StudyStudy DesignDesign forfor ChemopreventionChemoprevention CancerCancer Epidemiology,Epidemiology, PreventionPrevention andand ControlControl WorkshopWorkshop Shanghai,Shanghai, MarchMarch 12,12, 20082008 I.I. INTRODUCTIONINTRODUCTION ExperimentalExperimental studiesstudies areare conductedconducted toto assessassess thethe effecteffect ofof aa treatmenttreatment usingusing aa drug,drug, oror interventionintervention usingusing aa preventivepreventive agent,agent, etc.etc. •• TreatmentTreatment •• PreventionPrevention •• EarlyEarly detection/screeningdetection/screening •• DiagnosticDiagnostic •• QualityQuality ofof life/supportivelife/supportive carecare A.A. Defined:Defined: •• AA studystudy designdesign inin whichwhich thethe investigatorinvestigator activelyactively controlscontrols whowho isis exposedexposed andand whowho isis not.not. SubjectsSubjects areare randomlyrandomly assignedassigned toto variousvarious treatmenttreatment groupsgroups andand followedfollowed toto observeobserve outcomes.outcomes. ComparisonComparison ofof TwoTwo StudyStudy DesignsDesigns StratifiedStratified RandomizationRandomization B.B. ExperimentalExperimental studiesstudies comparedcompared toto cohortcohort studiesstudies 1.1. SimilaritiesSimilarities betweenbetween cohortcohort andand experimentalexperimental studies.studies. Both:Both: a.a. SubjectsSubjects mustmust bebe freefree ofof thethe outcomeoutcome atat thethe startstart ofof thethe study.study. b.b. PeoplePeople areare groupedgrouped intointo “exposed”/“exposed”/ “not“not exposed”exposed” categories.categories. c.c. GroupsGroups areare followedfollowed forfor aa periodperiod ofof timetime toto determinedetermine outcome.outcome. d.d. YieldYield incidenceincidence datadata soso allowallow thethe calculationcalculation ofof riskrisk andand relatedrelated measures.measures. e.e. SusceptibleSusceptible toto lostlost--toto--followfollow--upup bias.bias. B.B. ExperimentalExperimental studiesstudies comparedcompared toto cohortcohort studiesstudies 2.2. DifferencesDifferences betweenbetween cohortcohort andand experimentalexperimental studies:studies: a. Experimental studies involve active manipulation of exposure (treatment/alternative treatment), whereas in cohort studies, the investigator must merely observe the effect of exposure. b. Random allocation (or randomization) is an essential part of a good experimental study. Not possible in a cohort. c. Ethical issues often a major issue in experimental epidemiological studies. d. Compliance with study protocol is an important concern in experimental studies. C.C. RandomRandom allocation/allocation/ randomizationrandomization 1.1. Defined:Defined: AA procedureprocedure forfor assigningassigning patientspatients toto experimentalexperimental treatmenttreatment andand otherother treatmenttreatment groupsgroups soso thatthat chancechance alonealone isis responsibleresponsible forfor thethe groupgroup assignment…eachassignment…each subjectsubject hashas anan equalequal chancechance ofof beingbeing inin anyany ofof thethe treatmenttreatment groups.groups. 2.2. PurposePurpose ofof randomization:randomization: ToTo (attempt(attempt to)to) assureassure comparabilitycomparability ofof thethe studystudy groupsgroups withwith respectrespect toto factorsfactors whichwhich maymay bebe relatedrelated toto outcome.outcome. C.C. RandomRandom allocation/allocation/ randomizationrandomization 3.3. IMPORTANT:IMPORTANT: RandomizationRandomization isis donedone afterafter informedinformed consentconsent isis obtained!!!obtained!!! C.C. RandomRandom allocation/allocation/ randomizationrandomization 4.4. DoDo NotNot ConfuseConfuse RandomRandom AllocationAllocation withwith RandomRandom Selection!!!Selection!!! RandomRandom selectionselection ofof subjects:subjects: A procedure for selecting subjects so that each has the same chance of being included in the study. When we can’t afford to use all possible subjects in the source population. Purpose:Purpose: To assure representativeness of subjects (of source pop.) WhenWhen used?used? In any type of study design where a sample of the population is being selected. C.C. RandomRandom allocation/allocation/ randomizationrandomization 5.5. RandomizationRandomization doesdoes notnot guaranteeguarantee similaritysimilarity ofof groupsgroups D.D. UsesUses ofof experimentalexperimental studystudy design:design: 1.1. EvaluateEvaluate benefitsbenefits ofof anan intervention:intervention: •• TherapeuticTherapeutic •• PreventivePreventive 2.2. ConfirmConfirm etiologicetiologic relationshiprelationship II.II. TWOTWO MAJORMAJOR TYPESTYPES OFOF EXPERIEMENTALEXPERIEMENTAL STUDIES:STUDIES: ClinicalClinical andand communitycommunity trialstrials A.A. RandomizedRandomized clinicalclinical trialtrial (RCT):(RCT): 1. Defined (phase III): An experimental study where the effectiveness of the intervention is being tested on individuals. Phase I trials • How does the agent affect the human body? • What dosage is safe? Phase II trials • Does the agent or intervention have an effect on the disease? Phase III trials • Is the new agent or intervention (or new use of a treatment) better than the standard? • Participants have an equal chance to be assigned to one of two or more groups A.A. RandomizedRandomized clinicalclinical trialtrial (RCT):(RCT): 2.2. ClinicalClinical trialstrials areare conductedconducted forfor thethe treatment/preventiontreatment/prevention ofof bothboth infectiousinfectious diseasesdiseases andand chronicchronic diseases:diseases: a.a. InfectiousInfectious diseases:diseases: fieldfield trialstrials (often(often refersrefers toto vaccinevaccine trials)trials) b.b. ChronicChronic diseases:diseases: e.g.e.g. Women’sWomen’s HealthHealth InitiativeInitiative (WHI):(WHI): B.4.B.4. RecruitRecruit studystudy Population:Population: EffectivenessEffectiveness ofof InterventionIntervention From: Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of the estrogen plus progestin in healthy postmenopausal women. Principal results from the Women’s Health Initiative Randomized Controlled Trial.JAMA.2002;288:321-33 B.B. CommunityCommunity trialtrial 1.1. Defined:Defined: AnAn experimentalexperimental studystudy wherewhere thethe effectivenesseffectiveness ofof anan interventionintervention isis testedtested onon aa community.community. 2.2. ExampleExample ofof aa communitycommunity trial:trial: fluoridationfluoridation ofof water.water. FluoridationFluoridation ofof WaterWater B.B. CommunityCommunity trialtrial 3.3. ProblemsProblems ofof conductingconducting communitycommunity trials:trials: a.a. ObtainingObtaining anan appropriateappropriate controlcontrol group:group: 1) Same community before and after intervention 2) A control community: similar to experimental community with respect to possible confounders. b.b. OtherOther problems:problems: 1) It is hard to get individual’s informed concent 2) Intervention not at individuals level 3) Collaboration of communities III.III. STEPSSTEPS ININ CONDUCTINGCONDUCTING RANDOMIZEDRANDOMIZED CLINICALCLINICAL TRIALSTRIALS DiagramDiagram ofof aa designdesign flow:flow: B.1.B.1. StepsSteps •• 1.1. SpecifySpecify HypothesisHypothesis B.2.B.2. StepsSteps •• 2.2. SpecifySpecify targettarget andand sourcesource ofof populations:populations: B.3B.3 DefineDefine endpoints/possibleendpoints/possible sideside effectseffects ofof intervention:intervention: B.5.B.5. ObtainObtain informedinformed consentconsent fromfrom thosethose willingwilling toto participate:participate: 1.1. InformedInformed consent:consent: An agreement (signed) that the subject understands the benefits and risks of the study. 2.2. HumanHuman SubjectsSubjects ProtectionProtection Committees:Committees: act as watchdogs…review research applications the be sure they comply with issues pertaining to protection of human subjects. To receive research money from NIH (and other agencies), these committees must approve grand proposals. Require that all subjects must read and sign “Informed Consent” form. B.6B.6 RandomizeRandomize toto treatmenttreatment 1.1. ExperimentalExperimental treatment.treatment. 2.2. AlternativeAlternative treatmenttreatment (“controls”):(“controls”): a.a. TheThe currentcurrent standardstandard treatment:treatment: b.b. Placebo:Placebo: 1) Defined: An inert substance prepared to look as similar as possible to the experimental treatment. 2) Placebo effect: Am improvement on health, symptoms, due to fact of being treated…and not due to the treatment! RandomizationRandomization ThreeThree advantagesadvantages ofof thethe randomizedrandomized design:design: •• RandomizationRandomization removesremoves thethe potentialpotential ofof biasbias inin thethe allocationallocation ofof subjectssubjects toto thethe interventionintervention groupgroup oror toto thethe controlcontrol group;group; •• RandomizationRandomization tendstends toto produceproduce comparablecomparable groups;groups; thatthat is,is, thethe measuredmeasured oror unknownunknown prognosticprognostic factorsfactors andand otherother characteristicscharacteristics ofof thethe subjectssubjects atat thethe timetime ofof randomizationrandomization willwill be,be, onon thethe average,average, evevenlyenly balancedbalanced betweenbetween thethe interventionintervention andand controlcontrol groups;groups; •• TheThe internalinternal validityvalidity ofof statisticalstatistical teststests ofof significancesignificance isis guaranteed.guaranteed. B.7.B.7. BlindnessBlindness •• FundamentalFundamental PointPoint:: ToTo avoidavoid potentialpotential