The aim of this review was to summarize all available evidence on the cost effectiveness of potentially curative gene therapies and identify challenges that economic evaluations face in this area.
We conducted a systematic review of four databases (PubMed/MEDLINE, Embase, CINAHL, EconLit) and grey literature sources. We conducted the search on August 23, 2019 and updated it on November 26, 2020. We included all English, French and Spanish language studies that addressed a gene therapy that had received regulatory approval or had entered a phase III trial, and also reported on costs related to the therapy. Critical appraisal was conducted to assess quality of reporting in included studies.
Fifty-six studies were identified. Of the 42 full economic evaluations, 71% (n = 30) evaluated chimeric antigen receptor T-cell therapies, most used either a Markov model (n = 17, 40%) and/or a partitioned survival model (n = 17, 40%), and 76% (n = 32) adopted a public or private payer perspective. The model characteristics with the greatest impact on cost effectiveness included assumptions about the efficacy of the treatment and the comparators used.
All gene therapies in this review were shown to be more effective than their comparators, although due to high costs not all were considered cost effective at standard cost-effectiveness thresholds. Despite their high cost, some gene therapies have the potential to dominate the alternatives in conditions with high mortality/disability. The choice of comparator and assumptions regarding long-term effectiveness had substantial impacts on cost-effectiveness estimates and need to be carefully considered. Both the quality of inputs and the quality of reporting were highly variable.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Stein R. Zolgensma From Novartis Is The Most Expensive Drug Ever Approved : Shots - Health News : NPR [Internet]. 2019. https://www.npr.org/sections/health-shots/2019/05/24/725404168/at-2-125-million-new-gene-therapy-is-the-most-expensive-drug-ever. Accessed 31 Mar 2020.
Center for Disease Control. Publications and Information from the National Center for Health Statistics - National Vital Statistics Report [Internet]. 2019. https://www.cdc.gov/nchs/products/index.htm. Accessed 31 Mar 2020.
D’Amico A, Mercuri E, Tiziano FD, Bertini E. Spinal muscular atrophy [Internet]. Orphanet J Rare Dis. 2011. https://doi.org/10.1186/1750-1172-6-71.
Quinn C, Young C, Thomas J, Trusheim M. Estimating the clinical pipeline of cell and gene therapies and their potential economic impact on the US healthcare system. Value Health. 2019;22:621–6.
Drummond MF, Neumann PJ, Sullivan SD, Fricke FU, Tunis S, Dabbous O, et al. Analytic considerations in applying a general economic evaluation reference case to gene therapy. Value Health. 2019;22:661–8.
Pearson SD, Ollendorf DA, Chapman RH. New cost-effectiveness methods to determine value-based prices for potential cures: what are the options? Value in Health. 2019:22(6);656–660. https://doi.org/10.1016/j.jval.2019.01.012
Petrou P. Is it a Chimera? A systematic review of the economic evaluations of CAR-T cell therapy. Expert Rev Pharmacoecon Outcomes Res. 2019;19:529–36.
Whittington MD, McQueen RB, Campbell JD. Valuing chimeric antigen receptor T-cell therapy: Current evidence, uncertainties, and payment implications. J Clin Oncol [Internet]. 2020;38:359–66. https://doi.org/10.1200/JCO.19.01558.
Fiorenza S, Ritchie DS, Ramsey SD, Turtle CJ, Roth JA. Value and affordability of CAR T-cell therapy in the United States. Bone Marrow Transplant [Internet]. 2020;55:1706–15. https://doi.org/10.1038/s41409-020-0956-8.
Lloyd-Williams H, Hughes DA. A systematic review of economic evaluations of advanced therapy medicinal products. Br J Clin Pharmacol. 2021;87(6):2428–2443.
ten Ham RMT, Klungel OH, Leufkens HGM, Frederix GWJ. A review of methodological considerations for economic evaluations of gene therapies and their application in literature. Value Health. 2020;23:1268–80.
Trenaman L, Pearson SD, Hoch JS. How are incremental cost-effectiveness, contextual considerations, and other benefits viewed in health technology assessment recommendations in the United States? Value Health. 2020;23:576–84.
CADTH. Gene Therapy: International Regulatory and Health Technology Assessment (HTA) Activities and Reimbursement Status. [Internet] 2018. https://www.cadth.ca/gene-therapy-international-regulatory-and-health-technology-assessment-activities-and-reimbursement. Accessed 31 Mar 2020.
CADTH. Grey Matters: a practical tool for searching health-related grey literature [Internet]. 2019a. https://www.cadth.ca/resources/finding-evidence/grey-matters. Accessed 31 Mar 2020.
The Joanna Briggs Institute. The systematic review of economic evaluation evidence. [Internet]. 2014. https://nursing.lsuhsc.edu/JBI/docs/ReviewersManuals/Economic.pdf. Accessed 1 June 2019.
Husereau D, Drummond M, Petrou S, Carswell C, Moher D, Greenberg D, et al. Consolidated Health Economics Evaluation Reporting Standards (CHEERS) statement. BMJ. 2013;346:f1049. https://doi.org/10.1136/bmj.f1049.
Tyndall J. AACODS Checklist [Internet]. 2010. http://dspace.flinders.edu.au/dspace/. Accessed 1 June 2019.
Internal Revenue Service. Yearly Average Currency Exchange Rates - Internal Revenue Service [Internet]. 2020. https://www.irs.gov/individuals/international-taxpayers/yearly-average-currency-exchange-rates. Accessed 31 Mar 2020.
US Bureau of Labor Statistics. Consumer Price Index [Internet]. 2018. https://www.bls.gov/news.release/archives/cpi_02142018.pdf. Accessed 31 Mar 2020.
US Bureau of Labor Statistics. Consumer Price Index [Internet]. 2019. https://www.bls.gov/news.release/archives/cpi_02132019.pdf. Accessed 31 Mar 2020.
ICER. Voretigene neparvovec for biallelic rpe65-mediated retinal disease: effectiveness and value. [Internet] 2018. http://icer-review.org/wp-content/uploads/2017/06/MWCEPAC_VORETIGENE_EVIDENCE_REPORT_01122018.pdf. Accessed 26 Nov 2020.
Almutairi AR, Alkhatib NS, Oh M, Curiel-Lewandrowski C, Babiker HM, Cranmer LD, et al. Economic Evaluation of talimogene laherparepvec plus ipilimumab combination therapy vs ipilimumab monotherapy in patients with advanced unresectable melanoma. JAMA Dermatol. 2019;155:22–8.
Whittington MD, McQueen RB, Ollendorf DA, Kumar VM, Chapman RH, Tice JA, et al. Long-term survival and cost-effectiveness associated with axicabtagene ciloleucel vs chemotherapy for treatment of B-cell lymphoma. JAMA Netw open. 2019;2:e190035.
Whittington MD, McQueen RB, Ollendorf DA, Kumar VM, Chapman RH, Tice JA, et al. Long-term survival and value of chimeric antigen receptor T-cell therapy for pediatric patients with relapsed or refractory leukemia. JAMA Pediatr. 2018;172:1161–8.
NICE. Tisagenlecleucel for treating relapsed or refractory diffuse large B-cell lymphoma after 2 or more systemic therapies. [Internet]. 2019. https://www.nice.org.uk/guidance/indevelopment/gid-ta10269. Accessed 26 Nov 2020.
Cher BP, Gan KY, Aziz MIA, Lin L, Hwang WYK, Poon LM, 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. J Med Econ [Internet]. 2020;23:1321–9. https://doi.org/10.1080/13696998.2020.1808981.
Thielen FW, van Dongen-Leunis A, Arons AMM, Ladestein JR, Hoogerbrugge PM, 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. Eur J Haematol. 2020;105:203–15.
Santasusana R, De Andrés SA, García-Muñoz N, Gostkorzewicz J, Martínez Llinàs D, et al. Cost-effectiveness analysis of tisagenlecleucel in the treatment of relapsed or refractory B-cell acute lymphoblastic Leukaemia in children and young adults in Spain. Clin Outcomes Res. 2020;12:253–64.
Furzer J, Gupta S, Nathan PC, Schechter T, Pole JD, Krueger J, et al. Cost-effectiveness of tisagenlecleucel vs standard care in high-risk relapsed pediatric acute lymphoblastic leukemia in Canada. JAMA Oncol. 2020;6:393–401.
NCPE. Tisagenlecleucel (Kymriah®) for pALL [Internet]. 2019a. http://www.ncpe.ie/drugs/tisagenlecleucel-kymriah-for-all/. Accessed 26 Nov 2020.
NCPE. Tisagenlecleucel (Kymriah®) for DLBCL [Internet]. 2019b. http://www.ncpe.ie/drugs/tisagenlecleucel-kymriah-for-dlbcl/. Accessed 26 Nov 2020.
NCPE. Axicabtagene Ciloleucel (Yescarta®) [Internet]. 2020a. http://www.ncpe.ie/drugs/axicabtagene-ciloleucel-yescarta/. Accessed 26 Nov 2020.
SMC. axicabtagene ciloleucel (Yescarta) [Internet]. 2019a. https://www.scottishmedicines.org.uk/medicines-advice/axicabtagene-ciloleucel-yescarta-resubmission-smc2189/. Accessed 26 Nov 2020.
SMC. tisagenlecleucel (Kymriah) [Internet]. 2019b. https://www.scottishmedicines.org.uk/medicines-advice/tisagenlecleucel-kymriah-fullsubmission-smc2129/. Accessed 26 Nov 2020.
Roth JA, Sullivan SD, Lin VW, Bansal A, Purdum AG, Navale L, et al. Cost-effectiveness of axicabtagene ciloleucel for adult patients with relapsed or refractory large B-cell lymphoma in the United States. J Med Econ [Internet]. 2018;21:1238–45. https://doi.org/10.1080/13696998.2018.1529674.
SMC. tisagenlecleucel (Kymriah) [Internet]. 2019. https://www.scottishmedicines.org.uk/medicines-advice/tisagenlecleucel-kymriah-resubmission-smc2200/. Accessed 26 Nov 2020.
CADTH. Tisagenlecleucel for diffuse large B-cell lymphoma: economic review report. CADTH Optim Use Rep. 2019;9:1–66.
CADTH. Axicabtagene Ciloleucel for Diffuse Large B-Cell Lymphoma: Economic Review Report. [Internet]. 2019. https://www.cadth.ca/sites/default/files/pdf/car-t/ct0002-axicabtagene-ciloleucel-economic-report-redacted.pdf. Accessed 26 Nov 2020.
NICE. Axicabtagene ciloleucel for treating diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma after 2 or more systemic therapies. [Internet]. 2019. https://www.nice.org.uk/guidance/ta559/resources/managed-access-agreement-january-2019-pdf-6660053245. Accessed 26 Nov 2020.
Lin JK, Lerman BJ, Barnes JI, Boursiquot BC, Tan YJ, Robinson AQL, et al. Cost effectiveness of chimeric antigen receptor T-cell therapy in relapsed or refractory pediatric B-cell acute lymphoblastic leukemia. J Clin Oncol [Internet]. 2018. https://doi.org/10.1200/JCO.2018.79.0642.
Lin JK, Muffly LS, Spinner MA, Barnes JI, Owens DK, Goldhaber-Fiebert JD. Cost effectiveness of chimeric antigen receptor T-cell therapy in multiply relapsed or refractory adult large B-cell lymphoma. J Clin Oncol. 2019;37:2105–19.
ICER. Chimeric antigen receptor T-cell therapy for B-cell cancers: effectiveness and value. [Internet]. 2017. https://icer.org/wp-content/uploads/2020/10/ICER_CAR_T_Draft_Evidence_Report_121917.pdf. Accessed 26 Nov 2020.
Sarkar RR, Gloude NJ, Schiff D, Murphy JD. Cost-Effectiveness of chimeric antigen receptor T-cell therapy in pediatric relapsed/refractory B-cell acute lymphoblastic leukemia. J Natl Cancer Inst. 2019;111:719–26.
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. Pharmacoeconomics [Internet]. 2019;37:1209–17. https://doi.org/10.1007/s40273-019-00799-0.
NICE. Tisagenlecleucel for treating relapsed or refractory B-cell acute lymphoblastic leukaemia in people aged up to 25 years. [Internet]. 2018. https://www.nice.org.uk/guidance/ta554. Accessed 26 Nov 2020.
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. PharmacoEconomics Open [Internet]. 2019;3:151–61. https://doi.org/10.1007/s41669-018-0102-3.
NICE. Strimvelis for treating adenosine deaminase deficiency-severe combined immunodeficiency. [Internet]. 2019. https://www.nice.org.uk/guidance/hst7. Accessed 26 Nov 2020.
Fleeman N, Bagust A, Boland A, Beale S, Richardson M, Krishan A, et al. Talimogene laherparepvec for treating metastatic melanoma: an evidence review group perspective of a NICE single technology appraisal. Pharmacoeconomics. 2017;35:1035–46.
Johnson S, Buessing M, O’Connell T, Pitluck S, Ciulla TA. Cost-effectiveness of voretigene neparvovec-rzyl vs standard care for RPE65-mediated inherited retinal disease. JAMA Ophthalmol. 2019;137(10):1115–1123.
Zimmermann M, Lubinga SJ, Banken R, Rind D, Cramer G, Synnott PG, et al. Cost utility of voretigene neparvovec for biallelic RPE65-mediated inherited retinal disease. Value Health. 2019;22:161–7.
Farmer C, Bullement A, Packman D, Long L, Robinson S, Nikram E, et al. Voretigene neparvovec for treating inherited retinal dystrophies caused by rpe65 gene mutations: an evidence review group perspective of a NICE Highly Specialised Technology Appraisal. Pharmacoeconomics [Internet]. 2020;38:1309–18. https://doi.org/10.1007/s40273-020-00953-z.
Uhrmann MF, Lorenz B, Gissel C. Cost effectiveness of voretigene neparvovec for RPE65-mediated inherited retinal degeneration in Germany. Transl Vis Sci Technol. 2020;9:1–8.
Cook K, Forbes SP, Adamski K, Ma JJ, Chawla A, Garrison LP. Assessing the potential cost-effectiveness of a gene therapy for the treatment of hemophilia A. J Med Econ [Internet]. 2020;23:501–12. https://doi.org/10.1080/13696998.2020.1721508.
Viriato D, Bennett N, Sidhu R, Hancock E, Lomax H, Trueman D, et al. An economic evaluation of voretigene neparvovec for the treatment of biallelic RPE65-mediated inherited retinal dystrophies in the UK. Adv Ther [Internet]. 2020;37:1233–47. https://doi.org/10.1007/s12325-020-01243-y.
CADTH. Voretigene neparvovec. [Internet]. 2020. https://www.cadth.ca/voretigene-neparvovec. Accessed 26 Nov 2020.
NCPE. Voretigene neparvovec (Luxturna) [Internet]. 2020b. http://www.ncpe.ie/drugs/voretigene-neparvovec-luxturna/. Accessed 26 Nov 2020.
SMC. voretigene neparvovec (Luxturna) [Internet]. 2019d. https://www.scottishmedicines.org.uk/medicines-advice/voretigene-neparvovec-luxturna-uoia-smc2228/. Accessed 26 Nov 2020.
ICER. Valoctocogene roxaparvovec and emicizumab for hemophilia A: effectiveness and value. [Internet]. 2020. https://icer-review.org/wp-content/uploads/2019/12/ICER_Hemophilia-A_Evidence-Report_101620.pdf. Accessed 26 Nov 2020.
Ellis AG, Mickle K, Herron-Smith S, Kumar VM, Cianciolo L, Seidner M, et al. Spinraza® and Zolgensma® for spinal muscular atrophy: effectiveness and value. Inst Clin Econ Rev. 2019;2019:1–223.
Malone DC, Dean R, Arjunji R, Jensen I, Cyr P, Miller B, et al. Cost-effectiveness analysis of using onasemnogene abeparvocec (AVXS-101) in spinal muscular atrophy type 1 patients. J Mark Access Heal Policy ]Internet\. 2019;7:1601484. https://doi.org/10.1080/20016689.2019.1601484.
Connock M, Andronis L, Auguste P, Dussart C, Armoiry X. Will the US$5 million onasemnogene abeparvosec treatment for spinal muscular atrophy represent ‘value for money’ for the NHS? A rapid inquiry into suggestions that it may be cost-effective. Expert Opin Biol Ther [Internet]. 2020;20:823–7. https://doi.org/10.1080/14712598.2020.1772747.
FINOSE. Zynteglo (autologous cd34+ cells encoding βA-T87Q-globin gene). [Internet]. 2019. https://www.fimea.fi/documents/160140/1454401/FINOSE+joint+assessment+report+Zynteglo+FINAL.pdf/1a1d3dc5-db79-48c8-6622-cff9b04ce088?t=1589197458993. Accessed 26 Nov 2020.
Thomas K. Costly Drug for Fatal Muscular Disease Wins F.D.A. Approval - The New York Times [Internet]. 2016. https://www.nytimes.com/2016/12/30/business/spinraza-price.html. Accessed 31 Mar 2020.
NICE. Interim Process and Methods of the Highly Specialised Technologies Programme Updated to reflect 2017 changes. [Internet]. 2017. https://www.nice.org.uk/Media/Default/About/what-we-do/NICE-guidance/NICE-highly-specialised-technologies-guidance/HST-interim-methods-process-guide-may-17.pdf. Accessed 31 Mar 2020.
NICE. Changes to NICE drug appraisals: what you need to know [Internet]. 2017. https://www.nice.org.uk/news/feature/changes-to-nice-drug-appraisals-what-you-need-to-know. Accessed 31 Mar 2020.
ICER. Institute for Clinical and Economic Review Announces Final Modified Framework for Assessing Value of Treatments for Ultra-Rare Diseases. [Internet]. 2017. https://icer-review.org/announcements/ultra-rare-final-framework/. Accessed 31 Mar 2020.
ICER. 2020 Value Assessment Framework: Final Framework. [Internet]. 2020. https://icer-review.org/material/2020-value-assessment-framework-final-framework/. Accessed 31 Mar 2020.
Sherkow JS, Zettler PJ, Greely HT. Is it “gene therapy”? J Law Biosci. 2018;5:786–93.
ICER. 2019 Adapted Value Assessment Methods for High-Impact “Single and Short-Term Therapies” (SSTS) [Internet]. 2019. https://icerorg.wpengine.com/wp-content/uploads/2020/10/ICER_SST_FinalAdaptations_111219-1.pdf. Accessed 19 May 2021.
Angelis A, Naci H, Hackshaw A. Recalibrating health technology assessment methods for cell and gene therapies. PharmaoEconomics [Internet]. 2020;38:1297–308. https://doi.org/10.1007/s40273-020-00956-w.
Jain T. Litzow MR (2018) No free rides: management of toxicities of novel immunotherapies in ALL, including financial. Blood Adv [Internet]. 2018;2(22):25–34. https://doi.org/10.1182/bloodadvances.2018020198.
Yang H, Hao Y, Qi CZ, Chai X, Wu EQ. 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. J Manag Care Sp Pharm. 2020;26(8):971–9. https://doi.org/10.18553/jmcp.2020.20052.
Yang H, Hao Y, Qi CZ, Chai X, Wu EQ. Estimation of total costs in patients with relapsed or refractory diffuse large B-cell lymphoma receiving tisagenlecleucel from a US hospital’s perspective. J Med Econ [Internet]. 2020;23(9):1016–24. https://doi.org/10.1080/13696998.2020.1769109.
Jørgensen J, Hanna E, Kefalas P. Outcomes-based reimbursement for gene therapies in practice: the experience of recently launched CAR-T cell therapies in major European countries. J Mark Access Health Policy [Internet]. 2020. https://doi.org/10.1080/20016689.2020.1715536.
Kew KM. CAR T-cell therapy: a summary of evidence. Sax Institute. [Internet]. 2018. https://www.saxinstitute.org.au/wp-content/uploads/CAR-T-Cell-Therapy-Evidence-Check_with-preface-from-NSW-Health.pdf. Accessed 21 May 2021.
Lyman GH, Nguyen A, Snyder S, Gitlin M, Chung KC. Economic evaluation of chimeric antigen receptor T-cell therapy by site of care among patients with relapsed or refractory large B-cell lymphoma. JAMA Network Open. 2020;3(4):1–15. https://doi.org/10.1001/jamanetworkopen.2020.2072
Zhu F, Wei G, Zhang M, Zhao H. Factors associated with costs in chimeric antigen receptor T-cell therapy for patients with relapsed/refractory B-cell malignancies. Cell Transplant [Internet]. 2020;29(79):1–10. https://doi.org/10.1177/0963689720919434.
Darrow J. Luxturna: FDA documents reveal the value of a costly gene therapy. Drug Discovery Today. 2019;24:4:949–954. https://doi.org/10.1016/j.drudis.2019.01.019
Commercializing Living Therapies. Advanced therapies investment. [Internet]. 2017. https://www.ccrm.ca/wp-content/uploads/2017/02/Investment_for_Advanced_Therapies_Report.pdf. Accessed 26 Nov 2020.
Marsden G, Towse A, Dreitlein B, Henshall C. Gene therapy: understanding the science, assessing the evidence, and paying for value. ICER Membership Policy Summit. [Internet]. 2017. https://www.ohe.org/publications/gene-therapy-understanding-science-assessing-evidence-and-paying-value. Accessed 21 May 2021.
Covance. The challenges associated with evaluating the cost benefit of gene therapies and enabling patient access. [Internet] 2020. https://www.covance.com/content/dam/covance/assetLibrary/whitepapers/Gene-Therapy-WPCMA017.pdf. Accessed 26 Nov 2020.
Sinclair A, Islam S, Jones S. Gene Therapy: An Overview of Approved and Pipeline Technologies. In: CADTH Issues in Emerging Health Technologies. [Internet]. 2018. https://www.cadth.ca/dv/ieht/gene-therapy-overview-approved-and-pipeline-technologies. Accessed 21 May 2021.
This research was supported by unrestricted funds from Dr Larry Lynd’s research funding.
Conflicts of interest/Competing interests
The authors report no conflicts of interest or competing interests.
Availability of data and material
All included publications and grey literature were obtained through publically available sources. All data generated or analyzed during this study are included in this published article and its supplementary information files.
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by all authors. The first draft of the manuscript was written by JKH and KB and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Below is the link to the electronic supplementary material.
Online Resource 1: Supplemental Materials and Methods This document contains additional information about the methods used to conduct the literature review including the full search strategy used for the MEDLINE search, keywords used for the grey literature search strategy, details about the inclusion and exclusion criteria, and additional details about the methods used for study selection, data extraction, and data analysis
Online Resource 2: Results of Critical Appraisal These tables outline the quality of reporting in the included studies. Economic evaluations were critically appraised using the CHEERS checklist and we used the AACODS checklist for those studies that were not economic evaluations
About this article
Cite this article
Ho, J.K., Borle, K., Dragojlovic, N. et al. Economic Evidence on Potentially Curative Gene Therapy Products: A Systematic Literature Review. PharmacoEconomics (2021). https://doi.org/10.1007/s40273-021-01051-4