Navigating the unknown: how to best 'reflect' standard of care in indications without a dedicated treatment pathway in health technology assessment submissions.

There is an urgent need for expedited approval and access for new health technologies targeting rare and very rare diseases, some of which are associated with high unmet treatment needs. Once a new technology achieves regulatory approval, the technology needs to be assessed by health technology assessment (HTA) bodies to inform coverage and reimbursement decisions. This assessment quantitatively examines the clinical effectiveness, safety and/or economic impact of the new technology relative to standard of care (SoC) in a specific market. However, in rare and very rare diseases, the patient populations are small and there is often no established treatment pathway available to define 'SoC'. In these situations, several challenges arise to assess the added benefit of a new technology - both clinically and economically - due to lack of established SoC to guide an appropriate comparator selection. These challenges include: How should 'SoC' be defined and characterized in HTA submissions for new technologies aiming to establish new treatment standards? What is usual care without an established clinical pathway? How should the evidence for the comparator 'SoC' (i.e., usual care) arm be collected in situations with low patient representation and, sometimes, limited disease-specific clinical knowledge in certain geographies? This commentary outlines the evidence generation challenges in designing clinical comparative effectiveness for a new technology when there is a lack of established SoC. The commentary also proposes considerations to facilitate the reliable integration of real-world evidence into HTA and decision-making based on the collective experience of the authors.

Cost-Effectiveness of Once-Daily Single-Inhaler COPD Triple Therapy in Spain: IMPACT Trial.

Purpose: Given between-country differences in healthcare systems, treatment costs, and disease management guidelines, country-specific cost-effectiveness analyses are important. This study evaluated the cost-effectiveness of once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus FF/VI and UMEC/VI among patients with symptomatic chronic obstructive pulmonary disease (COPD) at risk of exacerbations from a Spanish healthcare system perspective. Patients and Methods: Baseline data and treatment effects from the IMPACT trial were populated into the validated GALAXY COPD progression model. Utilities were estimated using Spanish observational data. Direct healthcare costs (2019 €) were informed by Spanish public sources. A 3% discount rate for costs and benefits was applied. The time horizon and treatment duration were 3 years (base case). One-way sensitivity, scenario, and probabilistic sensitivity analyses were performed. Results: FF/UMEC/VI treatment resulted in fewer exacerbations over 3 years (4.130 vs 3.648) versus FF/VI, with a mean (95% confidence interval [CI]) incremental cost of €444 (€149, €713) per patient and benefit of 0.064 (0.053, 0.076) quality-adjusted life years (QALYs), resulting in an incremental cost-effectiveness ratio (ICER) of €6887 per QALY gained. FF/UMEC/VI was a dominant treatment strategy versus UMEC/VI, resulting in fewer exacerbations (4.130 vs 3.360), with a mean (95% CI) incremental cost of -€450 (-€844, -€149) and benefit of 0.054 (0.043, 0.064) QALYs. FF/UMEC/VI was cost-effective versus FF/VI and UMEC/VI across all analyses. Conclusion: FF/UMEC/VI was predicted to be a cost-effective treatment option versus FF/VI or UMEC/VI in symptomatic COPD patients at risk of exacerbations in Spain, across all scenarios and sensitivity analyses.

Cost-Utility of Nivolumab Plus Ipilimumab in First-Line Treatment of Advanced Melanoma in the United States: An Analysis Using Long-Term Overall Survival Data from Checkmate 067.

OBJECTIVE: The aim of this study was to evaluate the cost-utility of nivolumab plus ipilimumab (NIVO + IPI) versus other first-line therapies for advanced melanoma in the United States (US) from the third-party payer perspective. METHODS: This analysis estimated total expected life-years (LYs), quality-adjusted LYs (QALYs), and costs for first-line treatments of advanced melanoma during a 30-year time horizon using indirect treatment comparisons based on time-varying hazard ratios (HRs) and a three-state partitioned survival model. Overall survival (OS) and progression-free survival reference curves were extrapolated based on 5-year follow-up from the phase III Checkmate 067 trial (NCT01844505). Comparators of NIVO + IPI were NIVO, IPI, pembrolizumab, dabrafenib plus trametinib, encorafenib plus binimetinib (ENCO + BINI), and vemurafenib plus cobimetinib. Drug acquisition costs, treatment administration costs, follow-up time, subsequent therapy data, and adverse event frequencies were obtained from published sources. Utility weights were estimated from Checkmate 067, which compared NIVO + IPI or NIVO monotherapy with IPI monotherapy as first-line therapy in advanced melanoma. A 3% annual discount rate was applied to costs and outcomes. Sensitivity scenarios for BRAF-mutant subgroups were conducted. RESULTS: NIVO + IPI was estimated to generate the longest OS and the highest total costs versus all comparators, accruing 6.99 LYs, 5.70 QALYs, and $469,469 over the 30-year time horizon. The incremental cost utility of NIVO + IPI versus comparators ranged from $2130 per QALY (versus ENCO + BINI) to $76,169 per QALY (versus NIVO). In all base-case and most sensitivity analyses, the incremental cost-utility ratios for NIVO + IPI were below $100,000 per QALY. CONCLUSIONS: NIVO + IPI is estimated to be a life-extending and cost-effective treatment versus other therapies in the US, with base-case incremental cost-utility ratios below $100,000 per QALY.

Economic evaluation of nivolumab combined with ipilimumab in the first-line treatment of advanced melanoma in Japan.

AIMS: The objective of this study was to evaluate the cost-effectiveness of nivolumab in combination with ipilimumab (nivo + ipi) compared to current therapeutic alternatives in first-line treatment of patients with advanced melanoma from the Japanese national healthcare payer perspective using 48-month survival data from the CheckMate 067 Phase III trial. MATERIALS AND METHODS: A three-state partitioned survival model was developed from projections of overall survival (OS) and progression-free survival (PFS) to estimate accrued quality-adjusted survival and costs over a 30-year time horizon. The analysis included nivo + ipi, nivolumab, and ipilimumab monotherapies (the three treatments included in CheckMate 067). Drug acquisition, administration, disease management, subsequent therapy, and adverse event (AE) costs were obtained via published sources and expert input (solicited via Delphi panel). AE frequencies were collected from the Checkmate 067 trial. Utility weights were estimated from the Checkmate 067 trial, based on Japanese tariffs. Results were presented as incremental cost-utility ratios (ICURs, cost per quality-adjusted life-year (QALY)). RESULTS: Nivo + ipi had the greatest estimated survival among the three competing treatments, followed by nivolumab monotherapy accruing the second greatest survival. The incremental cost-effectiveness of nivo + ipi was ¥778,000 per QALY vs. nivolumab and ¥1,584,000 per QALY vs. ipilimumab. The results indicate that nivo + ipi is cost-effective in Japan when compared to a threshold of ¥7,500,000 per QALY. This finding was found to be generally robust to sensitivity and scenario analyses. LIMITATIONS: Limitations include uncertainty in long-term survival extrapolations and lack of Japan-specific clinical data. CONCLUSIONS: This analysis indicates that adding ipilimumab to nivolumab therapy represents a cost-effective new treatment option for patients with unresectable malignant melanoma in Japan.

Long-term cost and utility consequences of short-term clinically important deterioration in patients with chronic obstructive pulmonary disease: results from the TORCH study.

Purpose: Clinically important deterioration (CID) in chronic obstructive pulmonary disease (COPD) is a novel composite endpoint that assesses disease stability. The association between short-term CID and future economic and quality of life (QoL) outcomes has not been previously assessed. This analysis considers 3-year data from the TOwards a Revolution in COPD Health (TORCH) study, to examine this question. Patients and methods: This post hoc analysis of TORCH (NCT00268216) compared costs and utilities at 3 years among patients without CID (CID-) and with CID (CID+) at 24 weeks. A positive CID status was defined as either: a deterioration in forced expiratory volume in 1 second (FEV1) of ≥100 mL from baseline; or a ≥4-unit increase from baseline in St George's Respiratory Questionnaire (SGRQ) total score; or the incidence of a moderate/severe exacerbation. Patients from all treatment arms were included. Utility change was based on the EQ-5D utility index. Costs were based on healthcare resource utilization from 24 weeks to end of follow-up combined with unit costs for the UK (2016 GBP), and reported as per patient per year (PPPY). Adjusted estimates were generated controlling for baseline characteristics, treatment assignment, and number of CID criteria met. Results: Overall, 3,769 patients completed the study and were included in the analysis (stable CID- patients, n=1,832; unstable CID+ patients, n=1,937). At the end of follow-up, CID- patients had higher mean (95% confidence interval [CI]) utility scores than CID+ patients (0.752 [0.738, 0.765] vs 0.697 [0.685, 0.71]; difference +0.054; P<0.001), and lower costs PPPY (£538 vs £916; difference: £378 [95% CI: £244, £521]; P<0.001). The cost differential was primarily driven by the difference in general hospital ward days (P=0.003). Conclusion: This study demonstrated that achieving early stability in COPD by preventing short-term CID is associated with better preservation of future QoL alongside reduced healthcare service costs.

Survival, healthcare resource use and costs among stage IV ER + breast cancer patients not receiving HER2 targeted therapy: a retrospective analysis of linked SEER-Medicare data.

BACKGROUND: Few studies have evaluated survival, treatment, resource use, and costs among women with stage IV ER + breast cancer (BC) who did not receive HER2 targeted therapy. METHODS: Using linked Surveillance, Epidemiology, and End Results (SEER) and Medicare data from 2006-2009, women aged 66+ years with an incident diagnosis of stage IV ER + BC (index date) in 2007 and no HER2 targeted therapy were identified. A comparison cohort without cancer was created from the SEER 5% Medicare sample and matched 1:1 to the study cohort based on age, sex, and race. All patients had continuous enrollment for a 12-month baseline period prior to index and were followed until the end of the study window, disenrollment, or death, whichever came first. Resource utilization and costs (by place of service, reported per patient per month, PPPM) were compared across cohorts. Treatment patterns including receipt of surgery, radiation, chemotherapy, aromatase inhibitors (AI), and non-AI hormonal therapy were evaluated for study cohort patients with at least 2 months of follow-up. Kaplan-Meier survival analysis was also conducted. RESULTS: 325 women with stage IV ER + BC without HER2 targeted therapy were identified and matched to 325 women without cancer. Mean age was 77 years for both cohorts, with average follow-up of 18 months for study patients and 26 months for comparison patients. Compared to the comparison cohort, study patients had significantly higher mortality (60.3% versus 31.1%, P < 0.001), shorter survival (survival at 36 months 28% vs. 62%) and higher resource utilization across all settings except for oral prescription drugs. Total PPPM healthcare costs were also significantly higher among study patients ($7,271 vs. $1,778, P < 0.001). Approximately 57% of study patients with 2+ months of follow-up received chemotherapy and over 62% received an AI during follow-up. Within 4 months of cancer diagnosis, surgery and radiation were received by 39% and 32% of study patients, respectively. CONCLUSIONS: We found significant excess clinical and economic burden among women with stage IV ER + breast cancer who did not receive HER2 targeted therapy. Future studies with more precise and recent data are warranted to confirm and extend these results.

Hospital days, hospitalization costs, and inpatient mortality among patients with mucormycosis: a retrospective analysis of US hospital discharge data.

BACKGROUND: Mucormycosis is a rare and potentially fatal fungal infection occurring primarily in severely immunosuppressed patients. Because it is so rare, reports in the literature are mainly limited to case reports or small case series. The aim of this study was to evaluate inpatient mortality, length of stay (LOS), and costs among a matched sample of high-risk patients with and without mucormycosis in a large nationally representative database. METHODS: We conducted a retrospective analysis using the 2003-2010 Healthcare Cost and Utilization Project - Nationwide Inpatient Sample (HCUP-NIS). The NIS is a nationally representative 20% sample of hospitalizations from acute care United States (US) hospitals, with survey weights available to compute national estimates. We classified hospitalizations into four mutually exclusive risk categories for mucormycosis: A- severely immunocompromised, B- critically ill, C- mildly/moderately immunocompromised, D- major surgery or pneumonia. Mucormycosis hospitalizations ("cases") were identified by ICD-9-CM code 117.7. Non-mucormycosis hospitalizations ("non-cases") were propensity-score matched to cases 3:1. We examined demographics, clinical characteristics, and hospital outcomes (mortality, LOS, costs). Weighted results were reported. RESULTS: From 319,366,817 total hospitalizations, 5,346 cases were matched to 15,999 non-cases. Cases and non-cases did not differ significantly in age (49.6 vs. 49.7 years), female sex (40.5% vs. 41.0%), White race (53.3% vs. 55.9%) or high-risk group (A-49.1% vs. 49.0%, B-20.0% vs. 21.8%, C-25.5% vs. 23.8%, D-5.5% vs. 5.4%). Cases experienced significantly higher mortality (22.1% vs. 4.4%, P<0.001), with mean LOS and total costs more than 3-fold higher (24.5 vs. 8.0 days and $90,272 vs. $25,746; both P<0.001). CONCLUSIONS: In a national hospital database, hospitalizations with mucormycosis had significantly higher inpatient mortality, LOS, and hospital costs than matched hospitalizations without mucormycosis. Findings suggest that interventions to prevent or more effectively treat mucormycosis are needed.