Challenges raised by the economic evaluation of CAR-T-cell therapies. The review by the French National Authority for Health.

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.

The family accompaniment of persons with dementia seen through the lens of the capability approach.

Using the capability approach initially developed by A Sen as a theoretical framework, this paper analyses both what people with dementia and their families do in response to difficulties in their daily life brought about by the disease, and the reasons they give for acting as they do. Individual and collective interviews and ethnographic observations with 15 persons with dementia and one or more of their family members were conducted. Follow-up interviews were possible for nine families. Results highlight a great diversity in ways of doing things and in accompaniment by family members. Daily adjustments are often hidden or minimized, at least at the onset of the dementia. Later, they become more frequent, repetitive and indispensable but remain influenced by the social and gender roles that existed prior to the illness. The inventiveness of families, in a context marked by various kinds of constraints, is primarily motivated by their desire to maintain the apparently intact abilities of the person with dementia but especially to preserve forms of liberty and what counted for the person, what that person valued before the disease. There are some ways of living with dementia, even when accompanied, which may long remain preferable to others, which better answer to the past and present aspirations of persons with dementia and the purposes of the accompanying persons. It is thus essential that health professionals, as well as society in general, recognize and address this issue.

[Why are new drugs so expensive?] / Pourquoi les nouveaux médicaments sont-ils si chers ?

Putting an end to an innovation crisis, the reality of which is the subject of debate, recent pharmaceutical innovations, the result of a combination of scientific, industrial, financial, political and economic reasons, lead to a diversification of products and to a strong interest of pharmaceutical companies for the so-called "niche" products (targeted therapies, rare diseases, etc.). These new molecules are put on the market at much higher prices than in the past. In the absence of reliable information on the costs borne by manufacturers, and knowing that high levels of margins have been observed, these prices raise legitimate questions. These are also motivated by the lack of relationship between the price and the therapeutic benefit of these new molecules. In France, faced with levels of expenditure likely to weaken the financial sustainability of the social protection system, the public authorities have so far always favored interventions on prices or the conditions and volume of reimbursement, in accordance with the existing regulation. Other regulations (use of the statutory license, group purchase, etc.) could in the future be used in a growing concern for the efficiency of public expenditure. The difficulties encountered in regulating a deeply transformed industrial sector call for a reform of national evaluation and regulation systems.

[Evolution, determinants and regulation of drug expenditures in France]. / Évolution, déterminants et régulation des dépenses de médicaments en France.

According to the Organization for Economic Co-operation and Development (OECD), drug expenditures account for about 20 % of all health expenditures in high-income countries. The increase of these drug expenditures which has been observed in all these countries over a long period is due to the combination of aging populations, changes in medical practices and the dynamics of the pharmaceutical market, in particular the hospital market. France is no exception. Its consumption of drugs (which accounted for 17.5 % of health expenditures in 2014), historically among the highest in volume, has grown slower in the last decade than in other OECD countries. However, the particularly rapid and wide adoption of pharmaceutical innovations, which has always characterized France, has had in recent years a very significant effect on the soaring drug expenditures covered by the social protection system (plus 1.1 billion in 2014, a year marked by the introduction of new therapies against hepatitis C). This significant effect should continue with the introduction of new and very expensive therapies, particularly in oncology.

Health-state utility estimates for health technology assessment: a review of the manufacturers' submissions to the French National Authority for Health.

BACKGROUND: Our aim was to review the selection and methods used for deriving health state utility (HSU) estimates included in the cost-utility analyses (CUA) submitted by manufacturers to the National Authority for Health (HAS) during the first 2 years after the introduction of the economic evaluation for price setting in France. METHODS: We reviewed all manufacturers' submissions that included a CUA and were assessed by HAS by the end of October 2015 (N = 34). We reviewed the identification, selection, and methods used to estimate HSU and compared them with those recommended by HAS. RESULTS: A literature review to identify HSU was reported in only 13 (38%) submissions. The instruments for describing HSU were a preference-based generic instrument in 20 (59%) submissions; vignettes in five (15%); a condition-specific instrument in three (9%); and a combination of instruments in six (18%). The valuation perspective was the general population in 26 (76%) submissions; in only nine (26%) submissions, the valuation set was derived from the French general population. CONCLUSIONS: We identified numerous concerns in the selection, valuation and use of HSU, as well as a frequent lack of clarity in the methods used. Most submissions (79%) included HSU that did not meet HAS recommendations.

Capability deprivation of people with Alzheimer's disease: An empirical analysis using a national survey.

How can one assess the quality of life of older people--particularly those with Alzheimer's disease--from the point of view of their opportunities to do valued things in life? This paper is an attempt to answer this question using as a theoretical framework the capability approach. We use data collected on 8841 individuals above 60 living in France (the 2008 Disability and Health Household Survey) and propose a latent variable modelling framework to analyse their capabilities in two fundamental dimensions: freedom to perform self-care activities and freedom to participate in the life of the household. Our results show that living as a couple, having children, being mobile and having access to local shops, health facilities and public services enhance both capabilities. Age, household size and male gender (for one of the two capabilities) act as impediments while the number of impairments reduces both capabilities. We find that people with Alzheimer's disease have a lower level and a smaller range of capabilities (freedom) when compared to those without, even when the latter have several impairments. Hence they need a special attention in policy-making.

Cost-effectiveness of liquid-based cytology with or without hybrid-capture II HPV test compared with conventional Pap smears: a study by the French Society of Clinical Cytology.

Many articles concerning conventional Pap smears, ThinPrep liquid-based cytology (LBC) and Hybrid-Capture II HPV test (HC II) have been published. This study, carried out by the French Society of Clinical Cytology, may be conspicuous for several reasons: it was financially independent; it compared the efficiency of the conventional Pap smear and LBC, of the conventional Pap smear and HC II, and included an economic study based on real costs; for all the women, a "gold standard" reference method, colposcopy, was available and biopsies were performed whenever a lesion was detected; The conventional Pap smear, the LBC (split-sample technique), the colposcopy, and the biopsies were done at the same time. This study included 2,585 women shared into two groups: a group A of a high-risk population, a group B of a screening population. The statistical analysis of the results showed that conventional Pap smears consistently had superior or equivalent sensitivity and specificity than LBC for the lesions at threshold CIN-I (Cervical Intraepithelial Neoplasia) or CIN-II or higher. It underlined the low specificity of the HC II. Finally, the LBC mean cost was never covered by the Social Security tariff.

Reliability and validity of the Functional Assessment of Cancer Therapy General (FACT-G) in French cancer patients.

This report describes the reliability and validity of a French version of the Functional Assessment of Cancer Therapy - General (FACT-G) with a French sample of 493 cancer patients. The FACT-G consists of 27 items and four subscales: Physical (PWB), Functional (FWB), Social/Family (SFWB) and Emotional well-being (EWB). The study sample includes 64% with localized disease, 26% with metastases, 11% in remission, and 71% receiving radiation/chemotherapy. Internal consistency Cronbach alphas of the global FACT-G scale (0.90) and subscales (>0.75) are satisfactory (n = 126). Test-retest reproducibility is satisfactory for all subscales and the global scale (n = 87 to 93, r = 0.74 to 0.90). ANOVA models show that PWB differentiated between the three disease stages; the global FACT-G and FWB discriminated between patients with metastases and others with localized disease or in remission; EWB only discriminated between metastases and localized disease; while SFWB did not discriminate between groups at different stages of cancer. Only the PWB subscale discriminated between patients with no history from those receiving chemotherapy (p < or = 0.05). None of the scales discriminated between groups based on radiotherapy. These results may be useful in the design and interpretation of clinical trials involving French patients when the FACT-G is the outcome measure.

Postmarketing evaluation of drugs. Actual efficacy, population exposed and impact on public health.

Round table no. 2 was devoted to the postmarketing evaluation of drugs. The debates involved both the questions posed by postmarketing evaluation and the methods for responding to them. The major categories of questions likely to be posed are as follows: efficacy in actual situations; safety in actual situations; prognostic factors and patients responding; place in the therapeutic strategy; impact on the healthcare care system; the 'joined' population (those who actually obtain benefit); and drug utilisation review. In addition, the methodological approaches have been divided into three categories: the experimental approach, the observational approach and the modelling approach. Each of these methodological approaches has been qualified with respect to each of the questions. The objective was neither to establish a classification of the methods according to the level of proof, nor to propose methodological formulae. Instead, the participants applied themselves to describe the strengths and the limits of the different methods for each of the questions in turn. The debates then focused on the process of identification of pertinent questions and appropriate methods. In this context, the round-table participants applied an analysis of the current system of postmarketing study projects and formulated some propositions for their improvement. Finally, the place of existing databases in the postmarketing evaluation was discussed and the participants emphasised the importance of initiating a very detailed assessment of the information that could be provided by such databases before instituting ad hoc studies.

Efficiency of the hybrid capture 2 HPV DNA test in cervical cancer screening. A study by the French Society of Clinical Cytology.

The aim of this study was to determine the efficiency of the Hybrid Capture 2 (HC2; Digene, Gaithersburg, MD) human papillomavirus (HPV) assay for the detection of cervical neoplasia. Of the 1,785 patients recruited, 462 (25.88%) were referred for colposcopy owing to previously detected cytologic abnormalities, and 1,323 (74.12%) were voluntary candidates for screening. For all patients, a Papanicolaou smear and a monolayer smear (ThinPrep, Cytyc, Boxborough, MA) were done. HPV DNA was detected on the residual liquid-based material. False-positive results were observed in 111 cases and comprised 34 cross-reactions (1.90%) and 77 false-positive cases (4.31%) owing to a contiguous strong chemiluminescence signal. Interestingly, all these samples had a relative light units value of 1 to 3 and were contiguous to a sample with a very high HPV DNA load. The final results showed that high-risk and low-risk HPV DNA were detected in 480 samples (26.89%) and 135 samples (7.56%), respectively. Although HC2 can be considered a reliable and sensitive test for HPV DNA detection, we do not advocate its use for large-scale screening for cervical neoplasia.

[Assessing fatigue in the cancer patient: complementary contribution of quantitative and qualitative tools]. / Evaluer la fatigue chez le patient cancéreux: l'apport complémentaire des outils quantitatif et qualitatif.

Fatigue is a frequent symptom experienced by cancer patients. Many quantitative tools has been developed to measure and assess the impact of fatigue on the quality of life of cancer patients. This article: 1) summarises quantitative research that has investigated fatigue in cancer patients and 2) presents preliminary results of our quantitative and qualitative study which has been conducted at the Institut Gustave-Roussy. The aim of the quantitative part was the validation of a measurement instrument (Fact) before its utilisation in a clinical trial comparing the efficiency of blood transfusion and erythropoietin in the treatment of anemia in cancer patients. The aim of the qualitative part was to analyse the experience of fatigue in daily life, the impact on work, social life and family relations, and the strategies developed by the patients in order to reduce fatigue. This article shows the complementary contribution of a quantitative tool (standardized questionnaire and statistical treatment of findings) and a qualitative instrument (interview and qualitative analysis) in the assessment of fatigue in cancer patients.

Cross sectional study of conventional cervical smear, monolayer cytology, and human papillomavirus DNA testing for cervical cancer screening.

OBJECTIVES: To compare the sensitivity, specificity, and interobserver reliability of conventional cervical smear tests, monolayer cytology, and human papillomavirus testing for screening for cervical cancer. DESIGN: Cross sectional study in which the three techniques were performed simultaneously with a reference standard (colposcopy and histology). SETTING: Public university and private practices in France, with complete independence from the suppliers. PARTICIPANTS: 828 women referred for colposcopy because of previously detected cytological abnormalities and 1757 women attending for routine smears. MAIN OUTCOME MEASURES: Clinical readings and optimised interpretation (two blind readings followed, if necessary, by consensus). Sensitivity, specificity, and weighted kappa computed for various thresholds of abnormalities. RESULTS: Conventional cervical smear tests were more often satisfactory (91% v 87%) according to the Bethesda system, more reliable (weighted kappa 0.70 v 0.57), and had consistently better sensitivity and specificity than monolayer cytology. These findings applied to clinical readings and optimised interpretations, low and high grade lesions, and populations with low and high incidence of abnormalities. Human papillomavirus testing associated with monolayer cytology, whether systematic or for atypical cells of undetermined significance, performed no better than conventional smear tests. CONCLUSIONS: Monolayer cytology is less reliable and more likely to give false positive and false negative results than conventional cervical smear tests for screening for cervical cancer.

Cost of screening for cancerous and precancerous lesions of the cervix.

This paper is part of the cost-effectiveness study of cervical cancer screening conducted by the French Society of Clinical Cytology (SFCC). It describes the evaluation of costs of conventional smear tests, thin-layer smear tests (ThinPrep 2000 system), and viral typing by the HCS test. For 100,000 examinations per year, the average cost of a conventional smear test is 11.53 dollars in a private anatomo-pathology clinic. The cost of the thin-layer test for the same number of examinations and in the same type of clinic is 13.93 dollars. For 20,000 annual tests, the average cost of human papillomavirus (HPV) is 23.43 dollars in the public sector and 23.48 dollars in the private one. The higher price of the thin-layer method is only justifiable if this screening technique outperforms the conventional method. Furthermore, the high cost of the HPV test means that its integration into a population-based screening program must be carefully defined.

Influenza burden of illness: estimates from a national prospective survey of household contacts in France.

BACKGROUND: The burden of influenza among ambulatory patients is still relatively unknown, although this knowledge is crucial for evaluating strategies against influenza. We estimated the impact of influenza in terms of uncomplicated morbidity and its consequences on health care utilization and lost workdays. METHODS: A national prospective household contact study between January 4, 2000, and March 15, 2000, in France recruited the households of 946 persons who visited a physician (index cases); 395 households with influenza-positive index cases completed the follow-up, which assessed the clinical impact of influenza, medical visits, treatment, and lost workdays in these index cases and their contacts. RESULTS: Of 817 assessable household contacts, 313 developed clinical influenza (secondary cases); 178 (57%) of them visited a physician at least once (consulting secondary cases). The median duration of illness was 8 days (95% confidence interval [CI], 7-8 days) in index cases, 7 days (95% CI, 7-8 days) in consulting secondary cases, and 4 days (95% CI, 3-5 days) in nonconsulting secondary cases (P<.001); the median duration of treatment in these groups was 8 days (95% CI, 8-9 days), 8 days (95% CI, 7-10 days), and 5 days (95% CI, 4-6 days), respectively (P<.001); and their mean +/- SD number of lost workdays was 4.0 +/- 2.8, 2.9 +/- 2.5, and 0.3 +/- 0.6, respectively, in working adults (P<.001). CONCLUSIONS: These results confirm the substantial burden of illness of influenza. The results should be useful for evaluating the cost-effectiveness of strategies against influenza.

Development of a preference-weighted health status classification system in France: the Health Utilities Index 3.

The Health Utilities Index is a generic multiattribute preference-based system for assessing health-related quality of life, devised by Torrance et al. It is being used in cost-effectiveness evaluations in North America and in international multicentre studies but was not available in France. Following adaptation of the HUI3 classification in France, the purpose of the reported investigation was to derive French preference weights. This article provides a reminder of the theoretical foundations used to model the multiattribute utility function. Within this framework, a multiattribute multiplicative aggregate utility function was constructed in accordance with the explicitly decomposed approach. The study took place in June 1999 over a sample of 365 persons from the French general population, aged between 20 and 65, and not suffering from any chronic or incapacitating illness. The recruitment procedure was based upon a random selection of individuals, using the phone book. Interviews took place in the homes of the interviewees. The methods of revelation (VAS and SG) were applied by setting the value of the best possible state of the HUI3 a priori at 1, and leaving a choice between two states (worst possible state, death) for 0. The aggregated individuals (person-mean and median) were calculated and the multiplicative utility functions constructed. A comparison of the calculated utilities with the observed ones provides a primary indicator of the validity of the person-mean or median functions constructed. The slight absolute differences obtained between observed and calculated utilities and the low RMSE scores lead us towards a favourable conclusion.