clinicaltrials臨床試驗(yàn)方案Overview

Purposeof

ResearchStudiesClassificationsofEpidemiologicalResearchBasicResearchTerminologyFeaturesofClinicalTrialsDesign/ProtocolPhasesofaStudyEthicsProtectionofParticipantsContributionsofClinicalTrialsParticipatinginaTrialConclusion&TakeHomeMessageNY/VIAETCOverviewtoResearchStudiesWhyDoResearchStudies?Tocollectdataonusualandunusualevents,conditions,&populationgroupsTotesthypothesesformulatedfromobservationsand/orintuitionUltimately,tounderstandbetterone’sworldandmake“senseofit”NY/VIAETCOverviewtoResearchStudiesVarioustypesofresearchstudiesManyclassifiedas“EpidemiologicalStudies”Epidemiologyoftenisdefinedas:Thestudyofthedistributionofadiseaseorconditioninapopulationandthefactorsthatinfluencethatdistribution.NY/VIAETCClassificationsofResearchStudies:ThreeMainTypesObservationalStudies:Groupsarestudied&contrastsmadebetweengroupsTheobserveddatacollectedareanalyzedAnalyticStudies:

AlsocalledExperimentalStudytheimpactofacertaintherapyUltimatelytheinvestigatorcontrolsfactorbeingstudiedClinicalTrial:Consideredthe“true”experimentalstudy“GoldStandard”ofclinicalresearchOftenaprospectivestudythatcomparestheeffectandvalueofaninterventionagainstacontrolinhumansubjects NY/VIAETCAnotherClassificationSystem

Non-directedDataCapture

Ex:VitalStatisticsDirectedDataCapture&HypothesisTesting

Ex:CohortStudies,CaseControlStudiesClinicalTrials

Ex:InvestigationofTreatment/ConditionEx:DrugTrialsNY/VIAETCTheDifferentStudyDesignsCase-control ?CohortCaseReports ?CaseSeriesOutcomesBased: ?SurveyResearch:QualityofLife QuestionnairesDecisionanalysis PollsEconomicAnalysis SurveysMetaAnalysesSurvivalAnalysisRandomizedClinicalTrialNY/VIAETCBasicResearchTerminologyRetrospective:

ReferstotimeofdatacollectionProspective:

ReferstotimeofdatacollectionCaseControlStudy:

Personsw/disease&thosew/outarecomparedCohortStudy:

Personsw/and/orw/outdiseasearefollowedovertimeNY/VIAETCTerminology(Cont.)Cross-sectionalStudy:Presenceorabsenceofexposuretopossibleriskfactormeasuredatonepointintime.Prevalenceobtained.Prevalence:The#ofnewcasesandexistingcasesduringspecifiedtimeperiod.Incidence:The#ofNEWcasesperunitofapopulationatriskfordiseaseoccurringduringstatedtimeperiod.NY/VIAETCHistoricalMinute

First“ClinicalTrials”ClinicalTrialshavealonghistory–evenifnotacknowledgedasClinicaltrialsFormalrecordofclinicaltrialsdatesbacktothetimeofthe“Trialists”:Dr.VanHelmont’sproposalforatherapeutictrialofbloodlettingforfevers[1628]Dr.Lind’s,ashipsurgeon,trialoforanges&limesforscurvy[1747]NY/VIAETCHistoricalMinute

First“ClinicalTrials”HistoricalHighlightsofDrugTrials1909:

PaulEhrlich-Arsphenamine1929:

AlexanderFleming-Penicillin1935:GerhardDomagk-Sulfonamide1944:Schatz/Bugie/Waksman–StreptomycinBy1950,theBritishMedicalRes.Councildevelopedasystematicmethodologyforstudying&evaluatingtherapeuticinterventionsNY/VIAETCCoreComponentsofClinicalTrialsInvolvehumansubjectsMoveforwardintimeMosthaveacomparisonCONTROLgroupMusthavemethodtomeasureinterventionFocusonunknowns:effectofmedicationMustbedonebeforemedicationispartofstandardofcareConductedearlyinthedevelopmentoftherapiesNY/VIAETCCoreComponentsofClinicalTrialsMustreviewexistingscientificdata&buildonthatknowledgeTestacertainhypothesisStudyprotocolmustbebuiltonsoundðicalscienceControlforanypotentialbiasesMoststudymedications,procedures,and/orotherinterventionsNY/VIAETCThePossibleWorldofClinicalTrialDesignsRandomized/blindedtrialRandomized/doubleblindedtrialNon-randomizedconcurrentcontrolledtrialPlacebotrialHistoricalcontrolledtrialCrossoverTrialWithdrawaltrialNY/VIAETCSimplifiedRandomized:SchemesusedtoassignparticipanttoonegroupEx:Every3getshigherdoseNonrandomized:AllwithHep.C=cases;others=controlsProtocol:Studydesign-instructionsBlinded:ParticipantsdonotknowifinexperimentalorcontrolgroupDoubleBlinded:ParticipantsANDstaffdonotknowgroupassignmentPlacebo:Inactivepillw/notherapeuticvalueNY/VIAETCComponentsofClinicalTrialProtocolsInvestigatingtwoormoreconditionssohavetwo(+)groupsEx:drugvs.placebo;medicinevs.surgery;lowdosevs.highdoseSpecificinclusion/exclusioncriteriaSamplesize&powercalculationsPlanre:potentialbiasesPlanre:handlingofattrition/losstofollowupNY/VIAETCStudyParticipantRecruitmentIdentifyeligibleparticipantsExplainstudyProvideinformedconsentReassesseligibilityAssigntoonegroupParticipantsshouldbetold:Mayhavesideeffects(adverseeffects)TimecommitmentBenefits&risksMaywithdrawatanytimeEnrollment100%voluntaryNY/VIAETCPhasesofClinicalTrialsMosttrialsthatinvolvenewdrugsgothroughaseriesofsteps:#1:Experimentsinthelaboratory#2:Oncedeemedsafe,gothrough1-4phasesNY/VIAETCPhasesofClinicalTrialsPhaseI:Smallgroup[20-80]for1sttimetoevaluatesafety,determinesafedosagerange&identifySEPhaseII:

Rx/txgiventolargergroup[100-300]toconfirmeffectiveness,monitorSE,&furtherevaluatesafetyNY/VIAETCPhasesofClinicalTrials(cont.)PhaseIII:

Rx/txgiventoevenlargergroup[1,000-3,000]tofulfillallofPhaseIIobjectives&compareittoothercommonlyusedtxs&collectdatathatwillallowittobeusedsafelyPhaseIV:

Doneafterrx/txhasbeenmarketed-studiescontinuetotestrx/txtocollectdataabouteffectsinvariouspopulations&SEfromlongtermuse.NY/VIAETCSummaryofPhasesI-III#Subs.LengthPurpose%DrugsSuccessfullyTestedPhaseI20–100SeveralmonthsMainlySafety70%PhaseIIUptoseveral100Severalmonths-2yrs.Shorttermsafety;mainlyeffectiveness33%PhaseIII100s–several10001-4yrs.Safety,dosage&effectiveness25-30%NY/VIAETCEthicsofClinicalTrials:

ProtectionofParticipants3ethicalprinciplesguideclinicalresearch:RespectforPersons:TreatmentofpersonasautonomousBeneficence:Issuere:potentialconflictbetweengoodofsocietyvs.individualJustice:Treatmentofallfairly&allequallysharebenefits&risksNY/VIAETCEthicalNormsofClinicalTrialsSoundstudydesignstakeintoaccount:RandomizationorsharingofrisksProperuseofplaceboProcessestomonitorsafetyofrx/txCompetentinvestigatorsInformedconsentEquitableselectionofparticipantsCompensationforstudyrelatedinjuriesNY/VIAETCEthicalIssues:

ProtectionofHumanSubjectsRelyonintegrityofInvestigatorbutoutsidegroupsalsohaveoversightParticipants’rightsprotectedbyInstitutionalReviewBoards[IRBs]AnIRBisdefinedas:"anyboard,committeeorothergroupformallydesignatedbyaninstitutiontoreview,toapprovetheinitiationof,andtoconductperiodicreviewofbiomedicalresearchinvolvinghumansubjects"NY/VIAETCHumanSubjects’ProtectionIRBresponsibleforsuchtasks:ReviewresearchtoensurethatpotentialbenefitsoutweighrisksDevelopandissuewrittenproceduresReviewresearchforrisk/benefitanalysis&properprotectionofsubjectsIssuewrittennoticeofapproval/disapprovaltotheInvestigatorReviewandrespondtoproposedprotocolchangessubmittedbytheInvestigatorNY/VIAETCHumanSubjects’ProtectionReviewreportsofdeaths,andseriousandunexpectedadverseeventsreceivedfromtheInvestigatorConductperiodiccontinuingreviewofthestudy,studyrisks,selectionofsubjects,privacyofsubjects,confidentialityofdata,andtheconsentprocessIRBResponsibilities(continued):NY/VIAETCHistoricalMinute:

OriginofIRBs&HumanSubjectCodeAttentiontoprotectingparticipantsbeganafterWWIIw/theNurembergTrials(1947)Outofthosetrials,keypointswerecodifiedNY/VIAETCHistoricalMinute:

10KeyPointsVoluntaryinformedconsentExperimentmustbeforthegoodofsociety,&resultsnotobtainablebyothermeansExperimentshouldbebaseduponprioranimalstudiesPhysical&mentalsuffering&injuryshouldbeavoidedNoexpectationthatdeath/disablinginjurywilloccurfromtheexperimentRiskvs.benefitProtectsubjectsagainstinjury,disability,ordeathOnlyscientificallyqualifiedpersonstobeinvolvedSubjectcanterminateher/hisinvolvementNY/VIAETCHistoricalMinute:

OriginofIRBs&HumanSubjectCodesSince1947,additionalsubjectprotectionrequirementsdeveloped&implementedLatestadditions:Year-PresidentClinton&DHHSSecretaryShalalaannouncedadditionalstudyrequirementsrelatedto:informedconsent trainingreq. adverseeventsconflictofinterest civilmonetarypenaltiesimprovedmonitoringofPhaseI&IItrialsNY/VIAETCInformedConsent:

APartofHumanSubjectProtectionObjectivesofInformedConsentToEnsure:VoluntarinessComprehensionInformationToDemonstrateThat:PersonfreelygaveconsenttoparticipateConsentgivenbyacompetentpersonPersonhasbeengivenallinformationPersonknowsthisisresearch–nottreatmentNY/VIAETCComponentsofInformedConsentMustIncludetheFollowingInformation:Whyresearchbeingdone?WhatresearcherswanttoaccomplishWhatwillbedoneandforhowlongRisks&benefitsoftrialOthertreatmentsavailableCanwithdrawfromtrialwheneverdesireCompensationforunexpectedinjuriesNY/VIAETCVulnerablePopulationsGroupsthoughtnottohaveautonomytogiveinformedconsent:childrenmentallyimpaired,individualswithdementiaPrisonersORWhomaybeundulyinfluencedtoparticipate:studentssubordinatespregnantwomen(actually,thefetuses)patients(care-givervs.researcher)NY/VIAETCVulnerablePopulationsTosafeguardthesegroups,specialrequirementssuchas:OnlyparentcanconsentforminorConsentsmustbeinsubject’snativelang.Prisoners:onlysometypesofresearchallowedNY/VIAETCInclusioninClinicalTrialsNIHRevitalizationActof1993:Guidelinesthatrequireinclusionofwomen&minoritiesinclinicalstudiesNewguidelinesstipulatethat:Women&minoritiesaretobeincludedinallhumansubjectresearchTheyaretobeincludedinPhaseIIItrialstoallowsufficientpowertonotedifferencesCostcannotbeabarrierOutreachactivitiesmusttakeplacetoinclude&followthesegroupsNY/VIAETCInclusioninClinicalTrialsHistoricallywomenwereexcludedifofreproductiveage(ages18-45)FearofharmtopotentialunbornchildInessence,excludedMAJORITYofwomenNewguidelineseliminatesthisstipulationNY/VIAETCIssuesinClinicalTrials:

UseofPlaceboTrialsOninternationalrealm,1999“DeclarationofHelsinki”revisedtoaddressuseofplacebos:PlacebosnotethicalinvirtuallyallstudiesthatinvolvediseaseswithPROVENtxRemainethicalintrialswherenoproventxRevisionsduetocontroversyoveruseofplacebosinattemptingtofindeasy/cheapwaytoreduceHIVperinataltransmission

1998studyinIvoryCoast,Uganda,&Thailand:HIV+pregnantwomengiveneitherplaceboorshortercourseofAZT

NY/VIAETCParticipationinClinicalTrialsWhySomeParticipate:GivebacktosocietyExhaustedallothertxsHealthcareservicesPayment&incentivesSupportOthers??WhySomeDoNot?MistrustofstudiesDonotwanttobe“guineapig”DonotmeetcriteriaCannotgiveup