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NewNIHClinicalTrialRequirementsforGrants&Contracts
2017/2018
ChangesinHumanSubjectsResearch
• GrantApplicationProcess– ClinicalTrialApplications
• IRB– SingleIRB– CertificatesofConfidentiality
• ClinicalTrialRequirements– NIHClinicalTrialDefinition– GCPTraining– ClinicalTrials.gov Registration/ResultsReporting
3Steps:HowtoSubmitaClinicalTrialtotheNIH
NIHDecisionTreeforClinicalTrialDefinition
https://grants.nih.gov/policy/clinical-trials/CT-decision-tree.pdf
**RevisedOctober23,2014
FactorsContributingtoConfusion
• An"intervention"isdefinedasamanipulationofthesubjectorsubject’senvironmentforthepurposeofmodifyingoneormorehealth-relatedbiomedicalorbehavioral processesand/orendpoints.§ Examplesofinterventions:smallmolecules/compounds;deliverysystems(telemedicine,interviews);treatment,preventionordiagnosticstrategiestochangehealth-relatedbehavior(diet,exercise,cognitivetherapy).
§ Examplesofhealth-relatedoutcomes:+/- changestophysiologicalorbiologicalparameters(geneexpression);+/- changestopsychologicalorneurodevelopmentparameters(moodmanagementforsmokers,readingcomprehension/retention);+/- changestoqualityoflife.
WhatisaClinicalTrial?
• Investigationaldrugsanddevices(FDA-regulated)studies– Safety– Efficacy
• Somebehavioral/socialsciencestudies
• Somemechanisticexploratorystudies
ExamplesofMechanisticClinicalTrials
• Interventionwithdemonstratedefficacyforapopulationstudiedtounderstandmechanismsofresponse,non-response,orriskofadverseeffects
• Physiologicalorbehavioralmanipulationtoanswerbasicsciencequestions aboutnormalfunctions
• Experimentalmanipulationtounderstandnormalfunctioningorpathophysiologyofadisease butnotdemonstrateclinicalimprovement
• Prospectiveuseofefficaciousinterventionswithintenttoobtain&analyzebiospecimens toidentifygeneticriskassociations,novelbiomarkers,examinethediseaseprocess,orcharacterizemechanismsoftherapeuticresponse
ResearchNotConsideredCTs
• Not consideredaclinicaltrialifthefollowing:o Surveyso Questionnaireso Userpreferences,focusgroupso Secondaryresearchwithbiospecimens orhealthinformationo Educationalstudieswithoutcomesfocusingonmemorizationorretention&recallofinformationtoassessteachingmethods
WhydoesitmatterhowNIHdefinesaClinicalTrial?
ExpandedNIHdefinitionofaclinicaltrialbroadensrequirements:• Limits onapplyingforgrantstoclinicaltrial-specificFOAs
o Trainingawardsnotallowedforclinicaltrialso Newhumansubjects&clinicaltrialforms(proposalscouldberejectedifwrongform/informationsubmitted)
• GCPtrainingforallinvestigators&clinicaltrialstaff• UseofsingleIRBformulti-sitestudies• ClinicalTrials.gov registration,updates&resultsreporting
NIHCaseStudies
• Thesimplifiedcasestudiesillustratethedifferencesbetweenclinicaltrialsandclinicalstudies usingthecriteriafromtheNIHdecisiontree.
• Revisedversionslackclarity&causedconfusion
• Someinconsistentwithoriginaldefinition&greatlyexpandscope
• MayleadtodifferentconclusionsforNIHdefinitionofclinicaltrialNIHdeterminationsareFINAL
ComprehensionandRetention…
• Case#24:Involvesevaluatingdifferenttypesofprintedannouncementstoidentifythebestdesignsforensuringcomprehension&retentionofinformationinadults.Visitorstopubliclibrariesselectedatrandom&askedtoreadoneoftwoannouncements,thentakeashortsurveytoelicittheirperspectivesaboutreadability.
• ClinicalTrial?NO
• Case#26:Involvesrandomizingindividualstodifferentprocessesforinformedconsent.Designedtoassesstheeffectivenessofinteractive&multimediacomponentsinenhancingparticipants’understandingofthestudy’spurpose&procedures.
• ClinicalTrial?YES
Recording…
• Case#31a:Involvesrecruitmentofschoolchildrentoevaluatetwodifferenttoolsformonitoringfoodintake.Foodconsumptionbehaviormeasuredbyaskingchildrentoactivateapocketcameraduringmeals&useadiarytorecordconsumedfood.Theaccuracyofthetwofoodmonitoringmethodsinmeasuringenergyintakewillbeassessed.
• ClinicalTrial?NO
• Case#31b:Involvestherecruitmentofschoolchildrentoevaluatetwodifferenttoolsformonitoringfoodintake.Foodconsumptionbehaviormeasuredbyaskingchildrentoactivateapocketcameraduringmeals&useadiarytorecordconsumedfood.Changestoeatingbehaviorwillbeassessed.
• ClinicalTrial?YES
Whatcanyoudo?
• IncreaseknowledgeaboutthenewNIHrequirements
• Wehighlyencourage investigatorstocontacttheirNIHprogramofficertoconfirmwhethertheirstudymeetstheNIHdefinitionofaclinicaltrial.FDA-regulatedstudies(investigationaldrugs&devices)automaticallymeettheNIHdefinition.
ü Document&savethediscussionforfuturereference—willuploadinERMS
• EncouragescientificsocietiesandprofessionalassociationstocontactNIH
3Steps:HowtoSubmitaClinicalTrialtotheNIH
Allowability ofClinicalTrials
• AllNIHFundingOpportunityAnnouncements(FOAs)willbeupdatedinFall2017
• Implementationdate– applicationduedateson/afterJanuary25,2018– isconcurrentwithimplementationofNIHFormsEapplicationkitversion
• AllFOAswillexplicitlyspecifytheallowability ofclinicaltrials(inFOATitleandinSectionII– AwardInformation)
• AnyclinicaltrialapplicationMUSTbesubmittedtoanFOAthatacceptsorrequiresclinicaltrials
Allowability ofClinicalTrials
• NIHwillissue“parent”FOAsforclinicaltrials.• SomeNIHInstitutes/Centers(ICs)willparticipateintheparentFOAs.• SomeICswillissuetheirownIC-specificclinicaltrialFOAs.• WhenusingaparentCTFOA,itwillbeimportanttoinsurethattheintendedICparticipatesintheparent.
Allowability ofClinicalTrials
• Mechanism-specificconsiderations– Training(T)awards
• AllTrainingawardFOAswilldesignated“ClinicalTrialsNotAllowed”,but• AppointedtraineesAREpermittedtoobtainresearchexperienceinaclinicaltrialledbyamentor/co-mentor
• SomeD43andK12FOAswillbedesignatedas“ClinicalTrialOptional”– Fellowship(F)awards
• AllFellowshipawardFOAswillbedesignated“NoIndependentClinicalTrial”,but• FellowsarepermittedtoproposeresearchexperienceinaCTledbyasponsor/co-sponsor• Inthosecases,applicantswillprovidedetailsontheircontributionstothestudyintheResearchStrategy ratherthanintheCTspecificfieldsonthenewPHSHumanSubjectsandClinicalTrialsInformationform
Allowability ofClinicalTrials
• Mechanism-specificconsiderations(continued)– CareerDevelopment(K)awards
• CDAFOAswillindicateeither“ClinicalTrialsAllowed”or“NoIndependentClinicalTrials”intheTitleandSectionII
• AnFOAindicating“ClinicalTrialsAllowed”willsupportindependentclinicaltrialsconductedbytheCDAapplicant
• AnFOAindicating“NoIndependentClinicalTrials”willpermittheapplicanttoproposeresearchexperienceinaclinicaltrialledbyasponsor/co-sponsor– Inthesecases,theapplicantshouldprovidedetailsoftheircontributiontothestudyintheResearchStrategy ratherthanviathenewclinicaltrialspecificfieldsonthePHSHumanSubjects&ClinicalTrialsInformationform
– Additionally,itisthementororindividualreceivingsupportforthelargertrialwhoretainsoverallresponsibilityforthetrial
UnderstandingNIHFOAs
• AllFOAswillnowclearlyindicatewhetherclinicaltrialsmaybesubmittedtotheprogram• TheFOAwillbeclearlymarkedinboththeTitleandinSectionII– AwardInformation
ImplementationofNIHClinicalTrialsRequirements
• NIHisimplementinganewversionoftheNIHapplicationformskit(FORMS-E)inconcertwiththeimplementationoftheirnewpoliciesrelatedtoclinicaltrials
• Caremustbeusedduringthetransitionperiodtoprepareapplicationsusingthecorrectformskit
• FORMS-EcontainsanewPHSHumanSubjects&ClinicalTrialsInformationformthatwillbeusedtogatherrequiredinformationoneachclinicaltrial
ImplementationofNIHClinicalTrialsRequirements
WhichformdoIuse?
ImplementationofNIHClinicalTrialsRequirements
• FORMS-Eapplicationpackagesarenowavailable• PrimarydifferencebetweenFORMS-DandFORMS-EistheadditionofthenewPHSHumanSubjectsandClinicalTrialInformationForm
• Detailedinstructionsavailableat:https://grants.nih.gov/grants/how-to-apply-application-guide/forms-e/general/g.500-phs-human-subjects-and-clinical-trials-information.htm
PHSHumanSubjectsandClinicalTrialsInformationform
Auto-populatesfromRROtherProjectInformationform
AnsweredneededevenwhenNoHSresearch;narrativejustificationofanalysisleadingto“noHS”determination
Studyrecordedneededforeachhumansubjectsstudy.Containsdetailedstudyinformation.
UseforD43/K12andotherstudiesmeetingthedefinitionof“delayedonset”
PHSHumanSubjectsandClinicalTrialsInformationform
NIHDecisionTreeforClinicalTrialDefinition
PHSHumanSubjectsandClinicalTrialsInformationform
NEWATTACHMENTS!RequiredforallHSresearch,exceptthoseExemptunderExemption4
ContainsspecificrequirementsforPhaseIIItrials
PHSHumanSubjectsandClinicalTrialsInformationform
NewAttachment;RequiredifYes
RequiredifmeetingNIHDefinitionofClinicalTrial
DSMBrequiredforPhaseIIIClinicalTrials
NewAttachment!
PHSHumanSubjectsandClinicalTrialsInformationform
Completeonlyforclinicaltrialproposals.WillcauseerrorsifanyquestionsonCTQuestionnaireareanswered“No.”
PHSHumanSubjectsandClinicalTrialsInformationform
NEWATTACHMENTS!
UseonlyformaterialsexplicitlypermittedorrequiredbyanFOA.Onlyapplicabletoclinicaltrials.
3Steps:HowtoSubmitaClinicalTrialtotheNIH
NIHProtocolTemplate
• Applicantsconductingphase2or3clinicaltrialsthatrequireInvestigationalNewDrugapplications(IND)orInvestigationalDeviceExemption(IDE)applicationscanuseaNIH-FDAtemplatewithinstructionalandsampletexttohelpwriteprotocols.
• Useofthistemplateisoptional.• IRBwillreviewtheprotocolaswithanyotherprotocolsubmittedtous
• Youcanfindthetoolhere:https://osp.od.nih.gov/clinical-research/clinical-trials/
QuestionscanbereferredtotheIRBasyoudevelopyourprotocolusingthetool.
NIHProtocolTemplate
NIHSingleIRBPolicyEffectiveJanuary25,2018
• RequiresrelianceonsingleIRB(sIRB)for– Domesticsitesin…– NIH-funded…–Multisitestudies (notjustCTs)whereallsitesperformingsamenon-exemptprotocol
• Onlyappliestonewproposals submittedonoraftertheeffectivedate.
32
NIHSingleIRBPolicyEffectiveJanuary25,2018
• Whatwillchangeforyou?– MayrequirerevisiontosubawardlanguageifwearerelyingoncentralIRB
– MayrequiredifferenttypeofIRBdocumentationtoreleaseEmoryfunds(EmorysiteapprovalfromcentralIRB,vs.overallprotocolapproval)
– MayneedlettersofsupportfromparticipatingsitesifEmoryisleadsite,statingagreementwithsingleIRBplan
– Mayneedleadtimetogetquote forcommercialIRBreviewifEmoryisleadsite
33
NIHSingleIRBPolicyEffectiveJanuary25,2018
• Whatwillchangeforyou?– IfEmoryisprime,NIHgrantapplicationmustincludesingleIRBplan
– EmoryIRBwillposttemplatelanguage/guidelinesforthissectionofgrantapplication;NIHalsoprovidesguidance
34
NIHSingleIRBPolicy
• NIHwillnot selectthesIRB butwillapproveornot• Allowancefor“exceptions”basedonlocal/state/triballawOR“othercompelling”(includinglocalpolicies)
• Doesnot havetobeselectedpriortoaward;awardwouldberestricteduntilselected
• NIHsaysyoucanputcostinbudget;caveats
35
sIRB:RolesandResponsibilitiesforApplicantsperNIH
• Applicant/Offeror:Intheapplication/proposalforresearchfunding,theapplicant/offerorisexpectedtosubmitaplandescribingtheuseofansIRB thatwillbeselectedtoserveastheIRBofrecordforallstudysites.
• TheplanshouldincludeastatementconfirmingthatparticipatingsiteswilladheretothesIRB PolicyanddescribehowcommunicationsbetweensitesandsIRB willbehandled.
• If,indelayed-onsetresearch,ansIRB hasnotyetbeenidentified,applications/proposalsshouldincludeastatementthatawardeeswillfollowthisPolicyandcommunicateplanstousearegisteredIRBofrecordtothefundingNIHInstitute/Centerpriortoinitiatingamulti-sitestudy.
• Theapplicant/offerormayrequestdirectcostfundingfortheadditionalcostsassociatedwiththeestablishmentandreviewofthemulti-sitestudybythesIRB,withappropriatejustification;allsuchcostsmustbereasonableandconsistentwithcostprinciples,asdescribedintheNIHGrantsPolicyStatementandtheFederalAcquisitionRegulation(FAR)31.302(DirectCosts)andFAR31.203(IndirectCosts).
36
Emory’ssIRB Plan
RelyonsIRBs whenrequired
IfselectedassIRB,relyoncommercialIRBasdirectcost
37
AdditionalsIRB Q&A
• DoestheNIHsingleIRBpolicyapplytolargercooperativegroupsornetworksthatarefundedbeforethepolicyeffectivedatebutwithstudiesthatwillbedetermined/startedaftertheeffectivedate?
ØOnlyatrenewal– soyoumaybeaskedtostartrelyingonasingleIRBforcooperativegroupstudiesatsomepoint.
https://www.aamc.org/download/474322/data/nihfaqsforsingleirb.pdf
38
AdditionalsIRB Q&A
• MusttheparticipatingsitesproposedintheNIHapplicationagreeaheadoftimetorelyonthesingleIRBidentifiedintheapplication?Ø ItisstronglysuggestedthatthesitesagreetoasingleIRBarrangementpriortothesubmissionofanapplicationorproposal.ParticipatingsitescanindicatetheirwillingnesstorelyontheselectedsingleIRBinlettersofsupport.
• CananNIHFundingOpportunityAnnouncement(FOA)specifytheIRBthatwillserveasthesingleIRB?ØYes.SomeFOAswillspecifytheuseofaparticularsingleIRB.
https://www.aamc.org/download/474322/data/nihfaqsforsingleirb.pdf
39
RequeststoRelyonExternalIRBs– forResearchers
• TheEmoryIRBwillaskforinformationaboutthestudyandwhetherrelianceismandatory(RelianceAgreementWorksheet)
• WillrequireaneIRBsubmissionforadministrative(notethics)review– Localcontextitemslikeancillaryreviews,studyteamtraining,departmentalreview
• EmoryIRBmusthelpyouwithlocalcontextinputrequestedbycentralIRB• EmoryIRBwillbepostinginformationaboutthemainsIRBs thatEmoryrelies
on,withlinkstoSOPs,reportingrequirements,etc (butwillbegrowingquickly)• Seeourwebsiteforguidanceandupdates:
http://irb.emory.edu/forms/external-irbs/index.html
https://www.aamc.org/download/474322/data/nihfaqsforsingleirb.pdf
40
ResourcesforResearchers
http://irb.emory.edu/forms/external-irbs/index.htmlInformationavailable:
vHowdoIrequestanIAAorIIA?vWhathappensafterIsubmittheIRBRelianceAgreementWorksheet?vHowlongdoesittaketogetanIRBAuthorizationAgreementinplace?(Note:it’stakingawhile,butwehavepostedaRelianceSpecialistposition)
vAretherecollaborationsforwhichIRBAuthorizationAgreementsare not appropriate?
v…andmore
https://www.aamc.org/download/474322/data/nihfaqsforsingleirb.pdf
41
CertificatesofConfidentialityforNIH-FundedStudies
• AppliestoallHumanSubjectsResearchfunded(wholeorinpart)byNIHcommencedonorafterDecember13,2016.EffectiveOctober1st,2017.
• Inaddition,thiscoversstudiesinvolvingde-identifiedspecimensthatgenerategenomicdataandanyotherresearchwherethereis“atleastaverysmallrisk”thatonecoulddeducetheidentityofanindividual.
• “Forstudiesinwhichinformedconsentissought,NIHexpectsinvestigatorstoinformresearchparticipantsoftheprotectionsandthelimitstoprotectionsprovidedbyaCertificateissuedbythisPolicy.”
• IRBsentout(andposted)aCoC addendumjustpriortotheeffectivedate,tobeusedwhenconsentingprospective subjects
• Not yetrequiredtoreconsent subjectsenrolledpriortoeffectivedate• Appliestostudiesunderno-costextensions
CertificatesofConfidentialityforNIH-FundedStudies
Note:Emoryisresponsibleforinformingsubawardees/othercollaboratorsaboutthepresenceofCoC
3Steps:HowtoSubmitaClinicalTrialtotheNIH
NIHRequirementsforGCPTraining
• EffectiveJanuary1,2017
• RequiresallNIH-fundedinvestigatorsandstaffwhoconduct,oversee,ormanageclinicaltrialstobetrainedinGoodClinicalPractice(GCP),consistentwithInternationalConferenceonHarmonization(ICH-E6-R2)
• AvailableonCITIwebsite
• Mustretaindocumentationoftraining&refreshevery3years
DisseminationofInformation
• AllNIH-fundedawardeesconductingclinicaltrials,fundedinwholeorinpartbytheNIH,willensurethattheirNIH-fundedclinicaltrialsareregisteredat,andthatsummaryresultsinformationissubmittedto, ClinicalTrials.gov forpublicposting.
• AppliestoallNIH-fundedclinicaltrials regardlessofstudyphase,typeofintervention,orwhethertheyaresubjecttotheFDAregulation.
• ApplicationsorproposalsarerequiredtosubmitaplanforthedisseminationofNIH-fundedclinicaltrialinformation thatwilladdresshowtheexpectationsofthispolicywillbemet.
ClinicalTrials.gov Requirements
ForPI-initiatedclinicaltrials,thePIisrequiredto:
• RegisterprojectinClinicalTrials.govwithin21daysofenrollmentoffirstsubject(ICMJErequiresregistrationpriortoenrollmentoffirstsubject.)
• Completeperiodicupdatesasrequired
• Reportsummaryresultsinformationwithinoneyearofprimarycompletiondate
• Includestatementinconsentform onpostingofinformationatClinicalTrials.gov
RequiredinProposal/Application
• Addstatementonpostingofclinicaltrialinformation
• Addservicecenterfeetobudgetsection
Templatelanguageavailable:http://www.ocr.emory.edu/ct.gov/language.html
ClinicalTrials.govServiceCenter
EmoryestablishedaClinicalTrials.govServiceCentertofacilitatecompliance:
• ForallawardsissuedonorafterSeptember1,2017,theservicecenterinOCRwillmanageallPI-initiatedstudies
• NIHallowsdirectchargingforcostofcomplyingwithreportingrequirements
• Aone-timefeeof$3,500forstudyduration
NIHCommunication/EducationPlan
• AllRASUnitsincludingpre-awardteam&directorstrainedinOctober/November2017§ Quickreferenceguide/checklistforRASunits
• OSP/IRB/OCR trainingcompleted• Investigators/ClinicalResearchCoordinators
o EmailcommunicationsenttoOSP,IRB&OCRlistservs withNIHsummary§ Willsendremindermid-January
o NIHclinicaltrialresourcesectionaddedtoOSPwebsite§ http://osp.emory.edu/nih_clinical_trial_requirements/index.html
o ORANewsletter,IRBWebinars,ResearchMatterso Presentatdepartmentalresearchteammeetings:CHOAquarterlystaffmeeting,DOP/CHOAfaculty
meeting,WinshipMasteringClinicalResearchSeries,SONfacultymeeting,Psychologyfacultymeeting,&CardiologyECCRIResearchGroup.Awaitingresponsefromothers.
• Institutionalcommitteepresentations:ClinicalTrialsExecutiveCommittee,ClinicalTrialsOperationsCommittee,ClinicalInvestigatorsAdvisoryCommittee,ClinicalResearchCoordinatorsAdvisoryCommittee,SOMResearchDeans,&RAC.Awaitingresponsefromothers.
ForNIHclinicaltrialdeterminations,contactyourNIHProgramOfficer
ForquestionsonFOAsorNIHforms,contactyourRAS unit&[email protected]
ForquestionsonClinicalTrials.gov,contactJenniferProzonic ([email protected])
ForquestionsonsingleIRBorCoC,contactRebeccaRousselle ([email protected])
Formoreinfo,seehttp://osp.emory.edu/nih_clinical_trial_requirements/index.html