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.

[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.

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.

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.