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Challenges for gene therapy in the financial sustainability of health systems: a scoping review

Orphanet Journal of Rare Diseases volume 19, Article number: 243 (2024) Cite this article

Abstract

Aim

To review the available evidence about the strategies implemented or proposed for coverage or reimbursement for currently approved gene therapies.

Methods

A scoping review was conducted to analyze the evidence published during the years 2016 to 2023. The main search criteria were coverage or reimbursement of gene therapy by healthcare systems. The eligible articles were those that described or proposed a financing model used to provide coverage in the various systems around the world.

Results

The study identified 279 publications, and after removing duplicates and screening for eligibility, 10 were included in the study. The results show that various financing models have been proposed, including subscription-based payment models, outcome-based payment models, and amortization strategies. However, several barriers to implementing these models were identified, such as deficiencies in informatics systems for data collection, changes in laws or regulations, the lack of accessible clinical endpoints and administrative costs.

Conclusion

This scoping review provides an overview of financing strategies for gene therapies. Gene therapies can cure rare or previously intractable diseases, but their high cost can make access difficult. Publishing experiences with these models can help evaluate their use and gather more evidence for their effectiveness.

Background

Gene therapy is a technique to treat and prevent diseases by adding a new gene or replacing or repairing an altered gene [1, 2]. These advances hold great hope for treating some devastating rare and inherited conditions and incurable diseases [3, 4]. Understanding the precise pathogenic mechanisms of diseases which can then lead to the development of specific and efficient gene selection and delivery tools, is expected to revolutionize disease treatment and the pharmaceuticals market [3, 4].

One challenge associated with gene therapy is the limited accessibility for patients. This issue primarily arises from the substantial research and development costs borne by academia, pharmaceutical companies and others in the creation of these medical technologies, as well as the anticipation of significant returns of investment upon commercialization [5]. Furthermore, these therapies target a small population of individuals afflicted by rare or ultra-rare diseases [6]. Consequently, the manufacturers’ expectations of substantial profits rely on imposing high individual costs.

Despite presenting a curative potential, gene therapies must demonstrate health benefits. The design of the clinical studies is the main factor that generates uncertainty, because they are often performed with small sample sizes [7]. In addition, they are generally single-arm clinical trials and the follow-up is short [8]. This leads to a lack of demonstration of the efficacy and effectiveness of gene therapy, raising concerns about the sustainability of the long-term benefits beyond those demonstrated in clinical trials [9].

In order to ensure timely access to patients, it is critical that countries develop pricing and reimbursement strategies/models that continue to incentivize research and development without compromising the sustainability of healthcare systems. Therefore, payers and manufacturers need to acknowledge each other’s constraints and embrace innovative approaches to ensure timely delivery of therapies to patients [10]. This study aimed to review the available strategies that have been implemented or proposed for the coverage or reimbursement of gene therapies, as well as providing their main characteristics and barriers of use.

Methods

Aim

To review the evidence about strategies implemented or proposed for coverage or reimbursement for currently approved gene therapies across the world.

Study design

A scoping review was conducted with the aim of comprehensively identifying the strategies implemented or proposed for the coverage or reimbursement of gene therapies across the world. The review was conducted following the methodology of the Joanna Briggs Institute (JBI) [11]. We adhered to the guidance of the Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA) guidelines [12]. Subsequently, the research questions were: What are the strategies or mechanisms for coverage and reimbursement of gene therapies? What are their characteristics and barriers to implement these strategies in the different healthcare systems?

Databases and search strategy

PUBMED/MEDLINE and OVID/EMBASE were used to search from the earliest available dates until February 2023. The research was guided by three domains: the first related to gene therapy, the second to financing and reimbursement, and the third to health systems. These keywords were validated by obtaining their respective Medical Subject Headings (MeSH) for their application in PubMed. The databases were limited to Spanish and English. Grey literature was excluded for this searching. Search strategies for PubMed/MEDLINE and OVID/EMBASE databases are provided in the Appendix.

Citation management

The citations were imported into the citation manager EndNote X9. Then, the duplicates were removed, preparing the non-duplicate citations for title/abstract screening.

Eligibility criteria

We included the original and review research articles which were published in full text until February 2023. Only articles in English and Spanish language were included. Inclusion criteria were publications that described models implemented or proposed for the coverage or reimbursement of gene therapy drugs, including the barriers or limitations of these strategies. Articles that focused on a specific disease or treatment (e.g. spinal muscular atrophy, haemophilia, cancer, etc.) were excluded. Studies or reports on health technology assessments (HTA) or the cost-effectiveness of these technologies were also excluded. Finally, studies for which full access was not available were also excluded.

Screening of citations

Two rounds of screening were conducted to select eligible studies. Initially, two researchers independently screened titles and abstracts. In the event of a disagreement, a discussion was held until a consensus was reached. Titles without an available abstract were included for full text review. The relevant studies were subjected to a second level of screening, where two researchers reviewed the articles in full text. Only the studies that met the eligibility criteria were included. Any disagreements were resolved through discussion between the researchers.

Data extraction and presentation

The data of the articles considered relevant for this scoping review were the following: authors, name of the study, name of the journal, year of publication, jurisdiction of the article, type of study proposed/objective of the work, main results/conclusions of the study and proposed mechanism.

Results

The literature search identified a total of 279 articles. After duplicate removal and screening titles and abstracts, 50 articles were eligible for full-text review. Of these, 40 were not considered since they did not meet the inclusion criteria (Fig. 1). Ten publications met the inclusion criteria and were selected for this scoping review.

Fig. 1
figure 1

PRISMA flow diagram for the scoping review process

Full size image

General characteristics of the literature

The articles were published between 2016 [13] and 2023 [14]. Most studies were published since 2019 [15,16,17,18,19,20,21]. One study was published in 2016 [13], and another in 2018 [22] (Table 1).

Table 1 Characteristics of the studies selected in the review
Full size table

According to the jurisdiction of the selected papers, five indicated strategies proposed or developed for the United States of America (USA) [15, 16, 18, 19, 22]; five in Europe (France, Italy, Germany, Spain, United Kingdom) [14, 17,18,19, 21]; one in Canada [18]; one in South Korea [22], and two did not specify the country [13, 20].

Aim and scopes

Eight studies were literature reviews [13, 14, 17,18,19,20,21,22], reporting experiences on various reimbursement schemes and their characteristics for implementation. Specifically, three studies analysed the main challenges of addressing the coverage of gene therapy drugs in health systems and identified possible solutions [13, 18, 22]. Dabbous et al. [20] studied the feasibility of applying amortisation as a tool to finance gene therapy from an accounting point of view, proposing this strategy as a new innovative payment mechanism [20]. The other four articles described reimbursement and coverage strategies applied to innovative drugs. These studies explained the virtues and challenges of their mechanism in each country analysed [14, 17, 19, 21].

Additionally, one study conducted qualitative interviews with different payers of the USA to have a better understanding of their knowledge of new gene therapies, the sustainability of current financing mechanisms, and the need and preference for a new model of financing [15]. Finally, Ballreich et al. [16] presented various alternatives applied to Medicaid to finance gene therapies [16].

Proposals or mechanisms implemented for financing and coverage of gene therapy

Subscription-based payment models

Two studies proposed using subscription-based payment models known as “Netflix-like models” [16, 21]. In their study, Koleva-Kolarova et al. (2022) [21] defined this strategy as “a model based on the payment of a lump sum by the health system to the manufacturers in exchange for unlimited access for patients during a defined period”. However, the authors noted that it was unclear how the payment of these therapies would be implemented in practice, as the subscription fee, the uncertainty of expected results, and the duration of the subscription must be defined.

Ballreich et al. [16] suggested a potential strategy for the implementation of Medicaid in the USA. Specifically, the authors proposed that states could form a unified front to negotiate long-term contracts with manufacturers, enabling patients who satisfy selection criteria to access medications at a fixed price. This approach has the potential to be extended to a broader range of therapies, thereby enhancing scalability [16].

Outcome-based payment models

Outcome-based payment models were identified in seven articles [14, 15, 17,18,19, 21, 22]. Koleva-Kolarova et al. (2022) characterised these mechanisms as coverage conditioned to the generation of evidence, discounts based on results, payment in annuities, and personalised reimbursement systems based on performance, among others [21]. The authors indicate that these contracts can be short-term (one year) or long-term (multi-year), with advance payments or in instalments based on agreed milestones. This agreement reduces the financial risk for payers in case of treatment failure or poor performance by sharing the costs with producers [21]. Currently, these types of agreements have been used in European countries, more specifically in Italy and Spain, through payment in instalments associated with outcomes for the coverage of advanced therapy drugs and gene therapies, such as Kymriah®, Yescarta®, Luxturna® and Zolgensma® [14, 17, 19]. Barlow et al. (2019) reported that 47% of payers support the implementation of new payment models, especially performance-based arrangements, and risk pooling [15].

Several barriers to those agreements have been identified in the literature. These include deficiencies in computer systems for data collection to measure clinical outcomes [14, 17, 18, 21, 22], the need to define “success” or “failure” of therapies to determine what will or will not be reimbursed [22], changes in laws or regulations that impede the adoption of these strategies [14, 18], administrative costs and the lack of readily accessible clinical endpoints [21].

Amortisation

Amortisation was suggested as a financing strategy for gene therapies in two studies [20, 22]. This strategy can be defined as a key accounting principle that spreads the cost of an intangible asset over the periods in which a commercial organisation or entity receives the benefits of the asset [23].

Dabbous et al. [20] assessed the feasibility of amortisation as an accounting tool for gene therapy. The authors stated that this strategy might be a promising method to finance new health technologies. However, budget sustainability, health technologies eligibility, and financial regulations were identified as limitations and barriers. Hampson et al. (2018) identified some attributes that might make certain gene therapies better candidates for amortisation [22]. These attributes included: being a single treatment or having a short-term curative clinical impact, the durability of clinical benefit that is well established or can be controlled through an outcome-based mechanism, and sufficiently large population size [22].

Discussion

This scoping review aimed to identify the main strategies proposed or implemented for the financing of gene therapy in various countries in the published literature. The results show that the main strategies applied have been in high-income countries. Most of the studies identified in this review focused on gene therapy to treat rare diseases, as gene therapies approved by regulatory agencies to date are for treating this type of conditions [24]. However, the identified strategies might apply to other types of gene therapy, such as those for cancer treatments.

Subscription-based payment models, also known as “Netflix-like models” were recommended by two studies. These models have been implemented in Australia and USA to fund the treatment against hepatitis C (HCV) [25,26,27]. This subscription-based payment models resulted in significant cost savings and increased access to HCV treatment [26]. Since 2022, the NHS England has used this strategy to fund antibiotics [28]. The implementation of this model in the NHS England has the potential to reduce costs and improve patient outcomes related to antibiotic resistance [28, 29].

European countries have applied outcome-based payment models for coverage of advanced therapies, including gene therapy [17, 19]. Also, in the USA, some payers have supported the use of such measures [29]. These types of agreements seek to reduce the first-order uncertainty surrounding the effectiveness (and potentially cost-effectiveness) of a product at individual level [30,31,32] by transferring responsibility to manufacturers for its results in the real world after its regulatory approval [33]. While these models may be attractive to facilitate early access to these expensive therapies facing uncertain results at patient level, they also face implementation barriers. They include the need for institutional capacity to monitor follow-up and assign outcomes, coordination among insurers in the context of multi-payer systems, and the need for covering implementation and transaction costs [34,35,36,37].

The literature shows some evidence of dealing with the challenge of data collection for monitoring. Spain’s National Health Service implemented Valtermed, a clinical data collection and management system, to reduce uncertainty related to outcome-based models for access to new medicines [38, 39]; whereas, in Italy, establishing and managing such data has shown to be underestimated in costs, and the actual amount reimbursed by the companies is negligible [40, 41]. Defining the governance of managing these models is crucial, whether by a state health authority or by autonomous entities, such as private or mixed organizations, in either a single or multi-payer system, remains as one of the major challenges.

Another type of access scheme analysed was the use of amortization as a financial strategy for the distribution of costs of intangible assets, such as gene therapies [20]. This strategy would allow systems to distribute the costs of the treatment over the period in which the patient receives the benefits, reducing the economic pressure on the health system and facilitating access to these drugs for patients [20]. To implement this strategy, gene therapies must be declared as intangible assets, as they provide a health benefit rather than a physical product [20, 22]. Financial regulations of countries would need to be modified to apply amortization in gene therapy, and only treatments of a single administration or short term with long-term benefits would be eligible [20]. However, further research is needed prior to implementing this strategy for gene therapies. This would require a deeper understanding of the benefits and drawbacks of amortization as a financial tool for these types of drugs.

The fact that the evidence comes from high income countries may be explained because strategies applied in low and middle-income countries have yet to be published in indexed journals, or because they have been recently implemented. This is, for example, the case of Zolgensma® in Argentina, where the federal government led to the development of an outcome-based risk share agreement with Novartis, which was recently informed in February 2023 [42, 43]. In this case, the payment was made in four installments over a 3-year period. Then, each instalment would be conditional on the fulfilment of certain outcomes agreed between both Novartis and the government. Another recent case study is Brazil where Zolgensma® was also covered through instalments payments linked with outcomes based on clinically agreed milestones [44].

The main limitation of our scoping review is that we may not have comprehensively captured all available published literature, given our search was restricted to two databases and literature published in English and Spanish, and we did not capture data published in the grey literature. However, we argue that most scientific reports across the globe have been published in one of these two languages. The timeframe of our search, that may also be considered a limitation, is reasonable given it starts when the first gene therapy was launched into the market.

Gene therapy is in a continuous process of development [45,46,47,48]. In fact, a report published by PhRMA listed almost 300 gene and cell therapies under investigation to treat several diseases [49]. More than one hundred of these treatments are focused on different types of cancer [49]. The identification of new targets is promising to treat rare diseases and improve existing cancer treatments [50, 51]. The development of new, more precise and specific gene editing techniques is highlighted, such as CRISPR, which could allow efficient modifications in the genome to treat cancer and other diseases [52, 53]. Undoubtedly, the growing innovation in gene therapy will make it possible to meet numerous needs of a wide spectrum of diseases. Therefore, it is important to assess the different capacities that health systems have to facilitate sustainable access to such therapies.

Conclusion

Gene therapies are treatments that make it possible to cure or treat rare diseases and certain cancers, which until recently, were intractable. However, their high cost makes access to patients difficult. Our scoping review shows the main models proposed to finance and cover these disruptive treatments by health systems. This review revealed that there are different alternatives to cover these therapies. Each proposed strategy has its characteristics and barriers that are overcome for its implementation. Finally, it is necessary to continue publishing the experiences of the use of these models to continue obtaining evidence of their use and obtaining data for their evaluation.

Data availability

All data generated or analysed during this study are included in this published article (and its additional files).

Abbreviations

JBI:

Joanna Briggs Institute

PRISMA:

Preferred Reporting Items for Systematic Reviews and MetaAnalyses

PCC:

Population, Concept, and Context

USA:

United State of America

PhRMA:

Pharmaceutical Research and Manufacturers of America

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Acknowledgements

Not applicable.

Funding

Fondecyt grant 1211411 (ANID-Chile), FONDAP 152220002 (CECAN).

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Authors and Affiliations

  1. Departamento de Coordinación de Garantías y Prestaciones de Salud, División de Planificación Sanitaria, Ministerio de Salud de Chile, Enrique McIver 421, Santiago, Chile

    Hugo Ossandon

  2. Centro de Investigación Clínica, Unidad de Evaluación de Tecnologías en Salud (ETESA UC), Pontificia Universidad Católica de Chile, Santiago, Chile

    Nicolás Armijo & Manuel Antonio Espinoza

  3. Centre for Health Economics Research and Evaluation (CHERE), University of Technology Sydney, Sydney, Australia

    Constanza Vargas

  4. Rare Diseases Program, Institute of Science and Innovation in Medicine, Facultad de Medicina, Clinica Alemana Universidad del Desarrollo, Santiago, Chile

    Gabriela M. Repetto

  5. Centro Para la Prevención y Control del cáncer, Santiago, Chile

    Nicolás Armijo & Manuel Antonio Espinoza

  6. Departamento de Salud Pública, Pontificia Universidad Católica de Chile, Santiago, Chile

    Manuel Antonio Espinoza

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HO contributed to the acquisition of data (literature searches), analysis, protocol development, interpretation, drafting and approved the final draft. NA contributed to the acquisition of data (literature searches), analysis, interpretation, drafting and approved the final draft. CV contributed to analysis and approved the final draft. GR contributed to oversight of analysis and drafting and approved the final draft. ME contributed to oversight of analysis, protocol development, expertise in projections methodology, interpretation, drafting and approved the final draft.

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Correspondence to Manuel Antonio Espinoza.

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Ossandon, H., Armijo, N., Vargas, C. et al. Challenges for gene therapy in the financial sustainability of health systems: a scoping review. Orphanet J Rare Dis 19, 243 (2024). https://doi.org/10.1186/s13023-024-03249-z

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Orphanet Journal of Rare Diseases

ISSN: 1750-1172