Assessing the value of orphan drugs using conventional cost-effectiveness analysis: Is it fit for purpose?

Conventional cost-effectiveness analysis-i.e., assessing pharmaceuticals through a cost per quality-adjusted life year (QALY) framework-originated from a societal commitment to maximize population health given limited resources. This "extra-welfarist" approach has produced pricing and reimbursement systems that are not well- aligned with the unique considerations of orphan drugs. This framework has been slow to evolve along with our increased understanding of the impact of rare diseases, which in turn has complicated the assessment of orphan drugs meant to treat rare diseases. Herein, we (i) discuss the limitations of conventional cost-effectiveness analysis as applied to assessing access to, as well as the pricing and reimbursement of, orphan drugs, (ii) critically appraise alternative and supplemental approaches, and (iii) offer insights on plausible steps forward.

Cost effectiveness of axicabtagene ciloleucel versus tisagenlecleucel for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy in the United States.

AIMS: To assess from a US payer perspective the cost-effectiveness of the chimeric antigen receptor T (CAR T)-cell therapies axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) to treat relapsed or refractory (r/r) large B-cell lymphoma (LBCL) following ≥2 systemic therapy lines. METHODS: A three-state (i.e. pre-progression, post-progression, and death) partitioned survival model was used to estimate the quality-adjusted life-years (QALYs) and costs for patients on each treatment over a lifetime horizon. Progression-free survival (PFS) and overall survival (OS) were based on a matching-adjusted indirect treatment comparison (MAIC) that accounted for differences in trial population baseline characteristics. Mixture cure models (MCMs) were used to account for long-term survivors. Costs included drug acquisition and administration for the CAR T-cell therapies and conditioning chemotherapy, apheresis, CAR T-specific monitoring, transplant, hospitalization, adverse events, routine care, and terminal care. Health state utilities were derived from trial and published data. Sensitivity analyses included probabilistic sensitivity analyses (PSAs) and an analysis of extremes that assessed the results across a vast array of combinations of parametric OS and PFS curves across the two therapies. RESULTS: Compared to tisa-cel, axi-cel resulted in 2.31 QALYs gained and a cost reduction of $1,407 in the base case. In the PSA, the cost per QALY gained was ≤$31,500 in 95% of the 1,000 simulations. In the analysis of extremes, the cost per QALY gained was ≤$7,500 in 99% of the 1,296 combinations of MCMs and ≤$40,000 in 95% of the 1,296 combinations of standard models. LIMITATIONS: In absence of head-to-head comparative data, we relied on a MAIC, which cannot account for all possible confounders. Moreover, some outcomes (i.e. transplantations, hospitalizations, adverse events (AEs)) were not adjusted in the MAIC. CONCLUSIONS: In this simulation, axi-cel was a superior treatment option as it is predicted to achieve better outcomes at lower or minimal incremental costs versus tisa-cel.

Corneal cross-linking versus conventional management for keratoconus: a lifetime economic model.

AIMS: To assess the cost-effectiveness of corneal collagen cross-linking (CXL) versus no CXL for keratoconus in the United States (US). METHODS: A discrete-event microsimulation was developed to assess the cost-effectiveness of corneal cross-linking (CXL, Photrexa + KXL combination product) versus no CXL for patients with keratoconus. The lifetime model was conducted from a US payor perspective. The source for CXL efficacy and safety data was a 12-month randomized, open-label, sham-controlled, multi-center, pivotal trial comparing CXL versus no CXL. Other inputs were sourced from the literature. The primary outcome was the incremental cost per quality-adjusted life year gained. Costs (2019 USD) and effects were discounted 3% annually. The impacts of underlying uncertainty were evaluated by scenario, univariate, and probabilistic analyses. RESULTS: Starting at a mean baseline age of 31 years and considering a mixed population consisting of 80% slow-progressors and 20% fast-progressors, the CXL group was 25.9% less likely to undergo penetrating keratoplasty (PK) and spent 27.9 fewer years in advanced disease stages. CXL was dominant with lower total direct medical costs (-$8,677; $30,994 versus $39,671) and more QALYs (1.88; 21.80 versus 19.93) compared to no CXL. Considering the impact of reduced productivity loss in an exploratory scenario, CXL was associated with a lifetime cost-savings of $43,759 per patient. CXL was cost-effective within 2 years and cost-saving within 4.5 years. LIMITATIONS: Limitations include those that are common to similar pharmacoeconomic models that rely on disparate sources for inputs and extrapolation on short-term outcomes to a long-term analytical horizon. CONCLUSIONS: Keratoconus is a progressive and life-altering disease with substantial clinical, economic, and humanistic consequences. The economic value of cross-linking is maximized when applied earlier in the disease process and/or younger age, and extends to improved work productivity, out-of-pocket costs, and quality of life.

Medical oncology referral and systemic therapy of patients with advanced stage urothelial carcinoma.

Aim: To understand physician visit patterns among patients with stage IV (including nonmetastatic [M0] and metastatic [M1] disease) urothelial carcinoma (UC) and understand factors associated with a timely referral to a medical oncologist and systemic treatment. Patients & methods: Retrospective analysis of Surveillance, Epidemiology and End Results-Medicare data. Results: First physician encounter was with a urologist (M0: 69%; M1: 53%) or primary care physician ([PCP]; M0: 19%, M1: 25%) for the majority of patients around UC diagnosis. After the index urologist encounter, most patients had a subsequent medical oncologist visit at a median of 52 days (M0: 69.5 days, M1: 33 days). In an adjusted model, older age, index PCP visit, higher comorbidities and M0 disease were negatively associated with a medical oncologist referral. Among those referred to a medical oncologist, older age, Hispanic or non-Hispanic Black race and not being married were negatively associated with subsequent chemotherapy receipt (p < 0.05). Conclusion: Many patients with advanced UC encounter multiple specialists during their disease course. Older patients or those with a first UC-related encounter with a PCP are less likely to be referred to medical oncology. Once referred to medical oncology, social determinants, including race and marital status, are relevant predictors of receiving chemotherapy.

Survival, costs, and health care resource use by line of therapy in US Medicare patients with newly diagnosed glioblastoma: a retrospective observational study.

BACKGROUND: Glioblastoma (GBM) is associated with poor prognosis, large morbidity burden, and limited treatment options. This analysis evaluated real-world treatment patterns, overall survival, resource use, and costs among Medicare patients with GBM. METHODS: This retrospective observational study evaluated Medicare patients age 66 years or older with newly diagnosed GBM using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data from 2007 through 2013. Patients were followed from diagnosis to death or end of follow-up. An algorithm defined treatment patterns as lines of therapy (LOTs). The Kaplan-Meier method was used to estimate overall survival for the full sample as well as by LOT, surgical resection, Charlson Comorbidity Index (CCI), tumor size, and age. Resource use and costs during the follow-up period were reported in terms of total and per-patient-per-month (PPPM) estimates. RESULTS: A total of 4308 patients with GBM were identified (median age, 74 years; CCI of 0, 52%). The most commonly used first LOT was temozolomide (82%), whereas chemotherapy + bevacizumab was most prevalent for second-line (42%) and third-line (58%) therapy. The median overall survival was 5.9 months for resected patients and 3 months for unresected patients, with considerable heterogeneity depending on patient characteristics. A great proportion of patients had claims for an ICU admission (86.2%), skilled nursing facility (76.9%), and home health (56.0%) in the postdiagnosis period. The cumulative mean cost was $95 377 per patient and $18 053 PPPM, mostly attributed to hospitalizations. CONCLUSIONS: Limited treatment options, poor survival, and economic burden emphasize the need for novel interventions to improve care for Medicare patients with GBM.

Landscape of Health-Related Quality of Life in Patients With Early-Stage Pancreatic Cancer Receiving Adjuvant or Neoadjuvant Chemotherapy: A Systematic Literature Review.

OBJECTIVES: Pancreatic resection is associated with postoperative morbidity and reduced quality of life (QoL). A systematic literature review was conducted to understand the patient-reported outcome measure (PROM) landscape in early-stage pancreatic cancer (PC). METHODS: Databases/registries (through January 24, 2019) and conference abstracts (2014-2017) were searched. Study quality was assessed using the Newcastle-Ottawa Scale/Cochrane risk-of-bias tool. Searches were for general (resectable PC, adjuvant/neoadjuvant, QoL) and supplemental studies (resectable PC, European Organisation for Research and Treatment of Cancer QoL Questionnaire [QLQ] - Pancreatic Cancer [PAN26]). RESULTS: Of 750 studies identified, 39 (general, 22; supplemental, 17) were eligible: 32 used QLQ Core 30 (C30) and/or QLQ-PAN26, and 15 used other PROMs. Baseline QLQ-C30 global health status/QoL scores in early-stage PC were similar to all-stage PC reference values but lower than all-stage-all-cancer values. The QoL declined after surgery, recovered to baseline in 3 to 6 months, and then generally stabilized. A minimally important difference (MID) of 10 was commonly used for QLQ-C30 but was not established for QLQ-PAN26. CONCLUSIONS: In early-stage PC, QLQ-C30 and QLQ-PAN26 are the most commonly used PROMs. Baseline QLQ-C30 global health status/QoL scores suggested a high humanistic burden. Immediately after surgery, QoL declined but seemed stable over the longer term. The QLQ-C30 MID may elucidate the clinical impact of treatment on QoL; MID for QLQ-PAN26 needs to be established.

Overall survival, costs, and healthcare resource use by line of therapy in Medicare patients with newly diagnosed metastatic urothelial carcinoma.

Aims: Medicare patients with metastatic or surgically unresectable urothelial carcinoma (mUC) often receive platinum-based chemotherapy as first line of therapy (LOT), but invariably progress, requiring additional LOTs and healthcare resource use (HCRU). To better understand the evolving mUC treatment landscape, the economic burden of chemotherapy-based mUC treatments among US Medicare patients was estimated. Methods: Newly diagnosed Medicare patients with mUC were identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Patients were followed from diagnosis to death, disenrollment, or end of study to characterize LOTs (first [LOT1], second [LOT2], and third or greater [LOT3+]). Kaplan-Meier methods were used to estimate overall survival (OS) by LOT. HCRU and mean costs were reported over the follow-up period, LOT duration, and maximum LOT received. Results: Among 1,873 eligible patients with mUC (median age = 77 years; median follow-up = 7.5 months), 1,035 (55%) received no chemotherapy. Among chemotherapy-treated patients, 61% had LOT1 only, 25% had LOT1 and LOT2 only, and 14% had LOT3+. Median OS was 8.1 months, range was 4.3 (untreated) to 29.8 (LOT3+) months. HCRU frequency increased with additional LOTs. Mean cumulative per-patient cost was $82,912 for all patients, increasing with additional LOTs (untreated = $57,207; LOT1 = $99,213; LOT2 = $125,190; LOT3+ = $163,884). Mean per patient per month cost was $18,827 for all patients, decreasing with increasing number of LOTs received (untreated = $27,211; LOT1 = $9,601; LOT2 = $7,325; LOT3+ = $6,017). Limitations: Potential for treatment misclassification when using the algorithm defining LOTs and non-generalizability of results to younger patients. Conclusions: Over 50% of Medicare patients with mUC received no chemotherapy. Among chemotherapy-treated patients, most received only one LOT. Additional LOTs led to higher mean costs and HCRU, but as patients were followed longer, monthly costs decreased. As treatments evolve to include immuno-oncology agents, these findings provide a clinically relevant economic benchmark for mUC treatment across different traditional LOTs.

Overall survival, costs and healthcare resource use by number of regimens received in elderly patients with newly diagnosed metastatic triple-negative breast cancer.

AIM: This analysis estimated the overall survival, treatment patterns and economic burden of elderly metastatic triple-negative breast cancer patients. MATERIALS & METHODS: Patients (≥66 years) with metastatic triple-negative breast cancer were identified from the SEER-Medicare database. Treatment patterns were defined in terms of first, second and third or more regimens. Healthcare resource use and costs were reported over the follow-up period and over the treatment duration of each regimen. RESULTS:  A total of 51% of patients did not receive chemotherapy. Taxanes were most commonly used. Median survival was 7 months. The mean cumulative (per patient per month) cost per patient was US$73,586 (US$10,084). Mean cost in first and second regimen were US$26,950 and US$33,347. CONCLUSION: About half of patients did not receive chemotherapy. Receipt of increasing regimens led to higher mean costs and healthcare resource use.

Economic value of using partially hydrolysed infant formula for risk reduction of atopic dermatitis in high-risk, not exclusively breastfed infants in Singapore.

INTRODUCTION: Previous trials have demonstrated reductions in atopic dermatitis (AD) incidence when healthy, high-risk, non-exclusively breastfed infants were fed until four months of age with 100% whey-based partially hydrolysed formula (PHF-W) versus standard cow's milk formula (CMF). We assessed the cost-effectiveness of this intervention in Singapore. METHODS: Modelling techniques were used to simulate, from birth to Month 30, the incidence and clinical/economic burden of AD in high-risk, non-exclusively breastfed infants fed with PHF-W or CMF for up to four months. Epidemiologic and clinical data were from a local comparative trial. Expert opinion informed AD treatment patterns and outcomes. Outcomes included reduction in AD risk, time spent with AD, days without AD flare, quality-adjusted life years (QALYs) and direct/indirect costs. Multivariate probabilistic sensitivity analysis was used to assess model parameter uncertainty. RESULTS: Over 30 months, with the use of PHF-W instead of CMF, the proportion of children who developed AD and the time spent with AD decreased by 16.0% (28.3% vs. 44.3%) and 6.4 months, respectively, while time without AD flare and QALYs increased by 14.9 days and 0.021 QALYs per patient, respectively. Estimated AD-related discounted costs per child for PHF-W and CMF were SGD 771 and SGD 1,309, respectively (net savings: SGD 538). PHF-W was less expensive and more effective than CMF for 73%, and cost less than SGD 50,000 per QALY for 87% of all multivariate simulations. CONCLUSION: Early short-term nutritional intervention with PHF-W instead of CMF may reduce AD incidence and costs for healthy, high-risk, non-exclusively breastfed infants in Singapore.

The Importance of Economic Perspective and Quantitative Approaches in Oncology Value Frameworks of Drug Selection and Shared Decision Making.

The debate around value in oncology drug selection has been prominent in recent years, and several professional bodies have furthered this debate by advocating for so-called value frameworks. Herein, we provide a viewpoint on these value frameworks, emphasizing the need to consider 4 key aspects: (1) the economic underpinnings of value; (2) the importance of the perspective adopted in the valuation; (3) the importance of the difference between absolute and relative measures of risk and measuring patient preferences; and (4) the recognition of multiple quality-of-life (QoL) domains, and the aggregation and valuation of those domains, through utilities within a multicriteria decision analysis, may allow prioritization of QoL above the tallying of safety events, particularly in a value framework focusing on the individual patient. While several frameworks exist, they incorporate different attributes and-importantly-assess value from alternative perspectives, including those of patients, regulators, payers, and society. The various perspectives necessarily lead to potentially different, if not sometimes divergent, conclusions about the valuation. We show that the perspective of the valuation affects the framing of the risk/benefit question and the methodology to measure the individual patient choice, or preference, as opposed to the collective, or population, choice. We focus specifically on the American Society of Clinical Oncology (ASCO) Value Framework. We argue that its laudable intent to assist in shared clinician-patient decision making can be augmented by more formally adopting methodology underpinned by micro- and health economic concepts, as well as application of formal quantitative approaches. Our recommendations for value frameworks focusing on the individual patient, such as the ASCO Value Framework, are 3-fold: (1) ensure that stakeholders understand the importance of the adopted (economic) perspective; (2) consider using exclusively absolute measures of risk and formal patient-preference methodology; and (3) consider foregoing safety parameters for higher-order utility considerations. DISCLOSURES: No funding was received for conceptualizing, writing, and/or editing this manuscript. Waldeck and White are employees of, and received stock option grants from, Celldex Therapeutics. Van Hout and Botteman are employees and shareholders of Pharmerit International. Pharmerit International is a research contractor for Celldex. All authors have retained editorial control of the content of the manuscript. Conceptualization of this viewpoint article was contributed primarily by Waldeck, along with Botteman, White, and van Hout. Data analysis and revision of the manuscript was contributed equally by all the authors. The manuscript was written by Waldeck, Botteman, van Hout, and White.

Modelling the cost-effectiveness of combination therapy for early, rapidly progressing rheumatoid arthritis by simulating the reversible and irreversible effects of the disease.

OBJECTIVE: To estimate the cost-effectiveness of adalimumab plus methotrexate (MTX) versus MTX monotherapy in early, aggressive rheumatoid arthritis (RA) when explicitly modelling short-term (reversible) and long-term (irreversible, ie, joint damage) disease activity and physical function. METHODS: A microsimulation model was developed to unify, in a single cost-effectiveness model, measures of reversible and irreversible disease activity and physical function based on data from the PREMIER trial. Short term, reversible disease activity was modelled using DAS28 variables, including swollen joint counts, tender joint counts, C reactive protein concentration and pain. The DAS28 variables were then used in a logistic regression to predict short-term American College of Rheumatology (ACR) responses, which informed treatment continuation and switches. Long term, irreversible, radiographically documented joint damage was modelled using modified Total Sharp Score (mTSS). The model then linked both short-term disease activity and mTSS to the Health Assessment Questionnaire score, which was used to calculate direct and indirect costs, and quality adjusted life-years (QALYs). RESULTS: When both reversible and irreversible effects of therapy were included, combination therapy was estimated to produce 6-month 50% ACR responses in 75% of patients versus 54% in MTX monotherapy. Compared to MTX monotherapy, combination therapy resulted in 2.68 and 3.04 discounted life years and QALYs gained, respectively. Combination therapy also resulted in a net increase in direct costs of £106,207 for a resulting incremental cost/QALY gain of £32,425. When indirect costs were included in the analysis, the ICER (incremental cost-effectiveness ratio) decreased to £27,238. Disregarding irreversible effects increased the incremental cost-effectiveness ratio to £78,809 (when only direct costs were included). CONCLUSIONS: Starting with adalimumab plus MTX combination therapy in early, aggressive RA is cost-effective when irreversible damage is adequately considered.

Economic value of atopic dermatitis prevention via infant formula use in high-risk Malaysian infants.

BACKGROUND: Breastfeeding is best for infants and the World Health Organization recommends exclusive breastfeeding for at least the first 6 months of life. For those who are unable to be breastfed, previous studies demonstrate that feeding high-risk infants with hydrolyzed formulas instead of cow's milk formula (CMF) may decrease the risk of atopic dermatitis (AD). OBJECTIVE: To estimate the economic impact of feeding high-risk, not exclusively breastfed, urban Malaysian infants with partiallyhydrolyzed whey-based formula (PHF-W) instead of CMF for the first 17 weeks of life as an AD risk reduction strategy. METHODS: A cohort Markov model simulated the AD incidence and burden from birth to age 6 years in the target population fed with PHF-W vs. CMF. The model integrated published clinical and epidemiologic data, local cost data, and expert opinion. Modeled outcomes included AD-risk reduction, time spent post AD diagnosis, days without AD flare, quality-adjusted life years (QALYs), and costs (direct and indirect). Outcomes were discounted at 3% per year. Costs are expressed in Malaysian Ringgit (MYR; MYR 1,000 = United States dollar [US $]316.50). RESULTS: Feeding a high-risk infant PHF-W vs. CMF resulted in a 14% point reduction in AD risk (95% confidence interval [CI], 3%-23%), a 0.69-year (95% CI, 0.25-1.10) reduction in time spent post-AD diagnosis, additional 38 (95% CI, 2-94) days without AD flare, and an undiscounted gain of 0.041 (95% CI, 0.007-0.103) QALYs. The discounted AD-related 6-year cost estimates when feeding a high-risk infant with PHF-W were MYR 1,758 (US $556) (95% CI, MYR 917-3,033) and with CMF MYR 2,871 (US $909) (95% CI, MYR 1,697-4,278), resulting in a per-child net saving of MYR 1,113 (US $352) (95% CI, MYR 317-1,884) favoring PHF-W. CONCLUSION: Using PHF-W instead of CMF in this population is expected to result in AD-related costs savings.

Economic Burden of Atopic Dermatitis in High-Risk Infants Receiving Cow's Milk or Partially Hydrolyzed 100% Whey-Based Formula.

OBJECTIVE: To estimate the health and economic impact of feeding partially hydrolyzed formula-whey (PHF-W) instead of standard cow's milk formula (CMF) for the first 4 months of life among US infants at high risk for developing atopic dermatitis (AD). STUDY DESIGN: A Markov model was developed integrating published data, a survey of US pediatricians, costing sources and market data, and expert opinion. Key modeled outcomes included reduction in AD risk, time spent post AD diagnosis, days without AD flare, and AD-related costs. Costs and clinical consequences were discounted at 3% annually. RESULTS: An estimated absolute 14-percentage point reduction in AD risk was calculated with the use of PHF-W compared with CMF (95% CI for difference, 3%-22%). Relative to CMF, PHF-W decreased the time spent post-AD diagnosis by 8.3 months (95% CI, 2.78-13.31) per child and increased days without AD flare by 39 days (95% CI, 13-63) per child. The AD-related, 6-year total cost estimate was $495 less (95% CI, -$813 to -$157) per child with PHF-W ($724 per child; 95% CI, $385-$1269) compared with CMF ($1219 per child; 95% CI, $741-$1824). CONCLUSION: Utilization of PHF-W in place of CMF as the initial infant formula administered to high-risk US infants not exclusively breastfed during the first 4 months of life may reduce the incidence and economic burden of AD. Broad implementation of this strategy could result in a minimum savings of $355 million per year to society.

Cost efficiency of canagliflozin versus sitagliptin for type 2 diabetes mellitus.

OBJECTIVES: To compare 1-year clinical outcomes and cost efficiency of treating adults with type 2 diabetes mellitus (T2DM) with canagliflozin (300 mg/day) or sitagliptin (100 mg/day), both added on a background of metformin and sulfonylurea. STUDY DESIGN: An economic model integrated data from an active-controlled, randomized trial, claims database analyses, and published literature. METHODS: The model adopted a US managed care payer perspective and included the clinical and economic impact of achieving specific clinical quality goals. The model was run separately for 2 single clinical quality metrics, glycated hemoglobin (A1C) < 7% (used as base case) or < 8%, and 4 composite metrics (A1C < 7% or < 8% combined with body mass index < 30 kg/m2 and blood pressure < 140/90 mm Hg or low-density lipoprotein cholesterol < 100 mg/dL). Cost savings of achieving versus not achieving metrics were derived from a claims database analysis. Drug and adverse event costs were included. RESULTS: In the base case, compared with sitagliptin 100 mg, treatment with canagliflozin 300 mg resulted in $215 in annual cost savings and 12.3 absolute percentage points more patients achieving goal. Similar findings were found across all other quality metrics (difference in proportion achieving goal ranging from 6.7% to 19.0% and annual savings ranging from $1 to $669). Canagliflozin remained cost saving versus sitagliptin in sensitivity analyses. CONCLUSIONS: Canagliflozin 300 mg may represent a cost-efficient T2DM treatment option versus sitagliptin 100 mg for patients on metformin plus sulfonylurea due to lower overall costs and better achievement of A1C and quality composite goals.

Cost-Effectiveness of Partially Hydrolyzed Whey Protein Formula in the Primary Prevention of Atopic Dermatitis in At-Risk Urban Filipino Infants.

OBJECTIVE: To estimate, from a Filipino societal perspective, the cost-effectiveness of preventing atopic dermatitis (AD) via early nutritional intervention with 100% whey-based partially hydrolyzed formula (PHF-W) versus standard cow's milk formula (SF) in healthy, urban infants with atopic heredity who are not exclusively breast-fed. METHODS: A Markov model was used to simulate over 6 years the incidence of AD, days with AD symptoms, quality-adjusted life-years (QALYs), and AD-related direct and indirect (i.e., parents'/caregivers' productivity loss) costs incurred by hypothetical cohorts of healthy, at-risk infants fed with either PHF-W or SF as AD prevention for ≤ 17 weeks. Efficacy estimates of PHF-W versus SF in preventing AD were literature-based. The resources used to manage AD (by severity, age, and treatment modality) were estimated using clinical pathways derived from clinical expert opinion. Local costs were applied to resource use. Results were presented as point estimates and as 95 percent credible intervals (CIs, i.e., range of values around the point estimate that include 95% of model simulations) generated via multivariate probabilistic sensitivity analysis using Monte-Carlo simulation techniques. All costs are reported in Philippines pesos (₱, where ₱1000 = US $22.24). All reported outcomes were discounted at a rate of 3.5% per year. RESULTS: Based on the 6-year simulation, compared with SF, PHF-W was predicted to result in a 14-percentage point reduction (i.e., 39% vs. 25%) (95% CI 0.09-0.19) in the incidence of AD and a gain of 0.03 (i.e., 5.46 vs. 5.43) (95% CI 0.01-0.07) QALYs/patient. PHF-W's higher feeding formula cost (+₱1,304/patient) (95% CI -₱3,090 to ₱5,779) were offset by reductions in AD-related costs (-₱11,959/patient; i.e., ₱27,228 vs. ₱15,269) (95% CI -₱14,685 to -₱7,284), including, in particular, the costs of pharmacotherapy, formula used as treatment, and visits to physicians. As a result, PHF-W became a net cost-saving strategy within 38 weeks. Overall, PHF-W resulted in net savings of -₱10,654 (-US $237) (CI -₱4,240 [-US $94] to -₱14,544 [-US $323]) (i.e., ₱27,228 [US $606] vs. ₱16,574 [US $369]). Sensitivity analysis confirmed the robustness of results; the most influential variable was the first-year risk reduction in AD. CONCLUSIONS: Based on the present modeling exercise, compared with SF, PHF-W appears to substantially reduce the risk of AD and its associated direct and indirect medical costs in healthy, at-risk urban Filipino infants over a 6-year period.

Clinical, economic and humanistic burdens of skeletal-related events associated with bone metastases.

Despite effective skeletal-related event (SRE)-limiting therapies such as zoledronic acid and denosumab, SREs continue to place a meaningful burden on patients, providers and payers. However, studies of SRE-related effects on clinical (i.e., survival), economic (i.e., cost per event) and humanistic (i.e., quality of life) outcomes often report results in a composite manner and frequently do not differentiate the effects by SRE-type (i.e., bone radiation, bone surgery, hypercalcemia, pathological fracture and spinal cord compression). Nevertheless, understanding the differential burdens of individual SRE types, which vary in severity and duration of effect, is an important consideration - particularly in pharmacoeconomic evaluations of SRE-limiting therapies. In this review of the clinical, economic and humanistic SRE burden, it was found that SRE types can be differentiated by these outcomes, although economic outcomes are far more frequently reported than clinical or humanistic.

Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a cost-effectiveness analysis.

OBJECTIVE: Denosumab has been approved in the US for skeletal-related event (SRE) prevention in bone-metastatic prostate cancer on the basis of a phase III clinical trial in which denosumab reduced SREs relative to zoledronic acid. Overall survival, disease progression, and serious adverse events did not differ significantly between groups. This analysis assessed the cost-effectiveness of denosumab vs zoledronic acid in bone-metastatic prostate cancer from a US payer perspective. METHODS: A literature-based Markov model, wherein inputs were selected to reproduce clinical trial outcomes, was developed to estimate the survival, quality-adjusted life-years (QALYs), number and costs of SREs, and drug and administration costs for patients receiving denosumab or zoledronic acid over 27 months. QALYs were estimated by assigning health-state utilities. SRE-related costs and utilities were literature-based. Outcomes were discounted 3% per annum, and model robustness was tested via scenario, univariate, and probabilistic sensitivity analyses. RESULTS: Denosumab resulted in fewer estimated SREs (-0.241; 1.036 vs 1.277), more QALYs (0.0074; 0.9306 vs 0.9232), and lower SRE-related costs (-$2340; $8824 vs $11,164), but higher drug-related costs ($10,181; $23,144 vs $12,963) and total costs ($7841; $31,968 vs $24,127) vs zoledronic acid. The base case estimated cost per QALY-gained was $1,058,741. CONCLUSION: This analysis was limited by the restricted availability of clinical data and the need to use projection methods beyond the trial time frame. However, a wide range of scenarios predicted denosumab to have an incremental cost/QALY gained above what may be considered acceptable value for money in the US. This raises important questions regarding the pharmacoeconomic value of denosumab in bone-metastatic prostate cancer.

Health-economic review of zoledronic acid for the management of skeletal-related events in bone-metastatic prostate cancer.

Zoledronic acid is the only bisphosphonate approved for the prevention or delay of skeletal-related events in patients with bone metastases secondary to prostate cancer. Recently, the US FDA and the EMA approved denosumab (a fully human monoclonal antibody) to treat skeletal-related events in bone-metastatic prostate cancer. This article summarizes the cost-effectiveness literature pertaining to these two agents when used in the prevention of skeletal-related events secondary to malignancy. Zoledronic acid (and denosumab in comparison with zoledronic acid) have been found to be cost effective and cost ineffective depending on the analytical perspective and model parameters.

Cost-effectiveness of denosumab versus zoledronic acid in the management of skeletal metastases secondary to breast cancer.

BACKGROUND: Denosumab has been approved in the United States for the prevention of skeletal-related events (SREs) in metastatic breast cancer. In a Phase III trial in patients with bone-metastatic breast cancer (N = 2033), denosumab was associated with a significantly delayed time to first SRE (by 18%; P < 0.001 noninferiority; P = 0.01 superiority) and time to first and subsequent SREs (by 23%; P = 0.001). Overall survival (HR = 0.95; 95% CI, 0.81-1.11; P = 0.49) and disease progression (HR = 1.00; 95% CI, 0.89-1.11; P = 0.93) did not differ significantly between groups. Denosumab was associated with a nonsignificant reduction in serious adverse events (44.4% vs 46.5%). OBJECTIVES: Given the current ambiguity regarding the cost-effectiveness of these agents in light of these trial outcomes, the present analysis assessed, from a US payer perspective, the cost-effectiveness of denosumab versus zoledronic acid in patients with bone metastases secondary to breast cancer. METHODS: A literature-based Markov model was developed to estimate the survival, quality-adjusted life-years (QALYs) gained, number and costs of SREs, and drug and administration costs in patients receiving denosumab or zoledronic acid over 27 and 60 months. Clinical inputs reproduced the trial outcomes. SRE-related costs and utilities were literature based. Costs and QALYs were discounted 3% annually. RESULTS: In the 27-month base-case analysis, denosumab was associated with fewer SREs (-0.298), more QALYs (+0.0102), and lower SRE-related costs (-$2016), but higher drug-related (+$9123) and total costs (+$7107) versus zoledronic acid. The cost per QALY gained (ie, incremental cost-effectiveness ratio [ICER]) was $697,499. In sensitivity analyses, the ICER ranged from $192,472 to $1,340,901/QALY, depending on assumptions regarding treatment benefits, drug costs, and analytical horizon. In the probabilistic sensitivity analysis, denosumab was cost-effective in 2 of 5000 modeled replicates (0.04%). CONCLUSIONS: Despite the limitations of restricted availability of clinical data and uncertainty regarding the price of generic zoledronic acid, the findings from the present analysis suggest that the use of denosumab is associated with a high ICER compared with zoledronic acid. This finding may raise important questions regarding the economic value of denosumab in bone-metastatic breast cancer.

Clinical and economic burden of extra-articular manifestations in ankylosing spondylitis patients treated with anti-tumor necrosis factor agents.

OBJECTIVE: To assess concomitant extra-articular manifestation (EAM) rates in patients with ankylosing spondylitis (AS) treated with anti-tumor necrosis factor (anti-TNF) agents and examine the economic burden of uveitis and inflammatory bowel disease (IBD) in French and German AS patients. METHODS: Previous analyses of uveitis and IBD in AS patients treated with infliximab, etanercept or adalimumab were identified in PubMed/Medline (January 2000 to August 2011). A supplemental analysis incorporated more recent adalimumab clinical trial data (ATLAS [NCT00085644] and RHAPSODY [NCT00478660]). For resource utilization/costs associated with EAMs, the search was expanded to general spondyloarthritis (SpA) conditions (i.e., AS, reactive or psoriatic arthritis, psoriatic spondylitis, IBD and undifferentiated SpA). Direct and indirect yearly costs associated with AS-associated uveitis and IBD were estimated based on interviews with French and German clinicians and literature review. RESULTS: The pooled average rate of anterior uveitis (AU) flares for patients treated with anti-TNF therapy in two meta-analyses and supplemental adalimumab clinical trials was 4.9/100-patient-years (PYs). AU rates (per 100-PYs) were 3.4, 3.7 and 5.7 for infliximab (p=0.26 vs etanercept; p=0.86 vs adalimumab), adalimumab (p=0.033 vs etanercept) and etanercept, respectively. IBD flares (per 100-PYs) were 0.2 for infliximab (p<0.001 vs etanercept; p=0.18 vs adalimumab), 0.63 for adalimumab (p=0.009 vs etanercept) and 2.2 for etanercept. No studies assessing EAM-associated resource utilization or costs in AS patients were found. Direct medical costs associated with IBD treatment ranged from €483 (Germany) to €6443 (France). Clinician-estimated AS-related uveitis direct medical costs were €1410 (Germany) and €1812 (France). CONCLUSIONS: Clinical data synthesis demonstrated significantly lower AU flare rates with adalimumab vs etanercept and significantly lower IBD rates with both adalimumab and infliximab vs etanercept. Economic analysis indicated substantial costs associated with AU and IBD flares secondary to AS in France and Germany. Future economic evaluations of anti-TNF agents should incorporate EAMs and subsequent treatment costs. Limitations include restricted availability of randomized, placebo-controlled clinical trial data, inclusion of data from open-label studies, lack of real-world (i.e., non-trial-based) EAM rates and a lack of EAM-specific direct and indirect costs with which to compare the results presented herein.