clinical trials 临床试验方案

NY VIAETC UnderstandingClinicalTrials DevelopedbySaraBack NPBronx LebanonHospitalCenter NY VIAETC Overview PurposeofResearchStudiesClassificationsofEpidemiologicalResearchBasicResearchTerminologyFeaturesofClinicalTrialsDesign ProtocolPhasesofaStudyEthicsProtectionofParticipantsContributionsofClinicalTrialsParticipatinginaTrialConclusion TakeHomeMessage NY VIAETC OverviewtoResearchStudies WhyDoResearchStudies Tocollectdataonusualandunusualevents conditions populationgroupsTotesthypothesesformulatedfromobservationsand orintuitionUltimately tounderstandbetterone sworldandmake senseofit NY VIAETC OverviewtoResearchStudies VarioustypesofresearchstudiesManyclassifiedas EpidemiologicalStudies Epidemiologyoftenisdefinedas Thestudyofthedistributionofadiseaseorconditioninapopulationandthefactorsthatinfluencethatdistribution NY VIAETC ClassificationsofResearchStudies ThreeMainTypes ObservationalStudies Groupsarestudied contrastsmadebetweengroupsTheobserveddatacollectedareanalyzedAnalyticStudies AlsocalledExperimentalStudytheimpactofacertaintherapyUltimatelytheinvestigatorcontrolsfactorbeingstudiedClinicalTrial Consideredthe true experimentalstudy GoldStandard ofclinicalresearchOftenaprospectivestudythatcomparestheeffectandvalueofaninterventionagainstacontrolinhumansubjects NY VIAETC AnotherClassificationSystem Non directedDataCaptureEx VitalStatisticsDirectedDataCapture HypothesisTestingEx CohortStudies CaseControlStudiesClinicalTrialsEx InvestigationofTreatment ConditionEx DrugTrials NY VIAETC TheDifferentStudyDesigns Case control CohortCaseReports CaseSeriesOutcomesBased SurveyResearch QualityofLifeQuestionnairesDecisionanalysisPollsEconomicAnalysisSurveysMetaAnalysesSurvivalAnalysisRandomizedClinicalTrial NY VIAETC BasicResearchTerminology Retrospective ReferstotimeofdatacollectionProspective ReferstotimeofdatacollectionCaseControlStudy Personsw disease thosew outarecomparedCohortStudy Personsw and orw outdiseasearefollowedovertime NY VIAETC Terminology Cont Cross sectionalStudy Presenceorabsenceofexposuretopossibleriskfactormeasuredatonepointintime Prevalenceobtained Prevalence The ofnewcasesandexistingcasesduringspecifiedtimeperiod Incidence The ofNEWcasesperunitofapopulationatriskfordiseaseoccurringduringstatedtimeperiod NY VIAETC HistoricalMinuteFirst ClinicalTrials ClinicalTrialshavealonghistory evenifnotacknowledgedasClinicaltrialsFormalrecordofclinicaltrialsdatesbacktothetimeofthe Trialists Dr VanHelmont sproposalforatherapeutictrialofbloodlettingforfevers 1628 Dr Lind s ashipsurgeon trialoforanges limesforscurvy 1747 NY VIAETC HistoricalMinuteFirst ClinicalTrials HistoricalHighlightsofDrugTrials1909 PaulEhrlich Arsphenamine1929 AlexanderFleming Penicillin1935 GerhardDomagk Sulfonamide1944 Schatz Bugie Waksman StreptomycinBy1950 theBritishMedicalRes Councildevelopedasystematicmethodologyforstudying evaluatingtherapeuticinterventions NY VIAETC CoreComponentsofClinicalTrials InvolvehumansubjectsMoveforwardintimeMosthaveacomparisonCONTROLgroupMusthavemethodtomeasureinterventionFocusonunknowns effectofmedicationMustbedonebeforemedicationispartofstandardofcareConductedearlyinthedevelopmentoftherapies NY VIAETC CoreComponentsofClinicalTrials Mustreviewexistingscientificdata buildonthatknowledgeTestacertainhypothesisStudyprotocolmustbebuiltonsound ethicalscienceControlforanypotentialbiasesMoststudymedications procedures and orotherinterventions NY VIAETC ThePossibleWorldofClinicalTrialDesigns Randomized blindedtrialRandomized doubleblindedtrialNon randomizedconcurrentcontrolledtrialPlacebotrialHistoricalcontrolledtrialCrossoverTrialWithdrawaltrial NY VIAETC Simplified Randomized SchemesusedtoassignparticipanttoonegroupEx Every3getshigherdoseNonrandomized AllwithHep C cases others controlsProtocol Studydesign instructions Blinded ParticipantsdonotknowifinexperimentalorcontrolgroupDoubleBlinded ParticipantsANDstaffdonotknowgroupassignmentPlacebo Inactivepillw notherapeuticvalue NY VIAETC ComponentsofClinicalTrialProtocols Investigatingtwoormoreconditionssohavetwo groupsEx drugvs placebo medicinevs surgery lowdosevs highdoseSpecificinclusion exclusioncriteriaSamplesize powercalculationsPlanre potentialbiasesPlanre handlingofattrition losstofollowup NY VIAETC StudyParticipantRecruitment IdentifyeligibleparticipantsExplainstudyProvideinformedconsentReassesseligibilityAssigntoonegroup Participantsshouldbetold Mayhavesideeffects adverseeffects TimecommitmentBenefits risksMaywithdrawatanytimeEnrollment100 voluntary NY VIAETC PhasesofClinicalTrials Mosttrialsthatinvolvenewdrugsgothroughaseriesofsteps 1 Experimentsinthelaboratory 2 Oncedeemedsafe gothrough1 4phases NY VIAETC PhasesofClinicalTrials PhaseI Smallgroup 20 80 for1sttimetoevaluatesafety determinesafedosagerange identifySEPhaseII Rx txgiventolargergroup 100 300 toconfirmeffectiveness monitorSE furtherevaluatesafety NY VIAETC PhasesofClinicalTrials cont PhaseIII Rx txgiventoevenlargergroup 1 000 3 000 tofulfillallofPhaseIIobjectives compareittoothercommonlyusedtxs collectdatathatwillallowittobeusedsafelyPhaseIV Doneafterrx txhasbeenmarketed studiescontinuetotestrx txtocollectdataabouteffectsinvariouspopulations SEfromlongtermuse NY VIAETC SummaryofPhasesI III NY VIAETC EthicsofClinicalTrials ProtectionofParticipants 3ethicalprinciplesguideclinicalresearch RespectforPersons TreatmentofpersonasautonomousBeneficence Issuere potentialconflictbetweengoodofsocietyvs individualJustice Treatmentofallfairly allequallysharebenefits risks NY VIAETC EthicalNormsofClinicalTrials Soundstudydesignstakeintoaccount RandomizationorsharingofrisksProperuseofplaceboProcessestomonitorsafetyofrx txCompetentinvestigatorsInformedconsentEquitableselectionofparticipantsCompensationforstudyrelatedinjuries NY VIAETC EthicalIssues ProtectionofHumanSubjects RelyonintegrityofInvestigatorbutoutsidegroupsalsohaveoversightParticipants rightsprotectedbyInstitutionalReviewBoards IRBs AnIRBisdefinedas anyboard committeeorothergroupformallydesignatedbyaninstitutiontoreview toapprovetheinitiationof andtoconductperiodicreviewofbiomedicalresearchinvolvinghumansubjects NY VIAETC HumanSubjects Protection IRBresponsibleforsuchtasks ReviewresearchtoensurethatpotentialbenefitsoutweighrisksDevelopandissuewrittenproceduresReviewresearchforrisk benefitanalysis properprotectionofsubjectsIssuewrittennoticeofapproval disapprovaltotheInvestigatorReviewandrespondtoproposedprotocolchangessubmittedbytheInvestigator NY VIAETC HumanSubjects Protection Reviewreportsofdeaths andseriousandunexpectedadverseeventsreceivedfromtheInvestigatorConductperiodiccontinuingreviewofthestudy studyrisks selectionofsubjects privacyofsubjects confidentialityofdata andtheconsentprocess IRBResponsibilities continued NY VIAETC HistoricalMinute OriginofIRBs HumanSubjectCode AttentiontoprotectingparticipantsbeganafterWWIIw theNurembergTrials 1947 Outofthosetrials keypointswerecodified NY VIAETC HistoricalMinute 10KeyPoints VoluntaryinformedconsentExperimentmustbeforthegoodofsociety resultsnotobtainablebyothermeansExperimentshouldbebaseduponprioranimalstudiesPhysical mentalsuffering injuryshouldbeavoidedNoexpectationthatdeath disablinginjurywilloccurfromtheexperimentRiskvs benefitProtectsubjectsagainstinjury disability ordeathOnlyscientificallyqualifiedpersonstobeinvolvedSubjectcanterminateher hisinvolvement NY VIAETC HistoricalMinute OriginofIRBs HumanSubjectCodes Since1947 additionalsubjectprotectionrequirementsdeveloped implementedLatestadditions Year2000 PresidentClinton DHHSSecretaryShalalaannouncedadditionalstudyrequirementsrelatedto informedconsenttrainingreq adverseeventsconflictofinterestcivilmonetarypenaltiesimprovedmonitoringofPhaseI IItrials NY VIAETC InformedConsent APartofHumanSubjectProtection ObjectivesofInformedConsentToEnsure VoluntarinessComprehensionInformationToDemonstrateThat PersonfreelygaveconsenttoparticipateConsentgivenbyacompetentpersonPersonhasbeengivenallinformationPersonknowsthisisresearch nottreatment NY VIAETC ComponentsofInformedConsent MustIncludetheFollowingInformation Whyresearchbeingdone WhatresearcherswanttoaccomplishWhatwillbedoneandforhowlongRisks benefitsoftrialOthertreatmentsavailableCanwithdrawfromtrialwheneverdesireCompensationforunexpectedinjuries NY VIAETC VulnerablePopulations Groupsthoughtnottohaveautonomytogiveinformedconsent childrenmentallyimpaired individualswithdementiaPrisonersORWhomaybeundulyinfluencedtoparticipate studentssubordinatespregnantwomen actually thefetuses patients care givervs researcher NY VIAETC VulnerablePopulations Tosafeguardthesegroups specialrequirementssuchas OnlyparentcanconsentforminorConsentsmustbeinsubject snativelang Prisoners onlysometypesofresearchallowed NY VIAETC InclusioninClinicalTrials NIHRevitalizationActof1993 Guidelinesthatrequireinclusionofwomen minoritiesinclinicalstudiesNewguidelinesstipulatethat Women minoritiesaretobeincludedinallhumansubjectresearchTheyaretobeincludedinPhaseIIItrialstoallowsufficientpowertonotedifferencesCostcannotbeabarrierOutreachactivitiesmusttakeplacetoinclude followthesegroups NY VIAETC InclusioninClinicalTrials Historicallywomenwereexcludedifofreproductiveage ages18 45 FearofharmtopotentialunbornchildInessence excludedMAJORITYofwomenNewguidelineseliminatesthisstipulation NY VIAETC IssuesinClinicalTrials UseofPlaceboTrials Oninternationalrealm 1999 DeclarationofHelsinki revisedtoaddressuseofplacebos PlacebosnotethicalinvirtuallyallstudiesthatinvolvediseaseswithPROVENtxRemainethicalintrialswherenoproventxRevisionsduetocontroversyoveruseofplacebosinattemptingtofindeasy cheapwaytoreduceHIVperinataltransmission1998studyinIvoryCoast Uganda Thailand HIV pregnantwomengiveneitherplaceboorshortercourseofAZT NY VIAETC ParticipationinClinicalTrials WhySomeParticipate GivebacktosocietyExhaustedallothertxsHealthcareservicesPayment incentivesSupportOthers WhySomeDoNot MistrustofstudiesDonotwanttobe guineapig DonotmeetcriteriaCannotgiveuptimeforstudyvisitsBarri