Modeling Challenges in Cost-Effectiveness Analysis of First-Line Immuno-Oncology Therapies in Non-small Cell Lung Cancer: A Systematic Literature Review.

INTRODUCTION: The introduction of immuno-oncology (IO) therapies has changed the treatment landscape of non-small cell lung cancer (NSCLC). Numerous cost-effectiveness analyses (CEAs) and technology appraisals (TAs) evaluating IO therapies have been recently published. OBJECTIVE: We reviewed economic models of first-line (1L) IO therapies for previously untreated advanced or metastatic NSCLC to identify methodological challenges associated with modeling cost effectiveness from published literature and TAs and to make recommendations for future CEAs in this disease area. METHODS: A systematic literature review was conducted following Cochrane and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We searched MEDLINE, Embase, EconLit (January 2009-January 2020), and select conferences (since 2016) for CEAs of 1L IO treatments in patients with recurrent or metastatic, epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) mutation-negative NSCLC, published in English. TAs from England, Scotland, Canada, Australia, Germany, and France were also examined. Two reviewers screened the results and extracted the data. The quality of the CEAs was described using the Drummond checklist. RESULTS: In total, 46 records reporting on 38 unique models met protocol-defined criteria and were included. Five models adjusted for treatment switching or crossover in base-case analyses, and the remainder considered treatment switching or crossover to represent clinical practice and made no adjustment. Seven models used external real-world data for survival modeling or extrapolation validation. Six models that assumed long-term treatment benefit stopped at 3 or 5 years after initiation. Seven models used the observed time-on-treatment distribution from the trial, and eight used progression-free survival for treatment duration. All models compared one or more IO monotherapies or combination therapies with chemotherapy. Only one study directly compared different IO agents but did not consider the concordance issue across programmed death-ligand 1 (PD-L1) testing methods. Utilities were modeled by health state in 12 models, four applied a time-to-death approach, and ten explored both. None applied cure models. CONCLUSION: Variations in methodological challenges were seen across studies. Previous models took approaches that were followed in subsequent models, such as a 2-year stopping rule of IO duration or treatment-effect waning. Challenges such as heterogeneity in PD-L1 testing and survival extrapolation and validation using real-world data should be further considered for future models in advanced or metastatic NSCLC.

Health care resource utilization and costs associated with advanced or metastatic nonsmall cell lung cancer in the United States.

BACKGROUND: The treatment landscape for advanced nonsmall cell lung cancer (NSCLC) has evolved from 2015 onward, since the introduction of immune checkpoint inhibitors (ICIs). Considering this shift, there have been limited prior analyses that assess the economic burden of NSCLC within the current treatment landscape. OBJECTIVE: To present an analysis of health care resource utilization (HCRU) and costs associated with the treatment of patients with advanced or metastatic NSCLC in the United States between 2010 and 2019. METHODS: Patients with locally advanced or metastatic NSCLC who initiated first-line (1L) systemic treatment between January 1, 2010, and June 30, 2019, were included from the HealthCore Integrated Research Database using a previously developed claims-based predictive model algorithm. Mean total HCRU and costs and mean per-person-per-year (PPPY) HCRU and costs were estimated for 2 follow-up periods: the time during the entire follow-up period and the time during the 1L treatment period. Distribution of treatment classes (defined as chemotherapy, ICIs, targeted therapies, and others) were also analyzed by index year. RESULTS: 27,257 patients met the eligibility criteria and were included in the analysis. The mean duration of follow-up for all patients was 16.6 months (median 10.6 months), and the median time to discontinuation of 1L treatment was 2.8 months. The number of outpatient visits accounted for the majority of HCRU across the entire study follow-up (mean 97.7 in total and 147.1 PPPY) and for the 1L treatment period (mean 46.3 in total and 167.5 PPPY). The total mean cost across the entire study follow-up was $158,908 ($250,942 PPPY). For the 1L treatment period, the total mean cost was $72,760 ($271,590 PPPY). Total mean outpatient costs for systemic anticancer treatment were $61,797 for the entire study follow-up ($85,609 PPPY) and $27,138 during the 1L treatment period ($92,412 PPPY). Total costs increased over the study duration, which were mainly due to increasing outpatient costs for systemic therapy. In both follow-up periods, inpatient costs, other outpatient costs (nonsystemic therapy-related costs), and pharmacy costs remained relatively stable but still accounted for more than 60% of the total costs. Analysis of treatment classes over time showed that chemotherapy was the most frequently used treatment, regardless of line of therapy. A trend was observed for increased ICI use from 2015 onward. CONCLUSIONS: Despite the improvement in treatment options, a high economic burden associated with the treatment of NSCLC still exists. The total costs have been increasing, mainly driven by outpatient costs for systemic therapy, which might reflect the greater use of ICIs for advanced NSCLC. Costs for inpatient services, other outpatient services, and pharmacy services remained stable but still accounted for the majority of the economic burden. Further studies are required to assess the impact of innovative treatments on the disease management costs of advanced NSCLC. DISCLOSURES: This study was funded by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945) as part of an alliance between the healthcare business of Merck KGaA, Darmstadt, Germany, and Pfizer. Zhang, Liu, and Yang are employees of EMD Serono. Beachler, Dinh, and Jamal-Allial are employees of HealthCore Inc., which received funding from the healthcare business of Merck KGaA, Darmstadt, Germany, and Pfizer for the implementation of this study. Masters and Kolitsopoulos are employees of Pfizer. Lamy was an employee of the healthcare business of Merck KGaA, Darmstadt, Germany, at the time this study was conducted.

Cost Effectiveness of Blinatumomab Versus Inotuzumab Ozogamicin in Adult Patients with Relapsed or Refractory B-Cell Precursor Acute Lymphoblastic Leukemia in the United States.

BACKGROUND AND OBJECTIVE: The TOWER and INO-VATE-ALL trials demonstrated the efficacy and safety of blinatumomab and inotuzumab ozogamicin (inotuzumab), respectively, versus standard-of-care (SOC) chemotherapy in adults with relapsed or refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL). The cost effectiveness of blinatumomab versus inotuzumab has not previously been examined. METHODS: Cost effectiveness of blinatumomab versus inotuzumab in R/R B-cell precursor ALL patients with one or no prior salvage therapy from a United States (US) payer perspective was estimated using a partitioned survival model. Health outcomes were estimated based on published aggregate data from INO-VATE-ALL and individual patient data from TOWER weighted to match patients in INO-VATE-ALL using matching adjusted indirect comparison (MAIC). Analyses were conducted using five approaches relating to use of anchored versus unanchored comparisons of health outcomes and, for the anchored comparisons, the reference treatment to which treatment effects on health outcomes were applied. Estimates from TOWER including the probabilities of complete remission and allogeneic stem-cell transplant (allo-SCT), overall and event-free survival, utilities, duration of therapy, and use of subsequent therapies were MAIC adjusted to match INO-VATE-ALL. Costs of treatment, adverse events, allo-SCT, subsequent therapies, and terminal care were from published sources. A 50-year time horizon and 3% annual discount rate were used. RESULTS: Incremental costs for blinatumomab versus inotuzumab ranged from US$7023 to US$36,244, depending on the approach used for estimating relative effectiveness. Incremental quality-adjusted life-years (QALYs) ranged from 0.54 to 1.78. Cost effectiveness for blinatumomab versus inotuzumab ranged from US$4006 to US$20,737 per QALY gained. CONCLUSIONS: Blinatumomab is estimated to be cost effective versus inotuzumab in R/R B-cell precursor ALL adults who have received one or no prior salvage therapy from a US payer perspective.

Economic Burden of Veno-occlusive Disease in Patients With B-cell Acute Lymphoblastic Leukemia in the United States.

PURPOSE: The goal of this study was to evaluate the incidence, inpatient mortality, and economic burden of hepatic veno-occlusive disease (VOD) in adults with B-cell acute lymphoblastic leukemia (ALL) in the United States. METHODS: Using MarketScan Commercial Claims and Encounters Database and Medicare Supplemental and Coordination of Benefits Database, data for patients with B-cell ALL from April 1, 2009, to October 31, 2016, were extracted by using diagnosis codes. VOD was identified based on clinical criteria and expert opinions. Patients with VOD were followed up from diagnosis of VOD until the earliest occurrence of inpatient death, end of continuous enrollment, end of study period, or for a maximum of 100days. The incidence of VOD and VOD-associated inpatient mortality were calculated. VOD-related health care costs based on paid adjudicated claims were calculated. FINDINGS: Of the 2571 adults with B-cell ALL, the overall incidence of VOD was low at 3.4% (88 of 2571). Of these patients with VOD, 52% (46 of 88) experienced multiorgan failure and were identified as having severe VOD. VOD was only identified in patients having undergone hematopoietic stem cell transplantation (5.4% [88 of 1624]). The inpatient mortality rate of those with any VOD over the 100-day postindex period was 26.1%, and the inpatient mortality was even higher for patients with severe VOD (37.0%). Total mean (SD) medical costs per patient during the 100 days' post-VOD diagnosis were $55,975 ($160,335); mean (SD) costs per patient were ∼4-fold higher for severe ($86,953 [$206,906]) versus nonsevere ($22,047 [$72,847]) VOD. IMPLICATIONS: Clinical criteria were used to identify VOD events and thus VOD might be underdiagnosed. The mortality of VOD also might be underestimated because only inpatient deaths are captured in the data. The incidence and mortality of VOD could also be underestimated because we focused on adult patients who might receive reduced-intensity treatment. The economic burden of VOD may be underestimated because the Healthcare Common Procedure Coding System code specific for defibrotide was not available, and thus the cost for defibrotide might not be included. Finally, as the study population consisted of patients with commercial or Medicare supplemental insurance, results may not be generalizable to all patients with VOD in the United States. Although VOD occurred infrequently in adults with B-cell ALL, it was associated with high inpatient mortality and substantial costs. Patients with severe VOD were associated with highest mortality and highest costs. Given the clinical and economic burden associated with VOD, it is important that patients at high risk for VOD be identified and treated to minimize this risk.

Cost per response analysis of strategies for chronic immune thrombocytopenia.

OBJECTIVES: This analysis estimated the cost per response and the incremental cost per additional responder of romplostim, eltrombopag, and the "watch-and-rescue" (monitoring until rescue therapies are required) strategy in adults with chronic immune thrombocytopenia (ITP). STUDY DESIGN: The decision tree is designed to estimate the total cost per response for romiplostim, eltrombopag, and watch and rescue over a 24-week time horizon; cost-effectiveness was evaluated in terms of incremental cost per additional responder. METHODS: Model inputs including response rates, bleeding-related episode (BRE) rates, and costs were estimated from registrational trial data, an independent Bayesian indirect comparison, database analyses, and peer-reviewed publications. Costs were applied to the proportions of patients with treatment response and nonresponse (based on platelet count). The total cost per response and the incremental cost per additional responder for each treatment were calculated. Sensitivity analyses and alternative analyses were performed. RESULTS: With higher total costs and greater treatment efficacy, romiplostim and eltrombopag had a lower 24-week cost per response and a lower average number of BREs than watch and rescue. Eltrombopag was weakly dominated by romiplostim. The incremental cost-effectiveness ratio of romiplostim versus watch and rescue was $46,000 per additional responder. The model results are most sensitive to response rates of romiplostim and watch and rescue and the BRE rate for splenectomized nonresponders. Alternative analyses results were similar to the base case. CONCLUSIONS: In adults with chronic ITP, romiplostim represents an efficient way to achieve response, with lower costs per response than eltrombopag; both romiplostim and eltrombopag had lower costs per response than watch and rescue.

Economic burden associated with adverse events of special interest in patients with relapsed Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia in the United States.

BACKGROUND: Infections, cytopenia, and gastrointestinal (GI) toxicity are adverse events of special interest (AESI) affecting most relapsed Philadelphia chromosome-negative (Ph-) B-cell acute lymphocytic leukemia (ALL) patients. This study quantified real-world rates and economic burden of these events among relapsed Ph- B-cell ALL patients in the United States. METHODS: Adults with relapsed Ph- B-cell ALL during 1 April 2009-31 October 2016 were selected from MarketScan® healthcare claims databases. Outcomes included proportions of patients with AESIs and AESI-related costs during 100 days after relapsed hospitalization. RESULTS: Of 400 relapsed Ph- B-cell ALL patients, 92.5% experienced ≥1 AESI during the median 100-day follow-up, of which 64.6% had infections, 94.6% cytopenia, and 46.2% GI toxicities. Mean (SD; median) AESI-related total cost per patient during follow-up was $197,213 ($308,551; $105,731), with a mean of 2 AESI-related hospitalizations comprising 32.2 inpatient days. Mean (SD; median) healthcare costs were highest for infections ($164,461 [$347,083; $64,528]), followed by cytopenia ($125,210 [$165,141; $67,475]) and GI events ($11,652 [$40,231; $1349]). CONCLUSION: The economic burden of AESIs is substantial, with infections the most expensive, followed by cytopenia and GI toxicity. New therapies that can improve outcomes in relapsed Ph- B-cell ALL while offering a favorable safety profile are needed.

Financial burden of healthcare utilization in consumer-directed health plans.

OBJECTIVES: To evaluate the impact of enrollment in a consumer-directed health plan (CDHP) on out-of-pocket (OOP) spending and on the financial burden associated with healthcare utilization. STUDY DESIGN: Using commercial claims data from 2011 through 2013, we estimated difference-in-differences models that compared changes in outcomes for individuals who switched to CDHPs (CDHP group) with outcome changes for individuals who remained in traditional plans (traditional plan group). METHODS: We estimated the impact of CDHP enrollment on OOP spending at the point of care and on having high financial burden, defined as whether an enrollee spent 3% or more of household income on OOP spending. Additionally, we assessed these outcomes for 2 subgroups: those with lower household income and those with chronic conditions. RESULTS: Within the first year of CDHP enrollment, CDHP enrollees experienced a mean marginal increase in OOP spending of $285 (41% increase; 95% CI, $271-$299; P <.001) relative to traditional plan enrollees. The lower-income and chronic conditions subgroups experienced mean marginal increases in OOP costs of $306 (44% increase; 95% CI, $257-$353; P <.001) and $387 (56% increase; 95% CI, $339-$435; P <.001), respectively. The probability of an enrollee having excessive financial burden increased by 4.3 percentage points (95% CI, 4.0-4.6; P <.001) for the full CDHP sample. These effects were about 3 times larger for the lower-income subgroup (12.3 percentage points; 95% CI, 10.7-13.8; P <.001) and 2 times larger for the chronic conditions subgroup (8.0 percentage points; 95% CI, 6.9-9.1; P <.001). CONCLUSIONS: CDHP enrollment led to a significant increase in financial burden associated with healthcare utilization, especially for those with lower incomes and those with chronic conditions.

Does Enrollment in High-Deductible Health Plans Encourage Price Shopping?

OBJECTIVE: To investigate whether enrollment in high-deductible health plans (HDHPs) led enrollees to choose lower-priced providers for office visits and laboratory tests. STUDY SETTING: Claims data from more than 40 large employers. STUDY DESIGN: We compared the change in price for office visits and laboratory tests for enrollees who switched to HDHPs versus enrollees who remained in traditional plans. We estimated separate models for enrollees who changed providers versus those who remained with the same provider to disentangle the effects of HDHPs on provider choice and negotiated prices. DATA COLLECTION: Claims data from 2004 to 2010 on 1.8 million enrollees. PRINCIPAL FINDINGS: After enrollment in HDHPs, 28 percent of enrollees changed physicians for office visits (compared to 19 percent in the Traditional Plan group, p < .01); however, this did not result in a statistically significant reduction in price for office visits. About 25 percent of enrollees changed providers for laboratory tests (compared to 23 percent in the Traditional Plan group, p < .01), resulting in savings of about $2.09 or a 12.8 percent reduction in price per laboratory test. We found that HDHPs had lower negotiated prices for office visits but not for laboratory tests. CONCLUSIONS: High-deductible health plan enrollment may shift enrollees to lower cost providers, resulting in modest savings.

Cost of Bleeding-related Episodes in Adult Patients With Primary Immune Thrombocytopenia: A Population-based Retrospective Cohort Study of Administrative Claims Data for Commercial Payers in the United States.

PURPOSE: We estimated the real-world costs of bleeding-related episodes (BREs) in adults with primary immune thrombocytopenia (ITP). METHODS: This retrospective cohort study used the MarketScan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits databases. We identified adult patients diagnosed with primary ITP between 2007 and 2012, defined by at least 2 outpatient claims separated by ≥30 days or 1 inpatient claim (International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code for primary ITP [287.31]). BRE was defined according to a combination of diagnosis codes and/or procedure codes indicating bleeding or use of rescue therapies. Costs were estimated using total reimbursed amount received by providers (including out-of-pocket costs and reimbursement from insurance, adjusted to 2015 US dollars). FINDINGS: In 6551 patients, 14,115 BREs were identified, mean (SD) age was 55 (18) years, and 62% of patients were women. Mean total reimbursement per BRE was $6022, with significantly higher mean inpatient ($45,114) versus outpatient ($2150) reimbursements (P < 0.0001). Mean BRE reimbursements were higher in splenectomized patients compared with nonsplenectomized patients ($8365 vs $5858); however, the difference was not statistically significant. Mean reimbursement for BREs associated with bleeding alone was $10,396, and with rescue therapy alone it was $2787. Reimbursement for BREs that included both bleeding and rescue therapy was $11,065. IMPLICATIONS: The real-world reimbursement rates of BREs in adult patients with primary ITP can be substantial, with significantly higher values among patients requiring hospitalization and for those with bleeding events. Additionally, there is a trend toward higher reimbursement rates among splenectomized patients.

Cost effectiveness of fingolimod, teriflunomide, dimethyl fumarate and intramuscular interferon-ß1a in relapsing-remitting multiple sclerosis.

OBJECTIVE: The aim of the study was to compare the cost effectiveness of fingolimod, teriflunomide, dimethyl fumarate, and intramuscular (IM) interferon (IFN)-ß(1a) as first-line therapies in the treatment of patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: A Markov model was developed to evaluate the cost effectiveness of disease-modifying drugs (DMDs) from a US societal perspective. The time horizon in the base case was 5 years. The primary outcome was incremental net monetary benefit (INMB), and the secondary outcome was incremental cost-effectiveness ratio (ICER). The base case INMB willingness-to-pay (WTP) threshold was assumed to be US$150,000 per quality-adjusted life year (QALY), and the costs were in 2012 US dollars. One-way sensitivity analyses and probabilistic sensitivity analysis were conducted to test the robustness of the model results. RESULTS: Dimethyl fumarate dominated all other therapies over the range of WTPs, from US$0 to US$180,000. Compared with IM IFN-ß(1a), at a WTP of US$150,000, INMBs were estimated at US$36,567, US$49,780, and US$80,611 for fingolimod, teriflunomide, and dimethyl fumarate, respectively. The ICER of fingolimod versus teriflunomide was US$3,201,672. One-way sensitivity analyses demonstrated the model results were sensitive to the acquisition costs of DMDs and the time horizon, but in most scenarios, cost-effectiveness rankings remained stable. Probabilistic sensitivity analysis showed that for more than 90% of the simulations, dimethyl fumarate was the optimal therapy across all WTP values. CONCLUSION: The three oral therapies were favored in the cost-effectiveness analysis. Of the four DMDs, dimethyl fumarate was a dominant therapy to manage RRMS. Apart from dimethyl fumarate, teriflunomide was the most cost-effective therapy compared with IM IFN-ß(1a), with an ICER of US$7,115.