Access to expensive cancer drugs in Dutch daily practice: should we be concerned?

BACKGROUND: To investigate whether equal access to bortezomib has been achieved under the Dutch policy regulations that guarantee equal access to expensive inpatient drugs. METHODS: We investigated accessibility to bortezomib treatment at national and regional levels by (i) conducting interviews with stakeholders in the Dutch healthcare system to explore prescription barriers and (ii) tabulating sales data from 2004-2009 and trial participation rates. RESULTS: Interviews revealed awareness of the high treatment costs, although prescription barriers were not encountered. National use of bortezomib increased slowly (treating 2% of patients in 2004 to 17% in 2009), indicating a long adjustment period. Furthermore, use remains below the rate estimated by the professional association of haematologists (27%). Regional differences were found for both daily practice use (e.g. ranging from 13-27% in 2009) and clinical trial participation (e.g. ranging from 1-12% in 2006). CONCLUSION: Our results were somewhat conflicting: interviews did not reveal any prescription barriers, but quantitative methods showed regional differences, signs of underutilisation, and access inequality. Investigating use and accessibility, based on data triangulation, provides valuable feedback which can enhance evidence-based decision making for both physicians and policymakers. This could improve appropriate and efficient use and ensure equal access to expensive drugs.

Policymaker, please consider your needs carefully: does outcomes research in relapsed or refractory multiple myeloma reduce policymaker uncertainty regarding value for money of bortezomib?

INTRODUCTION: Dutch policy regulations require outcomes research for the assessment of appropriate drug use and cost-effectiveness after 4 years of temporary reimbursement. We investigated whether outcomes research reduced policymaker uncertainty regarding the question whether the costs are worth public funding. METHODS: Our cohort study included 139 patients with relapsed/refractory multiple myeloma who were treated outside of a clinical study; 72 received bortezomib and 67 did not receive bortezomib. Detailed data were retrospectively collected from medical records in 38% of Dutch hospitals. RESULTS: All patients received second-line treatment; 65%, 40%, and 14%, received three, four, or five or more lines of therapy. Neither a specific treatment sequence nor an appropriate comparator could be identified because of large variation in regimes. Kaplan-Meier curves showed an increased overall survival (mean [median] 29.5 [33.2] vs. 28.0 [21.6] months) for patients treated with bortezomib (Wilcoxon P = 0.01). Total mean costs were €81,626 (range €17,793-€229,783) and €52,760 (range €748-€179,571) for patients receiving bortezomib and patients not receiving bortezomib, respectively. Patients treated with bortezomib, however, were not comparable to other patients despite attempts to correct for confounding. Therefore, it was impossible to develop a feasible model to obtain a valid incremental cost-effectiveness estimate. CONCLUSIONS: It was possible to develop evidence on bortezomib's use, effects, and costs in everyday practice. Much uncertainty, however, remained regarding its cost-effectiveness. Policymakers should carefully consider whether outcomes research sufficiently decreases uncertainty or whether other options (e.g., finance- and/or outcomes-based risk-sharing arrangements) are more appropriate to ensure sufficient value for money of expensive drugs.

Comparative cost-effectiveness models for the treatment of multiple myeloma.

OBJECTIVES: To compare cost effectiveness models for the first-line treatment of multiple myeloma, and explore the differences between the models' structure, parameters, assumptions and results. METHODS: Three cost effectiveness models for the treatment of multiple myeloma, were compared that had been developed to inform resource allocation in the UK for the chemotherapy regimens bortezomib, melphalan and prednisolone (BMP); and melphalan, prednisolone and thalidomide (MPT) versus melphalan and prednisolone (MP). The models used alternative approaches and assumptions to estimate the overall survival and progression-free survival for each of the interventions. Through the use of sensitivity analyses, the most influential parameters and assumptions of each of the models were identified. RESULTS: The models developed by the manufacturers gave conflicting results, with each manufacturer favouring their drug. The differences between the model results were determined by two parameters: the hazard ratio for overall survival for MPT vs. MP and the cost of bortezomib. CONCLUSIONS: Using models developed for assessing treatments for multiple myeloma we demonstrated that it was feasible to compare models, which then aided decision makers in making reimbursement decisions.

Peripheral blood stem cell mobilization in multiple myeloma patients treat in the novel therapy-era with plerixafor and G-CSF has superior efficacy but significantly higher costs compared to mobilization with low-dose cyclophosphamide and G-CSF.

Studies comparing the efficacy and cost of peripheral blood stem and progenitor cells mobilization with low-dose cyclophosphamide (LD-CY) and granulocyte-colony stimulating factor (G-CSF) against plerixafor and G-CSF, in multiple myeloma (MM) patients treated in the novel therapy-era are not available. Herein, we report mobilization outcomes of 107 patients who underwent transplantation within 1-year of starting induction chemotherapy with novel agents. Patients undergoing mobilization with LD-CY (1.5 gm/m(2)) and G-CSF (n = 74) were compared against patients receiving plerixafor and G-CSF (n = 33). Compared to plerixafor, LD-CY was associated with a significantly lower median peak peripheral blood CD34+ cell count (68/µL vs. 36/µL, P = 0.048), and lower CD34+ cell yield on day 1 of collection (6.9 × 10(6)/kg vs. 2.4 × 10(6)/kg, P = 0.001). Six patients (8.1%) in the LD-CY group experienced mobilization failure, compared to none in the plerixafor group. The total CD34+ cell yield was significantly higher in the plerixafor group (median 11.6 × 10(6)/kg vs. 7 × 10(6)/kg; P-value = 0.001). Mobilization with LD-CY was associated with increased (albeit statistically non-significant) episodes of febrile neutropenia (5.4% vs. 0%; P = 0.24), higher use of intravenous antibiotics (6.7% vs. 3%; P = 0.45), and need for hospitalizations (9.4% vs. 3%; P = 0.24). The average total cost of mobilization in the plerixafor group was significantly higher compared to the LD-CY group ($28,980 vs. $19,626.5 P-value < 0.0001). In conclusion, in MM plerixafor-based mobilization has superior efficacy, but significantly higher mobilization costs compared to LD-CY mobilization. Our data caution against the use of LD-CY in MM patients for mobilization, especially after induction with lenalidomide-containing regimens.

Total cost comparison in relapsed/refractory multiple myeloma.

OBJECTIVES: Advances in survival in multiple myeloma have focused payer attention on the cost of care. An assessment was conducted to compare the costs of two recent treatments for relapsed/refractory multiple myeloma (rrMM), from the perspective of a US payer. METHODS: An economic model estimated the total costs of care for two guideline-recommended therapies in rrMM patients: bortezomib (BORT) and lenalidomide plus dexamethasone (LEN/DEX). To evaluate total treatment costs, the costs associated with drug treatment, medical resource utilization, and adverse event (AE) management were determined for each regimen over a common 1-year period. Medical costs and grade 3/4 AE costs were based on rates from published literature, package inserts, and fee schedules (US dollars). To evaluate cost per outcome, assessments determined the monthly costs without disease progression based on pivotal clinical trials (APEX [BORT] and MM-009/MM-010 [LEN/DEX]). Univariate sensitivity analyses and alternative scenarios were also conducted. RESULTS: Drug costs for the treatments were very similar, differing by under $10 per day. Medical and AE management costs for BORT were higher by more than $40 per day. Treatment with BORT had annual excess total costs of >$17,000 compared with LEN/DEX. A cost advantage for LEN/DEX was maintained across a variety of sensitivity analyses. Total cost per month without progression was 11% lower with LEN/DEX. LIMITATIONS: This analysis relied on separate studies having similar comparators, populations, and end-points. Actual treatment patterns and costs pre- and post-relapse may vary from the base scenario and sensitivities modeled. The 12-month time frame captures the preponderance of costs for a relapse line of therapy, yet may not reflect the entirety of costs. There is insufficient evidence to determine whether, or how, a difference in the lifetime costs of the two regimens would vary from the 1-year cost difference. CONCLUSION: While rrMM treatment with BORT and LEN/DEX had comparable drug costs, total treatment costs for BORT were higher due to ongoing direct medical and AE management costs. Total costs per outcome (a month without disease progression) were lower for LEN/DEX.

The clinical effectiveness and cost-effectiveness of bortezomib and thalidomide in combination regimens with an alkylating agent and a corticosteroid for the first-line treatment of multiple myeloma: a systematic review and economic evaluation.

BACKGROUND: Multiple myeloma (MM) is the second most common haematological cancer in the UK. MM is not curable but can be treated with a combination of supportive measures and chemotherapy that aim to extend the duration and quality of survival. The majority of patients are not able to withstand intensive treatment, such as high-dose chemotherapy with autologous stem cell transplantation (SCT), and so they are offered single-agent or combination chemotherapy. Combination therapies typically include chemotherapy with an alkylating agent and a corticosteroid. More recently, combination therapies have incorporated drugs such as thalidomide (Thalidomide Celgene®, Celgene) and bortezomib (Velcade®, Janssen-Cilag). OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of bortezomib or thalidomide in combination chemotherapy regimens with an alkylating agent and a corticosteroid for the first-line treatment of MM. DATA SOURCES: Electronic bibliographic databases, including MEDLINE, EMBASE and The Cochrane Library, were searched from 1999 to 2009 for English-language articles. Bibliographies of articles, grey literature sources and manufacturers' submissions were also searched. Experts in the field were asked to identify additional published and unpublished references. REVIEW METHODS: Titles and abstracts were screened for eligibility by two reviewers independently. The inclusion criteria specified in the protocol were applied to the full text of retrieved papers by one reviewer and checked independently by a second reviewer. Data extraction and quality assessment were undertaken by one reviewer and checked by a second reviewer. Differences in opinion were resolved through discussion at each stage. A cost-utility decision-analytic model was used to compare the cost-effectiveness estimates of bortezomib in combination with melphalan and prednisolone/prednisone (VMP), thalidomide in combination with cyclophosphamide and attenuated dexamethasone (CTDa), and thalidomide in combination with melphalan and prednisolone/prednisone (MPT) versus melphalan and prednisolone/prednisone (MP). RESULTS: A total of 1436 records were screened and 40 references were retrieved for the systematic review of clinical effectiveness. Five randomised controlled trials (RCTs) met the inclusion criteria for the review: one RCT evaluated VMP, three evaluated MPT and one evaluated CTDa. The comparator in all of the included trials was MP. The review found that VMP and MPT can both be considered more clinically effective than MP for the first-line treatment of MM in people for whom high-dose therapy and SCT would not be appropriate. CTDa was more effective than MP in terms of complete response but data on survival outcomes did not meet the inclusion criteria. Cost-effectiveness analysis indicated that MPT has a greater probability of being cost-effective than either VMP or CTDa. LIMITATIONS: For most RCTs, details needed to judge study quality were incompletely reported. All studies stated that the analyses followed intention-to-treat principles but none adequately reported data censoring. Only one RCT contributed data on VMP and the published peer-reviewed follow-up data were immature. For MPT, overall survival data from two trials were eligible for inclusion but the doses of thalidomide differed between the trials and the treatment period was not reflective of current UK practice so the generalisability of the findings was uncertain. Two RCTs had a maintenance phase with thalidomide that did not meet the inclusion criteria so some of these results were not eligible for the review. Limited evidence on health-related quality of life (HRQoL) was provided by the single trial of VMP versus MP. CONCLUSIONS: Service provision is unlikely to change greatly. As uncertainties remain, further research is needed regarding the use of bortezomib- and thalidomide-containing combination regimens. Head-to-head trials of bortezomib- and thalidomide-containing combination regimes are required, including assessments of patient HRQoL in response to treatment. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Cost-effectiveness of novel relapsed-refractory multiple myeloma therapies in Norway: lenalidomide plus dexamethasone vs bortezomib.

OBJECTIVE: To estimate the cost-effectiveness (cost per additional life-year [LY] and quality-adjusted life-year [QALY] gained) of lenalidomide plus dexamethasone (LEN/DEX) compared with bortezomib for the treatment of relapsed-refractory multiple myeloma (rrMM) in Norway. METHODS: A discrete-event simulation model was developed to predict patients? disease course using patient data, best response, and efficacy levels obtained from LEN/DEX MM-009/-010 trials and the bortezomib (APEX) published clinical trial. Predictive equations for time-to-progression (TTP) and post-progression survival (PPS) were developed by identifying the best fitting parametric survival distributions and selecting the most significant predictors. Disease and adverse event management was obtained via survey from Norwegian experts. Costs, derived from official Norwegian pricing data bases, included drug, administration, monitoring, and adverse event management costs. RESULTS: Complete or partial responders were 65% for LEN/DEX compared to 43% for bortezomib. Derived median TTP was 11.45 months for LEN/DEX compared to 5.15 months for bortezomib. LYs and QALYs were higher for LEN/DEX (4.06 and 2.95, respectively) than for bortezomib (3.11 and 2.19, respectively). The incremental costs per QALY and LY gained from LEN/DEX were NOK 247,978 and NOK 198,714, respectively, compared to bortezomib. Multiple sensitivity analyses indicated the findings were stable. The parameters with the greatest impact were 4-year time horizon (NOK 441,457/QALY) and higher bound confidence intervals for PPS (NOK 118,392). LIMITATIONS: The model analyzed two therapies not compared in head-to-head trials, and predicted results using an equation incorporating patient-level characteristics. It is a limited estimation of the costs and outcomes in a Norwegian setting. CONCLUSIONS: The simulation model showed that treatment with LEN/DEX leads to greater LYs and QALYs when compared to bortezomib in the treatment of rrMM patients. The incremental cost-effectiveness ratio indicated treatment with LEN/DEX to be cost-effective and was the basis of the reimbursement approval of LEN/DEX in Norway.

Ideal vial size for bortezomib: real-world data on waste and cost reduction in treatment of multiple myeloma in Brazil.

OBJECTIVES: Single-size vials of drugs may be a source of waste and increase in treatment costs. Bortezomib, indicated for multiple myeloma (MM) treatment, is available in 3.5-mg vials, a quantity higher than the average dose commonly prescribed. This analysis aimed to demonstrate, through real-world data, which would be the optimal vial presentation for bortezomib in Brazil and quantify the reduction in medication waste related to this option. METHODS: From November 2007 to October 2009 all patients with MM treated with bortezomib were identified via the Evidências database. Analysis of prescribed, dispensed, and wasted doses, their costs and projections of the ideal vial size were performed. RESULTS: Thirty-five patients (mean body surface area of 1.73 m(2)) received 509 infusions in 131 cycles of treatment (average of 3.77 cycles per patient). The average dose prescribed was 2.1 mg per infusion (95% confidence interval [CI] 1.97-2.26) with average waste of 39.5% of the vial content (95% CI 35.35-43.76). The mean waste per patient per day was 1.38 mg (95% CI 1.24-1.52). If a 3-mg vial were available, the average drug waste per patient per day would be 0.88 mg (95% CI 0.74-1.03) or 36.2% less. With a 2.5-mg vial the waste would be 1.05 mg (95% CI 0.81-1.29) or 23.9% less. If two presentations were available (2.5 mg and 0.5 mg), the waste would be 0.52 mg (95% CI 0.4-0.63) or 62.5% less. Considering the price of the different vials to be proportional to the original 3.5-mg vial, the cost would be also reduced by the same rates described above. CONCLUSIONS: A simple adjustment in vial size may reduce the waste of bortezomib by 36% to 62% and can also reduce the cost of treatment.

The role of bortezomib, thalidomide and lenalidomide in the management of multiple myeloma: an overview of clinical and economic information.

Bortezomib, thalidomide and lenalidomide can be aimed at treating patients with newly diagnosed multiple myeloma (both eligible and ineligible for transplantation) as well as those with relapsed or refractory disease. This review analysed the available clinical and economic data on these three drugs. Irrespective of which of the three agents is considered, the magnitude of the benefit in newly diagnosed cases (transplanted or non-transplanted) tends to be between 10 and 20 months per patient in terms of progression-free survival or survival; the survival benefit is smaller in relapsed or refractory disease. In addition, a single-institution observational analysis evaluated the outcomes in nearly 3000 consecutive patients examined between 1971 and 2006. The survival in patients diagnosed between 2001 and 2006 was longer than that observed in patients diagnosed between 1994 and 2000. This finding supports the conclusion that novel agents provide a survival improvement compared with traditional therapy. Formal cost-effectiveness studies on these three agents are still lacking. A MEDLINE search retrieved only four short papers or letters and no full-length analysis. Hence, the cost effectiveness of these agents needs further investigation, with separate assessments of the different therapeutic settings. In a simplified analysis, we tried to contrast the average cost of treatment for each of the novel agents versus their respective benefit, expressed in quality-adjusted survival. Despite its preliminary nature, our assessment indicates that the cost effectiveness of these three agents is likely to be within commonly accepted pharmacoeconomic thresholds.

Management of relapsed or refractory multiple myeloma in French hospitals and estimation of associated direct costs: a multi-centre retrospective cohort study.

WHAT IS KNOWN AND BACKGROUND: For relapsed or refractory multiple myeloma (RRMM), a series of novel agents (thalidomide, bortezomib and lenalidomide) has emerged during the latest decade, but their use in routine clinical practice is not well documented as well as the cost of RRMM. OBJECTIVE: Our aim is to review the therapeutic management of such patients in France and to estimate the associated costs. METHODS: A retrospective cohort study, based on chart reviews, was conducted in French Haematology Departments over the period 2004-2007 and the associated direct costs estimated. RESULTS: One hundred and two patients with a relapse after first-line therapy were selected from five centres. The average follow-up from diagnosis or the date of first relapse to death or to the latest news was respectively 56.25 and 23.53 months. Novel agents were used in 73% of all cases, and in all cases of first relapse. Thalidomide and bortezomib were respectively the most frequently used second-line (57%) and third-line treatments (44%). The average number of lines of treatment received per patient as from first relapse was 2.75 (min 1; max 8) and the mean direct cost per month was estimated at 3130 € after the first relapse. This cost was represented in greater part by the cost of chemotherapy drugs (66%). WHAT IS NEW AND CONCLUSION: The use of novel agents such as thalidomide, bortezomib and lenalidomide for RRMM is highly prevalent in France from the first relapse. The associated medical cost is substantial mainly due to the cost of the new agents.

The cost-effectiveness of bortezomib in relapsed/refractory multiple myeloma: Swedish perspective.

OBJECTIVES: To estimate the cost-effectiveness of bortezomib (BTZ) compared with dexamethasone (DEX) and lenalidomide plus dexamethasone (LEN/DEX) for the treatment of relapsed/refractory multiple myeloma in Sweden. METHODS: We used partitioned survival analysis to assess survival data decomposed into three states: (i) alive before disease progression; (ii) alive after progression; and (iii) dead. The effects of treatment on time to progression and overall survival (OS) were obtained from published reports of the APEX, MM-009, and MM-010 randomized clinical trials. Costs included drug and administration costs, adverse events, treatment of relapses, and end-of-life costs. Utility estimates were derived from the literature. RESULTS: BTZ mean OS was 57.4 months compared with 44.6 and 54.1 months for DEX and LEN/DEX, respectively. Mean lifetime direct medical costs per patient were approximately 2010 SEK 1,904,462, 1,278,854, and 2,450,588 for BTZ, DEX, and LEN/DEX, respectively. Mean incremental cost per quality-adjusted life-year of BTZ compared to DEX was 2010 SEK 902,874 (€95,073) (95% CI: 514,791, 962,416) and was dominant with respect to LEN/DEX. CONCLUSION: BTZ and LEN/DEX are projected to prolong survival relative to DEX. From a Swedish perspective, BTZ is cost-effective compared to DEX and LEN/DEX.

Bortezomib for the treatment of multiple myeloma patients.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of bortezomib for the treatment of multiple myeloma patients at first relapse and beyond, in accordance with the licensed indication, based upon the evidence submission from Ortho Biotech to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The outcomes stated in the manufacturer's definition of the decision problem were time to disease progression, response rate, survival and quality of life. The literature searches for clinical and cost-effectiveness studies were adequate and the one randomised controlled trial (RCT) included was of reasonable quality. Results from the RCT suggest that bortezomib increases survival and time to disease progression compared with high-dose dexamethasone (HDD) in multiple myeloma patients who have had a relapse after one to three treatments. Cost-effectiveness analysis based on the same trial and an observational study was reasonable and gave an estimated cost per life-year gained of 30,750 pounds, which ranged from 27,957 pounds to 36,747 pounds on sensitivity analysis. An attempt was made to replicate the results of the manufacturer's model and to compare the results to the Kaplan-Meier survival curve presented in the manufacturer's submission. In addition, a one-way sensitivity analysis and a probabilistic sensitivity analysis were undertaken, as well as additional scenario analyses. Based on these analyses the ERG suggests that the cost-effectiveness results presented in the manufacturer's submission may underestimate the cost per life-year gained for bortezomib therapy (versus high-dose dexamethasone) when potential UK practice and scenarios are considered. The guidance issued by NICE in June 2006 as a result of the STA states that bortezomib monotherapy for the treatment of relapsed multiple myeloma is clinically effective compared with HDD but has not been shown to be cost-effective and is not recommended for the treatment of progressive multiple myeloma in patients who have received at least one previous therapy and who have undergone, or are unsuitable for, bone marrow transplantation.

Bortezomib: a novel chemotherapeutic agent for hematologic malignancies.

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, safety, dosage and administration, place in therapy, and cost of bortezomib in the treatment of multiple myeloma and mantle cell lymphoma are reviewed. SUMMARY: Bortezomib is a modified dipeptidyl boronic acid that disrupts essential intracellular pathways by inhibiting proteasomes. The drug is metabolized by cytochrome P-450 isoenzymes 3A4, 2C19, and 1A2 to four inactive metabolites. Bortezomib was initially developed for the treatment of multiple myeloma based on the findings of early in vitro studies of patients with multiple myeloma who received at least one prior course of treatment; the drug received approval for the treatment of mantle cell lymphoma based on a single, noncomparative, Phase II study of previously treated patients. Significant toxicities have been reported with the use of bortezomib, including peripheral neuropathy, neutropenia, and thrombocytopenia. The dosage of bortezomib recommended by the manufacturer is 1.3 mg/m(2) per dose administered as an i.v. bolus injection twice weekly on days 1, 4, 8, and 11 of a three-week cycle. It is not necessary to adjust the dosage of bortezomib in patients with renal impairment. Bortezomib is being investigated as a treatment for several other malignant conditions. The current wholesale price of bortezomib is $1,322.40 for a single-use vial containing 3.5 mg of bortezomib lyophilized powder, with one course of treatment costing approximately $27,500 in drug cost alone. CONCLUSION: Bortezomib, an antineoplastic agent that reversibly inhibits the 26S proteasome, offers an important treatment option for patients with multiple myeloma or mantle cell lymphoma.