Market Access for Cell and Gene Therapies in Key European Countries

By Xcenda |

Cell and gene therapies are classified as advanced therapy medicinal products (ATMPs) by the European Medicines Agency (EMA), which offer groundbreaking new opportunities for the treatment of disease and injury. Several ATMPs have recently received marketing authorization in Europe, a trend that is likely to continue and accelerate. This article examines the current HTA landscape for ATMPs and the emerging HTA appraisal frameworks.


Market Access Spotlight: Market Access for Cell and Gene Therapies in Key European Countries

By Vishwas R. Agashe, MSc, PhD 

Cell and gene therapies are classified as advanced therapy medicinal products (ATMPs) by the European Medicines Agency (EMA), which offer groundbreaking new opportunities for the treatment of disease and injury. Several ATMPs have recently received marketing authorization in Europe (Table 1), a trend that is likely to continue and accelerate. Although the precise technology used in each therapy and the disease mechanism targeted for correction vary widely, overall, these therapies attempt to replace or regenerate human cells, tissues, or organs, either to restore or establish normal function.

Table 1. Key Recent ATMP Market Authorizations in Europe

Key: ΔLNGFR – low affinity nerve growth factor receptor; ALL – acute lymphoblastic leukemia; ATMP – advanced therapy medicinal product; DLBCL – diffuse large B-cell lymphoma; EMA – European Medicines Agency; CAR-T – chimeric antigen receptor T-cell; HSV-TK Mut2 – herpes simplex I virus thymidine kinase; PMBCL – primary mediastinal large B-cell lymphoma; RPE65 – retinoid isomerohydrolase RPE65 (gene).

Current HTA Landscape for ATMPs

Following regulatory approval, several ATMPs have been assessed by national health technology assessment (HTA) bodies, the outcomes of which provide an opportunity to obtain early insights into the current reimbursement landscape for these innovative therapies. The status of HTA decisions for a subset of recently authorized ATMPs across key European countries is summarized in Table 2. These decisions and accompanying appraisal notes from the respective HTA bodies permit some overarching conclusions to be drawn around current HTA perspectives on ATMPs in Europe:

  • HTA bodies recognize the innovative nature of ATMPs but have critiqued the limitations of submitted evidence (eg, data from single-arm registration trials with often very few patients, lack of overall survival [OS] and long-term follow up data).
  • Importantly, in spite of these data limitations, HTA bodies have made use of existing mechanisms to grant some form of early patient access to these products in recognition of their promise (eg, Temporary Authorization for Use [ATU] in France, and managed access via the Cancer Drug Fund [CDF] in England for both Kymriah and Yescarta)
  • To mitigate decision uncertainties resulting from shortcomings of the evidence package, most HTA bodies have mandated the collection of additional data to confirm the long-term sustainability of benefits seen in single-arm trials used for regulatory approval (eg, national HTA bodies in France and Germany have mandated reassessment of Kymriah and Yescarta within 1–2 years with a provision to collect and submit additional data in this period and after).
  • Although risk-sharing agreements have not been very common across Europe, the high price tag of ATMPs has prompted an emerging trend toward adoption of innovative payment models that may become the norm as more products are launched (eg, for the first time in Germany, a nationwide pay-for-performance contract for Kymriah requires the manufacturer to partially reimburse costs of treatment if the patient dies of their illness within a set period of time).
  • In Italy, where budget impact is the predominant decision driver for HTA bodies, assessment decisions for ATMPs have become publicly available much later compared with other EU5 countries. Although the reasons for this are not entirely clear, it is plausible that high upfront cost of ATMPs and the time required for negotiating a novel payment-by-results reimbursement model may have played a role.
Table 2. HTA Decisions for Select ATMPs Across Key European Countries
Key: ASMR – Improvement of Medical Benefit (France); ATU – Temporary Authorization for Use (France); B-ALL – B-cell acute lymphocytic leukemia; CDF – Cancer Drug Fund; DLBCL – diffuse large B-cell lymphoma; HAS – French National Authority for Health; NICE – National Institute for Health and Care Excellence (England); OS – overall survival; PMBCL – primary mediastinal large B-cell lymphoma; RPE65 – retinoid isomerohydrolase RPE65 (gene); R/R – relapsed/refractory; SMR – Medical Benefit (France).


Emerging HTA Appraisal Frameworks for ATMPs

Given considerable public interest in ATMPs and their potential life-changing impacts, HTA bodies in individual European countries are in the process of assessing the suitability of their existing decision-making frameworks to determine their value to patients and healthcare systems. In particular, the promise of exceptional efficacy of ATMPs coupled inevitably with their unprecedented price tags is causing real-world dilemmas about balancing affordability against hypothetical long-term patient benefits. These dilemmas are made worse when a given ATMP offers the prospect of being a 1-time curative treatment for an otherwise incurable condition, requiring HTA decision makers to confront the challenge of sitting in judgment over the value of a saved life and make such decisions without long-term data supporting the curative properties. 

Manufacturers have argued that current HTA methods are unsuitable for assessing ATMPs, precisely because they were not designed for curative technologies with upfront costs. They posit that lifelong benefits of such technologies can deliver exceptional patient value and that their non-trivial, immediate budget impact should be managed by HTA bodies by adopting adequately flexible decision making or specialized access pathways. Manufacturers also argue that when compared with the prevalent ineffective standards of care, ATMPs can never be cost-effective under existing willingness-to-pay thresholds. In response to this debate, HTA bodies and other stakeholders have investigated whether ATMPs deserve to be treated differently by the HTA process and, broadly, 2 opposing viewpoints have emerged (Figure 1).

  • The first viewpoint, exemplified by a mock technology appraisal for ATMPs conducted by the National Institute of Health and Care Excellence (NICE) in the United Kingdom (UK), concludes that the existing technology appraisal methods and decision-making framework of NICE were both capable and sufficient to assess ATMPs. This appraisal utilized a hypothetical chimeric antigen receptor T-cell (CAR-T) therapy product for treating relapsed or refractory B-cell acute lymphocytic leukemia. Two different target product profiles (TPPs) were created, along with 3 hypothetical datasets, for each TPP that were designed to explore the impact of different levels of precision and maturity in the evidence base. Following the construction of cost-effectiveness models for each TPP and the 3 associated hypothetical datasets, this exercise identified the quantification of decision uncertainty and application of a suitable discount rate as key decision drivers for ATMPs. However, it was concluded that instead of changing the appraisal framework, the exceptional evidentiary uncertainty in value that is typical of novel ATMPs could be mitigated through innovative payment mechanisms for the new technology.
  • The second viewpoint developed by Marsden (2017) critiques the mock ATMP appraisal above. It holds that although the NICE HTA process may be compatible with assessing some ATMPs, it may not be the most suitable framework to do so—especially because the HTA decision-making process finds it difficult to handle the triple combination of extreme decision uncertainty, exceptional clinical benefits, and high upfront costs. These authors acknowledge that the existing NICE process includes some flexibilities, such as differential discount rates where substantial benefits are expected in the long term, inclusion of non-health benefits in particular circumstances, and acknowledgement of less robust evidence where it is difficult to conduct full randomized controlled trials. However, they highlight a lack of clarity and consistency in how committees apply these flexibilities and suggest that NICE could help by issuing either an update to their methods manual or a separate summary document that outlines how each of these flexibilities are expected to apply to ATMPs.

This debate will likely continue and inform any potential future changes to the HTA frameworks as more ATMPs reach the market and are put through the existing HTA processes across Europe. 


Figure 1. Suitability of NICE HTA Framework for Novel ATMPs: CounterpointsFigure

Key: ATMP – advanced therapy medicinal product; HTA – health technology assessment; NICE – National Institute for Health and Care Excellence.


The number of ATMPs to have undergone European HTAs remains small and has been restricted to a small number of products largely targeting hemato-oncological indications. Therefore, it will take some time before a significant quantum of data becomes available to inform reimbursement strategies in Europe. At the same time, the ongoing debate about whether current HTA methods are best suited for the appraisal of ATMPs remains unresolved. Although it is unclear if this debate will lead to any substantive changes to HTAs in practice, it is realistic to conclude that in the near term, manufacturers of ATMPs will likely face increased data demands and discounting pressures from HTA bodies. Nevertheless, on the positive side, the unprecedented efficacy of ATMPs demonstrated in early trials has provided a sufficient incentive for HTA bodies to reimburse these products via temporary access pathways while longer-term efficacy and safety data are being collected. Furthermore, the lack of extensive experience with ATMPs among HTA bodies presents opportunities for manufacturers to propose innovative solutions and methods (eg, outcomes-based payment models, collaborative evidence generation activities) to mitigate the currently high decision uncertainty with robust, longer-term evidence demonstrating the value of ATMPs to patients and healthcare systems.  

Acknowledgement: My colleague Clémence Arvin-Berod, PharmD, is gratefully acknowledged for her generous help in reviewing the key outcomes from HTA reports in France, Italy, and Spain, and translating them into English from the respective local languages.




The article should be referenced as follows: 

Agashe V. Market access for cell and gene therapies in key European countries. HTA Quarterly. Fall 2019.