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.

Cost effectiveness of nusinersen for patients with infantile-onset spinal muscular atrophy in US.

BACKGROUND: Patients with infantile-onset spinal muscular atrophy (SMA), a rare, genetic neuromuscular disease, do not achieve key motor function milestones (e.g., sitting) and have short life expectancy in the absence of treatment. Nusinersen is a disease-modifying therapy for patients with SMA. OBJECTIVE: The aim of this study was to estimate the cost-effectiveness of nusinersen compared to best supportive care (BSC) in patients diagnosed with infantile-onset SMA in the US. METHODS: A de novo economic model was developed with the following health states: "permanent ventilation", "not sitting", "sitting", "walking", and "death". Short-term data were sourced from the pivotal clinical trials and studies of nusinersen (ENDEAR and SHINE). Motor function milestones achieved at the end of follow-up in the clinical trials were assumed to be sustained until death. Mortality risks were based on survival modelling of relevant published Kaplan-Meier data. Costs, life years (LYs), and quality-adjusted life years (QALYs) were discounted at 3% per annum, and the analyses were performed from a US health care sector perspective. Scenario analyses and sensitivity analyses were conducted to assess the robustness of the results to key parameters. RESULTS: In our base-case analysis, nusinersen treatment achieves greater QALYs and more LYs (3.24 and 7.64, respectively) compared with BSC (0.46 QALYs and 2.40 LYs, respectively), resulting in an incremental cost per QALY gained of approximately $1,112,000 and an incremental cost per LY gained of $590,000 for nusinersen compared to BSC. The incremental cost effectiveness ratios did not fall below $990,000 per QALY gained in scenario and sensitivity analyses. Results were most sensitive to the length of survival, background health care costs, and utility in the "not sitting" and "sitting" health states. CONCLUSIONS: The estimated incremental cost-effectiveness of nusinersen from a US health care sector perspective exceeded traditional cost-effectiveness thresholds. Cost-effectiveness was dependent on assumptions made regarding survival, costs, utilities, and whether the motor function milestones were sustained over lifetime. Given the relatively short-term effectiveness data available for the treatment, a registry to collect long-term data of infantile-onset SMA patients is recommended.

A Summary from the Institute for Clinical and Economic Review's New England Comparative Effectiveness Public Advisory Council.

DISCLOSURES: Funding for this summary was contributed by the Laura and John Arnold Foundation, Blue Shield of California, and California Health Care Foundation to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, AHIP Anthem, Blue Shield of California, CVS Caremark, Express Scripts, Harvard Pilgrim Health Care, Cambia Health Solutions, United Healthcare, Kaiser Permanente, Premera Blue Cross, AstraZeneca, Genentech, GlaxoSmithKline, Johnson & Johnson, Merck, National Pharmaceutical Council, Prime Therapeutics, Sanofi, Spark Therapeutics, Health Care Service Corporation, Editas, Alnylam, Regeneron, Mallinkrodt, Biogen, HealthPartners, and Novartis. Otuonye, Kumar, and Pearson are ICER employees. Banken received consulting fees from ICER for work on this report.

The Effectiveness and Value of Biologic Therapies for the Treatment of Uncontrolled Asthma.

DISCLOSURES: Funding for this summary was contributed by the Laura and John Arnold Foundation, Blue Shield of California, and California Health Care Foundation to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, AHIP, Anthem, Blue Shield of California, CVS Caremark, Express Scripts, Harvard Pilgrim Health Care, Cambia Health Solutions, United Healthcare, Kaiser Permanente, Premera Blue Cross, AstraZeneca, Genentech, GlaxoSmithKline, Johnson & Johnson, Merck, National Pharmaceutical Council, Prime Therapeutics, Sanofi, Spark Therapeutics, Health Care Service Corporation, Editas, Alnylam, Regeneron, Mallinkrodt, Biogen, HealthPartners, and Novartis. Synnott, Kumar, Adair, Rind, and Pearson are employees of ICER, which provided grants to the University of California, San Francisco, and the University of Colorado to perform work for these analyses. Tice and Walsh are employed by the University of California, San Francisco, and Campbell and Whittington are employed by the University of Colorado.

Impact of Abuse Deterrent Formulations of Opioids in Patients With Chronic Pain in the United States: A Cost-Effectiveness Model.

OBJECTIVE: Opioid abuse is a significant public health problem in the United States. We evaluate the clinical effectiveness and economic impact of abuse-deterrent formulations (ADF) of opioids relative to non-ADF opioids in preventing abuse. METHODS: We developed a cost-effectiveness model simulating 2 cohorts of 100 000 noncancer, chronic-pain patients newly prescribed either ADF or non-ADF extended-release (ER) opioids and followed them over 5 years, tracking new events of opioid abuse and opioid-related overdose deaths in addition to tracking 5-year cumulative costs of therapeutic use and abuse of ADF and non-ADF opioids. Patients in each cohort entered the model for therapeutic opioid use from where they could continue in that pathway, discontinue opioid use, or abuse opioids or die of opioid overdose-related or unrelated causes. In addition, one-way sensitivity and scenario analysis were conducted. RESULTS: Over a 5-year time period, using ADF opioids prevented an additional 2300 new cases of opioid abuse at an additional cost of approximately $535 million to the healthcare sector. Threshold analyses showed that a 40% decrease in ADF opioid costs was required to attain cost neutrality between the 2 cohorts, whereas a 100% effectiveness in abuse reduction still did not result in cost neutrality. A 43% decrease in diversion with ADFs relative to non-ADFs was required to attain cost neutrality. Including a societal perspective produced results directionally similar to the base-case analysis findings. CONCLUSION: ADF opioids have the potential to prevent new cases of opioid abuse, but at substantially higher costs to the health system.

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.

Assessing the Value of Sarilumab Monotherapy for Adults with Moderately to Severely Active Rheumatoid Arthritis: A Cost-Effectiveness Analysis.

BACKGROUND: Rheumatoid arthritis is associated with a societal burden greater than $39 billion annually. Novel treatments, known as targeted immune modulators (TIMs), are expensive but effective, producing improvements in response rates compared with conventional disease-modifying antirheumatic drugs (cDMARDs). Sarilumab, a TIM approved in 2017, shows superior improvements compared with cDMARDs and produced significantly greater likelihood of achieving response and improvement in the Health Assessment Questionnaire Disability Index than adalimumab monotherapy. Although sarilumab monotherapy has shown improvements over cDMARDs and the TIM market leader adalimumab, treatment with sarilumab is costly, with an annual wholesale acquisition cost of $39,000. OBJECTIVE: To estimate the lifetime cost-effectiveness of starting treatment with sarilumab monotherapy for adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to cDMARDs. METHODS: A sequential treatment cohort model followed a hypothetical cohort from initiation of sarilumab monotherapy until death. The model allowed patients to switch therapies up to 3 times due to effectiveness or adverse events. The first switch was to a TIM within the same treatment category; the second switch was to a TIM within a different treatment category; and the third switch was to a cDMARD. Sarilumab monotherapy was compared with a cDMARD (methotrexate) and the TIM market leader (adalimumab monotherapy). Key risk and benefit evidence came from clinical studies and network meta-analyses of data on radiographic progression and response. We used a lifetime time horizon and the U.S. health sector payer perspective assuming therapy net pricing. We also incorporated loss of productivity to reflect a restricted societal perspective. RESULTS: Over a lifetime time horizon, a treatment pathway starting with sarilumab resulted in 17.16 life-years and 13.66 quality-adjusted life-years (QALYs). Treatment pathways starting with the cDMARD resulted in 16.54 life-years and 11.77 QALYs; treatment pathways starting with adalimumab resulted in 17.05 life-years and 13.35 QALYs. Total costs for sarilumab ($492,000 for payer perspective, $634,000 for societal perspective) were less than total costs for adalimumab ($536,000 for payer perspective, $689,000 for societal perspective) but higher than total costs for the cDMARD ($63,000 for payer perspective, $272,000 for societal perspective). When compared with cDMARD therapy, sarilumab resulted in a cost-effectiveness estimate of $227,000 per QALY gained from the payer perspective and $191,000 per QALYs gained from the societal perspective. When compared with adalimumab, sarilumab was dominant from both perspectives. CONCLUSIONS: Sarilumab resulted in better health outcomes than conventional therapy alone. However, its additional cost with assumed class-level net prices led to cost-effectiveness estimates above commonly cited thresholds. When compared with the market leader, sarilumab achieved favorable value. This evaluation informs stakeholders of the value of sarilumab and its alternatives to promote high value practices in health care. DISCLOSURES: Funding for this research was contributed by the Institute for Clinical and Economic Review (ICER). Ollendorf, Chapman, Kumar, Synnott, and Agboola are employees of ICER, an independent organization that evaluates the evidence on the value of health care interventions, which is funded by grants from the Laura and John Arnold Foundation, Blue Shield of California Foundation, and the California HealthCare Foundation. The organization's annual policy summit is supported by dues from Aetna, AHIP, Anthem, Blue Shield of California, CVS Caremark, Express Scripts, Harvard Pilgrim Health Care, Omeda Rx, United Healthcare, Kaiser Permanente, Premera Blue Cross, AstraZeneca, Genentech, GlaxoSmithKline, Johnson & Johnson, Merck, National Pharmaceutical Council, Takeda, Pfizer, Novartis, Lilly, and Humana. This work is an extension of an analysis presented at the New England Comparative Effectiveness Public Advisory Council on March 24, 2017, where the authors received public feedback on the analysis, results, and effect of a value assessment for targeted immune modulators. At the time of presentation, sarilumab was still an investigational product; therefore, a price was not known, so cost-effectiveness estimates were not generated. Since the presentation of that material, additional evidence for sarilumab has become available. The additional evidence has been incorporated into this analysis to present cost-effectiveness estimates for sarilumab.

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.

Cost-Effectiveness Analysis of Sacubitril/Valsartan for the Treatment of Heart Failure with Reduced Ejection Fraction in the United States.

OBJECTIVE: Sacubitril/valsartan (SAC/VAL) has been shown to reduce mortality and hospitalization in patients with heart failure with reduced ejection fraction (HFrEF) compared with enalapril but at a substantially higher cost. This study evaluates the cost-effectiveness of SAC/VAL versus enalapril in patients with HFrEF over a 5-year time horizon from the U.S. payer perspective. METHODS: A cohort-based Markov model was developed to compare costs and quality-adjusted life years (QALYs) between SAC/VAL and enalapril in patients with HFrEF over a 5-year time horizon. Markov states included New York Heart Association (NYHA) class (II-IV) and death. Treatment discontinuation, HF-related hospitalizations, and NYHA class progression were modeled as transition states based on data from the PARADIGM trial. Other probabilities, costs, and utilities were obtained from published literature and public databases. RESULTS: In the base case analysis, SAC/VAL cost more than enalapril ($81,943 vs $67,287) and was more effective (2.647 QALYs vs 2.546 QALYs), resulting in an incremental cost-effectiveness ratio of $143,891/QALY gained. At a willingness to pay (WTP) of $100,000/QALY, SAC/VAL was cost-effective up to a cost of $298/month. Results were most sensitive to SAC/VAL cost, SAC/VAL mortality benefit, and NYHA progression probability. SAC/VAL had a 10% and 52% probability of being cost-effective at WTP thresholds of $100,000/QALY and $150,000/QALY, respectively. CONCLUSIONS: SAC/VAL is associated with clinical benefit and may be cost-effective compared with the current standard of care over realistic treatment durations from the payer perspective. Results of this analysis can inform discussions on the value and position of SAC/VAL in the current market.

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.