Human Research Protection Program (HRPP)

Human Research Protection Program (HRPP)

Procedures

FORTHEPROTECTIONOFHUMANSUBJECTSINRESEARCHOctober 1, 2013

TableofContents

I.Human ResearchProtection Program (HRPP)...... 5

A.Purpose and Mission ...... 5

B.Definitions ...... 6

C.InstitutionalAssurance...... 20

D.Scopeof theHRPP ...... 21

E.EthicalFoundationsandRegulatoryMandatesfortheProtectionofHuman Subjectsand Applicabilityto HSR at NF/SGVHS 21

F.Requirements ofFundingSources...... 22

G.ApplicabilityofFDA Regulations ...... 22

H.Engagement inHumanSubjects Research...... 22

I.Special Considerations inNF/SGVHSResearch...... 25

J.Identifyingand DisseminatingNewInformation...... 26

K.Allocation of Resourcesfor the HRPP Program ...... 27

II.Roles and Responsibilitiesin the NF/SGVHS HRPP ...... 28

A.The NF/SGVHS Director (“Director”)...... 28

B.AssociateChief of Staff/Researchand Development(ACOS/RD) ...... 29

C.Institutional Review Board(IRB) ...... 30

D.Administrative Officer/Researchand Development(AO/R&D) ...... 31

E.HRPPAdministrator ...... 32

F.Research Compliance Officer (RCO) ...... 32

G.Research Pharmacist ...... 33

H.InformationSecurityOfficer (ISO)andPrivacyOfficer (PO) ...... 33

I.Research and DevelopmentCommittee ...... 33

J.Subcommitteeon ResearchSafety ...... 34

K.Investigator ...... 35

III.RequirementsandProceduresrelated toHumanSubjectsResearch at NF/SGVHS 40

A.Researchunder the Auspices ofNF/SGVHS ...... 40

B.Investigator Eligibilityfor VA Research Support ...... 40

C.Protocol Submission, Reviews,and Approvals ...... 40

D.HumanSubjects Protection andOtherTrainingRequirements ...... 42

E.CredentialingandPrivileging ...... 42

F.Non Human Determinations ...... 43

G.Research ExemptfromIRB Review ...... 43

H.Expedited Review ofHumanStudies Research ...... 44

I.Informed Consent Process and Documentation ...... 44

J.HIPAA Authorization ...... 46

K.Continuingreview and Management of Protocols with Lapsed IRB Approval .....47

L.Protocol Conclusion orTermination ...... 47

M.Departing Investigators ...... 48

N.ResearchInvolvingVulnerablePopulations ...... 49

O.ContactingVeterans for Research Purposes ...... 49

P.Requirementsfor aVHA Health Record ...... 49

Q.Flaggingthe VHAHealth Record ...... 51

R.Non-Veteransas ResearchSubjects ...... 52

S.Payment ofResearch Subjects ...... 52

T.Conflict ofInterest ...... 53

U.Investigational Drugs in Research with Human Subjects ...... 53

V.Investigational Devices inResearch with Human Subjects ...... 55

W.ResearchInvolvingHumanBiological Specimens ...... 57

X.Research Involving HumanData ...... 57

Y.Use ofSocial SecurityNumbers in VAHumanResearch ...... 57

Z.Use Preparatoryto Research ...... 58

AA.Privacy, Confidentialityand HIPAA ...... 58

BB. Information Security ...... 60

CC. Treatment ofResearch Related-Injuries ...... 60

IV.UnanticipatedProblems,SeriousAdverseEventsandNon-Compliance Reporting 62

A.Reporting Unanticipated problem involving risk to subjects or others and serious adverse events 62

B.ReportingNon-compliance ...... 62

C.Reporting Requirement for Suspension or Termination of IRB approval, Seriousor ContinuingNon-Complianceand/or UnanticipatedProblems 63

V.Outreach Program for Human ResearchParticipants ...... 65

A.Informational BrochuresandPosters ...... 65

B.NF/SGVHSWebsite ...... 66

C.CommunityNews ...... 66

D.ResearchWeek ...... 66

E.Periodic ReviewofResearchWeek ...... 67

F.CommunityOutreach ...... 67

G.InclusionofCommunityMembers in Research Process ...... 68

VI.Sponsored Research ...... 69

A.Protection of ResearchParticipants ...... 69

B.Monitor of Study ...... 69

C.Research RelatedInjuries ...... 69

VII.References...... 71

Chapter I:North Florida South Georgia Human Research Protection Program (HRPP)

A.Purpose andMission

TheNF/SGVHSisresponsibleforprotectingtherightsandwelfareofhuman researchsubjects.TheNF/SGVHSHRPPisthecomprehensivesystemtoensurethe highestlevelofprotectionforhumansubjectsparticipatinginresearchwithinthe NF/SGVHS.TheHRPPcoordinatesandoverseestheprotectionofhumanresearch subjectsthroughthissystemconsistingofavarietyofindividuals andcommittees including,butnotlimitedto:theNF/SGVHSDirector,AssociateChiefofStaff(ACOS) forR&D,AdministrativeOfficer(AO)forR&D,HRPPAdministrator,Research ComplianceOfficer(RCO),R&DCommittee,IRB,othercommitteesorsubcommittees addressinghumansubjectsprotection(e.g.,SubcommitteeonResearchSafety(SRS), RadiationSafetyCommittee),Investigatorsandresearchstaff,IRBstaffandResearch Servicestaff,healthandsafetystaff(e.g.,BiosafetyOfficer,RadiationSafetyOfficer), researchpharmacystaffandothers.TheHRPPassiststheinstitutioninassuringthat allactivitiesrelatedtohumansubjectsresearchareguidedbyethicalprinciplesand meetregulatoryrequirementsfortheprotectionofhumansubjectsinresearch.Human researchsubjectsparticipatinginresearchatNF/SGVHSmustreceivethehighestlevel ofprotectionpossibleandanyquestionsoranyethicalorlegalambiguitieswillbe resolved infavor ofthehumanresearch subject.

PrivacyOfficer

NF/SGVHS

Director

(FWA

MOU)RD

Committee

InformationSecurityOfficer

Investigator

HumanResearchProtectionProgram

IRB

(Affiliate

andVA

Central)

HRPP

Administrator

InvestigationalDrugService(IDS)

ACOS/R&DAO/RD

ResearchComplianceOfficer

Thepurposeofthismanualistoestablish,implement,andcommunicate responsibilities,proceduresandrequirementsfortheNF/SGVHSHRPPandtoprovide guidancetoallindividualsorentitiesinvolvedinreviewing,approving,supporting, conducting, managing, or overseeingresearch involvinghuman subjects.

B.DefinitionsandAcronymsrelatedtoVAHumanResearchProtections(from VHAHandbook 1200.05 unless otherwisenoted)

1.Accreditation.AccreditationofaHumanResearchProtectionProgram(HRPP) istheprocessofobtainingindependentrecognitionthataHRPPaffords protectiontohumansubjectsbymeetingandexceedingtheprevailingethical, professional,andregulatoryrequirements,andthattheHRPPengagesin continuous qualityimprovement.

2.AccreditingOrganization.Theaccreditingorganizationisanindependentbody thathasdevelopedstandardsofperformancetoassesscompliancewiththe prevailingethical,professional,andregulatoryguidelinesfortheconductof human subjects research.

3.AdverseEvent(AE).AnAEisanyuntowardphysicalorpsychological occurrenceinahumansubjectparticipatinginresearch.AnAEcanbeany unfavorableandunintendedevent,includinganabnormallaboratory finding, symptom,or diseaseassociatedwiththeresearch or theuseofa medical investigationaltestarticle.AnAEdoesnotnecessarilyhavetohaveacausal relationship with the research.

4.AffiliatedInstitution.Anaffiliatedinstitutionisanacademicinstitutionthathasa relationshipfor the purpose of education, research, or enhanced patient care with aVAmedicalcenterdocumentedbyaformalAffiliationAgreementin conformancewithVArequirements(alsoreferredtoas“academicaffiliate”).In addition,specialpurposeagreementsdocumentedbyamemorandumof understanding(MOU)approvedbytheChiefResearchandDevelopmentOfficer (CRADO)maybedevelopedinresearchanddevelopment(R&D)areas,suchas health services or rehabilitation R&D.

5.Affiliation Agreement. AnAffiliationAgreementisawrittenagreement documentingtherelationshipforthepurposeofeducation,research,or enhanced patient carebetween aVAmedicalcenterandanaffiliatedinstitution.

6.Anonymous.ForthepurposesofVAresearch,anonymousmeansde-identified in accordancewith both:

(a)TheHealthInsurancePortabilityandAccountabilityAct(HIPAA)PrivacyRule

(45 CFR164.514(b) and

(b)TheCommonRuleprovisionthattheidentityofthesubjectcannotbereadily ascertainedbytheinvestigatororassociatedwiththeinformation(38CFR 16.102(f)).

(c)Suchdatamayalsobeknownas“anonymous.”NOTE: Codeddataisdataidentifiablebytheindividual(s)whohasaccesstothecode.Therefore,forthepurposesofthisManual,codeddataarenotconsideredtobede-identifiedoranonymous.

7.Assurance(AssuranceofCompliance)orFederalwideAssurance(FWA).

Forhumanresearch,anAssuranceisawrittencommitmenttoprotecthuman subjectsparticipatinginresearchandtocomplywiththerequirementsof38CFR Part16.AssurancesarereviewedandapprovedbytheHHSOfficeforHuman ResearchProtections(OHRP)andvariousotherdepartmentsandagencies undertheFederalPolicy(CommonRule)fortheProtectionofHumanSubjects (45 CFR part 46).Underfederalregulations,anyinstitution conductingorengagedinfederallysupportedresearchinvolvinghumansubjects mustobtainanAssuranceinaccordancewith38CFR16.103.NOTE:All researchconductedunderVAauspicesisconsideredtobeFederally-supported. Thisrequirementalsoappliestoanycollaborating“performancesite”institutions. Under38CFR16.102(f),aninstitutionisengagedinhumansubjectresearch wheneveritsemployeesoragents:interveneorinteractwithlivingindividualsfor researchpurposes;orobtain,release,oraccessindividually-identifiableprivate informationforresearchpurposes.ThetermsAssurance,Assuranceof Compliance, and FederalwideAssurance (FWA) are synonymous.

8.Blinded.Ablindedstudydesignisonecomparingtwoormoreinterventionsin whichtheresearchpersonnel,thesubjects,orsomecombinationthereof,donot knowthe treatmentgroup assignments of individual subjects.

9.VA Central Institutional Review Board. The VA Central Institutional Review Board (CIRB) was established in 2008 by the Office of Research and Development (ORD) to be the official IRB of record for funded VA muolti-site trials which intend to include human subject research. For details concerning the CIRB please refer to the NR/SGVHS Standard Operating Procedures for Use of VA Central IRB.

10.Children.Childrenarepersons under the age of 18whohavenotattainedthelegalageforconsent totreatmentsorproceduresinvolvedintheresearchundertheapplicablelawof the jurisdiction in which the research will be conducted(45CFR 46.402(a)).

11.ClinicalInvestigation.TheFDAconsidersthetermclinicalinvestigation to meananyexperimentthatinvolvesatestarticleandoneormorehuman subjects,and thateither:

(a)MeetstherequirementsforpriorsubmissiontotheFDAunder§505(i)or 520(g) ofthe Federal Food,Drug, andCosmetic Act;or

(b)DoesnotmeettherequirementsforpriorsubmissiontotheFDAunderthese sectionsoftheFederalFood,Drug,andCosmeticAct,buttheresultsofwhich areintended to belatersubmittedto,or held forinspectionby,theFDAaspart of an applicationfor a research ormarketingpermit (21CFR56.102(c)).

12.CodedData.Theterm“codeddata”means“codedprivateinformation”as definedinguidancepublishedbyHHSentitledGuidanceonResearchInvolving CodedPrivateInformationorBiologicalSpecimens,currentlyavailableat: Data identified with a unique study identification number or code would be considered “coded data”.

13.CommonRule.CommonRulemeanstheFederalPolicyfortheProtectionof HumanSubjectsadoptedbyFederaldepartmentsandagenciesconductingor supportinghumansubjectresearch.TheCommonRuleiscodifiedforVAattitle 38 CFRPart16.

14.Credentialing.Credentialingisthesystematicprocessofscreeningand evaluatingqualificationsandothercredentials of research investigators,includinglicensure,education, training, and experience, and current competenceandhealth status.

15.Data.Datameansnformationderiveddirectlyfrompatientsorhumanresearch subjectsorindirectlythroughaccessingdatabases.Itincludesinformationfrom DeoxyribonucleicAcid(DNA)sequencing.Itdoesnotincludeinformationderived fromresearchinvolvinganimalsorothertypesofresearchthatdonotinvolve human subjects.

16.Database.Adatabaseisacollectionofdataorinformationelementsorganized in amanner to permit systematic retrieval.

17.DataMonitoringCommittee(DMC),DataandSafetyMonitoringBoard(DSMB),orDataandSafetyMonitoringCommittee(DSMC).ADMC,DSMB, orDSMCisgroupofindividualswithrelevantexpertisethatreviews accumulatingdatafromoneormoreongoingresearchstudies.TheDMC, DSMB,orDSMCindependentlyadvisesthesponsorortheprincipalinvestigator (PI)regardingthecontinuingsafetyoftheresearchstudy‟ssubjects,aswellas thecontinuingvalidityandscientificmeritofthestudy.DMC,DSMB,andDSMC are consideredsynonymousfor thepurposes ofthis Handbook.

18.DataRepository.Adatarepository(datawarehouse)isadatabaseora collectionofdatabasesthathavebeencreatedororganizedtofacilitatethe conductofmultipleresearchprotocols,includingfutureprotocolsnotyet envisioned.Italsomayhavebeencreatedforotherpurposessuchas administrative andclinical purposes.

19.De-Identified Data.ForthepurposesofVAresearch,de-identifieddataaredatathathavebeen de-identifiedin accordance with both:

(i)TheHealthInsurancePortabilityandAccountabilityAct(HIPAA)Privacy

Rule (45CFR 164.514(b), and

(ii)TheCommonRuleprovisionthattheidentityofthesubjectcannotbe readilyascertainedbytheinvestigatororbeassociatedwiththeinformation (38 CFR16.102(f)).

Suchdatamayalsobeknownas“anonymous.”NOTE: Codeddataisdataidentifiablebytheindividual(s)whohasaccesstothecode.Therefore,forthepurposesofthisManual,codeddataarenotconsideredtobede-identifiedoranonymous.

20.Delivery.Inthecontextofpregnancy,delivery meanscompleteseparationofthe fetusfromthe womanbyexpulsion, extraction, or anyothermeans.

21.Embryo.Anembryoisanorganismintheearlystagesofdevelopment,whichin humans isthefirst 6 weeks.

22.ExemptResearch.Exemptresearchincludesresearchactivitiesinwhichthe onlyinvolvementofhumansubjectsisinoneormoreofthecategorieslistedin 38CFR16.101(b).TheexemptstatusmustbedeterminedbytheInstitutional ReviewBoard(IRB)ChairoranIRBvotingmemberdesignatedbytheChair. NOTE:Suchanexemptionappliesonlytorequirementsfoundin38CFRPart16.AllotherrelevantVAandFederalrequirementsapply.

23.ExpeditedReviewProceduresforResearch.IncontrasttoaconvenedIRB reviewprocess,theexpeditedreviewprocessconsistsofareviewcarriedoutby theIRBChairorbyoneormoreexperiencedvotingmembersoftheIRB designated bytheIRBChairin accordance with38 CFR16.110(b).

24.ExternalAE.Inthecontextof amulti-sitestudy,anexternalAEisanAE experiencedbysubjects,researchstaff,orothersatanotherinstitution, outside of the NF/SGVHS,engaged in thetrial.

25.Facility.ForpurposesofthisHandbook,theterm“facility”and“institution”are interchangeable. Please refer to definition under “Institution”.

26.Fetus.Afetusistheproductofconceptionfromthetimeofimplantationuntil delivery.

27.Generalizable Knowledge.Informationthatexpands the knowledge base ofascientificdisciplineorotherscholarlyfieldofstudy. Systematic investigations designed to develop or contribute to generalizable knowledge constitute research. Thus, systematic investigations designed to produce information to expand the knowledge base of a scientific discipline or other scholarly field of study constitute research.

28.HealthCareAgent.Ahealthcareagentisanindividualnamedbythepatientin a DurablePower ofAttorneyfor HealthCare (38 CFR17.32(a)(iii)).

29.HIPAA Authorization. The term HIPAA authorization means prior written

permission from the research participant (or legally authorized representative)foruseanddisclosureofprotectedhealthinformation(PHI). Thewrittenauthorization mustincludeallelementsofacompliantauthorizationpriortoanydisclosureof information.

30.HumanBiologicalSpecimens.Humanbiologicalspecimensaredefinedas materialsderivedfromhumanindividuals,suchasblood,urine,tissue,organs, hair,nailclippings,buccalswabs,oranyothermaterialsthatareeithercollected specificallyforresearchpurposesorasresidualspecimensfromdiagnostic, therapeutic,orsurgicalprocedures.Bacteria,fungi,orvirusesobtainedfrom humanbiologicalspecimensarenotconsideredhumanbiologicalspecimens,as longas the humanmaterial hasbeen removed.

31.HumanResearch.Humanresearchisresearchinvolvinghumansubjectsorone ormoreidentifiablehumanbiologicalspecimens.ForFDA-regulatedstudies, humansubjectresearchalsoincludesanyactivitythatisaclinicalinvestigation involvinga human subject asdefinedabove.

32.HumanResearchProtectionProgram(HRPP).AHRPPisacomprehensive systemtoensuretheprotectionofhumansubjectsparticipatinginresearch.Ata localVAfacility,theHRPPconsistsofavarietyofindividualsandcommittees including,butnotlimitedto:theVAfacilityDirector,AssociateChiefofStaff (ACOS)forR&D,AdministrativeOfficer(AO)forR&D,HRPP Administrator, ResearchCompliance Officer(RCO),R&DCommittee,IRB,othercommitteesorsubcommittees addressinghumansubjectsprotection(e.g.,SubcommitteeonResearchSafety (SRS), InstitutionalBiosafetyCommittee,RadiationSafetyCommittee, RadioactiveDrugResearchCommittee,ConflictofInterestCommittee), investigators,IRBstaff,researchstaff,healthandsafetystaff(e.g.,Biosafety Officer,RadiationSafetyOfficer)andresearchpharmacystaff.Theobjectiveof thissystemistoassisttheinstitutioninmeetingethicalprinciplesandregulatory requirementsfor theprotection of human subjects in research.

33.HumanSubject.Title38CFRPart16definesahumansubjectasalivingindividualabout whomaninvestigator(whetherprofessionalorstudent)conductingresearch obtains either:

(i)Datathroughinterventionorinteractionwiththeindividual;interaction includescommunicationorinterpersonalcontractbetweentheresearchers

andthesubject; or

(ii)entifiableprivateinformation (38CFR 16.102(f)).

ForresearchcoveredbyFoodandDrugAdministration(FDA)regulations, humansubjectsmeansanindividualwhoisorbecomesaparticipantina clinicalinvestigation,eitherasarecipientofthetestarticleorasacontrol.(21 CFR50.3(g), 21 CFR66.102(c)).

ForresearchcoveredbyFDAdeviceregulations,subjectmeansahuman whoparticipatesinaninvestigation,eitherasanindividualonwhomoron whosespecimenaninvestigationaldeviceis usedoras acontrol.A subject may beinnormalhealthormayhaveamedicalconditionordisease(21CFR 812.3(p)).

NOTE: Thisdefinitionofhumansubjectincludesinvestigators, technicians,andothersassistinginvestigators,whentheyserveina“subject” role bybeingobserved, manipulated, or sampled.

34.InVitroFertilization.Invitrofertilizationisanyfertilizationofhumanova,which occursoutsidethebodyofafemale,eitherthroughamixtureofdonorhuman spermand ova or byanyothermeans.

35.Institution.Aninstitutionisanypublicorprivateentityoragency(38CFR 16.102(b)).VHAHandbooks1200.05and1058.03distinguishVAfromnon-VA institutions.

(a)VAInstitution.AVAinstitutionisany entity thatisoperatedbyVA,including but not limited to:VA hospitals,medical centers, clinics, and health care systems; spaceowned,leased,orrentedbyVA;andspacethatis“shared”withanon-VA entity(unlesstheVAspaceisleasedtoanon-VAentityandspecifically designatedinwritingnottobeusedbyVAorVAemployeesforresearch).AVA facilitymayincludemultiplecampusesandsatellitecomponents.NOTE:ForpurposesofthisManual,theterms“facility,”“VAfacility,”and“VAinstitution”areconsideredsynonymous.

(b)Non-VAInstitution.Anon-VAinstitutionisanentitynotoperatedbyVA. Non-VA institutions include,butarenot limited to:

(i)Any entity thatisnotalegalcomponent ofVAorofaVA facility,including acontractresearchorganization(CRO),industryorprivatesponsor, or public orprivateresearch company, foundation, or group.

(ii)EntitiesoperatedunderacontractwithVAincluding,butnotlimitedto, contractCommunity-basedOutpatientClinics.

(iii)Academicinstitutions,includingVA–affiliatedmedicalschools,dental schools,andother academicaffiliates (see Affiliated Institution).

(iv)VA-affiliated Non-Profit Research and Education Corporations (NPCs).

(v)Other Federal, state, or local departmentsor agencies.

36.Institutional Official (IO).The IO is the individual legallyauthorized as Signatory OfficialtocommitaninstitutiontoanAssurance.TheIOservesastheofficial representativeoftheinstitutiontoexternalagenciesandoversightbodies,and providesallwrittencommunicationwithexternaldepartments,agencies,and oversightbodies.TheVAfacilityDirectorsaretheIOsforlocalVAfacilities.The IOisresponsiblefortheHRPPasdescribedinNF/SGVHSpoliciesand proceduresandas described inVHA Handbook 1200.05 the NF/SGVHS Medical Center Director is the IO for this institution.

37.InstitutionalReviewBoard(IRB).AnIRBisaboard,committee,orothergroup formallydesignatedbyaninstitutiontoreview,approve,requiremodificationin, disapprove,andconductcontinuingoversightofhumanresearchinaccordance with 38 CFRPart 16 and otherapplicable VAandFederal requirements. The NF/SGVHS has two IRBs of record: the University of Florida IRB-01 and the VA Central IRB.

38.Interaction. Interactionincludescommunicationorinterpersonalcontact between investigator and subject (38 CFR16.102(f)(2)).

39.InternalorLocalAE.Inthecontextofamulti-centerstudy,internalAEsare thoseAEsexperiencedbysubjects,researchstaff,orothersatthereporting individual’sownVAfacilityorVA-approvedresearchsite.

40.InternationalResearch.VAinternationalresearchisanyVA-approvedresearch conductedatinternationalsites(notwithintheUnitedStates(U.S.),itsterritories, orCommonwealths);anyVA-approvedresearchusingeitherhumanbiological specimens(identified,de-identified,orcoded)orhumandata(identified,de- identified,orcoded) originatingfrominternational sites;or anyVA-approved research sending suchspecimensordataoutoftheU.S.NOTE:ForthepurposesofVAHRPPs,researchconductedatU.S.militarybases,ships,orembassiesisnotconsideredinternationalresearch.

41.Intervention.Interventionincludesbothphysicalproceduresbywhichdataare gathered(e.g.,venipuncture)andmanipulationsofthesubjectorthesubject‟senvironmentthatareperformedforresearchpurposes(38CFR16.102(f)(2)). Interventionalstudiesarethoseinwhichtheresearchsubjectsareassignedby theinvestigatortoatreatmentorotherintervention,andtheiroutcomesare measured.

42.InvestigationalDevice.AsdefinedbytheFDA,aninvestigationaldeviceisa device thatis the object of an investigation (21 CFR812.3(g)).

43.InvestigationalDeviceExemption(IDE).AnIDEisanapplicationtoFDAthat allowsaninvestigationalsignificantriskdevicetobeusedinaclinical investigationtocollectsafetyandeffectivenessdata.Ifthedeviceisanon- significantriskdevice,itisconsideredtohaveanapprovedapplicationforIDE after IRBapproval is obtained (see 21 CFR 812).

44.InvestigationalDrug.AccordingtoVHAHandbook1108.04,aninvestigational drugisachemicalorbiologicaldrugthatisusedinaclinicalinvestigation.An investigational drugcan be:

(a)Anewchemicalcompound,whichhasnotbeenreleasedbytheFDAfor general use; or

(b)Anapproveddrugthatisbeingstudiedforanapprovedorunapproveduse, dose,dosageform,administrationschedule,orunderanInvestigationalNew Drug(IND) application,in acontrolled, randomized, or blindedstudy. (see VHA handbook 1108.04)

45.InvestigationalNewDrug(IND)Application.AnINDisanapplicationtothe FDAthat allowsaninvestigationaldrugorbiologicalproducttobestudiedinhumans. AnINDmustbeineffectpriortoshipmentandadministrationofinvestigational drugor biological products (see21 CFR312).

46.Investigator.Aninvestigatorisanyindividualwhoconductsresearchinvolving humansubjectsincluding,butnotlimitedto,thePI,co-PI,andLocalSite Investigator(LSI).Theinvestigatormustupholdprofessionalandethical standards andpractices,adhere toallapplicableFederal requirements,and comply with applicablelocal policies and procedures.

(a)VAInvestigator.AVAinvestigatorisanyindividualwhoconductsresearch approvedbytheVAR&DcommitteewhileactingunderaVAappointmentonVA time,includingfullandpart-timeemployees,withoutcompensation(WOC) employees,andindividualsappointedordetailedtoVAunderthe IntergovernmentalPersonnelAct(IPA)of1970.Inaddition,aVAinvestigator mustcomplywithallapplicableVAandVHArequirements,andcomplywith applicable localVAfacilitypolicies and procedures.

(b)PrincipalInvestigator(PI).ThePIisaqualifiedpersonorpersons designatedbyanapplicantinstitutiontodirectaresearchprojectorprogramand whousuallywritesthegrantapplication.ThePIoverseesscientific,technical, andday-to-daymanagementoftheresearch.Intheeventofaninvestigation

conductedbyateamofindividuals,thePIistheresponsibleleaderofthatteam.

NOTE:FDAconsidersInvestigatorandPItobesynonymous.

(c)Co-PrincipalInvestigator(Co-PI).ACo-PIiswhenoneoftwoormorePIs shareequallyintheaccountabilityforastudy.ACo-PImustmeetthesame qualifications of aPI.

(d)SiteInvestigatororLocalSiteInvestigator(LSI).TheSiteInvestigatoror LSIisaninvestigatoratasiteparticipatinginamulti-siteresearchproject.The LSIoverseesscientific,technical, andday-to-day managementoftheresearchat the local site.

47.LegalGuardian.Alegalguardianisapersonappointedbyacourtofcompetent jurisdictiontomaintainandcareforthepropertyofanindividual,oranindividual whothecourthasdeclaredincompetentduetophysicalormentalincapacityor age.

48.LegallyAuthorizedRepresentative(LAR).ALARisanindividualorjudicialor otherbodyauthorizedunderapplicablelawtoconsentonbehalfofaprospective subjecttothesubject'sparticipationintheprocedure(s)involvedintheresearch (38CFR16.102(c)).Forpurposesofthismanual,thefollowingpersonsare authorizedtoconsentonbehalfofpersonswholackdecision-makingcapacityin thefollowingorderofpriority:Healthcareagent(i.e.,anindividualnamedbythe individualinaDurablePowerofAttorneyforHealthCare(38CFR.17.32(a)(iii)); Legalguardianorspecialguardian;Nextofkininthisorder:acloserelativeof thepatient18yearsofageorolder,inthefollowingpriority:spouse,child, parent,sibling,grandparent, orgrandchild;orclosefriend.Theresponsibilitiesof theLAR aredescribedin VHA Handbook1200.05.

NOTE:AnindividualwhoisqualifiedasaLARtoprovideinformedconsentonbehalfofaprospectiveresearchsubjectmay notalways qualifyas apersonalrepresentativeforpurposesofconsenttouseordiscloseasubject’sProtectedHealthInformation(PHI)(i.e.,signingaHIPAAauthorization).Therefore,incircumstancesinvolvingauthorizationforuseordisclosureofahumansubject’s PHI,theinvestigatormustensuretheLARmeetstherequirementsofapersonalrepresentativeinHIPAAandthePrivacyActof1974(legalguardianorpower ofattorney)priortotheLAR’ssigningaHIPAAauthorization(VHAHandbook1605.1).

49.MinimalRisk.Minimalriskmeansthattheprobabilityandmagnitudeofharmor discomfortanticipatedintheresearcharenotgreaterinandofthemselvesthan thoseordinarilyencounteredindailylifeorduringtheperformanceofroutine physical or psychological examinationsor tests (38 CFR 16.102(i)).

50.MemorandumofUnderstanding.AnMOUisawrittenagreement betweentwo VAfacilitiesorbetweenaVAfacilityandanon-VAinstitutiondocumentingtheir relationshipanddefiningtheirrespectiverolesandresponsibilitieswithinthat

relationship(VHA Handbook 1058.03).

51.Neonate.ForthepurposesofVAresearch,aneonateisaninfantinthefirst28 days oflife.

52.ObservationalStudies.Observationalstudiesarenon-interventionalstudiesin whichindividualsareobservedandthoseobservationsarerecorded.Outcomes, includinghealthoutcomes,mayalso bemeasured bythe investigators.

53.OfficeforHumanResearchProtections(OHRP).OHRPisanofficewithinthe DepartmentofHealthandHumanServices(DHHS)thatreviewsandapproves Assurances,monitorshumanresearchsubjectsprotectionsthrougheducational efforts,clarificationandguidance,sitevisits,andreportingrequirements.OHRP has theauthorityto suspend researchforfailure toadheretothe regulations.

54.OfficeofResearchandDevelopment(ORD).WithinVHACentralOffice,ORD istheofficeresponsiblefortheoverallpolicy,planning,coordination,and direction ofVA research activities.

55.OfficeofResearchOversight(ORO).OROservesastheprimaryVHAofficein advisingtheUnderSecretaryforHealthonallmattersofcomplianceand assuranceregardinghumansubjectprotections,animalwelfare,researchsafety and security, researchinformationprotection,and researchmisconduct.

56.PersonalRepresentative.Apersonalrepresentativeisapersonwho,under applicablelaw,hasauthoritytoactonbehalfofanotherindividual.Thismay includepowerofattorney,legalguardianshipofanindividual,theexecutorofan estateofadeceasedindividual,orsomeoneunderFederal,state,local,ortribal law with such authority(e.g., the parent of aminor)(VHA Handbook 1605.1).

57.PilotStudies.Pilotstudiesarefull-fledgedresearchstudiesthatmustbe approvedbytheIRB(s),whenhumansubjectsareinvolved.Theyarenot considered to be activities preparatoryto research.

58.Pregnancy.Pregnancyencompassestheperiodoftimefromconceptionuntil delivery.

59.PreparatorytoResearch.WithinVHA,activities“preparatorytoresearch”refer toactivitiesthatarenecessaryforthedevelopmentofaspecificprotocol.PHI fromdatarepositoriesormedicalrecordsmaybereviewedduringthisprocess withoutIRBapproval,subjectauthorization,orawaiverofauthorization,butonly aggregatedatamayberecordedandusedintheprotocolapplication(e.g., potentialnumberofsubjectsmeetingstudycriteriaateachsite).WithinVHA,an activitypreparatorytoresearchdoesnotincludetheidentificationofpotential

subjectsandrecordingofdataforthepurposeofrecruitingthesesubjectsorto linkwithotherdata.Thepreparatorytoresearchactivityendsoncetheprotocol has beensubmittedtothe IRBfor review.

60.Prisoner.Aprisonerisanyindividualinvoluntarilyconfinedordetainedina penalinstitution.Thetermisintendedtoencompassindividualssentencedto suchaninstitutionunderacriminalorcivilstatute,individualsdetainedinother facilitiesbyvirtueofstatutesorcommitmentproceduresthatprovidealternatives tocriminalprosecutionorincarcerationinapenalinstitution,andindividuals detainedpendingarraignment, trial,or sentencing.

61.PrivacyBoard.UnderHIPAA,aPrivacyBoardisaboardthatisestablishedto reviewand approve requests for waivers or alterations of HIPAAauthorizations in connectionwithuseordisclosureofPHI.TheUFIRB-01actsastheprivacy board NF/SGVHSexceptfor research thatfalls under theVA CIRB.

62.Private Information

(a)Private information must be individually identifiable in order for the informationtoconstitute research involvinghuman subjects (38 CFR 16.102(f)).

(b)Privateinformationincludes:

(i)Informationaboutbehaviorthatoccursinacontextinwhichanindividual can reasonablyexpect thatnoobservation orrecordingis takingplace, and

(ii)Informationwhichhasbeenprovidedforspecificpurposesbyan individualandwhichtheindividualcanreasonablyexpectwillnotbemade public (e.g.,amedicalrecord).

62.Privileging

(a)ForthepurposesofthisManual,theterms“privileging”and"clinical privileging"arethesameandaredefinedastheprocessbywhichapractitioner, licensedforindependentpractice(i.e.,withoutsupervision,direction,required sponsor,preceptor,mandatorycollaboration,etc.),ispermittedbylawandthe facility:

(i)Topracticeindependently; and

(ii)Toprovidespecifiedmedicalorotherpatientcareserviceswithinthe scopeoftheindividual’slicense,basedontheindividual'sclinical competenceasdeterminedby peerreferences,professionalexperience, health status,education, training,andlicensure.

(b)Clinicalprivilegesmustbefacility-specificandprovider-specificperVHA Handbook1100.19.

63.Program for Research Integrity Development and Education (PRIDE).

PRIDEistheprogramwithinORDthatisresponsiblefortraining,education,and policydevelopment relatedtoVAhumansubjects protection.

64.Quorum.Aquorumisdefinedasamajorityofthevotingmembers.Atmeetings oftheR&DCommitteeanditssubcommittees,aquorummustbeestablished andmaintainedthroughouttheentiremeetinginorderforbusinesstobe conducted.Somecommittees,suchastheIRBhaveadditionalrequirementsfor theestablishmentofaquorum,suchaspresenceofamemberwhoseprimary concernsare innonscientific areas.A member withaconflict of interest cannot:

(a)Contribute to aquorum,

(b)Bepresentforthediscussionoftheissueforwhichtheyareconflicted, except toanswer questionsfromthe committee,or

(c)Be presentfor thevote on the issue.

65.Research.Researchmeansasystematicinvestigationincludingresearch development,testing,andevaluationdesignedtodeveloporcontributeto generalizableknowledge.Activitieswhichmeetthisdefinitionconstituteresearch forpurposesofthispolicywhetherornottheyareconductedorsupportedunder aprogramwhichisconsideredresearchforotherpurposes.Forexample,some demonstrationandserviceprogramsmayincluderesearchactivities(38CFR 16.102(d)). For more information regarding demonstration and service program activities and what may consititute research, please refer to VHA Handbook 1058.05.

66.ResearchComplianceOfficer(RCO).TheRCOisanindividualwhose primaryresponsibilityistoauditandreviewresearchprojectsrelativeto requirementsfortheprotectionofhumansubjects,laboratoryanimalwelfare, researchsafety,researchlaboratorysecurity,researchinformationprotection, andotherareasunderthejurisdictionofandasspecifiedbyORO.Inaddition toconductingrequired audits, theRCO may serveasanonvotingconsultant, as needed,tothefacility’sR&DCommittee,IRB,IACUC,Subcommitteeon ResearchSafety(SRS),andotherresearchreviewcommittees.TheRCOmay notserveasavotingornonvotingmemberofthesecommittees.TheRCOmay attendmeetingsofthesecommitteeswhenrequestedbythecommitteeoras specifiedbylocalSOP‟s.

67.Research and Development Committee. Every VA facility conducting research must have, or establish a Research and Development Committee (RDC). The RDC is a committee responsible, through the Chief of Staff to the VA facility Director, for oversight of the facility’s research program and for maintenance of high standards throughout that program. NOTE: Research and Development Committees are discussed in VHA Handbook 1200.01.

68.ResearchRecords.Researchrecordsinclude,butarenotlimitedto,IRBand R&DCommitteerecords,recordsofallobservations,otherdatarelevanttothe investigation,progressnotes,researchstudyforms,surveys,questionnaires, andother documentation regardingthe studyper VHA Handbooks1200.05 and 1907.01.

(a)IRBRecords.IRBrecordsinclude,butare notlimitedto:copiesofall researchproposalsandamendmentsreviewed;scientificevaluations,ifany,that accompanytheproposals;approvedinformedconsentdocuments;progress reportssubmittedbyinvestigators;reportsofinjuriestosubjects;reportsof complaintsfromsubjects;minutesofIRBmeetings;reportsofexpeditedreview activities;recordsofcontinuingreviewactivities;copiesofallcorrespondence betweenIRBandtheinvestigators;reportsof deviationsfromIRB-approved protocol;alistofIRBmembers;writtenproceduresforIRBinthesamedetailas describedin38CFR16.103(b)(4)and(5);andstatementsofsignificantnew findingsprovidedtosubjectsasrequiredby38CFR16.116(b)(5).ANF/SGVHS IRBofrecordmustmaintain andprepareadequatedocumentationof IRBactivitiestotheextentrequiredby38CFR16.115andVHAHandbook 1200.05.

(b)Investigators’ResearchRecords.Investigator researchrecordsinclude, but are not limited to:copies of the IRB and VA RDC study approvals, copiesofallIRB-approvedversionsoftheprotocol andamendments;casereport formsandsupportingdata(includingbut not limitedtosignedanddatedinformedconsentformsandHIPAAauthorization forms);documentationoneachsubjectincludinginformedconsent,interactions withsubjectsbytelephoneorinperson,observations,interventions,andother datarelevanttotheresearchstudy;reportsofadverseevents;dataanalyses; codesandkeysusedtode-identifyandre-identifysubjects‟PHI;reports (including,but notlimitedtoabstracts andotherpublications); allcorrespondence (including,butnotlimitedto,thatwiththefundingsourceorsponsor)andwith applicableoversightentities(including,butnotlimitedto,IRB,RDCommittee, ORO,andFDA);andamasterlistofallsubjectsforwhominformedconsenthas been obtained inthe study.

69.Researcher.A researcher is also considered aninvestigator. Please refer to definition of “Investigator”.

70.Subcommittee for Research Safety. The purpose of the Subcommittee for Research Safety (SRS) is to ensure the safety of all NF/SGVHS personnel conducting research involving the use of potential hazards encountered in research settings, including but not limited to biohazards such as, pathogens and etiologic agents corresponding to Biosafety Levels (BSL) 1-2, chemical, physical, and radiation hazards. NF/SGVHS does not currently have the capability to accommodate BSL-3 research.

71.Sensitive Information. VAsensitiveinformationisalldepartmentdata,onanystoragemediaorin anyformorformat,whichrequiresprotectionduetotheriskofharmthatcould resultfrominadvertentordeliberatedisclosure,alteration,ordestructionofthe information.

Thetermincludesinformationwhoseimproperuseordisclosurecould adverselyaffecttheabilityofanagencytoaccomplishitsmission;proprietary information;recordsaboutspecificindividualsrequiringprotectionundervarious confidentialityprovisions,suchasthePrivacyActandtheHIPAAPrivacyRule; and information that can bewithheld underthe Freedom of Information Act.

72.SeriousAdverseEvent(SAE).AlocalSAEinhumanresearchisanAEthat resultsindeath,alifethreateningexperience,inpatienthospitalization, prolongationofhospitalization,persistentorsignificantdisabilityorincapacity, congenitalanomaly,orbirthdefect.AnAEisalsoconsideredseriouswhen medical,surgical,behavioral,social,orotherinterventionisneededtoprevent such an outcome.

73.Sponsor.ForFDAstudies,theFDAconsidersasponsortobethepersonwho takesresponsibilityforandinitiatesaclinicalinvestigation.Thesponsormaybe anindividual,pharmaceuticalcompany,governmentalagency,academic institution,privateorganization,orother.Thesponsordoesnotactuallyconduct theinvestigationunlessthesponsorisasponsor-investigator.Apersonother thananindividualthatusesoneormoreoftheirownemployeestoconductan investigationthatithasinitiatedisasponsor,notasponsor-investigator,andthe employees are investigators (21CFR312.3and 21 CFR812.3).

74.Surrogate.AsurrogateisanindividualauthorizedunderVHApolicytomake decisionsonbehalfofa subject who lacks decision-makingcapacity.

75.SuspensionofIRBApproval.AsuspensionofIRBapprovalisadetermination bytheIRBtotemporarilyinterruptsomeorallpreviously-approved researchactivities.Thesuspendedactivitiescouldinclude,butnotbelimitedto, recruitingofnewsubjectsfortheresearch.Suspendedstudiesremainopenand require continuingreview.

76.Systematic Investigation.Asystematicinvestigationisanactivitythatis plannedinadvanceandthatusesdatacollectionandanalysistoanswera question.

77.TerminationofIRBApproval.AterminationofIRBapprovalisadetermination bytheconvenedIRBtopermanentlyhaltsomeorallpreviouslyapproved researchactivitiesincluding,butnotlimitedto,enrollmentofnewsubjectsin research.

NOTE:Theterms“suspension”and“termination”applytointerruptionsrelatedtoconcernsregardingthesafety,rights,orwelfareofhumanresearchsubjects,investigators,researchstaff,orothers.TheydonotincludeinterruptionsinhumanresearchresultingsolelyfromtheexpirationoftheIRBapprovalperiod(VHAHandbook1058.01).

78.TestArticle.Atestarticleisanydrugforhumanuse,biologicalproductfor humanuse,medicaldeviceforhumanuse,humanfoodadditive,coloradditive, electronicproduct,oranyotherarticlesubjecttoregulationundertheFederal

Food,Drug,andCosmeticActorunder§§351and354-60FofthePublicHealth Service Act (42 U.S.C.262and 263b-263n; 21 CFR50.3(j)).

79.Unanticipated(orunexpected)AdverseEvent(UAE).AnUAEisanAEthatis neworgreaterthanpreviouslyknown,intermsofnature,severity,orfrequency ofoccurrence,asdocumentedintheprotocolorothermaterialsapprovedby IRB.

80.UsualCare.Usualcareismedicalorothertreatmentorservicesaresearch subjectwouldreceiveifnotparticipatingintheresearchstudy(e.g.,the chemotherapyanoncologypatientwouldreceivewhetherornotthepatientwas participatingina research study).

81.VAResearch.VAresearchisresearchthatisapprovedbytheRDCommittee andconductedbyVAInvestigatorsincludingPIs,Co-PIs,andSiteInvestigators onVAtime(servingoncompensated,WOC,orIPAappointments),utilizingVA resources(e.g.,equipment),oronVApropertyincludingspaceleasedto,and usedbyVA.TheresearchmaybefundedbyVA,byothersponsors,orbe unfunded.

NOTE:Researchconductedbynon-VAinvestigatorsthatdoesnotutilizeVAresourcesandthatoccurs onspace, or with equipment, leasedfrom VA orcoveredunderauseagreementbetweenVAandanon-VAentityisnotconsideredVAresearch.

82.WithoutCompensation(WOC).AWOC appointmentisaVAappointment for a person whoperforms duties withoutanydirectmonetarycompensationfromVA.

C.InstitutionalAssurance

AllhumansubjectresearchconductedorsupportedbyVAmustcomplywiththe FederalPolicy(CommonRule)fortheProtectionofHumanSubjects,56FederalRegister(FR)28001,June18,1991,ascodifiedat38CFRPart16. EachVA facilityengagedinhumansubjectsresearchmustprovideawrittenAssurance, acceptable totheSecretaryofVeterans Affairs,committingthefacility tocomplywith 38CFRPart16.TheNF/SGVHS has aFederalwideAssurance(FWA) approved by theOfficeforHumanResearchProtections(OHRP)andaVAaddendumapproved bytheVAOfficeofResearchOversight.TheNF/SGVHSFWAcoversallhuman subjectsresearchconductedwithintheNF/SGVHSandbyNF/SGVHSinvestigators actingintheirofficialVAcapacity.TheNF/SGVHSDirectoristhesignatoryofficial totheFWAandtheInstitutionalOfficialresponsiblefortheoversightoftheHRPP. InformationonthecomponentsoftheNF/SGVHSAssuranceislistedontheOHRP website or is availableupon requestfromtheResearch Service Office.

AspartofitsAssurance,NF/SGVHShasdesignatedtheUniversityofFlorida(UF) IRB-01andtheVACentralIRB(VACIRB)asIRBsofrecordthroughMemorandaof

Understanding.NF/SGVHSinvestigatorsconductinghumansubjectsresearch must complywiththerequirementsanddeterminations oftheapplicableIRB.IRB policies andproceduresare available on the respectiveIRBwebsites.

D.Scope ofthe HRPP

TheNF/SGVHSHRPPappliestoactivitiesmeetingthedefinitionofhumansubjects researchor clinical investigationinwhichNF/SGVHSis engagedregardless of fundingsource,typeofresearchorplaceofconduct.Allactivitiesthatare determinedtomeetthesedefinitionsfallundertheauspicesoftheNF/SGVHS HRPPandaresubjecttotheallapplicableregulationsandrequirementsas describedinthe NF/SGVHSHRPPpoliciesandprocedures.Definitionsof“research,” “humansubjects”and“clinicalinvestigation”areprovidedinSectionI.B. Proceduresforobtainingadeterminationofwhetheranactivitymeetsthedefinition ofhumansubjectsresearch aredescribed inSectionIII. C.

HumanResearchStudiesconductedatNF/SGVHSincludebutarenotlimitedto: clinicalinvestigations;healthservicesresearch;rehabilitationresearchand may includepatients,patient data, healthy volunteers, staff,and/or students.

E.EthicalFoundationsandRegulatoryMandates

Ethical Foundations

NF/SGVHSassuresthatallofitshumansubjectsresearchactivitiesareguidedby theethicalprinciplesassetforthinthereportoftheNationalCommissionforthe ProtectionofHumanSubjectsinBiomedicalandBehavioralResearchEthical PrinciplesandGuidelinesfortheProtectionofHumanSubjectsofResearch(The BelmontReport).ThethreeguidingethicalprinciplesofTheBelmont Report include: