end points in clinicla trials final
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Endpointsinclinicaltrials
JaideepAGogtayMD
Cipla
LtdMumbai
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Outlineof
discussion
Introduction
Choosingendpoints
Objectiveandsubjectiveendpoints
Primaryandsecondaryendpoints HardVssurrogateendpoints
Developing
an
end
point Compositeendpoint
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Anendpoint
Terminationofalinesegment
Results,conditionoreventsassociatedwith
individualstudypatientsthatareusedtoassess
studytreatments
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The
end
point
must
be
clinically
relevant
Physicianand/orpatient
Howthepatientfeels,functionsorsurvives
Payer(thirdparty/govt)
ReductioninICUstay Influencethedecisionbybothtochoosea
particulartreatment
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Howdowechooseendpoints?
Dependingonthekindofstudy
Drug
trials Phase1:safetystudy
Phase2/3:efficacystudiesfortheindication
Pharmacoecomics
Resourcesavailableforthestudy
Money Facilities
Time
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There
can
be
many
end
points
in
clinical
trials Hypertension
Bloodpressure
Stroke
Osteoporosis
Bonemineraldensity
Nooffractures
Qualityofthebone
Newsurgicaltechniqueforhernia
Timetakenforthesurgery
Rateofpostoperativecomplications
Recurrenceofthehernia
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Somekey
features
of
end
points
Easytodiagnose
Easytoidentify;nojudgmentrequired(deador
alive;
recurrenceofhernia)
Minimalerrorinmeasurement
Reliablewhenmeasuredrepeatedly (blood
pressure;
FEV1,notinspiratorycapacity)
Internalvalidity
Directlylinkedtothepropertyofinterest(stroke) Externalvalidity
Applicabletothepopulation(bloodpressure)
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Objective
and
subjective
end
points
Objective
BP,HR,cholesterol
reproducible,andreliable
Notexpensive
Easilyavailable
Subjective
Painscores
Qualityoflife(HRQoL)
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Primaryand
secondary
end
points
Primaryendpoint
Usedforrejectionofthenullhypothesis
Dictatesthesamplesizeforthestudy
thekeyendpointinthestudyneededfordrug
approvale.g inaCOPDstudyitisusuallyFEV1
(oftentoldbytheregulators)
Secondaryendpoints
Otherendpointsofinterestandrelevancee.g.
symptomsand qualityoflife
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Hard(Direct)Vs Surrogateendpoints
Study Hardendpoints Surrogateend
points
Hypertension Stroke,Myocardial
infarction.
Bloodpressure
Osteoporosis Occurrenceof
fracture
Bonemineral
density
Diabeticneuropathy Footulcers Nerveconduction
velocity
Depression Suicidalideation,
suicides
HADRS, CGI
AIDS Deathor
Opportunistic
infection
CD4count/viral load
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When
do
we
use
surrogate
end
points?
Fasterandeasiertostudy
Cheaper
Loweventrates
Mustlieinthepathwaybetweenthedrugandthedisease
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Keypointaboutsurrogate
Disease Surrogateendpoint Trueclinical
outcome
TIME
DRUG
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Keypointaboutsurrogate
Disease Surrogateendpoint Trueclinical
outcome
TIME
DRUG
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ThecaseofOsteoporosis
Fracture Bonemineral
density
Biochemicalmarkers
Only10% 44%offracturesoccurredinpatientswithTscore
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The
case
of
chronic
liver
disease
Ascites
ALT,AST
Liverbiopsy
Fibroscan
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Hard Vs surrogate
Cash Cheque
Whatifitbounces?
Glycosylated Hb IncreasedCVmortality
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CombinationTherapyinBPH
Developing
anew
end
point:
The
MTOPS
study
Alpha
blockade
5reductaseinhibition
Dynamic
component
andirritative
symptoms
Static
component
andobstructive
symptoms
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RationaleforCombinationTherapy
Alpha1adrenergic
blockers
Rapidlyrelieve
symptoms
Combinationtherapy:arrestdiseaseprogression
and
rapidly
relieve
symptoms?
5ARIs
Arrestdisease
progression
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MedicalTreatmentOfProstateSymptoms
PrimaryResearch
Question
Todetermineifmedicaltherapypreventsor
delaystheclinicalprogressionofBPHasdefinedbyoneofthefollowing:
Acuteurinaryretention(AUR)
RenalinsufficiencyduetoBPH(>50%
rise
in
baseline
serumcreatinine&>1.5mg/dl)
RecurrentUTIorurosepsis
Incontinence
(socially
unacceptable) 4 PointRiseinBaselineAUASymptomScore
confirmedwithin2 4weeks
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StudyDesign:
Overview
Doubleblind,placebocontrolled,multicenter,randomized
Averagefollowup:4.5years
AUA=AmericanUrologicalAssociation;Qmax=maximumurinaryflow
AdaptedfromBautistaOMetalControlClinTrials 2003;24:224243.
Randomized
N=3047
EntryCriteria Men50yearsofage AUAsymptomscore830 Qmax 415ml/sec Voidedvolume125ml
Doxazosin
(n=756)
Finasteride
(n=768)
Finasteride+
doxazosin
(n=786)
Placebo
(n=737)
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PercentwithEvent
YearsfromRandomization
CumulativeIncidenceofBPHProgression
p
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Composite
end
point
Usedmoreoftennowadays
Loweventrates
Cardiovasculartrials
Death Myocardialinfarction
HospitaladmissionduetoCVdisease
Assumethattheeffectsoneacheventis
similar
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Hope
study
(N=9297)
Endpoint Ramipril (%) Placebo(%) Risk
reduction
CVdeath 8.1 6.1 26%,2%
MI 12.3 9.9 20%,2.4%
Stroke 4.9 3.4 34%, 1.5%
NEngl
JMed
2000;
342:145
153
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Casestudyof76yearoldman
Anginadespitebetablockers,CCB,nitrates,aspirin
andstatin
Invasivemanagement;reluctant
Howdoesonediscusswiththepatient?
TIMEstudy(>75years);OptimalmedicaltherapyVs
invasivetherapy
Compositeendpointofdeath,nonfatalMI,ACS
admissions
25%Vs64%
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Lets
see
in
detailEndpoint Invasive Medical Riskreduction
Composite 25% 64% 0.31(0.723.16)Death 17 6.1 1.51(0.723.16)
Nonfatal MI 12.3 9.9 0.75(0.361.55)
Admission forACS 4.9 3.4 0.19(0.120.3)
Questions
1. Aretheendpointsofsimilarimportancetothepatient?
2. Didthemoreorlessendpointsoccurwithsimilarfrequency?3. Arethecomponentendpointslikelytohavesimilarriskreductions?
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Co
primary
end
points
Atleast2
Bothmustshowsignificance
E.g.Multiplesclerosis
Relapserateat1year Disabilityat2years
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Conclusions
Endpoints
Criticalandchallengingstudydesigndecision
Consider
Phaseofdevelopment
Diseaseunderstudy
Characteristicsofmeasure
Questiontobeansweredbytrial
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PHASE4STUDIES
PatientPopulation
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Patient
PopulationSuitablePatients
whohavebeentakingthenewdrugortreatmentundersupervision
PhaseIVclinicaltrialsmoreintensiveandspecified,theyoftentestthedrugseffectonspecificdemographics
pregnantwomenor
peoplewhoarecurrentlytakingothermedicationtoseeifthereis
a
reaction
between
the
two
drugs geriatricpopulation
newmarketsforcompetitiveanalysisonthedrugortreatment
costeffectivenessofadrugtherapyrelativetoothertraditionalandnewtherapies
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Patient
Population Children
patientswithspecificdiseasecharacteristics,
suchasliver(hepatic)impairmentorkidney
(renal)impairment,
patientswithspecificreactionstotreatment,
suchaschangeinQTinterval(heartrate
measurement).
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