Abstract
Chimeric Antigen Receptor (CAR)-T cell therapies, as potentially curative treatments, are a group of immunotherapy agents that are changing the paradigm for the treatment of hematologic malignancies. Ongoing research on CAR-T cell therapy is expected to expand the currently approved indications, which, given the high prices of these innovative therapeutic solutions, will increase the pressure on the sustainability of health systems, enhancing the need to establish adjusted financial solutions and promote the implementation of post-marketing monitoring procedures. This study examines the specific challenges in the development of robust clinical evidence to support the value measurement and cost-effectiveness assessment of CAR-T cell therapies and in the selection of adequate financing solutions. Managed Entry Agreements, which create mechanisms in which the risk associated with the uncertainty in long-term outcomes of these therapies is shared between the manufacturer and the payer, have emerged as preferred solutions in several European Union countries. The access barriers to CAR-T cell therapies are described, and recommendations on potential solutions to address affordability concerns using a framework of a life cycle approach to value assessment involving different stakeholders and adapted financing tools are proposed.
Keywords: CAR-T cell therapy, value, affordability, health economic, access
ARTICLE HIGHLIGHTS
Chimeric Antigen Receptor (CAR)-T cell therapies, classified as Advanced Therapy Medicinal Products (ATMP) in the European Union, offer a potentially curative approach for treating hematologic malignancies.
The development of these therapies, however, faces several health economic challenges, including the collection of clinical evidence, the selection of health economic data, and health technology assessment methodological issues.
The specific challenges in the selection of appropriate financing solutions to allow access to CAR-T cell therapies may be addressed through solutions such as managed entry agreements, supported by the collection of real-world data on the performance of CAR-T cell therapies in clinical practice.
A holistic approach to the health economic assessment, involving collaboration among various stakeholders, is key to optimizing patient access to CAR-T cell therapies, while ensuring payer affordability.
1. Cell therapies: EU health policy framework
In the context of the European Union (EU) framework for medicinal products, cellular medicinal products, including Chimeric Antigen Receptor (CAR)-T cell therapy, are included in the group of Advanced Therapy Medicinal Products (ATMP), a heterogeneous class of medicinal products that also includes gene therapy medicinal products and tissue engineering medicinal products [1].
Within the ATMP group, the largest percentage of products is classified as cell and gene therapies, which often address rare diseases [2]. CAR-T cell therapies are transformative health technologies with the potential to cure hematologic malignancies with a single administration [3]. They represent a class of immunotherapy that requires re-engineering of the T-cells of the patient to target tumor-expressing antigens for the treatment of oncological diseases [4].
Autologous CAR-T cell therapies are manufactured from T-cells of the individual to be treated and are genetically modified to redirect the target of T-cell receptors. These receptors target specific proteins present on the surface of leukemia cells, namely the protein CD19, which is found in B-cell leukemias [5,6].
The hospital exemption tool was defined in ATMP Regulation No. 1394/2007, introducing the possibility of ATMP being developed outside the scope of the centralized marketing authorization procedure to be provided to patients with no available therapeutic alternatives [1,7].
In the scope of regulatory pathways adapted to innovative medicinal products that address unmet medical needs, often for reduced populations, the European Medicines Agency (EMA) developed an adaptive licensing program that consists of a prospectively planned adaptive approach to bring innovative medicinal products to the market following an iterative life cycle approach.
The 2022 Health Technology Assessment International Global Policy Forum developed a position statement and framework for lifecycle HTA (LC-HTA). LC-HTA has been defined as a systematic process that relies on sequential Health Technology Assessment (HTA) activities to inform decision-making where the evidence base, the health technology itself, or the context in which it is applied has the potential to undergo meaningful changes at various stages of its lifecycle. The framework for LC-HTA proposed consists of different stages: defining the decision problem, sequencing HTA activities, and developing optimization criteria [8].
This life-cycle approach to HTA, shown in Figure 1, which considers iterative product development and assessment starting from an initially restricted patient population and recognizes the value of real-world data to supplement clinical trial data, may more adequately address the regulatory challenges of cell therapy products [5,9].
Figure 1.
European Medicines Agency (EMA) Health technology Assessment (HTA) life cycle approach proposal. Adapted from [5,9].
In the EU, important changes are expected in the upcoming years in the economic assessment of ATMP, brought about by the implementation of Regulation No. 1394/2007 of the European Parliament, a policy framework that outlines guidance on HTA, impacting the financing and access of patients to innovative technologies. This Regulation defines that ATMP are subject to joint clinical assessments as of January 12, 2025, as opposed to national assessments as currently performed [10].
2. Health economic approach
Treatment with CAR-T cell therapies, potentially a one-time treatment, represents an important pharmaceutical innovation that presents significantly greater incremental effectiveness and equivalent cost–effectiveness compared to standard of care treatments.
CAR-T cell therapies present a significantly higher number of incremental quality-adjusted Life Yars (QALY) than other innovative treatments [11].
The overall extent and cost of oncological treatments are expected to increase in the coming years [2]. It has been described that the listed price of CAR-T cell therapy in EU countries ranges from €307.2000 to €350.000, being currently among the highest-priced treatments for oncological diseases [12]. Moreover, numerous CAR-T cell therapy products are currently under development, including products targeting oncological diseases of higher prevalence and addressing earlier stages of the disease. Consequently, the population eligible for treatment with CAR-T cell therapies is likely to increase in the near future, which will increase the need for effective market access and affordable approaches that promote equitable patient access to these treatments [13,14].
2.1. Clinical evidence data
The administration of CAR-T cell therapy is complex and may be associated with challenges for the patient, namely the need to be located close to the treatment facility and to have the support of a caregiver following treatment infusion [15].
In addition, the product administration process may last for a few weeks, and the patient may need to receive lymphodepleting chemotherapy before the administration of CAR-T cell therapy. It is worth emphasizing that many patients will be receiving these treatments has a last therapeutical resource, after having gone through other therapeutic protocols [13].
The administration of CAR-T cell therapy requires highly specialized staff and is demanding in terms of resources, limiting the administration of CAR-T cell therapies to accredited medical centers that are able to ensure adequate monitoring to patients [15,16].
Particular challenges to CAR-T cell therapy clinical trials have been described, namely narrow eligibility criteria and constrained resources. One solution for simplifying the clinical study management of these products is to use umbrella trials that allow a shared control arm, facilitating patient enrollment and allowing the use of a single infrastructure.
The main clinical evidence challenges identified in the development of CAR-T cell therapy are described in Table 1.
Table 1.
| CAR-T cell therapy: clinical evidence challenges |
|---|
| Lack of comparative evidence and use of single arm trials |
| Limited sample size in clinical studies |
| Use of surrogate endpoints |
| Immaturity of evidence and extrapolation of long-term endpoints |
| Safety issues that may emerge over time |
The development of CAR-T cell therapy products may benefit from the inclusion of validated surrogate endpoints, ideally using a systematic review, which would be aligned with short-duration clinical studies, thereby improving access to these therapies [5,15].
However, the use of non-validated surrogate endpoints in clinical trials can negatively affect the quality of regulatory decisions [17].
The credibility of extrapolations should be carefully inspected when making policy decisions, because they can significantly affect cost-effectiveness estimates [18].
The setup of clinical trials supporting the development of CAR-T cell therapy products can be optimized to address challenges related to small patient populations and ethical concerns that affect patient recruitment in this setting. A design in which the comparison arm uses a historical or synthetic cohort could be used. In addition, there is room for improvement in the utilization of real-world data collected from relevant databases, promoting the exchange of data across different countries [2].
Another relevant aspect that has been highlighted is that in clinical studies of CAR-T cell therapy in hematology, outcomes are often assessed from the point of infusion (per protocol analysis) rather than from leukapheresis (intention-to-treat [ITT] analysis) or a modified ITT approach, which only includes patients who reach the infusion stage.
Studies that do not consider patients who undergo leukapheresis but do not reach infusion owing to various risks, such as the time of administration of leukapheresis, bridging therapy, lymphodepleting regimens, and other factors, might introduce biases. This oversight may confound robust comparisons of the effectiveness of CAR-T cell therapies.
To this end, a CAR-T cell-specific endpoint has been proposed - CAR T EFS (Intention-to-Treat Event-Free Survival) - which would allow the estimation of the actual treatment benefit of CART-T cell therapy. By including all patients who initiate the CAR-T cell treatment process instead of only those who receive the infusion, this endpoint would provide a more comprehensive measure of the effectiveness of CAR-T cell therapy [19].
Moreover, recent studies have emphasized the real-world applications of CAR-T cell therapies, highlighting the significance of this type of data in bridging gaps in traditional clinical trials [19–21].
2.2. Health economic data
The challenges and methodologies for evaluating cell therapies within HTA frameworks have been described [2].
In addition, recent studies have highlighted the significant organizational and economic impacts of CAR-T cell therapy implementation, suggesting the need for dedicated resources [2,22,23].
In addition to the cost of CAR-T cell products, other costs that have a significant impact on healthcare expenditure should be included in health economic analysis [12].
The main costs associated with the administration of CAR-T cell therapies, which should be considered in the economic models developed to support financing requests for these products, are described in Table 2.
Table 2.
Distinct costs associated with CAR-T cell treatment. Adapted from [14].
| Therapeutical products cost | Procedure costs |
|---|---|
| CAR-T cell therapy | CAR-T cell administration |
| Other therapeutic agents | Other tests and procedures |
| Procedure costs | Hidden costs |
| Intensive Care Unit day | Additional specialized staff |
| Inpatient day | Train existing staff |
| Other costs | Educate patients and caregivers |
| Treatment of adverse events |
HTA assessment should consider the cost of CAR-T cell therapies, cost of care required by the patient, and incremental costs associated with the replacement of other therapies with CAR-T cell therapies. In addition, the potential for CAR-T cell therapies to require only a single administration should be considered in the economic analysis and constitutes an added challenge when selecting the optimized financing approach for these products [12].
Despite the high price of CAR-T cell products, the fact that alternative treatments require several administrations and are less effective should be considered when determining the long-term value of CAR-T cell products [14].
The health economic analysis will also include a budget impact analysis, which adds an additional perspective to the cost-effectiveness analysis by clearly presenting the impact on the payer budget of the introduction of the new intervention in current clinical practice [24].
Recent studies have assessed the cost-effectiveness of CAR-T cell therapies compared with standard care for hematologic malignancies. The findings support the potential cost-effectiveness of CAR-T cell therapies, emphasizing the importance of making these treatments accessible to patients who will benefit the most and the necessity for further research in this area [25–28].
2.3. HTA and market access challenges
Given the particular characteristics of CAR-T cell therapies, several questions arise regarding the best approach for health economic assessment, namely, what HTA technology is appropriate, what financing solutions best apply, and who should be responsible for the risks related to the uncertainties associated with these therapies [12,29]
CAR-T cell products face several market access challenges in the EU, namely difficulties in the adaptation of HTA methods to the particularities of these products, delayed and unpredictable HTA decisions, funding and affordability concerns, the focus of payers on the high price of these products versus the added value they bring to patients, and challenges in implementing novel payment models.
In terms of promoting access to CAR-T cell therapies, the stakeholders involved face distinct challenges, as described in Table 3.
Table 3.
Identified barriers to CAR-T cell treatment access. Adapted from [13].
| Provider company | Treatment centers |
|---|---|
| Reimbursement uncertainty | Impact on patient pathway |
| Product manufacturing challenges | Personnel training |
| Personnel additional time allocated | |
| Health authorities | Patients |
| Budget impact | Access policies |
| Affordability issues | Toxicity and adverse events |
| Costs with travel, etc. |
It is broadly recognized that efficacy does not automatically entail value. To tackle this challenge, QALY per value amount spent is a well-accepted measure of the cost-effectiveness of a novel technology. When assessing the value of CAR-T cell therapy, the social value gained, for example, in offering a cure to a pediatric oncology patient and allowing the child to live a productive life, should be considered [30].
Conventional HTA approaches may not effectively capture the long-term value of CAR-T cell therapy due to the immaturity of the data available at the time of HTA assessment and the failure of economic models to accurately portray the long-term value of CAR-T cell therapies for patients. The HTA challenge will increase in scenarios where CAR-T cell therapy is administered to patients with refractory diseases who have no alternative treatment options [15].
Given the specific characteristics of ATMP, including CAR-T cell therapies, value-based pricing methodologies are recommended in the HTA approach [31]. As CAR-T cell therapies often target orphan diseases and/or end-of-life stages, it has been proposed that perspectives that can influence the HTA decision should go beyond the core value domains of value assessment and incorporate values related to the patient and social aspects [31]. In line with this perspective, adapted elements of value adjusted for the specific characteristics of CAR-T cell therapies have been proposed for the HTA framework of these products (Figure 2).
Figure 2.
Relevant elements of value in the Health Technology Assessment (HTA) approach of CAR-T cell therapies. Adapted from [2].
An analysis of the HTA decisions of ATMP in eight EU countries revealed that the conclusions were heterogeneous and affected by different perspectives in the interpretation of the available evidence and subsequent uncertainties in the behavior of products in the clinical setting [31]. It is relevant to note that the promotion of real-world evidence studies would provide a valuable opportunity to study the societal costs associated with CAR-T cell therapy, including the impact on patients and caregivers regarding out-of-pocket costs, resource utilization outside the healthcare setting, and loss of productivity [32].
The cost-effectiveness of CAR-T cell products is greatly affected by patient selection and the timing of administration.
A comprehensive framework has been proposed to ensure fair and equitable prioritization of patients for CAR-T cell therapy. This framework is based on the principles of procedural justice and incorporates criteria, including medical benefits, safety and risk of complications, psychosocial factors, and medical urgency [33].
3. Affordability issues
Despite the potential positive impact of CAR-T cell therapies, many eligible patients have not been able to benefit from these treatments because of numerous access barriers. Concerns over payer affordability are among the most important hurdles [13]. The financing processes of ATMP across EU countries have demonstrated that a unique payment model is unlikely to fulfill the needs of these health technologies [31]. In the EU, countries have adopted financing solutions such as outcomes-based staged payment solutions (e.g., Italy and Spain), coverage with evidence development (managed entry agreements [MEA], e.g., the UK), outcome-based rebates (e.g., Germany), and outcomes-based risk-sharing agreements (e.g., Portugal). For example, in coverage with evidence development agreements, annual reassessments based on longer-term follow-up data from pivotal trials and post-launch data collection from use in local patients are implemented. In a model of outcomes-based rebates, rebates are linked to individual patient outcomes. In a coverage with evidence development solution (MEA), there will be a future price reassessment based on longer-term follow-up data from pivotal trials, and post-launch data from use in local patients will be gathered [29].
In countries where a payment solution dependent on the results obtained with the administration of cell therapies has not been introduced, a potential alternative tool could be the regular reassessment of the cost-effectiveness of the product based on emerging clinical or real-world evidence [31].
The EMA has described potential sources of real-world evidence data that can support the assessment of innovative health technologies. These evidence sources include existing disease registries, single-arm studies on rare diseases, open-label studies, data from early access/compassionate use programs, post-authorization registries, and drug registries linked to risk-sharing schemes [9].
A global framework to optimize access to cell therapies has been proposed, as shown in Figure 3.
Figure 3.
Proposed framework to optimize access to cell therapies. Adapted from [34].
PRO: Patient reported outcomes
The indications for CAR-T cell therapies are expected to increase in the future, amplifying the financial burden on payers and affecting patient access to these innovative solutions [12].
In Canada and Spain, there are ongoing programs aimed at implementing the manufacture of CAR-T cell therapies in an academic setting. This approach can lower the cost of CAR-T cell therapies, contributing to tackling payer affordability concerns as the application of CAR-T cell therapies becomes broader [32].
This approach could be beneficial in addressing affordability concerns; however, in the long term, it is important to ensure that there is an environment in place that stimulates the research and development of CAR-T cell therapies by manufacturers [12].
When addressing affordability concerns related to the increased use of CAR-T cell therapy, it should be considered that the barriers to the commercial success of these treatments may act as a deterrent for manufacturers to invest in innovation in this area [13].
4. Proposed financial solutions
CAR-T cell therapies have the potential to bring about significant clinical advances. However, at the time of marketing authorization, there is usually uncertainty regarding the long-term effectiveness of these products [5].
Alternative financing solutions for these innovative technologies have been described in Figure 4.
Figure 4.
Cell therapies: Potential financial solutions proposed. Adapted from [2,5].
MEA have become more common and are applicable when there is uncertainty regarding the clinical benefit of an innovative therapeutic solution, favoring patient access and addressing affordability concerns [35].
Nonetheless, it should be noted that the implementation of MEA requires the setup of a monitoring process, which can present challenges both for the manufacturer and the payer [31].
The specificities of MEA are described in Figure 5.
Figure 5.
Risk sharing/Managed Entry Agreements (MEA) solutions. Adapted from [35].
The data outcome sources for MEA may be data from ongoing clinical studies, new patient registries, or existing patient registries, initiated for different purposes [2,29]
Ultimately, the choice of financing mechanism depends on the following factors:
Capacity of the payer to take on financial risks and administrative burden
Characteristics of the indicated patient population
Attributes of the cell therapy
Feasibility of patient follow-up
Availability of a data collection infrastructure and resources such as technical staff and Registries [2,5]
Some manufacturers of CAR-T cell therapies are studying the development of allogeneic CAR-T cell therapies, which would act as off-the-shelf CAR-T cell therapies that, instead of being produced on demand for a specific patient, would be produced in batches, possibly reducing the price of these products [12].
Importantly, in the case of CAR-T cell therapies, to ensure the best use of the budget allocated to these therapies, it is critical to distinguish the subgroups of patients who will respond to the therapy [32].
Finally, ensuring timely patient access is a critical factor in the level of value achieved for each patient and, consequently, for the overall value achieved with the introduction of a given CAR-T cell therapy [30].
5. Future perspective
Future advancements in CAR-T cell therapy aim to enhance safety and efficacy, reduce costs, and extend accessibility to outpatient settings and non-hospital-affiliated centers. Ongoing research is focused on developing next-generation CAR-T cell therapies and expanding their applications to include solid tumors.
To effectively manage advanced therapies, such as CAR-T cell therapies, in which the distinctions between treatment methods and personalized gene- and cell-based medicines are challenging to define, the creation of an intermediate product category has been proposed. This category, situated between drugs and treatments, and supported by adaptive regulations, may provide a clearer framework for conceptual uncertainties associated with emerging biomodifying technologies [3,36].
6. Conclusions
Currently, in the EU, only CD19-targeted CAR-T cell therapy is available in clinical practice, and technological developments are expected on this front, which would broaden the use of these therapies and increase the need for optimized financing tools.
Importantly, to address the affordability concerns that arise with the increase in the use of CAR-T cell therapies, it is important to have a global view of the total cost of care of these therapeutic solutions.
MEA have become commonly used financing tools to promote patient access to these new technologies by allowing the risk sharing associated with uncertainties regarding the long-term use of these therapies between the manufacturer and the payer.
However, there are important challenges in the implementation of MEA, namely, the need to establish a data collection protocol and infrastructure that allows adequate patient follow-up and the need for qualified staff and other resources.
A holistic approach to HTA involving the collaboration of different stakeholders, namely regulatory agencies, manufacturers, patients, and professional societies, will remain key to finding an adequate solution to optimize patient access to CAR-T cell therapies while ensuring payer affordability through risk-sharing solutions.
Disclosure statement
No potential conflict of interest was reported by the author(s).
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