SQUEEZING VALUE OUT OF

LIMITED DATA

Kristian Thorlund, PhD

OUTLINE

•  HOWTEACUPSANDCROPFIELDSSHAPEDCLINICALRESEARCH

•  BAYESIANTHINKINGINRAREDISORDERSRESEARCH

•  4SLIDESWITHBULLETPOINTS(TIMETOCHECKYOUREMAIL)

•  THEGRANDFINALE

WHY WE ARE ALL P-VALUE JUNKIES -AMINUTEHISTORYOFSTATISTICSLECTURE

SirRonaldFischer(1890-1962)

UTILITY OF STATISTICS INRAREDISORDERS

Thepremiseofconven/onalsta/s/csisreplicabilityofexperiments!

InthehistoryofHTAdecision-making,howo@endidap-value>0.10s/mulateaposi/vedecisiontofund?

FROM BIG TO SMALL IN HEALTH RESEARCH

Replicable&adequately

powereddata

DatasizevsstaVsVcal/analyVcmethod

BIGDATA

Raredisorderdata

P-values95%CIsANOVA

Regression…

NeuralnetworksMachinelearningBayesianmethodsComb.Algorithms

…

BayesianthinkingBayesianmethodsNovelstudydesignsOpVmizedmonitoring

…

BEING A BAYESIAN THINKER Priorbelief+newinformaVon(data)=updatedbeliefThelesscertainweareinourpriorbeliefs,themorenewdataweightinourupdatedbelief,andviceversa

Priorbelief

Newdata

Newbelief

Txeffectcertainty

Priorbelief

Newdata

Newbelief

Txeffectcertainty

BAYESIAN THINKING FOR RARE DISORDERS

!me

1.Abrahayanetal.JPTCP2014:21(1):e66-e78.

BAYESIAN THINKING FOR RARE DISORDERS

!me

Bayesianapproachestohealthtechnologyassessmentcanbedefinedasan“explicitandqualitaVveuseofexternalevidenceinthedesign,monitoring,analysis,interpretaVonandreporVngoftheresults”1

1.Abrahayanetal.JPTCP2014:21(1):e66-e78.

LEARNING FROM UK … AND BEYOND

•  TheUKhasledthewaywithmanagedaccessagreements

•  ConVnualmonitoringanddatacollecVonisfacilitated

•  ForMPStypeVIa,paVentsaregrantedaccesstoelosulfasealfaifthey(agreementissuedNov2015)•  Akend3clinicalassessmentsperyear•  Respondtotreatmentwithinyear1thebymeeVngat

least4of5domainresponsecriteria

ONMONITORING

LEARNING FROM UK … AND BEYOND

4/5domainresponsecriteria:•  10%improvementon6MWT•  5%improvementonFVC/FEV-1•  StabilizaVonin2/3ofQoL,Depression,Pain•  20%reducVoninuKSs•  10%declineinejecVonfracVon

ONMONITORING

Sincethenonenaturalhistorystudyandfourclinicaltrialsinvariouspopula/onsandofvariousdesignshavebeenpublished

NOVEL CLINICAL TRIAL DESIGNS •  Randomizedplacebophasedesigns,randomlyassignspaVents

tovariousduraVonsofplacebobeforeswitchingtoacVvetreatment.SimulaVonshaveshowclosetosimilarpowertoconvenVonalRCTs.PastevidencecaninformresponseVme.

•  Simpleadap!vetrials(e.g.,playthewinner)canprovidequickanswers,parVcularlywithBayesianpriors.

•  Cross-overdesignsdramaVcallyreducessamplesizeandavoidsimbalanceinprognosVcfactors

MORE EXTERNAL EVIDENCE •  EXAMPLE(NCT02437253):PhaseII/III2x16wkcross-overtrial

ofAdalimumabvsplaceboforMSPtypeI,IIandIV.Opportunitytolearnabout(dis)similariVesacrosstypes.

•  Lymphangioleiomyomatosis(LAM)(condiVonofthelungs)andRenalAngiomyolipoma(AML)associatedwithTSCarebothcharacterisedbyadiffuseinfiltraVonbybioplasVcsmoothmuscle-likecellsthatinvadetheorgan’scells.SirolimusisusedforLAM,everolimusforAML.

TSC:TUBEROUSSCLEROSISCOMPLEX

SUMMARY •  ConvenVonalstaVsVcsbreakdownintheraredisease

scenario,sowhyarewesVllinsisVngonp-valuesandrandomizaVon?

•  DynamicandBayesianthinkingoffergreatawayofgerng(much)moreoutofthedata,butonlywithproperplanning

•  Well-designedinnovaVvetrialscoupledwithhistoricdataandexternalevidencearemoreefficientatextracVngvaluefromthedata

THANK YOU!