Validating Health Economic Models With the Probabilistic Analysis Check dashBOARD.

OBJECTIVES: Health economic (HE) models are often considered as "black boxes" because they are not publicly available and lack transparency, which prevents independent scrutiny of HE models. Additionally, validation efforts and validation status of HE models are not systematically reported. Methods to validate HE models in absence of their full underlying code are therefore urgently needed to improve health policy making. This study aimed to develop and test a generic dashboard to systematically explore the workings of HE models and validate their model parameters and outcomes. METHODS: The Probabilistic Analysis Check dashBOARD (PACBOARD) was developed using insights from literature, health economists, and a data scientist. Functionalities of PACBOARD are (1) exploring and validating model parameters and outcomes using standardized validation tests and interactive plots, (2) visualizing and investigating the relationship between model parameters and outcomes using metamodeling, and (3) predicting HE outcomes using the fitted metamodel. To test PACBOARD, 2 mock HE models were developed, and errors were introduced in these models, eg, negative costs inputs, utility values exceeding 1. PACBOARD metamodeling predictions of incremental net monetary benefit were validated against the original model's outcomes. RESULTS: PACBOARD automatically identified all errors introduced in the erroneous HE models. Metamodel predictions were accurate compared with the original model outcomes. CONCLUSIONS: PACBOARD is a unique dashboard aiming at improving the feasibility and transparency of validation efforts of HE models. PACBOARD allows users to explore the working of HE models using metamodeling based on HE models' parameters and outcomes.

Cost-effectiveness analysis of transthoracic echocardiographic assessment in patients with ischemic stroke or TIA of undetermined cause.

BACKGROUND: The multicenter ATTEST study recently assessed 1084 patients with ischemic stroke or transient ischemic attack (TIA) of undetermined cause and found that routine transthoracic echocardiography (TTE) detects abnormalities with treatment implications (i.e., major cardiac sources of embolism) in only 1 % of patients, of whom most (91 %) also had major electrocardiographic (ECG)-abnormalities. In this study, we performed a cost-effectiveness analysis of different TTE strategies. METHODS: We compared the cost-effectiveness of three strategies of TTE assessment: (1) TTE in all patients; (2) TTE only in patients with major ECG-abnormalities; and (3) TTE not performed. Input data were derived from ATTEST and systematic literature reviews. A Markov model was developed that simulated recurrent ischemic stroke or TIA and intracranial and gastro-intestinal bleeding complications in patients with ischemic stroke or TIA of undetermined cause. Primary outcome was the additional costs per additional quality-adjusted life-year (QALY) from a Dutch societal perspective. RESULTS: Performing TTE only in patients with major ECG-abnormalities led to 0.0083 additional QALYs and €108 additional costs per patient as compared with not performing TTE (€12,987/QALY). Performing TTE in all patients resulted in 0.0005 additional QALYs and €422 additional costs per patient as compared with performing TTE only in case of major ECG-abnormalities (€805,336/QALY). CONCLUSIONS: In patients with ischemic stroke or TIA of undetermined cause, a strategy of performing TTE only in patients who also had major ECG-abnormalities resulted in the most favorable ratio of additional costs per additional QALY. This supports performing TTE only in patients, who also have major ECG-abnormalities.

Opportunities and Barriers to the Development and Use of Open Source Health Economic Models: A Survey.

OBJECTIVES: Health economic (HE) models are routinely used to support health policy and resource allocation decisions but are often considered "black boxes" that may be prone to error and bias. Open source models (OSMs) have been advocated to increase the transparency, credibility, and reuse of HE models. Previous studies have demonstrated interest in OSMs among the health economics and outcomes research community, but the number of OSMs remains low. METHODS: We conducted an online survey of ISPOR (the leading professional society for health economics and outcomes research) members' perspectives on the usefulness of OSMs and barriers to their development and implementation. RESULTS: Respondents (N = 230) included academics (27%), pharmaceutical (or related) industry representatives (23%), health research or consulting representatives (21%), governmental or nonprofit agency representatives (10%), and others (19%). Respondents were generally not familiar with barriers to the development and adoption of OSMs. Most agreed that OSMs would improve transparency (92%), efficiency (76%), and HE model reuse (86%) and promote confidence in using HE models (75%). The use of OSMs by health technology assessment authorities was considered a very important indicator of the usefulness of OSMs by 49% of respondents. Three-quarters of respondents perceived legal concerns and the ability to transfer data as important barriers to the development and use of OSMs. CONCLUSIONS: Respondents believe that OSMs could increase the transparency, efficiency, and credibility of HE models, but that several barriers hamper their widespread adoption. Our results suggest that fundamental changes may be needed across the health economics and outcomes research community if OSMs are to become widely adopted.

Implementation Barriers to Value of Information Analysis in Health Technology Decision Making: Results From a Process Evaluation.

OBJECTIVES: Value of information (VOI) analysis can support health technology assessment decision making, but it is a long way from being standard use. The objective of this study was to understand barriers to the implementation of VOI analysis and propose actions to overcome these. METHODS: We performed a process evaluation of VOI analysis use within decision making on tomosynthesis versus digital mammography for use in the Dutch breast cancer population screening. Based on steering committee meeting attendance and regular meetings with analysts, we developed a list of barriers to VOI use, which were analyzed using an established diffusion model. We proposed actions to address these barriers. Barriers and actions were discussed and validated in a workshop with stakeholders representing patients, clinicians, regulators, policy advisors, researchers, and the industry. RESULTS: Consensus was reached on groups of barriers, which included characteristics of VOI analysis itself, stakeholder's attitudes, analysts' and policy makers' skills and knowledge, system readiness, and implementation in the organization. Observed barriers did not only pertain to VOI analysis itself but also to formulating the objective of the assessment, economic modeling, and broader aspects of uncertainty assessment. Actions to overcome these barriers related to organizational changes, knowledge transfer, cultural change, and tools. CONCLUSIONS: This in-depth analysis of barriers to implementation of VOI analysis and resulting actions and tools may be useful to health technology assessment organizations that wish to implement VOI analysis in technology assessment and research prioritization. Further research should focus on application and evaluation of the proposed actions in real-world assessment processes.

Direct Medical Costs of Advanced Breast Cancer Treatment: A Real-World Study in the Southeast of The Netherlands.

OBJECTIVES: Policy makers increasingly seek to complement data from clinical trials with information from routine care. This study aims to provide a detailed account of the hospital resource use and associated costs of patients with advanced breast cancer in The Netherlands. METHODS: Data from 597 patients with advanced breast cancer, diagnosed between 2010 and 2014, were retrieved from the Southeast Netherlands Advanced Breast Cancer Registry. Database lock for this study was in October 2017. We report the observed hospital costs for different resource categories and the lifetime costs per patient, adjusted for censoring using Lin's method. The relationship between patients' characteristics and costs was studied using multivariable regression. RESULTS: The average (SE) lifetime hospital costs of patients with advanced breast cancer were €52 709 (405). Costs differed considerably between patient subgroups, ranging from €29 803 for patients with a triple-negative subtype to €92 272 for patients with hormone receptor positive and human epidermal growth factor receptor 2 positive cancer. Apart from the cancer subtype, several other factors, including age and survival time, were independently associated with patient lifetime costs. Overall, a large share of costs was attributed to systemic therapies (56%), predominantly to a few expensive agents, such as trastuzumab (15%), everolimus (10%), and bevacizumab (9%), as well as to inpatient hospital days (20%). CONCLUSIONS: This real-world study shows the high degree of variability in hospital resource use and associated costs in advanced breast cancer care. The presented resource use and costs data provide researchers and policy makers with key figures for economic evaluations and budget impact analyses.

An economic evaluation of eribulin for advanced breast cancer treatment based on the Southeast Netherlands advanced breast cancer registry.

Background: In 2013, eribulin was reimbursed under a coverage with evidence development (CED) as third or later chemotherapy line for advanced breast cancer (ABC) patients in the Netherlands because of uncertain cost effectiveness. In 2016, the final decision of reimbursing eribulin was taken without considering the evidence collected during CED research. We analysed the cost effectiveness of eribulin versus non-eribulin chemotherapy, using real-world data.Methods: A three health states (progression-free, progressed disease, dead) partitioned survival model was developed. The SOuth East Netherlands Advanced BREast Cancer (SONABRE) registry informed the effectiveness and costs inputs. Health state utility values were obtained from the literature. Incremental cost-effectiveness ratio (ICER) between the eribulin and matched non-eribulin chemotherapy was estimated. Deterministic and probabilistic sensitivity analyses and scenario analyses were performed. The financial risk (i.e., the expected value of perfect information (EVPI) plus the expected monetary loss (eML) associated with reimbursing eribulin) and budget impact associated with reimbursing eribulin were calculated.Results: Eribulin led to higher health benefits (0.07 quality-adjusted life year (QALY)) and costs (€15,321) compared with non-eribulin chemotherapy. This resulted in an ICER of €220,608. At a €80,000 per QALY threshold, the risk of reimbursing eribulin was €9,791 per patient (EVPI €13, eML €9,778). Scaled up to the Dutch population, the estimated annual budget impact was €1.9 million and the annual risk of reimbursing eribulin was €2.7 million.Conclusion: From a Dutch societal perspective, eribulin is not cost effective when considering its list price as third and later chemotherapy line for ABC patients.

Uncertainty and Coverage With Evidence Development: Does Practice Meet Theory?

OBJECTIVES: In theory, a successful coverage with evidence development (CED) scheme is one that addresses the most important uncertainties in a given assessment. We investigated the following: (1) which uncertainties were present during the initial assessment of 3 Dutch CED cases, (2) how these uncertainties were integrated in the initial assessments, (3) whether CED research plans included the identified uncertainties, and (4) issues with managing uncertainty in CED research and ways forward from these issues. METHODS: Three CED initial assessment dossiers were analyzed and 16 stakeholders were interviewed. Uncertainties were identified in interviews and dossiers and were categorized in different causes: unavailability, indirectness, and imprecision of evidence. Identified uncertainties could be mentioned, described, and explored. Issues and ways forward to address uncertainty in CED schemes were discussed during the interviews. RESULTS: Forty-two uncertainties were identified. Thirteen (31%) were caused by unavailability, 17 (40%) by indirectness, and 12 (29%) by imprecision. Thirty-four uncertainties (81%) were only mentioned, 19 (45%) were described, and the impact of 3 (7%) uncertainties on the results was explored in the assessment dossiers. Seventeen uncertainties (40%) were included in the CED research plans. According to stakeholders, research did not address the identified uncertainty, but CED research should be designed to focus on these. CONCLUSIONS: In practice, uncertainties were neither systematically nor completely identified in the analyzed CED schemes. A framework would help to systematically identify uncertainty, and this process should involve all stakeholders. Value of information analysis, and the uncertainties that are not included in this analysis should inform CED research design.

Reviewing the quality, health benefit and value for money of chemotherapy and targeted therapy for metastatic breast cancer.

PURPOSE: To provide an overview of model characteristics and outcomes of model-based economic evaluations concerning chemotherapy and targeted therapy (TT) for metastatic breast cancer (MBC); to assess the quality of the studies; to analyse the association between model characteristics and study quality and outcomes. METHODS: PubMED and NHS EED were systematically searched. Inclusion criteria were as follows: English or Dutch language, model-based economic evaluation, chemotherapy or TT as intervention, population diagnosed with MBC, published between 2000 and 2014, reporting life years (LY) or quality-adjusted life-year (QALY) and an incremental cost-effectiveness ratio. General characteristics, model characteristics and outcomes of the studies were extracted. Quality of the studies was assessed through a checklist. RESULTS: 24 studies were included, considering 50 comparisons (20 concerning chemotherapy and 30 TT). Seven comparisons were represented in multiple studies. A health state-transition model including the following health states: stable/progression-free disease, progression and death was used in 18 studies. Studies fulfilled on average 14 out of the 26 items of the quality checklist, mostly due to a lack of transparency in reporting. Thirty-one per cent of the incremental net monetary benefit was positive. TT led to higher iQALY gained, and industry-sponsored studies reported more favourable cost-effectiveness outcomes. CONCLUSIONS: The development of a disease-specific reference model would improve the transparency and quality of model-based cost-effectiveness assessments for MBC treatments. Incremental health benefits increased over time, but were outweighed by the increased treatment costs. Consequently, increased health benefits led to lower value for money.

Introducing Open Science in Teaching Health Economic Modelling.

Open Science is gaining ground in all research fields, including health economics and outcomes research (HEOR). However, teaching Open Science is still in its infancy. This paper describes the design, implementation and evaluation of a teaching activity focusing on introducing Open Science during a Master's course during which participants have to develop a discrete event simulation. The teaching activity was organised as a series of lectures introducing different aspects of the Open Science philosophy and practices, such as good software coding practices, version control systems and reproducible research. The participants' increase in Open Science knowledge was elicited through a survey before and after the teaching innovation. After the teaching innovation, participants' knowledge of Open Science increased and they reported an improvement in Open Science-related skills, such as using a script-based statistical software, identifying and re-using open data, and collaborative script development. During the evaluation at the end of the course, the course participants mentioned that the Open Science-related content was interesting but would fit better within a course in which broader research-related content is taught. Based on this feedback, we will most likely narrow the scope of the Open-Science-related content in this course to Open Source Modelling which may better fit the scope of the course. This paper contains links to the teaching activities we developed and other resources which may be used to design teaching activities on Open Science. Herewith, we hope to inspire other teachers in including Open Science into their teaching.

Cost-effectiveness of screening for chronic kidney disease: existing evidence and knowledge gaps.

It is well known that the worldwide prevalence of chronic kidney disease (CKD) has risen to over 10% of the general population during the past decades. Patients with CKD are at increased risk of both kidney failure and cardiovascular disease (CVD), posing a substantial health challenge. Therefore, screening for CKD is warranted to identify and treat patients early to prevent progression and complications. In this issue of the Journal, Yeo and colleagues provide an updated systematic review of the cost-effectiveness of screening for CKD in the general adult population. They show that screening for CKD in high-risk populations is cost-effective and that there is limited evidence for screening the general population. It should be noted that most studies they discuss do not consider the benefit of screening to prevent CVD in addition to preventing kidney failure, the treatment effect of novel therapeutic agents such as SGLT2 inhibitors, and the possibility of screening in a home-based setting. These three aspects will likely improve the cost-effectiveness of CKD screening, making it feasible to move towards general population screening for CKD.

A Blueprint for Multi-use Disease Modeling in Health Economics: Results from Two Expert-Panel Consultations.

BACKGROUND: The current use of health economic decision models in HTA is mostly confined to single use cases, which may be inefficient and result in little consistency over different treatment comparisons, and consequently inconsistent health policy decisions, for the same disorder. Multi-use disease models (MUDMs) (other terms: generic models, whole disease models, disease models) may offer a solution. However, much is uncertain about their definition and application. The current research aimed to develop a blueprint for the application of MUDMs. METHODS: We elicited expert opinion using a two-round modified Delphi process. The panel consisted of experts and stakeholders in health economic modelling from various professional backgrounds. The first questionnaire concerned definition, terminology, potential applications, issues and recommendations for MUDMs and was based on an exploratory scoping review. In the second round, the panel members were asked to reconsider their input, based on feedback regarding first-round results, and to score issues and recommendations for priority. Finally, adding input from external advisors and policy makers in a structured way, an overview of issues and challenges was developed during two team consensus meetings. RESULTS: In total, 54 respondents contributed to the panel results. The term 'multi-use disease models' was proposed and agreed upon, and a definition was provided. The panel prioritized 10 potential applications (with comparing alternative policies and supporting resource allocation decisions as the top 2), while 20 issues (with model transparency and stakeholders' roles as the top 2) were identified as challenges. Opinions on potential features concerning operationalization of multi-use models were given, with 11 of these subsequently receiving high priority scores (regular updates and revalidation after updates were the top 2). CONCLUSIONS: MUDMs would improve on current decision support regarding cost-effectiveness information. Given feasibility challenges, this would be most relevant for diseases with multiple treatments, large burden of disease and requiring more complex models. The current overview offers policy makers a starting point to organize the development, use, and maintenance of MUDMs and to support choices concerning which diseases and policy decisions they will be helpful for.

Cost-Effectiveness of Three Different New-Generation Drug-Eluting Stents in the Randomised BIO-RESORT Trial at 3 Years.

BACKGROUND AND OBJECTIVE: Evidence on health economic outcomes for percutaneous coronary intervention (PCI) comparing different contemporary drug-eluting stents (DES) with each other is scarce, as most previous randomised DES trials did not assess such aspects. This prespecified health economic evaluation of the Comparison of Biodegradable Polymer and Durable Polymer Drug-Eluting Stents in an All Comers Population (BIO-RESORT) trial aimed to compare at 3-year follow-up both health effects and costs of PCI with one of three new-generation drug-eluting stents (DES) in patients with obstructive coronary artery disease. METHODS: The randomised BIO-RESORT trial assessed in 3514 patients the ultrathin-strut biodegradable polymer Orsiro sirolimus-eluting stent (SES) and very-thin-strut Synergy everolimus-eluting (EES) stent versus the thin-strut durable polymer Resolute Integrity zotarolimus-eluting stent (ZES). In the current analysis, we used the perspective of a health insurer in the Netherlands. The main endpoints were quality-adjusted life years (QALYs), and costs for each treatment strategy. Bootstrapping with 5000 resamples was performed to capture the uncertainty of results. RESULTS: Mean QALYs for each stent group were 2.566 for the SES, 2.551 for the EES, and 2.550 for the ZES. Mean costs per strategy were €14,670 for the SES, €14,946 for the EES, and €15,069 for the ZES. The SES had the highest probability of being cost-effective for every willingness-to-pay threshold up to €100,000 per QALY. Furthermore, in 79% of modelling scenarios, the SES was more effective and cheaper than ZES. CONCLUSION: At 3-year follow-up, PCI with the SES had the highest probability of being cost-effective due to greater effectiveness and lower costs compared with the ZES and EES. These findings suggest that, due to the overall high volume of coronary stenting in clinical practice, use of this SES could result in substantial cost savings, complemented by slight additional health benefits.

Cost-effectiveness of home-based screening of the general population for albuminuria to prevent progression of cardiovascular and kidney disease.

Background: Chronic kidney disease (CKD) is often detected late, leading to substantial health loss and high treatment costs. Screening the general population for albuminuria identifies individuals at high risk of kidney events and cardiovascular disease (CVD) who may benefit from early start of preventive interventions. Previous studies on the cost-effectiveness of albuminuria population screening were inconclusive, but were based on survey or cohort data rather than an implementation study, modelled screening as performed by general practitioners rather than home-based screening, and often included only benefits with respect to kidney events. We evaluated the cost-effectiveness of home-based general population screening for increased albuminuria based on real-world data obtained from a prospective implementation study taking into account prevention of CKD as well as CVD events. Methods: We developed an individual-level simulation model to compare home-based screening using a urine collection device with usual care (no home-based screening) in individuals of the general population aged 45-80, based on the THOMAS study (Towards HOMe-based Albuminuria Screening). Cost-effectiveness was assessed from the Dutch healthcare perspective with a lifetime horizon. The costs of the screening process and benefits of preventing CKD progression (dialysis and kidney transplantation) and CVD events (non-fatal myocardial infarction, non-fatal stroke, fatal CVD event) were reflected. Albuminuria detection led to treatment of identified risk factors. The model subsequently simulated CKD progression, the occurrence of CVD events, and death. The risks of experiencing CVD events were calculated using the SCORE2 CKD risk prediction model and individual-level data from the THOMAS study. Relative treatment effectiveness, quality of life scores, resource use, and cost inputs were obtained from literature. Model outcomes were the number of CKD and CVD-related events, total costs, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER) per QALY gained by screening versus usual care. All results were obtained through probabilistic analysis. Findings: The absolute difference between screening versus usual care in lifetime probability of dialysis, kidney transplantation, non-fatal myocardial infarction, non-fatal stroke, and fatal CVD events were 0.2%, 0.05%, 0.6%, 0.6%, and 0.2%, respectively. This led to relative decreases compared to usual care in lifetime incidence of these events of 10.7%, 11.1%, 5.1%, 4.1%, and 1.6%, respectively. The incremental costs and QALYs of screening were €1607 and 0.17 QALY, respectively, which led to a corresponding ICER of €9225/QALY. The probability of screening being cost-effective for the Dutch willingness-to-pay threshold for preventive population screening of €20,000/QALY was 95.0%. Implementing the screening in the subgroup of 45-64 years old reduced the ICER (€7946/QALY), whereas implementing screening in the subgroup of 65-80 years old increased the ICER (€10,310/QALY). A scenario analysis assuming treatment optimization in all individuals with newly diagnosed risk factors or known risk factors not within target range reduced the ICER to €7083/QALY, resulting from the incremental costs and QALY gain of €2145 and 0.30, respectively. Interpretation: Home-based screening for increased albuminuria to prevent CVD and CKD events is likely cost-effective. More health benefits can be obtained by screening younger individuals and better optimization of care in individuals identified with newly diagnosed or known risk factors outside target range. Funding: Dutch Kidney Foundation, Top Sector Life Sciences & Health of the Dutch Ministry of Economic Affairs.

Health Economic Research Assessing the Value of Early Detection of Cardiovascular Disease: A Systematic Review.

INTRODUCTION: Cardiovascular disease (CVD) is the most prominent cause of death worldwide and has a major impact on healthcare budgets. While early detection strategies may reduce the overall CVD burden through earlier treatment, it is unclear which strategies are (most) efficient. AIM: This systematic review reports on the cost effectiveness of recent early detection strategies for CVD in adult populations at risk. METHODS: PubMed and Scopus were searched to identify scientific articles published between January 2016 and May 2022. The first reviewer screened all articles, a second reviewer independently assessed a random 10% sample of the articles for validation. Discrepancies were solved through discussion, involving a third reviewer if necessary. All costs were converted to 2021 euros. Reporting quality of all studies was assessed using the CHEERS 2022 checklist. RESULTS: In total, 49 out of 5552 articles were included for data extraction and assessment of reporting quality, reporting on 48 unique early detection strategies. Early detection of atrial fibrillation in asymptomatic patients was most frequently studied (n = 15) followed by abdominal aortic aneurysm (n = 8), hypertension (n = 7) and predicted 10-year CVD risk (n = 5). Overall, 43 strategies (87.8%) were reported as cost effective and 11 (22.5%) CVD-related strategies reported cost reductions. Reporting quality ranged between 25 and 86%. CONCLUSIONS: Current evidence suggests that early CVD detection strategies are predominantly cost effective and may reduce CVD-related costs compared with no early detection. However, the lack of standardisation complicates the comparison of cost-effectiveness outcomes between studies. Real-world cost effectiveness of early CVD detection strategies will depend on the target country and local context. REGISTRATION OF SYSTEMATIC REVIEW: CRD42022321585 in International Prospective Registry of Ongoing Systematic Reviews (PROSPERO) submitted at 10 May 2022.

Efficacy, cost-minimization, and budget impact of a personalized discharge letter for basal cell carcinoma patients to reduce low-value follow-up care.

BACKGROUND: The incidence of keratinocyte carcinomas is high and rapidly growing. Approximately 80% of keratinocyte carcinomas consist of basal cell carcinomas (BCC) with 50% of these being considered as low-risk tumors. Nevertheless, 83% of the low-risk BCC patients were found to receive more follow-up care than recommended according to the Dutch BCC guideline, which is one visit post-treatment for this group. More efficient management could reduce unnecessary follow-up care and related costs. OBJECTIVES: To study the efficacy, cost-utility, and budget impact of a personalized discharge letter for low-risk BCC patients compared with usual care (no personalized letter). METHODS: In a multi-center intervention study, a personalized discharge letter in addition to usual care was compared to usual care in first-time BCC patients. Model-based cost-utility and budget impact analyses were conducted, using individual patient data gathered via surveys. The outcome measures were number of follow-up visits, costs and quality adjusted life years (QALY) per patient. RESULTS: A total of 473 first-time BCC patients were recruited. The personalized discharge letter decreased the number of follow-up visits by 14.8% in the first year. The incremental costs after five years were -€24.45 per patient. The QALYs were 4.12 after five years and very similar in both groups. The national budget impact was -€2,7 million after five years. CONCLUSIONS: The distribution of a personalized discharge letter decreases the number of unnecessary follow-up visits and implementing the intervention in a large eligible population would results in substantial cost savings, contributing to restraining the growing BCC costs.

State of the ART? Two New Tools for Risk Communication in Health Technology Assessments.

PURPOSE: Outcomes of health technology assessments (HTA) are uncertain, and decision-making is associated with a risk. This risk, consisting of the probability of making a wrong decision and its impact, is rarely considered in HTA. This hampers transparent and consistent risk assessment and management. The aim of this study was to develop risk communication tools in the context of health technology decision-making under uncertainty. METHODS: We performed a scoping review of tools for uncertainty and risk communication within HTA using citation pearl-growing. We developed two tools, drawing on existing publications on risk and uncertainty communication for inspiration. Individual semi-structured interviews with HTA stakeholders were performed to identify potential improvements in usefulness, user-friendliness, and information adequacy. Tools were amended and further evaluated in a real-world HTA and workshop with HTA stakeholders. RESULTS: The identified risk communication tools did not include non-quantified uncertainties, and did not link to risk management strategies. We developed two tools: the Assessment of Risk Table (ART), for a summary of quantified and non-quantified uncertainties and the resulting risk assessment, and the Appraisal of Risk Chart (ARCH), for linking net benefit and risk outcomes to appropriate risk management strategies. Stakeholders appreciated the usefulness of the tools. They also highlighted that more information on local policy options was required for optimal risk management use, and HTA processes may need adapting. CONCLUSION: The risk communication tools presented here can help assess risk, facilitate communication between analysts and decision-makers, and guide the appropriate use of available risk management strategies.

Building a trusted framework for uncertainty assessment in rare diseases: suggestions for improvement (Response to "TRUST4RD: tool for reducing uncertainties in the evidence generation for specialised treatments for rare diseases").

The aim of this letter to the editor is to provide a comprehensive summary of uncertainty assessment in Health Technology Assessment, with a focus on transferability to the setting of rare diseases. The authors of "TRUST4RD: tool for reducing uncertainties in the evidence generation for specialised treatments for rare diseases" presented recommendations for reducing uncertainty in rare diseases. Their article is of great importance but unfortunately suffers from a lack of references to the wider uncertainty in Health Technology Assessment and research prioritisation literature and consequently fails to provide a trusted framework for decision-making in rare diseases. In this letter to the editor we critique the authors' tool and provide pointers as to how their proposal can be strengthened. We present references to the literature, including our own tool for uncertainty assessment (TRUST; unrelated to the authors' research), apply TRUST to two assessments of orphan drugs in rare diseases and provide a broader perspective on uncertainty and risk management in rare diseases, including a detailed research agenda.

Lenalidomide with Rituximab for Previously Treated Follicular Lymphoma and Marginal Zone Lymphoma: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Celgene) of lenalidomide (Revlimid®), as part of the Single Technology Appraisal (STA) process, to submit evidence for the clinical effectiveness and cost-effectiveness of lenalidomide in combination with rituximab (MabThera®), together referred to as R2, for the treatment of adults with treated follicular lymphoma (FL) or marginal zone lymphoma (MZL). Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarises the company submission (CS), presents the ERG's critical review on the clinical and cost-effectiveness evidence in the CS, highlights the key methodological considerations, and describes the development of the NICE guidance by the Appraisal Committee. The CS included one relevant study, for the comparison of R2 versus rituximab monotherapy (R-mono): the AUGMENT trial. In addition, the company performed an unanchored indirect comparison of R2 versus rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) and rituximab combined with cyclophosphamide, vincristine, and prednisolone (R-CVP), using data for R2 from the AUGMENT trial and pooled data for R-CHOP/R-CVP from the Haematological Malignancy Research Network (HMRN) database. During the STA process, the company provided an addendum containing evidence on only the FL population, in line with the marketing authorisation obtained at that time, which did not include MZL. The probabilistic incremental cost-effectiveness ratios (ICERs) presented by the company were £27,768 per quality-adjusted life year (QALY) gained for R2 versus R-CHOP, £41,602 per QALY gained for R2 versus R-CVP, and £23,412 per QALY gained for R2 versus R-mono. The ERG's concerns included the validity of the unanchored comparison, the unavailability of a state transition model to verify the outcomes of the partitioned survival model, substantial uncertainty in survival curves, and potential over-estimation of utility values. The revised ERG base case resulted in ICERs ranging from £16,874 to £44,888 per QALY gained for R2 versus R-CHOP, from £23,135 to £59,810 per QALY gained for R2 versus R-CVP, and from £18,779 to £27,156 per QALY gained for R2 versus R-mono. Substantial uncertainty remained around these ranges. NICE recommended R2 within its marketing authorisation, as an option for previously treated FL (grade 1-3A) in adults, contingent on the company providing lenalidomide according to the commercial arrangement.

Rivaroxaban plus aspirin for the prevention of ischaemic events in patients with cardiovascular disease: a cost-effectiveness study.

BACKGROUND: Dual pathway inhibition with 2.5 mg rivaroxaban twice daily plus 100 mg aspirin once daily may be a promising alternative to 100 mg aspirin antiplatelet therapy for the prevention of cardiovascular events in patients with coronary artery disease and/or peripheral arterial disease. However, treatment costs and bleeding risks are higher, and there is another treatment option for peripheral arterial disease, 75 mg clopidogrel. A comprehensive assessment of benefits, risks and costs of dual pathway inhibition versus standard of care is needed. METHODS: We used a state transition model including cardiovascular, ischaemic limb and bleeding events to compare dual pathway inhibition to aspirin antiplatelet therapy in coronary artery disease, and additionally to clopidogrel antiplatelet therapy in peripheral arterial disease patients. We calculated the incremental cost-effectiveness ratio from costs and quality-adjusted life-years of lifelong treatment, and the cost-effectiveness probability at a €50,000/quality-adjusted life-year threshold. RESULTS: Quality-adjusted life-years and costs of dual pathway inhibition were highest, the incremental cost-effectiveness ratios versus aspirin were €32,109 in coronary artery disease and €26,381 in peripheral arterial disease patients, with 92% and 56% cost-effectiveness probability, respectively (clopidogrel was extendedly dominated). Incremental cost-effectiveness ratios were below €20,000 in comorbid peripheral arterial disease patients and coronary artery disease patients younger than 65 years, incremental cost-effectiveness ratios were above €50,000 in carotid artery disease patients and coronary artery disease patients older than 75 years. CONCLUSION: Lifelong preventive treatment of coronary artery disease and peripheral arterial disease patients at risk of cardiovascular events with dual pathway inhibition improves health outcomes and seems overall cost-effective relative to aspirin antiplatelet therapy and also to clopidogrel antiplatelet therapy for peripheral arterial disease, particularly in comorbid patients, but not in older patients and in carotid artery disease patients. These findings may warrant a targeted approach.