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Open Access 01-12-2024 | Gene Therapy in Oncology | Position statement

Real-world evidence for coverage determination of treatments for rare diseases

Authors: Victoria W. Dayer, Michael F. Drummond, Omar Dabbous, Mondher Toumi, Peter Neumann, Sean Tunis, Nelson Teich, Shadi Saleh, Ulf Persson, Johann-Matthias Graf von der Schulenburg, Daniel C. Malone, Tay Salimullah, Sean D. Sullivan

Published in: Orphanet Journal of Rare Diseases | Issue 1/2024

Abstract

Health technology assessment (HTA) decisions for pharmaceuticals are complex and evolving. New rare disease treatments are often approved more quickly through accelerated approval schemes, creating more uncertainties about clinical evidence and budget impact at the time of market entry. The use of real-world evidence (RWE), including early coverage with evidence development, has been suggested as a means to support HTA decisions for rare disease treatments. However, the collection and use of RWE poses substantial challenges. These challenges are compounded when considered in the context of treatments for rare diseases. In this paper, we describe the methodological challenges to developing and using prospective and retrospective RWE for HTA decisions, for rare diseases in particular. We focus attention on key elements of study design and analyses, including patient selection and recruitment, appropriate adjustment for confounding and other sources of bias, outcome selection, and data quality monitoring. We conclude by offering suggestions to help address some of the most vexing challenges. The role of RWE in coverage and pricing determination will grow. It is, therefore, necessary for researchers, manufacturers, HTA agencies, and payers to ensure that rigorous and appropriate scientific principles are followed when using RWE as part of decision-making.

U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, and Oncology Center of Excellence. Real-world data: assessing registries to support regulatory decision-making for drug and biological products. Guidance for industry. (2023). Accessed 31 December 2023. https://www.fda.gov/media/154449/download

U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, and Center for Biologics Evaluation and Research. Data standards for drug and biological product submissions containing real-world data. Guidance for industry. (2023). Accessed 31 December 2023. https://www.fda.gov/media/153341/download

Moloney R, Mohr P, Hawe E, Shah K, Garau M, Towse A. Payer perspectives on future acceptability of comparative effectiveness and relative effectiveness research. Int J Technol Assess Health Care. 2015;31(1–2):90–8. https://doi.org/10.1017/S0266462315000203.

Sievers H, Joos A, Hiligsmann M. Real-world evidence: perspectives on challenges, value, and alignment of regulatory and national health technology assessment data collection requirements. Int J Technol Assess Health Care. 2021;37:e40. https://doi.org/10.1017/S0266462321000131.

Capkun G, Corry S, Dowling O, Asad Zadeh Vosta Kolaei F, Takyar S, Furtado C, et al. Can we use existing guidance to support the development of robust real-world evidence for health technology assessment/payer decision-making? Int J Technol Assess Health Care. 2022;38(1):e79. https://doi.org/10.1017/S0266462322000605

Garrison LP Jr, Neumann PJ, Erickson P, Marshall D, Mullins CD. Using real-world data for coverage and payment decisions: the ISPOR Real-World Data Task Force report. Value Health. 2007;10(5)326–35. https://doi.org/10.1111/j.1524-4733.2007.00186.x

Berger ML, Sox H, Willke RJ, Brixner DL, Eichler HG, Goettsch W, et al. Good practices for real-world data studies of treatment and/or comparative effectiveness: recommendations from the Joint ISPOR-ISPE Special Task Force on Real-World evidence in Health Care decision making. Value Health. 2017;20(8):1003–8. https://doi.org/10.1002/pds.4297.

Wu J, Wang C, Toh S, Pisa FE, Bauer L. Use of real-world evidence in regulatory decisions for rare diseases in the United States - current status and future directions. Pharmacoepidemiol Drug Saf. 2020;29(10):1213–8. https://doi.org/10.1002/pds.4962.

Iglesias-Lopez C, Agustí A, Vallano A, Obach M. Current landscape of clinical development and approval of advanced therapies. Mol Ther Methods Clin Dev. 2021;23:606–18. https://doi.org/10.1016/j.omtm.2021.11.003

10.

Hampson G, Towse A, Dreitlein WB, Henshall C, Pearson SD. Real world evidence for coverage decisions: opportunities and challenges. A report from the 2017 ICER Membership Policy Summit. https://icer.org/wp-content/uploads/2020/11/ICER-Real-World-Evidence-White-Paper-03282018.pdf (2018). Accessed 20 February 2023.

11.

Eichler HG, Pignatti F, Schwarzer-Daum B, Hidalgo-Simon A, Eichler I, Arlett P et al. Randomized controlled trials versus real world evidence: neither magic nor myth. Clin Pharmacol Ther. 2021;109(5):1212–18. https://doi.org/10.1002/cpt.2083

12.

Canada’s Drug and Health Technology Agency (CADTH). Guidance for reporting real-world evidence. https://www.cadth.ca/sites/default/files/RWE/MG0020/MG0020-RWE-Guidance-Report-Secured.pdf (May 2023). Accessed 28 September 2023.

13.

National Institute for Health and Care Excellence (NICE). NICE real-world evidence framework. https://www.nice.org.uk/corporate/ecd9/chapter/overview (2022). Accessed 20 February 2023.

14.

Haute Autorité de Santé. Real world studies for the assessment of medicinal products and medical devices. https://www.has-sante.fr/upload/docs/application/pdf/2021-10/real-world_studies_for_the_assessment_of_medicinal_products_and_medical_devices.pdf (2021). Accessed 31 December 2023.

15.

EUnetHTA. EUnetHTA Joint Action 3 - WP1: A future model of HTA cooperation. https://www.eunethta.eu/wp-content/uploads/2021/09/FMC-HTA-WHITE-PAPER-FOR-PUBLICATION.pdf (2021). Accessed 20 February 2023.

16.

EUnetHTA. D4.3 Direct and Indirect Comparisons. https://www.eunethta.eu/d4-3/ (1 August 2023). Accessed 28 September 2023.

17.

Brixner D, Biskupiak J, Oderda G, Burgoyne D, Malone DC, Arondekar B, et al. Payer perceptions of the use of real-world evidence in oncology-based decision making. J Manag Care Spec Pharm. 2021;27(8):1096–105. https://doi.org/10.18553/jmcp.2021.27.8.1096.

18.

Zhang X, Chen L, Bracco OL, Setoguchi S, Zhou W, Burcu M. Regulator-requested non-interventional postauthorization safety and effectiveness studies for oncology drugs: a systematic review. Clin Pharmacol Ther. 2022;111(1):155–67. https://doi.org/10.1002/cpt.2450.

19.

US Food & Drug Administration. Considerations for the use of real-world data and real-world evidence to support regulatory decision-making for drug and biological products. (2023). Accessed 20 February 2023. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considerations-use-real-world-data-and-real-world-evidence-support-regulatory-decision-making-drug

20.

IQWiG Reports– Commission No. A20-61. Concept for a routine practice data collection according to the law for more safety in the supply of medicines (GSAV)– onasemnogene abeparvovec (Zolgensma). https://www.g-ba.de/downloads/17-98-5254/2022-01-20_AM-RL_Onasemnogen-Abeparvovec_abD_Studienprotokoll.pdf (2022). Accessed 20 February 2023.

21.

German Joint Federal Committee (Gemeinsamer Bundesausschuss). Premiere: Daten aus der Versorgung sollen Evidenzlücken bei neuem Arzneimittel schließen. https://www.g-ba.de/presse/pressemitteilungen-meldungen/932/ (2021). Accessed 20 February 2023.

22.

Berger ML, Dreyer N, Anderson F, Towse A, Sedrakyan A, Normand SL. Prospective observational studies to assess comparative effectiveness: the ISPOR good research practices task force report. Value Health. 2012;15(2):217–30. https://doi.org/10.1016/j.jval.2011.12.010.

23.

Coyle D, Durand-Zaleski I, Farrington J, Garrison L, von der Schulenburg JM G, Greiner W, et al. HTA methodology and value frameworks for evaluation and policy making for cell and gene therapies. Eur J Health Econ. 2020;21(9):1421–37. https://doi.org/10.1007/s10198-020-01212-w

24.

Hutton J, Trueman P, Henshall C. Coverage with evidence development: an examination of conceptual and policy issues. Int J Technol Assess Health Care. 2007;23(4):425–32. https://doi.org/10.1017/s0266462307070651.

25.

Walker S, Sculpher M, Claxton K, Palmer S. Coverage with evidence development, only in research, risk sharing, or patient access scheme? A framework for coverage decisions. Value Health. 2012;15(3):570–9. https://doi.org/10.1016/j.jval.2011.12.013.

26.

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(6):661–8. https://doi.org/10.1016/j.jval.2019.03.012.

27.

Burcu M, Dreyer NA, Franklin JM, Blum MD, Critchlow CW, Perfetto EM, et al. Real-world evidence to support regulatory decision-making for medicines: considerations for external control arms. Pharmacoepidemiol Drug Saf. 2020;29(10):1228–35. https://doi.org/10.1002/pds.4975.

28.

U. S. Food & Drug Administration. Human gene therapy for neurodegenerative diseases. Guidance for industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/human-gene-therapy-neurodegenerative-diseases (2022). Accessed 20 February 2023.

29.

Honigberg R, Belson N. Contemporary applications of real-world evidence in regulatory decision making: a case series review. https://medicalaffairs.org/real-world-evidence-regulatory-decision-making/ (2020). Accessed 20 February 2023.

30.

Li M, Chen S, Lai Y, Liang Z, Wang J, Shi J, et al. Integrating real-world evidence in the regulatory decision-making process: a systematic analysis of experiences in the US, EU, and China using a logic model. Front Med (Lausanne). 2021;8:669509. https://doi.org/10.3389/fmed.2021.669509.

31.

U. S. Food & Drug Administration. Framework for FDA’s real-world evidence program. https://www.fda.gov/media/120060/download (2018). Accessed 20 February 2023.

32.

NIH National Cancer Institute. FDA grants full approval to blinatumomab for acute lymphoblastic leukemia. https://www.cancer.gov/news-events/cancer-currents-blog/2017/blinatumomab-all-fda-full-approval (2017). Accessed 13 September 2022.

33.

Biogen. Spinraza highlights of prescribing information. (updated February 2023). Accessed 2 January 2024. https://www.spinraza-hcp.com/content/dam/commercial/spinraza/hcp/en_us/pdf/spinraza-prescribing-information.pdf

34.

Novartis Gene Therapies, Inc. Zolgensma highlights of prescribing information. https://www.novartis.com/us-en/sites/novartis_us/files/zolgensma.pdf (updated February 2023). Accessed 20 February 2023.

35.

Kolb SJ, Coffey CS, Yankey JW, Krosschell K, Arnold WD, Rutkove SB, et al. Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study. Ann Clin Transl Neurol. 2016;3(2):132–45. https://doi.org/10.1002/acn3.283.

36.

Bischof M, Lorenzi M, Lee J, Druyts E, Balijepalli C, Dabbous O. Matching-adjusted indirect treatment comparison of onasemnogene abeparvovec and nusinersen for the treatment of symptomatic patients with spinal muscular atrophy type 1. Curr Med Res Opin. 2021;37(10):1719–30. https://doi.org/10.1080/03007995.2021.1947216.

37.

Dabbous O, Maru B, Jansen JP, Lorenzi M, Cloutier M, Guérin A, et al. Survival, motor function, and motor milestones: comparison of AVXS-101 relative to nusinersen for the treatment of infants with spinal muscular atrophy type 1. Adv Ther. 2019;36(5):1164–76. https://doi.org/10.1007/s12325-019-00923-8.

38.

Benjamin K, Vernon MK, Patrick DL, Perfetto E, Nestler-Parr S, Burke L. Patient-reported outcome and observer-reported outcome assessment in rare disease clinical trials: an ISPOR COA Emerging Good practices Task Force Report. Value Health. 2017;20(7):838–55. https://doi.org/10.1016/j.jval.2017.05.015

39.

Ferrar J, Griffith GJ, Skirrow C, Cashdollar N, Taptiklis N, Dobson J, et al. Developing digital tools for remote clinical research: how to evaluate the validity and practicality of active assessments in field settings. J Med Internet Res. 2021;23(6):e26004. https://doi.org/10.2196/26004.

40.

U.S, Food. & Drug Administration. Surrogate endpoint resources for drug and biologic development. https://www.fda.gov/drugs/development-resources/surrogate-endpoint-resources-drug-and-biologic-development (2022). Accessed 13 September 2022.

41.

Russell S, Bennett J, Wellman JA, Chung DC, Yu ZF, Tillman A, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017;390(10097):849–60. https://doi.org/10.1016/S0140-6736(17)31868-8.

42.

Institute for Quality and Efficiency in Health Care (IQWig). Concepts for the generation of routine practice data and their analysis for the benefit assessment of drugs according to § 35a Social Code Book V (SGB V)¹. Rapid report A19-43. IQWiG Reports– Commission No. A19-43. https://www.iqwig.de/download/a19-43_routine-practice-data-for-the-benefit-assessment-of-drugs_rapid-report_v1-0.pdf (10 January 2020). Accessed 28 September 2023.

43.

Berger M, Daniel G, Frank K, Hernandez A, McClellan M, Okun S, et al. A framework for regulatory use of real-world evidence. (2017). Accessed 20 February 2023. https://healthpolicy.duke.edu/sites/default/files/2020-08/rwe_white_paper_2017.09.06.pdf

44.

Mahendraratnam N, Mercon K, Gill M, Benzing L, McClellan MB. Understanding use of real-world data and real-world evidence to support regulatory decisions on medical product effectiveness. Clin Pharmacol Ther. 2022;111(1):150–4. https://doi.org/10.1002/cpt.2272.

45.

Motheral B, Brooks J, Clark MA, Crown WH, Davey P, Hutchins D, et al. A checklist for retrospective database studies—report of the ISPOR Task Force on Retrospective databases. Value Health. 2003;6(2):90–7.

46.

Centers for Medicare & Medicaid Services. Coverage with evidence development. https://www.cms.gov/Medicare/Coverage/Coverage-with-Evidence-Development (2022). Accessed 13 September 2022.

47.

Centers for Medicare & Medicaid Services. Guidance for the public, industry, and CMS staff: coverage with evidence development. https://www.cms.gov/medicare-coverage-database/view/medicare-coverage-document.aspx?MCDId=27 (2014). Accessed 20 February 2023.

48.

Tunis SR, Pearson SD. Coverage options for promising technologies: Medicare’s ‘coverage with evidence development’. Health Aff (Millwood). 2006;25(5):1218–30. https://doi.org/10.1377/hlthaff.25.5.1218.

49.

Zeitler EP, Gilstrap LG, Coylewright M, Slotwiner DJ, Colla CH, Al-Khatib SM. Coverage with evidence development: where are we now? Am J Manag Care. 2022;28(8):382–9. https://doi.org/10.37765/ajmc.2022.88870.

50.

Centers for Medicare & Medicaid Services. CMS finalizes medicare coverage policy for monoclonal antibodies directed against amyloid for the treatment of alzheimer’s disease. https://www.cms.gov/newsroom/press-releases/cms-finalizes-medicare-coverage-policy-monoclonal-antibodies-directed-against-amyloid-treatment (2022). Accessed 20 February 2023.

51.

Klemp M, Frønsdal KB, Facey K. HTAi Policy Forum. What principles should govern the use of managed entry agreements? Int J Technol Assess Health Care. 2011;27(1):77–83. https://doi.org/10.1017/s0266462310001297.

52.

Wenzl M, Chapman S. Performance-based managed entry agreements for new medicines in OECD countries and EU member states: how they work and possible improvements going forward. No. 115. OECD Health Working Papers. Paris: OECD Publishing; 2019. https://doi.org/10.1787/6e5e4c0f-en.

53.

Kang J, Cairns J. “Don’t think twice, it’s all right”: using additional data to reduce uncertainty regarding oncologic drugs provided through managed access agreements in England. Pharmacoecon Open. 2023;7(1):77–91. https://doi.org/10.1007/s41669-022-00369-9

54.

Facey KM, Espin J, Kent E, Link A, Nicod E, O’Leary A, et al. Implementing outcomes-based managed entry agreements for rare disease treatments: nusinersen and tisagenlecleucel. PharmacoEconomics. 2021;39(9):1021–44. https://doi.org/10.1007/s40273-021-01050-5.

55.

Facey K, Xoxi E, Kent E, Junghans T, Whittal A, Drummond M, et al. Guidance on use and implementation of outcomes-based managed entry agreements for rare disease treatments. (2021). Accessed 20 February 2023. https://www.impact-hta.eu/_files/ugd/e1a359_884ba8242a564b0a8ae6899bdf9bb67d.pdf?index=true

56.

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. 2020;8(1):1715536. https://doi.org/10.1080/20016689.2020.1715536.

57.

Jørgensen J, Kefalas P. The use of innovative payment mechanisms for gene therapies in Europe and the USA. Regen Med. 2021;16(4):405–22. https://doi.org/10.2217/rme-2020-0169.

Title: Real-world evidence for coverage determination of treatments for rare diseases
Authors: Victoria W. Dayer
Michael F. Drummond
Omar Dabbous
Mondher Toumi
Peter Neumann
Sean Tunis
Nelson Teich
Shadi Saleh
Ulf Persson
Johann-Matthias Graf von der Schulenburg
Daniel C. Malone
Tay Salimullah
Sean D. Sullivan
Publication date: 01-12-2024
Publisher: BioMed Central
Keyword: Gene Therapy in Oncology
Published in: Orphanet Journal of Rare Diseases / Issue 1/2024
Electronic ISSN: 1750-1172
DOI: https://doi.org/10.1186/s13023-024-03041-z

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Real-world evidence for coverage determination of treatments for rare diseases

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