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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.

IntroductionSince 2013, the coverage of innovative and expensive drugs by the French National Health Insurance considers cost-effectiveness and budget impact, as assessed by the National Authority for Health (HAS) on the basis of an evaluation submitted by the firm. First CAR-T cell therapies were subject to economic evaluation in 2019 in France. We aim at describing the process and results of the economic evaluation of tisagenlecleucel and axicabtagene ciloleucel and the challenges these evaluations raised.MethodsPrimary evaluations were submitted by the firms to be reviewed by HAS. The final analyses were submitted to the Committee of Economic Evaluation and Public Health (CEESP), composed of independent economists, clinicians and patients’ representatives. The CEESP issued Opinions related to i) the methodological quality of economic evidence and ii) the cost-effectiveness and budget impact of the drugs under review.ResultsThe estimated incremental cost-utility ratio (ICUR) of tisagenlecleucel were rejected, being based on insufficient clinical evidence to estimate and extrapolate the long-term progression and to compare tisagenlecleucel with alternatives. Thus, the CEESP concluded that tisagenlecleucel was not proved cost-effective. The estimated ICUR of axicabtagene ciloleucel at 114,509EUR/QALY vs. chemotherapies was associated with an acceptable level of evidence despite being based on a frail indirect comparison and limited data on quality of life. In a context where France has no official cost-effectiveness threshold, the CEESP considered axicabtagene ciloleucel ICUR to be “very high” and questioned the collective acceptability of the claimed price.The CEESP stressed that the main source of uncertainty surrounding the ICUR estimates of both drugs was related to the lack of hindsight on effectiveness, especially in terms of overall survival and safety.ConclusionsThe economic evaluation of CAR-T cell therapies highlights the sources of uncertainty underlying the decision and the risk of inefficient resource allocation driven by limited clinical data. It calls for payment schemes accounting for the uncertainty, and effective collection of relevant post-marketing data.

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.

La loi de financement de la securite sociale (LFSS) pour 2012 a introduit le critere d’efficience dans la determination du prix des produits de sante innovants. La mise en œuvre de cette disposition par la Haute Autorite de sante (HAS) et le Comite economique des produits de sante (CEPS) met en lumiere les enjeux de l’evaluation economique pour eclairer la decision en sante. Pour documenter le critere d’efficience, la Haute Autorite de sante privilegie les analyses cout-resultat (ACR) comparant le gain en sante a son cout marginal. L’interpretation du resultat quantitatif issu de ces analyses est confrontee a la necessite de definir collectivement le montant que la collectivite est prete a depenser pour obtenir une unite de sante supplementaire. Quatre methodes permettant d’estimer cette valeur de reference sont identifiees dans la litterature. Elles permettent toutes d’estimer un indicateur d’acceptabilite, mais elles souffrent de limites qui appellent la poursuite de recherches academiques sur ce sujet. Pour autant, les evaluations produites par les industriels, l’analyse critique qui en est faite par la HAS et les avis d’efficience rendus par la Commission d’evaluation economique et de sante publique (CEESP) eclairent la relation entre le cout d’un produit de sante et les resultats de sante qu’il genere. L’elaboration recente des avis d’efficience en France semble jouer un role effectif dans la negociation des prix, meme si son usage dans la decision reste largement confidentiel. A l’image des pratiques observees dans les pays etrangers, le critere d’efficience dans les decisions en sante doit trouver sa place dans un arbitrage deliberatif et transparent parmi les autres criteres de jugement, identifies comme pertinents pour definir la valeur sociale d’un produit de sante.

International audience; Early access schemes for pharmaceuticals have been increasingly implemented worldwide with the objective of satisfying unmet medical needs or facilitating market access for certain innovative drugs. It allows for pharmaceuticals which have not yet obtained their marketing authorization (MA) to be administered and reimbursed to a pre-defined population of patients. Under the French regulatory framework, this scheme consists in a window of unregulated prices, which stands in contrast with the system of administered prices for reimbursed pharmaceuticals. Our study aims at filling a gap in the literature by analyzing the French Temporary Authorization for Use (TAU) scheme since its implementation in 1994 up to 2016. This long time span allows to document and describe the TAU scheme and its impact on prices. In this article, we review the price difference between the freely set price under TAU and the post-MA price, after negotiation with the French Pricing Committee. Our main result shows that the 2007 regulatory change, which compelled pharmaceutical companies to reimburse the difference between the TAU price and the post-MA price, is significantly correlated with decreasing or stable post-MA-to-TAU price ratios.

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.

Depuis le 3 octobre 2013 en France, les industriels qui revendiquent le remboursement d’un produit de sante innovant ayant, ou etant susceptible d’avoir, un impact significatif sur les depenses de l’assurance maladie ont l’obligation de fournir a la Haute Autorite de sante (HAS) une evaluation de l’efficience de leur produit. Cette evaluation est expertisee par le service d’evaluation economique et de sante publique (SEESP). A partir de cette expertise, la Commission d’evaluation economique et de sante publique (CEESP) emet un avis sur l’efficience previsible ou constatee du produit, qu’elle transmet au Comite economique des produits de sante (CEPS), charge de determiner le prix du produit de sante. En 22 mois d’activite, la HAS a rendu 30 avis d’efficience.Apres avoir rappele la place des avis d’efficience dans le circuit francais de remboursement et de fixation des prix, l’objectif de cet article est de dresser un premier bilan sur les avis d’efficience rendus par la HAS.Le processus, construit sur le principe d’un echange entre l’industriel et la HAS, a permis a la CEESP de documenter le critere economique dans la majorite des dossiers (20/30), tout en caracterisant le degre d’incertitude qui l’entoure. Pour dix dossiers, des reserves methodologiques majeures ont conduit la CEESP a rejeter la demonstration de l’industriel.

International audience; Drug prices are regulated in a legal framework that organizes the negotiation between pharmaceutical firms and a third-party payer responsible for healthcare reimbursement. This regulation aims at compensating for market failures associated with drug specificities. Explicit economic reasoning through the socalled health technology assessment framework is increasingly embedded in the institutional and administrative process of the evaluation procedure leading to market access, pricing and reimbursement for new drugs.

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.

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.