Availability and financing of CAR-T cell therapies: A cross-country comparative analysis [original]

Availability and financing of CAR-T cell therapies: A cross-country

comparative analysis

Yulia Litvinova

a,*

, Sherry Merkur

, Sara Allin

, Ester Angulo-Pueyo

, Daiga Behmane

Enrique Bernal-Delgado

, Miriam Dalmas

, Antonio De Belvis

, Nigel Edwards

Francisco Estupi˜

n´

an-Romero

, Peter Gaal

, Sophie Gerkens

, Margaret Jamieson

Alisha Morsella

, Dario Picecchi

, Hilde Røshol

, Ingrid Sperre Saunes

, Terry Sullivan

Bal´

azs Sz´

ecs´

enyi-Nagy

, Inneke Van De Vijver

, Ricciardi Walter

, Dimitra Panteli

Department of Health Care Management, Berlin University of Technology, Str. des 17. Juni 135, H80, 10623 Berlin, Germany

European Observatory on Health Systems and Policies, London School of Economics and Political Science, Houghton Street, London WC2A 2AE, UK

Institute of Health Policy, Management and Evaluation, University of Toronto, Health Sciences Building, 155 College Street, Toronto, ON M5T 3M6, Canada

Data Science for Health Services and Policy Research Group, Institute for Health Sciences, IACS, San Juan Bosco 13 50009 Zaragoza, Spain

Institute of Public, Riga Stradins University, 26a Annin

¸muiˇ

zas bulv¯

aris, R¯

ıga, Latvia

Office of the Chief Medical Officer, Department of Policy in Health, Ministry for Health, Palazzo Castellania, 15, Merchants str., Valletta, Malta VLT 1171

Universit`

a Cattolica del Sacro Cuore, Largo F. Vito, 1 00168 Rome, Italy

Nuffield Trust, 59 New Cavendish Street, London, W1G 7LP, England UK

Health Services Management Training Centre, Semmelweis University, Kútv¨

olgyi út 2., 1125 Budapest, Hungary

Belgian Health Care Knowledge Centre (KCE), Boulevard du Jardin Botanique 55, 1000 Brussels, Belgium

Faculty of Law, University of Luezern, Frohburgstrasse 3, 6002 Lucerne Switzerland

Norwegian Medicines Agency, Grensesvingen 26, 0663 Oslo, Norway

Division for Health Services, Norwegian Institute of Public Health, PO Box 222 Skøyen,N-0213 Oslo, Norway

National Institute for Health and Disability Insurance (RIZIV-INAMI), Directorate Pharmaceutical Policy - Health Care Department, Galileelaan 5/01, 1210 Brussels,

Belgium

European Observatory on Health Systems and Policies, Eurostation (Office 07C024), Place Victor Horta/Victor Hortaplein, 40/30, 1060 Brussels, Belgium

ARTICLE INFO

Keywords:

Chimeric antigen receptor (CAR) T-cell

therapies

Advanced Therapy Medicinal Products

(ATMPs)

Cancer, Pharmaceutical policy

Oncology care

ABSTRACT

Chimeric antigen receptor T-cell therapies (CAR-T therapies) are a type of advanced therapy medicinal product

(ATMP) that belong to a new generation of personalised cancer immunotherapies. This paper compares the

approval, availability and financing of CAR-T cell therapies in ten countries. It also examines the implementation of

this type of ATMP within the health care system, describing the organizational elements of CAR-T therapy delivery

andthechallengesofensuringequitableaccesstoallthoseinneed, takingamoresystems-orientedview.Itfinds that

the availability of CAR-T therapies varies across countries, reflecting the heterogeneity in the organization and

financing of specialised care, particularly oncology care. Countries have been cautious in designing reimbursement

models for CAR-T cell therapies, establishing limited managed entry arrangements under public payers, either

based on outcomes or as an evidence development scheme to allow for the study of real-world therapeutic efficacy.

The delivery model of CAR-T therapies is concentrated around existing experienced cancer centres and highlights

the need for high networking and referral capacity. Some countries have transparent and systematic eligibility

criteria to help ensure more equitable access to therapies. Overall, as with other pharmaceuticals, there is limited

transparency in pricing, eligibility criteria and budgeting decisions in this therapeutic area.

* Corresponding author at: Department of Health Care Management, Berlin University of Technology, Str. des 17. Juni 135, H80, 10623 Berlin, Germany.

E-mail addresses: [email protected] (Y. Litvinova), [email protected] (S. Merkur), [email protected] (S. Allin), [email protected]

(E. Angulo-Pueyo), [email protected] (D. Behmane), [email protected] (E. Bernal-Delgado), [email protected] (M. Dalmas), antonio.debelvis@

unicatt.it (A. De Belvis), [email protected] (N. Edwards), [email protected] (F. Estupi˜

n´

an-Romero), [email protected]

(P. Gaal), [email protected] (S. Gerkens), [email protected] (M. Jamieson), [email protected] (A. Morsella), hilde.roshol@

legemiddelverket.no (H. Røshol), [email protected] (I.S. Saunes), [email protected] (T. Sullivan), [email protected] (B. Sz´

ecs´

enyi-Nagy), Inneke.

[email protected] (I.V.D. Vijver), [email protected] (R. Walter), [email protected] (D. Panteli).

Contents lists available at ScienceDirect

Health policy

journal homepage: www.elsevier.com/locate/healthpol

https://doi.org/10.1016/j.healthpol.2024.105153

Received 21 February 2023; Received in revised form 12 July 2024; Accepted 28 August 2024

Health policy 149 (2024) 105153

Available online 12 September 2024

nc/4.0/ ).

1. Introduction

1.1. CAR-T therapy: background

Chimeric antigen receptor (CAR) T-cell therapies (CAR-T therapies)

are Advanced Therapy Medicinal Products (ATMPs) that belong to a new

generation of personalised cancer immunotherapies, where specialists

collect the patients’own immune cells and modify them to target cancer

cells. Current commercially available CAR-T therapies treat haemato-

logical cancers, including B-cell acute lymphoblastic leukaemia (ALL),

diffuse large B-cell lymphoma (DLBCL), Mantle cell lymphoma (MCL)

and multiple myeloma. In March 2022, more than 30% of all approved

ATMPs in the United Kingdom (UK) and European Union (EU) were

CAR-T therapies [1]. Over 63% of newly developed CAR-T treatments

target proteins of haematological cancers, with 37% targeting solid tu-

mours. The top three tumour types tested in clinical research are

gastrointestinal (10%), breast (6%) and nervous system (6%) [2].

CAR-T cell therapies involve modifying T-cells, which are white

blood cells that play a crucial role in the immune system. T-cells natu-

rally target specific foreign particles (antigens) and are vital in fighting

infections and cancer. The cellular memory of the immune response can

persist and control disease over time [3]. Scientists can program T-cells

to identify specific proteins, such as the CD19 or B-cell maturation an-

tigen (BCMA), present on the surface of cancer cells. This is achieved by

adding a new piece of genetic code to create a chimeric antigen receptor

(CAR). T-cells with a CAR (CAR-T cells) can then recognise cancer cells

and attack them more effectively [4].

This technology offers promising effects such as high and long-term

remission rates, including improved survival [5–7]. However, it also

carries risks like cytokine release syndrome (CRS) or neurotoxicity,

making careful planning and well-coordinated multidisciplinary

collaboration essential for successful treatment [8]. Additionally, the

uncertainty surrounding the long term effects of these novel therapies,

coupled with their high costs, raise concerns about their system-wide

implementation [9]. (Box 1)

1.2. CAR-T therapies available on the market

In 2017, the Food and Drug Administration (FDA) in the United

States (USA) approved the first CAR-T cell therapy (Kymriah®) for adult

patients with certain types of lymphoma and for children and young

adults with acute lymphoblastic leukaemia (ALL) who have not

responded to other treatments. As of July 2022, there were six CAR-T

therapies authorised by the FDA, the European Medicines Agency

(EMA) and some of them by Health Canada and the Swiss Agency for

Therapeutic Products (Swissmedic). Table 1 provides an overview of

authorised CAR-T cell therapies, the diseases they target, and eligible

patients.

All CAR-T therapies are indicated for patients who have completed at

least two rounds of systematic therapy and/or have refractory cancers (i.

e. cancers that are resistant at the beginning of treatment or become resistant

during treatment) or are in their second (or subsequent) relapses. While

these therapies are generally for adults, Novartis’s Kymriah®is also

authorised for treating paediatric patients with ALL.

Since these CAR-T products are produced on demand, their accessi-

bility depends on success in overcoming several challenges. First,

whether manufacturing agreements are in place and sufficient infra-

structure for manufacturing is available in the region. Second, whether

therapy delivery centres and the necessary staff with the necessary skills

are available. Third is financial accessibility - whether these expensive

treatments can be covered by public payer mechanisms and any limi-

tations on the number of therapies that can be reimbursed by public

funds. Extensive research has shown that not all ATMPs, including

recently approved CAR-T products, are made available to patients for a

number of reasons. Pricing and reimbursement are the first obstacles to

accessibility [10].

Against this backdrop, the objective of this analysis is to explore the

involvement of selected health systems in providing CAR-T therapies to

patients, specifically with regard to accessibility and delivery chal-

lenges. The main elements of interest are: (1) to identify the financing

models applied to CAR-T therapies –given their costs –and explore the

potential implications of full coverage for pharmaceutical budgets; (2)

to understand the infrastructural capacities and delivery models in

different settings; and (3) to draw lessons for policymakers involved in

decision-making around ATMPs.

2. Methods

2.1. Framework

This study was initiated through the Health Systems and Policy

Monitor (HSPM) Network, hosted by the European Observatory on

Health Systems and Policies [11]. Following a research pitch by network

members at the HSPM 2020 annual meeting, a rapid review of published

and grey literature was conducted, focusing on the period between

Table 1

Overview of authorised CAR-T therapies as of November 2022.

CAR-T

Technology

Product

name

Company Authorised

by FDA

Authorised

by EMA

Authorised by

Health

Canada

Authorised

Swissmedic

Disease Eligible

patients

Tisagenlecleucel Kymriah®Novartis 30 May

2017

23 August

2018

September

2018

18 October

2018

B-cell acute lymphoblasticleukemia

(ALL), Diffuse large B-cell

lymphoma (DLBCL), follicular

lymphoma (FL)

ALL - up to 25

years, Other

conditions -

Adults

Axicabtagene

ciloleucel

Yescarta®Kite Pharma /

Gilead

18 October

2017

23 August

2018

February

2019

17 April

2019

Diffuse large B-cell lymphoma

(DLBCL), primary mediastinal large

B-cell lymphoma and follicular

lymphoma (FL)

Adults

Brexucabtagene

autoleucel

Tecartus®Kite Pharma /

Gilead

24 July

2020

December

2020

August 2021 25 August

2021

Mantle-cell lymphoma Adults

Lisocabtagene

maraleucel

Breyanzi®Juno

Therapeutics /

BMS

02 May

2021

4 April 2022 May 2022 28 March

2022

Diffuse large B-cell lymphoma Adults

Idecabtagene

vicleucel

Abecma®Bluebird Bio /

BMS

26 March

2021

18 August

2021

May 2021 20 August

2021

Multiple myeloma Adults

Ciltacabtagene

autoleucel

Carvykti®Janssen 28 February

2022

26 May

2022

N/A N/A Multiple myeloma Adults

Note: N/A –not authorised as of 1 November 2022.

Y. Litvinova et al. Health policy 149 (2024) 105153

August 2018 (time of EMA market approval for the first CAR-T therapy)

and September 2020 (see Annex 1). It aimed to identify key themes

around the availability and delivery of CAR-T therapies towards

informing the conceptualization of the analytical framework for the

cross-country comparison.

The resulting framework comprises five main components (see

Fig. 2): i) the authorization of CAR-T therapies and their availability; ii)

funding mechanisms; iii) the potential expenditure on CAR-T therapy in

relation to total pharmaceutical budget; iv) the delivery model and

availability of referral networks; and v) equity considerations, particu-

larly regarding whether eligibility criteria for treatment have been

established.

2.2. Questionnaire and data collection

As detailed information on the above dimensions is rarely publicly

available, a standardised questionnaire was developed based on the

framework presented in Fig. 2 to collect relevant data from national

experts in the HSPM network countries (see Annex 2). The national

experts were initially contacted in August 2020 and asked to complete

the survey, reviewing national documents, and drawing on their own

experience and that of professional experts. The questionnaire was

explicitly limited to two commercial CAR-T therapies, Kymriah®and

Yescarta®, as a reasonable period of time had elapsed between market

access (2018) and the time of the survey. Completed questionnaires

were returned for Belgium, Canada, England, Hungary, Italy, Latvia,

Malta, Norway, Spain, and Switzerland by March 2021.

To estimate the financial impact that CAR-T therapies could have on

pharmaceutical budgets (item iii of the framework), country experts

were asked to provide available information on official drug prices and

the estimated number of patients to be treated annually, with 2020 as a

baseline year (Table 3). On this basis, cost projections were put in

relation to national pharmaceutical expenditure published in the OECD

Health Statistics to provide an idea of the magnitude of costs of CAR-T

therapies [12]. We did not distinguish between paediatric patients

with the B-cell acute lymphoblastic leukaemia (ALL) or adult patients

with DLBCL. In addition, we did not include estimates for associated

costs such as hospital care or bridging/conditioning therapy as shown in

the patient pathway (Box 1 or Annex 3). According to some estimates,

these costs can reach up to EUR 40 000 per case [9]. A comprehensive

budget impact analysis was beyond the scope of this study.

The analysis and validation of the survey results was completed by

December 2021, followed by a second round of rapid literature review.

The objective of the second review was to complement initial findings

with newly published work, given the rapid development in the field of

gene and cell therapies in oncology. It was undertaken using the same

search strategy (see Annex 1) and included literature published between

January 2020 and May 2022.

3. Results

3.1. Availability of CAR-T therapies

Most available commercial CAR-T therapies have been approved by

the FDA, the EMA, Health Canada, and Swissmedic (Table 1).

EU regulations for the authorization of orphan drugs, including CAR-

T therapies, apply for all Member States and applied to the United

Kingdom (England) until the end of 2020. Consequently, the approved

indications for Kymriah®and Yescarta®are identical throughout EU

Member States. Kymriah®is indicated for treating B-cell acute

lymphoblastic leukaemia (ALL) in patients up to 25 years and Diffuse

large B-cell lymphoma (DLBCL) and follicular lymphoma; while Yes-

carta®is indicated for the treatment of DLBCL and Primary mediastinal

large B-cell lymphoma (PMBCL). In all the countries studied, CAR-T

therapy is first offered to those who have not responded to two or

more previous treatments. Age limits apply in certain countries: in Italy,

the age limit for treatment of DLBCL with Yescarta®is limited to 70

years, and with Kymriah®to 75 years [13]. Health Canada approved the

two products with similar terms with the exception of paediatric ALL

patients, who have to be at least three years old in order to undergo

CAR-T therapy with Kymriah®.

However, despite the blanket applicability of the centralised EMA

approval, CAR-T therapies had not been launched in all European

countries in the sample at the time of writing. For example, Latvia

doesn’t deliver or reimburse this treatment at all; Hungary and Malta do

Box 1

Example of a patient pathway with CAR-T therapy

Treatment with CAR-T cells includes multiple steps and involves numerous health system stakeholders. A generalised overview of how the

patient and the health system interact in the complex provision of a single CAR-T therapy session is illustrated in Fig. 1 (more detailed illus-

tration in Annex 3). Generally, if a patient is deemed eligible for CAR-T treatment, they will be referred to the therapy provider. The admin-

istration of CAR-T therapies is possible in designated cancer centres. Due to the high toxicity of the treatments, these centres must be able to

ensure immediate care in the case of any adverse event (such as CRS, immune effector cell-associated neurotoxicity syndrome (ICANS), other

infections, and cytopenias). The actual therapy occurs over several stages: first, the treatment facility performs leukapheresis (collection of

patient’s T lymphocytes), then sends the cells to the CAR-T manufacturing site. While the individual’s cells are being reprogrammed in the lab, the

patient receives a bridging therapy, followed by a conditioning therapy prior to the reinfusion of the reprogrammed CAR-Ts. After the

administration of the medical product, the patient remains in the facility, or at least in close proximity, in order to be monitored. After

approximately 30 days of management by the therapy provider, the patient is released to the referring oncologist.

Fig. 2. Framework for analyzing CAR-T therapy across countries.

Y. Litvinova et al. Health policy 149 (2024) 105153

not systematically provide CAR-T therapies, but have covered treatment

administered abroad on occasion. In the case of Malta, the bilateral

agreement allows haematology patients requiring an ATMP to be treated

in the UK [10]. Furthermore, at the time of writing (July 2022), adult

patients with DLBCL in Norway could not receive Kymriah®or Yes-

carta®within the country.

3.2. Financing CAR-T therapies

Due to their potential to address unmet medical needs and promising

treatment outcomess, countries are increasingly opting to reimburse

these therapies, despite their high cost and scarcity of sufficient evidence

at launch. This is often achieved through a conditional coverage, which

involves further exploration of risk-sharing schemes already used for

reimbursing other cancer medicines [14–16]. Based on the survey re-

sponses, managed entry agreements (MEAs) proved to be common for

the reimbursement for CAR-T, with 1) individual performance-based

MEAs and 2) coverage with evidence development (CED) schemes

based on population data mentioned most frequently. In individual

performance-based MEAs, the assessment of outcomes was linked to

payment schemes, where payment only occurs if the desired response is

achieved. CED requires the collection of evidence at the population level

to inform reappraisal or pricing and reimbursement negotiations [17].

(Table 2)

In Switzerland, health insurers and hospitals have entered into tariff

agreements that define the terms of CED for CAR-T therapies in addition

to the diagnosis-related-group (DRG) flat rate. The reimbursement of

CAR-T therapies is temporarily included in the benefits basket provided

by health insurers, until further evidence is developed. The exact price

for the therapies remains confidential. However, it is known that health

insurers, hospitals and pharmaceutical companies may negotiate price

reductions on a case by case basis [18,19].

The Belgian National Institute for Health and Disability Insurance

(NIHDI-INAMI-RIZIV) Drug Reimbursement Commission (CRM)

proposed a population-based CED reimbursement scheme for CAR-T

therapies but with three staged payments. (Table 2)

The details of MEAs signed in Canada are unknown, although rec-

ommendations for further price reductions and direct interprovincial

agreements were issued by the Canadian Agency for Drugs and Tech-

nologies in Health (CADTH). Accordingly, the responsibility for funding

and providing CAR-T therapies, falls on provincial governments. In

Ontario, Canada, funding for CAR-T therapy is regularly negotiated to

meet demand and comes from the provincial cancer agency, Cancer Care

Ontario [20] (now part of Ontario Health), which receives its budget

from the provincial ministry of health. Since August 2020 the provincial

government of Alberta has been partnering with the Alberta Cancer

Foundation on a CAD 15 million (EUR 9 million) program to offer CAR-T

therapy in the province.

In England, due to the high uncertainty and limited clinical data

available, the National Institute for Health and Care Excellence (NICE)

did not recommend Kymriah®and Yescarta®for routine use due to the

high level of uncertainty and limited clinical data available, but instead

approved access to these treatments through the Cancer Drugs Fund

(CDF), which was also linked to the generation of evidence on real-world

evidence of effectiveness [21]. In January 2023 (after the closing date of

the survey underpinning this paper), NICE recommended Yescarta®for

routine use in adults with DLBCL and at a list price of GBP 208 451

(approx. EUR 245 000), following a review of real-world data to address

clinical uncertainties remaining from the original technology appraisal

[22]. Final approval of Kymriah®for children and young adults with

ALL followed in April 2024 at a list price of 282 000 GBP (approx. 332

000 EUR) per infusion [23]. Both listed prices are publicly available, but

there is a confidential discount applied to them [22,23].

In Italy, the MEAs for CAR-T therapies take the form of “payment by

result”and are generally limited to 18 months. For treatment with

Kymriah®, the payments are processed in three steps: at the beginning

of treatment, 6 months and 12 months (only in case of a remission). For

Yescarta®they occur at 6, 9 and 12 months after administration of

treatment. CAR-T therapies are funded for eligible patients by the Fund

for Innovative Drugs; the innovation status of Kymriah®was valid from

August 2019 to August 2022 and for Yescarta®from November 2019 to

November 2022. CAR-T therapies are considered innovative due to their

therapeutic need, added value, and robust scientific evidence. Drugs

with this status can be made available to patients immediately, even

without formal inclusion in reimbursement lists through regional hos-

pital therapeutic schedules [24]. After the innovative status of the

products comes to an end, the financial responsibility for the treatments

will fall to the regional budgets (which provide health services to its

population) [24]. Monitoring of pharmaceutical effectiveness through

registries is a longstanding tradition in Italy [25]. This allows for the

evaluation of the therapy performance in clinical practice. In the case of

CAR-T therapies, it supports the implementation of MEAs and enables

further evidence development based on the real-world data [26].

The Spanish National Health System reimburses Kymriah®in two

outcome-based staged payments: the first one (50%–52% of the full list

price) takes place upon treatment administration, whereas the second

one (50%–48%) occurs after 18 months, given that the patient has

achieved and sustained the expected response to the treatment. For

Yescarta®the payment scheme is similar: two-staged payments, where

the first (36% of the full list price) happens upon the therapy delivery

and the second (64%) 18-months later linked to the patient’s survival.

Other details concerning the MEA remain confidential [27,28]. In terms

of further investigation of treatment effectiveness, different solutions

were established. In Spain, the individual CAR-T patients’data are

collected in the web-based VALTERMED registry, developed by Spanish

Ministry of Health, which should help to determine the therapeutic

value in real-world settings [29].

Table 2

Overview of reimbursement mechanisms in selected countries.

Kymriah®Yescarta®

MEA

(outcome-

based or

CED)

Standard

reimbursement

MEA

(outcome-

based or

CED)

Standard

reimbursement

Belgium ✓

CED (in 3-

staged

payments)

✓

CED

(in 3-staged

payments)

Canada ✓

CED

✓

CED

Hungary Public payer reimbursement program under development

Italy ✓

Outcome-

based (in 3-

staged

payments)

✓

Outcome-

based (in 3-

staged

payments)

Latvia There is a possibility of reimbursement for treatment abroad, no

further details available

Malta Treatment for haematology patients reimbursed in the UK

Norway ✓N/A

Spain ✓

Outcome-

based (in 2-

staged

payments)

✓

Outcome-

based (in 2-

staged

payments)

Switzerland ✓

CED

✓

CED

United

Kingdom

(England)

✓

CED

✓

CED

Note: N/A –not available. CED –coverage with evidence development, MEA –

managed entry agreement.

Y. Litvinova et al. Health policy 149 (2024) 105153

3.3. Estimated expenditure on CAR-T therapy

It is important to note that price agreements between industry and

payers are mostly confidential; therefore, only list prices or rough esti-

mates of costs are available. In most cases, these costs include only the

prices for the CAR-T product itself, but not the treatment pathway

(Table 3). Italy and Spain listed a price of EUR 320 000 for Kymriah®

and EUR 327 000 for Yescarta®without specifying additional treatment

costs or terms for the staged payments. In Belgium, Kymriah®costs EUR

280 000 (ex-factory list price) on the day of administration, plus pay-

ments of EUR 20 000 at 6 and 12 months. Yescarta®has been reim-

bursed with the price EUR 287 000 (ex-factory list price) on the day of

administration, plus payments of EUR 20 000 at 12 and 20 months [30].

In Norway, the Kymriah®Single Technology Assessment report men-

tions the public price for tisagenlecleucel at NOK 3 167 606 [approx.

EUR 317 000] [31]. Publicly available information on prices for CAR-T

therapies in Switzerland also indicates similarly high levels –around

CHF 300 000 (approx. EUR 270 000).

Overall, the total cost of CAR-T therapy, accounting only for the

pharmaceutical products and based on the official ex-factory prices,

corresponds to an average of EUR 45.4 million (EUR 6.3 million to EUR

89.6 million), or 0.28% (0.20% to 0.37%) of pharmaceutical expendi-

ture annually (using 2020 as a reference year, Table 3).

3.4. Delivery model

CAR-T therapies are provided at designated cancer centres, which

are often embedded in the system of institutions (mainly large tertiary

hospitals) or part of a network of collaborating centres (university

hospitals). The number of treatment locations in the selected countries

are shown in Table 4.

Generally, the number of centres qualified to provide CAR-T thera-

pies ranges between 0.02 and 0.05 per 100 000 inhabitants in the

selected countries. With the current capacity, Switzerland, Belgium and

England treat more patients per 100 000 than the other countries in the

sample (1.09, 0.44 and 0.42 per 100 000 population, respectively)

(Table 4). Yet, for further assumptions of performance in CAR-T thera-

pies delivery, disease prevalence needs to be considered. In Norway, the

only provider of CAR-T therapies is the Radium Hospital (part of the

Oslo University Hospital), which has also become the centre for the

development of non-commercial CAR-T products (see Discussion). By

2022, ten centres in only four provinces in Canada - Ontario, Quebec,

Alberta, and Nova Scotia - could provide CAR-T therapies to their resi-

dents or those referred from other provinces.

In five out of the seven surveyed countries which provide CAR-T

therapies, referral networks have been established. These mostly build

on existing national referral systems, e.g., for stem-cell transplantation,

to organise the referral of patients for CAR-T therapies (Belgium, Can-

ada, England, Italy, Spain). In Italy, institutions from the National

Cancer Network “Alliance Against Cancer”(Alleanza Contro il Cancro,

ACC) have organised themselves as a referral network.

The delivery model for CAR-T therapy relies on tertiary care pro-

viders and related laboratory and hospital infrastructure. To be able to

manage potential severe risks associated with the administration of

these treatment, the designated CAR-T therapy centres have to fulfil

strict quality and safety criteria, and in most cases should 1) have ac-

creditations from the Joint Accreditation Committee of the International

Society for Cell &Gene Therapy (JACIE) and the European Society of

Blood and Marrow Transplantation (EBMT); 2) be certified as the na-

tional transplant centre; 3) have an intensive care and resuscitation unit;

for the allogeneic transplant: include clinical unit, unit of collection and

processing unit and 4) offer a multidisciplinary team suitable for the

clinical management of the patient and possible complications [36].

These criteria are similar throughout the studied countries and defined

at national level.

3.5. Equity considerations

In addition to the eligibility criteria defined by the manufacturer and

(national) regulators [37,38], some countries have established national

clinical or expert panels to grant approval and prioritise patients. Based

on the studied countries, these criteria mainly refer to clinical in-

dications rather than other characteristics. For instance, in the English

National Health Service (NHS), capacity has not been a problem for

young patients with ALL. However, for lymphoma patients, a National

CAR-T Clinical Panel (NCCP) had to prioritise adult patients before the

final evaluation in 2023 due to the limited financial resources of the

system. This meant that not all patients who could benefit from the

therapy were able to do so. After January 2023, the role of the NCCPs

became more about providing expert clinical advice on CAR-T therapies,

ensuring the clinical eligibility of patients, monitoring the outcomes of

these patients at different stages of treatment, and prioritising patients

Table 3

Estimated expenditure on CAR-T therapies, based on list prices of Kymriah®and numbers of patients treated in 2020.

Country Approx. price per

treatment, local

currency

Approx. price for

treatment, EUR

Number of

patients

treated

Approx. CAR-T

budget, total, EUR,

mln

Pharmaceutical

expenditure, EUR

, mln

Share of the CAR-T budget in

general pharmaceutical

expenditure, %,

Belgium 320 000 EUR 320 000 51 16.3 5754.3 0.28

Canada NA 320 000 153 49.0 24,602.3 0.20

Hungary 2717 0.00

Italy 320 000 EUR 320 000 236

75.5 28,227 0.27

Latvia 502.1 0.00

Malta 310.8 0.00

Norway 3 167 606 NOK 316 761 20

6.3 2796.4 0.23

Spain 320 000 EUR 323 500 160

51.8 18,117.6 0.29

Switzerland 300 000 CHF 307 000 95

29.2 7957.7 0.37

United Kingdom

(England)

NA 320 000 280

89.6 29,849.6 0.30

Note: NA - not available.

For Canada and England a price of 320 000 EUR was used for the calculations because no data on price was available upon the survey conduction;.

Local prices were changed to EUR, given the average exchange rate in 2020, provided by European Central Bank: 1 CAD =0.6 EUR, 1 CHF =0.9 EUR, 1 GBP =1.1

EUR, 1 HUF =0.003 EUR, 1 NOK =0.1 EUR. [32];.

OECD Health Statistics [12], 2020, for Malta –Eurostat, 2020;.

[33];.

for Norway and the UK (England) - an estimate of patients eligible for treatment, but not patients received treatment;.

[34];.

[35].

Y. Litvinova et al. Health policy 149 (2024) 105153

for treatment according to the capacity of the centres and the distribu-

tion of patients [39].

In Italy, the eligibility criteria formalise the requirements used in

clinical trials conducted by the pharmaceutical companies and listed in

the Italian Medicines Agency’s reports. Although this ensures that pa-

tients who are likely to benefit from the treatment are prioritised, it may

inadvertently exclude diverse patient populations that don’t meet strict

clinical criteria.

To receive CAR-T therapy in Spain, prospective patients must apply

to the national expert group, which evaluates eligibility on a case-by-

case basis. In 2020, a total of 265 treatment applications for CAR-T

therapy were received from 138 hospitals covering all 17 Spanish re-

gions. Of these, 242 requests were granted access to the therapy. How-

ever, as shown in Tables 3 and 4, only 160 patients actually received

treatment [34]. This gap may indicate challenges with capacity or lo-

gistics as well as potential decline in the clinical status of patients that

could hinder the administration of therapy.

4. Discussion

This study has identified a number of trends regarding the avail-

ability and affordability of CAR-T therapies in different countries along

the five areas of i) availability, ii) financing, iii) potential pharmaceu-

tical expenditure, iv) delivery, and v) equity. The following sections

each focus on one area.

4.1. Availability is inconsistent across member states

Despite the centralised approval by the EMA, CAR-T therapies are

currently not reimbursed in some EU Member States within our sample,

specifically Hungary, Latvia and Malta. Additionally, the reimbursement

of Kymriah®and Yescarta®is limited in countries outside our sample,

such as Bulgaria, Czechia, Denmark, Iceland, Slovenia and Sweden [10].

In Denmark, reimbursement decisions for both Kymriah®and Yescarta®

for Diffuse Large B-cell Lymphoma (DLBCL) were negative, aimed at

controlling expenditure. Similarly, in Sweden, Kymriah®is not reim-

bursed for DLCBL [10]. The reimbursement landscape for newer CAR-T

therapies, such as Tecartus®and Abecma®(see Table 1), is even more

restricted, with only France, Germany, Italy, and Spain having made any

arrangements [10].

Inconsistent availability may be due to several factors: the health

system’s inability to provide the therapy due to its high cost (as seen in

the reimbursement), a lack of necessary infrastructure in the laboratory

and/or hospital setting, the absence of specialised knowledge, and un-

predictable demand, especially in smaller countries like Malta. Addi-

tionally, pharmaceutical companies may choose not to launch their

products in certain countries. The newly proposed EU Pharmaceutical

Regulation [40] and Pharmaceutical Directive [41] (April 2023) aim to

incentivise the industry to launch therapies in all EU countries within

two years. This incentive includes extended market exclusivity and seeks

to create a single European market for medicines. It is unclear whether

these changes will impact the accessibility of ATMPs across Member

States, as the development of these products is costly and

time-consuming, requiring enhanced delivery capacity, and afford-

ability issues would still need to be addressed.

The proposal also introduces measures to improve the application of

the hospital exemption rule for ATMPs, including measures for collectng

and reporting safety and efficacy data. Currently, the application of this

rule varies between Member States [42]. A more consistent use of

‘hospital exemptions’could help address the high cost of commercial

products [42] and encourage the development of ‘local’treatments,

further tackling unmet need [43].

4.2. Development of ’local’treatments can enhance CAR-T accessibility

One way to increase the availability and affordability of these

innovative technologies is to reduce their cost by investing in the

development of ’local’CAR-T therapies. Taking advantage of the exist-

ing ’hospital exemption’authorisation pathway in European regulation,

university hospitals in several countries, including Belgium, Canada,

Italy, Norway, Spain and Switzerland, are actively engaged in this effort.

A notable example is CAR-T ARI-0001, developed by the Hospital

Clínic in Barcelona for patients over 25 with lymphoblastic leukemia

resistant to conventional treatments [43]. The Spanish Agency for

Medicines and Health Products (AEMPS) approved its use in February

2021 [44]. Its price has been set at EUR 89 270 and it has been included

in the Spanish reimbursement package since June 2021 [45]. The

product was granted a conditional licence for three years, subject to a

follow-up annual report and re-evaluation of the data for a further

five-year renewal. (44) Although this example illustrates the possibil-

ities of such developments, in Spain there are limitations to making the

therapy available to patients from other hospitals, as national legislation

only grants the licence to the hospital developer, whereas the European

Regulation limits the use of these products to the same Member State in

which they were developed.

In addition, the Radium Hospital in Norway became a ground for the

Table 4

Delivery of CAR T therapies in selected countries, 2020.

Country Number treatment centres Number of centres

per 100 000

population

Total

population,

mln.

Referral

Network (Yes /

No)

Total

number of

patients

Number of patients

per 100 000

population

Belgium 4 0.03 11.54 ✓51 0.44

Canada 10

0.03 37.74 ✓153

0.41

Hungary The first national centre at the Central Hospital of

Southern Pest National Institute of Haematology and

Infectious Diseases to be opened in 2023

NA 9.71

Italy 20

0.03 59.07 ✓236 0.40

Latvia NA 1.88

Malta NA 0.52

Norway 1 0.02 5.41 20 0.37

Spain 8

0.02 47.33 ✓160 0.34

Switzerland 4 0.05 8.7 95 1.09

United Kingdom

(England)

12 0.02 67.33 ✓280 0.42

World Bank, 2020;.

Of which 4 are in Ontario, 3 in Quebec, 2 in Alberta, and 1 in Nova Scotia;.

[33];.

[34].

Note: NA (not available).

Y. Litvinova et al. Health policy 149 (2024) 105153

development and manufacturing of non-commercial CAR-T therapies

with first results to undergo the trials [46]. In Italy, additional funding

was designated to research hospitals (Istituti di Ricovero e Cura a carattere

Scientifico, IRCCS) belonging to the Italian Alliance Against Cancer

(ACC) oncologic network and involved in the development of new

oncologic CAR-T therapies [47].

4.3. Conditional reimbursement is the primary financing model for CAR-T

treatments

Financing policies for ATMPs in different countries can reflect pur-

chasing power, health system priorities, experience, and available ca-

pacities and/or the population’s clinical needs. Due to the initially high

cost of developing CAR-T therapies as well as the treatment costs along

the patient pathway (see Annex 3), healthcare payers are largely relying

on conditional reimbursement to fund these treatments. This is also

relevant given the high upfront price for the potential of having a “one

shot therapy”.

To determine reimbursement, many of the countries in the sample

(Belgium, Canada, Italy, Spain, Switzerland, England) use forms of

MEAs. These MEAs may include milestone- or outcome-based contracts

to account for the uncertainties in clinical evidence but rather they

ensure value for money and help to facilitate a process by which real-

world evidence is generated. Individual performance-based agree-

ments, which are present in Italy and Spain, concern ensuring that only

eligible patients receive treatment, sometimes with assessment of out-

comes to determine treatment continuation (appropriate use) or linked

to payment schemes (paying only if response achieved or refund if

response not achieved) [16,48].

In Belgium, Canada, and England the MEAs cover CAR-T treatments

on the basis of evidence collection to inform re-appraisal or pricing re-

negotiations. Furthermore, payment models for CAR-T therapies can

be distinguished as a one-time (one-shot) payment or staged payments

spread over time regardless of MEAs. One-shot payments are less com-

mon in the financing of expensive and complex treatments because their

costs occur up front, whereas benefits accrue over a lifetime [17,49].

In terms of funding, most countries have used their public/statutory

healthcare budget, while others have used special funds created for spe-

cific disease areas, such as the Cancer Drugs Fund (CDF) in the UK or Fund

for Innovative Oncology Drugs in Italy. The extent to which such funds

ensure better access to appropriate medicines while making best use of

health system resources remains controversial. One of the challenges is

that such funds may be short-term and divert resources specifically to

cancer, raising questions about the equity of the resource allocation

within the broader context of population health needs [50].. Further-

more, they may not deliver meaningful value to individual patients and

society as a whole if they fund drugs based on uncertain evidence of

effectiveness(seealso thediscussiononMEAs, above) [51].Nevertheless,

these funds allow existing data gaps on uncertainties surrounding these

medicines to be filled by supporting data collection activities, including

ongoing clinical trials in parallel with publicly funded observational

research [52]. Recognising these issues, the establishment of the Inno-

vative Medicines Fund in the UK (in addition to the Cancer Drugs Fund) was

intended to ensure that cancer and non-cancer patients have equal op-

portunities to benefit from the latest clinical developments through

managed access at a reasonable price [53].

4.4. Concentrated delivery further enables collaboration and data

collection

Generally, two to six centres per 10 million residents were estab-

lished for the CAR-T therapy provision in the surveyed countries. This

covers treatments for the range of 9–57 patients per 1 million residents a

year. Also, many countries in the sample have established networks for

CAR-T therapy providers so that the relatively small number of patients

being treated will be concentrated among a small number of experienced

providers. These referral networks have the potential to serve other

purposes beyond managing patient care. They can establish working

groups to collaborate and share expertise across institutions with the

objective of improving the effectiveness of CAR-T therapy, as for

example in the aforementioned ACC Italian referral network and

working group.

At the supranational level, the European Society of Blood and

Marrow Transplantation (EBMT) and the International Society for Cell &

Gene Therapy (ISCT) play an important role in assessing and approving

the standards of treatment in clinics or administration centres through

the Joint Accreditation Committee of ISCT and EBMT (JACIE), which

applies not only to blood or marrow transplantation but also to CAR-T

therapies. Besides that, the EBMT initiated data collection on treat-

ments and outcomes for the patients treated with commercial CAR-T

therapies, with the notion that outcomes reporting and treatment data

management will provide necessary input for the analysis of treatment

efficacy and possible future improvements. The use of registry data

supports Post Authorisation Safety (PAS) studies for the manufacturers

but also advises the health authorities on value and reimbursement

decisions. EBMT requires that data on treatment be reported within one

month of treatment and at the follow up visits which are expected at day

100, 6 months and annually for 15 years. By June 2022, the registry

contained data on over 3 250 patients treated with CAR-T products and

collected through EBMT [54].

4.5. Affordability, availability, clear eligibility criteria and location of

treatment centres are linked to equity concerns

This study identified countries that have established eligibility

criteria for CAR-T therapies, focusing on clinical indications only.

However, the decision-making criteria of expert groups assessing patient

eligibility is variably transparent and the limited number of treatment

centres poses a challenge for the potential recipients of the CAR-T

therapies [18,55,56]. Furthermore, given the severity of the side ef-

fects associated with CAR-T therapy, patients must stay for at least four

weeks at the treatment centre or in close proximity to minimise harm to

patients. For patients who live further away from the nearest CAR-T

therapy centre, this requirement imposes another burden and may

limit access [55–57]. Therefore, disparities within a country, whether

based on urban or rural differences, or even on region (e.g. Italy) or

province (e.g. Canada), can exacerbate geographical inequities in ac-

cess. Furthermore, the limited affordability of these therapies necessi-

tates adherence to strict eligibility criteria based on potential

benefit-to-cost ratios for public coverage. As a result, only patients

most likely to benefit from the treatment are selected, which can exac-

erbate inequities [9,58,59].

Fig. 1. The main steps in a patient’s journey with CAR-T therapy.

Source: authors’version based on [62,63].

Y. Litvinova et al. Health policy 149 (2024) 105153

4.6. New CAR-T therapies may address health system challenges

All currently approved CAR-T treatments (including the studied

products of Kymriah®and Yescarta®) are based on the autologous

process, in which CAR-T cells are generated from the patient’s own

immune cells. Over 80% of therapies in development fall into this

category [2]. Autologous CAR-T cells are manufactured on demand basis

and are truly personalised treatments. However, the manufacturing

process increases the cost and time required to prepare, deliver and

administer these products, which limits their large-scale clinical appli-

cation as seen above. A potential solution to these limitations is offered

by allogeneic donor-derived CAR-T products, so-called “off-the-shelf”

cells. Currently, only 8% of CAR-T clinical trials are investigating these

[2,60]. These advances are being explored with the support of new gene

editing and cellular engineering tools [60]. With the extensive ongoing

research in this area, the CAR-T market will look very different in the

decades to come.

4.7. Study limitations

The number of analysed countries was limited to ten and only two

CAR-T therapies were investigated in detail. The latter was limited by

the short time frame since these treatments have been available on the

market. Furthermore, the information collected relied on the responses

from country experts and available literature and only encompasses

publishable data (e.g., not the exact terms of MEAs or the extent of

confidential discounts on price). In addition, the rough calculations on

budget impact were limited by the simplicity of the approach. The re-

sults are not indicative of real costs or real shares in expenditure, they do

not reflect staged payments done over the timespan, nor do they include

treatment administration costs in hospital, e.g., hospital stay, apheresis

or managing adverse events. Moreover, the national sources report

significantly lower net expenditures on this type of pharmaceuticals. For

instance, Italy’s expenditure was EUR 16.7 million [33] and Belgium’s

was EUR 3 million [61], which is considerably lower than our estimates.

Future analysis could include a wider list of countries for compari-

son, newer CAR-T therapies, and the views of clinicians and patients

regarding whether current eligibility criteria and reimbursement de-

cisions reflect the real need for this therapy to be used in practice. It was

beyond the scope of our analysis to determine whether Directive 2011/

24/EU (on patients’rights in cross-border healthcare) has been used in

the context of CAR-T therapy but there may be potential to explore this

possibility further, although the movement of severely ill patients across

borders poses significant challenges.

Based on the results of this research, further analysis could focus on

capturing the policy landscape regarding the regulation, financing, and

delivery of ATMPs at the national or regional level.

5. Conclusion

In summary, we studied some of the challenges in providing CAR-T

therapies related to availability and financing across countries. CAR-T

therapies are a relatively novel form of therapy, yet their promising

effects are drawn from studies with smaller samples and a higher degree

of uncertainty. For this reason, it is important to carefully monitor the

long-term benefits of these therapies and compare them with the high

promises made by the pharmaceutical industry. To address these un-

certainties while still ensuring access to these therapies, countries have

implemented conditional coverage. Until now, countries have

cautiously designed reimbursement models for CAR-T treatments, often

establishing evidence-development schemes or outcome-based MEAs to

study the efficacy and impact of the therapies in real-world settings. To

address the high prices, some health systems have invested in the

research and development of academic therapies derived from the

application of ATMPs under the hospital exemption in Europe.

To ensure equal access for all, regardless of their proximity to

delivery centres, it is important to maintain transparent and sys-

tematised eligibility criteria. Additionally, improving the organization

and clarity of the clinical pathway phases can help distribute account-

ability for the quality and safety of CAR-T therapies among the various

stakeholders involved in the process, including the treatment centre, the

manufacturing plant and the patients. In addition, the establishment of

strong networks and referral systems has the potential for collaboration

and sharing of expertise to improve the outcome of CAR-T therapies.

Due to the multi-dimensional nature of the CAR-T clinical pathway,

exchanging knowledge and learning from current best practices can

improve therapy provision within the healthcare system and ultimately

benefit relevant populations.

Funding information

This research did not receive any specific grant from funding

agencies in the public, commercial, or not-for-profit sectors.

CRediT authorship contribution statement

Yulia Litvinova: Writing –original draft, Visualization, Validation,

Project administration, Methodology, Investigation, Formal analysis.

Sherry Merkur: Writing –review &editing, Writing –original draft,

Validation, Methodology, Data curation, Conceptualization. Sara Allin:

Validation, Investigation, Data curation. Ester Angulo-Pueyo: Valida-

tion, Investigation, Data curation. Daiga Behmane: Validation, Inves-

tigation, Data curation. Enrique Bernal-Delgado: Validation,

Investigation, Data curation. Miriam Dalmas: Validation, Investigation,

Data curation. Antonio De Belvis: Validation, Investigation, Data

curation, Conceptualization. Nigel Edwards: Validation, Investigation,

Data curation. Francisco Estupi˜

n´

an-Romero: Validation, Investiga-

tion, Data curation. Peter Gaal: Validation, Investigation, Data cura-

tion. Sophie Gerkens: Validation, Investigation, Data curation.

Margaret Jamieson: Validation, Investigation, Data curation. Alisha

Morsella: Validation, Investigation, Data curation, Conceptualization.

Dario Picecchi: Writing –review &editing, Validation, Investigation,

Data curation. Hilde Røshol: Validation. Ingrid Sperre Saunes: Vali-

dation, Investigation, Conceptualization. Terry Sullivan: Investigation,

Data curation. Bal´

azs Sz´

ecs´

enyi-Nagy: Validation. Inneke Van De

Vijver: Validation. Ricciardi Walter: Validation, Methodology, Inves-

tigation, Data curation. Dimitra Panteli: Writing –review &editing,

Validation, Resources, Project administration, Methodology, Investiga-

tion, Formal analysis, Conceptualization.

Declaration of competing interest

None.

Acknowledgements

The authors would like to acknowledge the support of the European

Observatory on Health Systems and Policies and members of the HSPM

network for contributing key information.

Supplementary materials

Supplementary material associated with this article can be found, in

the online version, at doi:10.1016/j.healthpol.2024.105153.

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