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Summary Since 2013, the process of pricing of innovative drugs by the French National Health Insurance has considered both cost-effectiveness and budget impact. CAR-T cell therapies were first subject to economic evaluation from 2019 in France. We aim to describe the process and results of the economic evaluation of tisagenlecleucel and axicabtagene ciloleucel as well as the challenges these evaluations raised. Evaluations submitted by the firms were reviewed by HAS and submitted to the Committee of Economic Evaluation and Public Health (CEESP). The CEESP issued opinions related to: (1) the methodological quality of economic evidence and, (2) the cost-effectiveness and budget impact of the drugs. The CEESP invalidated the estimated incremental cost-utility ratios (ICUR) of tisagenlecleucel due to the insufficient clinical evidence and methodological quality to extrapolate the long-term progression of the disease after treatment and compare tisagenlecleucel with alternatives. The CEESP concluded that tisagenlecleucel was not proven cost-effective. The estimated ICUR of axicabtagene ciloleucel at €114,509/QALY vs. chemotherapies was associated with an acceptable level of methodological quality despite being based on a weak indirect comparison and limited data on quality of life. The CEESP considered axicabtagene ciloleucel ICUR to be “very high” and questioned the societal/community willingness-to-pay of the claimed price. The primary source of uncertainty surrounding the ICUR estimates of both drugs was the lack of hindsight on effectiveness. The economic evaluation of CAR-T cell therapies highlights the risk of inefficient resource allocation driven by limited clinical data. It calls for payment schemes accounting for this risk and effective collection of post-marketing data.

Chimeric antigen receptor T-cells (CAR-T cells) have the potential to be a major innovation as a new type of cancer treatment, but are associated with extremely high prices and a high level of uncertainty. This study aims to assess the cost of the hospital stay for the administration of anti-CD19 CAR-T cells in France. Data were collected from the French Medical Information Systems Program (PMSI) and all hospital stays associated with an administrated drug encoded 9439938 (tisagenlecleucel, Kymriah®) or 9440456 (axicabtagene ciloleucel, Yescarta®) between January 2019 and December 2020 were included. 485 hospital stays associated with an injection of anti-CD19 CAR-T cells were identified, of which 44 (9%), 139 (28.7%), and 302 (62.3%) were for tisagenlecleucel in acute lymphoblastic leukaemia (ALL), tisagenlecleucel in diffuse large B-cell lymphoma (DLBCL), and axicabtagene ciloleucel respectively. The lengths of the stays were 37.9, 23.8, and 25.9 days for tisagenlecleucel in ALL, tisagenlecleucel in DLBCL, and axicabtagene ciloleucel, respectively. The mean costs per hospital stay were € 372,400 for a tisagenlecleucel in ALL, € 342,903 for tisagenlecleucel in DLBCL, and € 366,562 for axicabtagene ciloleucel. CAR T-cells represented more than 80% of these costs. n=13 hospitals performed CAR-T cell injections, with two hospitals accounting for more than 50% of the total number of injections. This study provides original data in a context of limited information regarding the costs of hospitalization for patients undergoing CAR-T cell treatments. In addition to the financial burden, distance may also be an important barrier for accessing CAR T-cell treatment.

Objective This paper constitutes the first attempt to draw lessons from the recent uptake of health economic evaluation of innovative drugs in the French regulatory framework. Study Design Taking the example of new direct-acting antivirals against hepatitis C virus, the paper asks whether and how the cost-effectiveness (CE) opinions issued by the French National Health Authority improve the information available to support the pricing decisions. Methods The analysis compares the assessment of these drugs based on three different sources: CE opinions, clinical opinions, and the published cost-utility analyses (CUA) available in the literature and identified through a systematic review. Results The results show that CE opinions bring to the fore three issues prone to impact the incremental cost utility ratio and those were not available to the decision maker through clinical opinions or published CUA: the stage of treatment initiation, the modeling of the disease progression, and the uncertainty around the efficacy rates. Conclusions France has introduced the criterion of the cost per QALY gained in the pricing and regulation of innovative pharmaceuticals since 2013. Our analysis shows that the use of CUA does enhance the information available to the decision makers on the value of the treatments.

Objectives: This paper aims to describe the added value of combining cost-effectiveness and ethical evaluations when the preferences of the decision maker toward cost-effectiveness evaluation outcomes are not known, with the French national neonatal screening of cystic fibrosis (CF) as a case-study.Methods: A cost-effectiveness analysis comparing four CF neonatal screening strategies, with or without DNA testing, was performed. Ethical positions toward their outcomes were described. In addition, a post-hoc analysis of the ethical issues being considered relevant from the decision-makers’ perspective was conducted.Results: Two strategies were found equally cost-effective. Among them, choosing the non-DNA or a DNA-based strategy constrains the decision maker to render a judgement between different ethical issues or disagreements associated with the screening program.Conclusions: The analysis supports the relevance of combining cost-effectiveness and ethics evaluation in developing health policy, as a way to reveal or clarify the motives associated with health. The choice of the decision maker to favor the DNA-based strategy, which was not originally recommended, creates the opportunity to make explicit the role played by ethical issues in the decision.

Since 3rd October 2013 in France, drug companies applying for reimbursement of an innovative and expensive drug or medical device are required to provide the French National Authority for Health (HAS) with a cost-effectiveness assessment of their product. After a methodological audit of the economic evaluation submitted by the drug company, the Health Economics and Public Health Committee (CEESP) issues an opinion on the expected or observed cost-effectiveness. This opinion is sent to the Pricing Committee (CEPS) which determines the price of the product. After summarizing the French reimburse'!lent and pricing system, the objective of this article is to review the first 22 months of activity, in which HAS issued 30 cost-effectiveness opinions. The process, based on exchanges between drug companies and HAS, allowed the pricing committee to document the economic criterion in the majority of applications, while characterizing the degree of uncertainty of the results. For ten applications, major methodological concerns led the CEESP to reject the drug company's assessment.

Recently, National agencies in charge of the development of clinical practice guidelines (CPGs) have started to improve the usual narrative CPGs to provide guidance for different clinical pathways. In France, in conjunction with the development of the type 2 diabetes National CPGs, we have developed the system RecosDoc-Diabète which allows to interactively build a patient-centred pathway and get the appropriate recommendations. National narrative CPGs and RecosDoc-Diabète were published and made available online at the same time (February 2013). A questionnaire was provided to collect visitors' judgement about the system. Between February 12th and December 31st, 2013, 55,203 visitors accessed the narrative CPGs whereas 10,565 accessed the system. Among them, 186 (2%) responded to the questionnaire. One third of the comments were criticisms towards the CPG content. The system was globally positively evaluated although assessments were mixed illustrating that users' needs may be contradictory.

International audience; When evaluating new drugs or treatments eligible for reimbursement, health technology assessment (HTA) agencies are repeatedly faced with cost-effectiveness analyses that evidence lack of adequate data and modeling biases. The case of type 2 diabetes illustrates this difficulty. In spite of its high disease burden, type 2 diabetes is poorly documented through existing cost-effectiveness analyses. We support this statement by an exhaustive literature review that enables us to precisely pinpoint the limitations of models used for the assessment of newly marketed (and expensive) drugs. We find thatmodels are mostly restricted to surrogate endpoints and based on non-inferiority clinical trial data; they also show biases in the choice of comparators and inclusion criteria. Such limitations undermine the scope and applicability of HTA practice guidelines based on cost-effectiveness evidence. Nevertheless, cost-effectiveness models remain an opportunity to better inform decision makers and to reduce the uncertainty surrounding their decisions. HTA agencies are best placed to provide incentives for companies to improve the quality of the cost-effectiveness studies submitted for pricing and reimbursement decisions. One such incentive is to include stages of discussion between the company and the health authority during the evaluation process.