Market Entry Agreements for Innovative Pharmaceuticals Subject to Indication Broadening: A Case Study for Pembrolizumab in The Netherlands.

OBJECTIVES: Managed entry agreements and especially financial-based agreements are commonly used in European countries for innovative cancer pharmaceuticals. These agreements facilitate access to innovative treatments while mitigating financial risks for payers. This study focuses on the confidential price agreement made by the Dutch government for the reimbursement of pembrolizumab, the implications of broadening indications on cost-effectiveness, and the viability or desirability of said agreement. METHODS: We selected 5 indications in which pembrolizumab was deemed effective and developed portioned survival models for each indication. Survival and progression-free survival data from the published trials were utilized to recreate individual patient data, and we extrapolated-using parametric models-to a time horizon of 30 years. Inputs for both quality of life and costs were derived from the available literature and were indexed. RESULTS: The incremental cost-effectiveness ratios ranged between €35 313 and €322 349 per quality-adjusted life-year, depending on the indication. Only 1 indication fell under the €80 000 (or €100 000) cost-effectiveness threshold. When applying the average reported discount on intramural pharmaceuticals in The Netherlands, incremental cost-effectiveness ratios ranged between €20 881 and €252 934 per quality-adjusted life-year gained, and the €80 000 (or €100 000) threshold was met in 3 indications out of 5. CONCLUSIONS: Our results show that pembrolizumab could be cost-effective in some indications, depending on the confidential price agreement established. However, the possibility of reimbursing not cost-effective care when the price is anchored in 1 indication remains possible. Indication-based pricing could help align value and price for innovative pharmaceuticals that are subject to indication broadening.

A health technology assessment of personalized nutrition interventions using the EUnetHTA HTA Core Model.

OBJECTIVES: Poor nutrition links to chronic diseases, emphasizing the need for optimized diets. The EU-funded project PREVENTOMICS, introduced personalized nutrition to address this. This study aims to perform a health technology assessment (HTA) comparing personalized nutrition interventions developed through this project, with non-personalized nutrition interventions (control) for people with normal weight, overweight, or obesity. The goal is to support decisions about further development and implementation of personalized nutrition. METHODS: The PREVENTOMICS interventions were evaluated using the European Network for HTA Core Model, which includes a methodological framework that encompasses different domains for value assessment. Information was gathered via [1] different statistical analyses and modeling studies, [2] questions asked of project partners and, [3] other (un)published materials. RESULTS: Clinical trials of PREVENTOMICS interventions demonstrated different body mass index changes compared to control; differences ranged from -0.80 to 0.20 kg/m2. Long-term outcome predictions showed generally improved health outcomes for the interventions; some appeared cost-effective (e.g., interventions in UK). Ethical concerns around health inequality and the lack of specific legal regulations for personalized nutrition interventions were identified. Choice modeling studies indicated openness to personalized nutrition interventions; decisions were primarily affected by intervention's price. CONCLUSIONS: PREVENTOMICS clinical trials have shown promising effectiveness with no major safety concerns, although uncertainties about effectiveness exist due to small samples (n=60-264) and short follow-ups (10-16 weeks). Larger, longer trials are needed for robust evidence before implementation could be considered. Among other considerations, developers should explore financing options and collaborate with policymakers to prevent exclusion of specific groups due to information shortages.

Health-related quality of life in patients with steroid-refractory acute graft-versus-host disease.

BACKGROUND: Evidence regarding health-related quality of life (HRQoL) in patients with steroid-refractory acute graft-versus-host disease (SR-aGvHD) is lacking. Evaluating HRQoL was a secondary objective of the HOVON 113 MSC trial. Here we describe the outcomes of the EQ-5D-5L, EORTC QLQ-C30, and FACT-BMT for all adult patients who completed these questionnaires at baseline (i.e., before the start of treatment; n = 26). METHODS: Descriptive statistics were used to describe baseline patient and disease characteristics, EQ-5D dimension scores and values, EQ VAS scores, EORTC QLQ-C30 scale/item and summary scores, and FACT-BMT subscale and total scores. RESULTS: The mean EQ-5D value was 0.36. In total, 96% of the patients reported problems with usual activities, 92% with pain/discomfort, 84% with mobility, 80% with self-care, and 72% with anxiety/depression. The mean EORTC QLQ-C30 summary score was 43.50. Mean scale/item scores ranged from 21.79 to 60.00 for functioning scales, from 39.74 to 75.21 for symptom scales, and from 5.33 to 91.67 for single items. The mean FACT-BMT total score was 75.31. Mean subscale scores ranged from 10.09 for physical well-being to 23.94 for social/family well-being. CONCLUSION: Our study showed that HRQoL in patients with SR-aGvHD is poor. Improving HRQoL and symptom management in these patients should be a top priority.

Cost-Effectiveness and Budget Impact of Future Developments With Whole-Genome Sequencing for Patients With Lung Cancer.

OBJECTIVES: This study aimed to investigate the cost-effectiveness, budget impact (BI), and impact of uncertainty of future developments concerning whole-genome sequencing (WGS) as a clinical diagnostic test compared with standard of care (SoC) in patients with locally advanced and metastatic non-small cell lung cancer. METHODS: A total of 3 likely scenarios to take place within 5 years (according to experts) were simulated using a previously developed, peer reviewed, and published decision model. The scenarios concerned "WGS results used for treatment selection" (scenario 1), "WGS-based biomarker for immunotherapy" (scenario 2), and "off-label drug approval for WGS results" (scenario 3). Two diagnostic strategies of the original model, "SoC" and "WGS as a diagnostic test" (base model), were used to compare our scenarios with. Outcomes were reported for the base model, all scenarios separately, combined (combined unweighted), and weighted by likelihood (combined weighted). Cost-effectiveness, BI, and value of information analyses were performed for WGS compared with SoC. RESULTS: Total costs and quality-adjusted life-years for SoC in metastatic non-small cell lung cancer were €149 698 and 1.235. Incremental outcomes of WGS were €1529/0.002(base model), -€222/0.020(scenario 1), -€2576/0.023(scenario 2), €388/0.024(scenario 3), -€5041/0.060(combined unweighted), and -€1715/0.029(combined weighted). The annual BI for adopting WGS for this population in The Netherlands ranged between €682 million (combined unweighted) and €714 million (base model). The consequences of uncertainty amounted to €3.4 million for all scenarios (combined weighted) and to €699 000 for the diagnostic yield of WGS alone (combined weighted). CONCLUSIONS: Our findings suggest that it is likely for WGS to become cost-effective within the near future if it identifies more patients with actionable targets and show the impact of uncertainty regarding its diagnostic yield. Modeling future scenarios can be useful to consider early adoption of WGS while timely anticipating on unforeseen developments before final conclusions are reached.

Differences in Treatment Patterns and Outcomes of Acute Myocardial Infarction for Low- and High-Income Patients in 6 Countries.

Importance: Differences in the organization and financing of health systems may produce more or less equitable outcomes for advantaged vs disadvantaged populations. We compared treatments and outcomes of older high- and low-income patients across 6 countries. Objective: To determine whether treatment patterns and outcomes for patients presenting with acute myocardial infarction differ for low- vs high-income individuals across 6 countries. Design, Setting, and Participants: Serial cross-sectional cohort study of all adults aged 66 years or older hospitalized with acute myocardial infarction from 2013 through 2018 in the US, Canada, England, the Netherlands, Taiwan, and Israel using population-representative administrative data. Exposures: Being in the top and bottom quintile of income within and across countries. Main Outcomes and Measures: Thirty-day and 1-year mortality; secondary outcomes included rates of cardiac catheterization and revascularization, length of stay, and readmission rates. Results: We studied 289 376 patients hospitalized with ST-segment elevation myocardial infarction (STEMI) and 843 046 hospitalized with non-STEMI (NSTEMI). Adjusted 30-day mortality generally was 1 to 3 percentage points lower for high-income patients. For instance, 30-day mortality among patients admitted with STEMI in the Netherlands was 10.2% for those with high income vs 13.1% for those with low income (difference, -2.8 percentage points [95% CI, -4.1 to -1.5]). One-year mortality differences for STEMI were even larger than 30-day mortality, with the highest difference in Israel (16.2% vs 25.3%; difference, -9.1 percentage points [95% CI, -16.7 to -1.6]). In all countries, rates of cardiac catheterization and percutaneous coronary intervention were higher among high- vs low-income populations, with absolute differences ranging from 1 to 6 percentage points (eg, 73.6% vs 67.4%; difference, 6.1 percentage points [95% CI, 1.2 to 11.0] for percutaneous intervention in England for STEMI). Rates of coronary artery bypass graft surgery for patients with STEMI in low- vs high-income strata were similar but for NSTEMI were generally 1 to 2 percentage points higher among high-income patients (eg, 12.5% vs 11.0% in the US; difference, 1.5 percentage points [95% CI, 1.3 to 1.8 ]). Thirty-day readmission rates generally also were 1 to 3 percentage points lower and hospital length of stay generally was 0.2 to 0.5 days shorter for high-income patients. Conclusions and Relevance: High-income individuals had substantially better survival and were more likely to receive lifesaving revascularization and had shorter hospital lengths of stay and fewer readmissions across almost all countries. Our results suggest that income-based disparities were present even in countries with universal health insurance and robust social safety net systems.

Impact of DNA damage repair defects and aggressive variant features on response to carboplatin-based chemotherapy in metastatic castration-resistant prostate cancer.

Platinum-based chemotherapy is not standard of care for unselected or genetically selected metastatic castration-resistant prostate cancer (mCRPC) patients. A retrospective assessment of 71 patients was performed on platinum use in the Netherlands. Genetically unselected patients yielded low response rates. For a predefined subanalysis of all patients with comprehensive next-generation sequencing, 30 patients were grouped based on the presence of pathogenic aberrations in genes associated with DNA damage repair (DDR) or aggressive variant prostate cancer (AVPC). Fourteen patients (47%) were DDR deficient (DDRd), of which seven with inactivated BRCA2 (BRCA2mut). Six patients classified as AVPC. DDRd patients showed beneficial biochemical response to carboplatin, largely driven by all BRCA2mut patients having >50% prostate-specific antigen (PSA) decline and objective radiographic response. In the wild-type BRCA2 subgroup, 35% had a >50% PSA decline (P = .006) and 16% radiographic response (P < .001). Median overall survival was 21 months for BRCA2mut patients vs 7 months (P = .041) for those with functional BRCA2. AVPC patients demonstrated comparable responses to non-AVPC, including a similar overall survival, despite the poor prognosis for this subgroup. In the scope of the registration of poly-(ADP)-ribose polymerase inhibitors (PARPi) for mCRPC, we provide initial insights on cross-resistance between PARPi and platinum compounds. By combining the literature and our study, we identified 18 patients who received both agents. In this cohort, only BRCA2mut patients treated with platinum first (n = 4), responded to both agents. We confirm that BRCA2 inactivation is associated with meaningful responses to carboplatin, suggesting a role for both PARPi and platinum-based chemotherapy in preselected mCRPC patients.

Leveraging the Similarities Between Cost-Effectiveness Analysis and Value-Based Healthcare.

OBJECTIVES: This article aims to explore overlaps and differences between the emerging concept of value-based healthcare (VBHC) and the established field of cost-effectiveness analysis (CEA), as well as the feasibility of integrating them together. Interest in VBHC has grown significantly in developed countries that seek to preserve the sustainability of their healthcare systems. Consequently, it is likely that VBHC will soon play a meaningful role in health economic policy and decision making. Because VBHC and CEA share many similarities, academics have pointed out that integration could lead to opportunities for improvements in both fields. METHODS: An exploration of overlapping topics in VBHC and CEA literature was performed to establish initial links between them. A new methodologic approach is described to consolidate key value frameworks from the respective fields. RESULTS: Several key themes emerged in which these 2 concepts can reinforce each other: interpretation of value, sensitivity to outcome changes, scientific credibility, methodology and measurement, and usability in decision making. Subsequently, an initial method is described of how the VBHC framework for value could be integrated into CEA through a so-called value-based healthcare quality-adjusted life year (VBHC-QALY). CONCLUSION: This article introduces the existing VBHC value framework to the cornerstone of modern CEA and substantiates the presumption of health economists that valuable synergies arise from consolidating the individual strengths of CEA and VBHC. Through integration CEA can help establish robust methods for VBHC implementation, while the latter can complement the former with a new viewpoint and conceptual toolbox for patient centricity and the definition of value.

A Systematic Review of Cost-Effectiveness Studies of Interventions With a Personalized Nutrition Component in Adults.

OBJECTIVES: Important links between dietary patterns and diseases have been widely applied to establish nutrition interventions. However, knowledge about between-person heterogeneity regarding the benefits of nutrition intervention can be used to personalize the intervention and thereby improve health outcomes and efficiency. We performed a systematic review of cost-effectiveness analyses (CEAs) of interventions with a personalized nutrition (PN) component to assess their methodology and findings. METHODS: A systematic search (March 2019) was performed in 5 databases: EMBASE, Medline Ovid, Web of Science, Cochrane CENTRAL, and Google Scholar. CEAs involving interventions in adults with a PN component were included; CEAs focusing on clinical nutrition or undernutrition were excluded. The CHEERS checklist was used to assess the quality of CEAs. RESULTS: We identified 49 eligible studies among 1792 unique records. Substantial variation in methodology was found. Most studies (91%) focused only on psychological concepts of PN such as behavior and preferences. Thirty-four CEAs were trial-based, 13 were modeling studies, and 4 studies were both trial- and model-based. Thirty-two studies used quality-adjusted life year as an outcome measure. Different time horizons, comparators, and modeling assumptions were applied, leading to differences in costs/quality-adjusted life years. Twenty-eight CEAs (49%) concluded that the intervention was cost-effective, and 75% of the incremental cost-utility ratios were cost-effective given a willingness-to-pay threshold of $50 000 per quality-adjusted life year. CONCLUSIONS: Interventions with PN components are often evaluated using various types of models. However, most PN interventions have been considered cost-effective. More studies should examine the cost-effectiveness of PN interventions that combine psychological and biological concepts of personalization.

Measurement Instruments of Productivity Loss of Paid and Unpaid Work: A Systematic Review and Assessment of Suitability for Health Economic Evaluations From a Societal Perspective.

OBJECTIVES: This study aimed (1) to perform a systematic literature review of instruments for measuring productivity loss of paid and unpaid work and (2) to assess the suitability (in terms of identification, measurement, and valuation) of these instruments for use in health economic evaluations from a societal perspective. METHODS: Articles published from 2018 were sourced from PubMed/Medline, PsycInfo, Embase, and Econlit. Using 2 separate search strategies, eligible economic evaluations and validation studies were selected and unique measurement instruments identified. A data-extraction form was developed by studying previous literature and consulting an international panel of experts in the field of productivity costs. This data-extraction form was applied to assess the suitability of instruments for use in economic evaluations. RESULTS: A total of 5982 articles were retrieved from the databases, of which 99 economic evaluations and 9 validation studies were included in the review. A total of 42 unique measurement instruments were identified. Nine instruments provided quantified measures of absenteeism, presenteeism, and unpaid work. Five instruments supplied the necessary information to enable the use of at least 1 common valuation method. The Health and Labour Questionnaire-Short Form, Health and Labour Questionnaire, and Institute for Medical Technology Assessment Productivity Cost Questionnaire met both criteria. Nevertheless, the developers replaced the Health and Labour Questionnaire-Short Form and Health and Labour Questionnaire by the more recently developed Institute for Medical Technology Assessment Productivity Cost Questionnaire. CONCLUSIONS: Although many instruments for measuring productivity loss were identified, most were not suitable for capturing productivity changes for economic evaluations from a societal perspective. Future research can benefit from this study by making an informed instrument choice for the measurement of productivity loss of paid and unpaid work.

Practice Variation in Skin Cancer Treatment and Follow-Up Care: A Dutch Claims Database Analysis.

BACKGROUND: Quality indicators are used to benchmark and subsequently improve quality of healthcare. However, defining good quality indicators and applying them to high-volume care such as skin cancer is not always feasible. OBJECTIVES: To determine whether claims data could be used to benchmark high-volume skin cancer care and to assess clinical practice variation. METHODS: All skin cancer care-related claims in dermatology in 2016 were extracted from a nationwide claims database (Vektis) in the Netherlands. RESULTS: For over 220,000 patients, a skin cancer diagnosis-related group was reimbursed in 124 healthcare centres. Conventional excision reflected 75% of treatments for skin cancer but showed large variation between practices. Large practice variation was also found for 5-fluorouracil and imiquimod creams. The practice variation of Mohs micrographic surgery and photodynamic therapy was low under the 75th percentile, but outliers at the 100th percentile were detected, which indicates that few centres performed these therapies far more often than average. On average, patients received 1.8 follow-up visits in 2016. CONCLUSIONS: Claims data demonstrated large practice variation in treatments and follow-up visits of skin cancer and may be a valid and feasible data set to extract quality indicators. The next step is to investigate whether detected practice variation is unwarranted and if a reduction improves quality and efficiency of care.

How can we discover the most valuable types of big data and artificial intelligence-based solutions? A methodology for the efficient development of the underlying analytics that improve care.

BACKGROUND: Much has been invested in big data and artificial intelligence-based solutions for healthcare. However, few applications have been implemented in clinical practice. Early economic evaluations can help to improve decision-making by developers of analytics underlying these solutions aiming to increase the likelihood of successful implementation, but recommendations about their use are lacking. The aim of this study was to develop and apply a framework that positions best practice methods for economic evaluations alongside development of analytics, thereby enabling developers to identify barriers to success and to select analytics worth further investments. METHODS: The framework was developed using literature, recommendations for economic evaluations and by applying the framework to use cases (chronic lymphocytic leukaemia (CLL), intensive care, diabetes). First, the feasibility of developing clinically relevant analytics was assessed and critical barriers to successful development and implementation identified. Economic evaluations were then used to determine critical thresholds and guide investment decisions. RESULTS: When using the framework to assist decision-making of developers of analytics, continuing development was not always feasible or worthwhile. Developing analytics for progressive CLL and diabetes was clinically relevant but not feasible with the data available. Alternatively, developing analytics for newly diagnosed CLL patients was feasible but continuing development was not considered worthwhile because the high drug costs made it economically unattractive for potential users. Alternatively, in the intensive care unit, analytics reduced mortality and per-patient costs when used to identify infections (- 0.5%, - €886) and to improve patient-ventilator interaction (- 3%, - €264). Both analytics have the potential to save money but the potential benefits of analytics that identify infections strongly depend on infection rate; a higher rate implies greater cost-savings. CONCLUSIONS: We present a framework that stimulates efficiency of development of analytics for big data and artificial intelligence-based solutions by selecting those applications of analytics for which development is feasible and worthwhile. For these applications, results from early economic evaluations can be used to guide investment decisions and identify critical requirements.

Cost-effectiveness of a Pharmacogenomic Test for Stratified Isoniazid Dosing in Treatment of Active Tuberculosis.

BACKGROUND: There is marked interindividual variability in metabolism and resulting toxicity and effectiveness of drugs used for tuberculosis treatment. For isoniazid, mutations in the N-acetyltransferase 2 (NAT2) gene explain >88% of pharmacokinetic variability. However, weight-based dosing remains the norm globally. The potential clinical impact and cost-effectiveness of pharmacogenomic-guided therapy (PGT) are unknown. METHODS: We constructed a decision tree model to project lifetime costs and benefits of isoniazid PGT for drug-susceptible tuberculosis in Brazil, South Africa, and India. PGT was modeled to reduce isoniazid toxicity among slow NAT2 acetylators and reduce treatment failure among rapid acetylators. The genotyping test was assumed to cost the same as the GeneXpert test. The main outcomes were costs (2018 US dollars), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. RESULTS: In Brazil, PGT gained 19 discounted life-years (23 QALYs) and cost $11 064 per 1000 patients, a value of $476 per QALY gained. In South Africa, PGT gained 15 life-years (19 QALYs) and cost $33 182 per 1000 patients, a value of $1780 per QALY gained. In India, PGT gained 20 life-years (24 QALYs) and cost $13 195 per 1000 patients, a value of $546 per QALY gained. One-way sensitivity analyses showed the cost-effectiveness to be robust to all input parameters. Probabilistic sensitivity analyses were below per capita gross domestic product in all 3 countries in 99% of simulations. CONCLUSIONS: Isoniazid PGT improves health outcomes and would be cost-effective in the treatment of drug-susceptible tuberculosis in Brazil, South Africa, and India.

Lenalidomide as maintenance treatment for patients with multiple myeloma after autologous stem cell transplantation: A pharmaco-economic assessment.

OBJECTIVE: Autologous stem cell transplantation (ASCT) has improved progression-free survival (PFS) and overall survival in eligible patients with newly diagnosed multiple myeloma (NDMM); however, relapse occurs. Maintenance therapy with lenalidomide (Len-Mt) extends survival and delays relapse and the subsequent initiation of costly second-line regimens. Here, we report the cost-effectiveness of Len-Mt following ASCT from a Dutch healthcare service perspective. METHODS: A partitioned survival model was developed to assess the lifetime costs and benefits for patients with NDMM. Efficacy was taken from a pooled meta-analysis of clinical trial data. Costs and subsequent therapy data were taken from sources appropriate for the Dutch market. RESULTS: Lenalidomide produced a quality-adjusted life year gain of 2.46 and a life year gain of 2.79 vs no maintenance treatment. The cost of lenalidomide was partially offset by savings of EUR 77 462 in subsequent treatment costs. The incremental cost-effectiveness ratio of Len-Mt vs no maintenance treatment was EUR 30 143. Key model drivers included subsequent therapies, dosing schedule, and time horizon. CONCLUSION: Lenalidomide is cost-effective after ASCT vs no maintenance therapy in the Netherlands. By extending PFS, lenalidomide delays the cost burdens associated with relapse and subsequent treatment lines.

Cost-effectiveness of Anti-CD19 chimeric antigen receptor T-Cell therapy in pediatric relapsed/refractory B-cell acute lymphoblastic leukemia. A societal view.

INTRODUCTION: In several studies, the chimeric antigen receptor T-cell therapy tisagenlecleucel demonstrated encouraging rates of remission and lasting survival benefits in pediatric patients with relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL). We assessed the cost-effectiveness of tisagenlecleucel (list price: 320 000 EUR) among these patients when compared to clofarabine monotherapy (Clo-M), clofarabine combination therapy (Clo-C), and blinatumomab (Blina) from both a healthcare and a societal perspective. We also assessed future medical and future non-medical consumption costs. METHODS: A three-state partitioned survival model was used to simulate a cohort of pediatric patients (12 years of age) through different disease states until the end of life (lifetime horizon). Relevant outcomes were life years, quality-adjusted life years (QALYs), healthcare costs, societal costs, and the incremental cost-effectiveness ratio (ICER). Uncertainty was explored through deterministic and probabilistic sensitivity analyses as well as through several scenario analyzes. RESULTS: Total discounted costs for tisagenlecleucel were 552 679 EUR from a societal perspective, which was much higher than the total discounted costs from a healthcare perspective (ie, 409 563 EUR). Total discounted societal costs for the comparator regimens ranged between 160 803 EUR for Clo-M and 267 259 EUR for Blina. Highest QALYs were estimated for tisagenlecleucel (11.26), followed by Blina (2.25), Clo-C (1.70) and Clo-M (0.74). Discounted societal ICERs of tisagenlecleucel ranged between 31 682 EUR/QALY for Blina and 37 531 EUR/QALY for Clo-C and were considered cost-effective with a willingness-to-pay (WTP) threshold of 80 000 EUR/QALY. None of the scenarios exceeded this threshold, and more than 98% of the iterations in the probabilistic sensitivity analysis were cost-effective. DISCUSSION: At the current price and WTP threshold, tisagenlecleucel is cost-effective from both a healthcare and a societal perspective. Nevertheless, long-term effectiveness data are needed to validate the several assumptions that were necessary for this model.

Expanded Access as a source of real-world data: An overview of FDA and EMA approvals.

AIMS: To identify, characterize and compare all Food and Drug Administration (FDA) and European Medicines Agency (EMA) approvals that included real-world data on efficacy from expanded access (EA) programmes. METHODS: Cross-sectional study of FDA (1955-2018) and EMA (1995-2018) regulatory approval documentation. We automated searching for terms related to EA in 22,506 documents using machine learning techniques. We included all approvals where EA terms appeared in the regulatory documentation. Our main outcome was the inclusion of EA data as evidence of clinical efficacy. Characterization was based on approval date, disease area, orphan designation and whether the evidence was supportive or pivotal. RESULTS: EA terms appeared in 693 out of 22,506 (3.1%) documents, which referenced 187 approvals. For 39 approvals, data from EA programmes were used to inform on clinical efficacy. The yearly number of approvals with EA data increased from 1.25 for 1993-2013 to 4.6 from 2014-2018. In 13 cases, these programmes formed the main evidence for approval. Of these, patients in EA programmes formed over half (median 71%, interquartile range: 34-100) of the total patient population available for efficacy evaluation. Almost all (12/13) approvals were granted orphan designation. In 8/13, there were differences between regulators in approval status and valuation of evidence. Strikingly, 4 treatments were granted approval based solely on efficacy from EA. CONCLUSION: Sponsors and regulators increasingly include real-world data from EA programmes in the efficacy profile of a treatment. The indications of the approved treatments are characterized by orphan designation and high unmet medical need.

Assessment of Studies Evaluating Incremental Costs, Effectiveness, or Cost-Effectiveness of Systemic Therapies in Breast Cancer Based on Claims Data: A Systematic Review.

OBJECTIVES: Large secondary databases, such as those containing insurance claims data, are increasingly being used to compare the effects and costs of treatments in routine clinical practice. Despite their appeal, however, caution must be exercised when using these data. In this study, we aimed to identify and assess the methodological quality of studies that used claims data to compare the effectiveness, costs, or cost-effectiveness of systemic therapies for breast cancer. METHODS: We searched Embase, the Cochrane Library, Medline, Web of Science, and Google Scholar for English-language publications and assessed the methodological quality using the Good Research for Comparative Effectiveness principles. This study was registered with the International Prospective Register of Systematic Reviews (PROSPERO) under number CRD42018103992. RESULTS: We identified 1251 articles, of which 106 met the inclusion criteria. Most studies were conducted in the United States (74%) and Taiwan (9%) and were based on claims data sets (35%) or claims data linked to cancer registries (58%). Furthermore, most included large samples (mean 17 130 patients) and elderly patients, and they covered various outcomes (eg, survival, adverse events, resource use, and costs). Key methodological shortcomings were the lack of information on relevant confounders, the risk of immortal time bias, and the lack of information on the validity of outcomes. Only a few studies performed sensitivity analyses. CONCLUSIONS: Many comparative studies of cost, effectiveness, and cost-effectiveness have been published in recent decades based on claims data, and the number of publications has increased over time. Despite the availability of guidelines to improve quality, methodological issues persist and are often inappropriately addressed or reported.

Evaluation of the performance of algorithms mapping EORTC QLQ-C30 onto the EQ-5D index in a metastatic colorectal cancer cost-effectiveness model.

BACKGROUND: Cost-effectiveness models require quality of life utilities calculated from generic preference-based questionnaires, such as EQ-5D. We evaluated the performance of available algorithms for QLQ-C30 conversion into EQ-5D-3L based utilities in a metastatic colorectal cancer (mCRC) patient population and subsequently developed a mCRC specific algorithm. Influence of mapping on cost-effectiveness was evaluated. METHODS: Three available algorithms were compared with observed utilities from the CAIRO3 study. Six models were developed using 5-fold cross-validation: predicting EQ-5D-3L tariffs from QLQ-C30 functional scale scores, continuous QLQ-C30 scores or dummy levels with a random effects model (RE), a most likely probability method on EQ-5D-3L functional scale scores, a beta regression model on QLQ-C30 functional scale scores and a separate equations subgroup approach on QLQ-C30 functional scale scores. Performance was assessed, and algorithms were tested on incomplete QLQ-C30 questionnaires. Influence of utility mapping on incremental cost/QALY gained (ICER) was evaluated in an existing Dutch mCRC cost-effectiveness model. RESULTS: The available algorithms yielded mean utilities of 1: 0.87 ± sd:0.14,2: 0.81 ± 0.15 (both Dutch tariff) and 3: 0.81 ± sd:0.19. Algorithm 1 and 3 were significantly different from the mean observed utility (0.83 ± 0.17 with Dutch tariff, 0.80 ± 0.20 with U.K. tariff). All new models yielded predicted utilities drawing close to observed utilities; differences were not statistically significant. The existing algorithms resulted in an ICER difference of €10,140 less and €1765 more compared to the observed EQ-5D-3L based ICER (€168,048). The preferred newly developed algorithm was €5094 higher than the observed EQ-5D-3L based ICER. Disparity was explained by minimal diffences in incremental QALYs between models. CONCLUSION: Available mapping algorithms sufficiently accurately predict utilities. With the commonly used statistical methods, we did not succeed in developping an improved mapping algorithm. Importantly, cost-effectiveness outcomes in this study were comparable to the original model outcomes between different mapping algorithms. Therefore, mapping can be an adequate solution for cost-effectiveness studies using either a previously designed and validated algorithm or an algorithm developed in this study.

Real-world outcomes of radium-223 dichloride for metastatic castration resistant prostate cancer.

Aim: Timing of radium-223 (Ra-223) in metastatic castration-resistant prostate cancer (mCRPC) remains challenging due to alternative options and short window of opportunity. Methods: Ra-223 treated patients in the CAPRI-registry were included. Outcomes were evaluated based on treatment line of Ra-223. Results: Out of 285 patients, 49% received Ra-223 in line ≥3. 51% completed six Ra-223 injections and 34% had a symptomatic skeletal event after first Ra-223 without differences between subgroups. After correction of known prognostic factors Ra-223 in line ≥3 (HR: 3.267; 95% CI: 1.689-6.317; p < 0.01) remained associated with worse OS. Conclusion: In the Netherlands, Ra-223 was mainly started as second or third mCRPC-treatment in 2014-2018. Later timing of Ra-223 did affect OS, but not treatment completion and occurrence of symptomatic skeletal events.

Increasing Costs of Skin Cancer due to Increasing Incidence and Introduction of Pharmaceuticals, 2007-2017.

Skin cancer is the most common type of cancer and its incidence is increasing. The objective of this study was to describe the trends in reimbursed drug and hospital costs of benign and (pre)malignant skin tumours, and to present future projections. Therefore, nationwide hospital and drug reimbursement data (for the period 2007-17) were used. In 2017, malignant skin tumours were the 4th most costly cancer in the Netherlands (after breast, colorectal, and lung cancer). The total costs for skin tumours increased from €278 million for 384,390 patients (in 2007) to €465 million for 578,355 patients (in 2017). Drug costs increased from €0.7 million to €121 million (over the period 2007-17), resulting in a 26% share of overall costs in 2017. Future costs are projected to reach €1.35 billion in 2030. In conclusion, the increasing costs of skin cancer are strongly affected by the increasing incidence and introduction of expensive drugs, and future projections are for an alarming increase.

Efficacy of first-line treatments for multiple myeloma patients not eligible for stem cell transplantation: a network meta-analysis.

Decision making for patients with multiple myeloma (MM) not transplant eligible (NTE) is complicated by a lack of head-to-head comparisons of standards of care, the increase in the choice of treatment modalities, and the promising results that are rapidly evolving from studies with novel regimens. To support evidence-based decision making, we performed a network meta-analysis for NTE MM patients that synthesizes direct and indirect evidence and enables a comparison of all treatments. Relevant randomized clinical trials were identified by a systematic literature review in EMBASE®, MEDLINE®, MEDLINE®-in-Process and the Cochrane Central Register of Controlled Trials for January 1999 to March 2016. Efficacy outcomes [i.e. the hazard ratio (HR) and 95% confidence interval (95%CI) for progression-free survival] were extracted and synthesized in a random effects network-meta analysis. In total, 24 studies were identified including 21 treatments. According to the network-meta analysis, the HR for progression-free survival was favorable for all NTE MM treatments compared to dexamethasone (HR: 0.19-0.90). Daratumumab-bortezomib-melphalan-prednisone and bortezomib-melphalan-prednisone-thalidomide with bortezomib-thalidomide maintenance were identified as the most effective treatments (HR: 0.19, 95%CI: 0.08-0.45 and HR: 0.22, 95%CI: 0.10-0.51, respectively). HR and 95%CI for currently recommended treatments, bortezomib-lenalidomide-dexamethasone, bortezomib-melphalan-prednisone, and lenalidomide-dexamethasone compared to dexamethasone, were 0.31 (0.16-0.59), 0.39 (0.20-0.75), and 0.44 (0.29-0.65), respectively. In addition to identifying the most effective treatment options, we illustrate the additional value and evidence of network meta-analysis in clinical practice. In the current treatment landscape, the results of network meta-analysis may support evidence-based decisions and ultimately help to optimize treatment and outcomes of NTE MM patients.