Multi-RegionalClinicalTrials(MRCTs):PracticeandIssuesofMulti-RegionalClinicalTrials’GlobalAcceptance

Withthanksto:BarbaraBiererMilaOwen

RebeccaLi,PhDExecutiveDirector

Disclaimer:

• TheopinionscontainedhereinarethoseoftheauthorsandarenotintendedtorepresentthepositionofBrighamandWomen'sHospitalorHarvardUniversity.

• TheMRCTCenterissupportedbyvoluntarycontributionsfromfoundations,corporations, internationalorganizations,academicinstitutionsandgovernmententities(seewww.MRCTCenter.org)andwellasbygrants.

• Wearecommittedtoautonomy inourresearchandtotransparency inourrelationships.TheMRCTCenter—and itsdirectors—retainresponsibilityandfinalcontrolofthecontentofanyproducts,resultsanddeliverables.

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OurMission

Engagediversestakeholderstodefineemergingissuesinglobalclinicaltrialsandtocreateandimplementethical,actionable,andpracticalsolutions.

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AgendaMRCTs:Science,andRegulations

• WhyMRCTs?• MRCTexpectations,benefitsandchallenges• Internationalandregulatoryconsiderations• Rationaleforacceptanceofforeigncountrydata• Bridgingstudyrequirements

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AgendaMRCTs:Science,andRegulations

• WhyMRCTs?• MRCTexpectations,benefitsandchallenges• Internationalandregulatoryconsiderations• Rationaleforacceptanceofforeigncountrydata• Bridgingstudyrequirements

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TwoStagesinNewDrugDevelopment1.Learningstage(phase1andphase2trials):

– Safety,Dosingselection,Patientpopulationselection– Efficacyscreeningusingsurrogateendpoint

2. Confirmingstage(phase3trials,e.g.,MRCT):– Efficacy(consistencyacrosssubgroups),– Safety,dosing,– Benefit/risk ratio

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StagesofDrugDevelopment

MRCTs:PrinciplesandLogic

• MRCTsrarelyemployed inPhase1and2trials• MRCTsinPhase3clinicaltrials:

– Expeditedrugdevelopmentandrisk/benefitanalysis– Betterbasisforsubsequentgeneralizationofthefindings– Maintainsamestandardsformultipleregulatorysubmissions– Reduceunnecessarycostanddelay

• Assumptionofconsistency:thatregionsareequivalentandnosignificantdifferencesexist– Understandingofandstatistical

assessmentofconsistency– Impactofintrinsic/extrinsicfactorson

outcome

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Coordinator

Region 1 Region 2 Region 3

Site 1 Site 2 Site 9 Site 10Site 11Site 12Site 13Site 7 Site 8Site 3 Site 4 Site 5 Site 6

MRCT:Definition

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Aclinicaltrialwithacommonprotocol,involvingdifferentcentersandparticipantsenrolledfromdifferentregions(countries),wherethedata

collectedisanticipatedtobeanalyzedasawhole.*

*adaptedfromICH-E3

Coordinator

Region 1 Region 2 Region 3

Site 1 Site 2 Site 9 Site 10 Site 11 Site 12 Site 13Site 7 Site 8Site 3 Site 4 Site 5 Site 6

WhyMRCTs?

• Morepatientpopulationsavailableforstudy• Potentiallytreatmentnaïveindividuals• Maybeonlypracticalwayofaccruingsufficient

numbersofparticipantswithinagiventimeframe• Morerapidenrollmentfromwiderpopulationand

differingclinicalsituations• Potential importantinternalcomparisonsanddatato

defendgeneralizationofthefindings• Simultaneousratherthansequentialsubmissionsfor

registration

DrugLaginClinicalDevelopmentAmongVariousRegulatorySubmissionsStrategiesinJapan

ClinicalPharmacology&TherapeuticsVolume95,Issue5,pages533-541,8NOV2013DOI:10.1038/clpt.2013.223http://onlinelibrary.wiley.com/doi/10.1038/clpt.2013.223/full#cptclpt2013223-fig-0001

MRCTsIncreaseEfficiencyandReduceDrugLag

Yourroleasregulatorisbecomingincreasinglycomplex

MAXIMIZEBENEFITBringbeneficialdrugstopatients

asquicklyaspossible

Maintainincentivesforcompanies&researchers to

innovate

DECREASERISKEnsuresafetyof

patientsbykeepingineffective/unsafedrugsoutofthe

market10/13/16 ©MRCT 11

HowdoMRCTsfitin?

FocusonMRCTsExaminingtheKeyIssues

Trueinconsistencyvs Randomvariation

Countryspecificpatient

requirements

DefiningRegion

Disparateresultsbyregion/roleofethnicity

Regulatorcapacityandtraining

Differingendpointsrequiredby

region

Dataquality

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MRCTs:notwithoutprecedentorguidance

• ICH-E5EthnicFactorsinAcceptabilityofForeignClinicalData– Bridgingstudies:

• Allowsextrapolationofdatafromoneregiontoanother

• Expeditesdrugdevelopmentprogram

• Formulti-regionalclinicaltrialtoserveasabridgingstudyforaparticularregion,shouldbe“persuasive”

• Therefore,MRCTshouldbeplannedwithsufficientnumbersofsubjectstohaveadequatepowertohaveareasonablelikelihoodofshowinganeffect ineachregionofinterest

• Iftoserveasbridgingstudy,provideefficacyandsafetybyregion,andexamineconsistencyofeffectsacrossregions(andifdose-responserelationshipthenefficacyandsafetywithinandacrossregions.

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MRCTs:PrecedentandGuidance

• ICH-E3StructureandContentofClinicalStudyReport– Individualcenterresultsshouldbepresentedwhenappropriate(sufficient

#,etc.)

– Treatment-by-center (country)analysisshouldbeexplored

– “…Anyextremeoroppositeresultsamongcentersshouldbenotedanddiscussed,consideringsuchpossibilitiesasdifferences instudyconduct,patientcharacteristics,orclinicalsettings.”

• ICH-E9StatisticalPrinciplesforClinicalTrials– Protocolimplementationshouldbeclearandsimilaratallsites

– Procedures standardized,variationreduced

– “…theusualsamplesizeandpowercalculationsdependupontheassumptionthatthedifferences between thecomparedtreatmentsinthecentersareunbiasedestimatesofthesamequantity.”

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MRCTDesign

• Implicationsfor– Studydesign– Choiceofendpoint(s)

• Particularlyproblematicifregulatoryguidancediffersastowhatisacceptablestudydesignorendpoint

If results of an MRCT are positive with acceptable benefit/risk ratio for a new drug, then further region subgroup analysis can be explored through different statistical methods depending on the level of “consistency” required.

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Howisconsistencyconsidered?

Howis“subgroup”defined?

AgendaMRCTs:Science,andRegulations

• WhyMRCTs?• MRCTexpectationsanddesign• MRCTchallenges• Internationalandregulatoryconsiderations• Rationaleforacceptanceofforeigncountrydata• Bridgingstudyrequirements

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CurrentChallengesGloballyontheStatusofMRCTs

• No clear global guidance on MRCTs

• Individual countries have published statements on topics related to MRCTs (including China)

• Use of foreign clinical data varies across countries

• Need for bridging studies or separate studies in the region’s population– Ethnic factors and considerations (ICH 5)

– Subgroup analysis

MRCT:Ethnicvariationvs.RandomVariation(continued)

• ManyofusmakeanaprioriassumptionofMRCTsthatnooronlyminorregionalvariationexists

• Nodatanowtopredictwhichtrials(ordrugs,interventions,devices)arelikelytodemonstratesubgroupdifferencesandnowaytodistinguishtrueconsistencyissuesorethnicvariationfrommererandomvariability.

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MRCTChallenges

•Whiletheresultsofmostmulti-nationaltrialsdonotdemonstrateanyinternalinconsistencyamongregionsorcountries,onoccasioninconsistencybetweenregionsorcountries isobservedandmaybedueto:

• Inaccuraciesindiagnosesordifferences innaturalhistoryorstageofdisease

• Differences inmedicalorstudypractice(s)orconcurrentmedications• Differences inlifestyle,diet,orenvironmentalinfluences• Truegenetic,racial,orethnicdifferences amongtheregions• Randomvariation• Inconsistencyatsite,regionorcountrylevel

AgendaMRCTs:Science,andRegulations

• WhyMRCTs?• MRCTexpectations,benefitsandchallenges• Internationalandregulatoryconsiderations• Rationaleforacceptanceofforeigncountrydata• Bridgingstudyrequirements

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ComparisonTableforForeignDataAcceptance

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ForeignData LocalParticipants DataAnalysisU.S. Foreigndataallowedif

relevant andapplicable.Notrequiredbutsometimespreferred

Recommendsdecreasingdatavariability

China Accepted(exceptforbiologics),butlocaldatarequired.

Preciserequirementsforeachphase.100pairs.Draft ProvisionsforDrugRegistrationissued.

Trend consistencyacrosslocalandglobalpopulation

India AllowedexceptforphaseItrialsandvaccinetrials.

Precise requirementsforeachphase.

Nospecificrequirements

E.U AcceptedifincompliancewithmemberandEUlaw.

Notrequired. Intrinsic/Extrinsicfactorsconsideredwhenextrapolatingdata.

Japan Accepted unlessissueswithlocalparticipantordatarequirements.

15-20%required. Datamustbe consistentacrosslocalandglobalpopulation– specificmethods

Aus,Can, S.Africa,Brazil,Mex,Turkey,S.Korea

No specificrequirements Notrequired Nospecificrequirements

MRCTs:AsiaPacificCountries

• Simplerregulatoryframeworks– Korea,Taiwan,HongKong,Singapore,Australia,NewZealand

• Morerigorousrequirementsandprocedures– Japan– requiresspecificparticipantnumbersandconsistencyacrossglobaltrialandlocally

– ImpactfulnewlegislationwithshortimplementationwindowØ China:IMCTapplicationinChinaØ India:PhaseIallowedonlyifIndiancompany,bridgingrequiredand

otherregulationsimposedoverlast3years

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Sample Size Requirement in New Drug Registration – China (May change with new draft legislation)

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Current China Regulatory Policies for the Registration - Interpretation

•如果不考虑在中国注册上市：样本量无要求(No requirement for sample size if not considering China registration)

•MRCT数据用于国内上市注册（首先在国外上市)(MRCT data and results for China registration, must be used for approval (and approved) in overseas)

– 如果中国部分结果与总体结果一致, 则按照进口药品注册的临床试验要求(If China subgroup results are consistent with overall results, then China registration needs:)

• 药代+至少100对受试者 (100 pairs + PK/PD)

– 如果中国部分结果与总体结果不一致，则按照适宜的桥接策略或重新进行针对中国人群的临床试验（要求具有统计显著性）(If China subgroup results are NOT consistent with overall results, then China registration needs a independent phase III trial with statistical significance)

HowtheUSFDAhasevolvedinConsideringMRCTs

• FollowingICH-E51,FDAdoesnotrequirestudiesthatareconductedsolelyoutsidetheU.S.tobeperformedunderanInvestigationalNewdrugApplication(IND)IntheU.S.,CFR21.314.106governswhichforeigndataareacceptable.

• localdataisnotneeded ifthreecriteriaaremet:– Theforeigndatamustbe“relevantandapplicable”totheUSpopulation.– Theforeignstudiesmustbeperformedbycompetentinvestigators.– TheFDAmusthaveconfidenceinandtheabilitytovalidateorverifythe

data.3

– AnapplicationbasedsolelyonforeignclinicaldatamaybeapprovedifdataareapplicabletotheUSpopulationandmedicalpractice.

– TheFDAmayrequirea“bridgingstudy”ifitisconcernedabouttheapplicabilityofastudy’sresultstoitspopulation.4

1. Khin,etal.“RegulatoryandScientificIssuesRegardingUseofForeignDatainSupportofNewDrugApplicationsintheUnitedStates:AnFDAPerspective,”Nature2. Food,DrugsandCosmeticsActof1938,mostrecentlyamended20163. 21CFR314.106.Theacceptanceofforeigndatainanewdrugapplication.4. ChinandBairu,“GlobalClinicalTrials:EffectiveImplementationandManagement“,AcademicPress2011

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UnitedStatesFDA(Cont’d)

• Canaskfora“bridgingstudy”ifconcernsabouttheapplicabilityofastudy’sresultstoitspopulation

• Inthecaseofclearevidenceofanethnicdifference,separatetrialsarehighlyrecommendedsoregionalconsiderationscanbeincorporatedintothedesign;thetrialcanbeconductedtocontrolextrinsicfactorsenterastudypopulationwithrelativelyhomogenousintrinsicfactors

1.Khin,etal.“RegulatoryandScientificIssuesRegardingUseofForeignDatainSupportofNewDrugApplicationsintheUnitedStates:AnFDAPerspective,”Nature

FDA’sreviewofMRCT’sgenerallyinvolvesevaluationofstudyresults(statisticalanalyses)accordingtoregion/country

• Evaluatethestudydataandtheconductandkeymetricsofquality

• Evaluate statisticaldisplaysofkeysourcesofvariation,biasanduncertainty

• Regionalandsiteoutcomesevaluated:– Dropouts,differencesinresponserates,outcomes,covariates,exposures,follow-up,concomitantdrugs

• Individualpatientprofileswithinsites- whichsitesandwhichpatientrecordstoevaluateinmoredetail- possibleauditingstrategies(usuallyreliesonelectronicrecords)

• Possiblyintrinsicfactors(markers,gender,ethnicity)orpossiblyextrinsicfactors)recruitmentpatterns,medicalsupportsystem,standardsofcare

• Aligninspectionwithreviewofdataandinsightsforaudits

Interpretationoftheglobalestimateandregionspecificestimatesischallenging

andthecausesforheterogeneity

• Interpretationoftheglobalestimateandregionandspecificestimatesischallenging

• Oftenthecauseofheterogeneity(variabilitybetweenregions)isunknown

• Differencesintreatmenteffectsareexpected;however,toomuchheterogeneityisproblematic

• ArethesetreatmentdifferencesrealandaretheysystematicinthesensethattreatmenteffectsareconsistentlybetterorworseintheU.S.andwhatarethereasonsforit

WhatUSFDAconsiderswhenencounteringheterogeneity

StudyundertakenbyFDAstatisticianstoevaluatepossibilityofsystematicregionaldifferences

• Majorcardiovascularoutcomestudiesevaluatedoverthelast10years

• Overallstudyresultstatisticallypositive,ie.demonstratedoveralleffect

• Regionneverpre-specifiedasafactortobeevaluatedstatistically

• 24independentstudies

In 16/24 studies, the effect was less in US

P = 0.023

P = 0.007

“Heterogeneity” could be observed by chance

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When fraction of Japanese is 6.7%, negative treatment effect is observed in Japanese with probability of ~20% by chance

Example: What should we do when difference is observed between Japanese & overall?

Basic Principles on Global Clinical Trials (Reference Cases)

• the reason for the difference should be considered by using data such as subgroup analysis

– not enough to conclude that difference is chance finding without any exploration

– one approach could be to evaluate to evaluate the difference in background characteristics between Japanese and overall population & to assess effect of the difference on efficacy results by using subgroup analysis in overall population

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AnExample:Toprol–XL;theCurrentDrugLabel;“ClinicalTrials”

MERIT-HFwasadouble-blind, placebo-controlled studyofToprol-XLconducted in14countries including theUS.Itrandomized 3991patients(1990toToprol-XL)withejectionfraction </=0.40andNYHAClassII-IVheartfailureattributabletoischemia,hypertension,orcardiomyopathy.

Theprotocolexcludedpatientswithcontraindications tobeta-blockeruse,thoseexpectedtoundergoheartsurgery,andthosewithin28daysofmyocardial infarctionorunstableangina.

Theprimaryendpoints ofthetrialwere(1)all-causemortalityplusall-causehospitalization (timetofirstevent),and(2)all-causemortality.

The trial was terminated early for a statistically significant reduction in all-cause mortality (34%, nominal p=0.00009). …The figure below illustrates principal results for a wide variety of subgroup comparisons, including US vs. non-US populations (the latter of which was not pre-specified). The combined endpoints of all-cause mortality plus all-cause hospitalization and of mortality plus heart failure hospitalization showed consistent effects in the overall study population and the subgroups, including women and the US population. However, in the US subgroup and women, overall mortality and cardiovascular mortality appeared less affected. Analyses of female and US patients were carried out because they each represented about 25% of the overall population. Nonetheless, subgroup analyses can be difficult to interpret and it is not known whether these represent true differences or chance effects.

MERIT-HFResults

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HowtoAssessConsistencyinanMRCT?

“Trend”AnalysisLinkagetoConsistency

Benefit

Risk

Overall Population

Overall Population

Benefit

Risk

Consistent

Consistent

Consistent

Safetyrisksobservedfromsubpopulation/region

EfficacybenefitobservedfromasubpopulationorInaregion

“Trend”AnalysisInterpretation&Elaboration- LinkagetoConsistency

Benefit

Risk

Overall Population

Overall Population

Benefit

Risk

Consistent?

Consistent?

Consistent?

Safetyrisksobservedfromsubpopulation

Efficacybenefitobservedfromsubpopulation

“Trend”AnalysisInterpretation&Elaboration- LinkagetoConsistency

Similarrisks

Similarefficacy

PositiveTrend

Similarrisks

Betterefficacy

PositiveTrend

Chinesesubpopulation vs.overallpopulationinapositivetrial

Lowerrisks(?)

Similarefficacy

PositiveTrend

√

√

√Lowerrisks(?)

Lowerefficacy

PositiveTrend(?) ?

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ConsistencyAssessmentinMRCT- LevelofConsistencywithStatisticalMethods

Consistency and Disease Categories

Consistency should be considered with different disease settings. Considering medical needs and potential impact of ethnic factors in clinical practice, three different disease categories may be considered:

Category 1: Unmet medical needs and/or rare disease

Category 2: Common disease without potential ethnic differences

Category 3: Common disease with potential ethnic differences

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Consistency and Disease Categories

Consistency should be considered with different disease settings. Considering medical needs and potential impact of ethnic factors in clinical practice, three different disease categories may be considered:

Category 1: Unmet medical needs and/or rare diseaseSame trend required

Category 2: Common disease without potential ethnic differencesTreatment effect proportional

Category 3: Common disease with potential ethnic differences Treatment effect in region demonstrates clinicalsignificance with statistical rigor.

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Disease Category 1

• Level1consistencyrequired:toassessregionaltreatmenteffectindiseasewithunmetmedicalneeds,e.g.,HIV/AIDS,somemalignanttumor,raredisease,etal.

Disease Category 2

• Level2consistencyrequired:toassessregionaltreatmenteffectforcommondiseasewithnoevidenceofpotentialethnicdifferenceintreatment.Inthissetting, certainregionaleffectsizeisrequired

Disease Category 3

• Level3consistencyrequired: toassessregionaltreatmenteffectforcommondiseasewithevidenceofpotentialethnicdifferenceintreatment. Inthissettingclinicalsignificancewithstatistical rigorofregional treatmenteffectisrequired.

Level of Consistency for Different Disease Categories

Equivalency Proportionality Clinical significance with statistical rigor

Level1

Level2

Level3

Statistical Rigor

Quantitative

Qualitative

LevelofConsistency:from“weak”to“strong”定量

定性

统计学严谨性

Level1Consistency;ObservationaltrendAlltreatmenteffects>0

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Level2Consistency，Treatmenteffectsareproportional;Atleast50%retention

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Level 3 Consistency，Treatment effect in region demonstrates clinical significance with statistical rigor.

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10# 10#

7#

0#1#2#3#4#5#6#7#8#9#

10#11#

Global#Effect# Regional#Effect#Example#

Regional#Effect#Example#

Treatment(Effect(

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Level3Consistency:Overalltreatmenteffectsandforregionachieveclinicalsignificancewithstatisticalrigor

• Toachievestatisticalrigorforbothoverallandregionalsubgroup,useeitherdatawithinMRCTOR datafromMRCTplusanextensiontrial, ifthesamplesizeintheMRCTisnotadequatetoassessclinicallymeaningfultreatmenteffectwith statisticalrigor.

• Toachievestatisticalrigorfortheregionalresults, informationfortheregionanalysismaycombinebothregioninformationandtheinformationborrowedfromotherregions.Theinformationborrowedwillbedown-weighted

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MRCT

NTETE

ExtensionofMRCT

TE

NTE(down-weighted when

combined for analyses)

TE

Where:TE: targeted ethnic groupNTE: non-targeted ethnic group

Conclusions

IncreasinguseofMRCTdesigninworldwidedrugdevelopment

• Toexpeditesimultaneous newdrugdevelopmentwithgreaterpatientpopulations

• Tomaintainthesamelevelofscientificrigorinthetrialdesignwhentheoutcomesarepresentedtodifferentregulatoryagenciesforevaluation

• Positiveresultsandbenefit/riskratioofMRCTprovidesolidbasis forthetotalityofevidenceforanewdrugregistrationglobally

Opportunities

• Continuerefinementofconsiderationofrequirementsfor“consistency”

• Enhancepost-approvalmonitoringandpharmacovigilance globally

• RegulatoryconvergencesurroundingcountryspecificrequirementsforMRCTs

MRCT– theOpportunityandPromise

• AdvancingthepracticeofMRCTsgloballywillsupportsimultaneousglobalsubmissions– Shiftingfocusfrompatientnumberrequirementstoaregionalperspectiveofthetotalstudypopulationsizedrivenbythestudyobjectiveandoverallhypothesis

– Emphasisonregulatorydecisionsbasedonbenefit-riskofdiseasestate,patientpopulation,unmetmedicalneedindeterminationofPhase3requirements

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QuestionsforDiscussion

• WhenconductinganMRCT withsequentialparticipantsenrolled,– Whatistheimpactontheoverallresults?– Arethecountry/regionalresultsaloneinterpretable?

• WheninterpretingtheregionalresultsinMRCT– Ifvariabilityexists,howtointerpretand/ordealwithit?Validityissueor

Qualityissueorboth?• Extrapolationoftreatmenteffects toChinapopulationwithheterogeneity(QuantitativeandQualitative) oftreatmenteffectsamongregions/Countries.

• Interpretationoftreatmenteffects:whichfactor(s)mostimportanttoevaluaterelationshipoftreatmenteffects:Site/center/clinic,Country,Region?

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Thankyou

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