Understanding

ClinicalTrialsDevelopedbySaraBack,NPBronx-LebanonHospitalCenter第1頁Overview

Purposeof

ResearchStudiesClassificationsofEpidemiologicalResearchBasicResearchTerminologyFeaturesofClinicalTrialsDesign/ProtocolPhasesofaStudyEthicsProtectionofParticipantsContributionsofClinicalTrialsParticipatinginaTrialConclusion&TakeHomeMessage第2頁OverviewtoResearchStudiesWhyDoResearchStudies?Tocollectdataonusualandunusualevents,conditions,&populationgroupsTotesthypothesesformulatedfromobservationsand/orintuitionUltimately,tounderstandbetterone’sworldandmake“senseofit”第3頁OverviewtoResearchStudiesVarioustypesofresearchstudiesManyclassifiedas“EpidemiologicalStudies”Epidemiologyoftenisdefinedas:Thestudyofthedistributionofadiseaseorconditioninapopulationandthefactorsthatinfluencethatdistribution.第4頁ClassificationsofResearchStudies:ThreeMainTypesObservationalStudies:Groupsarestudied&contrastsmadebetweengroupsTheobserveddatacollectedareanalyzedAnalyticStudies:AlsocalledExperimentalStudytheimpactofacertaintherapyUltimatelytheinvestigatorcontrolsfactorbeingstudiedClinicalTrial:Consideredthe“true”experimentalstudy“GoldStandard”ofclinicalresearchOftenaprospectivestudythatparestheeffectandvalueofaninterventionagainstacontrolinhumansubjects 第5頁AnotherClassificationSystem

Non-directedDataCapture

Ex:VitalStatisticsDirectedDataCapture&HypothesisTesting

Ex:CohortStudies,CaseControlStudiesClinicalTrials

Ex:InvestigationofTreatment/ConditionEx:DrugTrials第6頁TheDifferentStudyDesignsCase-control ?CohortCaseReports ?CaseSeriesOutesBased: ?SurveyResearch:QualityofLife QuestionnairesDecisionanalysis PollsEconomicAnalysis SurveysMetaAnalysesSurvivalAnalysisRandomizedClinicalTrial第7頁BasicResearchTerminologyRetrospective:ReferstotimeofdatacollectionProspective:ReferstotimeofdatacollectionCaseControlStudy:Personsw/disease&thosew/outareparedCohortStudy:Personsw/and/orw/outdiseasearefollowedovertime第8頁Terminology(Cont.)Cross-sectionalStudy:Presenceorabsenceofexposuretopossibleriskfactormeasuredatonepointintime.Prevalenceobtained.Prevalence:The#ofnewcasesandexistingcasesduringspecifiedtimeperiod.Incidence:The#ofNEWcasesperunitofapopulationatriskfordiseaseoccurringduringstatedtimeperiod.第9頁HistoricalMinute

First“ClinicalTrials”ClinicalTrialshavealonghistory–evenifnotacknowledgedasClinicaltrialsFormalrecordofclinicaltrialsdatesbacktothetimeofthe“Trialists”:Dr.VanHelmont’sproposalforatherapeutictrialofbloodlettingforfevers[1628]Dr.Lind’s,ashipsurgeon,trialoforanges&limesforscurvy[1747]第10頁HistoricalMinute

First“ClinicalTrials”HistoricalHighlightsofDrugTrials1909:

PaulEhrlich-Arsphenamine1929:

AlexanderFleming-Penicillin1935:GerhardDomagk-Sulfonamide1944:Schatz/Bugie/Waksman–StreptomycinBy1950,theBritishMedicalRes.Councildevelopedasystematicmethodologyforstudying&evaluatingtherapeuticinterventions第11頁CoreComponentsofClinicalTrialsInvolvehumansubjectsMoveforwardintimeMosthaveaparisonCONTROLgroupMusthavemethodtomeasureinterventionFocusonunknowns:effectofmedicationMustbedonebeforemedicationispartofstandardofcareConductedearlyinthedevelopmentoftherapies第12頁CoreComponentsofClinicalTrialsMustreviewexistingscientificdata&buildonthatknowledgeTestacertainhypothesisStudyprotocolmustbebuiltonsoundðicalscienceControlforanypotentialbiasesMoststudymedications,procedures,and/orotherinterventions第13頁ThePossibleWorldofClinicalTrialDesignsRandomized/blindedtrialRandomized/doubleblindedtrialNon-randomizedconcurrentcontrolledtrialPlacebotrialHistoricalcontrolledtrialCrossoverTrialWithdrawaltrial第14頁SimplifiedRandomized:SchemesusedtoassignparticipanttoonegroupEx:Every3getshigherdoseNonrandomized:AllwithHep.C=cases;others=controlsProtocol:Studydesign-instructionsBlinded:ParticipantsdonotknowifinexperimentalorcontrolgroupDoubleBlinded:ParticipantsANDstaffdonotknowgroupassignmentPlacebo:Inactivepillw/notherapeuticvalue第15頁ComponentsofClinicalTrialProtocolsInvestigatingtwoormoreconditionssohavetwo(+)groupsEx:drugvs.placebo;medicinevs.surgery;lowdosevs.highdoseSpecificinclusion/exclusioncriteriaSamplesize&powercalculationsPlanre:potentialbiasesPlanre:handlingofattrition/losstofollowup第16頁StudyParticipantRecruitmentIdentifyeligibleparticipantsExplainstudyProvideinformedconsentReassesseligibilityAssigntoonegroupParticipantsshouldbetold:Mayhavesideeffects(adverseeffects)TimemitmentBenefits&risksMaywithdrawatanytimeEnrollment100%voluntary第17頁P(yáng)hasesofClinicalTrialsMosttrialsthatinvolvenewdrugsgothroughaseriesofsteps:#1:Experimentsinthelaboratory#2:Oncedeemedsafe,gothrough1-4phases第18頁P(yáng)hasesofClinicalTrialsPhaseI:Smallgroup[20-80]for1sttimetoevaluatesafety,determinesafedosagerange&identifySEPhaseII:

Rx/txgiventolargergroup[100-300]toconfirmeffectiveness,monitorSE,&furtherevaluatesafety第19頁P(yáng)hasesofClinicalTrials(cont.)PhaseIII:Rx/txgiventoevenlargergroup[1,000-3,000]tofulfillallofPhaseIIobjectives&pareittoothermonlyusedtxs&collectdatathatwillallowittobeusedsafelyPhaseIV:Doneafterrx/txhasbeenmarketed-studiescontinuetotestrx/txtocollectdataabouteffectsinvariouspopulations&SEfromlongtermuse.第20頁SummaryofPhasesI-III#Subs.LengthPurpose%DrugsSuccessfullyTestedPhaseI20–100SeveralmonthsMainlySafety70%PhaseIIUptoseveral100Severalmonths-2yrs.Shorttermsafety;mainlyeffectiveness33%PhaseIII100s–several10001-4yrs.Safety,dosage&effectiveness25-30%第21頁EthicsofClinicalTrials:

ProtectionofParticipants3ethicalprinciplesguideclinicalresearch:RespectforPersons:TreatmentofpersonasautonomousBeneficence:Issuere:potentialconflictbetweengoodofsocietyvs.individualJustice:Treatmentofallfairly&allequallysharebenefits&risks第22頁EthicalNormsofClinicalTrialsSoundstudydesignstakeintoaccount:RandomizationorsharingofrisksProperuseofplaceboProcessestomonitorsafetyofrx/txCompetentinvestigatorsInformedconsentEquitableselectionofparticipantsCompensationforstudyrelatedinjuries第23頁EthicalIssues:

ProtectionofHumanSubjectsRelyonintegrityofInvestigatorbutoutsidegroupsalsohaveoversightParticipants’rightsprotectedbyInstitutionalReviewBoards[IRBs]AnIRBisdefinedas:"anyboard,mitteeorothergroupformallydesignatedbyaninstitutiontoreview,toapprovetheinitiationof,andtoconductperiodicreviewofbiomedicalresearchinvolvinghumansubjects"第24頁HumanSubjects’ProtectionIRBresponsibleforsuchtasks:ReviewresearchtoensurethatpotentialbenefitsoutweighrisksDevelopandissuewrittenproceduresReviewresearchforrisk/benefitanalysis&properprotectionofsubjectsIssuewrittennoticeofapproval/disapprovaltotheInvestigatorReviewandrespondtoproposedprotocolchangessubmittedbytheInvestigator第25頁HumanSubjects’ProtectionReviewreportsofdeaths,andseriousandunexpectedadverseeventsreceivedfromtheInvestigatorConductperiodiccontinuingreviewofthestudy,studyrisks,selectionofsubjects,privacyofsubjects,confidentialityofdata,andtheconsentprocessIRBResponsibilities(continued):第26頁HistoricalMinute:

OriginofIRBs&HumanSubjectCodeAttentiontoprotectingparticipantsbeganafterWWIIw/theNurembergTrials(1947)Outofthosetrials,keypointswerecodified第27頁HistoricalMinute:

10KeyPointsVoluntaryinformedconsentExperimentmustbeforthegoodofsociety,&resultsnotobtainablebyothermeansExperimentshouldbebaseduponprioranimalstudiesPhysical&mentalsuffering&injuryshouldbeavoidedNoexpectationthatdeath/disablinginjurywilloccurfromtheexperimentRiskvs.benefitProtectsubjectsagainstinjury,disability,ordeathOnlyscientificallyqualifiedpersonstobeinvolvedSubjectcanterminateher/hisinvolvement第28頁HistoricalMinute:

OriginofIRBs&HumanSubjectCodesSince1947,additionalsubjectprotectionrequirementsdeveloped&implementedLatestadditions:Year2023-PresidentClinton&DHHSSecretaryShalalaannouncedadditionalstudyrequirementsrelatedto:informedconsent trainingreq. adverseeventsconflictofinterest civilmonetarypenaltiesimprovedmonitoringofPhaseI&IItrials第29頁InformedConsent:

APartofHumanSubjectProtectionObjectivesofInformedConsentToEnsure:VoluntarinessComprehensionInformationToDemonstrateThat:PersonfreelygaveconsenttoparticipateConsentgivenbyapetentpersonPersonhasbeengivenallinformationPersonknowsthisisresearch–nottreatment第30頁ComponentsofInformedConsentMustIncludetheFollowingInformation:Whyresearchbeingdone?WhatresearcherswanttoacplishWhatwillbedoneandforhowlongRisks&benefitsoftrialOthertreatmentsavailableCanwithdrawfromtrialwheneverdesireCompensationforunexpectedinjuries第31頁VulnerablePopulationsGroupsthoughtnottohaveautonomytogiveinformedconsent:childrenmentallyimpaired,individualswithdementiaPrisonersORWhomaybeundulyinfluencedtoparticipate:studentssubordinatespregnantwomen(actually,thefetuses)patients(care-givervs.researcher)第32頁VulnerablePopulationsTosafeguardthesegroups,specialrequirementssuchas:OnlyparentcanconsentforminorConsentsmustbeinsubject’snativelang.Prisoners:onlysometypesofresearchallowed第33頁InclusioninClinicalTrialsNIHRevitalizationActof1993:Guidelinesthatrequireinclusionofwomen&minoritiesinclinicalstudiesNewguidelinesstipulatethat:Women&minoritiesaretobeincludedinallhumansubjectresearchTheyaretobeincludedinPhaseIIItrialstoallowsufficientpowertonotedifferencesCostcannotbeabarrierOutreachactivitiesmusttakeplacetoinclude&followthesegroups第34頁InclusioninClinicalTrialsHistoricallywomenwereexcludedifofreproductiveage(ages18-45)FearofharmtopotentialunbornchildInessence,excludedMAJORITYofwomenNewguidelineseliminatesthisstipulation第35頁IssuesinClinicalTrials:

UseofPlaceboTrialsOninternationalrealm,1999“DeclarationofHelsinki”revisedtoaddressuseofplacebos:PlacebosnotethicalinvirtuallyallstudiesthatinvolvediseaseswithPROVENtxRemainethicalintrialswherenoproventxRevisionsduetocontroversyoveruseofplacebosinattemptingtofindeasy/cheapwaytoreduceHIVperinataltransmission

1998studyinIvoryCoast,Uganda,&Thailand:HIV+pregnantwomengiveneitherplaceboorshortercourseofAZT

第36頁P(yáng)articipationinClinicalTrialsWhySomeParticipate:GivebacktosocietyExhaustedallothertxsHealthcareservicesPayment&incentivesSupportOthers??WhySomeDoNot?MistrustofstudiesDonotwanttobe“guineapig”Donot