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Are Accelerated Approval Mechanisms a Predictor to Early Access and Coverage? A Global Study of Cancer Drugs Tzouma V 1 , Efthymiadou O 1 , Mills M 1 and Kanavos PG 1 Background Methods Results • Accelerated regulatory pathways created by the FDA in the US, the EMA in the EU and other regulators have the capacity to dramatically change the patient treatment paradigm. Drugs that are of major interest for public health or that are therapeutic innovations may be subject to these accelerated approval procedures; cancer treatments are key among them. • Aim: To explore the interrelationship between accelerated approval schemes for cancer drugs and national HTA processes across four jurisdictions globally (England, Scotland, Australia and Canada), by investigating the impact HTA and value assessment has on drugs approved through accelerated pathways. Acknowledgments The authors would like to thank all experts who participated in this study. We would also like to thank Colin P. Flannelly for excellent research assistance. This study was sponsored via an unrestricted educational grant from AstraZeneca. Conclusions • 16 drug-indication pairs with cancer indications (melanoma, lung and haematology) were selected based on whether they received accelerated approval in the US or Europe via one of the FDA Accelerated Approval pathways or the EMA Conditional Marketing Authorisation (CMA), or both, until December 2015. • In-depth analysis of HTA impact on coverage and funding pathways in the four selected countries relied on an analytical methodological framework investigating: (a) Similarities and differences in clinical and economic evidence submitted; (b) Evidence interpretation; (c) Uncertainties; (d) Other considerations, drug or therapeutic-area related; and (e) Time difference between MA and HTA recommendation. Author affiliations: 1 London School of Economics and Political Science, UK Uncertainties most commonly discussed across countries Time difference between regulatory approval and HTA recommendation Clinical and economic evidence submitted Marketing Authorisation dates and decisions and HTA dates and recommendations for 16 oncology drug-indication pairs across 4 countries • Despite the early regulatory approval schemes, HTA agencies do require robust clinical and economic evidence that would allow a positive coverage recommendation. • However, social value judgements can act as decision modifiers enabling HTA agencies to arrive at positive – mostly restricted - recommendations. Dates of regulatory decisions of the 16 drug-indication pairs and HTA recommendation dates for the HTA agencies in England (NICE), Scotland (SMC), Australia (PBAC) and Canada (pCODR): Regardless of early access scheme granted, timing of HTA recommendation varies widely. Appraisal Interpretation of evidence Main reasons for recommendation Uncertainties Clinical Economic Other Other considerations Elicited Non-elicited Assessment Evidence Clinical Quality criteria Metrics (OS,PFS) Economic Model type Budget impact 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 Body and Respective Regulatory Body 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 Agency Average Number of Days Between FDA Market Authorization and HTA Agency Recommendation Average length of time for HTA agencies in England, Scotland, Australia and Canada to publish an HTA recommendation following either MA in Europe, Australia or Canada (left-hand figure), or FDA approval (right-hand figure): FDA approval happened earlier than MA in other countries, with the exception of pembrolizumab in lung cancer and melanoma. The potential time frame from when the drug is in the market (FDA approval), and thus potentially could be accessed by patients, is longer than the amount of time between regulatory approval and HTA recommendation dates in other countries. Additionally, the speed at which pCODR reaches a recommendation becomes less significantly different to the time the other HTA bodies reach a decision when held to the baseline of FDA approval. Clinical Uncertainties • Lack of adequate clinical trials to show the comparative effectiveness to what is currently the standard of care (SoC) • Inability of clinical trials to establish a clear net clinical benefit • Uncertainty about whether adverse events are more or less tolerable than current best practice Economic Uncertainties • Uncertainty around the setup of the economic analysis model and the ICER range • Uncertainty around the comparators selected Type of evidence submitted to the HTA body for approval, type of economic model used, and pricing arrangements negotiated: Although most HTA bodies received submissions with similar clinical and economic evidence, recommendation outcomes vary greatly. Top five social-value judgements considered by HTA agencies England - NICE 1. Unmet clinical need 2. Special criteria (end-of-life, orphan) 3. Extension of life 4. Innovative compound 5. Higher comparative safety Scotland - SMC 1. Unmet clinical need 2. Special criteria (end-of-life, orphan) 3. Impact on patient’s work/activities 4. Impact on the society/health budget 5. Innovative compound Australia - PBAC 1. Unmet clinical need 2. Impact on the society/health budget 3. Extension of life 4. Quality of life 5. Higher comparative safety Canada - pCODR 1. Unmet clinical need 2. Emotional burden on carers 3. Impact on the society/health budget 4. Quality of life 5. Higher comparative safety Social value judgements can be seen as the reasoning behind recommendation variations. PBAC discussed social values the most infrequently, and rejected the highest amount of drugs among the study agencies. PBAC rejections were all due to issues of cost-effectiveness, often in the face of uncertain clinical benefit. NICE SMC PBAC pCODR NICE x 0.7333 -0.2195 -0.0526 SMC x x -0.2195 -0.0526 PBAC x x x -0.1940 pCODR x x x x Conclusions Cohen’s kappa scores measuring inter-rater agreement Cohen’s kappa scores seen were calculated to provide a statistical measure of agreement between the HTA agencies in interpreting the same evidence. Substantial agreement was found between NICE and SMC. None of the other Cohen kappa scores had any agreement between HTA agencies and their respective recommendations across drug-indication pairs. Although kappa values are not as robust as would be preferred, their values highlight the low level of agreement between the various HTA body recommendations.

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Page 1: Are Accelerated Approval Mechanisms a Predictor to Early ... · other HTA bodies reach a decision when held to the baseline of FDA approval. Clinical Uncertainties •Lack of adequate

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.

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