Discrete Event Simulation to Incorporate Infusion Wait-Time When Assessing Cost-Effectiveness of a Chimeric-Antigen Receptor T Cell Therapy.

OBJECTIVES: The main objective was to use discrete event simulation to model the impact of wait-time, defined as the time between leukapheresis and chimeric antigen receptor (CAR-T) infusion, when assessing the cost-effectiveness of tisagenlecleucel in young patients with relapsed/refractory acute lymphoblastic leukemia. METHODS: The movement of patients through the model was determined by parametric time-to-event distributions, with the competing risk of an event determining the costs and quality-adjusted life-years (QALYs) assigned. Cost-effectiveness was expressed using the incremental cost-effectiveness ratio (ICER) for tisagenlecleucel compared with chemotherapy over the lifetime. RESULTS: The base case generated a total of 5.79 QALYs and $622 872 for tisagenlecleucel and 1.19 QALYs and $181 219 for blinatumomab, resulting in an ICER of $96 074 per QALY. An increase in mean CAR-T wait-time to 6.20 months reduced the benefit and costs of tisagenlecleucel to 2.78 QALYs and $294 478 because of fewer patients proceeding to infusion, reducing the ICER to $71 112 per QALY. Alternatively, when the cost of tisagenlecleucel was assigned pre-infusion in sensitivity analysis, the ICER increased with increasing wait-time. CONCLUSIONS: Under a payment arrangement where CAR-T cost is incurred post-infusion, the loss of benefit to patients is not reflected in the ICER. This may be misguiding to decision makers, where cost-effectiveness ratios are used to guide resource allocation. discrete event simulation is an important tool for economic modeling of CAR-T as it is amenable to capturing the impact of wait-time, facilitating better understanding of factors affecting service delivery and consequently informed decision making to deliver faster access to CAR-T for patients.

A Systematic Review of Health Technology Assessments of Chimeric Antigen Receptor T-Cell Therapies in Young Compared With Older Patients.

OBJECTIVES: The objective of this review was to identify sources of variability in cost-effectiveness analyses of chimeric antigen receptor T-cell (CAR-T) therapies, tisagenlecleucel and axicabtagene ciloleucel, evaluated by health technology assessment (HTA) agencies, focusing on young compared with older patients. METHODS: HTA evaluations in pediatric acute lymphoblastic leukemia (ALL) and adult diffuse large B-cell lymphoma (DLBCL) were included from Australia, Canada, England, Norway, and the United States. Key clinical evidence, economic approach, and outcomes (costs, quality-adjusted life-years [QALYs] and incremental cost-effectiveness ratios) were summarized. RESULTS: Fourteen HTA evaluations were identified (5 ALL, 9 DLBCL [4 tisagenlecleucel, 5 axicabtagene]). Analyses were naive comparisons of prospective single-arm studies for the CAR-Ts with retrospective cohort studies for the comparators. Key clinical evidence and economic model approaches were generally consistent by CAR-T and indication, although outcomes varied. Notably, incremental QALYs varied substantially in ALL (3.67-10.6 QALYs gained), whereas variation in DLBCL was less (1.21-1.97 [tisagenlecleucel], 1.97-3.40 [axicabtagene]). Discounting of costs and outcomes varied, with the highest QALYs generated for tisagenlecleucel in ALL (10.95) associated with the lowest discount rate (1.5%) and vice versa (4.97 QALYs; 5% discount rate). The approach to extrapolation of overall survival data varied, even where the same empirical data were used. CONCLUSION: Modeled, long-term treatment benefit in young patients may be associated with greater uncertainty compared with adults because of potential life-long benefits with cell and gene therapies. This reflects the methodological challenges identified by HTA agencies associated with single-arm, short-term studies.

Cost-effectiveness Analysis of Tisagenlecleucel Versus Blinatumomab in Children and Young Adults with Acute Lymphoblastic Leukemia: Partitioned Survival Model to Assess the Impact of an Outcome-Based Payment Arrangement.

OBJECTIVE: This research assesses the impact of an outcome-based payment arrangement (OBA) linking complete remission (CR) to survival as a means of maintaining cost-effectiveness for a chimeric antigen receptor T cell (CAR-T) therapy in young patients with acute lymphoblastic leukemia (ALL). METHODS: A partitioned survival model (PSM) was used to model the cost-effectiveness of tisagenlecleucel versus blinatumomab in ALL from the Australian healthcare system perspective. A decision tree modeled different OBAs by funneling patients into a series of PSMs based on response. Outcomes were informed by individual patient data, while costs followed Australian treatment practices. Costs and quality-adjusted life years (QALYs) were combined to calculate a single incremental cost-effectiveness ratio (ICER), reported in US dollars (2022) at a discount rate of 5% on costs and outcomes. RESULTS: For the base case, incremental costs and benefit were $379,595 and 4.27 QALYs, giving an ICER of $88,979. The ICER was most sensitive to discount rate ($57,660-$75,081), "cure point" ($62,718-$116,206) and extrapolation method ($76,018-$94,049). OBAs had a modest effect on the ICER when response rates varied. A responder-only payment was the most effective arrangement for maintaining the ICER ($88,249-$89,434), although this option was associated with the greatest financial uncertainty. A split payment arrangement (payment on infusion followed by payment on response) reduced variability in the ICER ($82,650-$99,154) compared with a single, upfront payment ($77,599-$107,273). CONCLUSION: OBAs had a modest impact on reducing cost-effectiveness uncertainty. The value of OBAs should be weighed against the additional resources needed to administer such arrangements, and importantly overall cost to government.