Azacitidine for Treating Acute Myeloid Leukaemia with More Than 30 % Bone Marrow Blasts: An Evidence Review Group Perspective of a National Institute for Health and Care Excellence Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer of azacitidine (Celgene) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of acute myeloid leukaemia with more than 30 % bone marrow blasts in adults who are not eligible for haematopoietic stem cell transplantation, as part of the NICE's Single Technology Appraisal process. The Peninsula Technology Assessment Group was commissioned to act as the Evidence Review Group (ERG). The ERG produced a critical review of the evidence contained within the company's submission to NICE. The clinical effectiveness data used in the company's economic analysis were derived from a single randomised controlled trial, AZA-AML-001. It was an international, multicentre, controlled, phase III study with an open-label, parallel-group design conducted to determine the efficacy and safety of azacitidine against a conventional care regimen (CCR). The CCR was a composite comparator of acute myeloid leukaemia treatments currently available in the National Health Service: intensive chemotherapy followed by best supportive care (BSC) upon disease relapse or progression, non-intensive chemotherapy followed by BSC and BSC only. In AZA-AML-001, the primary endpoint was overall survival. Azacitidine appeared to be superior to the CCR, with median overall survival of 10.4 and 6.5 months, respectively. However, in the intention-to-treat analysis, the survival advantage associated with azacitidine was not statistically significant. The company submitted a de novo economic evaluation based on a partitioned survival model with four health states: "Remission", "Non-remission", "Relapse/Progressive disease" and "Death". The model time horizon was 10 years. The perspective was the National Health Service and Personal Social Services. Costs and health effects were discounted at the rate of 3.5 % per year. The base-case incremental cost-effectiveness ratio (ICER) of azacitidine compared with the CCR was £20,648 per quality-adjusted life-year (QALY) gained. In the probabilistic sensitivity analysis, the mean ICER was £17,423 per QALY. At the willingness-to-pay of £20,000, £30,000 and £50,000 per QALY, the probability of azacitidine being cost effective was 0.699, 0.908 and 0.996, respectively. The ERG identified a number of errors in Celgene's model and concluded that the results of the company's economic evaluation could not be considered robust. After amendments to Celgene's model, the base-case ICER was £273,308 per QALY gained. In the probabilistic sensitivity analysis, the mean ICER was £277,123 per QALY. At a willingness-to-pay of £100,000 per QALY, the probability of azacitidine being cost effective was less than 5 %. In all exploratory analyses conducted by the ERG, the ICER exceeded the NICE's cost-effectiveness threshold range of £20,000-30,000 per QALY. Given the evidence provided in the submission, azacitidine did not fulfil NICE's end-of-life criteria. After considering the analyses performed by the ERG and submissions from clinician and patient experts, the NICE Appraisal Committee did not recommend azacitidine for this indication.

The impact of hypomethylating agents on the cost of care and survival of elderly patients with myelodysplastic syndromes.

During 2004-2006, two hypomethylating agents (HMAs) were approved for the treatment of myelodysplastic syndromes (MDS) in the United States. We assessed the impact of HMAs on the cost of care and survival of MDS patients, by constructing a cohort of patients who were diagnosed during 2001-2007 (n=6556, age ≥66.5 years) and comparable non-cancer controls. We assessed MDS patients' and controls' Medicare expenditures to derive MDS-related cost. We evaluated the two-year survival of patients as a group and by major subtypes. Taking into account the survival probabilities of MDS, the expected MDS-related 5-year cost was $63,223 (95% confidence interval: $59,868-66,432 in 2009 dollars), higher than the reported comparable cost for any of the 18 most prevalent cancers in the United States. Compared with MDS patients diagnosed in the earlier period (January 2001-June 2004) who received no HMAs, patients diagnosed later (July 2004-December 2007) who received HMAs had a significantly higher 24-month cost ($97,977 vs. $42,628 in 2009 dollars) and an improved 24-month survival (especially among patients with refractory anemia or refractory anemia with excess blasts). The magnitude of the cost of care underscores a need for comparative cost-effectiveness studies to reduce the clinical and economic burden of MDS.

[Cost-effectiveness analysis of azacitidine for myelodysplastic syndromes in Japan].

The aim of this study was to assess the cost-effectiveness of azacitidine therapy for patients with myelodysplastic syndromes. A Markov model was developed to estimate the total additional direct cost and quality adjusted life years (QALYs) gained with azacitidine therapy versus best-supportive care in patients with high-risk MDS. The cost-effectiveness of azacitidine was evaluated with incremental cost-effectiveness ratio, which represents the additional cost per QALY gained from the more effective treatment. Azacitidine therapy was 1.83 million yen more costly per patient but yielded an additional 0.353 QALYs. The ICER (Increment of Cost-effectiveness Ratio) was 5.18 million yen per QALY. In conclusion, because the ICER was less than the threshold for acceptable cost-effectiveness in Japan, azacitidine therapy for MDS patient was assumed to be cost-effective.

A cost-effectiveness analysis of using azacitidine vs. decitabine in treating patients with myelodysplastic syndromes.

OBJECTIVE: Azacitidine and decitabine are used to treat patients with myelodysplastic syndromes (MDS) in the United States (US). This study sought to assess their relative cost-effectiveness. DESIGN AND METHODS: The authors developed a cost-effectiveness Markov model (1-month cycles) tracking hypothetical cohorts of MDS patients treated with azacitidine or decitabine over 2 years. The model used a US payer perspective and 2009 costs. Health states modeled included MDS with Transfusion Dependence, MDS with Transfusion Independence, Progression to Acute Myelogenous Leukemia (AML), and Death. Incremental cost-effectiveness outcomes included cost per quality-adjusted life year (QALY), cost per life year (LY), cost per patient-month of transfusion independence, and cost per case of AML progression avoided. One-way sensitivity analyses were performed on key model parameters. RESULTS: Compared to decitabine, azacitidine was associated with better survival (1.512 LYs vs 1.292), more QALYs gained (1.041 vs 0.870), more patient-months with transfusion independence (8.328 vs 6.224), and a greater proportion of patients avoiding progression to AML (50.9% vs 28.5%). Total per-patient costs over 2 years for azacitidine were lower than for decitabine ($150,322 vs $166, 212). LIMITATIONS: To inform and update the model over time, it will be important that randomized or observational clinical studies be conducted to directly compare azacitidine and decitabine, provide new information on how these medicines are used, and on their relative clinical effectiveness. CONCLUSION: Results demonstrate that azacitidine provides greater clinical benefit and costs less than decitabine across all key outcomes. These results accentuate the positive role of azacitidine in providing cost-effective care for MDS.

Cautions regarding the fitting and interpretation of survival curves: examples from NICE single technology appraisals of drugs for cancer.

The UK National Institute for Health and Clinical Excellence (NICE) has used its Single Technology Appraisal (STA) programme to assess several drugs for cancer. Typically, the evidence submitted by the manufacturer comes from one short-term randomized controlled trial (RCT) demonstrating improvement in overall survival and/or in delay of disease progression, and these are the pre-eminent drivers of cost effectiveness. We draw attention to key issues encountered in assessing the quality and rigour of the manufacturers' modelling of overall survival and disease progression. Our examples are two recent STAs: sorafenib (Nexavar®) for advanced hepatocellular carcinoma, and azacitidine (Vidaza®) for higher-risk myelodysplastic syndromes (MDS). The choice of parametric model had a large effect on the predicted treatment-dependent survival gain. Logarithmic models (log-Normal and log-logistic) delivered double the survival advantage that was derived from Weibull models. Both submissions selected the logarithmic fits for their base-case economic analyses and justified selection solely on Akaike Information Criterion (AIC) scores. AIC scores in the azacitidine submission failed to match the choice of the log-logistic over Weibull or exponential models, and the modelled survival in the intervention arm lacked face validity. AIC scores for sorafenib models favoured log-Normal fits; however, since there is no statistical method for comparing AIC scores, and differences may be trivial, it is generally advised that the plausibility of competing models should be tested against external data and explored in diagnostic plots. Function fitting to observed data should not be a mechanical process validated by a single crude indicator (AIC). Projective models should show clear plausibility for the patients concerned and should be consistent with other published information. Multiple rather than single parametric functions should be explored and tested with diagnostic plots. When trials have survival curves with long tails exhibiting few events then the robustness of extrapolations using information in such tails should be tested.

Azacitidine for the treatment of myelodysplastic syndrome, chronic myelomonocytic leukaemia and acute myeloid leukaemia.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of azacitidine (aza) compared with conventional care regimes (CCR) for higher risk patients with myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia (AML), based on the evidence submission from the manufacturer to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The patient outcomes governing relative effectiveness and cost-effectiveness were defined as overall survival, time to progression (TTP) to AML, adverse events and health-related quality of life (HRQoL). The clinical evidence was derived from an open-label randomised controlled trial referred to as study AZA-001. It compared aza with CCR in 358 patients with higher risk MDS, CMML and AML 20-30% blasts. The outcomes reported in AZA-001 included overall survival, TTP to AML and adverse events. No HRQoL results were reported; however, outcomes likely to impact on HRQoL were provided. The results showed that: the median overall survival was 24.5 months on aza, compared with 15.0 months in the CCR group (p = 0.0001); the response rates were low (complete remission 17% aza versus 8% CCR); the median time to transformation to AML was greater in the aza group (17.8 versus 11.5 months; p < 0.0001); and of patients who were red blood cell (RBC) transfusion-dependent at baseline, 45% of those on aza became RBC transfusion-independent during the treatment period, compared with 11.8% in the CCR group (p < 0.0001). The ERG reran the submission's search strategies after some modifications incorporating minor improvements. The ERG analysed the submitted economic model (model 1) and identified a number of inconsistencies and errors within the model. The manufacturer submitted a revised model for analysis by the ERG. Using the issues identified in the earlier analysis, the ERG conducted those repairs to the revised model that were feasible within time constraints. The ERG ran this version in probabilistic sensitivity analyses to generate cost-effectiveness acceptability frontiers. The results of these exploratory analyses indicated that: for standard-dose chemotherapy (SDC)-treated patients, of six treatment options available, best supportive care (BSC) was likely the most cost-effective option up to a threshold of 51,000 pounds/quality-adjusted life-year (QALY) [beyond 51,000 pounds/QALY, aza + low-dose chemotherapy (LDC) became cost-effective]; for LDC-treated patients, of four options available, BSC was again the most cost-effective option up to a willingness-to-pay threshold of 51,000 pounds/QALY (aza + LDC became cost-effective after 51,000 pounds/QALY); for BSC-treated patients, aza + BSC became cost-effective relative to BSC at a threshold of about 52,000 pounds/QALY. The ERG considers these results exploratory and considers that they should be viewed with caution. The AZA-001 study showed that, compared with CCR, those MDS patients receiving aza had prolonged median survival, had delayed progression to AML, had reduced dependence on transfusions and had a small improvement in response rate. Given the general paucity of economic modelling work in MDS and the limitations of the submitted industry model there is an evident need for an independent cost-effectiveness analysis of aza in MDS. At the time of writing, the guidance appraisal consultation document issued by NICE on 4 March 2010 states that azacitidine is not recommended as a treatment option for people not eligible for haemopoietic stem cell transplantation with the the following conditions: intermediate-2 and high-risk MDS according to the International Prognostic Scoring System, CMML with 10-29% marrow blasts without myeloproliferative disorder, or with AML with 20-30% blasts and multilineage dysplasia, according to World Health Organization classification.

Economic analysis of decitabine versus best supportive care in the treatment of intermediate- and high-risk myelodysplastic syndromes from a US payer perspective.

BACKGROUND: Myelodysplastic syndromes (MDS) are blood and bone marrow disorders that occur primarily in the elderly population, with 30% of all cases progressing to acute myeloid leukemia (AML). Red blood cell transfusions--a conventional treatment of MDS--have been associated with high costs and decreased quality of life compared with transfusion independence. Phase III clinical trial data suggest that decitabine may offer an improved AML-free survival versus best supportive care (BSC), which consists of red blood cell transfusions, deferoxamine, erythropoiesis-stimulating agents, platelet transfusions, and colony-stimulating factors. The US Food and Drug Administration has approved a 5-day outpatient decitabine dosing regimen, which might reduce administration costs compared with the standard 3-day inpatient regimen. OBJECTIVE: The aim of this study was to assess the cost-effectiveness of 5-day dosing of decitabine versus BSC in US patients with intermediate- and high-risk MDS from a US payer perspective. METHODS: A Markov model with 3 health states (MDS, AML, and death) was constructed to simulate natural disease progression. The model followed patients in 4-week cycles for ≤ 5 years. Clinical inputs and patient characteristics were based on decitabine Phase III clinical trial data. Costs of supportive care and adverse events were based on trial resource utilization data. Drug and AML costs were obtained from published sources. Deterministic and probabilistic sensitivity analyses were performed to determine the impact of model parameters on results. RESULTS: In the base-case model, decitabine yielded 0.276 additional year of AML-free survival and 0.052 more quality-adjusted life-year (QALY) compared with BSC. Total decitabine and administration costs over the 5-year time horizon were $28,933. Total direct medical costs were $122,940 in the decitabine arm and $122,666 in the BSC arm. The incremental cost-effectiveness ratio for decitabine versus BSC was $5277 per QALY gained. Sensitivity analyses indicated that decitabine had a higher probability than BSC of being cost-effective despite the uncertainty around some model parameters, including survival. CONCLUSION: In this study, decitabine administered on a 5-day dosing schedule was likely a cost-effective treatment option in patients with intermediate- and high-risk MDS from a US payer perspective.

Myelodysplastic syndromes: health care management considerations.

Costs associated with treating cancers such as MDS are increasing as new medicines are developed and combination regimens gain hold. This trend presents an important challenge to MCOs who must respond to changing protocols and rising costs. Whereas the new oncology medications offer a unique opportunity to improve outcomes in patients with MDS, they also demand high financial outlay, which in turn necessitates adjustments in benefits programs. As payers look to manage expenses in ways that satisfy all stakeholders, increasing importance is placed on scientific evidence, survival and QoL benefits, tolerability factors, and evidence-based standards of care. In the treatment of higher-risk MDS, this means weighing those differences between the two hypomethylating agents approved for this indication--azacitidine and decitabine--in terms of proven effectiveness, safe delivery, and survival gains validated in clinical trials as well as potentially reduced costs related to administration method and fewer treatment-related toxicities. The future of MDS treatment in the managed care setting will require complex decision making to determine new treatment guidelines, benefit design, reimbursement plans, ethical considerations, and formulary development. Economic and clinical strategies must aim to make optimal use of novel treatment approaches while meeting the financial objectives of MCOs. The goal is improved patient outcomes at reasonable cost, a challenge that will be addressed only with continued discussion and study. The therapies azacitidine and decitabine may offer a good model for decision making to drive best treatment for MDS while moderating cost.

The costs of drugs used to treat myelodysplastic syndromes following National Comprehensive Cancer Network Guidelines.

Guidelines for management of patients with myelodysplastic syndromes (MDS) have been generated by the National Comprehensive Cancer Network (NCCN) Myelodysplastic Syndromes Panel. Because MDS is a heterogeneous spectrum of disorders, these patients have been categorized into prognostic subgroups, predominantly using the International Prognostic Scoring System (IPSS). Several drugs have been used to treat these patients, and their selection and sequential recommended use by the panel depend on disease characteristics and responses to treatment. Recombinant erythropoietin alfa and darbepoetin alfa have been the mainstay of therapy for treating anemia associated with MDS. The FDA has recently approved several other drugs for treating MDS, including azacytidine and decitabine for all stages of disease, lenalidomide for low-risk anemic patients with del(5q) chromosomal abnormality, and deferasirox for treating iron overload. For iron chelation, deferoxamine is also used occasionally. Treatment with immunosuppressive therapy (antithymocyte globulin and cyclosporin) has been therapeutically beneficial for a subset of younger patients with MDS. Because the financial cost of these therapies are substantial and have received only limited attention, this article evaluates the costs of specific drugs and their sequential use in the lower-risk IPSS (low and intermediate-1) subgroups based on the NCCN guidelines. Results estimate an average annual cost for potentially anemia-altering drugs of $63,577 per patient, ranging from $26,000 to $95,000, depending on the specific therapies. In patients for whom the therapies fail, annual costs for iron chelation plus red blood cell transfusions are estimated to average $41,412. The economic impact of drug therapy should be weighed against the patient's potential for improvement in clinical outcomes, quality of life, and transfusion requirements.

Phase II trial and cost analysis of fazarabine in advanced non-small cell carcinoma of the lung: a Southwest Oncology Group study.

BACKGROUND: Fazarabine is a novel nucleoside with broad spectrum pre-clinical activity and was chosen for study in patients with incurable non-small cell carcinoma of the lung. The expenses associated with investigational treatment have been assumed to be more than what would occur with conventional therapy, however, data are limited. METHODS: Twenty-three patients with metastatic non-small cell lung cancer were treated with fazarabine. Fazarabine was administered as a 72 hour continuous infusion at 2.0 mg/M2/hour. A cost analysis of treatment was calculated for patients treated in Springfield, MO. RESULTS: There were no responses (0%, 95% confidence interval = 0-15%) and median survival was 8 months. An analysis of the cost of treatment in the 4 patients treated in Springfield, MO, was compared to the costs of treatment with 4 cycles of cisplatinum and etoposide. There were no significant differences in costs for patients treated with the investigational agent as compared with conventional chemotherapy. CONCLUSIONS: Fazarabine has no demonstrable activity in patients with metastatic non-small cell carcinoma of the lung. Treatment with this agent in an investigational setting was no more expensive than treatment with conventional chemotherapy.