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&copyOSP@emory.edu

ForquestionsonClinicalTrials.gov,contactJenniferProzonic (jprozon@emory.edu)

ForquestionsonsingleIRBorCoC,contactRebeccaRousselle (rrouss2@emory.edu)

Formoreinfo,seehttp://osp.emory.edu/nih_clinical_trial_requirements/index.html