverse94stakeholders,includingindustrypartnersthatmaypro-95ducecompetinggoodsorcommercialproductslater96intheR&Dprocess.
Precompetitivecollaboration97improvestheprospectsofallstakeholdersrelativeto98commonchallengestheyface.
Itcanalsobenetthe99publicbyreducingduplicationofeffort,increasing100theeffectivenessofR&Dinvestments,andestablish-101ingcommonstandardsandresources.
Consortiaand102precompetitivecollaborationsarehighlightedinthe103recentNatureReviewsDrugDiscoveryissuededi-104catedtoUSprecompetitiveconsortia[11](http://www.
105nature.
com/nrd/focus/consortia/index.
html)andare106embracedinEuropethroughtheInnovativeMedicines107Initiative(IMI)[12,13]withendorsementofpublic108privatepartnerships[14].
109UncorrectedAuthorProof4D.
Stephensonetal.
/PrecompetitiveDataSharinginParkinson'sDiseaseTobegindevelopingastrategicframeworkfocused110ondatasharingasthepathtowardssuccessful111drugdevelopmentinParkinson'sdisease,Parkin-112son'sUnitedKingdom(Parkinson'sUK)conveneda113meetinginLondoninMay,2014.
Diversestakehold-114ersincludedrepresentativesfromacademia,patient115advocacyandcharitableorganizations,government116agencies,regulatoryagenciesandprecompetitivecon-117sortia.
Thegoalsofthismeetingweretoidentify118questionsthat,ifanswered,couldtangiblyimpactPD119drugdevelopment,explorehowexistingdatamight120provideanswerstothosequestions,andidentifythe121barrierstousingthosedata,withthegoalofmap-122pingoutapathforward.
Inparallelwiththeabove123efforts,notably,governmentagencieshavealsoiniti-124ateddevelopmentofstrategicrecommendationsthat125aredesperatelyneededtollthegapsinPDresearch126anddrugdevelopment.
Forexample,inJanuary,2014127theNationalInstituteonNeurologicDisordersand128Stroke(NINDS)convenedanexpertmeetingaimed129atbuildingconsensusonresearchprioritiesforPD130acrossbasic,clinical,andtranslationaldomains[15].
131Bigdatawasakeyareaoffocusandastrategicpriority132forthefuture.
Recognizingthatpoolingandsharing133dataisacostlyendeavorthatrequirescollaboration134fromdiversestakeholders{e.
g.
,[16]},workshoppar-135ticipantsaddressedimpedimentstodatasharingand136potentialsolutionsthathavegainedtractioninother137elds.
Theyalsoconsiderednewdatasourcesincluding138datacollectedfrompersonal-andhome-monitoring139devices,whichmayproviderelevantmeasuresofthe140functionalimpairmentsassociatedwithPD.
Finally,141theymappedoutplansforusingthesedatatobuild142quantitativedrugdevelopmenttoolsthroughregula-143torypathstoincreasetheefciencyofclinicaltrials.
144Thefollowingthemeswereidentiedasgapsin145theeldandareasoffocusduringtheParkinson's146UK/CoalitionAgainstMajorDiseases(CAMD)two-147dayworkshop:148Theneedforregulatoryapprovedendpoints,trial149designs,andmodelingtools.
150Identicationofindicatorsofveryearlydis-151easestatemarkerstofosterdevelopmentof152pre-symptomaticandpotentialneuroprotectiveor153neuromodulatorytreatments.
154Developmentofreliablebiomarkerstomonitor155diseaseprogression,particularlytoassessagents156thatmaymodifythecourseofthedisease.
157Understandingdiseasesubtypestoenablethe158straticationofpatientstoallowformoreefcient159clinicaltrials.
160REVIEWOFDATASOURCES(SEE161TABLE1)162Informationthatcouldprovidegreaterunderstand-163ingofhowPDprogressesacrossthetrajectoryofthe164diseaseliesinlargedatasetscollectedinclinicaland165observationalstudiesoverthepastdecades.
Unfortu-166nately,thesedatasetsareinherentlycomplexinnature167andhavebeenlargelyinaccessibletoresearchers,168therebylimitinginnovativeanalysesandgenera-169tionofnewknowledge.
Workshopparticipantsthus170prioritizedeffortstoobtainaccesstoanddevelopa171meansofaggregating,comparing,andanalyzingsuch172data.
Existingdatasetsheldbypharmaceuticalcompa-173niesaswellasacademicresearchgroupsweretargeted174forinclusionwiththeaimofenablingdata-sharingof175clinical,imaging,andbiomarkerdata.
Otherpotential176datasourcesincludeelectronicmedicalrecords,claims177datafrompublicandprivatepayers.
Notably,theintent178ofthismeetingwasnottocatalogueandinventoryall179possiblesourcesofPDdataglobally.
Rather,datasets180ownedbymeetingparticipantsthatmaybeavailable181forsharingweredescribedanddiscussedcollectively,182withthecommongoalofintegrationforthefuture.
183Pharmaceuticalclinicaldata,Teva184Pharmaceuticals185TevaPharmaceuticalsplanstoreleasetreatmentand186controlarmdatafromtwoclinicaltrials:PRECEPT,a187trialofthekinaseinhibitorCEP-1347,whichenrolled188806patientswithearlyPD[17];andADAGIO(Atten-189uationofDiseaseprogressionwithAzilectGivenOnce190Daily),atrialofrasagilineinearlyidiopathicPDthat191enrolled1176participants[18].
Outcomemeasuresin192PRECEPTincludedtheUniedParkinson'sDisease193RatingScale(UPDRS)and-CITSPECTimaging194ofthedopaminetransporter[5].
Thetrialterminated195earlywhenpre-speciedendpointsforfutilitywere196reached;butthesponsorcontinuedtofollowsubjects197withbiomarkerstudiesinthePostCEPTobservational198study,nowthelargestcohortofPDpatientsactively199followedinNorthAmerica.
PostCEPTprovidedblood200samplesforgeneticstudiesandcelllinerepositoryand201conductedasubstudyof-synucleinandRNAbiomark-202ers.
TheADAGIOstudyisalargerandomizedclinical203trialevaluatingtheeffectsofrasagalineinadelayedstart204design.
Thesedata,availabletotheCAMDConsortium,205willsupportdevelopmentofbiomarkersandinnovative206clinicaltrialmodelingtoolsforpavingtheregulatory207routeforParkinson'streatment.
208UncorrectedAuthorProofD.
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/PrecompetitiveDataSharinginParkinson'sDisease5Table1SourcesofParkinson'sdiseaseclinicaldataforintegrationandfutureanalysesStudyTypeofstudyNumberofpatientsDurationofstudy(iflongitudinal)Reasonforcohort(drugtrial/cohortstudy.
other)Studyongoing(yes/no)AssessmentsTissuesampleavailable(serum,plasma,CSFetc.
)GenotypedScanning(MRI,PETetc)OtherICICLELongitudinal(predictingdementia)1608yearsPredictingdementiaYesUPDRS,motor,non-motor,cognitivedeclineSerum,CSF,DNA,RNAYesMRIbaseline&18mo&FDGPETin45Gait&sleepdataCamPaIGNLongitudinal(fromtimeofdiagnosis)142(diagnosedbetween2000–2002)13–15yearsCommunity-basedincidencecohortYesUPDRS,motor,non-motor,cognitivedeclineNoYes(n=129)(MAPTH1vsH2,COMTval(158)met,SNCA,APOE,MAOA),DNAstoredNoNeuropsychologic,mood,function,qualityoflifePICNICSLongitudinal(fromtimeofdiagnosis)286(diagnosedDec2007–June2013)2–7yearsCommunity-basedcohortstudyYesUPDRS,motor,non-motor,cognitivedeclinePlasmaandserum(n=98),CSF(n=11)Yes(n=276)(MAPTH1vsH2,COMTVal158Met,SNCA,BuChE,ApoE),DNAstoredYes(n=48)Neuropsychologic,mood,function,qualityoflifeTrackingParkinson'sLongitudinal(fromtimeofdiagnosisforPD)3000(2000patientswithin3yrsofdiagnosis,240youngonsetand760relatives)3–5yearsCommunity-basedcohortstudyYesUPDRS,motor,non-motor,cognitivedeclineSerumYes,LRRK2andGBA(allsubjects)andParkinandPINK1(youngonset)Sub-studyin4-5centresOlfactoryfunction,Sleep,Autonomicfunction,Qualityoflife,EnvironmentalexposuresOPDCDiscoverycohortLongitudinal(within3yearsofdiagnosis)1650(1100PDpatientswithin3yrsofdiagnosis;100PDrelativeearlystage;150prodromalRBD;300control10yearsCommunity-basedcohortstudyYesUPDRSI-IV,motor,non-motor,cognitivedeclineSerumandDNSinall.
Plasma,CSF,G.
Ibiopsytissue,skininsubgroupYes(n=869)SNPanalysis,DNAstored.
250wholeexomeanalysis.
MRI(structuralandfunctional)in80PD,30controls,25RBDsubjectsOlfactoryfunction,Objectivemotortesting(androidphoneapptest,saccadometry)TEVA-PRECEPTLongitudinal806earlyPDTerminatedearly(averageof21.
4monthsfollow-up)ClinicaltrialNoUPDRS,cognition,depression,qualityoflifeNoNoBeta-CITSPECTimagingTEVA-ADAGIOLongitudinal1176earlyPD72weeksDelayedstartclinicaltrialNoUPDRSNoNoBeta-CITSPECTimagingRasagilineasadisease-modifyingtherapyinPDPostCept(andLABS-PD)Longitudinal709subjectsfromPRECEPTenrolledintoPostCEPTandLABS-PDOngoingsince2008Population-basedstudyYesUPDRS,qualityoflife,cognitionSerum,bloodbiomarkers(alpha-synuclein,proteomics)yes(DNAbanking)Beta-CITSPECTimaging,DATimagingPostCEPTrolledintoLABS-PD(seeref)UncorrectedAuthorProof6D.
Stephensonetal.
/PrecompetitiveDataSharinginParkinson'sDiseaseStudyTypeofstudyNumberofpatientsDurationofstudy(iflongitudinal)Reasonforcohort(drugtrial/cohortstudy.
other)Studyongoing(yes/no)AssessmentsTissuesampleavailable(serum,plasma,CSFetc.
)GenotypedScanning(MRI,PETetc)OtherParkinsonProgressionMarkerInitiative(PPMI)BiomarkerStudyLongitudinal(fromtimeofdiagnosis)400newlydiagnosedPD,200controls,64SWEDD,100prodromal,600geneticregistryparticipantsOngoingsince2010Community-basedcohortstudyYesUPDRS-III,motor,non-motor,cognitivedeclineMDS-UPDRSDNA,RNA,serum,plasma,urine,CSFYes(ApoEandselectedSNPs)MRI,DAT,PET([18F]orbetaben)CT(somesites)DATATOPLongitudinal8008yearsClinicaltrialNoUPDRS,cognition,depression,qualityoflifeSerum,urine,CSF,DNAYesbyrequestingforaccesstobiospecimenrepositoryNoVideorepositoryCALM-PDLongitudinal3012–4yearsClinicaltrialNodopaminergicmotorcomplication,UPDRS,qualityoflife,MMSENoNoBeta-CITSPECTimagingHealthcareutilizationTEMPOLongitudinal404(earlyPD)1yearClinicaltrialNoUPDRS,qualityoflife,MMSE,depressionNoNoNoRasagilinepharmacokinetics,plateletMAO-BactivityELLDOPALongitudinal36142–44weeksClinicaltrialNoUPDRS,qualityoflife,MMSE,HamiltondepressionNoNoBeta-CITSpectimaging(selectsubjects)VideorepositoryPRESTOLongitudinal472(advancedPD)6monthsClinicaltrialNoUPDRS,"on-off"diaries,qualityoflife,MMSENoNoNoRasagilinepharmacokinetics,plateletMAO-BactivityTheNationalInstituteofNeurologicalDisordersandStroke(NINDS)Parkinson'sDiseaseBiomarkerProgram(PDBP).
439Crosssectional,825Longitudinal(3–5years)748PD,386control,50MultisystemAtrophy,50ProgressiveSupranuclearPalsy,30EssentialTremor3-5yearsCommunity-basedcohortstudyYesMDS-UPDRS,motor,non-motor,cognitivedeclineCSF(269),plasma(674),serum(775),RNA(1,234),DNA(1,191)Yes,NeuroXchipMRI(290),DTI(440),fMRI(150)Gait(120),biosampleQC(hemoglobinanalysisforplasma,serumandCSF),qualityoflifeThestudiesinthistablerepresentthecandidatePDclinicalstudiesthatweredescribedatthePDdatasharingconsensusconferenceaspotentialsourcesofdataforstandardization,integrationandfutureanalysesbyprincipleinvestigatorsandmeetingparticipants.
ThisisnotacomprehensivelistofallpossiblePDstudiesyetprovidedaframeworkforthestakeholdersandpotentialroadmap(Fig.
1).
UncorrectedAuthorProofD.
Stephensonetal.
/PrecompetitiveDataSharinginParkinson'sDisease7TheOxfordParkinson'sDiseaseCentre(OPDC)209Discoverycohort(http://opdc.
medsci.
ox.
ac.
uk)was210establishedin2009withfundingfromParkinson'sUK211asalongitudinalstudyof1000earlystage,population-212ascertainedPDsubjectsrecruitedfromtheThames213Valley,UK.
Itsprimarygoalistoinvestigatetheearli-214estgenetic,molecular,cellular,andneuronalpathways215affectedinPD,andtoidentifynovelbiomarkersfor216earlydiagnosisandprognostication.
Dataandtissue217collectedfromOPDCsubjectsincludesawiderange218ofclinicalmotor,non-motor,andcognitiveassess-219ments,serum,plasma,DNAandCSFsamples,skin220biopsieswithinducedpluripotentstemcellgeneration,221andMRIbrainstudies[19–21].
Threehundredcontrol222and170PDat-risksubjectshavebeenrecruitedtothe223Discoverycohortthusfar,with18-monthlongitudinal224follow-upnowongoingandguaranteedfora10-year225observationperiodinthePDandPDat-riskgroups.
226TheTrackingParkinson'sStudy-Parkinson's227RepositoryofBiosamplesandNetworkedDatasets228(PRoBaND)229PRoBaNDhasenrolled2000subjectswithrecent230onset,including240youngonsetpatients,andis231enrolling840unaffectedsiblingsfrom60activerecruit-232ingcenters(http://proband.
org.
uk/).
Inadditionto233clinical,demographic,andgeneticdata,PRoBaNDhas234collecteddataoncognition,olfactoryfunction,sleep,235autonomicfunction,qualityoflife,andenvironmen-236talexposures.
Investigatorswillbeaskingmultiple237researchquestions,includingcomparingyoungand238recentonsetPD(e.
g.
,progression,responsetotherapy),239denitionofsubtypes(includinggenetics),andtherela-240tionshipbetweennon-motorandmotorfeatures.
241CambridgeshireParkinson'sIncidencefromGPto242Neurologist(CamPaIGN)243TheCamPaIGNstudycollectedapopulation-based244cohortofnewlydiagnosedPDcasesinthecountyof245Cambridgeshire,UKovertwo-yearperiod(Dec2000-246Dec2002),inordertoestimatetheincidenceofPD247andparkinsonisminthisregion,andtocharacterize248thefrequencyandpatternofcognitiveimpairmentin249apopulation-representativeincidentPDcohort[22].
250Thecohorthassincebeenprospectivelyfollowed,251with10-yeardatarecentlypublished[23].
Longitu-252dinalassessmentshaveincludedstandardizedmotor253assessmentssuchastheUPDRSandHoehnandYahr254scale,neuropsychologicalassessments,andstandard-255izedmeasuresofmood,functionandqualityoflife.
256DNAsampleshavealsobeencollected.
Thecohortcom-257prises142casesmeetingUKPDSBrainBankcriteriafor258PD.
Followingattritionduetodeathandlosstofollow-259up,49remainedatthe10-yeartimepoint.
Follow-upis260ongoing,with12-yeardatacurrentlybeingcollected.
261Parkinsonism:IncidenceandCognitive262HeterogeneityinCambridgeshire(PICNICS)263PICNICSisasequentialcomparativeincidence264studyinthesameCambridgeshirepopulation.
Dur-265inganextendedrecruitmentperiod(2008–2013),286266casesmeetingUKPDSBrainBankcriteriaidiopathic267PDwereenrolled.
Patientsarebeingfollowedupat26818-monthintervalswithamoreextendedpanelof269assessmentsthantheCamPaIGNcohort,includingthe270revisedMovementDisordersSociety-UPDRS(MDS-271UPDRS)[24]andincorporatingtheAddenbrooke's272CognitiveExaminationRevised(ACE-R)intothecog-273nitivebattery[25].
AsubgroupofPICNICSsubjects274arealsoenrolledintheIncidenceofCognitiveImpair-275mentinCohortswithLongitudinalEvaluationPD276(ICICLE-PD)study,whichincorporatesanumber277ofadditionalnon-motorquestionnaires,moreexten-278siveneuropsychologicaltesting,saccadometry,and279biomarkeranalysis[26].
Themaximumdurationof280follow-upofthePICNICScohortis72monthsatthe281timeofthismeeting.
282TheParkinsonProgressionMarkerInitiative283(PPMI)biomarkerstudy284PPMImimicsthelandmarkAlzheimer'sDisease285NeuroimagingInitiative(ADNI)intermsofafocus286onstandardizingprotocolsandprovidingtheresearch287communitywithopenaccesstodataandbiosamples.
288AtthetimeoftheLondonmeeting,over180,000data289downloadsandover40biologicalspecimenshadbeen290requestedthroughtheADNI.
Datacollectedthrough291thePPMIincludeclinical(motorandnon-motor,neu-292robehavioral/cognitive,autonomic,olfaction,sleep),293imaging(DaTscan,AV133,amyloid,DTI/RSMRI),294andcorrespondingbiologicalsamples(DNA,blood,295CSF).
ThePPMIstudypopulationoriginallyincluded296400newlydiagnosedandunmedicatedPDsubjects297aswellas200age-andgender-matchedhealthycon-298trols,and70subjectswithaclinicaldiagnosisof299PDbutwithoutevidenceofdopaminergicdeciency300(SWEDD)bydopaminetransporterSPECTimaging301[27].
Subsequently,threeothersubgroupswereadded:302100pre-motor,500subjectswithLRRK2mutations,303and100with-synucleinmutations(50withPDand304UncorrectedAuthorProof8D.
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/PrecompetitiveDataSharinginParkinson'sDisease50unaffectedfamilymembers).
Therearealsofuture305planstoincorporatenoveldatasourcesthatinclude306wearablesensorsinPPMI.
307Parkinson'sStudyGroup(PSG)andtheUniversity308ofRochesterCenterforHumanTherapeutics309(CHET)310PSGisanetworkof132Parkinsoncentersinthe311UnitedStates,CanadaandPuertoRico,createdto312conductclinicaltrialsinaconsistentlyrigorousman-313ner.
PSGconductedtheclinicaltrialsthatledtothe314approvalofvePDmarketeddrugs,aswellasmany315othertrialsconductedthroughtheNIHExploratory316TrialsinPD(NET-PD).
DatafromPSG,NET-PD,and317thePPMIstudiesaremanagedbytheCenterforHuman318ExperimentalTherapeutics(CHET)attheUniversity319ofRochester.
TheCHETcoordinatingcentercurrently320housesdatafromover40PDclinicalstudiesenrolling3217000PDparticipantsaswellasfromobservational322studies,includingdatafromphysician-ratedclinical323scalessuchastheUPDRS,Mini-MentalStateExami-324nation(MMSE)andtheBeckDepressionInventory,as325wellaspatient-reportedoutcomesdata,imaging,lab-326oratoryandbiomarkers,genetics,anddemographics.
327ThePSGhostsalistofdataonthewebsite,ashort328narrativeaboutwhatthestudycovers,andguidanceon329howtoaccessthedata(http://www.
parkinson-study-330group.
org/).
Thereviewprocessiscoordinatedbythe331MichaelJFoxFoundationandanyresearchercan332apply.
Therehavebeenover200publicationsresult-333ingfromtheuseofthesedatatodateandfutureuse334isencouraged,especiallyformodelingdiseasepro-335gressionDatausedinmodelingisonlyabout20%of336thedataavailablethroughthePSG,butadditionaldata337sourcesarerelevantforthispurpose(Table1).
Mod-338elingandsimulationareakeypartoflearningand339conrmingdrugs,dosesandoutcomesandshouldbe340usedtoimprovethedesignofclinicaltrials.
341TheNationalInstituteofNeurologicalDisorders342andStroke(NINDS)Parkinson'sDisease343BiomarkerProgram(PDBP).
344InNovemberof2012,NINDSlaunchedacom-345prehensivePDbiomarkerinitiativethatfocuseson346standardizedprotocolsforbiospecimencollection347(DNA,RNA,blood,andCSF)andlongitudinalclin-348icalassessments(motor/non-motor,neurobehavioral,349cognitive,sleep,olfaction,familyhistoryandmedica-350tions)forPDparticipantsacrossthediseasespectrum.
351Astandardsetofclinicalassessmentsandbiosample352collectionsaremadeat6and12-monthintervals.
Asof353May2014,clinical,geneticandbiomarkerdatafrom354618casesand310age-andgender-matchedhealthy355controlswerebroadlyavailabletotheresearchcom-356munitythroughthePDPBdatamanagementresource357(DMR).
Asubsetofparticipants(290)willalso358undergoMRIand150participantswillundergoDTI359andfMRIanalysis.
UniquetothePDBPprogramisa360subsetofparticipantswhohavebeendiagnosedwith361MultisystemAtrophy(50MSA),ProgressiveSupranu-362clearPalsy(50PSP),andEssentialTremor(30ET).
363TheoveralltargetenrollmentforthePDBPinitiative364is1500.
365ThePDBPDMRistherstdatabaseforParkin-366son'sdiseasethatbringstogetherdisparatetypesof367datasets(clinical,genetic,imagingandbiomarker)and368biorepositoryinformationunderonedataresourcefor369queryinganddownloadingofdataandrequestingof370relatedbiosamples.
LikeADNIandPPMI,thePDBP371alsosharesdatainternationallywithacademicand372industryinvestigators.
AsofMay2014,morethan3731000datadownloadsandover1500biosampleshad374beenrequested.
375Otherpotentialdatasources376UnderstandingPDprogressionwillrequireintegra-377tionofdatanotjustglobally,butalsofrommorehet-378erogeneoussources,includingasymptomaticcohorts379suchasPREDICT-PDintheUK[28],EPIPARKinGer-380many[29],andtheHonoluluAgingStudy[30];primary381andsecondarycaredatasets(e.
g.
,electronicmedical382records);andcollectionsofbiologicalspecimens.
Inthe383UK,theDementiasPlatformUKisaggregatingdata384fromuptotwomillionparticipantsfromexistingcohort385studies,isestablishinganetworkofaccesstoelectronic386medicalrecords,andisenhancingUKBiobankwith387verylargeprogramsofneuroimagingandbiomarker388studiestogetherwithoutcomedatacollectedfrommed-389icalrecords.
AstheprimarypurposeoftheDementias390PlatformUK(DPUK)willbetoidentifyriskfactors391andbiomarkersandtoenableandconductexperimental392medicineinprimarydementiaconditions,diseaseswith393dementiaasacomponentsuchasPDandotherneurode-394generativedisorderswillbewithinsightoftheDPUK395objectives.
Datafromconsumertechnologiessuchas396smartphonesandwearabledevicescancaptureinfor-397mationaboutmotorsymptoms,sleeppatterns,andother398functionalbehavioralaspectsthatmayreectearlysigns399ofPD.
SuchdataincludesthatrecordedintheJohnHop-400kinspilotstudy[31],theOxfordOPDCcohort,andas401partofUKBiobank.
Otherdatasetsfrominvestigations402ofexposuretopesticidesorotherenvironmentalrisk403factorscouldalsobeuseful.
404UncorrectedAuthorProofD.
Stephensonetal.
/PrecompetitiveDataSharinginParkinson'sDisease9DATATRANSFERABILITY,405STANDARDIZATIONANDINTEGRATION406Whiledatasharingiswidelyacknowledgedacross407stakeholdersasessentialtoscienticprogressinclud-408ingthedevelopmentofnewtreatmentsfordiseases409suchasPD,technicalandculturalroadblockshave410limitedourabilitytoexploitthepotentialofthese411vastandgrowingdataresources.
Themainroadblocks412discussedwere:datatransferability,remotedataacces-413sibilityandprivacy/consentissues,dataremappingto414comprehensivestandards,anddataintegration.
Over415thepastdecade,datasharingmodelshaveemergedthat416havebeguntobreakdownsomeofthebarriers[16].
417ADNI,apublic-privatepartnershipcreatedin2003to418expeditedrugdevelopmentbystandardizingandvali-419datingimagingandotherbiomarkersforAlzheimer's420disease.
ADNIprovidesresearcherswithopenaccess421torawandprocessedimaging,clinical,genomic,422andbiomarkerdatathroughtheLaboratoryofNeuro423Imaging(LONI)ImagingDataArchive(IDA)atthe424UniversityofSouthernCalifornia.
Openaccesshas425resultedinsevenmilliondatadownloadsand500peer-426reviewedarticlesfromresearchersaroundtheworld427[32].
However,withtheincreasingnumberofsophis-428ticatedimagingprotocolsandtheincreaseduseof429genomesequencing,theamountofdatacollectedhas430increasedexponentially,suchthatithasbecomeimprac-431ticaltohousealldataatonesite.
TheGlobalAlzheimer's432AssociationInteractiveNetwork(GAAIN)isafeder-433atedcloud-enabledplatformforsharingandproviding434accesstodataanalytictools(www.
gaain.
org).
GAAIN435nowhasmanycontributors,includingADNI.
436LessonsfromADNIrelevanttothePDinitiative437includetheneedtodenethekeyscienticquestions438tobeanswered,standardizedatacollectionprotocols,439buildtoolsthataresophisticatedandmatchedtothe440datacollected,maintainopencommunicationwiththe441researchcommunityabouttheirneedstopredictfuture442needs;andanticipatewhatinformaticstools/resources443willbeneededtoaddressnewresearchquestions.
Sev-444eralplatformsandnetworksrecentlyestablishedorin445developmentarepositionedtoaddresssomeofthese446issues:447TheMRCDementiasPlatformUK(DPUK)plans448tobringtogether22cohortsfromacrosstheUK,449includingtheUKBiobank,integratedintoasingle450informaticsplatform.
DPUKalsoplanstodevelop451areadinesscohortwithbaselineimagingdataas452wellasamyloid,geneticsdiscovery,and-omics453discoverycohorts.
454TheEuropeanMedicalInformationFramework455(EMIF)isave-yearIMIwith56partnersin14456Europeancountries,establishedtomakedatasets457visibletoresearchers,tointegrateresearch458cohortsforcombinedanalysis,andtoenable459re-useofmedicalandotherdataforresearch.
IMI-460EMIFisestablishingthreebroadapproachesto461datareutilizingandsharing.
Firstly,tomakedata462visibleandpotentiallyutilizablebyresearchers,it463hasestablishedabrowserformeta-dataordescrip-464tionsofdatatypesandrulesofengagementacross465cohortswithupto50,000ormoreparticipants466inEurope.
Secondly,theprogramhasbegunto467harmonizedataacrossdiversecohortstogener-468atemeta-cohortsforcombinedanalysis.
Thirdly,469EMIFisestablishingsafeandsecureplatforms,470respectinglocallegislative,ethicalandotherdata-471governancemodels,whichenablenetworkedor472distributedanalysisofverylargedatasetsinclud-473ingatotalofmorethan50millionpersons.
The474primarydatasetsincludedeliberatelydifferent475typesofstudiesanddatasourcestoestablishscal-476ablesolutionsfordataaccessandanalysis.
These477datasourcesincludemade-for-purpose,ADNI-478likebiomarkerstudiessuchasAddNeuroMed479andDESCRIPA,largepopulation-basedepidemi-480ologicalcohortsnowre-purposedorenhanced481forneurodegenerativeormetabolicdiseasepur-482poses,andverylargeelectronicmedicalrecords483databasessuchasTheHealthImprovementNet-484work(THIN),aUKdatasetcoveringatotalof485nearlyfourmillionactivepatientsfrommorethan486500primarycarephysicians.
487SageBionetworks,anonprotbiomedical488researchorganization,aimstocreateglobally489integrated,open-sourcesystemsthatwillenable490investigatorstoleveragemulti-dimensionaldata491todistillmeaningfulinformationrelatedto492humanhealthanddisease.
Sageisapartnerin493theCommonMindConsortium,whichgenerates494diseasemodelsforneuropsychiatricdisease495bybringingtogetherlarge,wellcuratedbrain496samplesanddatamanagementandanalysis497expertisetoenableintegratedanalysisofmolec-498ular,genomic,anddiseasedata.
Inpartnership499withtheGlobalCEOInitiativeonAlzheimer's500disease,Sagehasalsolaunchedbigdatachal-501lengestotheADresearchcommunity,seeking502toleverageopensourcebiomarker,cognitive,503genetic,anddemographicdatafromADNI,Rush504UniversityMedicalCenter,andtheEuropean505AddNeuroMedstudytocreatearoadmapofAD506UncorrectedAuthorProof10D.
Stephensonetal.
/PrecompetitiveDataSharinginParkinson'sDiseasepredictivebiomarkers.
InthePDarena,Sage507ispartneringwiththepatientnetworkPatients-508LikeMe(http://www.
patientslikeme.
com)to509combinepatient-reportedinformationwithdata510collectedfromthephone-basedvoicerecordings.
511ThegoalistoidentifyPD-relatedvoiceimpair-512mentsthatmaybeusefulintrackingdisease513progressionandresponsetotherapy.
514Integratingdataacrossdiversedomainsanddata515generatorsrequirestheapplicationofcommonlyused516datastandards.
InsupportofthePDBP,NINDSdevel-517opedasetofcommondataelements(CDEs)in2010518foruseinthePDBPdatarepository,alongwithadata519dictionaryandanalytictools,toenabledatacompari-520sonandmeta-analysesacrossstudies.
NINDSplansto521capturelegacydatafromtheMorrisK.
UdallCenters522ofExcellenceforParkinson'sDiseaseandNINDS-523sponsoredPDclinicaltrials.
524C-PathandNINDSworkedwithindustrypartners525andtheClinicalDataInterchangeStandardsCon-526sortium(CDISC,www.
cdisc.
org)totransformthese527CDEsintoglobalstandardsforcollectionofPDclin-528icaltrialsdata.
TheFDAhasrecognizedthatCDISC529standardswillberequired,beginningin2017,forreg-530ulatorysubmissionstofacilitateefcientreviewof531medicalproducts[33].
TheCDISCstandardswillbe532updatedasnewconceptsorinformationimportantto533PDdrugdevelopmentareidentied.
534BARRIERSTODATASHARINGAND535INTEGRATION(SEETABLE2)536Someofthechallengestodatasharingandintegra-537tionincludelackofpatientconsent,diversityofdata538formatsinlegacydata,legalconcerns,patientprivacy539issues,protectingtheinterestsofjuniorresearchersand540PhDstudentswhohavecontributedtothedatacollec-541tion,giventhecurrentacademicrewardsystemsthat542maynotrewardcollaborationandsharingofdata,and543possibleconictbetweenindividualandconsortium544studygroupgoalsandachievements[6].
However,545datasharingbetweenstudygroupshasbecomerou-546tineinlargescalegeneticsstudies,e.
g.
,theStructural547GenomicsConsortium,apublic-privatepartnership548thatsupportsthediscoveryofnewmedicinesthrough549openaccessresearch(http://www.
thesgc.
org).
Dif-550ferentdata-sharingmodelshavebeensuccessfully551pursued,e.
g.
,acommondatarepositorywithcon-552trolledaccessorcollaborativeaccesswithspecic553summarydatabeingreleasedbyspecicstudyinvesti-554gatorsthatarethenincorporatedintoameta-analytical555framework.
Itisimportanttodifferentiatebetween556studiesthathavebeendesignedfromtheiroutsettobe557open-accessandforwhichparticipantswereclearly558informed,andthosethatareledbyaspecicaca-559demicgrouporcompanywiththepotentialforexternal560collaboration.
Anadditionalconsiderationiswhether561studiesarehistoricalandnofurtherfollow-upisenvis-562aged(closed)orwhetherdataarefromprospective563Table2IssuesandpotentialpathstoenabledatasharinginPDIssues/challengesPossibleSolutionsDifferentformatsofdataImplementationofdatastandardsCountryfocusedinitiativesatpresentImplementationofglobalPPPsandconsortiaRegulatorylandscape–needforbiomarkersRegulatoryendorsementofdrugdevelopmenttoolsNeedforreliablelongitudinaldataFundingstreamsforhighqualityobservationalstudiesApprovaltoaccessvariedpatientleveldatasetsDatasharinginitiativesthroughglobalPPPsandconsortiaCostforestablishingandespeciallyBusinesscaseforfundingstreamsfromgovernment,maintainingglobaldatabasenon-protandprivatesectorsPrivacyprotectionAdherencetopatientprivacyregulationsandde-identicationofpatient-leveldataPatientconsentforsharingImplementationofbroadinformedconsentdocumentsinlinewithnationalguidelinesIncentivesfordatacontributorsImmediateaccesstointegrateddatabasestofurtherresearchRecognitionfordatacontributorsCoauthorshipandwidespreaddisseminationDataaccessandsharingPublicationstrategyanddisseminationmechanismInfrastructureneededforfuturesustainabilitySelfsustainedconsortiabasedmodelsandinfrastructureAlignmentacrossconsortiaFocusonsynergisticresearchareasandregulatoryalignmentDeneincentivesforindustryDeriskingofdrugdevelopmentprogramsthroughimpactonregulatoryscienceImproveddrugsafetyReportingandmonitoringofdrugadverseeffectsImpactonpatientsandfamiliesRewardinginadvancingthecauseforall,altruistictoothersandforselfYounginvestigatorstobenetAcceleratepathwayforadvanceddegreesandtrainingUncorrectedAuthorProofD.
Stephensonetal.
/PrecompetitiveDataSharinginParkinson'sDisease11cohortswithfuturecollectionroundswhereitisessen-564tialthatnoactionsaretakenthatcouldharmfuture565cohortretention(open).
566AsurveyofParkinson'sUKmembersreportedthat567thevastmajorityofpeoplewithPDwereeagerfor568theirdatatobeaccessedandmadeavailabletoadvance569researchandtherapeuticdevelopment.
Barrierssuchas570informedconsentwillbeaddressedindiverseforae.
g.
,571universalInstitutionalReviewBoard(IRB)forneu-572rodegeneration,SageBionetworksportableconsent.
573Focusedattentiononissuesofdatasharinghasbeenthe574subjectofnumerousfora.
Thisisclearlyanevolving575concerninresearch,industryandregulatorysettings.
576QUANTITATIVEDRUGDEVELOPMENT577PLATFORMSENABLEMODELINGOF578DISEASEPROGRESSION579Thereisgrowingrecognitionoftheheterogene-580ityofPDbasedonadvancesingenetics,biomarkers,581pathologyanddiversityofclinicalphenotypes.
Aquan-582titative,data-drivenunderstandingofPDprogression583iskeytoadvancingapersonalizedmedicineapproach584tosuccessfultreatments.
Modelingmultiplesourcesof585variabilityinheterogeneouspopulationscouldprovide586avaluableplatformtosupportimprovedclinicaltrials,587includingdevelopingenrichmentstrategiesandsim-588ulatingdifferenttrialdesigns.
Indeed,modelingand589simulationtoolshavebeenendorsedbytheFDAasa590meansofassessingthevalueofdifferenttrialdesignsto591detectdiseasemodifyingeffectsoftreatmentsinearly592stagePD[34].
593CAMDdevelopedandgainedregulatoryinsightand594endorsementfrombothFDAandEMAforsucha595model-baseddrugdevelopmenttoolforAD[9].
The596CAMDADclinicaltrialsimulationtoolwasdesigned597tounderstandandoptimizeclinicaltrialdesignformild598tomoderateADbasedonadisease-drugmodelthat599incorporatesaquantitativeunderstandingofdisease600progression,drugeffects,dropoutrates,placeborates,601andsourcesofvariability[9].
Datausedtodevelop602thistoolcamefrompatient-leveldatafromclinical603trialsandobservationalstudies,andsummary-level604datafromtheliterature.
TheCAMDADclinicaltrial605databaseconsistsofplaceboarmdatafrom6500AD606patientsfromglobalclinicaltrialsandcanbeaccessed607byresearchersforbroadapplications[33].
Regulatory608endorsementoftheADclinicaltrialsimulationtool609[35]demonstratesregulators'supportforsuchtoolsto610optimizetrialdesign.
611Fromaregulatoryperspective,datasharingis612importantfortransparency,reproducibility,andiden-613ticationofnewinformationviaanalysiswiththe614purposeofansweringbroadrangingdrugdevelopment615questions.
FDArecognizesthatanalysisofmulti-616pleclinicaland/orpre-clinicaldatasetsprovidesan617opportunitytoadvancedrugdevelopment[36].
EMA618andFDAareaimingtoalignonregulatoryprocesses619andguidance,wherepossible.
Atpresent,thereisno620regulatory-denedconceptofprodromalPDasatar-621getpopulationfordrugapprovalsyetdatainthefuture622mayimpactthispath,ashasbeenthecasewithAD.
623PROPOSEDROADMAPFORA624MODEL-BASEDCLINICALTRIAL625ENRICHMENTPLATFORMFOR626EARLYPD627Personalizedmedicinestrategiesenabletreatments628thattargettherighttherapytotherightpatientatthe629righttime.
Enrichingtrialsforsubjectslikelytoshow630clinicalbenethasbeenendorsedbyboththeFDA631andEMAasameansofincreasingtheefciencyof632thosetrials[37,38].
Todate,trialsinPDhavetypically633recruitedallsubjectsthatmeethistoricallydened634diagnosticcriteriaforthedisease.
Yetatpresent,diag-635nosticcriteriaforPDarebeingredened[24,39,40]636andthereisanurgentneedtoidentifysubsetsofPD637patientswithdeneddiseasetrajectories.
Regulatory638endorsementofmodelingandsimulationtoolsina639denedcontextofuse,servestode-riskdrugdevel-640opmentindesignoftrialsandstreamlinethereview641ofnewdrugcandidatesthrougharegulatoryendorsed642modelthatappliesacrosstherapeutictargetsandcanbe643utilizedbymultiplesponsors.
Figure1illustrateshow644availabledatamightbeappliedtothedevelopment645ofamodel-basedclinicaltrialenrichmentstrategy646withregulatoryfocus.
Observationaldatafromboth647theliteratureandatleastsevenindividualdatasets,648includingbiomarkerdatafromseveralcohortstud-649ies(OPDC,ProBaND,CamPaIGN,andPPMI)and650clinicaltrialswillbeusedtomodeldiseaseprogres-651sionsimilarlytothewayADNIandotherdatawere652usedtobuildandthenconrmahypotheticalmodel653ofdiseaseprogressioninAD[9,41,42].
Success654oftheproposedPDregulatorypathwaywillrequire655theimplementationofPDdatastandardsandthecon-656structionofadatasharingmechanismofanintegrated657databasetoeffectivelyutilizethosedata.
Themodel658willenablesimulationofPDprogressiontrajectories659ofdifferentsubpopulations,thusindicatingparticular660UncorrectedAuthorProof12D.
Stephensonetal.
/PrecompetitiveDataSharinginParkinson'sDiseaseFig.
1.
ProposedRoadmapforbuildingPDdrugdevelopmenttoolswithexistingdata.
ProposedroadmapoutliningapotentialfuturepathforintegratingglobaldatafromPDobservationalandclinicaltrialstargetingearlystages.
Integrationofdiversedatafromatleastsevenindependentclinicalstudiesintoaunieddatabasewillenablearegulatorypathforuseofbiomarkersandquantitativediseaseprogressionmodelsthatservetostreamlineandderiskdrugdevelopmentofnewtherapies.
endophenotypes,whichcanthenbeusedtooptimize661entrycriteriaforclinicaltrials,improvethestatistical662powerandincreasechancesofsuccess.
Theproposed663roadmapfollowsapathtoenableregulatorydecisions664withbroadapplicationtoclinicaltrials.
Furthermore,665enhanceddata-sharingwillcatalyzenoveldiscoveries666inPDresearch.
667CONCLUSIONS668Theneedforaglobaldatabasethatintegrateslarge669amountsofdiversedatawasidentiedasessential670tofuelprogressinidentifyingindicatorsofpre-671clinicalandearlymotorPD,whichwouldenablethe672developmentofpre-symptomaticdiseasemodifying673treatmentsandimprovedsymptomatictreatments.
674Theworkshopalignedoninterimstepstowardthe675eventualgoalofbuildingandachievingconsensuson676precompetitivedatasharingasacatalysttoadvanc-677ingresearchforPD.
Oneproposalistheregulatory678endorsementofnewdrugdevelopmenttools,including679aclinicaltrialenrichmentplatformandatrialmodeling680andsimulationtool.
Thiswillrequire:681Catalogingexistingclinicalandobservational682datasetsandthetypesofdatawithinthosedatasets683thatarerelevanttotheresearchquestion(s)being684posed.
685Developingandapplyingdatastandardsthatwill686enableintegrationofdataacrossmultipledatasets,687includingnoveltypesofdatasuchasthatcollected688fromremotemonitoringdevicesandbiosensors.
689Maximizingtheuseofexistingdatabyestablish-690ingacceptableguidelinesfordatasharing.
691Supportingthefurtherdevelopmentofnew692biomarkersandassessmenttoolsthatwillprovide693abetterunderstandingofthephenotypicvaria-694tionsofPD.
695Promotetheimplementationofnewtechnologies696suchaswearabledevicesintoPDforenabling697personalizedmedicine.
698Promotingfurthercollaborationacrossallstake-699holders.
700ACKNOWLEDGMENTS701Theauthorsthankthefollowingcolleaguesfortheir702participationandcontributionstothesuccessofthe703UncorrectedAuthorProofD.
Stephensonetal.
/PrecompetitiveDataSharinginParkinson'sDisease13meeting:SueDubman(UCSF),KarlKieburtz(Univ704Rochester),MadelineKelly(GSK),KatieLeBlond,705ArthurRoach,andBuniaGorelick(Parkinson'sUK),706VincentLow(UCB),AnnetteSchrag(UCL),Richard707Moscicki(FDA),JanJohannessen(FDA),NancyB708Sager(FDA),andVikramSinha(FDA).
709Disclaimer:Theviewsexpressedinthisarticleare710thoseoftheauthoranddonotnecessarilyreect711theofcialviewsofFDA.
Themanuscriptmeetsall712requirementsforauthorshipasperTheInternational713CommitteeofMedicalJournalEditors(ICMJE)guide-714lines.
TheroadmapoutlinedinFig.
1andthesummary715ofworkshopisaconsensualagreementoftheauthors.
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