Does Cost-Effectiveness Analysis Overvalue Potential Cures? Exploring Alternative Methods for Applying a "Shared Savings" Approach to Cost Offsets.

OBJECTIVES: To evaluate alternative methods to calculate and/or attribute economic surplus in the cost-effectiveness analysis of single or short-term therapies. METHODS: We performed a systematic literature review of articles describing alternative methods for cost-effectiveness analysis of potentially curative therapies whose assessment using traditional methods may suggest unaffordable valuations owing to the magnitude of estimated long-term quality-adjusted life-year (QALY) gains or cost offsets. Through internal deliberation and discussion with staff at the Health Technology Assessment bodies in England and Canada, we developed the following 3 alternative methods for further evaluation: (1) capping annual costs in the comparator arm at $150 000 per year; (2) "sharing" the economic surplus with the health sector by apportioning only 50% of cost offsets or 50% of cost offsets and QALY gains to the value of the therapy; and (3) crediting the therapy with only 12 years of the average annual cost offsets or cost offsets and QALY gains over the lifetime horizon. The impact of each alternative method was evaluated by applying it in an economic model of 3 hypothetical condition-treatment scenarios meant to reflect a diversity of chronicity and background healthcare costs. RESULTS: The alternative with greatest impact on threshold price for the fatal pediatric condition spinal muscular atrophy type 1 was the 12-year cutoff scenario. For a hypothetical one-time treatment for hemophilia A, capping cost offsets at $150 000 per year had the greatest impact. For chimeric antigen receptor T-cell treatment of non-Hodgkin's lymphoma, capping cost offsets or using 12-year threshold had little impact, whereas 50% sharing of surplus including QALY gains and cost offsets greatly reduced threshold pricing. CONCLUSIONS: Health Technology Assessment bodies and policy makers will wrestle with how to evaluate single or short-term potentially curative therapies and establish pricing and payment mechanisms to ensure sustainability. Scenario analyses using alternative methods for calculating and apportioning economic surplus can provide starkly different assessment results. These methods may stimulate important societal dialogue on fair pricing for these novel treatments.

Long-term Survival and Cost-effectiveness Associated With Axicabtagene Ciloleucel vs Chemotherapy for Treatment of B-Cell Lymphoma.

Importance: Axicabtagene ciloleucel, a chimeric antigen receptor T-cell therapy, represents a new and potentially curative treatment option for B-cell lymphoma. It is expected to have long-term survival benefits; however, long-term survival data are limited. Objective: To estimate the long-term survival and cost-effectiveness of axicabtagene ciloleucel for treatment of relapsed or refractory B-cell lymphoma. Design, Setting, and Participants: Economic evaluation study using a survival analysis that digitized and extrapolated survival curves published in the ZUMA-1 trial (Safety and Efficacy of KTE-C19 in Adults With Refractory Aggressive Non-Hodgkin Lymphoma), which enrolled patients between November 2015 and September 2016 and had a maximum follow-up of 24 months. Five different survival models (standard parametric, flexible parametric, 2 mixture cure models, and a flexible parametric mixture model) were used to extrapolate the survival curves to a lifetime horizon from January through June 2018. A cost-effectiveness analysis, from both a trial-based and lifetime horizon, was also conducted to inform the value of this novel therapy. The model was based on data from 111 patients with B-cell lymphoma who were enrolled in the ZUMA-1 trial. Interventions: One-time administration of axicabtagene ciloleucel compared with chemotherapy. Main Outcomes and Measures: Undiscounted and discounted life-years (LYs) and quality-adjusted life-years (QALYs), total costs, and incremental costs per LY and QALY gained. Results: The modeled cohort of 111 patients started at 58 years of age. At the end of the trial, treatment with axicabtagene ciloleucel resulted in 0.48 more LYs and 0.34 more QALYs than chemotherapy, producing a cost-effectiveness estimate of $896 600 per QALY for public payers and $1 615 000 per QALY for commercial payers. Extrapolated long-term survival for patients treated with axicabtagene ciloleucel ranged from 2.83 to 9.19 discounted LYs and from 2.07 to 7.62 discounted QALYs. Incrementally, treatment with axicabtagene ciloleucel was associated with 1.89 to 5.82 discounted LYs and 1.52 to 4.90 discounted QALYs vs chemotherapy. With the use of these incremental estimates of survival, cost-effectiveness estimates ranged from $82 400 to $230 900 per QALY gained for public payers and from $100 400 to $289 000 per QALY gained for commercial payers. Conclusions and Relevance: Treatment with axicabtagene ciloleucel appears to be associated with incremental gains in survival over chemotherapy. The range in projected long-term survival was wide and reflected uncertainty owing to limited follow-up data. Cost-effectiveness is associated with long-term survival, with further evidence needed to reduce uncertainty.

Long-term Survival and Value of Chimeric Antigen Receptor T-Cell Therapy for Pediatric Patients With Relapsed or Refractory Leukemia.

Importance: Among children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia, the rate of 5-year disease-free survival is 10% to 20%. Approval of tisagenlecleucel, a chimeric antigen receptor T-cell therapy, represents a new and potentially curative treatment option. However, tisagenlecleucel is expensive, with a current list price of $475 000 per one-time administration. Objective: To estimate the long-term survival and value of tisagenlecleucel for children and young adults with B-cell acute lymphoblastic leukemia. Design, Setting, and Participants: In this cost-effectiveness analysis, a decision analytic model was designed to extrapolate trial evidence to a patient lifetime horizon. The survival evidence for the model was extracted from 3 studies: B2202 (enrolled patients from April 8, 2015, to November 23, 2016), B2205J (enrolled patients from August 14, 2014, to February 1, 2016), and B2101J (enrolled patients from March 15, 2012, to November 30, 2015). Long-term survival and outcomes of patients younger than 25 years with B-cell acute lymphoblastic leukemia that is refractory or in second or later relapse were derived using flexible parametric modeling from the direct extrapolation of event-free survival and overall survival curves. The published Kaplan-Meier curves were digitized from November 1, 2017, to November 30, 2017, using an algorithm to impute patient-level time-to-event data. Sensitivity and scenario analyses assessed uncertainty in the evidence and model assumptions to further bound the range of cost-effectiveness. Data were analyzed from December 1, 2017, to March 31, 2018. Interventions: The primary intervention of interest was tisagenlecleucel. The comparator of interest was the chemoimmunotherapeutic agent clofarabine. Main Outcomes and Measures: Model outcomes included life-years gained, quality-adjusted life-years (QALYs) gained, and incremental costs per life-year and QALY gained. Results: Forty percent of patients initiating treatment with tisagenlecleucel are expected to be long-term survivors, or alive and responding to treatment after 5 years. Tisagenlecleucel had a total discounted cost of $667 000, with discounted life-years gained of 10.34 years and 9.28 QALYs gained. The clofarabine comparator had a total discounted cost of approximately $337 000, with discounted life-years gained of 2.43 years and 2.10 QALYs gained. This difference resulted in an incremental cost-effectiveness ratio of approximately $42 000 per life-year gained and approximately $46 000 per QALY gained for tisagenlecleucel vs clofarabine. These results were robust to probabilistic sensitivity analyses. Across scenario analyses that included more conservative assumptions regarding long-term relapse and survival, the incremental cost-effectiveness ratio ranged from $37 000 to $78 000 per QALY gained. Conclusions and Relevance: Tisagenlecleucel likely provides gains in survival and seems to be priced in alignment with these benefits. This study suggests that payers and innovators should develop novel payment models that reduce the risk and uncertainty around long-term value and provide safeguards to ensure high-value care.

Explaining variation in the uptake of HPV vaccination in England.

BACKGROUND: In England, two national programmes of HPV vaccination for girls have been instituted, a routine programme for 12- and 13-year-olds and a catch-up programme for 17- and 18-year-olds. Uptake rates across the country have been far from uniform, and this research sought to identify factors explaining the variation in uptake by locality. METHODS: An association between uptake, deprivation and ethnic background had been established in pilot research. The present analysis was conducted at an aggregate, Primary Care Trust (PCT), level for the first year of the programmes. Published measures of HPV vaccination uptake, material deprivation, ethnic composition of PCT populations, primary care quality, and uptake of cervical screening and of other childhood immunisations were collated. Strong evidence of collinearity amongst the explanatory variables required a factor analysis to be undertaken. This provided four independent factors, used thereafter in regression models to explain uptake by PCT. RESULTS: The factor analysis revealed that ethnic composition was associated with attitudes towards cervical screening and other childhood vaccinations, whilst material deprivation and quality of primary care were orthogonal. Ethnic composition, early childhood vaccination, cervical screening and primary care quality were found to be influential in predicting uptake in both the routine and the catch-up cohorts, although with a lower degree of confidence in the case of the last two independent variables. Lower primary care quality was significant in explaining a greater fall in vaccination uptake between the first two doses in the catch-up cohort. Greater deprivation was a significant explanatory factor for both uptake and the fall in uptake between doses for the catch-up cohort but not for uptake in the routine cohort. CONCLUSION: These results for uptake of the first year of the national programme using aggregate data corroborate findings from intentions surveys and pilot studies. Deprivation, the ethnic composition of the population, the effectiveness of primary care and the acceptability of childhood vaccinations are salient factors in explaining local HPV vaccine uptake in England.