Endpointsinclinicaltrials

JaideepAGogtayMD CiplaLtd Mumbai

Outlineofdiscussion
Introduction Choosingendpoints Objectiveandsubjectiveendpoints Primaryandsecondaryendpoints HardVssurrogateendpoints Developinganendpoint Compositeendpoint

Anendpoint
Terminationofalinesegment

Results,conditionoreventsassociatedwith individualstudypatientsthatareusedtoassess studytreatments

Theendpointmustbeclinicallyrelevant Physicianand/orpatient
Howthepatientfeels,functionsorsurvives

Payer(thirdparty/govt)
ReductioninICUstay

Influencethedecisionbybothtochoosea particulartreatment

Howdowechooseendpoints? Dependingonthekindofstudy
Drugtrials
Phase1:safetystudy Phase2/3:efficacystudiesfortheindication

Pharmacoecomics

Resourcesavailableforthestudy
Money Facilities Time

Therecanbemanyendpointsinclinicaltrials
Hypertension Bloodpressure Stroke Osteoporosis Bonemineraldensity Nooffractures Qualityofthebone Newsurgicaltechniqueforhernia Timetakenforthesurgery Rateofpostoperativecomplications Recurrenceofthehernia

Somekeyfeaturesofendpoints
Easytodiagnose
Easytoidentify;nojudgmentrequired(deadoralive; recurrenceofhernia)

Minimalerrorinmeasurement
Reliablewhenmeasuredrepeatedly(bloodpressure; FEV1,notinspiratorycapacity)

Internalvalidity
Directlylinkedtothepropertyofinterest(stroke)

Externalvalidity
Applicabletothepopulation(bloodpressure)

Objectiveandsubjectiveendpoints
Objective
BP,HR,cholesterol reproducible,andreliable Notexpensive Easilyavailable

Subjective
Painscores Qualityoflife(HRQoL)

Primaryandsecondaryendpoints
Primaryendpoint
Usedforrejectionofthenullhypothesis Dictatesthesamplesizeforthestudy thekeyendpointinthestudyneededfordrug approvale.g inaCOPDstudyitisusuallyFEV1 (oftentoldbytheregulators)

Secondaryendpoints
Otherendpointsofinterestandrelevancee.g. symptomsandqualityoflife

Hard(Direct)Vs Surrogateendpoints
Study
Hypertension Osteoporosis

Hardendpoints
Stroke,Myocardial infarction. Occurrenceof fracture

Surrogateend points
Bloodpressure Bonemineral density Nerveconduction velocity HADRS, CGI CD4count/viral load

Diabeticneuropathy Footulcers Depression AIDS Suicidalideation, suicides Deathor Opportunistic infection

Whendoweusesurrogateendpoints?
Fasterandeasiertostudy Cheaper Loweventrates Mustlieinthepathwaybetweenthedrugand thedisease

Keypointaboutsurrogate
TIME

DRUG Disease
Surrogateendpoint Trueclinical outcome

Keypointaboutsurrogate
TIME

DRUG Disease
Surrogateendpoint Trueclinical outcome

ThecaseofOsteoporosis

Fracture

Bone mineral density

Biochemical markers

Only10% 44% of fractures occurred in patients with T score< 2.5. Proportion of fractures attributable to DEXA defined osteoporosis is modest
Calcif Tissue Int 2006; 78: 257270

Thecaseofchronicliverdisease
Ascites ALT,AST Liver biopsy Fibroscan

HardVssurrogate

Cash

Cheque Whatifitbounces?

Glycosylated Hb

IncreasedCVmortality

CombinationTherapyinBPH Developinganewendpoint:TheMTOPSstudy

Alpha blockade

5reductase inhibition

Dynamic component andirritative symptoms

Staticcomponent andobstructive symptoms

RationaleforCombinationTherapy

5ARIs
Arrestdisease progression

Alpha1adrenergic blockers
Rapidlyrelieve symptoms

Combinationtherapy:arrestdiseaseprogression andrapidlyrelievesymptoms?

MedicalTreatmentOfProstateSymptoms PrimaryResearchQuestion
Todetermineifmedicaltherapypreventsor delaystheclinicalprogressionofBPHasdefined byoneofthefollowing:
Acuteurinaryretention(AUR) RenalinsufficiencyduetoBPH(>50%riseinbaseline serumcreatinine&>1.5mg/dl) RecurrentUTIorurosepsis Incontinence(sociallyunacceptable) 4 PointRiseinBaselineAUASymptomScore confirmedwithin2 4weeks

StudyDesign:Overview
Doubleblind,placebocontrolled,multicenter,randomized Averagefollowup:4.5years
Randomized
N=3047

EntryCriteria

Men50yearsofage AUAsymptomscore830 Qmax 415ml/sec Voidedvolume125ml

Doxazosin (n=756)

Finasteride (n=768)

Finasteride+ doxazosin (n=786)

Placebo (n=737)

AUA=AmericanUrologicalAssociation;Qmax=maximumurinaryflow AdaptedfromBautistaOMetalControlClinTrials 2003;24:224243.

CumulativeIncidenceofBPHProgression
25 p<0.0001;df =3 20

PercentwithEvent

15

10

0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5

YearsfromRandomization
Placebo Doxazosin Finasteride Combination

Compositeendpoint
Usedmoreoftennowadays Loweventrates Cardiovasculartrials
Death Myocardialinfarction HospitaladmissionduetoCVdisease

Assumethattheeffectsoneacheventis similar

Hopestudy(N=9297)
Endpoint CVdeath MI Stroke Ramipril (%) 8.1 12.3 4.9 Placebo(%) 6.1 9.9 3.4 Riskreduction 26%,2% 20%,2.4% 34%, 1.5%

NEnglJMed2000;342:145153

Casestudyof76yearoldman
Anginadespitebetablockers,CCB,nitrates,aspirin andstatin Invasivemanagement;reluctant Howdoesonediscusswiththepatient? TIMEstudy(>75years);OptimalmedicaltherapyVs invasivetherapy Compositeendpointofdeath,nonfatalMI,ACS admissions
25%Vs64%

Letsseeindetail
Endpoint Composite Death Nonfatal MI Admission forACS Invasive 25% 17 12.3 4.9 Medical 64% 6.1 9.9 3.4 Riskreduction 0.31(0.723.16) 1.51(0.723.16) 0.75(0.361.55) 0.19(0.120.3)

Questions 1. Aretheendpointsofsimilarimportancetothepatient? 2. Didthemoreorlessendpointsoccurwithsimilarfrequency? 3. Arethecomponentendpointslikelytohavesimilarriskreductions?

Coprimaryendpoints
Atleast2 Bothmustshowsignificance E.g.Multiplesclerosis
Relapserateat1year Disabilityat2years

Conclusions Endpoints
Criticalandchallengingstudydesigndecision Consider
Phaseofdevelopment Diseaseunderstudy Characteristicsofmeasure Questiontobeansweredbytrial

PatientPopulation

PHASE4STUDIES

PatientPopulation
SuitablePatients whohavebeentakingthenewdrugortreatmentundersupervision PhaseIVclinicaltrialsmoreintensiveandspecified,theyoftentest thedrugseffectonspecificdemographics pregnantwomenor peoplewhoarecurrentlytakingothermedicationtoseeifthereis areactionbetweenthetwodrugs geriatricpopulation newmarketsforcompetitiveanalysisonthedrugortreatment costeffectivenessofadrugtherapyrelativetoothertraditionaland newtherapies

PatientPopulation
Children patientswithspecificdiseasecharacteristics, suchasliver(hepatic)impairmentorkidney (renal)impairment, patientswithspecificreactionstotreatment, suchaschangeinQTinterval(heartrate measurement).