Applying a cost-based pricing model for innovative cancer treatments subject to indication expansion: A case study for pembrolizumab and daratumumab.

BACKGROUND: Expanding the indication of already approved immuno-oncology drugs presents treatment opportunities for patients but also strains healthcare systems. Cost-based pricing models are discussed as a possibility for cost containment. This study focuses on two drugs, pembrolizumab (Keytruda) and daratumumab (Darzalex), to explore the potential effect of indication broadening on the estimated price when using the cost-based pricing (CBP) model proposed by Uyl-de Groot and Löwenberg (2018). METHODS: The model was used to calculate cumulative yearly prices, cumulative prices per indication, and non-cumulative indication-based prices using inputs such as research and development (R&D) costs, manufacturing costs, eligible patient population, and a profit margin. A deterministic stepwise analysis and scenario analysis were conducted to examine how sensitive the estimated price is to the different input assumptions. RESULTS: The yearly cumulative cost-based prices (CBPs) ranged from €52 to €885 for pembrolizumab per vial and €823 to €31,941 for daratumumab per vial. Prices were higher in initial years or indications due to smaller patient populations, decreased over time or after additional indications. Sensitivity analysis showed that the number of eligible patients had the most significant impact on the estimated price. In the scenario analysis the profit margin contributed most to a higher CBPs for both drugs. Lower estimates resulted from assumed lower R&D costs. DISCUSSION: The estimated CBPs are consistently lower than Dutch list prices for pembrolizumab (€2,861), mainly resulting from larger patient populations in registered indications. However, daratumumab's list prices fall within the range of modeled CBPs depending on the year or indication (€4,766). Both CBPs decrease over time or with additional indications. The number of eligible patients and initial R&D costs have the most significant influence on the CBPs. These findings contribute to the ongoing discussions on pharmaceutical pricing, especially concerning cancer drugs with expanding indications.

Trends in survival and costs in metastatic melanoma in the era of novel targeted and immunotherapeutic drugs.

BACKGROUND: The objective of this study was to evaluate trends in survival and health care costs in metastatic melanoma in the era of targeted and immunotherapeutic drugs. MATERIALS AND METHODS: Data on survival and health care resource use were retrieved from the Dutch Melanoma Treatment Registry. The Kaplan-Meier method was used to estimate overall survival. Health care costs and budget impact were computed by applying unit costs to individual patient resource use. All outcomes were stratified by year of diagnosis. RESULTS: Baseline characteristics were balanced across cohort years. The percentage of patients receiving systemic treatment increased from 73% in 2013 to 90% in 2018. Patients received on average 1.85 [standard deviation (SD): 1.14] lines of treatment and 41% of patients received at least two lines of treatment. Median survival increased from 11.8 months in 2013 [95% confidence interval (CI): 10.7-13.7 months] to 21.1 months in 2018 (95% CI: 18.2 months-not reached). Total mean costs were €100 330 (SD: €103 699); systemic treatments accounted for 84% of the total costs. Costs for patients who received systemic treatment [€118 905 (SD: €104 166)] remained reasonably stable over the years even after the introduction of additional (combination of) novel drugs. From mid-2013 to 2018, the total budget impact for all patients was €452.79 million. CONCLUSION: Our study shows a gain in survival in the era of novel targeted and immunotherapeutic drugs. These novel drugs came, however, along with substantial health care costs. Further insights into the cost-effectiveness of the novel drugs are crucial for ensuring value for money in the treatment of patients with metastatic melanoma.

Cost-effectiveness of adjuvant systemic therapies for patients with high-risk melanoma in Europe: a model-based economic evaluation.

BACKGROUND: The introduction of adjuvant systemic treatment has significantly improved recurrence-free survival in patients with resectable high-risk melanoma. Adjuvant treatment with immune checkpoint inhibitors and targeted therapy, however, substantially impacts health care budgets, while the number of patients with melanoma who are treated in the adjuvant setting is still increasing. To evaluate the socioeconomic impact of the three adjuvant treatments, a cost-effectiveness analysis (CEA) was carried out. MATERIALS AND METHODS: Data were obtained from the three pivotal registration phase III clinical trials on the adjuvant treatment of patients with resected high-risk stage III in melanoma (KEYNOTE-054, CheckMate 238, and COMBI-AD). For this CEA, a Markov model with three health states (no evidence of disease, recurrent/progressive disease, and death) was applied. From a societal perspective, different adjuvant strategies were compared according to total costs, life years (LYs), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios. To evaluate model uncertainty, sensitivity analyses (deterministic and probabilistic) were carried out. RESULTS: In the adjuvant setting, total costs (per patient) were €168 826 for nivolumab, €194 529 for pembrolizumab, and €211 110 for dabrafenib-trametinib. These costs were mainly determined by drug acquisition costs, whereas routine surveillance costs varied from €126 096 to €134 945. Compared with routine surveillance, LYs improved by approximately 1.41 for all therapies and QALYs improved by 2.02 for immune checkpoint inhibitors and 2.03 for targeted therapy. This resulted in incremental cost-effectiveness ratios of €21 153 (nivolumab), €33 878 (pembrolizumab), and €37 520 (dabrafenib-trametinib) per QALY gained. CONCLUSIONS: This CEA compared the three EMA-approved adjuvant systemic therapies for resected stage III melanoma. Adjuvant treatment with nivolumab was the most cost-effective, followed by pembrolizumab. Combination therapy with dabrafenib-trametinib was the least cost-effective. With the increasing number of patients with high-risk melanoma who will be treated with adjuvant treatment, there is an urgent need to reduce drug costs while developing better prognostic and predictive tools to identify patients who will benefit from adjuvant treatment.

An implantable device to treat multiple sclerosis: A discrete choice experiment on patient preferences in three European countries.

BACKGROUND: Persons with multiple sclerosis (MS) take their treatment via pills, injections or infusions. A novel mode of disease-modifying treatment administration, an implantable device, is under development. This study determined MS patient preferences for three modes of first-line treatment administration (implant, pills, injectables), and trade-offs regarding treatment characteristics. METHODS: A survey including a discrete choice experiment was conducted among MS patients in the Netherlands, France, and the United Kingdom. Respondents had to repeatedly choose between various treatment scenarios with four treatment characteristics: risk of relapse, reduction of disease progression, risk of side effects and mode of administration. Data was analysed using a panel latent class logit model. RESULTS: Based on the preferences of 753 MS patients (response rate 7%: 753/11202), two latent classes were identified (class probability of 74% vs 26%). Persons with relapsing-remitting MS and who administered medication via injections generally preferred any treatment over no treatment. Patients who could walk without an aid were more likely to prefer no treatment. Reducing disease progression was the most important treatment characteristic class 1. Mode of administration was the most important characteristic in class 2. Patients were willing to accept an increase in risk of relapse and disease progression to get their treatment via an implant rather than injections. Predicted uptake was the highest for the implant, followed by pills, injections, and no treatment. CONCLUSION: We found that a drug-delivery implant could be a potential addition to the MS treatment landscape: MS patients are willing to trade-off risk of relapse and disease progression for an implant, and predicted uptake for an implant is relatively high.

The effects of new life-prolonging drugs for metastatic castration-resistant prostate cancer (mCRPC) patients in a real-world population.

BACKGROUND: In 2004 docetaxel was the first life-prolonging drug (LPD) registered for metastatic castration-resistant prostate cancer (mCRPC) patients. Between 2011 and 2014 new LPDs for mCRPC (cabazitaxel, abiraterone, enzalutamide, and radium-223) were introduced in the Netherlands. The objective of this study is to assess the impact of the introduction of new LPDs on treatment patterns and overall survival (OS) over time. PATIENTS AND METHODS: CRPC patients diagnosed in the years 2010-2016 in the observational, retrospective CAPRI registry (20 hospitals) were included and followed up to 2018. Two subgroups were analyzed: treatment-naïve patients (subgroup 1, n = 3600) and post-docetaxel patients (subgroup 2, n = 1355). RESULTS: In both subgroups, the use of any LPD increased: from 57% (2010-2011) to 69% (2014-2015) in subgroup 1 and from 65% (2011-2012) to 79% (2015-2016) in subgroup 2. Chemotherapy as first mCRPC-treatment (i.e., docetaxel) and first post-docetaxel treatment (i.e., cabazitaxel or docetaxel rechallenge) decreased (46-29% and 20-9% in subgroup 1 and 2, respectively), while the use of androgen-receptor targeting treatments (ART) increased from 11% to 39% and 46% to 64% in subgroup 1 and 2, respectively. In subgroup 1, median OS (mOS) from diagnosis CRPC increased from 28.5 months to 31.0 months (p = 0.196). In subgroup 2, mOS from progression on docetaxel increased from 7.9 months to 12.5 months (p < 0.001). After multiple imputations of missing values, in multivariable cox-regression analysis with known prognostic parameters, the treatment period was independent significant for OS in subgroup 1 (2014-2015 vs. 2010-2011 with HR 0.749, p < 0.001) and subgroup 2 (2015-2016 vs. 2011-2012 with HR 0.811, p = 0.037). CONCLUSION: Since 2010, a larger proportion of mCRPC patients was treated with LPDs, which was related to an increased mOS.

The cost-effectiveness of dapagliflozin compared to DPP-4 inhibitors in the treatment of type 2 diabetes mellitus in the Netherlands.

AIM: When glycaemic control for people with type 2 diabetes is not achieved with metformin and sulfonylurea alone, adding another oral anti-diabetes drug, such as a sodium-glucose co-transporter 2 (SGLT2) or dipeptidyl peptidase-4 (DPP-4) inhibitor, is an alternative to starting insulin. The aim of this study is to determine the cost-effectiveness of dapagliflozin (an SGLT2 inhibitor) compared with DPP-4 inhibitors when added to metformin and sulfonylurea in people with type 2 diabetes in the Netherlands. METHODS: A cost-utility analysis is performed using the Cardiff diabetes model, a fixed-time increment stochastic simulation model informed by 'United Kingdom Prospective Diabetes Study 68' risk equations. The base-case analysis uses a 40-year time horizon, a Dutch societal perspective and differential discounting (4% for costs, 1.5% for effects). Inputs are obtained from the literature and Dutch price lists. Univariate and probabilistic sensitivity analysis are performed. RESULTS: Dapagliflozin is dominant compared with DPP-4 inhibitors, resulting in a €990 cost saving and a 0.28 quality-adjusted life year gain over 40 years. Cost savings are associated mainly with treatment costs and a reduced incidence of micro- and macrovascular complications, among others nephropathy, myocardial infarction and stroke. Results are robust to changes in input parameters. CONCLUSIONS: Dapagliflozin is a cost-saving alternative to DPP-4 inhibitors when added to metformin and sulfonylurea. The incidence of micro- and macrovascular complications is lower for people treated with dapagliflozin. Uncertainty around this outcome is low.

Patient needs and preferences in relapsing-remitting multiple sclerosis: A systematic review.

BACKGROUND: Considering the multiple treatments approved for multiple sclerosis (MS) by the Food and Drug Administration (FDA) and European Medicines Agency (EMA), determining a treatment strategy for patients with clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS) can be challenging. To date, an overview of the needs and preferences of patients at each treatment decision-making moment is lacking. Therefore, the aim of this systematic review is to examine the existing literature about the needs and preferences of patients with CIS and RRMS when making treatment decisions. METHODS: A systematic search was done using Embase, Medline, PsychINFO, Web of Science and Google Scholar. Eligibility criteria included whether the article described a study of adults with CIS/RRMS and reported patient needs or preferences regarding first-line disease modifying treatment (DMT) decisions. Publications were categorized by treatment decision: initiation of first DMT (D1), DMT adherence/discontinuation (D2a/D2b), and switch to a second DMT (D3). A separate category was created for stated preference studies such as discrete choice experiment methods to examine the relative importance of different treatment attributes. Publications were compared to identify key factors. RESULTS: The search yielded 2789 articles after removal of duplicates and 434 full-text publications were reviewed for eligibility. Twenty-four articles fulfilled all criteria: n = 5 (D1), n = 12 (D2a), n = 13 (D2b), and n = 3 (D3); six articles studied more than one treatment decision. The need for social support is important during D1. The most commonly reported reasons for adherence/discontinuation/switch included forgetfulness, side-effects, and injection-related reasons. Eight articles described preference studies; the most important DMT attributes were efficacy, mode and frequency of administration, and side-effect profile. CONCLUSIONS: Understanding the needs and preferences of CIS/RRMS patients regarding DMT attributes and non-treatment related attributes are important to improve treatment decision-making and reduce non-adherence. Studies are needed to understand patient preferences upon treatment initiation. Furthermore, preference studies should include attributes based on the patient perspective.

Selecting the optimal position of CDK4/6 inhibitors in hormone receptor-positive advanced breast cancer - the SONIA study: study protocol for a randomized controlled trial.

BACKGROUND: Combining cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors with endocrine therapy is an effective strategy to improve progression-free survival in hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. There is a lack of comparative data to help clinicians decide if CDK4/6 inhibitors can best be added to first- or second-line endocrine therapy. Improvement in median progression-free survival in first-line studies is larger than in second-line studies, but CDK4/6 inhibitors have not consistently shown to improve overall survival or quality of life. They do come with added toxicity and costs, and many patients have lasting disease remission on endocrine therapy alone. No subgroup has been identified to select patients who are most likely to benefit from the addition of CDK4/6 inhibition in any line of treatment. Altogether, these factors make that the optimal strategy for using CDK4/6 inhibitors in clinical practice is unknown. METHODS: The SONIA study is an investigator-initiated, multicenter, randomized phase III study in patients with HR+/HER2-negative advanced breast cancer. Patients are randomly assigned to receive either strategy A (first-line treatment with a non-steroidal aromatase inhibitor combined with CDK4/6 inhibition, followed on progression by fulvestrant) or strategy B (first-line treatment with a non-steroidal aromatase inhibitor, followed on progression by fulvestrant combined with CDK4/6 inhibition). The primary objective is to test whether strategy A is more effective than strategy B. The primary endpoint is time from randomization to second objective progression (PFS2). Secondary endpoints include overall survival, safety, quality of life, and cost-effectiveness. Five-hundred seventy-four events yield 89% power to show that strategy A has statistically significant, clinically meaningful superior PFS2 (according to ESMO-MCBS) in a log-rank test at the two-sided 95% confidence level. Given an accrual period of 42 months and an additional 18 months follow-up, inclusion of 1050 evaluable patients is required. DISCUSSION: This study design represents daily clinical practice, and the results will aid clinicians in deciding when adding CDK4/6 inhibitors to endocrine therapy will benefit their patients most. Additional biomarker analyses may help to optimize patient selection. TRIAL REGISTRATION: http://clinicaltrials.gov: NCT03425838 (8 February 2018). EudraCT-number: 2017-002334-23 (29 September 2017).

Health-related quality of life and its determinants in patients with metastatic renal cell carcinoma.

PURPOSE: Based on improvements of progression-free survival (PFS), new agents for metastatic renal cell carcinoma (mRCC) have been approved. It is assumed that one of the benefits is a delay in health-related quality of life (HRQoL) deterioration as a result of a delay in progression of disease. However, little data are available supporting this relationship. This study aims to provide insight into the most important determinants of HRQoL (including progression of disease) of patients with mRCC. METHODS: A patient registry (PERCEPTION) was created to evaluate treatment of patients with (m)RCC in the Netherlands. HRQoL was measured, using the EORTC QLQ-C30 and EQ-5D-5L, every 3 months in the first year of participation in the study, and every 6 months in the second year. Participation started as soon as possible following a diagnosis of (m)RCC. Random effects models were used to study associations between HRQoL and patient and disease characteristics, symptoms and treatment. RESULTS: Eighty-seven patients with mRCC completed 304 questionnaires. The average EORTC QLQ-C30 global health status was 69 (SD, 19) before progression and 61 (SD, 22) after progression of disease. Similarly, the average EQ-5D utility was 0.75 (SD, 0.19) before progression and 0.66 (SD, 0.30) after progression of disease. The presence of fatigue, pain, dyspnoea, and the application of radiotherapy were associated with significantly lower EQ-5D utilities. CONCLUSIONS: Key drivers for reduced HRQoL in mRCC are disease symptoms. Since symptoms increase with progression of disease, targeted therapies that increase PFS are expected to postpone reductions in HRQoL in mRCC.

Treatment of sporadic Burkitt lymphoma in adults, a retrospective comparison of four treatment regimens.

Burkitt lymphoma is an aggressive B cell malignancy accounting for 1-2% of all adult lymphomas. Treatment with dose-intensive, multi-agent chemotherapy is effective but associated with considerable toxicity. In this observational study, we compared real-world efficacy, toxicity, and costs of four frequently employed treatment strategies for Burkitt lymphoma: the Lymphome Malins B (LMB), the Berlin-Frankfurt-Münster (BFM), the HOVON, and the CODOX-M/IVAC regimens. We collected data from 147 adult patients treated in eight referral centers. Following central pathology assessment, 105 of these cases were accepted as Burkitt lymphoma, resulting in the following treatment groups: LMB 36 patients, BFM 19 patients, HOVON 29 patients, and CODOX-M/IVAC 21 patients (median age 39 years, range 14-74; mean duration of follow-up 47 months). There was no significant difference between age, sex ratio, disease stage, or percentage HIV-positive patients between the treatment groups. Five-year progression-free survival (69%, p = 0.966) and 5-year overall survival (69%, p = 0.981) were comparable for all treatment groups. Treatment-related toxicity was also comparable with only hepatotoxicity seen more frequently in the CODOX/M-IVAC group (p = 0.004). Costs were determined by the number of rituximab gifts and the number of inpatients days. Overall, CODOX-M/IVAC had the most beneficial profile with regards to costs, treatment duration, and percentage of patients completing planned treatment. We conclude that the four treatment protocols for Burkitt lymphoma yield nearly identical results with regards to efficacy and safety but differ in treatment duration and costs. These differences may help guide future choice of treatment.

Developing a decision tool to identify patients with personality disorders in need of highly specialized care.

BACKGROUND: Current guidelines recommend referral to highly specialized care for patients with severe personality disorders. However, criteria for allocation to highly specialized care are not clearly defined. The aim of the present study was to develop a decision tool that can support clinicians to identify patients with a personality disorder in need of highly specialized care. METHODS: Steps taken to develop a decision tool were a literature search, concept mapping, a meeting with experts and a validation study. RESULTS: The concept mapping method resulted in six criteria for the decision tool. The model used in concept mapping provided a good fit (stress value = 0.30) and reasonable reliability (ρ = 0.49). The bridging values were low, indicating homogeneity. The decision tool was subsequently validated by enrolling 368 patients from seven centers. A multilevel model with a Receiver Operating Characteristic Curve (ROC) was applied. In this way, an easily implementable decision tool with relatively high sensitivity (0.74) and specificity (0.69) was developed. CONCLUSIONS: A decision tool to identify patients with personality disorders for highly specialized care was developed using advanced methods to combine the input of experts with currently available scientific knowledge. The tool appeared to be able to accurately identify this group of patients. Clinicians can use this decision tool to identify patients who are in need of highly specialized treatment.

Potential health gains for patients with metastatic renal cell carcinoma in daily clinical practice: A real-world cost-effectiveness analysis of sequential first- and second-line treatments.

INTRODUCTION: Randomised controlled trials have shown that targeted therapies like sunitinib are effective in metastatic renal cell carcinoma (mRCC). Little is known about the current use of these therapies, and their associated costs and effects in daily clinical practice. We estimated the real-world cost-effectiveness of different treatment strategies comprising one or more sequentially administered drugs. METHODS: Analyses were performed using patient-level data from a Dutch population-based registry including patients diagnosed with primary mRCC from January 2008 to December 2010 (i.e., treated between 2008 and 2013). The full disease course of these patients was estimated using a patient-level simulation model based on regression analyses of the registry data. A healthcare sector perspective was adopted; total costs included healthcare costs related to mRCC. Cost-effectiveness was expressed in cost per life-year and cost per quality-adjusted life-year (QALY) gained. Probabilistic sensitivity analysis was conducted to estimate the overall uncertainty surrounding cost-effectiveness. RESULTS: In current daily practice, 54% (336/621) of all patients was treated with targeted therapies. Most patients (84%; 282/336) received sunitinib as first-line therapy. Of the patients receiving first-line therapy, 30% (101/336) also received second-line therapy; the majority was treated with everolimus (40%, 40/101) or sorafenib (28%, 28/101). Current treatment practice (including patients not receiving targeted therapy) led to 0.807 QALYs; mean costs were €58,912. This resulted in an additional €105,011 per QALY gained compared to not using targeted therapy at all. Forty-six percent of all patients received no targeted therapy; of these patients, 24% (69/285) was eligible for sunitinib. If these patients were treated with first-line sunitinib, mean QALYs would improve by 0.062-0.076 (where the range reflects the choice of second-line therapy). This improvement is completely driven by the health gain seen amongst patients eligible to receive sunitinib but did not receive it, who gain 0.558-0.684 QALYs from sunitinib. Since additional costs would be €7,072-9,913, incremental costs per QALY gained are €93,107-111,972 compared to current practice. DISCUSSION: Health can be gained if more treatment-eligible patients receive targeted therapies. Moreover, it will be just as cost-effective to treat these patients with sunitinib as current treatment practice.

Cost-effectiveness of capecitabine and bevacizumab maintenance treatment after first-line induction treatment in metastatic colorectal cancer.

AIM: Capecitabine and bevacizumab (CAP-B) maintenance therapy has shown to be more effective compared with observation in metastatic colorectal cancer patients achieving stable disease or better after six cycles of first-line capecitabine, oxaliplatin, bevacizumab treatment in terms of progression-free survival. We evaluated the cost-effectiveness of CAP-B maintenance treatment. METHODS: Decision analysis with Markov modelling to evaluate the cost-effectiveness of CAP-B maintenance compared with observation was performed based on CAIRO3 study results (n = 558). An additional analysis was performed in patients with complete or partial response. The primary outcomes were the incremental cost-effectiveness ratio (ICER) defined as the additional cost per life year (LY) and quality-adjusted life years (QALY) gained, calculated from EQ-5D questionnaires and literature and LYs gained. Univariable sensitivity analysis was performed to assess the influence of input parameters on the ICER, and a probabilistic sensitivity analysis represents uncertainty in model parameters. RESULTS: CAP-B maintenance compared with observation resulted in 0.21 QALYs (0.18LYs) gained at a mean cost increase of €36,845, yielding an ICER of €175,452 per QALY (€204,694 per LY). Varying the difference in health-related quality of life between CAP-B maintenance and observation influenced the ICER most. For patients achieving complete or partial response on capecitabine, oxaliplatin, bevacizumab induction treatment, an ICER of €149,300 per QALY was calculated. CONCLUSION: CAP-B maintenance results in improved health outcomes measured in QALYs and LYs compared with observation, but also in a relevant increase in costs. Despite the fact that there is no consensus on cost-effectiveness thresholds in cancer treatment, CAP-B maintenance may not be considered cost-effective.

Variation in use of targeted therapies for metastatic renal cell carcinoma: Results from a Dutch population-based registry.

BACKGROUND: For patients with metastatic renal cell carcinoma (mRCC), targeted therapies have entered the market since 2006. The aims of this study were to evaluate the uptake and use of targeted therapies for mRCC in The Netherlands, examine factors associated with the prescription of targeted therapies in daily clinical practice and study their effectiveness in terms of overall survival (OS). METHODS: Two cohorts from PERCEPTION, a population-based registry of mRCC patients, were used: a 2008-2010 Cohort (n = 645) and a 2011-2013 Cohort (n = 233). Chi-squared tests for trend were used to study time trends in the use of targeted therapy. Patients were grouped based on the eligibility criteria of the SUTENT trial, the trial that led to sunitinib becoming standard of care, to investigate the use of targeted therapies amongst patients fulfilling those criteria. Multi-level logistic regression was used to identify patient subgroups that are less likely to receive targeted therapies. RESULTS: Approximately one-third of patients fulfilling SUTENT trial eligibility criteria did not receive any targeted therapy (29 % in the 2008-2010 Cohort; 35 % in the 2011-2013 Cohort). Patients aged 65+ years were less likely to receive targeted therapy in both cohorts and different risk groups (odds ratios range between 0.84-0.92); other factors like number of metastatic sites were of influence in some subgroups. Amongst treated patients, there was a decreasing trend in sunitinib use over time (p = 0.0061), and an increasing trend in pazopanib use (p = 0.0005). CONCLUSIONS: Targeted therapies have largely replaced interferon-alfa as first-line standard of care. Nevertheless, many eligible patients in Dutch daily practice did not receive targeted therapies despite their ability to improve survival. Reasons for their apparent underutilisation should be examined more carefully.

Costs of non-small cell lung cancer in the Netherlands.

OBJECTIVES: Real-world resource use and cost data on non-small cell lung cancer (NSCLC) are scarce. This data is needed to inform health-economic modelling to assess the impact of new diagnostic and/or treatment technologies. This study provides detailed insight into real-world medical resource use and costs of stage I-IV NSCLC in the Netherlands. MATERIALS AND METHODS: A random sample of patients newly diagnosed with NSCLC (2009-2011) was selected from four Dutch hospitals. Data was retrospectively collected from patient charts. This data included patient characteristics, tumour characteristics, treatment details, adverse events, survival and resource use. Resource use was multiplied by Dutch unit costs expressed in EUR 2012. Total mean costs were corrected for censoring using the Bang and Tsiatis weighted complete-case estimator. Furthermore, costs of adverse events, costs per phase of NSCLC management and costs of second opinions are presented. RESULTS: Data was collected on 1067 patients. Total mean costs for NSCLC diagnosis, treatment and follow-up are €28,468 during the study period and €33,143 when corrected for censoring. Adverse events were recorded in the patient charts for 369 patients (41%) and 82 patients (9%) experienced an adverse event of grade III or higher. For these patients, adverse event-related hospital admissions cost on average €2,091. Mean total costs are €1,725 for the diagnostic period, €17,296 for first treatment line, and €13,236 for each later treatment line. Costs of providing a second opinion are €2,580 per patient. CONCLUSIONS: Total mean hospital costs per NSCLC patient are €33,143 for the total duration of the disease. Ignoring censoring in our data underestimates these costs by 14%. Main limitations of the study relate to the short follow-up time, staging difficulties and missing data. Its main strength is that it provides highly detailed, real-world data on the costs of NSCLC.

Quality of life of patients with chronic lymphocytic leukaemia in the Netherlands: results of a longitudinal multicentre study.

PURPOSE: To describe the health-related quality of life (HRQoL) of an unselected population of patients with chronic lymphocytic leukaemia (CLL) including untreated patients. METHODS: HRQoL was measured by the EORTC QLQ-C30 including the CLL16 module, EQ-5D, and VAS in an observational study over multiple years. All HRQoL measurements per patient were connected and analysed using area under the curve analysis over the entire study duration. The total patient group was compared with the general population, and three groups of CLL patients were described separately, i.e. patients without any active treatment ("watch and wait"), chlorambucil treatment only, and patients with other treatment(s). RESULTS: HRQoL in the total group of CLL patients was compromised when compared with age- and gender-matched norm scores of the general population. CLL patients scored statistically worse on the VAS and utility score of the EQ-5D, all functioning scales of the EORTC QLQ-C30, and the symptoms of fatigue, dyspnoea, sleeping disturbance, appetite loss, and financial difficulties. In untreated patients, the HRQoL was slightly reduced. In all treatment stages, HRQoL was compromised considerably. Patients treated with chlorambucil only scored worse on the EORTC QLQ-C30 than patients who were treated with other treatments with regard to emotional functioning, cognitive functioning, bruises, uncomfortable stomach, and apathy. CONCLUSIONS: CLL patients differ most from the general population on role functioning, fatigue, concerns about future health, and having not enough energy. Once treatment is indicated, HRQoL becomes considerably compromised. This applies to all treatments, including chlorambucil, which is considered to be a mild treatment.

Real-world resource use and costs of adjuvant treatment for stage III colon cancer.

Since the generalisability of trial-based economic evaluations may be limited, there is an increasing focus on real-world cost-effectiveness. Real-world studies involve evaluating the effects and costs of treatments in daily clinical practice. This study reports on the real-world resource use and costs of adjuvant treatments of stage III colon cancer in a population-based observational study. Analyses were based on a detailed retrospective medical chart review which was conducted for 206 patients with colon cancer treated in 2005 and 2006 in the Netherlands. Mean total costs per patient were €9681 for 5-FU/LV, €9736 for capecitabine, €32,793 for FOLFOX and €18,361 for CAPOX. Drug costs and the costs related to hospitalisations for chemotherapy administration were the main cost drivers. We identified a potential for substantial cost-savings when the 48 h administration of 5FU/LV in the FOLFOX regimen were to take place in an outpatient setting or be replaced by oral capecitabine as in the CAPOX regimen. This analysis based on detailed real-life data clearly indicates that clinical choices made in oncology based on efficacy of therapy have economic consequences. Considering today's reality of finite healthcare resources, these economic consequences deserve a formal role in clinical decision making, for instance in guideline development.

Cost-effectiveness of red blood cell transfusion vs. non-intervention in women with acute anaemia after postpartum haemorrhage.

BACKGROUND: Red blood cell (RBC) transfusion is frequently used to treat women with acute anaemia after postpartum haemorrhage. We aimed to assess the economic consequences of red blood cell transfusion compared to non-intervention in these women. METHODS: A trial-based cost-effectiveness analysis was performed alongside the Well-Being of Obstetric patients on Minimal Blood transfusions (WOMB) trial. Women with acute anaemia [Hb 4·8-7·9 g/dl (3·0-4·9 mm)] after postpartum haemorrhage, without severe anaemic symptoms, were randomly allocated to RBC transfusion or non-intervention. Primary outcome of the trial was physical fatigue (Multidimensional Fatigue Inventory, scale 4-20; 20 represents maximal fatigue). Total costs per arm were calculated using a hospital perspective with a 6 weeks time horizon. RESULTS: Per woman, mean costs in the RBC transfusion arm (n = 258) were €1957 compared to €1708 in the non-intervention arm (n = 261; P = 0·024). The 13% difference in costs between study arms predominantly originated from costs of RBC units, as costs of RBC units were six times higher in the RBC transfusion arm. RBC transfusion led to a small improvement in physical fatigue of 0·58 points per day; thus, the costs to improve the physical fatigue score with one point would be €431. CONCLUSION: In women with acute anaemia after postpartum haemorrhage (PPH), RBC transfusion is on average €249 more expensive per woman than non-intervention, with only a small gain in HRQoL after RBC transfusion. Taking both clinical and economic consequences into account, implementation of a non-intervention policy seems justified.

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.

Transfusion policy after severe postpartum haemorrhage: a randomised non-inferiority trial.

OBJECTIVE: To assess the effect of red blood cell (RBC) transfusion on quality of life in acutely anaemic women after postpartum haemorrhage. DESIGN: Randomised non-inferiority trial. SETTING: Thirty-seven Dutch university and general hospitals. POPULATION: Women with acute anaemia (haemoglobin 4.8-7.9 g/dl [3.0-4.9 mmol/l] 12-24 hours postpartum) without severe anaemic symptoms or severe comorbidities. METHODS: Women were allocated to RBC transfusion or non-intervention. MAIN OUTCOME MEASURES: Primary outcome was physical fatigue 3 days postpartum (Multidimensional Fatigue Inventory, scale 4-20; 20 represents maximal fatigue). Non-inferiority was demonstrated if the physical fatigue difference between study arms was maximal 1.3. Secondary outcomes were health-related quality of life and physical complications. Health-related quality of life questionnaires were completed at five time-points until 6 weeks postpartum. RESULTS: In all, 521 women were randomised to non-intervention (n = 262) or RBC transfusion (n = 259). Mean physical fatigue score at day 3 postpartum, adjusted for baseline and mode of delivery, was 0.8 lower in the RBC transfusion arm (95% confidence interval: 0.1-1.5, P = 0.02) and at 1 week postpartum was 1.06 lower (95% confidence interval: 0.3-1.8, P = 0.01). A median of two RBC units was transfused in the RBC transfusion arm. In the non-intervention arm, 33 women received RBC transfusion, mainly because of anaemic symptoms. Physical complications were comparable. CONCLUSIONS: Statistically, non-inferiority could not be demonstrated as the confidence interval crossed the non-inferiority boundary. Nevertheless, with only a small difference in physical fatigue and no differences in secondary outcomes, implementation of restrictive management seems clinically justified.