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This is a repository copy of The assessment and appraisal of regenerative medicines and cell therapy products : an exploration of methods for review, economic evaluation and appraisal. White Rose Research Online URL for this paper: https://eprints.whiterose.ac.uk/113090/ Version: Published Version Article: Hettle, Robert, Corbett, Mark orcid.org/0000-0002-5937-1493, Hinde, Sebastian orcid.org/0000-0002-7117-4142 et al. (4 more authors) (2017) The assessment and appraisal of regenerative medicines and cell therapy products : an exploration of methods for review, economic evaluation and appraisal. Health technology assessment. pp. 1-204. ISSN 2046-4924 https://doi.org/10.3310/hta21070 Reuse Items deposited in White Rose Research Online are protected by copyright, with all rights reserved unless indicated otherwise. They may be downloaded and/or printed for private study, or other acts as permitted by national copyright laws. 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[email protected] https://eprints.whiterose.ac.uk/ HEALTH TECHNOLOGY ASSESSMENT VOLUME 21 ISSUE 7 FEBRUARY 2017 ISSN 1366-5278 The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal Robert Hettle, Mark Corbett, Sebastian Hinde, Robert Hodgson, Julie Jones-Diette, Nerys Woolacott and Stephen Palmer DOI 10.3310/hta21070 The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal Robert Hettle,1 Mark Corbett,2 Sebastian Hinde,1 Robert Hodgson,2 Julie Jones-Diette,2 Nerys Woolacott2 and Stephen Palmer1* 1Centre for Health Economics, University of York, York, UK 2Centre for Reviews and Dissemination, University of York, York, UK *Corresponding author Declared competing interests of authors: none Published February 2017 DOI: 10.3310/hta21070 This reportshould be referenced as follows: Hettle R, Corbett M, Hinde S, Hodgson R,Jones-Diette J, Woolacott N,Palmer S. The assessment and appraisal ofregenerative medicines and celltherapy products: anexploration of methods for review,economic evaluation and appraisal. Health TechnolAssess2017;21(7). HealthTechnology Assessment isindexed and abstracted in IndexMedicus/MEDLINE, Excerpta Medica/EMBASE, ScienceCitation Index Expanded (SciSearch®) andCurrent Contents®/ Clinical Medicine. Health Technology Assessment HTA/HTATAR ISSN1366-5278(Print) ISSN2046-4924(Online) Impactfactor:4.058 HealthTechnologyAssessmentisindexedinMEDLINE,CINAHL,EMBASE,TheCochraneLibraryandtheISIScienceCitationIndex. ThisjournalisamemberofandsubscribestotheprinciplesoftheCommitteeonPublicationEthics(COPE)(www.publicationethics.org/). Editorialcontact:[email protected] ThefullHTAarchiveisfreelyavailabletoviewonlineatwww.journalslibrary.nihr.ac.uk/hta.Print-on-demandcopiescanbepurchasedfromthe reportpagesoftheNIHRJournalsLibrarywebsite:www.journalslibrary.nihr.ac.uk CriteriaforinclusionintheHealthTechnologyAssessmentjournal ReportsarepublishedinHealthTechnologyAssessment(HTA)if(1)theyhaveresultedfromworkfortheHTAprogramme,and(2)they areofasufficientlyhighscientificqualityasassessedbythereviewersandeditors. ReviewsinHealthTechnologyAssessmentaretermed‘systematic’whentheaccountofthesearchappraisalandsynthesismethods(to minimisebiasesandrandomerrors)would,intheory,permitthereplicationofthereviewbyothers. HTAprogramme TheHTAprogramme,partoftheNationalInstituteforHealthResearch(NIHR),wassetupin1993.Itproduceshigh-qualityresearch informationontheeffectiveness,costsandbroaderimpactofhealthtechnologiesforthosewhouse,manageandprovidecareintheNHS. ‘Healthtechnologies’arebroadlydefinedasallinterventionsusedtopromotehealth,preventandtreatdisease,andimproverehabilitation andlong-termcare. ThejournalisindexedinNHSEvidenceviaitsabstractsincludedinMEDLINEanditsTechnologyAssessmentReportsinformNationalInstitute forHealthandCareExcellence(NICE)guidance.HTAresearchisalsoanimportantsourceofevidenceforNationalScreeningCommittee(NSC) policydecisions. FormoreinformationabouttheHTAprogrammepleasevisitthewebsite:http://www.nets.nihr.ac.uk/programmes/hta Thisreport TheresearchreportedinthisissueofthejournalwasfundedbytheHTAprogrammeasprojectnumber14/151/06.Thecontractualstartdate wasinJuly2015.ThedraftreportbeganeditorialreviewinJanuary2016andwasacceptedforpublicationinJune2016.Theauthorshave beenwhollyresponsibleforalldatacollection,analysisandinterpretation,andforwritinguptheirwork.TheHTAeditorsandpublisherhave triedtoensuretheaccuracyoftheauthors’reportandwouldliketothankthereviewersfortheirconstructivecommentsonthedraft document.However,theydonotacceptliabilityfordamagesorlossesarisingfrommaterialpublishedinthisreport. ThisreportpresentsindependentresearchfundedbytheNationalInstituteforHealthResearch(NIHR).Theviewsandopinionsexpressedby authorsinthispublicationarethoseoftheauthorsanddonotnecessarilyreflectthoseoftheNHS,theNIHR,NETSCC,theHTAprogramme ortheDepartmentofHealth.Ifthereareverbatimquotationsincludedinthispublicationtheviewsandopinionsexpressedbythe intervieweesarethoseoftheintervieweesanddonotnecessarilyreflectthoseoftheauthors,thoseoftheNHS,theNIHR,NETSCC,theHTA programmeortheDepartmentofHealth. ©Queen’sPrinterandControllerofHMSO2017.ThisworkwasproducedbyHettleetal.underthetermsofacommissioning contractissuedbytheSecretaryofStateforHealth.Thisissuemaybefreelyreproducedforthepurposesofprivateresearchand studyandextracts(orindeed,thefullreport)maybeincludedinprofessionaljournalsprovidedthatsuitableacknowledgement ismadeandthereproductionisnotassociatedwithanyformofadvertising.Applicationsforcommercialreproductionshouldbe addressedto:NIHRJournalsLibrary,NationalInstituteforHealthResearch,Evaluation,TrialsandStudiesCoordinatingCentre, AlphaHouse,UniversityofSouthamptonSciencePark,SouthamptonSO167NS,UK. PublishedbytheNIHRJournalsLibrary(www.journalslibrary.nihr.ac.uk),producedbyPrepressProjectsLtd,Perth,Scotland (www.prepress-projects.co.uk). Health Technology Assessment Editor-in-Chief Professor Hywel Williams Director, HTA Programme, UK and Foundation Professor and Co-Director of the Centre of Evidence-Based Dermatology, University of Nottingham, UK NIHR Journals Library Editor-in-Chief Professor Tom Walley Director, NIHR Evaluation, Trials and Studies and Director of the EME Programme, UK NIHR Journals Library Editors Professor Ken Stein Chair of HTA Editorial Board and Professor of Public Health, University of Exeter Medical School, UK Professor Andree Le May Chair of NIHR Journals Library Editorial Group (EME, HS&DR, PGfAR, PHR journals) Dr Martin Ashton-Key Consultant in Public Health Medicine/Consultant Advisor, NETSCC, UK Professor Matthias Beck Chair in Public Sector Management and Subject Leader (Management Group), Queen’s University Management School, Queen’s University Belfast, UK Dr Tessa Crilly Director, Crystal Blue Consulting Ltd, UK Dr Eugenia Cronin Senior Scientific Advisor, Wessex Institute, UK Ms Tara Lamont Scientific Advisor, NETSCC, UK Dr Catriona McDaid Senior Research Fellow, York Trials Unit, Department of Health Sciences, University of York, UK Professor William McGuire Professor of Child Health, Hull York Medical School, University of York, UK Professor Geoffrey Meads Professor of Health Sciences Research, Health and Wellbeing Research Group, University of Winchester, UK Professor John Norrie Chair in Medical Statistics, University of Edinburgh, UK Professor John Powell Consultant Clinical Adviser, National Institute for Health and Care Excellence (NICE), UK Professor James Raftery Professor of Health Technology Assessment, Wessex Institute, Faculty of Medicine, University of Southampton, UK Dr Rob Riemsma Reviews Manager, Kleijnen Systematic Reviews Ltd, UK Professor Helen Roberts Professor of Child Health Research, UCL Institute of Child Health, UK Professor Jonathan Ross Professor of Sexual Health and HIV, University Hospital Birmingham, UK Professor Helen Snooks Professor of Health Services Research, Institute of Life Science, College of Medicine, Swansea University, UK Professor Jim Thornton Professor of Obstetrics and Gynaecology, Faculty of Medicine and Health Sciences, University of Nottingham, UK Professor Martin Underwood Director, Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick, UK Please visit the website for a list of members of the NIHR Journals Library Board: www.journalslibrary.nihr.ac.uk/about/editors Editorial contact: [email protected] NIHRJournalsLibrary www.journalslibrary.nihr.ac.uk DOI:10.3310/hta21070 HEALTHTECHNOLOGYASSESSMENT2017 VOL.21 NO.7 Abstract The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal Robert Hettle,1 Mark Corbett,2 Sebastian Hinde,1 Robert Hodgson,2 Julie Jones-Diette,2 Nerys Woolacott2 and Stephen Palmer1* 1Centre forHealth Economics, University ofYork, York, UK 2Centre forReviews andDissemination, University of York, York, UK *Corresponding author [email protected] Background: The National Institute for Health andCare Excellence (NICE) commissioned a‘mock technology appraisal’toassess whether changesto itsmethods and processes are needed.This report presents the findingsofindependent research commissioned toinform this appraisal and thedeliberations ofa panelconvened by NICE toevaluate themock appraisal. Methods: Our research included reviews to identify issues, analysis methods and conceptual differences and therelevance of alternative decision frameworks, alongside the development ofanexemplar case study ofchimeric antigen receptor (CAR) T-cell therapy for treating acute lymphoblastic leukaemia. Results: An assessment of previousevaluations of regenerative medicines foundthat, although there wereanumberofevidentialchallenges,nonewasuniquetoregenerativemedicinesorwasbeyondthe scopeofexistingmethodsusedtoconceptualisedecisionuncertainty.Regardingtheclinicalevidencefor regenerativemedicines,theissueswerethoseassociatedwithalimitedevidencebasebutwerenotuniqueto regenerativemedicines:smallnon-randomisedstudies,highvariationinresponseandtheinterventionsubject tocontinuingdevelopment.Therelativetreatmenteffectsgeneratedfromsingle-armtrialsarelikelytobe optimisticunlessitiscertainthatthehistoricaldatahaveaccuratelyestimatedtheefficacyofthecontrolagent. Pivotaltrialsmayusesurrogateendpoints,which,onaverage,overestimatetreatmenteffects.Toreduce overalluncertainty,multivariatemeta-analysisofallavailabledatashouldbeconsidered.Incorporating indirectlyrelevantbutmorereliable(moremature)dataintotheanalysiscanalsobeconsidered;suchdata maybecomeavailableasaresultoftheevolvingregulatorypathwaysbeingdevelopedbytheEuropean MedicinesAgency.FortheexemplarcaseofCART-celltherapy,targetproductprofiles(TPPs)were developed,whichconsideredthe‘curative’and‘bridgingtostem-celltransplantation’treatmentapproaches separately.WithineachTPP,three‘hypothetical’evidencesets(minimum,intermediateandmature)were generatedtosimulatetheimpactofalternativelevelsofprecisionandmaturityintheclinicalevidence. Subsequentassessmentsofcost-effectivenesswereundertaken,employingtheexistingNICEreferencecase alongsideadditionalanalysessuggestedwithinalternativeframeworks.Theadditionalexploratoryanalyses wereundertakentodemonstratehowassessmentsofcost-effectivenessanduncertaintycouldbeimpacted byalternativemanagedentryagreements(MEAs),includingpricediscounts,performance-relatedschemes andtechnologyleasing.ThepaneldeliberatedontherangeofTPPs,evidencesetsandMEAs,commenting onthelikelyrecommendationsforeachscenario.Thepaneldiscussedthechallengesassociatedwiththe exemplarandregenerativemedicinesmorebroadly,focusingontheneedforarobustquantificationofthe levelofuncertaintyinthecost-effectiveestimatesandthepotentialvalueofMEAsinlimitingtheexposure oftheNHStohighupfrontcostsandlossassociatedwithawrongdecision. ©Queen’sPrinterandControllerofHMSO2017.ThisworkwasproducedbyHettleetal.underthetermsofacommissioningcontractissuedbytheSecretaryofStatefor Health.Thisissuemaybefreelyreproducedforthepurposesofprivateresearchandstudyandextracts(orindeed,thefullreport)maybeincludedinprofessionaljournals v providedthatsuitableacknowledgementismadeandthereproductionisnotassociatedwithanyformofadvertising.Applicationsforcommercialreproductionshouldbe addressedto:NIHRJournalsLibrary,NationalInstituteforHealthResearch,Evaluation,TrialsandStudiesCoordinatingCentre,AlphaHouse,UniversityofSouthamptonScience Park,SouthamptonSO167NS,UK. ABSTRACT Conclusions: It isto beexpected thatthere willbe asignificant level ofuncertainty in determining the clinical effectiveness of regenerative medicines and their long-term costs andbenefits, butthe existing methods available toestimate theimplications of thisuncertainty aresufficient. Theuse ofrisk sharing and MEAs between the NHSand manufacturers ofregenerative medicines should beinvestigated further. Funding: TheNational Institute for Health Research HealthTechnology Assessment programme. vi NIHRJournalsLibrary www.journalslibrary.nihr.ac.uk DOI:10.3310/hta21070 HEALTHTECHNOLOGYASSESSMENT2017 VOL.21 NO.7 Contents List oftables xi List offigures xv Glossary xvii List ofabbreviations xxi PlainEnglish summary xxiii Scientificsummary xxv Chapter1Introduction and aims 1 Chapter2Background 3 Issues identified bythe European MedicinesAgency asbeing specific toadvanced therapy medicinal products 3 Overviewof wider regulatory evidence requirement issues and the evolvingpathways for approval 4 The ethics, feasibility and reliability of small randomised controlled trials 4 Possible alternatives totherandomised controlled trial 4 Evolving regulatory pathways 5 Regenerative medicines in the newregulatory environment 7 Chapter3Technology appraisal methodologyissues that maybe particularly relevantto regenerativemedicines 9 Clinical efficacy and safety issues arising from European Medicines Agency,National Institutefor Healthand Care Excellence and Foodand DrugAdministration assessments oflicensedregenerative medicines 9 Methods 9 Results 9 Summary 13 Study biases: anoverview oftheir importance and methods to quantifyand adjust for theirimpact 13 Methods 14 Results 14 Relevance tofuture regenerative medicinesubmissions 18 Reviewofthe useofsurrogate end pointsasprimary outcomemeasures in definitive effectiveness trials ofnewtherapeutic agents 19 Introduction 19 Methods 19 Definition and examplesof surrogate outcomes 20 Validation 20 Current issues for healthtechnology assessment and cost-effectiveness models 23 Summary 24 Scopingreview ofpotential cost-effectiveness issues 25 Previous regenerative medicine evaluations evaluated within theNational Institute for Health and Care Excellencetechnology appraisal process 25 ©Queen’sPrinterandControllerofHMSO2017.ThisworkwasproducedbyHettleetal.underthetermsofacommissioningcontractissuedbytheSecretaryofStatefor Health.Thisissuemaybefreelyreproducedforthepurposesofprivateresearchandstudyandextracts(orindeed,thefullreport)maybeincludedinprofessionaljournals vii providedthatsuitableacknowledgementismadeandthereproductionisnotassociatedwithanyformofadvertising.Applicationsforcommercialreproductionshouldbe addressedto:NIHRJournalsLibrary,NationalInstituteforHealthResearch,Evaluation,TrialsandStudiesCoordinatingCentre,AlphaHouse,UniversityofSouthamptonScience Park,SouthamptonSO167NS,UK.
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