clinicaltrials臨床試驗方案

Understanding

ClinicalTrialsDevelopedbySaraBack,NPBronx-LebanonHospitalCenterOverview

Purposeof

ResearchStudiesClassificationsofEpidemiologicalResearchBasicResearchTerminologyFeaturesofClinicalTrialsDesign/ProtocolPhasesofaStudyEthicsProtectionofParticipantsContributionsofClinicalTrialsParticipatinginaTrialConclusion&TakeHomeMessageOverviewtoResearchStudiesWhyDoResearchStudies?Tocollectdataonusualandunusualevents,conditions,&populationgroupsTotesthypothesesformulatedfromobservationsand/orintuitionUltimately,tounderstandbetterone’sworldandmake“senseofit”O(jiān)verviewtoResearchStudiesVarioustypesofresearchstudiesManyclassifiedas“EpidemiologicalStudies”Epidemiologyoftenisdefinedas:Thestudyofthedistributionofadiseaseorconditioninapopulationandthefactorsthatinfluencethatdistribution.ClassificationsofResearchStudies:ThreeMainTypesObservationalStudies:Groupsarestudied&contrastsmadebetweengroupsTheobserveddatacollectedareanalyzedAnalyticStudies:

AlsocalledExperimentalStudytheimpactofacertaintherapyUltimatelytheinvestigatorcontrolsfactorbeingstudiedClinicalTrial:Consideredthe“true”experimentalstudy“GoldStandard”ofclinicalresearchOftenaprospectivestudythatcomparestheeffectandvalueofaninterventionagainstacontrolinhumansubjects AnotherClassificationSystem

Non-directedDataCapture

Ex:VitalStatisticsDirectedDataCapture&HypothesisTesting

Ex:CohortStudies,CaseControlStudiesClinicalTrials

Ex:InvestigationofTreatment/ConditionEx:DrugTrialsTheDifferentStudyDesignsCase-control ?CohortCaseReports ?CaseSeriesOutcomesBased: ?SurveyResearch:QualityofLife QuestionnairesDecisionanalysis PollsEconomicAnalysis SurveysMetaAnalysesSurvivalAnalysisRandomizedClinicalTrialBasicResearchTerminologyRetrospective:

ReferstotimeofdatacollectionProspective:

ReferstotimeofdatacollectionCaseControlStudy:

Personsw/disease&thosew/outarecomparedCohortStudy:

Personsw/and/orw/outdiseasearefollowedovertimeTerminology(Cont.)Cross-sectionalStudy:Presenceorabsenceofexposuretopossibleriskfactormeasuredatonepointintime.Prevalenceobtained.Prevalence:The#ofnewcasesandexistingcasesduringspecifiedtimeperiod.Incidence:The#ofNEWcasesperunitofapopulationatriskfordiseaseoccurringduringstatedtimeperiod.HistoricalMinute

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

First“ClinicalTrials”HistoricalHighlightsofDrugTrials1909:

PaulEhrlich-Arsphenamine1929:

AlexanderFleming-Penicillin1935:GerhardDomagk-Sulfonamide1944:Schatz/Bugie/Waksman–StreptomycinBy1950,theBritishMedicalRes.Councildevelopedasystematicmethodologyforstudying&evaluatingtherapeuticinterventionsCoreComponentsofClinicalTrialsInvolvehumansubjectsMoveforwardintimeMosthaveacomparisonCONTROLgroupMusthavemethodtomeasureinterventionFocusonunknowns:effectofmedicationMustbedonebeforemedicationispartofstandardofcareConductedearlyinthedevelopmentoftherapiesCoreComponentsofClinicalTrialsMustreviewexistingscientificdata&buildonthatknowledgeTestacertainhypothesisStudyprotocolmustbebuiltonsoundðicalscienceControlforanypotentialbiasesMoststudymedications,procedures,and/orotherinterventionsThePossibleWorldofClinicalTrialDesignsRandomized/blindedtrialRandomized/doubleblindedtrialNon-randomizedconcurrentcontrolledtrialPlacebotrialHistoricalcontrolledtrialCrossoverTrialWithdrawaltrialSimplifiedRandomized:SchemesusedtoassignparticipanttoonegroupEx:Every3getshigherdoseNonrandomized:AllwithHep.C=cases;others=controlsProtocol:Studydesign-instructionsBlinded:ParticipantsdonotknowifinexperimentalorcontrolgroupDoubleBlinded:ParticipantsANDstaffdonotknowgroupassignmentPlacebo:Inactivepillw/notherapeuticvalueComponentsofClinicalTrialProtocolsInvestigatingtwoormoreconditionssohavetwo(+)groupsEx:drugvs.placebo;medicinevs.surgery;lowdosevs.highdoseSpecificinclusion/exclusioncriteriaSamplesize&powercalculationsPlanre:potentialbiasesPlanre:handlingofattrition/losstofollowupStudyParticipantRecruitmentIdentifyeligibleparticipantsExplainstudyProvideinformedconsentReassesseligibilityAssigntoonegroupParticipantsshouldbetold:Mayhavesideeffects(adverseeffects)TimecommitmentBenefits&risksMaywithdrawatanytimeEnrollment100%voluntaryPhasesofClinicalTrialsMosttrialsthatinvolvenewdrugsgothroughaseriesofsteps:#1:Experimentsinthelaboratory#2:Oncedeemedsafe,gothrough1-4phasesPhasesofClinicalTrialsPhaseI:Smallgroup[20-80]for1sttimetoevaluatesafety,determinesafedosagerange&identifySEPhaseII:

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

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

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

ProtectionofParticipants3ethicalprinciplesguideclinicalresearch:RespectforPersons:TreatmentofpersonasautonomousBeneficence:Issuere:potentialconflictbetweengoodofsocietyvs.individualJustice:Treatmentofallfairly&allequallysharebenefits&risksEthicalNormsofClinicalTrialsSoundstudydesignstakeintoaccount:RandomizationorsharingofrisksProperuseofplaceboProcessestomonitorsafetyofrx/txCompetentinvestigatorsInformedconsentEquitableselectionofparticipantsCompensationforstudyrelatedinjuriesEthicalIssues:

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

OriginofIRBs&HumanSubjectCodeAttentiontoprotectingparticipantsbeganafterWWIIw/theNurembergTrials(1947)Outofthosetrials,keypointswerecodifiedHistoricalMinute:

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

OriginofIRBs&HumanSubjectCodesSince1947,additionalsubjectprotectionrequirementsdeveloped&implementedLatestadditions:Year2023-PresidentClinton&DHHSSecretaryShalalaannouncedadditionalstudyrequirementsrelatedto:informedconsent trainingreq. adverseeventsconflictofinterest civilmonetarypenaltiesimprovedmonitoringofPhaseI&IItrialsInformedConsent:

APartofHumanSubjectProtectionObjectivesofInformedConsentToEnsure:VoluntarinessComprehensionInformationToDemonstrateThat:PersonfreelygaveconsenttoparticipateConsentgivenbyacompetentpersonPersonhasbeengivenallinformationPersonknowsthisisresearch–nottreatmentComponentsofInformedConsentMustIncludetheFollowingInformation:Whyresearchbeingdone?WhatresearcherswanttoaccomplishWhatwillbedoneandforhowlongRisks&benefitsoftrialOthertreatmentsavailableCanwithdrawfromtrialwheneverdesireCompensationforunexpectedinjuriesVulnerablePopulationsGroupsthoughtnottohaveautonomytogiveinformedconsent:childrenmentallyimpaired,individualswithdementiaPrisonersORWhomaybeundulyinfluencedtoparticipate:studentssubordinatespregnantwomen(actually,thefetuses)patients(care-givervs.researcher)VulnerablePopulationsTosafeguardthesegroups,specialrequirementssuchas:OnlyparentcanconsentforminorConsentsmustbeinsubject’snativelang.Prisoners:onlysometypesofresearchallowedInclusioninClinicalTrialsNIHRevitalizationActof1993:Guidelinesthatrequireinclusionofwomen&minoritiesinclinicalstudiesNewguidelinesstipulatethat:Women&minoritiesaretobeincludedinallhumansubjectresearchTheyaretobeincludedinPhaseIIItrialstoallowsufficientpowertonotedifferencesCostcannotbeabarrierOutreachactivitiesmusttakeplacetoinclude&followthesegroupsInclusioninClinicalTrialsHistoricallywomenwereexcludedifofreproductiveage(ages18-45)FearofharmtopotentialunbornchildInessence,excludedMAJORITYofwomenNewguidelineseliminatesthisstipulationIssuesinClinicalTrials:

UseofPlaceboTrialsOninternationalrealm,1999“DeclarationofHelsinki”revisedtoaddressuseofplacebos:PlacebosnotethicalinvirtuallyallstudiesthatinvolvediseaseswithPROVENtxRemainethicalintrialswherenoproventxRevisionsduetocontroversyoveruseofplacebosinattemptingtofindeasy/cheapwaytoreduceHIVperinataltransmission

1998studyinIvoryCoast,Uganda,&Thailand:HIV+pregnantwomengiveneitherplaceboorshortercourseofAZT

ParticipationinClinicalTrialsWhySomeParticipate:GivebacktosocietyExhaustedallothertxsHealthcareservicesPayment&incentivesSupportOthers??WhySomeDoNot?MistrustofstudiesDonotwanttobe“guineapig”