Evolving Evidence-Based Value Assessment of One-Time Therapies: Tisagenlecleucel as a Case Study

Abstract

Background: Economic evaluation of one-time therapies during reimbursement decision-making is challenging due to uncertain long-term outcomes. The availability of 5-year outcome data from the ELIANA trial and real-world evidence of tisagenlecleucel, the first chimeric antigen receptor T-cell (CAR-T) therapy, presents an opportunity to re-evaluate the predictions of prior cost-effectiveness analyses (CEAs).

Objective: To conduct a systematic literature review (SLR) of prior CEAs of tisagenlecleucel for pediatric/young adult relapsed or refractory acute lymphoblastic leukemia (r/r ALL) and evaluate the impact of recently available 5-year efficacy data from ELIANA and advances in CAR-T manufacturing in an updated CEA model.

Methods: OVID MEDLINE/Embase and health technology assessment (HTA) databases were searched for full-text economic evaluations in English reporting cost-effectiveness results for tisagenlecleucel for r/r ALL. Evaluations with publicly reported incremental cost-effectiveness ratios (ICERs) were included in the SLR. Study screening and data abstraction were conducted following PRISMA guidelines. Data extracted included the country/currency, perspective, clinical trial evidence, model structures, long-term efficacy extrapolation approaches (i.e., overall survival [OS]), time horizon, discount rates, and outcomes (i.e., life years [LY], quality-adjusted LY [QALY], and ICERs). The CEA model reported in Wakase et al. was updated using 5-year OS data from ELIANA and the CAR-T infusion rate informed by real-world practice.

Results: Sixteen records corresponding to 15 unique studies were included in the SLR (11 publications and 5 HTA reports); all were conducted from the health care system perspective of the respective countries. Most studies found tisagenlecleucel to be cost effective, but all studies' projected 3- and 5-year OS rates for tisagenlecleucel were lower than the observed 3- and 5-year rates, respectively, derived from 5-year ELIANA data. When applying updated OS projections from the most recent ELIANA data cut and higher infusion rates of 92.5% (per the real-world infusion rate)-96.0% (per the manufacturer success rate) to the CEA of Wakase et al., the associated QALYs for tisagenlecleucel increased from 11.6 to 14.6-15.0, and LYs increased from 13.3 to 17.0-17.5. Accordingly, the ICERs for tisagenlecleucel decreased from ¥2,035,071 to ¥1,787,988-¥1,789,048 versus blinatumomab and from ¥2,644,702 to ¥2,257,837-¥2,275,181 versus clofarabine combination therapy in the updated CEA model.

Conclusions and relevance: Projections at launch of the likely cost effectiveness of tisagenlecleucel appear to have underestimated its ultimate economic value given more recent trial and real-world data. To balance uncertainty in initial valuation with the need to provide access to novel oncology therapies, payers can consider flexible reimbursement policies alongside ongoing assessments as new data emerge.

Fig. 1

PRISMA flow diagram of studies and reports included in the systematic literature review (SLR). HTA health technology assessment, PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses, SLR systematic literature review. ^aThe searches in OVID MEDLINE/Embase and the HTA databases were conducted on March 16, 2023 and March 28, 2023, respectively. ^bRecords were excluded if results were not separately reported for pediatric patients with relapsed/refractory acute lymphoblastic leukemia. ^cRecords were excluded if they were not full-text articles or HTA reports (e.g., note, letter, comment, case report, editorial, protocol, review, meta-analysis, or conference abstract). ^dRecords were excluded if results were not separately reported for the cost-effectiveness analysis. ^eRecords were excluded if the incremental cost-effectiveness ratio of tisagenlecleucel was not reported or was not publicly available

Fig. 2

Cost effectiveness of tisagenlecleucel for r/r ALL compared with other therapies, based on WTP threshold of the country. The dots represent the comparison of the base-case incremental cost-effectiveness ratio against the respective WTP threshold while the ranges represent the comparison of incremental cost-effectiveness ratios from sensitivity/scenario analyses against the WTP threshold. The red dashed line represents the WTP threshold where incremental cost-effectiveness ratios on the left of this line reflect that tisagenlecleucel was found to be cost-effective at the study country’s WTP for a comparator. C2H Center for Outcomes Research and Economic Evaluation for Health, CADTH Canadian Agency for Drugs and Technologies in Health, Com comparator, ICER Institute for Clinical and Economic Review, NICE National Institute of Health and Care Excellence, RFS relapse-free survival, r/r ALL relapsed/refractory acute lymphoblastic leukemia, SMC Scottish Medicines Consortium, WTP willingness to pay. a In Furzer et al. 2020, a cure state was included to account for the limited long-term survival information currently available for tisagenlecleucel. The base-case estimates used a range of cure rates from 10 to 40% for those offered treatment based on expert opinion. b In Lin et al. 2018, three scenarios that cover a broad range of plausible long-term outcomes on the basis of observed variance and expert opinion were evaluated: 0%, 20% and 40% 5-year RFS rates without hematopoietic stem-cell transplantation and tisagenlecleucel as a bridge to transplantation under a 0% transplantation-free 5-year RFS scenario. c In Lin et al. 2018, tisagenlecleucel was dominated by blinatumomab in the base-case analysis and all scenario analyses for the scenario applying 0% as the 5-year RFS rate. d In Moradi-Lakeh et al. 2021 and Wakase et al. 2022 the lowest sensitivity/scenario analysis result was tisagenlecleucel being dominant over comparators. e In CADTH 2019, only the results of price-reduction scenario analyses were reported. f In SMC 2019, only the results of selected sensitivity analyses were reported. The lowest sensitivity/scenario analysis result was not available

Fig. 3

The impact of 5-year ELIANA data and improved infusion rate on the predicted LYs, QALYs and ICERs. ICER incremental cost-effectiveness ratio, LY life year, OS overall survival, QALY quality-adjusted life year