Strengthening health systems for access to gene therapy in rare genetic disorders

After decades of innovation, the promise of gene therapy is becoming a reality for patients with certain rare genetic disorders. Several cell and gene therapies have already been approved by regulators worldwide, 1Landfeldt E. Gene Therapy for Neuromuscular Diseases: Health Economic Challenges and Future Perspectives. J. Neuromuscul. Dis. 2022; 9: 675-688https: //doi. org/10. 3233/JND-221540Crossref PubMed Scopus (2) Google Scholar with many more expected at a rate of up to 10%–20% annually by 2025. 2FDA: Statement from FDA Commissioner Scott Gottlieb, M. D. and Peter Marks, M. D. , Ph. DDirector of the Center for Biologics Evaluation and Research on New Policies to Advance Development of Safe and Effective Cell and Gene Therapies. 2023https: //www. fda. gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-peter-marks-md-phd-director-center-biologicsGoogle Scholar These therapies have the potential to be transformative, changing the course of a disease and reducing the long-term patient and health system burdens associated with chronic disease management (Figure 1). 2FDA: Statement from FDA Commissioner Scott Gottlieb, M. D. and Peter Marks, M. D. , Ph. DDirector of the Center for Biologics Evaluation and Research on New Policies to Advance Development of Safe and Effective Cell and Gene Therapies. 2023https: //www. fda. gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-peter-marks-md-phd-director-center-biologicsGoogle Scholar Around 80% of rare diseases are genetic in origin, 3European CommissionRare Diseases. 2023https: //health. ec. europa. eu/non-communicable-diseases/expert-group-public-health/rare-diseasesₑn#: ∼: text=Around%2080%25%20of%20rare%20diseases, 70%25%20already%20start%20in%20childhoodGoogle Scholar making them ideal targets for gene therapy. With an estimated 10, 000 rare diseases affecting over 300 million people worldwide, they are considered a public health priority in many regions. 3European CommissionRare Diseases. 2023https: //health. ec. europa. eu/non-communicable-diseases/expert-group-public-health/rare-diseasesₑn#: ∼: text=Around%2080%25%20of%20rare%20diseases, 70%25%20already%20start%20in%20childhoodGoogle Scholar While the definition of rare disease varies, they are characterized by low incidence (e. g. , 1 in 2, 000 in Europe) and often have degenerative and irreversible disease progression. 4Delaye J. Cacciatore P. Kole A. Valuing the "Burden" and Impact of Rare Diseases: A Scoping Review. Front. Pharmacol. 2022; 13914338https: //doi. org/10. 3389/fphar. 2022. 914338Crossref PubMed Scopus (8) Google Scholar As such, they place a heavy burden on patients, families, and caregivers, with disease management incurring substantial resource utilization and costs for health systems. 4Delaye J. Cacciatore P. Kole A. Valuing the "Burden" and Impact of Rare Diseases: A Scoping Review. Front. Pharmacol. 2022; 13914338https: //doi. org/10. 3389/fphar. 2022. 914338Crossref PubMed Scopus (8) Google Scholar Gene therapies have the potential to transform the lives of people living with devastating rare diseases. However, patient access to these new therapies is not straightforward. In October 2022, Pfizer and the Alliance for Regenerative Medicine convened a roundtable at the World Health Summit in Berlin, Germany, with representatives across stakeholder groups —including academia, civil society, industry, patient communities, healthcare professionals (HCPs), and governments to discuss these topics. Here, we present a summary of barriers and opportunities to accessing gene therapies identified at the roundtable (Table 1), which are described in a report titled "A Framework to Strengthen Health Systems for Gene Therapy for Rare Genetic Diseases. "Table 1Barriers and opportunities regarding real-world access to gene therapiesBarriersOpportunities to address barrierLack of infrastructure for diagnosis and determining patient eligibility for gene therapy•Support multistakeholder education•Strengthen infrastructure and workforce for newborn screening (NBS) •Develop governance frameworks supporting eligibility and referralsLack of infrastructure for gene therapy delivery•Certify national clinical centers of excellence (COEs) •Create integrated hub-and-spoke care pathways•Connect COEs across countriesChallenges for the appropriate value assessment for gene therapies and adoption of innovative financing models•Engage in early dialogue across all stakeholders, including regulators, payers, healthcare professionals (HCPs), biopharma, patient advocacy groups (PAGs), and policymakers•Review value assessment methodologies to ensure processes are fit for gene therapies•Support multistakeholder models of advanced therapy development (e. g. , academic, non-profit entities, etc. ) •Support the use of novel payment models Open table in a new tab Early diagnosis and intervention offer the largest potential to delay disease progression for people with rare genetic disorders. However, individuals typically face a complex and lengthy path to diagnosis, 5Global CommissionEnding the Diagnostic Odyssey. Global Commission Year One Report for Children with a Rare Disease. 2023https: //irp. cdn-website. com/9a6a913a/files/uploaded/GlobalCommission-print-021919-a68c8ce2a5. pdfGoogle Scholar which can be caused by a lack of awareness among patients, families, and HCPs, a lack of trained therapeutic area specialists, and a lack of access to the appropriate diagnostic tests. 5Global CommissionEnding the Diagnostic Odyssey. Global Commission Year One Report for Children with a Rare Disease. 2023https: //irp. cdn-website. com/9a6a913a/files/uploaded/GlobalCommission-print-021919-a68c8ce2a5. pdfGoogle Scholar For example, in Latin America, the average number of years among those who have suffered a delay in diagnosis of a rare disease is 8. 9, with misdiagnoses along the way. 6Diseases, I. -A. A. f. R. Study on Socio-Health Needs of People with Rare Diseases in Latin America. September 25, 2023, pp 52–53. https: //www. enfermedades-raras. org/sites/default/files/2022-07/01₂022ₚublicacionENSERioLATAMₑstudioₑsp₂8%20de%20julio%20de%202022₀. pdfGoogle Scholar These misdiagnoses can result in additional burden for patients and health systems and delays in care, sometimes with serious or fatal consequences. A particularly cost-effective method for preventing delays in diagnosis for some genetic conditions is newborn screening (NBS). 7Shih S. T. F. Keller E. Wiley V. Farrar M. A. Wong M. Chambers G. M. Modelling the Cost-Effectiveness and Budget Impact of a Newborn Screening Program for Spinal Muscular Atrophy and Severe Combined Immunodeficiency. Int. J. Neonatal Screen. 2022; 8: 45https: //doi. org/10. 3390/ijns8030045Crossref PubMed Scopus (8) Google Scholar Recent studies have shown that inclusion of NBS, coupled with early intervention, is cost effective in comparison to current diagnostic and treatment practices for some diseases. 7Shih S. T. F. Keller E. Wiley V. Farrar M. A. Wong M. Chambers G. M. Modelling the Cost-Effectiveness and Budget Impact of a Newborn Screening Program for Spinal Muscular Atrophy and Severe Combined Immunodeficiency. Int. J. Neonatal Screen. 2022; 8: 45https: //doi. org/10. 3390/ijns8030045Crossref PubMed Scopus (8) Google Scholar Greater investment in infrastructure for NBS could reduce the burden on patients and health systems and facilitate timely access to interventions. Following diagnosis, determining eligibility for gene therapy poses further challenges to access. Assessing eligibility requires evaluation of multiple factors, such as age, disease status, general health status, previous or current therapies, and the presence of neutralizing antibodies. 8FDAHuman Gene Therapy for Rare Diseases: Guidance for Industry. 2023https: //www. fda. gov/media/113807/downloadGoogle Scholar Given the likely clinically restricted time windows for many gene therapies, development of clear governance frameworks for eligibility referrals and timely diagnostic tests is critical for effective access to gene therapy. These frameworks need to be multifactorial, encompassing regulatory and reimbursement policies. Recent experience with Zolgensma in Australia saw pediatric hospitals facing financial issues due to existing procurement and reimbursement policies, which resulted in delayed patient access to Zolgensma. As such, government-level horizon scanning of gene and cell therapies in the clinical trial pipeline with support from regulators and payers is needed to drive access processes, ensuring governance frameworks are in place following regulatory approval and reimbursement. The care pathway for gene therapies is complex, requiring a multidisciplinary team and coordination with specialized healthcare providers. 9Ward A. J. Murphy D. Marron R. McGrath V. Bolz-Johnson M. Cullen W. Daly A. Hardiman O. Lawlor A. Lynch S. A. et al. Designing Rare Disease Care Pathways in the Republic of Ireland: A Co-Operative Model. Orphanet J. Rare Dis. 2022; 17162https: //doi. org/10. 1186/s13023-022-02309-6Crossref Scopus (5) Google Scholar For many rare diseases, clinical centers of excellence (COEs) have been established to facilitate the diagnosis, care, and treatment of patients with ultra-rare conditions. In addition to centralized, stand-alone COEs, another approach to building these care pathways is the "hub-and-spoke" model, which connects community healthcare practices with specialized clinical COEs or specialized gene therapy treatment facilities. These COEs may be referred to differently across geographies, and there will be a variety of ways in which hubs and spokes work together, though the unifying principles will remain the same: providing patient access to expert and specialist facilities while providing relevant care locally. 10Miesbach W. Chowdary P. Coppens M. Hart D. P. Jimenez-Yuste V. Klamroth R. Makris M. Noone D. Peyvandi F. Delivery of AAV-Based Gene Therapy through Haemophilia Centres—A Need for Re-Evaluation of Infrastructure and Comprehensive Care: A Joint Publication of EAHAD and EHC. Haemophilia. 2021; 27: 967-973https: //doi. org/10. 1111/hae. 14420Crossref PubMed Scopus (22) Google Scholar For example, COEs could manage the immediate post-infusion time period, with long-term follow-up and surveillance occurring at local practices. Building such hub-and-spoke networks may also allow access to and sharing of resources, such as diagnostic testing, facilitating budgetary efficiencies, and streamlining care delivery. To scale up this innovative approach and facilitate hub-and-spoke implementation, policy frameworks are needed to standardize models of care, ensure the availability of qualified COEs, and ensure reimbursement. The value of a particular gene therapy for reimbursement and access will depend on multiple factors, including safety, efficacy, the durability of clinical benefits, the size of the treatable population, and the financial impact on health systems and patients. Following regulatory approval, evaluation of comparative effectiveness for gene therapies is often complicated by uncertainties due to small clinical trial sizes, lack of appropriate direct comparators, and the need for long-term follow-up. 1Landfeldt E. Gene Therapy for Neuromuscular Diseases: Health Economic Challenges and Future Perspectives. J. Neuromuscul. Dis. 2022; 9: 675-688https: //doi. org/10. 3233/JND-221540Crossref PubMed Scopus (2) Google Scholar Traditional health technology assessment (HTA) methodologies cannot capture the full potential value of gene therapies to patients, health systems, and society, as they are not able to appropriately account for long-term impact on healthcare expenditures following one-time administration. As such, the development of methodologies with greater flexibility that can appropriately incorporate estimates of future benefits is required to support reimbursement decisions, for example incorporating a lifetime perspective in modeling and utilizing appropriate discount rates in budget sensitivity. 1Landfeldt E. Gene Therapy for Neuromuscular Diseases: Health Economic Challenges and Future Perspectives. J. Neuromuscul. Dis. 2022; 9: 675-688https: //doi. org/10. 3233/JND-221540Crossref PubMed Scopus (2) Google Scholar Beyond methodologies, alignment is needed on assessment criteria and long-term real-world data requirements for gene therapy assessments. Establishment of a formal process for early dialogue among payers, HTA bodies, and manufacturers would facilitate alignment on feasible evidence packages for submission. Post-launch processes for addressing uncertainty and enabling reassessment should also be established, including robust real-world evidence generation and indirect comparisons with other therapeutic options. Many of the same uncertainties that pose challenges for assessing value appropriately during reimbursement decisions also make it difficult for health systems to pay the upfront prices of some gene therapies while sustaining healthcare budgets. As such, novel payment models that spread payment over time and link to real-world outcomes could help payers to manage the budget impact of gene therapies while recognizing the innovative one-time approach. 1Landfeldt E. Gene Therapy for Neuromuscular Diseases: Health Economic Challenges and Future Perspectives. J. Neuromuscul. Dis. 2022; 9: 675-688https: //doi. org/10. 3233/JND-221540Crossref PubMed Scopus (2) Google Scholar, 11Dabbous M. Toumi M. Simoens S. Wasem J. Saal G. Wang Y. Osuna J. L. H. François C. Annemans L. Schulenburg J. -M. G. v. d. et al. Amortization of Gene Replacement Therapies: A Health Policy Analysis Exploring a Mechanism for Mitigating Budget Impact of High-Cost Treatments. Health Pol. 2022; 126: 49-59https: //doi. org/10. 1016/j. healthpol. 2021. 11. 005Crossref PubMed Scopus (5) Google Scholar Piloting innovative outcomes-based agreements, updating legal and regulatory frameworks, and sharing best practices around innovative financing would be useful to facilitate access to gene therapies. 11Dabbous M. Toumi M. Simoens S. Wasem J. Saal G. Wang Y. Osuna J. L. H. François C. Annemans L. Schulenburg J. -M. G. v. d. et al. Amortization of Gene Replacement Therapies: A Health Policy Analysis Exploring a Mechanism for Mitigating Budget Impact of High-Cost Treatments. Health Pol. 2022; 126: 49-59https: //doi. org/10. 1016/j. healthpol. 2021. 11. 005Crossref PubMed Scopus (5) Google Scholar To enable this, registries need to be identified or established to collect patient outcome data to evaluate the safety and durability of gene therapies over time. With several gene therapies now approved by health regulators globally and with more expected to be approved over the coming years, 1Landfeldt E. Gene Therapy for Neuromuscular Diseases: Health Economic Challenges and Future Perspectives. J. Neuromuscul. Dis. 2022; 9: 675-688https: //doi. org/10. 3233/JND-221540Crossref PubMed Scopus (2) Google Scholar focus must now be placed on how individuals with rare genetic disorders can achieve timely access to these potentially transformative therapies and what health systems need to due to enable this. Patient centricity is key and is essential to co-create solutions with patients. Collaboration among all stakeholders, including HCPs, patient advocacy groups, policymakers, biopharma, and payers is imperative to ensure that health systems and societies are fully prepared to adopt gene therapies sustainably.