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Challenges for Economic Evaluations of Advanced Therapy Medicinal Products: A Systematic Review

Open AccessPublished:August 28, 2022DOI:https://doi.org/10.1016/j.jval.2022.07.004

      Highlights

      • Advanced therapy medicinal products are challenging to evaluate and generate high financial and evidentiary uncertainty for regulators and payers.
      • This article provides an up-to-date review of economic analyses of these medicines.
      • Recommendations for manufacturers, analysts, and payers are made to improve evidence generation, evaluation, and decision making.

      Abstract

      Objectives

      Advanced therapy medicinal products (ATMPs) are drugs for human use for the treatment of chronic, degenerative, or life-threatening diseases that are based on genes, tissues, or cells. This article aimed to identify and critically review published economic analyses of ATMPs.

      Methods

      A systematic review of economic analyses of ATMPs was undertaken. Study characteristics, design, sources of data, resources and unit costs, modeling and extrapolation methods, study results, and sensitivity analyses were assessed.

      Results

      A total of 46 economic analyses of ATMP (from 45 articles) were included; 4 were cell therapy medicinal products, 33 gene therapy medicinal products, and 9 tissue-engineered products. 30 therapies had commercial marketing approval; 39 studies were cost-utility analysis, 5 were cost-effectiveness analysis, and 2 were cost only studies. Four studies predicted that the ATMP offered a step change in the management of the condition and 10 studies estimated that the ATMP would offer a lower mean cost.

      Conclusions

      Comparison with historical controls, pooling of data, and use of techniques such as mixture cure fraction models should be used cautiously. Sensitivity analyses should be used across a plausible range of prices. Clinical studies need to be designed to align with health technology assessment requirements, including generic quality of life, and payers should aim for clarity of criteria. Regulators and national payers should aim for compatibility of registers to allow interchange of data. Given the increasing reliance on industry-funded economic analyses, careful critical review is recommended.

      Keywords

      Introduction

      Advanced therapy medicinal products (ATMPs) are drugs for human use for the treatment of chronic, degenerative, or life-threatening diseases that are based on genes, tissues, or cells.
      Advanced therapy medicinal product. European Medicines Agency.
      There are currently > 2500 active clinical trials of ATMP, of those 250 are phase III.
      Getting ready for advanced therapy medicinal products (ATMPs) in Europe. Alliance for Regenerative Medicine.
      More than 50% of these are for treatments of cancer, although investigation is underway in almost all clinical specialties.
      Getting ready for advanced therapy medicinal products (ATMPs) in Europe. Alliance for Regenerative Medicine.
      Many ATMPs are for very specific, rare, or highly debilitating conditions and have curative intent, but others have much wider application, such as treatments for repair of knee cartilage or stress urinary incontinence.
      Given the number of ATMPs under development, health service planners are concerned that new innovations offer sufficient evidence of benefits for patients at an acceptable cost. In many countries, economic evaluation is therefore an important instrument in the health technology assessment (HTA) toolkit, alongside other types of evidence (systematic review, consultation, patient perception, and so on).
      • Jönsson B.
      • Hampson G.
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      Advanced therapy medicinal products and health technology assessment principles and practices for value-based and sustainable healthcare.
      This article systematically reviews the economic evidence associated with ATMPs for the treatment of different pathologies across multiple countries. Authors sometimes claim that their study “demonstrates” that a therapy is cost-effective or not but no universal threshold can be applied.
      • Woods B.
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      Country-level cost-effectiveness thresholds: initial estimates and the need for further research.
      Moreover, wider judgments often come into play, and national decision-making bodies have indicated that they may be willing to apply higher thresholds for therapies that address specific circumstances, such as unmet need or disabling diseases. For example, England conventionally applies a threshold of GBP 20 000 to 30 000 per quality-adjusted life-year (QALY),
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      although it has indicated that it may apply a higher threshold where certain criteria are met
      • Jönsson B.
      • Hampson G.
      • Michaels J.
      • Towse A.
      • von der Schulenburg J.G.
      • Wong O.
      Advanced therapy medicinal products and health technology assessment principles and practices for value-based and sustainable healthcare.
      and up to GBP 100 000 per QALY for highly specialized technologies, where the patient population is very small and the condition is chronic and severely disabling, among other criteria.
      Interim process and methods of the highly specialised technologies programme. Updated to reflect 2017 changes. National Institute for Health and Care Excellence.
      Nevertheless, not all countries have explicitly stated their thresholds, if they use any. In this study, thresholds of GBP 20 000, 50 000, and 100 000 per QALY are shown, corresponding to US $28 571, $71 429, and $142 857. We use these thresholds for comparative and illustrative purposes only and do not make any statement about what the appropriate threshold should be.
      Previous systematic reviews have been published in some of these areas. Some specifically addressed economic evaluations of chimeric antigen receptor (CAR) T-cell therapies
      • Petrou P.
      Is it a chimera? A systematic review of the economic evaluations of CAR-T cell therapy.
      • Whittington M.D.
      • McQueen R.B.
      • Campbell J.D.
      Valuing chimeric antigen receptor T-cell therapy: current evidence, uncertainties, and payment implications.
      • Fiorenza S.
      • Ritchie D.S.
      • Ramsey S.D.
      • Turtle C.J.
      • Roth J.A.
      Value and affordability of CAR T-cell therapy in the United States.
      or gene therapies.
      • Ten Ham R.M.T.
      • Hövels A.M.
      • Hoekman J.
      • et al.
      What does cell therapy manufacturing cost? A framework and methodology to facilitate academic and other small-scale cell therapy manufacturing costings.
      ,
      • Ho J.K.
      • Borle K.
      • Dragojlovic N.
      • et al.
      Economic evidence on potentially curative gene therapy products: a systematic literature review.
      Other reviews assessed the procedures and criteria used by certain US or European HTA bodies to assess ATMPs.
      • Trenaman L.
      • Pearson S.D.
      • Hoch J.S.
      How are incremental cost-effectiveness, contextual considerations, and other benefits viewed in health technology assessment recommendations in the United States?.
      ,
      • Ten Ham R.M.T.
      • Frederix G.W.J.
      • Wu O.
      • et al.
      Key considerations in the health technology assessment of advanced therapy medicinal products in Scotland, The Netherlands, and England.
      Lloyd-Williams conducted a systematic review covering economic evaluations of all types of ATMPs. These articles identified 5 broad challenges associated with the evidence underpinning ATMPs: the size and design of trials, understanding disease progression and long-term effects, estimating efficacy and comparative effectiveness, estimating impact on health-related quality of life (QOL), and generalizability. Besides effectiveness and cost-effectiveness, HTA agencies also paid attention to novel mechanisms of action, health disparities,
      • Trenaman L.
      • Pearson S.D.
      • Hoch J.S.
      How are incremental cost-effectiveness, contextual considerations, and other benefits viewed in health technology assessment recommendations in the United States?.
      financing mechanisms, and social, ethical, and legal dimensions.
      • Ten Ham R.M.T.
      • Frederix G.W.J.
      • Wu O.
      • et al.
      Key considerations in the health technology assessment of advanced therapy medicinal products in Scotland, The Netherlands, and England.
      In this article, we build on previous work in the following ways. The search strategy used by Lloyd-Williams was limited to mainly commercial names of gene therapy medicinal products (GTMPs) and so omitted several ATMPs derived from the use of cell therapy medicinal products (CTMPs) or tissue-engineered products (TEPs) (see definitions Appendix 1 in Supplementary Materials 1 found at https://doi.org/10.1016/j.jval.2022.07.004). We perform a complete systematic review by including not only commercial ATMPs but also other ATMPs under development. Where we find several models for a particular therapy and indication, we are able to compare evidence and methodology. In the specific cases where different authors have based their models around the same clinical data sources, we can pinpoint how methodological choices influence the results. This approach enables us to examine in greater detail how authors addressed the 5 broad challenges identified by Lloyd-Williams. Thus, this article aimed to identify and critically review the published economic analyses and costing studies of ATMPs to understand their strengths and weaknesses and draw out the implications for HTA for adoption, pricing, and reimbursement by health services.

      Methods

      Search Strategy

      A systematic review was conducted on September 11, 2020. The searches were validated by a specialized librarian in public health and adapted for PubMed, Embase, Web of Science, Google Scholar, and The Cochrane Library (see Supplemental Material Annexes 1-3 for search terms in Appendix 2 in Supplementary Materials 2 found at https://doi.org/10.1016/j.jval.2022.07.004). Our search strategy includes commercial names and International Nonproprietary Names of ATMPs with marketing authorization in United States, Europe, Japan, or South Korea (main market drivers) and “tissue-engineered,” “somatic-cell therapy,” and “gene therapy” as general terms.
      The grey literature search included economic analyses published by the Institute for Clinical and Economic Review group, the National Institute for Health and Care Excellence (NICE), the Scottish Medicines Agency, and Grupo de Evaluación de Novedades, Estandarización e Investigación en Selección de Medicamentos (GENESIS), a Spanish HTA agency. The protocol was registered in the International Prospective Register of Systematic Reviews (CRD42021233727). The reference lists of the reviews and identified articles were examined, and colleagues and experts active in the field were also consulted, including suggestions by reviewers of this article.

      Study Selection and Data Extraction

      Articles that conducted an economic analysis (cost, cost-effectiveness, or cost-utility analysis) of ATMPs were included. The search was limited to a period of 15 years (2005-2020). The results of the literature search were stored in a Rayyan Qatar Computing Research Institute library, and the screening process was performed in pairs, first by title and abstract (D.E. and A.O.L.), and subsequently the full-text articles were reviewed for eligibility. Differences were discussed and resolved by consensus among all authors. Articles published in a language other than English or Spanish, duplicates, congress communications, and nonsystematic reviews were excluded. No a priori exclusion criteria were applied with respect to the quality of the studies because the risk of bias associated with the study was one of the variables that we wished to analyze. Data were extracted using a template that was previously piloted, discussed, and modified by the authors.
      • van Mastrigt G.A.
      • Hiligsmann M.
      • Arts J.J.
      • et al.
      How to prepare a systematic review of economic evaluations for informing evidence-based healthcare decisions: a five-step approach (part 1/3).
      Key information included study characteristics, study design, sources for identifying resource use, unit costs and utilities, sources of effectiveness data in the intervention and comparator groups, modeling and extrapolation methods, main study results, and sensitivity analyses.

      Risk of Bias

      We evaluated the methodological quality and risk of bias of each article, using a checklist (Appendix Table S1 in Supplementary Materials 3 found at https://doi.org/10.1016/j.jval.2022.07.004) based on guidelines for systematic review of economic evaluations
      • Wijnen B.
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      • Redekop W.K.
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      • De Kinderen R.
      • Evers S.
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      ,

      Jaime Caro J, Eddy DM, Kan H, et al. Questionnaire to assess relevance and credibility of modeling studies for informing health care decision making: an ISPOR-AMCP-NPC Good Practice Task Force report [published correction appears in Value Health. 2016;19(1):121]. Value Health. 2014;17(2):174–182.

      and graded using the Oxford Centre for Evidence-Based Medicine scale.
      • Howick J.
      • Chalmers I.
      • Glasziou P.
      • et al.
      Explanation of the 2011 Oxford Centre for Evidence-Based Medicine (OCEBM) levels of evidence [background document]. Oxford Centre for Evidence-Based Medicine.
      Any discrepancies were discussed and agreed by consensus.

      Data Analysis

      Costs and incremental cost-utility ratio (ICUR) were updated to 2020 prices
      • Curtis L.A.
      • Burns A.
      Unit costs of health & social care. PSSRU.
      and converted from local currency to international dollars at 2020 purchasing power parity ($1 = GBP0.70 = €0.706). The choice of the international dollar as common currency is simply for convenience.
      Conversion rates – purchasing power parities (PPP). OECD.
      Some reports publish the ICUR but for confidentiality reasons do not report the incremental cost and incremental QALY.
      • Walton M.
      • Sharif S.
      • Simmonds M.
      • Claxton L.
      • Hodgson R.
      Tisagenlecleucel for the treatment of relapsed or refractory B-cell acute lymphoblastic leukaemia in people aged up to 25 years: an evidence review group perspective of a NICE single technology appraisal.
      Tisagenlecleucel 1.2 X 106 to 6 X 108 cells dispersion for infusion (Kymriah®). Scottish Medicines Consortium.
      Axicabtagene ciloleucel 0.4-2 X 108 cells dispersion for infusion dispersion for infusion (Yescarta®). Scottish Medicines Consortium.
      Although the ICUR informs an assessment of the efficiency of the intervention, we also wished to know whether the innovation was estimated to offer a step change in the management of the disease or just a moderate added benefit and to obtain a visual overview of the incremental costs and benefits on the cost-QALY plane (see Appendix Figs. S1, S2 and S3 in Supplementary Materials 4 found at https://doi.org/10.1016/j.jval.2022.07.004). In these cases, we assumed that the incremental QALY could be appropriately proxied by that reported in another study for the same indication using similar methods for the same ATMP-comparator pair (see Methods and notes to Table 1
      • Clar C.
      • Cummins E.
      • Mcintyre L.
      • et al.
      Clinical and cost-effectiveness of autologous chondrocyte implantation for cartilage defects in knee joints: systematic review and economic evaluation.
      • Vilsbøll A.W.
      • Mouritsen J.M.
      • Jensen L.P.
      • et al.
      Cell-based therapy for the treatment of female stress urinary incontinence: an early cost-effectiveness analysis.
      • Svensson J.
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      • Lindgren A.
      • et al.
      Societal value of stem cell therapy in stroke–a modeling study.
      • Retèl V.P.
      • Steuten L.M.G.
      • Geukes Foppen M.H.
      • et al.
      Early cost-effectiveness of tumor infiltrating lymphocytes (TIL) for second line treatment in advanced melanoma: a model-based economic evaluation.

      Roth JA, Sullivan SD, Lin VW, et al. Cost-effectiveness of axicabtagene ciloleucel for adult patients with relapsed or refractory large B-cell lymphoma in the United States [published correction appears in J Med Econ. 2018;21(12):1255]. J Med Econ. 2018;21(12):1238–1245.

      • Samuelson E.M.
      • Brown D.E.
      Cost-effectiveness analysis of autologous chondrocyte implantation: a comparison of periosteal patch versus type I/III collagen membrane.
      • Malone D.C.
      • Dean R.
      • Arjunji R.
      • et al.
      Cost-effectiveness analysis of using onasemnogene abeparvocec (AVXS-101) in spinal muscular atrophy type 1 patients.
      • Cher B.P.
      • Gan K.Y.
      • Aziz M.I.A.
      • et al.
      Cost utility analysis of tisagenlecleucel vs salvage chemotherapy in the treatment of relapsed/refractory diffuse large B-cell lymphoma from Singapore’s healthcare system perspective.
      • Lin J.K.
      • Lerman B.J.
      • Barnes J.I.
      • et al.
      Cost effectiveness of chimeric antigen receptor T-cell therapy in relapsed or refractory pediatric B-cell acute lymphoblastic leukemia.
      • Ribera Santasusana J.M.
      • de Andrés Saldaña A.
      • García-Muñoz N.
      • Gostkorzewicz J.
      • Martínez Llinàs D.
      • Díaz De Heredia C.
      Cost-effectiveness analysis of tisagenlecleucel in the treatment of relapsed or refractory B-cell acute lymphoblastic leukaemia in children and young adults in Spain.
      • Gerlier L.
      • Lamotte M.
      • Wille M.
      • et al.
      The cost utility of autologous chondrocytes implantation using ChondroCelect® in symptomatic knee cartilage lesions in Belgium.
      • Hettle R.
      • Corbett M.
      • Hinde S.
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      The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal.
      • Mistry H.
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      Autologous chondrocyte implantation in the knee: systematic review and economic evaluation.
      • Ellis A.G.
      • Mickle K.
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      • et al.
      Spinraza® and Zolgensma® for spinal muscular atrophy: effectiveness and value prepared for. ICER.
      • Thielen F.W.
      • van Dongen-Leunis A.
      • Arons A.M.M.
      • Ladestein J.R.
      • Hoogerbrugge P.M.
      Uyl-de Groot CA. Cost-effectiveness of anti-CD19 chimeric antigen receptor T-cell therapy in pediatric relapsed/refractory B-cell acute lymphoblastic leukemia. A societal view.
      • Corbett M.
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      • Walker S.
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      Tisagenlecleucel for treating relapsed or refractory diffuse large B-cell lymphoma. Single Technology Appraisal.
      • Corbett M.
      • Duarte A.
      • Melton H.
      • et al.
      Axicabtagene ciloleucel for treating diffuse large B-cell lymphoma, mediastinal B-cell lymphoma and follicular lymphoma. Single Technology Appraisal.
      • Beinfeld M.
      • Atlas S.J.
      • Touchette D.
      • McKenna A.
      • Rind D.
      • Pearson S.D.
      The effectiveness and value of nadofaragene firadenovec, oportuzumab monatox, and pembrolizumab for BCG-unresponsive non-muscle-invasive bladder cancer.
      • Agboola F.
      • Rind D.M.
      • Walton S.M.
      • Herron-Smith S.
      • Quach D.
      • Pearson S.D.
      The effectiveness and value of emicizumab and valoctocogene roxaparvovec for the management of hemophilia A without inhibitors.
      • Lin J.K.
      • Muffly L.S.
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      • Bames J.I.
      • Owens D.K.
      • Goldhaber-Fiebert J.
      Cost-effectiveness of chimeric antigen receptor T-cell therapy in multiply relapsed or refractory adult large B-cell lymphoma.
      • Zimmermann M.
      • Lubinga S.J.
      • Banken R.
      • et al.
      Cost utility of voretigene neparvovec for biallelic RPE65-mediated inherited retinal disease.
      • Viriato D.
      • Bennett N.
      • Sidhu R.
      • et al.
      An economic evaluation of voretigene neparvovec for the treatment of biallelic RPE65-mediated inherited retinal dystrophies in the UK.
      • Uhrmann M.F.
      • Lorenz B.
      • Gissel C.
      Cost effectiveness of voretigene neparvovec for RPE65-mediated inherited retinal degeneration in Germany.
      ). Hence, the incremental cost associated with that ATMP-comparator pair could be back-calculated as the proxy incremental QALY multiplied by the ICUR reported in the study.
      Table 1Treatment comparisons evaluated within a cost-utility analysis.
      TherapyComparatorIncremental cost ($)Incremental QALYICUR
      Therapies that offer lower QALY than the current SOC
       Stress urinary incontinence (TEP)
      Vilsbøll et al, 2018
      • Vilsbøll A.W.
      • Mouritsen J.M.
      • Jensen L.P.
      • et al.
      Cell-based therapy for the treatment of female stress urinary incontinence: an early cost-effectiveness analysis.
      MM vs MUS−806−0.05813 966
      Vilsbøll et al, 2018
      • Vilsbøll A.W.
      • Mouritsen J.M.
      • Jensen L.P.
      • et al.
      Cell-based therapy for the treatment of female stress urinary incontinence: an early cost-effectiveness analysis.
      IVM vs MUS440−0.008Dominated
      Therapies that may offer a major improvement in the management of the condition with considerably greater cost
       Adenosine deaminase deficiency (GTMP)
      South et al, 2018
      • South E.
      • Cox E.
      • Meader N.
      • Woolacott N.
      • Griffin S.
      Strimvelis® for treating severe combined immunodeficiency caused by adenosine deaminase deficiency: an evidence review group perspective of a NICE highly specialised technology evaluation.
      Strimvelis vs HSCT MUD951 9368.5111 992
       Spinal muscular atrophy (GTMP)
      Ellis et al, 2019
      • Ellis A.G.
      • Mickle K.
      • Herron-Smith S.
      • et al.
      Spinraza® and Zolgensma® for spinal muscular atrophy: effectiveness and value prepared for. ICER.
      Nusinersen vs SOC3 095 0002.781 113 309
      Ellis et al, 2019
      • Ellis A.G.
      • Mickle K.
      • Herron-Smith S.
      • et al.
      Spinraza® and Zolgensma® for spinal muscular atrophy: effectiveness and value prepared for. ICER.
      Zolgensma vs SOC2 868 00011.77243 670
      Malone et al, 2019
      • Malone D.C.
      • Dean R.
      • Arjunji R.
      • et al.
      Cost-effectiveness analysis of using onasemnogene abeparvocec (AVXS-101) in spinal muscular atrophy type 1 patients.
      Zolgensma vs nusinersen−2 175 84610.36Dominates
       Relapsed/refractory B-ALL (GTMP)
      Ribera Santasusana et al, 2020
      • Ribera Santasusana J.M.
      • de Andrés Saldaña A.
      • García-Muñoz N.
      • Gostkorzewicz J.
      • Martínez Llinàs D.
      • Díaz De Heredia C.
      Cost-effectiveness analysis of tisagenlecleucel in the treatment of relapsed or refractory B-cell acute lymphoblastic leukaemia in children and young adults in Spain.
      Kymriah vs SOC264 3478.9729 470
      Thielen et al, 2020
      • Thielen F.W.
      • van Dongen-Leunis A.
      • Arons A.M.M.
      • Ladestein J.R.
      • Hoogerbrugge P.M.
      Uyl-de Groot CA. Cost-effectiveness of anti-CD19 chimeric antigen receptor T-cell therapy in pediatric relapsed/refractory B-cell acute lymphoblastic leukemia. A societal view.
      Kymriah vs Blinatoma567 87710.8452 729
      SMC 2019a
      Tisagenlecleucel 1.2 X 106 to 6 X 108 cells dispersion for infusion (Kymriah®). Scottish Medicines Consortium.
      Incremental QALY or cost not reported. It was assumed for the graphs that the incremental QALY would be the same as that reported in Lin et al, 2019.42
      Kymriah vs SOCConfidentialConfidential36 054
      Walton 2018
      • Walton M.
      • Sharif S.
      • Simmonds M.
      • Claxton L.
      • Hodgson R.
      Tisagenlecleucel for the treatment of relapsed or refractory B-cell acute lymphoblastic leukaemia in people aged up to 25 years: an evidence review group perspective of a NICE single technology appraisal.
      Incremental QALY or cost not reported. It was assumed for the graphs that the incremental QALY would be the same as that reported in Lin et al, 2019.42
      Kymriah vs SOCConfidentialConfidential43 493
      Whittington et al, 2019
      • Whittington M.D.
      • McQueen R.B.
      • Ollendorf D.A.
      • et al.
      Long-term survival and value of chimeric antigen receptor T-cell therapy for pediatric patients with relapsed or refractory leukemia.
      Kymriah vs SOC341 0207.1847 496
      Lin et al, 2018
      • Lin J.K.
      • Lerman B.J.
      • Barnes J.I.
      • et al.
      Cost effectiveness of chimeric antigen receptor T-cell therapy in relapsed or refractory pediatric B-cell acute lymphoblastic leukemia.
      Kymriah vs SOC328 0855.1763 459
      Sarkar et al, 2018
      • Sarkar R.R.
      • Gloude N.J.
      • Schiff D.
      • Murphy J.D.
      Cost-effectiveness of chimeric antigen receptor T-cell therapy in pediatric relapsed/refractory B-cell acute lymphoblastic leukemia.
      Kymriah vs SOC558 2598.1868 247
      Furzer et al, 2020
      • Furzer Jill
      • Gupta Sumit
      • Nathan Paul
      • et al.
      Cost-effectiveness of Tisagenlecleucel vs Standard Care in High-risk Relapsed Pediatric Acute Lymphoblastic Leukemia in Canada.
      Kymriah vs SOC357 0206.79141 000
      Hettle et al, 2017
      • Hettle R.
      • Corbett M.
      • Hinde S.
      • et al.
      The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal.
      CAR T vs SOC (bridge to HSCT)565 4047.4675 791
      Hettle et al, 2017
      • Hettle R.
      • Corbett M.
      • Hinde S.
      • et al.
      The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal.
      CAR T vs SOC (curative intent)762 51110.0775 721
       Relapsed or refractory DLBCL (GTMP)
      SMC 2019a
      Tisagenlecleucel 1.2 X 106 to 6 X 108 cells dispersion for infusion (Kymriah®). Scottish Medicines Consortium.
      Incremental QALY or cost not reported. It was assumed for the graphs that the incremental QALY would be the same as that reported in Whittington et al, 2019.53
      Kymriah vs SOCConfidentialConfidential71 393
      Lin et al, 2019
      • Lin J.K.
      • Muffly L.S.
      • Spinner M.A.
      • Bames J.I.
      • Owens D.K.
      • Goldhaber-Fiebert J.
      Cost-effectiveness of chimeric antigen receptor T-cell therapy in multiply relapsed or refractory adult large B-cell lymphoma.
      Kymriah vs SOC368 3162.14172 110
      Cher et al, 2020
      • Cher B.P.
      • Gan K.Y.
      • Aziz M.I.A.
      • et al.
      Cost utility analysis of tisagenlecleucel vs salvage chemotherapy in the treatment of relapsed/refractory diffuse large B-cell lymphoma from Singapore’s healthcare system perspective.
      Kymriah vs SOC264 3540.508520 381
      Roth et al, 2018

      Roth JA, Sullivan SD, Lin VW, et al. Cost-effectiveness of axicabtagene ciloleucel for adult patients with relapsed or refractory large B-cell lymphoma in the United States [published correction appears in J Med Econ. 2018;21(12):1255]. J Med Econ. 2018;21(12):1238–1245.

      Yescarta vs SOC393 4786.5460 165
      SMC 2019b
      Axicabtagene ciloleucel 0.4-2 X 108 cells dispersion for infusion dispersion for infusion (Yescarta®). Scottish Medicines Consortium.
      Yescarta vs SOC287 7974.170 194
      Whittington et al, 2019
      • Whittington M.D.
      • McQueen R.B.
      • Ollendorf D.A.
      • et al.
      Long-term survival and value of chimeric antigen receptor T-cell therapy for pediatric patients with relapsed or refractory leukemia.
      Yescarta vs SOC351 1001.89230 900
      Lin et al, 2019
      • Lin J.K.
      • Muffly L.S.
      • Spinner M.A.
      • Bames J.I.
      • Owens D.K.
      • Goldhaber-Fiebert J.
      Cost-effectiveness of chimeric antigen receptor T-cell therapy in multiply relapsed or refractory adult large B-cell lymphoma.
      Yescarta vs SOC493 1343.72132 563
      Tice 2019
      • Tice J.A.
      • Walsh J.M.E.
      • Otuonye I.
      • et al.
      Chimeric antigen receptor T-cell therapy for B-cell cancers: effectiveness and value.
      Yescarta vs SOC478 2003.39141 062
      Corbett et al, 2018b
      • Corbett M.
      • Duarte A.
      • Melton H.
      • et al.
      Axicabtagene ciloleucel for treating diffuse large B-cell lymphoma, mediastinal B-cell lymphoma and follicular lymphoma. Single Technology Appraisal.
      Yescarta vs SOCConfidentialConfidentialN/A
      Therapies that offer some (or uncertain) additional health benefit with greater (or uncertain) total mean cost
       BCG-unresponsive non–muscle invasive bladder cancer (GTMP)
      Altas et al, 2020
      • Beinfeld M.
      • Atlas S.J.
      • Touchette D.
      • McKenna A.
      • Rind D.
      • Pearson S.D.
      The effectiveness and value of nadofaragene firadenovec, oportuzumab monatox, and pembrolizumab for BCG-unresponsive non-muscle-invasive bladder cancer.
      Nadofaragene Fir. Vs hypothetical comparator119 0000.79150 633
       Biallelic RPE65-mediated retinal disease (GTMP)
      Banken et al, 2018
      • Zimmermann M.
      • Lubinga S.J.
      • Banken R.
      • et al.
      Cost utility of voretigene neparvovec for biallelic RPE65-mediated inherited retinal disease.
      Luxturna vs SOC854 4901.3657 300
      Uhrmann et al, 2020
      • Uhrmann M.F.
      • Lorenz B.
      • Gissel C.
      Cost effectiveness of voretigene neparvovec for RPE65-mediated inherited retinal degeneration in Germany.
      Luxturna vs SOC32 5424.82156 853
      Viriato et al, 2020
      • Viriato D.
      • Bennett N.
      • Sidhu R.
      • et al.
      An economic evaluation of voretigene neparvovec for the treatment of biallelic RPE65-mediated inherited retinal dystrophies in the UK.
      Luxturna vs SOC612 4046.495 072
      Johnson 2019
      • Johnson S.
      • Buessing M.
      • O’Connell T.
      • Pitluck S.
      • Ciulla T.A.
      Cost-effectiveness of voretigene Neparvovec-rzyl vs standard care for RPE65-mediated inherited retinal disease.
      Johnson 2019 (reference 64) estimates lower cost and greater QALY for the intervention compared with standard of care.
      Luxturna vs SOC−104 6109.4Dominates
       Cartilage defect in knee (TEP)
      Samuelson et al, 2012
      • Samuelson E.M.
      • Brown D.E.
      Cost-effectiveness analysis of autologous chondrocyte implantation: a comparison of periosteal patch versus type I/III collagen membrane.
      ACI-C vs ACI-P−10710.07Dominates
      Clar et al, 2005
      • Clar C.
      • Cummins E.
      • Mcintyre L.
      • et al.
      Clinical and cost-effectiveness of autologous chondrocyte implantation for cartilage defects in knee joints: systematic review and economic evaluation.
      ACI vs MF38050.5646746
      Clar et al, 2005
      • Clar C.
      • Cummins E.
      • Mcintyre L.
      • et al.
      Clinical and cost-effectiveness of autologous chondrocyte implantation for cartilage defects in knee joints: systematic review and economic evaluation.
      MACI vs MFN/AN/AN/A
      Mistry et al, 2017
      • Mistry H.
      • Connock M.
      • Pink J.
      • et al.
      Autologous chondrocyte implantation in the knee: systematic review and economic evaluation.
      ACI vs MF22 1680.99422 292
      Gerlier et al, 2010
      • Gerlier L.
      • Lamotte M.
      • Wille M.
      • et al.
      The cost utility of autologous chondrocytes implantation using ChondroCelect® in symptomatic knee cartilage lesions in Belgium.
      CC vs MF34 7451.28227 102
      de Windt et al, 2016
      • de Windt T.S.
      • Sorel J.C.
      • Vonk L.A.
      • Kip M.M.A.
      • Ijzerman M.J.
      • Saris D.B.F.
      Early health economic modelling of single-stage cartilage repair. Guiding implementation of technologies in regenerative medicine.
      CC vs MF36 3300.04908 251
      de Windt et al, 2016
      • de Windt T.S.
      • Sorel J.C.
      • Vonk L.A.
      • Kip M.M.A.
      • Ijzerman M.J.
      • Saris D.B.F.
      Early health economic modelling of single-stage cartilage repair. Guiding implementation of technologies in regenerative medicine.
      IMPACT vs MF87770.04219 424
      Asymptomatic metastatic castration-resistant prostate cancer (CTMP)
       Gong et al, 2014
      • Gong Cynthia
      • Hay Joel
      Cost-Effectiveness Analysis of Abiraterone and Sipuleucel-T in Asymptomatic Metastatic Castration-Resistant Prostate Cancer.
      Sipuleucel-T vs prednisone94 4110.16547 298
      Therapies that offer some additional health benefit with lower total mean cost
       Advanced metastatic melanoma (GTMP)
      Retèl et al, 2018
      • Retèl V.P.
      • Steuten L.M.G.
      • Geukes Foppen M.H.
      • et al.
      Early cost-effectiveness of tumor infiltrating lymphocytes (TIL) for second line treatment in advanced melanoma: a model-based economic evaluation.
      TIL vs Ipilimubab−19 8860.07Dominates
       Dopamine cell therapy for Parkinson disease (C)
      Hjelmgren et al, 2005
      • Hjelmgren Jonas
      • Ghatnekar Ola
      • Reimer Jan
      • et al.
      Estimating the value of novel interventions for Parkinson’s disease: an early decision-making model with application to dopamine cell replacement. 2006 Oct;12(7):443-52. doi: 10.1016/j.parkreldis.2006.04.006. Epub 2006 Jun 22. PMID: 16798054..
      Cell therapy vs SOC−47 4151.133Dominates
       Hemophilia A (GTMP)
      Rind et al, 2020
      • Agboola F.
      • Rind D.M.
      • Walton S.M.
      • Herron-Smith S.
      • Quach D.
      • Pearson S.D.
      The effectiveness and value of emicizumab and valoctocogene roxaparvovec for the management of hemophilia A without inhibitors.
      Valoctocogene rox. vs FVIII−5 029 0000.004Dominates
      Cook et al, 2020
      • Cook Keziah
      • Forbes Shaun
      • Adamski Kelly
      • et al.
      Assessing the potential cost-effectiveness of a gene therapy for the treatment of hemophilia A.
      Valoctocogene rox. vs FVIII−6 810 3740.750Dominates
      Machin et al, 2020
      • Machin N.
      • Ragni M.V.
      • Smith K.J.
      Gene therapy in hemophilia A: a cost-effectiveness analysis.
      Gene Tx vs FVIII−716 1701.71Dominates
       Ischemic stroke (CTMP)
      Svensson et al, 2012
      • Svensson J.
      • Ghatnekar O.
      • Lindgren A.
      • et al.
      Societal value of stem cell therapy in stroke–a modeling study.
      Stem cell therapy vs SOC−22 3361.34Dominates
      ACI indicates autologous chondrocyte implantation; B-ALL, B cells acute lymphoblastic leukemia; BCG, Bacille Calmette-Guérin; CAR T, chimeric antigen receptor T-cell therapy; C, I/III collagen patch; CC, ChondroCelect; CTMP, cell therapy medicinal product; DLBCL, diffuse large B-cell cell lymphoma; FVIII, factor VIII; GTMP, gene therapy medicinal product; HSCT, hematopoietic stem cell transplant; ICUR, incremental cost utility ratio; IMPACT, Instant MSC Product Accompanying ACI; IVM, in vitro expanded myoblasts; MACI, matrix-guided autologous chondrocyte implantation; MF, microfracture; MM, minced myofibers; MUD, matched unrelated donor; MUS, midurethral sling; N/A, not applicable; P, periosteal patch; QALY, quality-adjusted life-year; rox., roxaparvfovec; RPE, retinal pigment epithelium; SOC, standard of care; SMC Scottish Medicines Consortium; TEP, tissue-engineered product; TIL, tumor infiltrating lymphocyte; Tx, therapy.
      Incremental QALY or cost not reported. It was assumed for the graphs that the incremental QALY would be the same as that reported in Lin et al, 2019.
      • Lin J.K.
      • Muffly L.S.
      • Spinner M.A.
      • Bames J.I.
      • Owens D.K.
      • Goldhaber-Fiebert J.
      Cost-effectiveness of chimeric antigen receptor T-cell therapy in multiply relapsed or refractory adult large B-cell lymphoma.
      Incremental QALY or cost not reported. It was assumed for the graphs that the incremental QALY would be the same as that reported in Whittington et al, 2019.
      • Whittington M.D.
      • McQueen R.B.
      • Ollendorf D.A.
      • et al.
      Long-term survival and value of chimeric antigen receptor T-cell therapy for pediatric patients with relapsed or refractory leukemia.
      Johnson 2019 (reference 64) estimates lower cost and greater QALY for the intervention compared with standard of care.
      The authors worked together to elaborate recommendations for HTA evidence, procedure, and criteria of relevance for ATMP, based on the evidence extracted from the review. Nevertheless, all conclusions are exclusively those of the authors.

      Results

      Selection of Included Studies

      A total of 1522 articles were assessed for eligibility (Appendix Fig. S4 in Supplementary Materials 5 found at https://doi.org/10.1016/j.jval.2022.07.004). After excluding those articles not related with the review, duplications, and congress communications (n = 1522), 46 evaluations were selected for analysis (Appendix Table S2 in Supplementary Materials 6 found at https://doi.org/10.1016/j.jval.2022.07.004).
      • Walton M.
      • Sharif S.
      • Simmonds M.
      • Claxton L.
      • Hodgson R.
      Tisagenlecleucel for the treatment of relapsed or refractory B-cell acute lymphoblastic leukaemia in people aged up to 25 years: an evidence review group perspective of a NICE single technology appraisal.
      Tisagenlecleucel 1.2 X 106 to 6 X 108 cells dispersion for infusion (Kymriah®). Scottish Medicines Consortium.
      Axicabtagene ciloleucel 0.4-2 X 108 cells dispersion for infusion dispersion for infusion (Yescarta®). Scottish Medicines Consortium.
      • Clar C.
      • Cummins E.
      • Mcintyre L.
      • et al.
      Clinical and cost-effectiveness of autologous chondrocyte implantation for cartilage defects in knee joints: systematic review and economic evaluation.
      • Vilsbøll A.W.
      • Mouritsen J.M.
      • Jensen L.P.
      • et al.
      Cell-based therapy for the treatment of female stress urinary incontinence: an early cost-effectiveness analysis.
      • Svensson J.
      • Ghatnekar O.
      • Lindgren A.
      • et al.
      Societal value of stem cell therapy in stroke–a modeling study.
      • Retèl V.P.
      • Steuten L.M.G.
      • Geukes Foppen M.H.
      • et al.
      Early cost-effectiveness of tumor infiltrating lymphocytes (TIL) for second line treatment in advanced melanoma: a model-based economic evaluation.

      Roth JA, Sullivan SD, Lin VW, et al. Cost-effectiveness of axicabtagene ciloleucel for adult patients with relapsed or refractory large B-cell lymphoma in the United States [published correction appears in J Med Econ. 2018;21(12):1255]. J Med Econ. 2018;21(12):1238–1245.

      • Samuelson E.M.
      • Brown D.E.
      Cost-effectiveness analysis of autologous chondrocyte implantation: a comparison of periosteal patch versus type I/III collagen membrane.
      • Malone D.C.
      • Dean R.
      • Arjunji R.
      • et al.
      Cost-effectiveness analysis of using onasemnogene abeparvocec (AVXS-101) in spinal muscular atrophy type 1 patients.
      • Cher B.P.
      • Gan K.Y.
      • Aziz M.I.A.
      • et al.
      Cost utility analysis of tisagenlecleucel vs salvage chemotherapy in the treatment of relapsed/refractory diffuse large B-cell lymphoma from Singapore’s healthcare system perspective.
      • Lin J.K.
      • Lerman B.J.
      • Barnes J.I.
      • et al.
      Cost effectiveness of chimeric antigen receptor T-cell therapy in relapsed or refractory pediatric B-cell acute lymphoblastic leukemia.
      • Ribera Santasusana J.M.
      • de Andrés Saldaña A.
      • García-Muñoz N.
      • Gostkorzewicz J.
      • Martínez Llinàs D.
      • Díaz De Heredia C.
      Cost-effectiveness analysis of tisagenlecleucel in the treatment of relapsed or refractory B-cell acute lymphoblastic leukaemia in children and young adults in Spain.
      • Gerlier L.
      • Lamotte M.
      • Wille M.
      • et al.
      The cost utility of autologous chondrocytes implantation using ChondroCelect® in symptomatic knee cartilage lesions in Belgium.
      • Hettle R.
      • Corbett M.
      • Hinde S.
      • et al.
      The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal.
      • Mistry H.
      • Connock M.
      • Pink J.
      • et al.
      Autologous chondrocyte implantation in the knee: systematic review and economic evaluation.
      • Ellis A.G.
      • Mickle K.
      • Herron-Smith S.
      • et al.
      Spinraza® and Zolgensma® for spinal muscular atrophy: effectiveness and value prepared for. ICER.
      • Thielen F.W.
      • van Dongen-Leunis A.
      • Arons A.M.M.
      • Ladestein J.R.
      • Hoogerbrugge P.M.
      Uyl-de Groot CA. Cost-effectiveness of anti-CD19 chimeric antigen receptor T-cell therapy in pediatric relapsed/refractory B-cell acute lymphoblastic leukemia. A societal view.
      • Corbett M.
      • Duarte A.
      • Walker S.
      • Wright K.
      • Palmer S.
      Tisagenlecleucel for treating relapsed or refractory diffuse large B-cell lymphoma. Single Technology Appraisal.
      • Corbett M.
      • Duarte A.
      • Melton H.
      • et al.
      Axicabtagene ciloleucel for treating diffuse large B-cell lymphoma, mediastinal B-cell lymphoma and follicular lymphoma. Single Technology Appraisal.
      • Beinfeld M.
      • Atlas S.J.
      • Touchette D.
      • McKenna A.
      • Rind D.
      • Pearson S.D.
      The effectiveness and value of nadofaragene firadenovec, oportuzumab monatox, and pembrolizumab for BCG-unresponsive non-muscle-invasive bladder cancer.
      • Agboola F.
      • Rind D.M.
      • Walton S.M.
      • Herron-Smith S.
      • Quach D.
      • Pearson S.D.
      The effectiveness and value of emicizumab and valoctocogene roxaparvovec for the management of hemophilia A without inhibitors.
      • Lin J.K.
      • Muffly L.S.
      • Spinner M.A.
      • Bames J.I.
      • Owens D.K.
      • Goldhaber-Fiebert J.
      Cost-effectiveness of chimeric antigen receptor T-cell therapy in multiply relapsed or refractory adult large B-cell lymphoma.
      • Zimmermann M.
      • Lubinga S.J.
      • Banken R.
      • et al.
      Cost utility of voretigene neparvovec for biallelic RPE65-mediated inherited retinal disease.
      • Viriato D.
      • Bennett N.
      • Sidhu R.
      • et al.
      An economic evaluation of voretigene neparvovec for the treatment of biallelic RPE65-mediated inherited retinal dystrophies in the UK.
      • Uhrmann M.F.
      • Lorenz B.
      • Gissel C.
      Cost effectiveness of voretigene neparvovec for RPE65-mediated inherited retinal degeneration in Germany.
      • de Windt T.S.
      • Sorel J.C.
      • Vonk L.A.
      • Kip M.M.A.
      • Ijzerman M.J.
      • Saris D.B.F.
      Early health economic modelling of single-stage cartilage repair. Guiding implementation of technologies in regenerative medicine.
      • Tappenden P.
      • Saccardi R.
      • Confavreux C.
      • et al.
      Autologous haematopoietic stem cell transplantation for secondary progressive multiple sclerosis: an exploratory cost-effectiveness analysis.
      • Aae T.F.
      • Randsborg P.H.
      • Lurås H.
      • Årøen A.
      Lian ØB. Microfracture is more cost-effective than autologous chondrocyte implantation: a review of level 1 and level 2 studies with 5 year follow-up.
      • Machin N.
      • Ragni M.V.
      • Smith K.J.
      Gene therapy in hemophilia A: a cost-effectiveness analysis.
      • Coquerelle S.
      • Ghardallou M.
      • Rais S.
      • et al.
      Innovative curative treatment of beta thalassemia: cost-efficacy analysis of gene therapy versus allogenic hematopoietic stem-cell transplantation.
      • Yang H.
      • Hao Y.
      • Qi C.Z.
      • Chai X.
      • Wu E.Q.
      Estimation of total costs in pediatric and young adult patients with relapsed or refractory acute lymphoblastic leukemia receiving tisagenlecleucel from a U.S. hospital’s perspective.
      • Sarkar R.R.
      • Gloude N.J.
      • Schiff D.
      • Murphy J.D.
      Cost-effectiveness of chimeric antigen receptor T-cell therapy in pediatric relapsed/refractory B-cell acute lymphoblastic leukemia.
      • Whittington M.D.
      • McQueen R.B.
      • Ollendorf D.A.
      • et al.
      Long-term survival and value of chimeric antigen receptor T-cell therapy for pediatric patients with relapsed or refractory leukemia.
      • Castañeda-Macías I.
      • Selvi Sabater P.
      Darvadstrocel Para El Tratamiento de Fístulas Perianales Complejas Refractarias En Enfermedad de Crohn. Darvadstrocel Para El Tratamiento de Fístulas Perianalescomplejas Refractarias En Enfermedad de Crohn.
      • Tan T.E.
      • Peh G.S.
      • George B.L.
      • et al.
      A cost-minimization analysis of tissue-engineered constructs for corneal endothelial transplantation.

      Sierra Sánchez J.F., Fraga Fuentes M.D., Arocas Casañ V. Condrocitos Humanos Autólogos. Reparación de Lesiones Del Cartílago Del Cóndilo Femoral de La Rodilla. Grupo GENESIS de La SEFH. https://gruposdetrabajo.sefh.es/genesis/genesis/Enlaces/InformesHosp_abc.htm?ml=1#C. Accessed August 9, 2022.

      • Tan T.E.
      • Peh G.S.
      • Finkelstein E.A.
      • Mehta J.S.
      A practical model for economic evaluation of tissue-engineered therapies.
      • South E.
      • Cox E.
      • Meader N.
      • Woolacott N.
      • Griffin S.
      Strimvelis® for treating severe combined immunodeficiency caused by adenosine deaminase deficiency: an evidence review group perspective of a NICE highly specialised technology evaluation.
      • Tice J.A.
      • Walsh J.M.E.
      • Otuonye I.
      • et al.
      Chimeric antigen receptor T-cell therapy for B-cell cancers: effectiveness and value.
      • Furzer Jill
      • Gupta Sumit
      • Nathan Paul
      • et al.
      Cost-effectiveness of Tisagenlecleucel vs Standard Care in High-risk Relapsed Pediatric Acute Lymphoblastic Leukemia in Canada.
      • Gong Cynthia
      • Hay Joel
      Cost-Effectiveness Analysis of Abiraterone and Sipuleucel-T in Asymptomatic Metastatic Castration-Resistant Prostate Cancer.
      • Cook Keziah
      • Forbes Shaun
      • Adamski Kelly
      • et al.
      Assessing the potential cost-effectiveness of a gene therapy for the treatment of hemophilia A.
      • Hjelmgren Jonas
      • Ghatnekar Ola
      • Reimer Jan
      • et al.
      Estimating the value of novel interventions for Parkinson’s disease: an early decision-making model with application to dopamine cell replacement. 2006 Oct;12(7):443-52. doi: 10.1016/j.parkreldis.2006.04.006. Epub 2006 Jun 22. PMID: 16798054..
      A total of 4 evaluations reviewed CTMPs, 33 GTMPs, and 9 TEPs (Table 2). A total of 31 were for therapies with commercial marketing approval from the European, US, Japanese, or Korean regulators, and 14 were for therapies that do not yet have approval for the indication or are hypothetical products. 39 studies were cost-utility analysis, 5 were cost-effectiveness analysis, and 2 were cost only studies. One study was trial based,
      • Coquerelle S.
      • Ghardallou M.
      • Rais S.
      • et al.
      Innovative curative treatment of beta thalassemia: cost-efficacy analysis of gene therapy versus allogenic hematopoietic stem-cell transplantation.
      that is, based exclusively on primary data on resource use and effectiveness, whereas all other studies were models, that is, mainly based on secondary data extracted from other studies and literature. Twenty-five articles had not been included in the previous review of economic evaluations of ATMPs.
      • Lloyd-Williams H.
      • Hughes D.A.
      A systematic review of economic evaluations of advanced therapy medicinal products.
      Table 2Characteristics of the included articles (N = 46).
      n = 3n = 31n = 9N = 46100%
      PathologyCTMPsGTMPsTEPsTotal%
      R/R DLBCL-9-920
      R/R B-ALL-9-920
      Cartilage defects in knee joints-07715
      Hemophilia A-3-24
      Spinal muscular atrophy-2-24
      RPE65-mediated inherited retinal degeneration448
      Other3821328
      Source of human cellsCTMPsGTMPsTEPsTotal%
      Allogeneic21149
      Autologous23284291
      Therapies with MA (commercial name)CTMPsGTMPsTEPsTotal (N = 31)%
      Alofisel1--13
      Chondrocelect--226
      Imlygic-1-13
      Kymriah-12-1239
      Luxturna-4-413
      MACI--113
      Strimvelis-1-13
      Yescarta-5-516
      Yescarta & Kymriah-1-13
      Zolgensma-2-26
      Zynteglo-1-13
      Therapies without MA or unspecifiedCTMPsGTMPsTEPsTotal (N = 14)%
      ACI--3321
      CAR T/TIL-2-214
      Dopamine cell replacement therapy1--17
      Hypothetical gene therapy-1-17
      In vitro expanded myoblasts--117
      IMPACT--117
      Nadofaragene firadenovec-1-17
      Stem cell therapy1--17
      Valoctocogene roxaparcvovec2214
      Corneal tissue-engineered constructs--117
      SettingCTMPsGTMPsTEPsTotal (N = 46)%
      Belgium--112
      Germany112
      Canada112
      Denmark--112
      France-1-12
      The Netherlands-2137
      Norway--112
      Singapore-1124
      Spain11137
      Sweden2--24
      UK-1124
      UK–Scotland-3-37
      UK–England-51613
      US-1511941
      Type of economic evaluationCTMPsGTMPsTEPsTotal%
      CEA11249
      CUA33164087
      Costs only01124
      Type of studyCTMPsGTMPsTEPsTotal%
      Within trial-1-12
      Decision tree model2171024
      Microsimulation model-1-12
      Markov model11221434
      Partitioned survival model-15-1537
      Publication yearCTMPsGTMPsTEPsTotal%
      20061--12
      2010--112
      20121-237
      2014--112
      2016--112
      2017-2137
      201811021330
      2019-2-921
      2020 (Jan-Sept)-1011126
      ACI indicates autologous chondrocyte implantation; CAR T, chimeric antigen receptor T-cell therapy; CEA, cost-effectiveness analysis; CTMP, cell therapy medicinal product; CUA, cost-utility analysis; GTMP, gene therapy medicinal product; IMPACT, Instant MSC Product Accompanying ACI; Jan, January; MA, market authorization; MACI: matrix-guided autologous chondrocyte implantation; R/R B-ALL: relapsed/refractory B-cell acute lymphoblastic leukemia; R/R DLBCL: relapsed or refractory diffuse large B-cell lymphoma; relapsed/refractory B-cell acute lymphoblastic leukemia; RPE, retinal pigment epithelium; Sept, September; TEP, tissue-engineered product; TIL, tumor infiltrating lymphocyte; UK, United Kingdom; US, United States.

      Cost-Utility Analyses of ATMP

      Of the 39 cost-utility analysis studies, 1
      • Corbett M.
      • Duarte A.
      • Melton H.
      • et al.
      Axicabtagene ciloleucel for treating diffuse large B-cell lymphoma, mediastinal B-cell lymphoma and follicular lymphoma. Single Technology Appraisal.
      reported only methods but did not report costs, QALY, or ICUR for confidentiality reasons. Of the remaining 38 studies, 5 reported cost and QALY, for 3 treatment options (ie, 2 ATMPs plus a comparator or 1 ATMP vs 2 comparators). From this literature, we were able to obtain incremental cost and incremental QALY or ICUR estimates for 42 ATMP-comparator pairs, listed in Table 1. These were classified in 4 broad groups, according to their base-case point estimates on the cost-QALY plane: those that offer no added benefit, those that offer a major improvement in the management of the disease at increased cost, those that offer some (or highly uncertain) added benefit at increased (or uncertain) cost, and those that offer added benefit at a lower cost.
      Vilsbøll et al
      • Vilsbøll A.W.
      • Mouritsen J.M.
      • Jensen L.P.
      • et al.
      Cell-based therapy for the treatment of female stress urinary incontinence: an early cost-effectiveness analysis.
      concluded that neither in vitro expanded myoblasts nor minced myofibers would offer an improvement in QALY for stress urinary incontinence relative to standard of care (SOC), in this case, midurethral sling (Appendix Fig. S1 in Supplementary Materials 4 found at https://doi.org/10.1016/j.jval.2022.07.004). The other ATMPs included in this review were associated with some positive QALY gain. In the cases of Strimvelis for adenosine deaminase deficiency, Zolgensma for spinal muscular atrophy, Yescarta for relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL), and Kymriah relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), the expected point estimate of gain in QALY was large or extremely large, ranging from 3.4 years (Yescarta) to 11.7 years (Zolgensma). HTA agencies have stated that expected gains in the upper range of this magnitude can be considered a step change in the clinical management of these diseases
      Interim process and methods of the highly specialised technologies programme. Updated to reflect 2017 changes. National Institute for Health and Care Excellence.
      (Appendix Fig. 3Supplemental MaterialsAppendix Fig. S2 in Supplementary Materials 4 found at https://doi.org/10.1016/j.jval.2022.07.004). Nevertheless, in these cases, the ATMPs were associated with a considerable incremental cost compared with SOC, even after offsetting expected cost savings associated with reduced need for other healthcare. Yescarta for DLBCL was expected to require an additional expenditure of between $290 000 and $490 000 per patient, Kymriah for B-ALL an additional expenditure of between $260 000 and $560 000, Strimvelis an additional expenditure of almost $1 million per patient, and Zolgensma an additional expenditure of >$2.8 million per patient over SOC. Strimvelis was considered cost-effective by NICE as the ICUR was estimated to be <£100 000 ($142 000)/QALY, the threshold for specialized technologies. Zolgensma was found by Malone et al
      • Malone D.C.
      • Dean R.
      • Arjunji R.
      • et al.
      Cost-effectiveness analysis of using onasemnogene abeparvocec (AVXS-101) in spinal muscular atrophy type 1 patients.
      to be cost-saving compared with nusinersen (another costly innovative medicine) but Ellis et al
      • Ellis A.G.
      • Mickle K.
      • Herron-Smith S.
      • et al.
      Spinraza® and Zolgensma® for spinal muscular atrophy: effectiveness and value prepared for. ICER.
      found an ICUR in excess of $250 000/QALY when Zolgensma was compared with SOC.
      In the cases of ATMPs to treat advanced metastatic melanoma, Bacille Calmette-Guérin unresponsive non–muscle invasive bladder cancer, biallelic retinal pigment epithelium (RPE)-65 mediated retinal disease, cartilage defects in knee joints, hemophilia A, and ischemic stroke, the expected QALY gains were smaller or greatly varying among studies (Appendix Fig. S3 in Supplementary Materials 4 found at https://doi.org/10.1016/j.jval.2022.07.004). In the case of autologous chondrocyte implantation (ACI) versus microfracture for cartilage defects in knee joints, 3 studies found the ICUR would be < £20 000 ($28 571)/QALY whereas 1 study
      • de Windt T.S.
      • Sorel J.C.
      • Vonk L.A.
      • Kip M.M.A.
      • Ijzerman M.J.
      • Saris D.B.F.
      Early health economic modelling of single-stage cartilage repair. Guiding implementation of technologies in regenerative medicine.
      found the incremental cost-effectiveness ratio would be considerably > £100 000 ($142 000)/QALY. In four indications (advanced metastatic melanoma, haemophilia A, Parkinson's disease and ischaemic stroke) the product is associated with QALY gains and cost savings (Appendix Fig. S4 in Supplementary Materials 4 found at https://doi.org/10.1016/j.jval.2022.07.004). Hence, the ICUR would be negative and is not relevant for decision making.

      Utilities Used in the Cost-Utility Analyses

      Only a few clinical trials included health-state utilities obtained from generic instruments that use preference-based weights (EQ-5D, Short Form 6-Dimension, or Health Utilities Index). Examples were the ZUMA-1
      • Neelapu S.S.
      • Locke F.L.
      • Bartlett N.L.
      • et al.
      Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma.
      trial (Yescarta for R/R DLBCL) and the JULIET trial
      • Schuster S.J.
      • Bishop M.R.
      • Tam C.S.
      • et al.
      Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma.
      (Kymriah for R/R DLBCL). One evaluation of Zolgensma and one of Luxturna elicited patient QOL from physicians.
      • Malone D.C.
      • Dean R.
      • Arjunji R.
      • et al.
      Cost-effectiveness analysis of using onasemnogene abeparvocec (AVXS-101) in spinal muscular atrophy type 1 patients.
      ,
      • Viriato D.
      • Bennett N.
      • Sidhu R.
      • et al.
      An economic evaluation of voretigene neparvovec for the treatment of biallelic RPE65-mediated inherited retinal dystrophies in the UK.
      The evaluation of Strimvelis assumed that treated patients would enjoy the same QOL as the general population for that age. A study of Luxturna used utility weights associated with other retinal disease populations, although it noted that these are often older patients.
      • Zimmermann M.
      • Lubinga S.J.
      • Banken R.
      • et al.
      Cost utility of voretigene neparvovec for biallelic RPE65-mediated inherited retinal disease.
      Other studies used values from the literature to map from disease-specific severity instruments (such as the Rankin score for stroke severity
      • Svensson J.
      • Ghatnekar O.
      • Lindgren A.
      • et al.
      Societal value of stem cell therapy in stroke–a modeling study.
      or oncology QOL scales
      • Lin J.K.
      • Lerman B.J.
      • Barnes J.I.
      • et al.
      Cost effectiveness of chimeric antigen receptor T-cell therapy in relapsed or refractory pediatric B-cell acute lymphoblastic leukemia.
      to utility scales such as the EQ-5D or Health Utilities Index).

      Sources of Clinical Evidence and Modeling Methods Used in the Cost-Utility Analyses

      Data from <25 patients were available in the intervention arms for adenosine deaminase deficiency, biallelic RPE-65, hemophilia A, and spinal muscular atrophy (Table 3). The data used for the comparator group treatment ranged in duration from 1 year to 28 years of follow-up (Table 3), whereas the duration of the data for the ATMP patients was from 1 to 13 years of follow-up.
      Table 3Duration and number of patients in the clinical trials used by the models to estimate comparative efficacy (N = 39).
      PathologyNo. of studiesDuration of source data for control group (years)Duration of source data for intervention group (years)No. of patients in the intervention study arm
      Adenosine deaminase deficiency1101318
      Advanced metastatic melanoma11151
      BCG-unresponsive non–muscle invasive bladder cancer1N/AN/AN/A
      Biallelic RPE65-mediated retinal disease4283-8.921
      Cartilage defect in knee63-103-1051-101
      Hemophilia A35-100.515
      Ischemic stroke110N/AN/A
      Spinal muscular atrophy312-415
      Stress urinary incontinence21120-177
      Relapsed or refractory DLBCL91-101.2-293-108
      Relapsed/refractory B-ALL91.7-31.7-5N/A-75
      B-ALL indicates B cells acute lymphoblastic leukemia; BCG, Bacille Calmette-Guérin; DLBCL, diffuse large B-cell cell lymphoma; N/A, these data were neither reported in the study nor were available from the reference list of the study; RPE, retinal pigment epithelium.
      For some modeling studies, several sources of data were available, and the authors pooled those data sets. For instance, the evaluations of TEP for urinary stress incontinence pooled aggregate published data from 3 case series with between 20 and 117 patients ignoring between-study differences.
      • Vilsbøll A.W.
      • Mouritsen J.M.
      • Jensen L.P.
      • et al.
      Cell-based therapy for the treatment of female stress urinary incontinence: an early cost-effectiveness analysis.
      By contrast, several evaluations of Yescarta for R/R DLBCL used the SCHOLAR-1 study to estimate survival with the comparator (salvage chemotherapy). SCHOLAR-1 pooled carefully selected individual data from 2 randomized controlled trials (RCTs) and 2 cohort studies and considered possible sources of between-study variation.
      • Crump M.
      • Neelapu S.S.
      • Farooq U.
      • et al.
      Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study.
      There were also 4 economic evaluations of Luxturna, one of which estimated a small added benefit at high incremental cost,
      • Zimmermann M.
      • Lubinga S.J.
      • Banken R.
      • et al.
      Cost utility of voretigene neparvovec for biallelic RPE65-mediated inherited retinal disease.
      1 estimated a very large added benefit with cost savings,
      • Johnson S.
      • Buessing M.
      • O’Connell T.
      • Pitluck S.
      • Ciulla T.A.
      Cost-effectiveness of voretigene Neparvovec-rzyl vs standard care for RPE65-mediated inherited retinal disease.
      and 2 estimated a large added benefit with additional cost.
      • Viriato D.
      • Bennett N.
      • Sidhu R.
      • et al.
      An economic evaluation of voretigene neparvovec for the treatment of biallelic RPE65-mediated inherited retinal dystrophies in the UK.
      ,
      • Uhrmann M.F.
      • Lorenz B.
      • Gissel C.
      Cost effectiveness of voretigene neparvovec for RPE65-mediated inherited retinal degeneration in Germany.
      All used efficacy evidence from the same small 4-year RCT.
      • Maguire A.M.
      • Russell S.
      • Chung D.C.
      • et al.
      Durability of voretigene neparvovec for biallelic RPE65-mediated inherited retinal disease: phase 3 results at 3 and 4 years.
      The economic evaluations differed in various ways (discount rates, number of health states, and perspective) but 2 factors stand out. The RCT did not collect QOL variables that could be used to estimate utility. Hence, the economic studies used different sources for the utility associated with visual difficulty (studies in a different pathology or the opinion of experts). The second crucial difference was the assumption about how long the treatment benefit might last. All models affirmed that the costs of the disease increase with the severity of visual impairment, particularly the indirect (nonhealthcare) costs, and so a gene therapy that could slow the progression of visual impairment would gradually offset the high acquisition cost. Nevertheless, there were no data on the duration of effectiveness of the gene therapy beyond 4 years, so the models relied on assumptions, 1 assuming the effect gradually wanes over 10 years,
      • Zimmermann M.
      • Lubinga S.J.
      • Banken R.
      • et al.
      Cost utility of voretigene neparvovec for biallelic RPE65-mediated inherited retinal disease.
      1 assuming it is maintained for 40 years,
      • Viriato D.
      • Bennett N.
      • Sidhu R.
      • et al.
      An economic evaluation of voretigene neparvovec for the treatment of biallelic RPE65-mediated inherited retinal dystrophies in the UK.
      and 2 assuming it is maintained over the lifetime.
      • Uhrmann M.F.
      • Lorenz B.
      • Gissel C.
      Cost effectiveness of voretigene neparvovec for RPE65-mediated inherited retinal degeneration in Germany.
      ,
      • Johnson S.
      • Buessing M.
      • O’Connell T.
      • Pitluck S.
      • Ciulla T.A.
      Cost-effectiveness of voretigene Neparvovec-rzyl vs standard care for RPE65-mediated inherited retinal disease.

      Time Horizons Used in the Cost-Utility Analyses

      Most studies (34 of 39) used mathematical models to extrapolate clinical effectiveness from trial data in the intervention and control group to longer term outcomes, using time horizons of 40 years or more. The remainder (5 of 39) used a time horizon no longer than the length of the trial data (between 1 and 9 years).

      Prices of ATMPs Used in the Cost-Utility Analyses

      In some studies, the price of the ATMPs was unknown to the authors, and a “placeholder” price was used instead. For example, Malone et al
      • Malone D.C.
      • Dean R.
      • Arjunji R.
      • et al.
      Cost-effectiveness analysis of using onasemnogene abeparvocec (AVXS-101) in spinal muscular atrophy type 1 patients.
      varied the price of Zolgensma from $2.5 million to $5 million per patient. Whittington et al
      • Whittington M.D.
      • McQueen R.B.
      • Ollendorf D.A.
      • et al.
      Long-term survival and value of chimeric antigen receptor T-cell therapy for pediatric patients with relapsed or refractory leukemia.
      in an evaluation of Kymriah versus SOC for R/R B-ALL used a price of $575 000 including hospital markup. Nevertheless, they assumed an outcome-based agreement where payment would only be charged for patients who respond to Kymriah treatment at 1 month. It was expected that approximately 15% of patients would be unresponsive and hence incur no therapy acquisition cost.
      Three economic evaluations of ChondroCelect (a TEP) used commercial prices ranging from $16.000 to $20.802 depending on the national health system.
      • Gerlier L.
      • Lamotte M.
      • Wille M.
      • et al.
      The cost utility of autologous chondrocytes implantation using ChondroCelect® in symptomatic knee cartilage lesions in Belgium.
      ,
      • Mistry H.
      • Connock M.
      • Pink J.
      • et al.
      Autologous chondrocyte implantation in the knee: systematic review and economic evaluation.
      ,

      Sierra Sánchez J.F., Fraga Fuentes M.D., Arocas Casañ V. Condrocitos Humanos Autólogos. Reparación de Lesiones Del Cartílago Del Cóndilo Femoral de La Rodilla. Grupo GENESIS de La SEFH. https://gruposdetrabajo.sefh.es/genesis/genesis/Enlaces/InformesHosp_abc.htm?ml=1#C. Accessed August 9, 2022.

      Many other studies of TEP were undertaken while the therapy was under development, before the commercial price was established, and manufacturing costs were used instead.
      • Clar C.
      • Cummins E.
      • Mcintyre L.
      • et al.
      Clinical and cost-effectiveness of autologous chondrocyte implantation for cartilage defects in knee joints: systematic review and economic evaluation.
      ,
      • Vilsbøll A.W.
      • Mouritsen J.M.
      • Jensen L.P.
      • et al.
      Cell-based therapy for the treatment of female stress urinary incontinence: an early cost-effectiveness analysis.
      ,
      • Samuelson E.M.
      • Brown D.E.
      Cost-effectiveness analysis of autologous chondrocyte implantation: a comparison of periosteal patch versus type I/III collagen membrane.
      ,
      • de Windt T.S.
      • Sorel J.C.
      • Vonk L.A.
      • Kip M.M.A.
      • Ijzerman M.J.
      • Saris D.B.F.
      Early health economic modelling of single-stage cartilage repair. Guiding implementation of technologies in regenerative medicine.
      ,
      • Tan T.E.
      • Peh G.S.
      • George B.L.
      • et al.
      A cost-minimization analysis of tissue-engineered constructs for corneal endothelial transplantation.
      The health services in England and Scotland also negotiate discounts or other reimbursement agreements with manufacturers, referred to as “Patient Access Schemes.” Corbett et al
      • Corbett M.
      • Duarte A.
      • Walker S.
      • Wright K.
      • Palmer S.
      Tisagenlecleucel for treating relapsed or refractory diffuse large B-cell lymphoma. Single Technology Appraisal.
      published the ICUR estimated for Kymriah versus SOC for R/R DLBCL but did not reveal the incremental costs or QALYs. A study of Yescarta versus SOC for R/R DLBCL did not report the ICUR.
      • Corbett M.
      • Duarte A.
      • Melton H.
      • et al.
      Axicabtagene ciloleucel for treating diffuse large B-cell lymphoma, mediastinal B-cell lymphoma and follicular lymphoma. Single Technology Appraisal.
      Luxturna has a list price of $850 000 per patient.
      • Zimmermann M.
      • Lubinga S.J.
      • Banken R.
      • et al.
      Cost utility of voretigene neparvovec for biallelic RPE65-mediated inherited retinal disease.
      Nevertheless, Luxturna was recommended in Germany at a reported €345 000 ($489 000) per patient and for use in National Health Services in England at a confidential discount.
      • Ronco V.
      • Dilecce M.
      • Lanati E.
      • Canonico P.L.
      • Jommi C.
      Price and reimbursement of advanced therapeutic medicinal products in Europe: are assessment and appraisal diverging from expert recommendations?.

      Studies That Estimated Costs or Cost-Effectiveness

      As shown in Table 4,
      • Aae T.F.
      • Randsborg P.H.
      • Lurås H.
      • Årøen A.
      Lian ØB. Microfracture is more cost-effective than autologous chondrocyte implantation: a review of level 1 and level 2 studies with 5 year follow-up.
      ,
      • Coquerelle S.
      • Ghardallou M.
      • Rais S.
      • et al.
      Innovative curative treatment of beta thalassemia: cost-efficacy analysis of gene therapy versus allogenic hematopoietic stem-cell transplantation.
      ,
      • Yang H.
      • Hao Y.
      • Qi C.Z.
      • Chai X.
      • Wu E.Q.
      Estimation of total costs in pediatric and young adult patients with relapsed or refractory acute lymphoblastic leukemia receiving tisagenlecleucel from a U.S. hospital’s perspective.
      ,
      • Castañeda-Macías I.
      • Selvi Sabater P.
      Darvadstrocel Para El Tratamiento de Fístulas Perianales Complejas Refractarias En Enfermedad de Crohn. Darvadstrocel Para El Tratamiento de Fístulas Perianalescomplejas Refractarias En Enfermedad de Crohn.
      • Tan T.E.
      • Peh G.S.
      • George B.L.
      • et al.
      A cost-minimization analysis of tissue-engineered constructs for corneal endothelial transplantation.

      Sierra Sánchez J.F., Fraga Fuentes M.D., Arocas Casañ V. Condrocitos Humanos Autólogos. Reparación de Lesiones Del Cartílago Del Cóndilo Femoral de La Rodilla. Grupo GENESIS de La SEFH. https://gruposdetrabajo.sefh.es/genesis/genesis/Enlaces/InformesHosp_abc.htm?ml=1#C. Accessed August 9, 2022.

      • Tan T.E.
      • Peh G.S.
      • Finkelstein E.A.
      • Mehta J.S.
      A practical model for economic evaluation of tissue-engineered therapies.
      ,
      • Almutairi A.R.
      • Alkhatib N.S.
      • Oh M.
      • et al.
      Economic evaluation of talimogene laherparepvec plus ipilimumab combination therapy vs ipilimumab monotherapy in patients with advanced unresectable melanoma.
      1 study only estimated costs in the intervention group (not the difference in cost), and 1 estimated costs for a TEP for corneal blindness, compared with procured donor tissue. Notably, 5 estimated cost-effectiveness (ie, measures of health outcome that were not QALY), namely, patient response and patient reported measures,
      • Aae T.F.
      • Randsborg P.H.
      • Lurås H.
      • Årøen A.
      Lian ØB. Microfracture is more cost-effective than autologous chondrocyte implantation: a review of level 1 and level 2 studies with 5 year follow-up.
      ,

      Sierra Sánchez J.F., Fraga Fuentes M.D., Arocas Casañ V. Condrocitos Humanos Autólogos. Reparación de Lesiones Del Cartílago Del Cóndilo Femoral de La Rodilla. Grupo GENESIS de La SEFH. https://gruposdetrabajo.sefh.es/genesis/genesis/Enlaces/InformesHosp_abc.htm?ml=1#C. Accessed August 9, 2022.

      avoidance of complications and hospital admissions,
      • Coquerelle S.
      • Ghardallou M.
      • Rais S.
      • et al.
      Innovative curative treatment of beta thalassemia: cost-efficacy analysis of gene therapy versus allogenic hematopoietic stem-cell transplantation.
      disease remission,
      • Castañeda-Macías I.
      • Selvi Sabater P.
      Darvadstrocel Para El Tratamiento de Fístulas Perianales Complejas Refractarias En Enfermedad de Crohn. Darvadstrocel Para El Tratamiento de Fístulas Perianalescomplejas Refractarias En Enfermedad de Crohn.
      and “progression-free quality-adjusted life-years.”
      • Almutairi A.R.
      • Alkhatib N.S.
      • Oh M.
      • et al.
      Economic evaluation of talimogene laherparepvec plus ipilimumab combination therapy vs ipilimumab monotherapy in patients with advanced unresectable melanoma.
      Table 4Results of studies that estimated costs or cost-effectiveness (N = 7).
      StudyTherapy vs comparatorDifference in cost, $Difference in effectiveness (if reported)
      Relapsed or refractory DLBCL (GTMP)
       Yang et al
      • Yang H.
      • Hao Y.
      • Qi C.Z.
      • Chai X.
      • Wu E.Q.
      Estimation of total costs in pediatric and young adult patients with relapsed or refractory acute lymphoblastic leukemia receiving tisagenlecleucel from a U.S. hospital’s perspective.
      Kymriah vs N/AN/AN/A
      Corneal blindness due to endothelial dysfunction (TEP)
       Tan et al
      • Tan T.E.
      • Peh G.S.
      • George B.L.
      • et al.
      A cost-minimization analysis of tissue-engineered constructs for corneal endothelial transplantation.
      Tissue-engineered constructs vs procured donor tissue−2830N/A
      Crohn’s disease and fistulas (CTMP)
       Castañeda et al
      • Castañeda-Macías I.
      • Selvi Sabater P.
      Darvadstrocel Para El Tratamiento de Fístulas Perianales Complejas Refractarias En Enfermedad de Crohn. Darvadstrocel Para El Tratamiento de Fístulas Perianalescomplejas Refractarias En Enfermedad de Crohn.
      Alofisel vs surgery75 561NNT of 6 (for combined remission at 24 weeks)
      Cartilage defect (TEP)
       Sierra et al

      Sierra Sánchez J.F., Fraga Fuentes M.D., Arocas Casañ V. Condrocitos Humanos Autólogos. Reparación de Lesiones Del Cartílago Del Cóndilo Femoral de La Rodilla. Grupo GENESIS de La SEFH. https://gruposdetrabajo.sefh.es/genesis/genesis/Enlaces/InformesHosp_abc.htm?ml=1#C. Accessed August 9, 2022.

      Chondrocelect vs MF30 501NNT of 5 (for response on KOOS scale)
       Aae et al
      • Aae T.F.
      • Randsborg P.H.
      • Lurås H.
      • Årøen A.
      Lian ØB. Microfracture is more cost-effective than autologous chondrocyte implantation: a review of level 1 and level 2 studies with 5 year follow-up.
      ACI vs MF14 3537-point improvement in KOOS (0-100 scale)
      β-thalassemia (GTMP)
       Coquerelle et al
      • Coquerelle S.
      • Ghardallou M.
      • Rais S.
      • et al.
      Innovative curative treatment of beta thalassemia: cost-efficacy analysis of gene therapy versus allogenic hematopoietic stem-cell transplantation.
      Zynteglo vs HSCT575 411No difference in survival; 3 times fewer complications than HSCT group
      Melanoma (GTMP)
       Almutairi et al
      • Almutairi A.R.
      • Alkhatib N.S.
      • Oh M.
      • et al.
      Economic evaluation of talimogene laherparepvec plus ipilimumab combination therapy vs ipilimumab monotherapy in patients with advanced unresectable melanoma.
      Imlygic/ipilimumab vs ipilimumab362 0330.16 progression-free quality-adjusted life-years
      ACI indicates autologous chondrocyte implantation; CTMP, cell therapy medicinal product; DLBCL, diffuse large B-cell cell lymphoma; GTMP, gene therapy medicinal product; HSCT, hematopoietic stem cell transplant; KOOS: Knee injury and Osteoarthritis Outcome Score; MF, microfracture; N/A, not available; NNT, number needed to treat; TEP, tissue-engineered product.

      Risk of Bias

      The main risks of bias (Appendix Table S3 in Supplementary Materials 7 found at https://doi.org/10.1016/j.jval.2022.07.004) identified were conflict of interest, lack of generalizability (unknown prices or prices based on confidential agreements), and concerns about the adequacy of evidence and modeling of treatment benefit beyond the trial data (lack of detailed resources and unit costs, insufficient time horizon, lack of data on long-term efficacy and safety, and structural modeling choices).
      A common risk of bias arose from the inadequacy of the clinical evidence. Studies of Luxturna and ACI used evidence from RCTs (level 2 evidence).
      • Howick J.
      • Chalmers I.
      • Glasziou P.
      • et al.
      Explanation of the 2011 Oxford Centre for Evidence-Based Medicine (OCEBM) levels of evidence [background document]. Oxford Centre for Evidence-Based Medicine.
      The 2 studies of Yescarta compared the intervention group cohort and a historical control group after adjusting statistically for differences in the 2 cohorts (level 3 evidence). A study of cell therapy for ischemic stroke only used expert opinion (level 5 evidence), whereas all other studies compared single-arm intervention groups with historic controls without adjusting for differences in the 2 cohorts (level 4 evidence). These issues are commented on further in the discussion section.

      Discussion

      In the following sections, we pinpoint in more depth how the studies in this review addressed the 5 evidentiary challenges identified by Lloyd-Williams
      • Lloyd-Williams H.
      • Hughes D.A.
      A systematic review of economic evaluations of advanced therapy medicinal products.
      and discuss the implications of our findings for regulatory approval and Price & Reimbursement (P&R) of ATMPs in national health systems.

      Size and Design of Trials

      As far as medicine regulators (European Medicines Agency [EMA] and Food and Drug Administration) were concerned, the key trials for Strimvelis, Luxturna, and valoctocogene roxaparvovec had very low patient numbers, but this was not necessarily a barrier to evaluation. For example, despite considerable uncertainty, regulators accepted that Strimvelis and Luxturna showed demonstrable benefit and these medicines were approved under conditional marketing approval (CMA). Likewise, these medicines obtained recommendation for use in some national health services.
      • Ronco V.
      • Dilecce M.
      • Lanati E.
      • Canonico P.L.
      • Jommi C.
      Price and reimbursement of advanced therapeutic medicinal products in Europe: are assessment and appraisal diverging from expert recommendations?.
      Conversely, the low quality of evidence for valoctocogene roxaparvovec led to both the EMA and Food and Drug Administration (at that time) to reject marketing approval citing lack of effectiveness emerging from a preliminary analysis of a phase III study.,
      • Ozelo M.C.
      • Mahlangu J.
      • Pasi K.J.
      • et al.
      Valoctocogene roxaparvovec gene therapy for hemophilia A.
      The clinical studies of Strimvelis and Luxturna had long follow-up (18 years and 3 years, respectively) of clinically relevant outcomes, providing some reassurance that therapeutic benefit would be maintained, whereas the study of valoctocogene roxaparvovec was for only 6 months and did not report bleed events. These examples show that even when there are low patient numbers, the evidence can meet decision makers’ criteria for approval provided other aspects of the study design are appropriate.
      Other evaluations in this review pooled clinical data across multiple small studies. This can augment precision, but must be conducted with methodological rigor. Investigating the causes of the differences between studies may be more useful than estimating some average effect by uncritically pooling primary studies.
      • Song F.
      • Sheldon T.A.
      • Sutton A.J.
      • Abrams K.R.
      • Jones D.R.
      Methods for exploring heterogeneity in meta-analysis.

      Evidence on Efficacy and Comparative Effectiveness

      RCTs are considered high grade evidence of the treatment effect.
      • Howick J.
      • Chalmers I.
      • Glasziou P.
      • et al.
      Explanation of the 2011 Oxford Centre for Evidence-Based Medicine (OCEBM) levels of evidence [background document]. Oxford Centre for Evidence-Based Medicine.
      Studies of Luxturna and ACI obtained treatment effects from RCTs.
      • Gerlier L.
      • Lamotte M.
      • Wille M.
      • et al.
      The cost utility of autologous chondrocytes implantation using ChondroCelect® in symptomatic knee cartilage lesions in Belgium.
      ,
      • Mistry H.
      • Connock M.
      • Pink J.
      • et al.
      Autologous chondrocyte implantation in the knee: systematic review and economic evaluation.
      ,
      • Zimmermann M.
      • Lubinga S.J.
      • Banken R.
      • et al.
      Cost utility of voretigene neparvovec for biallelic RPE65-mediated inherited retinal disease.
      ,
      • de Windt T.S.
      • Sorel J.C.
      • Vonk L.A.
      • Kip M.M.A.
      • Ijzerman M.J.
      • Saris D.B.F.
      Early health economic modelling of single-stage cartilage repair. Guiding implementation of technologies in regenerative medicine.
      ,

      Sierra Sánchez J.F., Fraga Fuentes M.D., Arocas Casañ V. Condrocitos Humanos Autólogos. Reparación de Lesiones Del Cartílago Del Cóndilo Femoral de La Rodilla. Grupo GENESIS de La SEFH. https://gruposdetrabajo.sefh.es/genesis/genesis/Enlaces/InformesHosp_abc.htm?ml=1#C. Accessed August 9, 2022.

      Nevertheless, regulators and payers have accepted lower grade evidence for some ATMPs.
      • Hettle R.
      • Corbett M.
      • Hinde S.
      • et al.
      The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal.
      ,
      • Goring S.
      • Taylor A.
      • Müller K.
      • et al.
      Characteristics of non-randomised studies using comparisons with external controls submitted for regulatory approval in the USA and Europe: a systematic review.
      When RCT evidence is unavailable, it is important that analysts use appropriate methods to ensure that intervention and control groups are comparable. For example, our review includes 6 evaluations of Yescarta versus SOC for R/R DLBCL (Table 1). In these cases, the single-arm study ZUMA-1
      • Neelapu S.S.
      • Locke F.L.
      • Bartlett N.L.
      • et al.
      Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma.
      was compared with historical controls (SCHOLAR-1).
      • Crump M.
      • Neelapu S.S.
      • Farooq U.
      • et al.
      Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study.
      Two studies

      Roth JA, Sullivan SD, Lin VW, et al. Cost-effectiveness of axicabtagene ciloleucel for adult patients with relapsed or refractory large B-cell lymphoma in the United States [published correction appears in J Med Econ. 2018;21(12):1255]. J Med Econ. 2018;21(12):1238–1245.

      ,
      • Corbett M.
      • Duarte A.
      • Melton H.
      • et al.
      Axicabtagene ciloleucel for treating diffuse large B-cell lymphoma, mediastinal B-cell lymphoma and follicular lymphoma. Single Technology Appraisal.
      (essentially based on the same model) statistically matched the treatment and SOC cohorts and stated that the matching did not affect the results.

      Evidence and Modeling Methods Used to Describe Disease Progression and Long-Term Effects

      In a model, there are often a number of options about how disease progression or overall survival can be predicted after the time horizon of the clinical study. For example, using data from the same clinical study, some of the Yescarta economic studies
      • Tice J.A.
      • Walsh J.M.E.
      • Otuonye I.
      • et al.
      Chimeric antigen receptor T-cell therapy for B-cell cancers: effectiveness and value.
      measured clinical response (partial or complete) and survival conditional on response, whereas others

      Roth JA, Sullivan SD, Lin VW, et al. Cost-effectiveness of axicabtagene ciloleucel for adult patients with relapsed or refractory large B-cell lymphoma in the United States [published correction appears in J Med Econ. 2018;21(12):1255]. J Med Econ. 2018;21(12):1238–1245.

      measured the “cure rate” using a mixture cure fraction model
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      Estimating and modeling the cure fraction in population-based cancer survival analysis.
      and survival conditional on cure. “Response” and “cure” are not synonyms. For example, the ZUMA-1
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      Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma.
      trial estimated that 39% of patients had “ongoing response,” that is, durable remission, considerably fewer than the 50% estimated by the mixture cure model. A mixture cure model is not based on any clinical definition of a cure or information on the patient’s pathology. The cure fraction is derived from a perceived “statistical” property of the survival curve, that is, the point at which survival is estimated to plateau. Hence, although it is tempting to interpret the output of the mixture cure model in clinical terms such as the proportion of patients in long-term remission or similar terms, such an interpretation is not warranted. In this case, the apparent disconnect between the clinical response rate and the modeled cure fraction was noted by the evaluation committee at NICE, but not considered to be a major limitation. Nevertheless, analysts and decision makers should be aware of these issues.
      Another potentially important source of uncertainty is whether the early treatment effect might diminish (wane) over time. In the example of Yescarta, several approaches were used across the different studies, including extrapolating based on parametric functions,
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      Chimeric antigen receptor T-cell therapy for B-cell cancers: effectiveness and value.
      assumptions based on optimistic and pessimistic scenarios,
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      • et al.
      Cost effectiveness of chimeric antigen receptor T-cell therapy in relapsed or refractory pediatric B-cell acute lymphoblastic leukemia.
      assumptions about minimal further risk if a patient survives 5 years without progression,
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      • Barnes J.I.
      • et al.
      Cost effectiveness of chimeric antigen receptor T-cell therapy in relapsed or refractory pediatric B-cell acute lymphoblastic leukemia.
      or minimal further risk for patients identified as “cured” by the mixture cure fraction model.

      Roth JA, Sullivan SD, Lin VW, et al. Cost-effectiveness of axicabtagene ciloleucel for adult patients with relapsed or refractory large B-cell lymphoma in the United States [published correction appears in J Med Econ. 2018;21(12):1255]. J Med Econ. 2018;21(12):1238–1245.

      Lin et al
      • Lin J.K.
      • Muffly L.S.
      • Spinner M.A.
      • Bames J.I.
      • Owens D.K.
      • Goldhaber-Fiebert J.
      Cost-effectiveness of chimeric antigen receptor T-cell therapy in multiply relapsed or refractory adult large B-cell lymphoma.
      noted that industry-funded analyses

      Roth JA, Sullivan SD, Lin VW, et al. Cost-effectiveness of axicabtagene ciloleucel for adult patients with relapsed or refractory large B-cell lymphoma in the United States [published correction appears in J Med Econ. 2018;21(12):1255]. J Med Econ. 2018;21(12):1238–1245.

      of Yescarta generally used more favorable assumptions and estimated lower ICURs than nonindustry studies.
      The example of Luxturna also permits an insight into how different assumptions about waning can influence results. Extrapolating from the same short term clinical study data, studies differed in how long the gene therapy would prevent deterioration of vision. Those that assumed a longer time free of progression consequently also predicted that the acquisition cost of the therapy would be offset by savings in healthcare and costs to wider society. As with Yescarta, industry funding may have influenced authors in their choice of base-case assumptions.

      Evidence on Health-Related QOL

      Although some ATMPs may aim to offer increased survival, others aim to relieve diseases that affect QOL. These data are often lacking in clinical studies. In the study of Luxturna, the main areas of uncertainty centered around mapping visual acuity to utility.
      • Zimmermann M.
      • Lubinga S.J.
      • Banken R.
      • et al.
      Cost utility of voretigene neparvovec for biallelic RPE65-mediated inherited retinal disease.
      Given a lack of data in the target population, the sponsor used data from patients with another retinal condition. In this case, the NICE decision committee agreed with the sponsor that the gains in visual acuity would translate into large gains in QOL.
      Voretigene neparvovec for treating inherited retinal dystrophies caused by RPE65 gene mutations. National Institute for Health and Care Excellence.
      Other studies reached similar conclusions based on the opinion of clinical experts about patient utility.
      • Johnson S.
      • Buessing M.
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      • Pitluck S.
      • Ciulla T.A.
      Cost-effectiveness of voretigene Neparvovec-rzyl vs standard care for RPE65-mediated inherited retinal disease.

      Generalizability

      The price of ATMPs can limit the generalizability of a study given that prices in one jurisdiction do not apply to others, or price data are confidential. By comparing reported results, we made some very approximate guesses about what these confidential prices might be. For example, in the case of Luxturna, at the list price of $850 000 per patient, the ICUR estimated by NICE was almost GBP100 000 ($143 000)/QALY, well in excess of the usual reference threshold.
      • Viriato D.
      • Bennett N.
      • Sidhu R.
      • et al.
      An economic evaluation of voretigene neparvovec for the treatment of biallelic RPE65-mediated inherited retinal dystrophies in the UK.
      Nevertheless, Luxturna was recommended in Germany at a reported discounted price of €345 000 ($489 000) per patient,
      • Ronco V.
      • Dilecce M.
      • Lanati E.
      • Canonico P.L.
      • Jommi C.
      Price and reimbursement of advanced therapeutic medicinal products in Europe: are assessment and appraisal diverging from expert recommendations?.
      and although the discount in England was confidential, a similar price to Germany would bring the ICUR much closer toward NICEs usual threshold.
      • Viriato D.
      • Bennett N.
      • Sidhu R.
      • et al.
      An economic evaluation of voretigene neparvovec for the treatment of biallelic RPE65-mediated inherited retinal dystrophies in the UK.

      Criteria for HTA for Adoption Into Health Services

      There has been debate about whether ATMP should be evaluated (or priced or reimbursed) using different criteria to other therapies.
      • Hampson G.
      • Towse A.
      • Pearson S.D.
      • Dreitlein W.B.
      • Henshall C.
      Gene therapy: evidence, value and affordability in the US health care system.
      Some gene therapies potentially could produce lifelong benefits, but with high financial risk (a one-off treatment with uncertain outcome) and considerable evidentiary uncertainty (difficulty of conducting RCTs in rare diseases with no effective alternative therapies). Some of the medicines in this review have these properties. Strimvelis, Zolgensma, and chimeric antigen receptor T-cell therapy (CAR T) are in the top-right quadrant (Appendix Fig. S2 in Supplementary Materials 4 found at https://doi.org/10.1016/j.jval.2022.07.004) and could be considered to offer a step change in clinical management, but they are also among the medicines with the highest prices ever seen. Payers have shown willingness to adopt these therapies despite very high ICURs, often with outcome-based reimbursement agreements. At GBP 1.79 million ($2.56 million) Zolgensma is one of the most expensive drugs worldwide and was recommended by NICE for very young patients.
      NICE final draft guidance approves life-changing gene therapy for treating spinal muscular atrophy. National Institute for Health and Care Excellence.
      Strimvelis has a price of €594 000 ($841 000) per person and is recommended by health authorities in England and Italy. Kymriah and Yescarta were recommended in England at a confidential discounted price under the Cancer Drugs Fund.
      Cancer drugs fund managed access agreement axicabtagene ciloleucel for treating diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma after 2 or more systemic therapies. National Institute for Health and Care Excellence.
      Valoctocogene roxaparvovec for hemophilia A falls in the bottom right quadrant (Appendix Fig. S4 in Supplementary Materials 4 found at https://doi.org/10.1016/j.jval.2022.07.004). Rind et al
      • Agboola F.
      • Rind D.M.
      • Walton S.M.
      • Herron-Smith S.
      • Quach D.
      • Pearson S.D.
      The effectiveness and value of emicizumab and valoctocogene roxaparvovec for the management of hemophilia A without inhibitors.
      estimated that the expected lifetime cost savings compared with factor VIII might be $5 million per patient, but regulators in Europe and the United States denied marketing approval
      • Withdrawal of application for the marketing authorization of roctavian (valoctocogene roxaparvovec)
      because the effectiveness of this gene therapy was then thought to wane over time. Payers are also sometimes disposed to reject ATMPs. EMA gave CMA for Zynteglo for a rare blood disorder, but the sponsor was not able to demonstrate positive net benefit for payers in key European systems.
      • Ronco V.
      • Dilecce M.
      • Lanati E.
      • Canonico P.L.
      • Jommi C.
      Price and reimbursement of advanced therapeutic medicinal products in Europe: are assessment and appraisal diverging from expert recommendations?.
      ,
      Is Blue Bird Bio’s European exit a canary in the coal mine? Linkedin.
      ,
      NICE Appraisal consultation document. Betibeglogene autotemcel for treating transfusion-dependent beta-thalassaemia.
      In contrast, darvadstrocel (Alofisel) was adopted by Spain, France, and Germany
      • Ronco V.
      • Dilecce M.
      • Lanati E.
      • Canonico P.L.
      • Jommi C.
      Price and reimbursement of advanced therapeutic medicinal products in Europe: are assessment and appraisal diverging from expert recommendations?.
      ,
      Ministry of Health, Consumption and Welfare, Spain
      at a price of $75 000 to $88 000 based on minimal information about cost-effectiveness.
      • Castañeda-Macías I.
      • Selvi Sabater P.
      Darvadstrocel Para El Tratamiento de Fístulas Perianales Complejas Refractarias En Enfermedad de Crohn. Darvadstrocel Para El Tratamiento de Fístulas Perianalescomplejas Refractarias En Enfermedad de Crohn.
      Stakeholders state that they sometimes find it difficult to anticipate which medicines are likely to be financed.
      Is Blue Bird Bio’s European exit a canary in the coal mine? Linkedin.
      Consistency and clarity about the evidence requirements and criteria for P&R would help stakeholders navigate the HTA process and target investment capital more effectively.
      • McAteer H.
      • Cosh E.
      • Freeman G.
      • Pandit A.
      • Wood P.
      • Lilford R.
      Cost-effectiveness analysis at the development phase of a potential health technology: examples based on tissue engineering of bladder and urethra.
      ,
      • Moreno S.G.
      • Epstein D.
      The price of innovation – the role of drug pricing in financing pharmaceutical innovation. A conceptual framework.
      The forthcoming European Union regulation on HTA is intended as a step toward this goal with the harmonization of clinical evidence assessment.
      Health technology assessment regulation. European Medicines Agency.
      Not all ATMPs offer step changes. There are several examples where benefits are modest and incremental (Appendix Fig. S3 in Supplementary Materials 4 found at https://doi.org/10.1016/j.jval.2022.07.004). It would seem reasonable that the default position should be for routine HTA evidentiary requirements, procedures, and criteria to apply in these cases.

      Managing Uncertainty

      To manage high uncertainty, regulatory agencies are increasingly granting CMA or exceptional circumstances and mandating postauthorization safety and efficacy studies.
      First two CAR-T cell medicines recommended for approval in the European Union. European Medicines Agency.
      ,
      • Management I
      List of medicinal products under additional monitoring. European Medicines Agency.
      Between 2006 and 2020, a total of 59 medicines were approved with CMA, 50% of these in the last 4 years.
      Annual Report 2020. The European Medicines Agency’s Contribution to Science, Medicines and Health in 2020. European Medicines Agency.
      Likewise, payers faced with ATMPs that demand an up-front payment of hundreds of thousands of dollars, coupled with uncertainty about whether a long-term cure will be achieved, are increasingly turning to outcome-based reimbursement agreements. Payers are also concerned about impact on budgets as new ATMPs are approved or therapies approved in one indication show promise in others. For example, there are currently 3 ongoing phase III RCTs that aim to explore the benefits of moving the currently approved CD-19 CAR Ts in R/R DLBCL into the second line setting by challenging autologous stem cell transplant (NCT03391466, NCT03570892, NCT03575351).
      • Al-Juhaishi T.
      • Ahmed S.
      CAR-T in B-cell lymphomas: the past, present, and future.
      Hence, health ministries have initiated proprietary data collection systems to support outcome-based reimbursement and monitor clinical progress.
      • Angulo-Pueyo E.
      • Bernal-Delgado E.
      A new information system to assess the therapeutic value of drugs in real practice. HSPM.
      Cross-border initiatives such as the EU Data Analysis and Real World Interrogation Network are still in early stages. Given that these are often rare diseases, data protectionism will limit researchers’ ability to resolve key uncertainties. European regulators and national payers should accelerate efforts for alignment and apply minimum common standards.
      • Facey K.M.
      • Rannanheimo P.
      • Batchelor L.
      • Borchardt M.
      • de Cock J.
      Real-world evidence to support Payer/HTA decisions about highly innovative technologies in the EU-actions for stakeholders.
      ,
      • Eichler H.G.
      • Adams R.
      • Andreassen E.
      • et al.
      Exploring the opportunities for alignment of regulatory postauthorization requirements and data required for performance-based managed entry agreements.
      Furthermore, intervention registries do not address the problem of uncertainty about outcomes with current SOC.
      • Eichler H.G.
      • Adams R.
      • Andreassen E.
      • et al.
      Exploring the opportunities for alignment of regulatory postauthorization requirements and data required for performance-based managed entry agreements.
      Therefore, it may also be advantageous consider greater use of “disease” registries rather than “intervention” registries.
      • Gliklich R.E.
      • Dreyer N.A.
      • Leavy M.B.
      Registries for Evaluating Patient Outcomes. National Library of Medicine.
      ,
      • Portal atrofia muscular espinhal

      Use of ATMP Without Centralized Marketing Approval

      Commercial ACI therapies have not prospered in Europe despite obtaining both marketing authorization from EMA and adoption recommendations from HTA agencies in England and Spain.
      Getting ready for advanced therapy medicinal products (ATMPs) in Europe. Alliance for Regenerative Medicine.
      ,
      • Autologous chondrocyte implantation for treating symptomatic articular cartilage defects of the knee
      National Institute for Health and Care Excellence.
      One of the reasons suggested for withdrawal of the commercial ACIs was that hospitals were able to obtain similar products more cheaply under hospital exemption.
      • Hills A.
      • Awigena-Cook J.
      • Genenz K.
      • et al.
      An assessment of the hospital exemption landscape across European Member States: regulatory frameworks, use and impact.
      European hospital exemption regulation allows national regulators, without centralized approval, to authorize and supervise the nonroutine use of an innovative therapy for patients who lack therapeutic alternatives. Nevertheless, there is wide variation between member states concerning the authorization process, evidence requirements, conditions for use and supervision arrangements, and a general lack of transparency.
      • Hills A.
      • Awigena-Cook J.
      • Genenz K.
      • et al.
      An assessment of the hospital exemption landscape across European Member States: regulatory frameworks, use and impact.

      Risk of Bias Arising From Conflict of Interest

      This review has noted a particular risk of bias associated with conflict of interest. The studies of CAR T-cell therapy and Luxturna sponsored by manufacturers seemed to predict greater health gains than those produced by research centers without direct financial interest, although the models were based essentially on the same landmark clinical studies. HTA agencies such as NICE and Scottish Medicines Agency have broadly accepted the manufacturers’ estimates in these 2 cases. Given that these models are predictions of future effect based on extrapolation from limited current evidence, it is impossible of course to know the “true” effect size. In almost all other respects, these models scored highly in terms of the quality of their analyses and reporting. Nevertheless, industry-funded models sometimes seem to make subtle choices that favor the sponsor, and payers need to be mindful of the risk of bias when evaluating such models, ensure thorough validation, and continue evidence generation.
      • Fabbri A.
      • Lai A.
      • Grundy Q.
      • Bero L.A.
      The influence of industry sponsorship on the research agenda: a scoping review.

      Strengths and Weaknesses of This Review

      We have systematically reviewed a heterogeneous set of economic studies of ATMP across multiple pathologies and countries. This enabled us to take a broad overview of the state-of-the-art in economic evaluation in these areas and compare sources of evidence, modeling assumptions, and risk of bias where possible. This approach has a number of weaknesses. Comparison of economic analyses across countries must always be undertaken cautiously given that outcomes are conditioned by the local healthcare system, prices, and treatment guidelines. Definition and classification of ATMPs are usually conducted by regulatory authorities during the marketing approval process. In cases where marketing approval was not yet requested, we classified the therapies according to our interpretation of current European Union regulation. Studies were not always clear about the sources of their clinical data. Where possible, we followed up citations where we needed more information about sample sizes, follow-up, and other details. In publications where reporting was restricted by commercial confidentiality, we made educated guesses about the QALYs associated with ATMP strategies based on the available information. Likewise, price data were often confidential. By comparing reported results, we made some very approximate guesses about what these confidential prices might be in different jurisdictions.

      Conclusions and Recommendations for Analysts and Policy Makers

      Our main findings and the conclusions we draw from these are summarized in Table 5.
      Table 5Main conclusions and recommendations.
      DomainFinding of the literature reviewImplications for regulatory approval, HTA, pricing, and reimbursementRecommendations
      Size and design of clinical studiesEvaluations of ATMP in rare diseases often are based on studies with very few patients.Regulators and payers have accepted small studies provided other aspects of study design are adequate.Appropriate length of follow-up and endpoints are crucial. Sources of between-study heterogeneity must be explored.
      Efficacy and clinical effectivenessRCTs are often infeasible in indications where standard of care is ineffective.Regulators and payers have accepted well-conducted nonrandomized study designs.Analyses should take account of baseline differences between intervention and control groups.
      Modeling disease progression and extrapolationClinical studies may be short term or use surrogate outcomes.Regulators and payers are concerned that treatment effects may be temporary or not lead to measurable and clinically relevant benefits for patients.Use of statistical models such as mixture cure fraction models should be undertaken cautiously and results compared with clinical measures of freedom from remission.
      Health-related quality of lifeClinical studies often lack quality of life data.Regulators and payers are demanding outcomes relevant for patients.Clinical studies should include generic quality of life instruments.
      GeneralizabilityBetween-country differences in prices of ATMPs and reimbursement schemes may be threats to generalizability of economic studies.Prices and reimbursement schemes are often confidential.Economic evaluations should conduct sensitivity analyses and threshold analyses for a plausible range of prices.
      Criteria for HTAHTA criteria set by payers for P&R are often opaque and inconsistent.Payers should aim for consistency and clarity. Routine HTA evidentiary requirements and criteria should apply unless there is a strong case otherwise. Manufacturers need to ensure they design clinical studies that align with HTA criteria.
      Managing uncertaintyATMP are often associated with high financial and clinical uncertainty.Market entry is increasingly initiated using outcome-based reimbursement agreements.There is a patchwork of post marketing surveillance platforms. Regulators and national payers should aim for compatibility and interchange of data.
      Use of hospital exemptionNational medicine regulatory agencies in the European community can authorize and supervise some ATMP without European Medicines Agency centralized approval.Hospital exemption should be reviewed to ensure transparency and best interests of patients.
      Risk of biasEconomic models can be highly sensitive to assumptions. In some cases, industry-funded economic studies estimated more favorable net benefit.HTA agencies are increasingly reliant on industry dossiers to provide clinical and economic evidence.Careful critical evaluation of industry dossiers is required, alongside comparison with non–industry-funded models where possible.
      ATMP indicates advanced therapy medicinal product; HTA, health technology assessment; P&R, Price & Reimbursement; RCT, randomized controlled trial.
      Evaluation of ATMPs is challenging. Nevertheless, innovation should not proceed without evaluation.
      • Hirst A.
      • Philippou Y.
      • Blazeby J.
      • et al.
      No surgical innovation without evaluation: evolution and further development of the IDEAL framework and recommendations.
      Regulators and payers have accepted small studies, particularly in rare diseases, provided other aspects of study design (follow-up, adequacy of endpoints) are adequate, as shown by Strimvelis and Luxturna. Heterogeneity must be considered if data are pooled.
      Single-arm studies are often used where current SOC is considered ineffective. Regulators have accepted these to demonstrate efficacy, but this presents a challenge for HTA where assessment of added therapeutic benefit and value for money requires a quantitative analysis against a comparator. This review has identified various approaches using historical controls. Analysts need to be transparent about the assumptions and limitations inherent in their chosen method and properly quantify the degree of uncertainty.
      • Hettle R.
      • Corbett M.
      • Hinde S.
      • et al.
      The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal.
      Studies in these therapies are sometimes short term and use surrogate outcomes with weak association with QOL and survival. This is problematic and regulators have rejected applications for marketing approval in such cases. This review has identified various statistical approaches to gain further insight from the available data, such as mixture cure fraction models. As before, analysts need to be transparent about their assumptions and limitations. Clinical trialists (and their sponsors) should be aware of the need to collect health-related QOL, preferably using generic instruments, alongside other measures.
      Where clinical data are immature (short term), regulators may place conditions on the marketing approval for additional monitoring, or payers may collect further data as a requirement of managed entry agreements. Hence, there is a patchwork of postmarketing surveillance platforms operated by different actors (regulators, patient organizations, healthcare providers, and manufacturers) and lack of sharing. Sponsors should aim for collaboration, compatibility, and interchange of data registers, especially for rare diseases.
      P&R decisions are assessed by the competent authority in each country. So far in the field of ATMP, only Kymriah and Yescarta have achieved reimbursement in the European major 5 countries (Italy, UK, France, Germany, and Spain). Opinions differed about Holoclar, Imyligic, Strimvelis, Spherox, and Alofisel. Although different criteria are understandable, payers should aim for consistency and clarity to facilitate developers’ decisions about investment. Meaningful engagement of all stakeholders (including patient groups) is needed to properly value ATMP. There has been debate about whether HTA agencies should apply “special” criteria for ATMP.
      • Trenaman L.
      • Pearson S.D.
      • Hoch J.S.
      How are incremental cost-effectiveness, contextual considerations, and other benefits viewed in health technology assessment recommendations in the United States?.
      ,
      • Ten Ham R.M.T.
      • Frederix G.W.J.
      • Wu O.
      • et al.
      Key considerations in the health technology assessment of advanced therapy medicinal products in Scotland, The Netherlands, and England.
      As a general rule, it would seem reasonable that routine HTA evidence requirements and criteria should be applied unless there is a strong case otherwise. Hospital exemption should be reviewed to ensure transparency and best interests of patients. Finally, payers increasingly rely on industry-sponsored economic analyses but critical review needs to be exercised because of conflict of interests.

      Article and Author Information

      Author Contributions: Concept and design: Olry de Labry-Lima, Ponce-Polo, Epstein
      Acquisition of data: Olry de Labry-Lima, Ponce-Polo, García-Mochón, Ortega-Ortega, Pérez-Troncoso, Epstein
      Analysis and interpretation of data: Olry de Labry-Lima, Ponce-Polo, García-Mochón, Ortega-Ortega, Epstein
      Drafting of the manuscript: Olry de Labry-Lima, Ponce-Polo, García-Mochón, Ortega-Ortega, Epstein
      Critical revision of the paper for important intellectual content: Epstein
      Statistical analysis: Olry de Labry-Lima, Ponce-Polo, Pérez-Troncoso, Epstein
      Provision of study materials or patients: Ortega-Ortega,
      Obtaining funding: Epstein
      Administrative, technical, or logistic support: Pérez-Troncoso
      Supervision: Epstein
      Conflict of Interest Disclosures: The authors reported no conflicts of interest. Dr Epstein is an editor for Value in Health and had no role in the peer-review process of this article.
      Funding/Support: This work was supported by grant PID2019-105597RA-100 from the Spanish Ministry of Science, Innovation and Universities .
      Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
      Acknowledgment: The authors thank Camila Higueras Callejón, librarian of the Andalusian School of Public Health.

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