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InterventionStudies

ClinicalTrials

Introduction

Theprimarygoalofobservationalstudies,e.g.,casecontrolstudiesandcohortstudies,istotesthypothesesabout
thedeterminantsofdisease.Incontrast,thegoalofinterventionstudiesistotesttheefficacyofspecifictreatments
orpreventivemeasuresbyassigningindividualsubjectstooneoftwoormoretreatmentorpreventionoptions.
Interventionstudiesoftentesttheefficacyofdrugs,butonemightalsousethisdesigntotesttheefficacyofdiffering
managementstrategiesorregimens.Therearetwomajortypesofinterventionstudies:

Controlledclinicaltrialsinwhichindividualsubjectsareassignedtooneoranotherofthecompeting
interventions,or
Communityinterventions,inwhichaninterventionisassignedtoanentiregroup.

Inmanyrespectsthedesignofaclinicaltrialisanalogoustoaprospectivecohortstudy,exceptthattheinvestigators
assignorallocatetheexposure(treatment)understudy.

Thisprovidesclinicaltrialswithapowerfuladvantageoverobservationalstudies,providedtheassignmenttoa
treatmentgroupisdonerandomlywithasufficientlylargesamplesize.Underthesecircumstancesrandomized
clinicaltrials(RCTs)providethebestopportunitytocontrolforconfoundingandavoidcertainbiases.Consequently,
theyprovidethemosteffectivewaytodetectsmalltomoderatebenefitsofonetreatmentoveranother.However,in
ordertoprovidedefinitiveanswers,clinicaltrialsmustenrollasufficientnumberofappropriatesubjectsandfollow
themforanadequateperiodoftime.Consequently,clinicaltrialscanbelongandexpensive.

LearningObjectives

Aftersuccessfullycompletingthissection,thestudentwillbeableto:

Explainthedistinguishingfeaturesofaclinicaltrial(interventionstudy).
Discussthetwomajorpotentialadvantagesofinterventionstudiesandtheirlimitations.
Differentiatebetweenpreventive,therapeutic,individualandcommunityRCTs
BrieflyexplainthedifferencesamongphaseI,II,III,&IVclinicaltrials.
Definerandomizationinthecontextofaclinicaltrialandgiveexamplesofappropriatemethodsof
randomization.
Explainwhyrandomizationisused.
Explainhowtodeterminewhetherrandomizationhasbeensuccessful.
Defineblindingandexplainthepurposeofblinding.
Distinguishbetweensingleanddoubleblinding.
Explainwhattheplaceboeffectis.
Definetheterm"placebo"andexplainwhyplacebosareused.
Explainwhentheuseofaplaceboisnotappropriateanddiscussalternativestrategies.
Explainwhyitisimportanttomaintainhighratesoffollowupinaprospectivecohortstudyoraclinicaltrial.
Explainwhycomplianceisimportantandtheeffectsofnoncompliance.
Defineanddistinguishbetween"intentiontotreatanalysis"andanefficacyanalysis.
Definewhataruninphaseisandexplainitspurpose.

TypesofInterventionStudies

IndividualversusGroup(Community)Trials
Mosttrialsareconductedbyallocatingtreatmentsorinterventionstoindividualsubjects,i.e.,thetreatment
orinterventionisallocatedtoindividuals.Forexample,investigatorsrecentlycomparedtheeffectivenessof
glucosamineandchondroitinandseveralotherdrugsintheirabilitytorelievesymptomsofosteoarthritis.
Subjectswererandomlyassignedtoreceiveoneofseveralpossibletreatments,andtheywerefollowedand
assessedforpainreliefandothermeasures.
Incontrast,grouptrialsallocatetheinterventiontogroupsofsubjects.Thesetypesoftrialsaregenerally
conductedwhentheinterventionisinherentlyoperatesatagrouplevel(e.g.,changingalaworpolicy)or
becauseitwouldbedifficulttogivetheinterventiontosomepeopleinthegroupwhilewithholdingitfrom
others.Groupunitsmightbefamilies,schools,ormedicalpractices.Awellknowntypeofgrouptrialisa
communitytrial,inwhichtheinterventionisallocatedtherapytoentirecommunitiesorneighborhoods.Inthe
1940stheeffectivenessoffluorideinpreventingdentalcarieswastestedcomparingthefrequencyofcariesin
thechildreninKingstonandNewburgh.NewYorkafterNewburghhadhadfluorideaddedtothetown's
drinkingwater.Acopyofthefirstresearchreport,publishedin1950canbeseenhere.Othercommunitytrials
mighttestcommunitybasedinterventionsthatprovideeducationalprogramstosomecommunities,butnot
othersinordertodeterminetheireffectiveness.Anexamplemightbetocomparetheeffectivenessofa
communitybasededucationalprograminTanzaniainwhichsomevillagesreceivetheeducationalprogram,
butothersdonot.

TheKingstonNewburghFluorideTrial

Preventiontrials(orprophylactictrials)versusTherapeuticTrials
Clinicaltrialsmightalsobedistinguishedbasedonwhethertheyareaimedatassessingpreventiveinterventionsor
evaluatingnewtreatmentsforexistingdisease.ThePhysiciansHealthStudyestablishedthatlowdoseaspirin
reducedtheriskofmyocardialinfarctions(heartattacks)inmales.Othertrialshaveassessedwhetherexerciseor
lowfatdietcanreducetheriskofheartdiseaseorcancer.AstudycurrentlyunderwayatBUSPHistestingwhether
peercounselingiseffectiveinhelpingsmokerswholiveinpublichousingquitsmoking.Alloftheseareprevention
trials.Incontrast,therehavebeenmanytrialsthathavecontributedtoourknowledgeaboutoptimumtreatmentof
manydiseasesthroughmedication,surgery,orothermedicalinterventions.

PhasesofTrialsEvaluatingNewDrugs
Clinicaltrialsfornewdrugsareconductedinphaseswithdifferentpurposesthatdependonthestageof
development.

1.PhaseItrials:ClinicalTrials.govdescribesphaseItrialsas"Initialstudiestodeterminethemetabolismand
pharmacologicactionsofdrugsinhumans,thesideeffectsassociatedwithincreasingdoses,andtogainearly
evidenceofeffectivenessmayincludehealthyparticipantsand/orpatients."Frequently,anexperimentaldrug
ortreatmentinitiallyistestedinasmallgroupofpeople(880)toevaluateitssafetyandtoexplorepossible
sideeffectsandthedosesatwhichtheyoccur.
2.PhaseIItrials:ClinicalTrials.govdescribestheseas"Controlledclinicalstudiesconductedtoevaluatethe
effectivenessofthedrugforaparticularindicationorindicationsinpatientswiththediseaseorconditionunder
studyandtodeterminethecommonshorttermsideeffectsandrisks."Thenewtreatmentmightbetestedina
somewhatlargergroup(80200)togetmoreinformationabouteffectivenessandpotentialsideeffectsat
differentdosages.
3.PhaseIIItrials:ClinicalTrials.govdefinestheseas"Expandedcontrolledanduncontrolledtrialsafter
preliminaryevidencesuggestingeffectivenessofthedrughasbeenobtained,andareintendedtogather
additionalinformationtoevaluatetheoverallbenefitriskrelationshipofthedrugandprovideandadequate
basisforphysicianlabeling."Thesearetypicallyconductedinlargergroups(20040,000)toformallytest
effectivenessandestablishthefrequencyandseverityofsideeffectscomparedtonotreatment,or,compared
tocurrentlyusedtreatments("usualcare")
4.PhaseIVreferstopostmarketing"surveillance"tocollectinformationregardingrisks,benefits,andoptimal
use.Thisphasecanbeparticularlyimportantforidentifyingrare,butpotentiallydevastatingsideeffects.
Example:SafetyofInfluenzaA(H1N1)VaccineinPostmarketingSurveillanceinChina

TheSubjects

PopulationHierarchy
Whenclinicaltrialsareperformedthereisgenerallyatargetpopulationorreferencepopulationtowhichone
wouldliketoapplythefindings.Forexample,researchersreportedontheefficacyoflowdoseaspirininpreventing
myocardialinfarctioninwomen[RidkerP,etal.:Arandomizedtrialoflowdoseaspirinintheprimarypreventionof
cardiovasculardiseaseinwomen.NEnglJMed2005352:1293304].Thereferencepopulationwasadultfemales
whohavenothadamyocardialinfarction.

Theexperimentalpopulation(studypopulation)arethepotentialparticipants,i.e.,apracticalsubsetofpeople
whoarerepresentativeofthereferencepopulation.Importantpracticalconsiderationsmightincludechoosinga
groupthatwassufficientlylargeandlikelytoproduceanadequatenumberofendpoints(outcomesofinterest)in
ordertoallowvalidstatisticalanalysisandareasonablypreciseestimateofthemeasureofeffect.Theparticipants
wouldbethosewhowerewillingtoparticipate(i.e.,consentedafterbeingfullyinformedaboutthestudy)andalso
meteligibilitycriteriathattakeintoaccountscientificandsafetyconsiderations.Forexample,aninclusioncriterion
mightbeage45orolderinordertoachieveastudysamplethatwouldproduceasufficientnumberofendpoints.In
astudyoftheeffectofaspirinoncardiovasculardiseaseitwouldalsobeimportanttospecifyexclusioncriteria,e.g.,
peoplewithpreexistingcardiovasculardiseaseorthosewhowerealreadytakingaspirinoranticoagulantsforother
medicalconditions.
ThefollowingisanexcerptfromthereportbyRidkeretal.describinghowtheyobtainedtheirstudypopulation:

"Inbrief,betweenSeptember1992andMay
1995,lettersofinvitationweremailedtomore
than1.7millionfemalehealthprofessionals.A
totalof453,787completedthequestionnaires,
with65,169initiallywillingandeligibletoenroll.
Womenwereeligibleiftheywere45yearsof
ageorolderhadnohistoryofcoronaryheart
disease,cerebrovasculardisease,cancer
(exceptnonmelanomaskincancer),orother
majorchronicillnesshadnohistoryofside
effectstoanyofthestudymedicationswere
nottakingaspirinornonsteroidalanti
inflammatorymedications(NSAIDs)morethan
onceaweek(orwerewillingtoforegotheiruse
duringthetrial)werenottakinganticoagulants
orcorticosteroids

Eligiblewomenwereenrolledinathreemonthruninphaseofplaceboadministrationtoidentifyagrouplikelytobe
compliantwithlongtermtreatment.Atotalof39,876womenwerewilling,eligible,andcompliantduringtherunin
periodandunderwentrandomization:19,934wereassignedtoreceiveaspirinand19,942toreceiveplacebo."

InternalandExternalValidity
Theeligibilitycriterianeedtobalancetheneedsforinternalandexternalvalidity.Internalvalidityreferstothe
accuracyoftheconclusionswithinthatparticularstudysample,whileexternalvalidityreferstowhetherornotthe
resultsofaparticularstudyarerelevanttoamoregeneralpopulation.Forexample,in1981thePhysiciansHealth
Studysentinvitationletters,consentforms,andenrollmentquestionnairestoall261,248malephysiciansbetween
40and84yearsofagewholivedintheUnitedStatesandwhowereregisteredwiththeAmericanMedical
Association.Lessthanhalfrespondedtotheinvitation,andonlyabout59,000werewillingtoparticipate.Ofthose
33,223werebothwillingandeligible.
Thesephysicianswereenrolledinaruninphaseduringwhichallreceivedactiveaspirinandplacebobetacarotene
(bothoftheseweretobetestedinatwobytwofactorialdesign,tobedescribedlaterinthismodule).After18
weeks,participantsweresentaquestionnaireaskingabouttheirhealthstatus,sideeffects,compliance,and
willingnesstocontinueinthetrial.Atotalof11,152changedtheirminds,reportedareasonforexclusion,ordidnot
reliablytakethestudypills.Theremaining22,071physicianswerethenrandomlyassignedtoexperimentalgroups
andfollowedforthedurationofthestudy.Thestudywasrestrictedtophysiciansinordertofacilitatefollowup,since
allsubjectswereregisteredphysiciansintheAMA.Thestudyexcludedfemalephysicians,becausein1981the
numberofregisteredfemalephysiciansovertheageof40wasquitesmallandwouldnothaveprovidedenough
statisticalpowertoprovidevalidresultsinfemales.(Notethattheexclusionoffemalesisnotanexampleofselection
bias.Itdoesnotaffectthevalidityoftheresultsofthestudybutratherthenatureofthetargetpopulationand
thereforethegeneralizabilityoftheresults.)Thestudyconvincinglydemonstratedthattheregimenoflowdose
aspirinreducedtheriskofmyocardialinfarction(heartattack)inthesesubjectsbyabout44%,andtheresultswere
reportedin1989intheNewEnglandJournalofMedicine.However,oneoftheunansweredquestionswaswhether
theresultswereapplicabletofemales(oreventothenonphysicianpopulationatlarge).Consequently,the
questionsabouttheexternalvalidity,i.e.thegeneralizability,ofthestudylingeredandeventuallyledtoaseparate
clinicaltrialinTheWomen'sHealthStudy.Theresultswerepublishedin2005andconcluded:

"Inthislarge,primarypreventiontrialamongwomen,
aspirinloweredtheriskofstrokewithoutaffectingthe
riskofmyocardialinfarctionordeathfromcardiovascular
causes,leadingtoanonsignificantfindingwithrespect
totheprimaryendpoint."

Ridkeretal.:Arandomizedtrialoflowdoseaspirinin
theprimarypreventionofcardiovasculardiseasein
women.NEnglJMed2005352:1293304.

Inotherwords,theeffectofaspirininpreventingmyocardialinfarctionsdidappeartobedifferentinwomenand
men.

SampleSize
Themajoradvantageoflargerandomizedclinicaltrialsisthatthattheyarethemosteffectivewaytoreduce
confounding.Assuch,theyoffertheopportunitytoidentifysmalltomoderateeffectsthatmaybeclinicallyvery
important.Forexample,coronaryarterydisease(CAD)isthemostfrequentcauseofdeathanddisabilityinthethe
USandworldwide.Consequently,interventionsthatreduceriskby1520%wouldbeextremelyimportant,because
somuchdeathanddisabilityisattributedtoCAD.Whilecontrolofconfoundingmakesiteasiertoaccuratelyassess
modestbutimportanteffects,itisstillnecessarytohaveanadequatesamplesizeinordertoproduceameasureof
associationthatisreasonablyprecise.Ifthestudydoesnothaveasufficientsamplesize(i.e.,ifitis"under
powered"),thestudymightfailtoidentifyameaningfulbenefitthattrulyexisted,andmuchtimeandmoneywould
havebeenwastedonanincorrectconclusion.

Actually,thekeyfactorinfluencingthepowerofthestudyisthenumberofoutcomes(oftenreferredtoas
"endpoints")ratherthanstudysizeperse.Ofcourse,increasingstudysizewillincreasethenumberofendpoints,
buttwootherfactorsthataffectthepowerofthestudyarethelikelihoodoftheoutcomeamongthestudysubjects
andthedurationofthestudy.Forexample,boththePhysicians'HealthStudyandtheWomen'sHealthStudy
requiredparticipantstobeabovetheageof40atthetimeofenrollment,sinceyoungersubjectswouldbe
substantiallylesslikelytohaveamyocardialinfarctionduringtheplannedfollowupperiod.Thedurationofthefollow
upperiodisobviouslyalsorelevant,sinceshorterperiodsoffollowupwillproducefewereventsandreduce
statisticalpower

Inordertoavoidconductingstudiesthatareunderpowered,investigatorswillperformaseriesofcalculations
referredtoassamplesizeestimates.Thisisnotasinglecalculation,butaseriesofcalculationsthat,inessence,
address"whatif"questions.Forexample,theobservationalstudiesthatleduptothePhysiciansHealthStudyfailed
tofindstatisticallysignificantbenefitsofaspirin,buttheyseemedtosuggestthatiftherewereabenefit,itwouldlikely
beontheorderofa1530%reductioninriskofmyocardialinfarction.Ifonehasestimatesofthemagnitudeofrisk
(theexpectedcumulativeincidence)inthereferencepopulation,onecanthanperformcalculationstoestimatehow
manysubjectsonewouldneedineachoftwostudygroupstodetectagiveneffect,ifitexisted.Forexample,ifthe
expectedincidenceofmyocardialinfarctionoverfiveyearsinmalesover40yearsofagewerearound5%,andif
lowdoseaspirintrulyreducedtheriskbyabout20%,thentheexpectedfrequenciesintheuntreatedplacebogroup
andtheaspirintreatedgroupwouldbeexpectedtobe0.05and0.04respectively.TheExcelfile"Epi_Tools.XLS"
hasaworksheetentitled"SampleSize"thatperformsthesecalculationsforyou.

Theillustrationaboveshowsthata"whatif"situation,i.e.whatifthefrequencyofmyocardialinfarctionis5%without
aspirinand4%withthelowdoseaspirinregimen(i.e.,a20%reductioninrisk).Thecalculationsindicatethatin
ordertohavea90%probability(statisticalpower)offindingastatisticallysignificantdifferenceusingp<0.05asthe
criterionofsignificance,wewouldneedalittleover9,000subjectsineachgroup.TheinvestigatorsinthePhysicians'
HealthStudywiselysoughtasomewhatlargersamplethantheestimatesindicated.

AssignmenttoTreatmentsorRegimens
Confounding
Manyfactorscaninfluencewhetherornotasubjectwilldevelopanoutcomeofinterest.Asasimpleexample,
considerastudywiththegoalofdeterminingwhetherphysicalactivityreducestheriskofheartdisease.Anoverly
simplisticapproachwouldbetoenrollacohortofsubjectswithoutpreexistingheartdiseaseanddividetheminto
exposuregroupsbasedontheiractivitylevelatthetimeofenrollment.Theycouldthenbefollowedlongitudinallyin
ordertomeasureandcomparetheincidenceofheartdiseaseineachgroup.Bothgroupswouldlikelyhavesubjects
witharangeofages,butthe'active'groupwouldprobablyhaveasomewhatyoungeragedistributionthanthe
inactivegroup,becauseyoungerpeopletendtobemoreactivethanolderpeople.Theproblem,ofcourse,isthat
ageisalsoanindependentriskfactorfordevelopingheartdisease,sowewouldn'tbeevaluatingjusttheeffectof
activity.The"risk"ineachgroupismeasuredastheircumulativeincidenceofheartdisease,buttheriskratioorrisk
differencethatwemeasureisreallygoingtoreflectthesumtotalofalldifferencesbetweenthegroupsthatinfluence
theirprobabilityofdevelopingheartdisease.Thiswouldincludenotonlydifferencesinage,butalsodifferencesina
hostofknown(andyettobediscovered)riskfactorssuchassmoking,gender,bodymassindex,bloodpressure,
familyhistory,medicationsused,etc.Allofthesearefactorsthatinfluencetheriskofheartdisease,andthey
confoundourestimationoftheassociationbetweenactivityandheartdisease.

Confoundingdistortsthemeasureofassociationthatisourmainconcernintheexampleabove,itistheassociation
betweenactivityandheartdisease.However,allofthese'otherriskfactors'candistortthemeasureofassociation
weareinterestediniftheyareunevenlydistributedamongthegroupswearecomparing.Theprimaryadvantageto
randomizedclinicaltrialsisthatrandomassignmentofasufficientlylargenumberofsubjectstendstoresultin
similardistributionsofallotherfactors,includingfactorsunknowntous,amongthegroups.Ifthegroupshavethe
samedistributionsofalloftheseotherriskfactorsatbaseline(i.e.,thebeginningofthetrial)thentheywillnotdistort
ourestimateofeffect(measureofassociation).

MethodsofAssignment
Thedistinguishingfeatureofaninterventionstudyisthattheinvestigatorsassignsubjectstoatreatment(or
"exposure")inordertoestablishactivelytreatedgroupsofsubjectsandacomparisongroup.Thereareseveral
meansofassigningexposureforthepurposesofcomparison,manyofwhichdonot,infact,randomlyassign
subjectstodifferentgroupsorhavetoofewsubjectstorelyontherandomizationprocesstobalancefactors
betweengroups.

Historicalcomparisongroup:Onecansimplycompareresultswithaninterventiontoanhistoricalcontrol
group.Forexample,vascularsurgeonsatBostonMedicalCenterwantedtotesttheefficacyofa"critical
pathway,"aprotocolforpatientmanagementaftersurgeryforatheroscleroticocclusionsinthearteriesinthe
leg.Theycompared67consecutivelytreatedpatientsbeforeinstitutionofthepathwaywithcareof69
consecutivelytreatedpatientswiththecriticalpathwayinplace.Thisisaconvenientmethodwhenthereisa
suddenshiftintreatmentormanagementthatisappliedtoallpatients,butthelimitationofthisapproachisan
inabilitytocontrolforconfoundingfactors.
Nonrandomassignment:Nonrandomassignmentmethodssuchasalternatepatientsoralternatedaysof
theweekarenotoptimalbecausetheyarepredictableandcanbeexploitedbycaretakerseitherconsciously
orunconsciously.Thismayleadtobiasedassignment.
Randomization:Randomizedassignmentmeansthatallsubjectshaveanequalchanceofbeingallocatedto
anyoftheavailabletreatmentoptions.Tobeeffective,Itmustbedonebyamethodthatisunpredictable.One
canusepublishedtablesofrandomnumbersandsimplyassignsubjectsbasedonthenextnumberlistedon
thetable,oronecanusearandomnumbergeneratedbyacomputer,suchastherandomnumberfunctionin
Excel.TheEpi_Toolsapplicationhasaworksheetthatallowsyoutospecifythenumberofstudygroupsand
thenentera"seed"numberthattriggersthegenerationofarandomnumberthatspecifieswhichtreatment
groupasubjectshouldbeassignedto.Theunpredictabilitymeansthat,ifasufficientlylargenumberof
subjectsarerandomlyassignedtotreatmentgroups,thegroupswillhavesimilardistributionsofall
characteristics.Asaresultbothknownandunknownconfounderswilltendtobeequallydistributedamongthe
studygroups.Byavoidinganimbalanceinotherriskfactors,theestimateofassociationislesslikelytobe
influencedbyconfounding.However,inordertoensurebaselinecomparabilityofthegroups,thesamplesize
mustbesufficientlylarge.Theotheradvantagetoassigningsubjectstotreatmentgroupsbyarandommethod
isthatitavoidsthepotentialforbiasinassignment.Thus,twomajoradvantagestorandomallocationto
treatmentgroups(randomization)are:
1.Controlofconfoundingbyproducingbaseline
comparabilityofthegroupswithrespecttoall
otherfactorsthatmightinfluencetheoutcome
2.Unbiasedassignmenttotreatmentgroups.

Importantly,itisthenumberofunitsrandomized,notthenumberofpeople,thatdeterminewhetherrandomizationis
likelytowork.Ifthestudyisanindividualtrial,thenthenumberofsubjectsequalthenumberofunits.However,ina
grouprandomizedtrial,thenumberofunitsissmallerthanthenumberofindividualsinthetrial.Forexample,inthe
trialofpeercounselingforsmokersinpublichousing,entirepublichousingdevelopmentswereassignedtoeither
theinterventionorcontrolarm,sothateveryparticipantataparticulardevelopmentreceivedthesametreatment.
Twentydevelopmentswererandomized.Thelikelihoodthatthe10developmentsineacharmwerebalancedon
potentialconfoundingfactorswasthesameasifthestudyconsistedof20individuals(orthesameasthelikelihood
thatflippingacoin20timeswouldproduceabalancednumberofheadsandtails),eventhoughtherewere500
individualsinthestudy.Inthefluoridetrialdescribedpreviously,eventhoughtensofthousandsofpeoplewere
involved,therewereonlytwocities,andrandomizationcanneverbalanceconfoundersbetweentwounits,whether
theyareindividualsorgroups.However,inboththesecases,randomassignmentdidavoidthepossibilitythatthe
investigatorswouldconsciouslyorunconsciouslyassignthegroupsbasedontheirfeelingaboutwhatwouldbemost
likelytoproducearesultconsistentwiththeirhypothesis.

Blinding(Masking),Placebos,andShams

Blinding(ormasking)referstowithholdingknowledgeabouttreatmentassignmentfromsubjectsand/orinvestigators
inordertopreventbiasinassessmentofsubjectiveoutcomes,suchaspainrelief.Thereareseveralschemesfor
blinding:

Singleblind:subjectsdon'tknowwhichtreatmenttheyarereceiving
Doubleblind:neithersubjectsnortheinvestigatorwhoisassessingthepatientareawareofthetreatment
assignmentuntiltheendofthestudy
Tripleblind:Thistermissometimesusedwhenthepersonwhoadministerstreatmenttothestudysubjectsis
keptunawareoftheassignedtreatment.

Blindingisfacilitatedbytheuseofplacebotreatmentsorshamprocedures.Forexample,inastudydesignedto
evaluatetheefficacyofarthroscopicsurgeryintreatingpainfulosteoarthritisoftheknee,subjectsinthesham
surgerygrouphadasmallincisionplacedonthekneeundersedation,butarthroscopicsurgerywasnotactually
performed.Instead,thesurgeonssimulatedtheprocedurebyaskingtobegiventheusualinstrumentsand
manipulatingthekneeofthesubjectasiftherealprocedurewerebeingperformed.Shamsurgeryismore
problematicthanuseofaplacebo,becauseithasthepotentialforcausingharmandbecausethepatientisbeing
activelydeceived.(Foradetaileddiscussionontheethicsofshamsurgeries,seeMillerFGandKaptchukTJ:Sham
proceduresandtheethicsofclinicaltrials.JRSocMed.2004December97(12):576578.)

Placebo:apharmacologicallyinert(inactive)substancethatisotherwiseindistinguishablefromtheactive
treatment.Whenacertain"standardofcare"isroutineforagivencondition,itisprobablynotethicaltoassign
subjectstoaplacebogroup.
Sham:similartoaplacebo,ashamisafakeproceduredesignedtoresemblearealprocedurethatisbeing
testedforefficacy.

Maskingisnotalwaysnecessary,norisitalwayspossible.Iftheprimaryoutcomeofinterestisdefinitiveand
objective,suchasdeath,thenmaskingisn'tnecessary.Inaddition,ifthetreatmentisanelaboratesurgical
procedure,theethicsofdoingashamprocedurewouldbequestionable.

ThePlaceboEffect
Theuseofplacebosandshamproceduresfacilitatesmaskingandtherebypreventsbiasinassessmentofsubjective
outcomes,suchaspainrelief.However,anothermajoradvantagetousingthemisthattheyenableinvestigatorsto
distinguishthedegreetowhichimprovementsaresolelytheresultofthe"placeboeffect."Whenpeopleare
enrolledinastudy,orprescribedamedicationorofferedanymedicaltreatmentorcare,thereisgenerallyan
expectationthattheywillimproveorbenefitfromit.Thetendencyforpeopletoreportimprovementsevenwhenthe
treatmenthasnorealtherapeuticeffectisreferredtoas"theplaceboeffect,"anditcanvarywidelyinmagnitude.In
aclinicaltrialdesignedtotesttheeffectivenessofglucosamineandchondroitininrelievingsymptomsof
osteoarthritistheauthorsdefinedtheoutcomeofinterestasgreaterthan20%reliefofpainonananalogscale,
shownbelow.

Intheplacebotreatedgroup,60%reportedgreaterthan20%reliefofpain,comparedto67%inthegrouptreated
withglucosamineandchondroitin.

AnotherillustrationofthepotentialimpactoftheplaceboeffectisseeninthearticlebelowfromtheNewYorkTimes.

Perceptions:PositiveSpinAddstoa
Placebo'sImpact
ByNICHOLASBAKALAR,NewYorkTimes,December
27,2011

Inastudypublishedonlinelastweekintheonline
journalPLoSOne,researchersexplainedto80
volunteerswithirritablebowelsyndromethathalfof
themwouldreceiveroutinetreatmentandtheotherhalf
wouldreceiveaplacebo.Theyexplainedtoallthatthis
wasaninertsubstance,likeasugarpill,thathadbeen
foundto"producesignificantimprovementinI.B.S.
symptomsthroughmindbodyselfhealingprocesses."
Thepatients,alltreatedwiththesameattention,warmth
andempathybytheresearchers,werethenrandomly
assignedtogetthepillornot.

Attheendofthreeweeks,theytestedallthepatients
withquestionnairesassessingtheleveloftheirpainand
othersymptoms.Thepatientsgiventhesugarpillina
bottleclearlymarked"placebo"reportedsignificantly
betterpainreliefandgreaterreductionintheseverityof
othersymptomsthanthosewhogotnopill.Theauthors
speculatethatthedoctors'communicationofapositive
outcomewasonefactorintheapparenteffectivenessof
theplacebo.

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ComplianceandLosstoFollowUp

Noncomplianceisthefailuretoadheretothestudyprotocol.Forexample,inthePhysiciansHealthStudyabout
15%ofthesubjectsrandomizedtoreceivelowdoseaspirindidnotregularlytakethecapsulestheyreceived,and
about15%ofthesubjectsintheplacebogroupwereactuallytakingaspirinonafairlyregularbasis.

EffectsofNoncompliance:
Noncompliancetendsminimizeanydifferencebetweenthegroups.Asaresult,thestatisticalpowertodetectatrue
differenceisreduced,andthetrueeffectwillbebiasedtowardthenull.

WaystoMaintainCompliance
1.Designprotocolsandregimensthatareassimpleandeasyaspossibletofollowandcomplywith.For
example,usegivepillsinconvenient"blisterpacks"withthedaysofthemonthonthepack,orusespecialpill
boxestomakeiteasiertoremembertotakemedications.
2.Enrollmotivatedandknowledgeablesubjectswholeadfairlyorganizedlives(e.g.ThePhysicians'Health
StudyorTheNurses'sHealthStudy).
3.Paintanaccuratepictureofwhatwillberequiredduringtheenrollmentandinformedconsentprocess.
4.Duringenrollmenttakeacarefulmedicalhistorytotrytoidentifyindividualswhowouldhaveadifficulttime
complying,andexcludethesepeople.Forexample,ThePhysicians'HealthStudyexcludedsubjectswitha
historyofgastritis,sincetheywouldbelesslikelytotoleratetheaspirinregimenandathigherriskofulcers
andgastritis.
5.Whenpossible,maskthesubjectsinthecomparisongroup,becauseiftheyknowtheyarenotreceivingan
activeingredient,theywillbelesslikelytocomply
6.Haveyourstudystaffcontactsubjectsfrequentlytomaintaininterestandmotivation.
7.Conducta"runinphase"toidentifysubjectswhoareunableorunmotivatedtocomply.

AssessingCompliance
Evenwhenmeasuresaretakentomaximizecompliance,itisimportanttoassesscomplianceintheparticipants.

1.Askthesubjectsiftheyadheredtotheprotocol.
2.Collectpillpackstocountunusedpills.
3.Collectbloodorurinesamplestoassesscompliance(measuretheactiveingredientoraninertmarkerif
possible.)

LosstoFollowUp
Followuponsubjectscanbeaccomplishedthroughperiodicvisitsandexaminations,byphoneinterviews,bymail
questionnaires,orviatheInternet.Patientsmaydropoutofastudyasaresultoflossorinterest,adversereactions,
orsimpleaburdensomeprotocolthatbecomestiring.Othersmightbecomelosttofollowupbecauseofdeath,
relocationorotherreasons.Losstofollowupisaproblemfortwomainreasons:

1.Itreducestheeffectivesamplesizebecausetheinvestigatorswillbemissingoutcomemeasuresonthosewho
arelost.
2.Iffollowupratesdifferamongcomparisongroupsandifattritionisrelatedtotheoutcome,theresultsofthe
studycanbebiased.Thisisaspecialtypeofselectionbiascausednotbydifferencesinenrollment,but
insteadbydifferentialratesofretentionthatarerelatedtotheoutcome.Forexample,astudyontheefficacy
ofhighimpactexerciseonriskfactorsforosteoporosishadgreaterlosstofollowupinthegroupassignedto
exercise(seebelow).Womenwhodroppedoutmayhavehadinherentlylowerbonestrengththatmadethe
highimpactregimenlesstolerableforthem.Ifso,thiswouldhaveproducedselectivelossofwomenmore
likelytodeveloposteoporosisfromtheactivetreatmentgroup,andthiswouldcauseabiasedestimate,
specificallyanoverestimateofthebenefitofexercise.

IssuesintheAnalysisofClinicalTrials

TheBasicAnalysis
Thebasicdataanalysisissimilartothatofatypicalcohortstudy,andtheresultscanbesummarizedina
contingencytable.Onecanthencomputecumulativeincidenceorincidencerates,asappropriate.Fromthese,one
cancalculatetheriskratio,riskdifference,pvaluesand95%confidenceintervals.Mostofthesecalculationscanbe
donequiteeasilyusingtheExcelworksheetforcohortstudiesprovidedin"Epi_Tools.XLS".Theillustrationbelow
showstheresultsofanalysisofatriallookingattheabilityofzidovudine(anantiretroviraldrugusedinthetreatment
andpreventionofHIV)toreducematernaltochildtransmission.
Datasource:ConnorEM,etal.:Reductioninmaternalinfancytransmissionofhumanimmunodeficiencyvirustype1
withzidovudinetreatment.N.Engl.J.Med.1994331:11731180,asquotedinthetextbookbyAschegrauand
SeageinTable75,page191inthe2ndedition.)

Theanalysistotherightresultedinariskratioof0.33(a67%reductioninrisk)whenzidovudinetreatmentwas
comparedtoplacebotreatedcontrols.The95%confidenceintervalfortheriskratiowas0.180.60.(Thiswaspartof
protocol076referredtoabovethistrialwastheonethatoriginallydemonstratedtheefficacyofzidovudinein
womenintheUnitedStatesandFrance.)

DidRandomizationControlforConfounding?
Whenanalyzingorreadingarandomizedclinicaltrial,animportantconsiderationiswhetherornotrandomization
actuallyachievedbaselinecomparabilityamongthegroups.Thiscanbeassessedbycomparingthegroupswith
respecttotheircharacteristicsandpotentialconfoundingfactorsatbaseline,i.e.,atthebeginningofthestudy.

Frequently,apublishedpaperwillhaveaninitialtablewhichsummarizesthebaselinecharacteristicsandcompares
thoseusingappropriatestatisticaltests.Ifthegroupsaresimilarwithrespecttoallofthesecharacteristics,thenitis
morelikelythattheyaresimilarwithrespecttootherfactorsaswell,andonecanassumethatrandomizationwas
successful.Itisimportanttorememberthatwecanneverreallyknowwhetherrandomizationwastrulysuccessful,
becausewecanonlyjudgebasedonthosebaselinecharacteristicsthatwehavemeasured.Wemaynothave
measuredallknownconfounders,andinanycase,wecan'thavemeasuredtheunknownones.Therefore,the
largerthesamplesize,themoreconfidentwecanbethattheprocessofrandomization,whichreliesonthe"laws"of
chance,hasworkedtobalancebaselinecharacteristics.

Pitfall:AccordingtoRothman,analmostuniversalmistakeinthereportingofclinicaltrialsisto
determinewhetherrandomizationwassuccessfulbycomparingthebaselinecharacteristics
amongthegroupsusingastatisticaltestandpvaluestodecidewhetherconfoundingoccurred.
However,theextenttowhichaconfoundingfactordistortsthemeasureofeffectwilldependnot
onlyontheextenttowhichitdiffersamongthegroupsbeingcompared,butalsoonthestrength
ofassociationbetweentheconfounderandtheoutcome(i.e.,theriskratiooftheconfoundingfactor.)

Ifallbaselinecharacteristicsarenearlyidenticalin
thegroupsbeingcompared,thentherewillbelittle,if
any,confounding.However,ifsomefactorsappearto
differ,theonlyeffectivewaytodeterminewhether
theycausedconfoundingistocalculatethemeasure
ofeffectbeforeandafteradjustingforthatfactor
usingeitherstratificationanalysisorregression
analysis.Iftheadjustedmeasureofassociation
differsfromtheunadjustedmeasurebymorethan
about10%,thenconfoundingoccurred,andsteps
shouldbetakentoadjustforitinthefinalanalysis.
Bearinmindthat,evenwithrandomizationof
treatmentstatus,differencesinotherriskfactorscan
occur,justbychance.Ifthisoccurs,theappropriate
thingtodoistoadjustfortheimbalancesinthe
analysis,usingeitherstratificationorregression
analysis.

IntentiontoTreatAnalysis:
Fortheprimaryanalysisallsubjectsshouldbeincludedinthegroupstowhichtheywererandomlyassigned,evenif
theydidnotcompleteorevenreceivetheappropriatetreatment.Thisisreferredtoasan"intentiontotreat"analysis,
anditisimportantbecause:

Itpreservesbaselinecomparabilityandprovidescontrolofconfoundingbyknownandunknownconfounders.
Itmaintainsthestatisticalpoweroftheoriginalstudypopulation.
Sincecompliersandnoncompliersarelikelytodifferonimportantprognosticfactors,retentionofallsubjects
intheanalysiswillreducebias.
Itreflectsefficacyineverydaypractice.Inreallife,peoplewhohavebeenprescribedcertainmedicationsor
givenadvicemaynotcomplyforthesamereasonsthatsubjectsfailtocomplyinaclinicaltrial.Forthis
reason,anintentiontotreatanalysismayprovideamoreaccuratemeasureofthepotentialbenefittobe
derivedfromannewtherapy.

EfficacyAnalysis
Iftherehasbeenaproblemwithcompliance,theinvestigatorscanalsoconductanefficacyanalysis(sometimes
referredtoasa'secondaryanalysis'),whichcomparessubjectswhoactuallycompliedwiththeassignedprotocols.
Inessence,itdeterminestheefficacyofthenewtherapyunderidealcircumstances,i.e.,itteststhebenefitoftaking
thetherapyasopposedtothealternative.Theproblemwithanefficacyanalysisisthatthesamplesizewillbe
smaller,anditdoesnotcontrolforconfoundingasrigorouslyasanintentiontotreatanalysis,becausetheremoval
ofsubjectsfromeitherorbothgroupsmeanstheoriginalrandomizationnolongerisinplace.

WeighingRiskVersusBenefit

Manyreportsofepidemiologicstudiesfocusonthestrengthofassociation,i.e.,riskratiosandrateratios.However,
whentryingtoweighdecisionsforanindividualpersonititimportanttoconsider:

Theindividual'spersonalcircumstances,i.e.,whataretheirrisksfortheprimaryoutcome?
Whatadverseeffectsoftheproposedtreatmentaretheyatriskfor?
Whataretheabsolutebenefitsandabsoluterisksoftheproposedtherapy?

IsLowDoseAspirinBeneficial?
Anumberofdescriptivestudiessuggestedthatpeoplewhotookaspirinregularlyseemedtohavealowerriskof
myocardialinfarction(heartattack).Observationalstudiessuggestedperhapsa30%reductioninriskofmyocardial
infarction,butofcoursethesubjectswerenotrandomized,sotherewereconcernsaboutunrecognized
confounding.Severalsmallclinicaltrialssuggestedsimilarreductions,butthesamplesizesweretoosmalltoarrive
atasolidconclusion.Intheearly1980sThePhysician'sHealthStudywasconductedtotestthehypothesisthat325
mg.ofaspirin(one'adult'sizedaspirin)takeneveryotherdaywouldreducemortalityfromcardiovasculardisease
(N.Engl.J.Med.320:1238,1989).Malephysicians40to84yearsofagelivingintheUSin1980wereeligibleto
participate.Physicianswereexcludediftheyhadapersonalhistoryofmyocardialinfarction,strokeortransient
ischemicattackcancercurrentgoutliver,renalorpepticulcerdiseasecontraindicationtoaspirinconsumption
currentuseofaspirin,plateletactivedrugsornonsteroidalantiinflammatoryagentsintolerancetoaspirinor
inabilitytocomplywiththeprotocol.Eligiblesubjectswhomettheinclusioncriteriaandwhosuccessfullycompleteda
runinphasewererandomlyassignedtoreceiveaspirinoraplacebo.Eventually22,071physicianswereenrolled
11,037wereassignedtoaspirin,and11,034wereassignedtoplacebo.Theagents(aspirinandplacebo)were
identicalinappearanceandweremailedtothesubjects.Therecipients'treatmentgroupwascoded,andneitherthe
subjectnortheinvestigatorsknewwhichtreatmentgroupagivensubjectwasin.Thetablebelowsummarizesthe
numberof'events'thathadoccurredineachtreatmentgroupafterabout5yearsoffollowup.Theprimaryoutcome
ofinterestwasmyocardialinfarction,butpossibleadverseeffectsofchronicaspirinuse,suchasstroke,ulcer
disease,andbleedingproblemswerealsorecorded.

Aspirin Placebo
Endpoints
Group Group
(N=11,037) (N=11,034)
Myocardial
Infarction
FatalMI 10 26
NonfatalMI 129 213
TotalMI 139 239
Ischemic 91 82
Stroke
Hemorrhagic 23 12
Stroke
Upper
Gastrointestinal 169 138
Ulcer

38 22
UpperGIulcer
38 22
UpperGIulcer
withbleeding
Bleeding 2,979 2,249
Problems
Bleeding
requiringblood 48 28
transfusion

Thedataclearlyshowasubstantialdecreaseintheoccurrenceofbothfatalandnonfatalmyocardialinfarctions
amongthoserandomizedtoaspirincomparedtoplacebo.However,therealsowereanincreasednumberof
hemorrhagicstrokes,ulcers,andbleedingproblems.Theseresultswerecontroversialatthetime.Mostofthe
investigatorswantedtocontinuethestudytoclarifywhethertherewasanincreasedriskofstroke.However,thedata
safetyandmonitoringboardforthestudystronglyrecommendedthatthestudybeterminated,becausethebenefit
ofaspirinhadbeenclearlydemonstrated,andtheyfeltitwasunethicaltowithholditsusefromhalfofthe
participants.

Asanexercise,youcancalculatetheriskratioscomparingtheaspirinandplacebogroupsonthedifferent
outcomes.Howmuchdotheriskratioshelpyouweighthebenefitsandrisksofaspirintherapy.

Yourrecommendations?
Basedontheresultsofyouranalysis,whatrecommendationswouldyoumakeregardingthebenefitsand
risksofthisregimenwithlowdoseaspirin?Writedownyourrecommendations,basedonyouranalysisof
thisdata,regardingtheuseoflowdoseaspirin.

Analternativeapproach?
Beforeyoulookatthefeedback,considerwhetherthereisanalternatewayoflookingatthedatainthe
table.Wouldanalternateapproachofferanyadvantagesinweightingtherisksandbenefits?

Feedback

For"A"StudentsAnotherUsefulToolforWeighingRisk/Benefit

TheCostofPrevention

Whenthinkingaboutthepotentialbenefitofcompetingtreatmentoptions,onehastoconsiderboththeeffectiveness
oftherapyanditscost.Aninterestingwaytothinkaboutthisistocalculatethenumberofpeopleyouwouldneedto
treatinordertopreventoneadverseoutcome.Ifyoualsoknowthecostoftreatment,itiseasytocalculatethecost
ofpreventingoneadverseoutcomewithagiventreatmentorpreventivestrategy.Ifyouweretocalculatethisfor
competingpreventivestrategies,youwouldhaveaconvenientwayofcomparingtheircosteffectiveness.

Youalreadyhavethetoolstodothis.Supposeyouwereinterestedinpreventingcardiovasculardiseaseinpeople
whowereclassifiedashavinganincreasedrisk.Statinsareaclassofdrugsthathavebeendemonstratedtobe
effectiveinloweringbloodlevelsofcholesterolandsignificantlyreducingtheincidenceofmajorcardiacevents(heart
attack,stroke,severeangina)inpatientswithelevatedcholesterollevels.However,certaingroupsofpeoplewhodo
nothaveelevatedcholesterollevelsarestillatincreasedriskofhavingamajorcardiacevent,includingpeoplewho
haveelevationsinaninflammatorymarkercalledCreactiveprotein.InNov.2008theNewEnglandJournalof
Medicinepublishedtheresultsofastudyinwhichtheinvestigatorsenrolled17,802subjectswhohadnohistoryof
heartdisease.AllsubjectshadelevatedlevelsofCreactiveprotein,buttheyallhadnormalcholesterollevels.
SubjectswererandomlyassignedtoreceiveeitherthestatinRosuvastatin(Crestor)20mg.perdayoraplacebo
thatlookedidenticaltotheactiveagent.Thedrugswerecoded,andneithertheinvestigatorsnorthesubjectsknow
whowasreceivingtheactivedrug.Subjectswerefollowedforanaveragedurationofabouttwoyears.

SeveralpointsfromtheMethodssectionofthepaper:

"Followupvisitswerescheduledtooccurat13weeksandthen6,12,18,24,30,36,42,48,54,and60
monthsafterrandomization.Followupassessmentsincludedlaboratoryevaluations,pillcounts,and
structuredinterviewsassessingoutcomesandpotentialadverseevents."
"Theprimaryoutcomewastheoccurrenceofafirstmajorcardiovascularevent,definedasnonfatal
myocardialinfarction,nonfatalstroke,hospitalizationforunstableangina,anarterialrevascularization
procedure,orconfirmeddeathfromcardiovascularcauses."
"AllreportedprimaryendpointsthatoccurredthroughMarch30,2008,wereadjudicatedonthebasisof
standardizedcriteriabyanindependentendpointcommitteeunawareoftherandomizedtreatment
assignments.Onlydeathsclassifiedasclearlyduetocardiovascularorcerebrovascularcausesbytheend
pointcommitteewereincludedintheanalysisoftheprimaryendpoint."

Otherimportantinformation:CanadianDrugs.comishasbeenselling20mg.Crestorforabout$2.00
(US)perpill(i.e.,$2.00perdaytotreat).ThiswasthelowestcostsourcethatIwasabletoidentify.

Thefollowingtablesummarizesthemainfindingsofthestudy.

Group Subjects Major Person


Cardiac years
Events
atrisk
Crestor 8,901 142 18,442
(astatin)
Placebo 8,901 251 18,529

Onecouldeasilycomputetherateratio:

RateRatio=(142/18,442)/(251/18,529)=0.57
The95%confidenceintervalfortherateratiois0460.70,andthepvalue<0.00001.

However,toevaluatecostversusbenefit,itwouldbemoreusefultoconsiderhowmuchitcoststopreventa
singlemajorcardiovascular'event.'Howwouldyoucomputethisfromthedatashowninthetableand
knowingthatthecostofCrestortherapyisabout$2.00perday?


Onecaneasilycomputethisfromtheratedifference:

RateDifference=(142/18,442)(251/18,529)=0.005847perpersonyear
Sincetheresultisanegativenumber,Icaninterpretthisasareductioninriskofabout58majorcardiovascular
eventsamong10,000treatedpersonsoverayear.Inotherwords,ifwetreated10,000suchsubjectswithstatinsfor
oneyear,wecouldexpecttoprevent58majorCVDevents.

"NumberNeededtoTreat"

Anotherwayofthinkingtheratedifferenceistoconsiderhowmanypeopleonewouldhavetotreatforayearin
ordertopreventasingleCVDevent.Thisisoftenreferredtoasthe"numberneededtotreat"orNNT.

If10,000treatedsubjectsprevented58.47events,thenthenumberthatwouldneedtobetreatedtopreventone
eventis

NNT=10,000treatedforayear/58.47=171treatedforoneyeartopreventone
event
NotethattheNNTissimplythereciprocaloftheratedifferenceforayear,andnotealsothatNNTisconveniently
calculatedforyouinEpiTools.XLSintheworksheetforcohort.typestudies.

Ratedifference=58.47/10,000overayear
NNT=10,000overayear/58.47=171
Finally,ifoneneedstotreat171peopleforayeartopreventonemajorCVDevent,thenthecostofpreventingone
sucheventis:

171x$2.00/dayx365days=$124,830peryeartopreventonemajorevent
Andthecostoftreating10,000suchpersonswouldbe$7,300,000peryear.

Withthesecalculationsinmind,considerthemanagementofa50yearoldwhohasnormalcholesterol
levels,butelevatedCreactiveprotein.Thisindividualwould,ofcourse,havetobetreatedformanyyears.
WouldyousupportorrecommendlongtermtreatmentofsuchindividualswithCrestor?Whyorwhynot?