Cost-Effectiveness Model for Chemoimmunotherapy Options in Patients with Previously Untreated Chronic Lymphocytic Leukemia Unsuitable for Full-Dose Fludarabine-Based Therapy.

OBJECTIVES: To evaluate the cost-effectiveness of treatment with anti-CD20 monoclonal antibody obinutuzumab plus chlorambucil (GClb) in untreated patients with chronic lymphocytic leukemia unsuitable for full-dose fludarabine-based therapy. METHODS: A Markov model was used to assess the cost-effectiveness of GClb versus other chemoimmunotherapy options. The model comprised three mutually exclusive health states: "progression-free survival (with/without therapy)", "progression (refractory/relapsed lines)", and "death". Each state was assigned a health utility value representing patients' quality of life and a specific cost value. Comparisons between GClb and rituximab plus chlorambucil or only chlorambucil were performed using patient-level clinical trial data; other comparisons were performed via a network meta-analysis using information gathered in a systematic literature review. To support the model, a utility elicitation study was conducted from the perspective of the UK National Health Service. RESULTS: There was good agreement between the model-predicted progression-free and overall survival and that from the CLL11 trial. On incorporating data from the indirect treatment comparisons, it was found that GClb was cost-effective with a range of incremental cost-effectiveness ratios below a threshold of £30,000 per quality-adjusted life-year gained, and remained so during deterministic and probabilistic sensitivity analyses under various scenarios. CONCLUSIONS: GClb was estimated to increase both quality-adjusted life expectancy and treatment costs compared with several commonly used therapies, with incremental cost-effectiveness ratios below commonly referenced UK thresholds. This article offers a real example of how to combine direct and indirect evidence in a cost-effectiveness analysis of oncology drugs.

The value of innovation under value-based pricing.

OBJECTIVE: The role of cost-effectiveness analysis (CEA) in incentivizing innovation is controversial. Critics of CEA argue that its use for pricing purposes disregards the 'value of innovation' reflected in new drug development, whereas supporters of CEA highlight that the value of innovation is already accounted for. Our objective in this article is to outline the limitations of the conventional CEA approach, while proposing an alternative method of evaluation that captures the value of innovation more accurately. METHOD: The adoption of a new drug benefits present and future patients (with cost implications) for as long as the drug is part of clinical practice. Incidence patients and off-patent prices are identified as two key missing features preventing the conventional CEA approach from capturing 1) benefit to future patients and 2) future savings from off-patent prices. The proposed CEA approach incorporates these two features to derive the total lifetime value of an innovative drug (i.e., the value of innovation). RESULTS: The conventional CEA approach tends to underestimate the value of innovative drugs by disregarding the benefit to future patients and savings from off-patent prices. As a result, innovative drugs are underpriced, only allowing manufacturers to capture approximately 15% of the total value of innovation during the patent protection period. In addition to including the incidence population and off-patent price, the alternative approach proposes pricing new drugs by first negotiating the share of value of innovation to be appropriated by the manufacturer (>15%?) and payer (<85%?), in order to then identify the drug price that satisfies this condition. CONCLUSION: We argue for a modification to the conventional CEA approach that integrates the total lifetime value of innovative drugs into CEA, by taking into account off-patent pricing and future patients. The proposed approach derives a price that allows manufacturers to capture an agreed share of this value, thereby incentivizing innovation, while supporting health-care systems to pursue dynamic allocative efficiency. However, the long-term sustainability of health-care systems must be assessed before this proposal is adopted by policy makers.

Cross-market cost-effectiveness analysis of erlotinib as first-line maintenance treatment for patients with stable non-small cell lung cancer.

BACKGROUND: Platinum-doublet, first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) is limited to 4-6 cycles. An alternative strategy used to prolong the duration of first-line treatment and extend survival in metastatic NSCLC is first-line maintenance therapy. Erlotinib was approved for first-line maintenance in a stable disease population following results from a randomized, controlled Phase III trial comparing erlotinib with best supportive care. We aimed to estimate the incremental cost-effectiveness of erlotinib 150 mg/day versus best supportive care when used as first-line maintenance therapy for patients with locally advanced or metastatic NSCLC and stable disease. METHODS: An economic decision model was developed using patient-level data for progression-free survival and overall survival from the SATURN (SequentiAl Tarceva in UnResectable NSCLC) study. An area under the curve model was developed; all patients entered the model in the progression-free survival health state and, after each month, moved to progression or death. A time horizon of 5 years was used. The model was conducted from the perspective of national health care payers in France, Germany, and Italy. Probabilistic sensitivity analyses were performed. RESULTS: Treatment with erlotinib in first-line maintenance resulted in a mean life expectancy of 1.39 years in all countries, compared with a mean 1.11 years with best supportive care, which represents 0.28 life-years (3.4 life-months) gained with erlotinib versus best supportive care. In the base-case analysis, the cost per life-year gained was €39,783, €46,931, and €27,885 in France, Germany, and Italy, respectively. CONCLUSION: Erlotinib is a cost-effective treatment option when used as first-line maintenance therapy for locally advanced or metastatic NSCLC.

An evaluation of the cost-effectiveness of rituximab in combination with chemotherapy for the first-line treatment of follicular non-Hodgkin's lymphoma in the UK.

OBJECTIVES: In this study, the cost-effectiveness of rituximab was evaluated in comparison with commonly used chemotherapy regimens for patients with advanced follicular lymphoma (FL), from the perspective of the UK National Health Service (NHS). METHODS: Results from four randomized controlled trials comparing the addition of rituximab to chemotherapy regimens: mitoxantrone, chlorambucil, and prednisolone (MCP); cyclophosphamide, vincristine, and prednisolone (CVP); cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP); or cyclophosphamide, etoposide, doxorubicin, prednisolone, and interferon alpha (CHVP + IFNalpha) versus chemotherapy alone were used to develop a Markov model. The rates of disease progression and the duration of treatment effect were obtained from the trial data. Treatments were compared in two ways: 1) an individual comparison of rituximab + chemotherapy versus chemotherapy and 2) a multiple treatment comparison using league tables. Economic and clinical outcomes (quality-adjusted life-years (QALYs)) were estimated over patient lifetimes and discounted at 3.5% per annum. RESULTS: In the individual comparison, the addition of rituximab increased QALYs by (mean, 95% confidence interval) 1.174 (1.02-1.30), 0.909 (0.79-1.01), 0.823 (0.71-0.91), and 0.453 (0.40-0.50) for MCP, CVP, CHOP, and CHVP, respectively, compared with chemotherapy alone. The incremental costs per QALY gained were pound7474, pound8621, pound10,732, and pound8551, respectively. Sensitivity analyses indicated that rituximab plus chemotherapy was a cost-effective treatment option, with incremental cost-effectiveness ratios below a threshold of pound30,000 per QALY gained. When compared across the chemotherapy regimens, rituximab plus MCP appeared to be the single most cost-effective treatment option, but further randomized trials are required to substantiate this. CONCLUSIONS: The addition of rituximab to chemotherapy in advanced FL was found to be highly cost-effective in the UK.

Cost-effectiveness of early versus late cinacalcet treatment in addition to standard care for secondary renal hyperparathyroidism in the USA.

OBJECTIVES: The objective of this research was to estimate lifetime cost-effectiveness of treating patients with cinacalcet early (when parathyroid hormone [PTH] levels are in the range of 300-500 pg/ml) versus delaying treatment with cinacalcet (cinacalcet initiated when PTH levels are > 800 pg/ml) in patients with secondary hyperparathyroidism (SHPT) in the US setting. METHODS: A Markov model was developed to simulate the effects of early versus delayed use of cinacalcet (plus standard of care). Four different PTH ranges (< or = 300 pg/ml; 301-500 pg/ml; 501-800 pg/ml; > 800 pg/ml) were used to represent four different health states within the Markov model. Associated with each Markov state (PTH range) were varying risks of major SHPT complications, including cardiovascular disease (CVD), fracture (Fx), and parathyroidectomy (PTx). Baseline cohort characteristics and risks of CVD, Fx, and PTx by PTH category were derived from a large US renal database and published sources. Costs were estimated from the US Renal Data System database and reported in 2006 US Dollars ($). Clinical and economic outcomes were discounted at 3.0% per annum. RESULTS: Early treatment was projected to improve quality-adjusted life years (QALYs) by 0.337 years compared to delaying treatment. The incremental cost-effectiveness ratio was $17,275 per QALY gained. CONCLUSIONS: Early treatment with cinacalcet was associated with improvements in QALYs and would represent good value for money compared to delaying treatment with cinacalcet.

Cost-effectiveness of diabetes case management for low-income populations.

OBJECTIVE: To evaluate the cost-effectiveness of Project Dulce, a culturally specific diabetes case management and self-management training program, in four cohorts defined by insurance status. DATA SOURCES/STUDY SETTING: Clinical and cost data on 3,893 persons with diabetes participating in Project Dulce were used as inputs into a diabetes simulation model. STUDY DESIGN: The Center for Outcomes Research Diabetes Model, a published, peer-reviewed and validated simulation model of diabetes, was used to evaluate life expectancy, quality-adjusted life expectancy (QALY), cumulative incidence of complications and direct medical costs over patient lifetimes (40-year time horizon) from a third-party payer perspective. Cohort characteristics, treatment effects, and case management costs were derived using a difference in difference design comparing data from the Project Dulce program to a cohort of historical controls. Long-term costs were derived from published U.S. sources. Costs and clinical benefits were discounted at 3.0 percent per annum. Sensitivity analyses were performed. PRINCIPAL FINDINGS: Incremental cost-effectiveness ratios of $10,141, $24,584, $44,941, and $69,587 per QALY gained were estimated for Project Dulce participants versus control in the uninsured, County Medical Services, Medi-Cal, and commercial insurance cohorts, respectively. CONCLUSIONS: The Project Dulce diabetes case management program was associated with cost-effective improvements in quality-adjusted life expectancy and decreased incidence of diabetes-related complications over patient lifetimes. Diabetes case management may be particularly cost effective for low-income populations.

An economic assessment of analogue basal-bolus insulin versus human basal-bolus insulin in subjects with type 1 diabetes in the UK.

BACKGROUND: A recent study demonstrated that treatment of type 1 diabetes with an analogue basal-bolus insulin regimen was associated with improved glycaemic control (HbA(1c) -0.22% points, p < 0.001), reduced risk of hypoglycaemic events (-21%, p = 0.036) and reduction in body mass index (-0.30 kg/m(2), p < 0.001) compared to a human basal-bolus regimen after 18 weeks. METHODS: A published and validated computer simulation model was used to project long-term economic and clinical outcomes in a simulated cohort of type 1 diabetes patients treated with either insulin detemir plus insulin aspart (analogue) or Neutral Protamine Hagedorn plus human soluble insulin (human), in a UK setting. Probabilities of complications and HbA(1c)-dependent adjustments were derived from major clinical and epidemiological studies. Complication and treatment costs were projected over patient lifetimes from a National Health Service perspective. Costs and clinical benefits were discounted at 3.5% annually. RESULTS: Quality-adjusted life expectancy (QALE) was 0.66 quality-adjusted life years (QALY) higher in the analogue insulin versus the human insulin group (mean +/- SD) (7.65 +/- 0.09 versus 6.99 +/- 0.08). Direct lifetime costs were 1654 pounds greater with analogue versus human insulin treatment (40,876 pounds +/- 1119 versus 39,222 pounds+/- 1141), producing an incremental cost effectiveness ratio (ICER) of 2500 pounds per QALY gained. Sensitivity analyses showed the results were robust under a range of plausible scenarios. CONCLUSIONS: Treatment with analogue insulin was associated with a decreased incidence of long-term complications and improved QALE, but slightly higher treatment costs compared to human insulin therapy. Analogue insulin treatment had an ICER within the range generally considered to represent good value for money in the UK.

Exenatide versus insulin glargine in patients with type 2 diabetes in the UK: a model of long-term clinical and cost outcomes.

OBJECTIVES: The aim of this study was to evaluate the long-term clinical and economic outcomes associated with exenatide or insulin glargine, added to oral therapy in individuals with type 2 diabetes inadequately controlled with combination oral agents in the UK setting. METHODS: A published and validated computer simulation model of diabetes was used to project long-term complications, life expectancy, quality-adjusted life expectancy and direct medical costs. Probabilities of diabetes-related complications were derived from published sources. Treatment effects and patient characteristics were extracted from a recent randomised controlled trial comparing exenatide with insulin glargine. Simulations incorporated published quality of life utilities and UK-specific costs from 2004. Pharmacy costs for exenatide were based on 20, 40, 60, 80 and 100% of the US value (as no price for the UK was available at the time of analysis). Future costs and clinical benefits were discounted at 3.5% annually. Sensitivity analyses were performed. RESULTS: In the base-case analysis exenatide was associated with improvements in life expectancy of 0.057 years and in quality-adjusted life expectancy of 0.442 quality-adjusted life years (QALYs) versus insulin glargine. Long-term projections demonstrated that exenatide was associated with a lower cumulative incidence of most cardiovascular disease (CVD) complications and CVD-related death than insulin glargine. Using the range of cost values, evaluation results showed that exenatide is likely to fall in a range between dominant (cost and life saving) at 20% of the US price and cost-effective (with an ICER of 22,420 pounds per QALY gained) at 100% of the US price, versus insulin glargine. CONCLUSIONS: Based on the findings of a recent clinical trial, long-term projections indicated that exenatide is likely to be associated with improvement in life expectancy and quality-adjusted life expectancy compared to insulin glargine. The results from this modelling analysis suggest that that exenatide is likely to represent good value for money by generally accepted standards in the UK setting in individuals with type 2 diabetes inadequately controlled on oral therapy.

Health economic implications of irbesartan treatment versus standard blood pressure control in patients with type 2 diabetes, hypertension and renal disease: a Hungarian analysis.

To perform a health economic analysis on treatment with irbesartan in patients with type 2 diabetes and hypertension. A Markov model was adapted to the Hungarian setting to simulate renal deterioration from the development of microalbuminuria to nephropathy, doubling of serum creatinine, end-stage renal disease (ESRD) and all-cause mortality. Outcomes for two treatments were evaluated: (1) a placebo regimen of standard antihypertensive medications, and (2) the addition of irbesartan 300 mg administered daily, with both treatment initiated after developing microalbuminuria. Outcomes were discounted at 5% annually to correspond with national guidelines. Treatment with irbesartan was estimated to improve undiscounted life expectancy by 0.98 +/- 0.05 years, reduce the cumulative incidence of ESRD by 7.5 +/- 0.4%, and reduce lifetime costs by Hungarian Forints (HUF) 519,993 +/- 70,814, compared to placebo. Irbesartan was projected to improved life expectancy and reduce costs compared to placebo in the Hungarian setting in hypertensive patients with type 2 diabetes and microalbuminuria.

A French cost-consequence analysis of the renoprotective benefits of irbesartan in patients with type 2 diabetes and hypertension.

OBJECTIVES: We performed a cost-consequence analysis in a French setting of the renoprotective benefit of irbesartan in hypertensive type 2 diabetes patients over a 25-year period. RESEARCH DESIGN AND METHODS: A previously published Markov model simulated progression from microalbuminuria to overt nephropathy, doubling of serum creatinine, end-stage renal disease and death. Three treatment strategies with analogous blood pressure control were compared: (A) control--conventionally medicated antihypertensive therapy (excluding angiotensin converting enzyme inhibitors, other angiotensin-2-receptor antagonists and dihydropyridine calcium channel blockers) initiated at microalbuminuria; (B) early irbesartan--(300 mg daily added to control, initiated with microalbuminuria) and (C) late irbesartan--(300 mg daily, initiated with overt nephropathy). Probabilities came from the Irbesartan in Reduction of Microalbuminuria-2 study, Irbesartan in Diabetic Nephropathy Trial and other sources. Clinical and economic outcomes were projected over 25 years. Annual discount rates were 3%. RESULTS: Compared to control, early use of irbesartan added (mean +/- standard deviation) 1.51 +/- 0.08 undiscounted life years (discounted: 0.94 +/- 0.05 years), while late irbesartan added 0.07 +/- 0.01 (0.04 +/- 0.01) years/patient. Early irbesartan added 1.03 +/- 0.06 discounted quality-adjusted life years (QALYs), while late irbesartan added 0.06 +/- 0.01 QALYs. Early and late irbesartan treatments were projected to save 22,314 +/- 1273 euro and 6619 +/- 820 euro/patient, respectively versus control. Sensitivity analysis showed that even over short time horizons both irbesartan treatments were superior to the control group. CONCLUSIONS: In France, early irbesartan treatment improved quality and length of life and reduced costs in hypertensive patients with type 2 diabetes and microalbuminuria. Late irbesartan therapy is beneficial, but earlier irbesartan leads to better outcomes.

Cost-effectiveness of basal insulin from a US health system perspective: comparative analyses of detemir, glargine, and NPH.

The purpose of this study was to compare in clinical and economic terms the long-acting insulin analogue detemir with intermediate-acting Neutral Protamine Hagedorn (NPH) insulin and with long-acting insulin glargine. Investigators used the validated Center for Outcomes Research (CORE) Diabetes Model to project clinical and cost outcomes over a 35-year base case time horizon; outcome data were extracted directly from randomized, controlled trials designed to compare detemir with NPH and with insulin glargine. Modeled patient characteristics were derived from corresponding trials, and simulations incorporated published quality-of-life utilities with cost data obtained from a Medicare perspective. Detemir, when compared with NPH, increased quality-adjusted life expectancy by 0.698 quality-adjusted life-years (QALYs). Lifetime direct medical costs were increased by 10,451 dollars per patient, although indirect costs were reduced by 4688 dollars. On the basis of direct costs, the cost per QALY gained with detemir was 14,974 dollars. In comparison with glargine, detemir increased quality-adjusted life expectancy by 0.063 QALYs, reduced direct medical costs by 2072 dollars per patient, and decreased indirect costs by 3103 dollars (dominant). Reductions in diabetes-related comorbidities were also associated with detemir in both instances, most notably in the complications of retinopathy and nephropathy. Relative reductions in rates of complications were greatest in the comparison of detemir with NPH. Results were most sensitive to variation in hemoglobin A1c (HbA1c) levels. However, variation among any of the key assumptions, including HbA1c, did not alter the relative results. Detemir represents an attractive clinical and economic intervention in the US health care setting compared with both NPH insulin and insulin glargine.

Health economic implications of irbesartan plus conventional antihypertensive medications versus conventional blood pressure control alone in patients with type 2 diabetes, hypertension, and renal disease in Switzerland.

OBJECTIVES: The aim of this health economic modelling study was to investigate the effect of irbesartan combined with conventional antihypertensive medications compared to conventional antihypertensive therapy alone on the progression of nephropathy in patients with hypertension, type 2 diabetes and microalbuminuria in a Swiss setting. METHODS: In simulated patients with hypertension and type 2 diabetes, treatment of microalbuminuria with irbesartan 300 mg daily plus conventional antihypertensive medications was compared to a control regimen (conventional medications excluding angiotensin converting enzyme inhibitors, other angiotensin-2-receptor antagonist and dihydropyridine calcium channel blockers). Progression from microalbuminuria to nephropathy, doubling of serum creatinine, ESRD, and all-cause mortality was simulated over a 25-year time horizon using a published Markov model adapted to a Swiss setting. Transition probabilities were based on the Irbesartan in Reduction of Microalbuminuria-2 Study, Irbesartan in Diabetic Nephropathy Trial and other sources. Costs and clinical outcomes were discounted at 5% annually according to Swiss guidelines, and a third party payer perspective was taken. RESULTS: Treatment with irbesartan was projected to improve mean life expectancy by 0.57 years compared to conventional antihypertension treatment (undiscounted 1.22 years). Irbesartan treatment was associated with cost savings of CHF 21,488 per patient over the 25-year time horizon. Sensitivity analysis showed that irbesartan therapy remained dominant to conventional antihypertension treatment over a range of plausible assumptions. CONCLUSIONS: Addition of irbesartan to conventional antihypertension therapy was projected to improve life expectancy and reduce costs in hypertensive patients with type 2 diabetes and microalbuminuria in a Swiss setting.

Counting the costs of overweight and obesity: modeling clinical and cost outcomes.

OBJECTIVE: To quantify changes in clinical and cost outcomes associated with increasing levels of body mass index (BMI) in a US setting. RESEARCH METHODS AND PROCEDURES: A semi-Markov model was developed to project and compare life expectancy (LE), quality-adjusted life expectancy (QALE) and direct medical costs associated with distinct levels of BMI in simulated adult cohorts over a lifetime horizon. Cohort definitions included age (20-65 years), gender, race, and BMI (24-45 kg m(-2)). Cohorts were exclusively male or female and either Caucasian or African-American. Mortality rates were adjusted according to these factors using published data. BMI progression over time was modeled. BMI-dependent US direct medical costs were derived from published sources and inflated to year 2004 values. A third party reimbursement perspective was taken. QALE and costs were discounted at 3% per annum. RESULTS: In young Caucasian cohorts LE decreased as BMI increased. However, in older Caucasian cohorts the BMI associated with greatest longevity was higher than 25 kg m(-2). A similar pattern was observed in young adult African-American cohorts. A survival paradox was projected in older African-American cohorts, with some BMI levels in the obese category associated with greatest longevity. QALE in all four race/gender cohorts followed similar patterns to LE. Sensitivity analyses demonstrated that simulating BMI progression over time had an important impact on results. Direct costs in all four cohorts increased with BMI, with a few exceptions. CONCLUSIONS: Optimal BMI, in terms of longevity, varied between race/gender cohorts and within these cohorts, according to age, contributing to the debate over what BMI level or distribution should be considered ideal in terms of mortality risk. Simulating BMI progression over time had a substantial impact on health outcomes and should be modeled in future health economic analyses of overweight and obesity.

Review of the cost of diabetes complications in Australia, Canada, France, Germany, Italy and Spain.

OBJECTIVES: To provide a comprehensive source document on previously published cost data for diabetic complications in Australia, Canada, France, Germany, Italy and Spain for use in a peer-reviewed, validated diabetes model. METHODS: A search for published cost of diabetes complications data was performed in peer-reviewed journals listed in PubMed and health economic conference proceedings from 1994 to March 2005. Where country specific data were not available, we referred to government websites and local cost experts. All costs were inflated to 2003 Euros (E). Major complication costs are presented. RESULTS: First year costs of non-fatal myocardial infarction varied between E19277 in Spain and E12292 in Australia. In subsequent years of treatment, this range was E1226 (France) to E203 (Australia). Angina costs were similar across all four countries: E1716 in Australia; E2218 in Canada; E2613 in France; E3342 in Germany; E2297 in Italy; and E2207 in Spain. Event costs of non-fatal stroke were higher in Canada (E23173) than in other countries (Australia E13443; France E11754; Germany E19399; Italy E6583; Spain E4638). Event costs of end-stage renal disease varied depending on the type of dialysis: in Australia (E17188-27552); Canada (E33811-58159); France (E24608-56487); Germany (E46296-68175); Italy (E43075-56717); and Spain (E28370-32706). Lower extremity amputation costs were: E18547 (Australia); E17130 (Canada); E31998 (France); E22096 (Germany); E10177 (Italy); and E14787 (Spain). CONCLUSIONS: Overall, our search showed costs are well documented in Australia, Canada, France and Germany, but revealed a paucity of data for Spain and Italy. Spanish costs, collected by contacting local experts and from government reports, generally appeared to be lower for treating cardiovascular complications than in other countries. Italian costs reported in the literature were primarily hospitalization costs derived from diagnosis-related groups, and therefore likely to misrepresent the cost of specific complications. Additional research is required to document complication costs in Spain and Italy. Australian and German values were collected primarily by referring to diagnostic related group (DRG) tariffs and, as a result, there may be a need for future economic evaluations measuring the accuracy of the costs and resource utilization in the reported values. These cost data are essential to create models of diabetes that are able to accurately simulate the cumulative costs associated with the progression of the disease and its complications.

Cost-effectiveness studies of diabetes prevention in high-risk patients.

The incidence of Type 2 diabetes is increasing annually. Impaired glucose tolerance has been described as a prediabetic state, which confers an increased risk of developing Type 2 diabetes along with its associated costly complications. Interventions targeted at individuals with impaired glucose tolerance can delay or prevent the onset of Type 2 diabetes. Several recent studies have shown that the incidence of Type 2 diabetes is reduced by lifestyle changes or pharmacological interventions. A literature search for studies investigating the costs and cost-effectiveness of diabetes prevention was performed, and the results summarized in this review. The limited health economic evidence currently published suggests that financial concerns should not be a barrier to the implementation of diabetes prevention strategies.