7/30/2019 End Points in Clinicla Trials Final

1/31

Endpointsinclinicaltrials

JaideepAGogtayMD

Cipla

LtdMumbai

7/30/2019 End Points in Clinicla Trials Final

2/31

Outlineof

discussion

Introduction

Choosingendpoints

Objectiveandsubjectiveendpoints

Primaryandsecondaryendpoints HardVssurrogateendpoints

Developing

an

end

point Compositeendpoint

7/30/2019 End Points in Clinicla Trials Final

3/31

Anendpoint

Terminationofalinesegment

Results,conditionoreventsassociatedwith

individualstudypatientsthatareusedtoassess

studytreatments

7/30/2019 End Points in Clinicla Trials Final

4/31

The

end

point

must

be

clinically

relevant

Physicianand/orpatient

Howthepatientfeels,functionsorsurvives

Payer(thirdparty/govt)

ReductioninICUstay Influencethedecisionbybothtochoosea

particulartreatment

7/30/2019 End Points in Clinicla Trials Final

5/31

Howdowechooseendpoints?

Dependingonthekindofstudy

Drug

trials Phase1:safetystudy

Phase2/3:efficacystudiesfortheindication

Pharmacoecomics

Resourcesavailableforthestudy

Money Facilities

Time

7/30/2019 End Points in Clinicla Trials Final

6/31

There

can

be

many

end

points

in

clinical

trials Hypertension

Bloodpressure

Stroke

Osteoporosis

Bonemineraldensity

Nooffractures

Qualityofthebone

Newsurgicaltechniqueforhernia

Timetakenforthesurgery

Rateofpostoperativecomplications

Recurrenceofthehernia

7/30/2019 End Points in Clinicla Trials Final

7/31

Somekey

features

of

end

points

Easytodiagnose

Easytoidentify;nojudgmentrequired(deador

alive;

recurrenceofhernia)

Minimalerrorinmeasurement

Reliablewhenmeasuredrepeatedly (blood

pressure;

FEV1,notinspiratorycapacity)

Internalvalidity

Directlylinkedtothepropertyofinterest(stroke) Externalvalidity

Applicabletothepopulation(bloodpressure)

7/30/2019 End Points in Clinicla Trials Final

8/31

Objective

and

subjective

end

points

Objective

BP,HR,cholesterol

reproducible,andreliable

Notexpensive

Easilyavailable

Subjective

Painscores

Qualityoflife(HRQoL)

7/30/2019 End Points in Clinicla Trials Final

9/31

Primaryand

secondary

end

points

Primaryendpoint

Usedforrejectionofthenullhypothesis

Dictatesthesamplesizeforthestudy

thekeyendpointinthestudyneededfordrug

approvale.g inaCOPDstudyitisusuallyFEV1

(oftentoldbytheregulators)

Secondaryendpoints

Otherendpointsofinterestandrelevancee.g.

symptomsand qualityoflife

7/30/2019 End Points in Clinicla Trials Final

10/31

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

7/30/2019 End Points in Clinicla Trials Final

11/31

When

do

we

use

surrogate

end

points?

Fasterandeasiertostudy

Cheaper

Loweventrates

Mustlieinthepathwaybetweenthedrugandthedisease

7/30/2019 End Points in Clinicla Trials Final

12/31

Keypointaboutsurrogate

Disease Surrogateendpoint Trueclinical

outcome

TIME

DRUG

7/30/2019 End Points in Clinicla Trials Final

13/31

Keypointaboutsurrogate

Disease Surrogateendpoint Trueclinical

outcome

TIME

DRUG

7/30/2019 End Points in Clinicla Trials Final

14/31

ThecaseofOsteoporosis

Fracture Bonemineral

density

Biochemicalmarkers

Only10% 44%offracturesoccurredinpatientswithTscore

7/30/2019 End Points in Clinicla Trials Final

15/31

The

case

of

chronic

liver

disease

Ascites

ALT,AST

Liverbiopsy

Fibroscan

7/30/2019 End Points in Clinicla Trials Final

16/31

Hard Vs surrogate

Cash Cheque

Whatifitbounces?

Glycosylated Hb IncreasedCVmortality

7/30/2019 End Points in Clinicla Trials Final

17/31

CombinationTherapyinBPH

Developing

anew

end

point:

The

MTOPS

study

Alpha

blockade

5reductaseinhibition

Dynamic

component

andirritative

symptoms

Static

component

andobstructive

symptoms

7/30/2019 End Points in Clinicla Trials Final

18/31

RationaleforCombinationTherapy

Alpha1adrenergic

blockers

Rapidlyrelieve

symptoms

Combinationtherapy:arrestdiseaseprogression

and

rapidly

relieve

symptoms?

5ARIs

Arrestdisease

progression

7/30/2019 End Points in Clinicla Trials Final

19/31

MedicalTreatmentOfProstateSymptoms

PrimaryResearch

Question

Todetermineifmedicaltherapypreventsor

delaystheclinicalprogressionofBPHasdefinedbyoneofthefollowing:

Acuteurinaryretention(AUR)

RenalinsufficiencyduetoBPH(>50%

rise

in

baseline

serumcreatinine&>1.5mg/dl)

RecurrentUTIorurosepsis

Incontinence

(socially

unacceptable) 4 PointRiseinBaselineAUASymptomScore

confirmedwithin2 4weeks

7/30/2019 End Points in Clinicla Trials Final

20/31

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)

7/30/2019 End Points in Clinicla Trials Final

21/31

PercentwithEvent

YearsfromRandomization

CumulativeIncidenceofBPHProgression

p

7/30/2019 End Points in Clinicla Trials Final

22/31

Composite

end

point

Usedmoreoftennowadays

Loweventrates

Cardiovasculartrials

Death Myocardialinfarction

HospitaladmissionduetoCVdisease

Assumethattheeffectsoneacheventis

similar

7/30/2019 End Points in Clinicla Trials Final

23/31

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

7/30/2019 End Points in Clinicla Trials Final

24/31

Casestudyof76yearoldman

Anginadespitebetablockers,CCB,nitrates,aspirin

andstatin

Invasivemanagement;reluctant

Howdoesonediscusswiththepatient?

TIMEstudy(>75years);OptimalmedicaltherapyVs

invasivetherapy

Compositeendpointofdeath,nonfatalMI,ACS

admissions

25%Vs64%

7/30/2019 End Points in Clinicla Trials Final

25/31

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?

7/30/2019 End Points in Clinicla Trials Final

26/31

Co

primary

end

points

Atleast2

Bothmustshowsignificance

E.g.Multiplesclerosis

Relapserateat1year Disabilityat2years

7/30/2019 End Points in Clinicla Trials Final

27/31

Conclusions

Endpoints

Criticalandchallengingstudydesigndecision

Consider

Phaseofdevelopment

Diseaseunderstudy

Characteristicsofmeasure

Questiontobeansweredbytrial

7/30/2019 End Points in Clinicla Trials Final

28/31

PHASE4STUDIES

PatientPopulation

7/30/2019 End Points in Clinicla Trials Final

29/31

7/30/2019 End Points in Clinicla Trials Final

30/31

Patient

PopulationSuitablePatients

whohavebeentakingthenewdrugortreatmentundersupervision

PhaseIVclinicaltrialsmoreintensiveandspecified,theyoftentestthedrugseffectonspecificdemographics

pregnantwomenor

peoplewhoarecurrentlytakingothermedicationtoseeifthereis

a

reaction

between

the

two

drugs geriatricpopulation

newmarketsforcompetitiveanalysisonthedrugortreatment

costeffectivenessofadrugtherapyrelativetoothertraditionalandnewtherapies

7/30/2019 End Points in Clinicla Trials Final

31/31

Patient

Population Children

patientswithspecificdiseasecharacteristics,

suchasliver(hepatic)impairmentorkidney

(renal)impairment,

patientswithspecificreactionstotreatment,

suchaschangeinQTinterval(heartrate

measurement).