Are Accelerated Approval Mechanisms a Predictor to Early Access and Coverage? A Global Study of Cancer DrugsTzouma V1, Efthymiadou O1, Mills M1 and Kanavos PG1

Background Methods

Results

• Accelerated regulatory pathways created by the FDA in the US, theEMA in the EU and other regulators have the capacity to dramaticallychange the patient treatment paradigm. Drugs that are of majorinterest for public health or that are therapeutic innovations may besubject to these accelerated approval procedures; cancer treatmentsare key among them.

• Aim: To explore the interrelationship between accelerated approvalschemes for cancer drugs and national HTA processes across fourjurisdictions globally (England, Scotland, Australia and Canada), byinvestigating the impact HTA and value assessment has on drugsapproved through accelerated pathways.

AcknowledgmentsTheauthorswouldliketothankallexpertswhoparticipatedinthisstudy.WewouldalsoliketothankColinP.Flannellyforexcellentresearchassistance.ThisstudywassponsoredviaanunrestrictededucationalgrantfromAstraZeneca.

Conclusions

• 16 drug-indication pairs with cancer indications (melanoma, lungand haematology) were selected based on whether they receivedaccelerated approval in the US or Europe via one of the FDAAccelerated Approval pathways or the EMA Conditional MarketingAuthorisation (CMA), or both, until December 2015.

• In-depth analysis of HTA impact on coverage and funding pathwaysin the four selected countries relied on an analyticalmethodological framework investigating: (a) Similarities anddifferences in clinical and economic evidence submitted; (b)Evidence interpretation; (c) Uncertainties; (d) Otherconsiderations, drug or therapeutic-area related; and (e) Timedifference between MA and HTA recommendation.

Authoraffiliations:1 LondonSchoolofEconomicsandPoliticalScience,UK

Uncertaintiesmostcommonlydiscussedacrosscountries

TimedifferencebetweenregulatoryapprovalandHTArecommendation

Clinicalandeconomicevidencesubmitted

MarketingAuthorisationdatesanddecisionsandHTAdatesandrecommendationsfor16oncologydrug-indicationpairsacross4countries

• Despitetheearlyregulatoryapprovalschemes,HTAagenciesdorequirerobustclinicalandeconomicevidencethatwouldallowapositivecoveragerecommendation.

• However,socialvaluejudgementscanactasdecisionmodifiersenablingHTAagenciestoarriveatpositive– mostlyrestricted- recommendations.

Datesofregulatorydecisionsofthe16drug-indicationpairsandHTArecommendationdatesfortheHTAagenciesinEngland(NICE),Scotland(SMC),Australia(PBAC)andCanada(pCODR):Regardlessofearlyaccessschemegranted,timingofHTArecommendationvarieswidely.

Appraisal

Interpretationofevidence

Mainreasonsforrecommendation

Uncertainties

Clinical

Economic

Other

Otherconsiderations

Elicited

Non-elicited

Assessment Evidence

ClinicalQualitycriteria

Metrics(OS,PFS)

Economic

Modeltype

Budgetimpact

ICER

HTA

Legend: Green box: List; Yellow box: List with criteria; Red box: Do not list; Orange box: Not submitted; Grey box: Deferred/Under review; FTD: Fast Track Designation; BTD: Breakthrough Therapy Designation; AA: Accelerated Approval (FDA) or Accelerated Assessment (EMA); PR: Priority Review; MA: Marketing Authorisation; CMA: Conditional Marketing Authorisation; * = CMA to MA after conditions have been met; ** = Pre-NOC Submission (Parallel Processing); *** = Early Access to Medicines Scheme

558

427

418

213

0 100 200 300 400 500 600 700

NICE/EMA

SMC/EMA

PBAC/TGA

pCODR/Health Canada

Number of Days

HTA

Bod

y an

d R

espe

ctiv

e R

egul

ator

y B

ody

Average Number of Days Between Regulatory Body Drug Approval and HTA Agency Recommendation

735

615

724

530

0 100 200 300 400 500 600 700 800 900

NICE

SMC

PBAC

pCODR

Number of Days

HTA

Age

ncy

Average Number of Days Between FDA Market Authorization and HTA Agency Recommendation

AveragelengthoftimeforHTAagenciesinEngland,Scotland,AustraliaandCanadatopublishanHTArecommendationfollowingeitherMAinEurope,AustraliaorCanada(left-handfigure),orFDAapproval(right-handfigure):FDAapprovalhappenedearlierthanMAinothercountries,withtheexceptionofpembrolizumab inlungcancerandmelanoma.Thepotentialtimeframefromwhenthedrugisinthe

market(FDAapproval),andthuspotentiallycouldbeaccessedbypatients,islongerthantheamountoftimebetweenregulatoryapprovalandHTArecommendationdatesinothercountries.Additionally,thespeedatwhichpCODR reachesarecommendationbecomeslesssignificantlydifferenttothetimethe

otherHTAbodiesreachadecisionwhenheldtothebaselineofFDAapproval.

ClinicalUncertainties• Lackofadequateclinicaltrialstoshowthecomparativeeffectivenesstowhatiscurrentlythestandardofcare(SoC)

• Inabilityofclinicaltrialstoestablishaclearnetclinicalbenefit

• Uncertaintyaboutwhetheradverseeventsaremoreorlesstolerablethancurrentbestpractice

EconomicUncertainties• Uncertaintyaroundthe

setupoftheeconomicanalysismodelandtheICERrange

• Uncertaintyaroundthecomparatorsselected

TypeofevidencesubmittedtotheHTAbodyforapproval,typeofeconomicmodelused,andpricingarrangementsnegotiated:AlthoughmostHTAbodiesreceivedsubmissionswithsimilarclinicalandeconomicevidence,

recommendationoutcomesvarygreatly.

Topfivesocial-valuejudgementsconsideredbyHTAagenciesEngland- NICE1. Unmetclinicalneed2. Specialcriteria(end-of-life,orphan)3. Extensionoflife4. Innovativecompound5. Highercomparativesafety

Scotland- SMC1. Unmetclinicalneed2. Specialcriteria(end-of-life,orphan)3. Impactonpatient’swork/activities4. Impactonthesociety/healthbudget5. Innovativecompound

Australia- PBAC1. Unmetclinicalneed2. Impactonthesociety/healthbudget3. Extensionoflife4. Qualityoflife5. Highercomparativesafety

Canada- pCODR1. Unmetclinicalneed2. Emotionalburdenoncarers3. Impactonthesociety/healthbudget4. Qualityoflife5. Highercomparativesafety

Socialvaluejudgementscanbeseenasthereasoningbehindrecommendationvariations.PBACdiscussedsocialvaluesthemostinfrequently,andrejectedthehighestamountofdrugsamongthestudyagencies.PBACrejectionswerealldue

toissuesofcost-effectiveness,ofteninthefaceofuncertainclinicalbenefit.

NICE SMC PBAC pCODRNICE x 0.7333 -0.2195 -0.0526SMC x x -0.2195 -0.0526PBAC x x x -0.1940pCODR x x x x

Conclusions

Cohen’skappascoresmeasuringinter-rater

agreement

Cohen’skappascoresseenwerecalculatedtoprovideastatisticalmeasureofagreementbetweentheHTAagenciesininterpretingthesameevidence.SubstantialagreementwasfoundbetweenNICEandSMC.NoneoftheotherCohenkappascoreshadanyagreementbetweenHTAagenciesandtheirrespectiverecommendationsacrossdrug-indicationpairs.Althoughkappavaluesarenotasrobustaswouldbepreferred,theirvalueshighlightthelowlevelofagreementbetweenthevariousHTAbodyrecommendations.