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Abstract Background With increasing age and longevity, the rising number of frail elders with complex and numerous health-related needs demands a coordinated health care delivery system integrating cure, care and welfare. Studies on the effectiveness of such comprehensive chronic care models targeting frail elders show inconclusive results. The CareWell-primary care program is a complex intervention targeting community-dwelling frail elderly people, that aims to prevent functional decline, improve quality of life, and reduce or postpone hospital and nursing home admissions of community dwelling frail elderly. Methods/design The CareWell-primary care study includes a (cost-) effectiveness study and a comprehensive process evaluation. In a one-year pragmatic, cluster controlled trial, six general practices are non-randomly recruited to adopt the CareWell-primary care program and six control practices will deliver ‘care as usual’. Each practice includes a random sample of fifty frail elders aged 70 years or above in the cost-effectiveness study. A sample of patients and informal caregivers and all health care professionals participating in the CareWell-primary care program are included in the process evaluation. In the cost-effectiveness study, the primary outcome is the level of functional abilities as measured with the Katz-15 index. Hierarchical mixed-effects regression models / multilevel modeling approach will be used, since the study participants are nested within the general practices. Furthermore, incremental cost-effectiveness ratios will be calculated as costs per QALY gained and as costs weighed against functional abilities. In the process evaluation, mixed methods will be used to provide insight in the implementation degree of the program, patients’ and professionals’ approval of the program, and the barriers and facilitators to implementation. Discussion The CareWell-primary care study will provide new insights into the (cost-) effectiveness, feasibility, and barriers and facilitators for implementation of this complex intervention in primary care. Trial registration The CareWell-primary care study is registered in the ClinicalTrials.gov Protocol Registration System: NCT01499797

Background: Venetoclax is a first-in-class targeted therapy option that is an inducer of apoptosis in chronic lymphocytic leukemia (CLL) cells. The open-label phase III CLL14 clinical trial showed that venetoclax combined with obinutuzumab (VEN+O) is superior to obinutuzumab combined with chlorambucil in newly diagnosed patients with CLL. The aim of this study was to assess the health economic value of VEN+O for the frontline treatment of CLL in Canada from a publicly funded healthcare system perspective., Methods: A partitioned survival analyses model was developed including three health states: progression free, progressed, and death. A cycle length of 28 days and a time horizon of 10 years was assumed. VEN+O treatment for a fixed duration of 12 months was compared to obinutuzumab combined with chlorambucil, fludarabine plus cyclophosphamide plus rituximab, bendamustine plus rituximab, chlorambucil plus rituximab, ibrutinib, and acalabrutinib. The population in the model included both unfit and overall frontline CLL patients, two subgroups were also assessed (patients with del17p/TP53 mutations and patients without del17p/TP53 mutations). Survival data extrapolated from the CLL14 trial were used to populate the model. Uncertainty was assessed via one-way sensitivity analyses, probabilistic analyses, and scenario analyses., Results: Based on the probabilistic analyses, unfit frontline CLL patients receiving VEN+O were estimated to incur costs of Canadian dollars ($) 217,727 [confidence interval (CI) $170,725, $300,761] (del17p/TP53: $209,102 [CI $159,698, $386,190], non-del17p/TP53: $217,732 [CI $171,232, $299,063]) and accrue 4.96 [CI 4.04, 5.82] quality-adjusted life-years (del17p/TP53: 3.11 [CI 2.00, 4.20], non-del17p/TP53: 5.04 [CI 4.05, 5.92]). Obinutuzumab combined with chlorambucil, bendamustine plus rituximab, chlorambucil plus rituximab, and ibrutinib accrued lower quality-adjusted life-years and higher costs and as such, VEN+O was the dominant treatment option. The full incremental analysis showed that acalabrutinib was more expensive and more efficacious compared with VEN+O with an incremental-cost-effectiveness-ratio of $2,139,180/quality-adjusted life-year versus VEN+O and not a cost-effective option in Canada. Probabilistic analyses show that at a willingness to pay of $50,000/quality-adjusted life-year gained, VEN+O has the greatest probability of being cost effective., Conclusions: VEN+O is a cost-effective treatment option for unfit frontline CLL patients and provides value for money to healthcare payers., (© 2022. The Author(s).)

Objective: Nivolumab plus ipilimumab (NIVO + IPI) and pembrolizumab plus axitinib (PEM + AXI) have demonstrated significant clinical benefits as first-line (1 L) treatments for intermediate/poor-risk advanced renal cell carcinoma (aRCC) patients. This study aimed to assess the cost-effectiveness of NIVO + IPI versus PEM + AXI from a Brazilian private healthcare system perspective, utilizing a novel approach to estimate comparative efficacy between the treatments., Methods: A three-state partitioned survival model (progression-free, progressed, and death) was developed to estimate costs, life-years (LYs), quality-adjusted LYs (QALYs), and the incremental cost-utility ratio (ICUR) over a 40-year time horizon. In the absence of head-to-head comparisons between NIVO + IPI and PEM + AXI, clinical data for NIVO + IPI was obtained from CheckMate 214 (NCT02231749) and for PEM + AXI from KEYNOTE-426 (NCT02853331). A matching-adjusted indirect comparison was conducted to account for the imbalance of treatment effect modifiers between the trials. Patient characteristics, resource use, health state utilities, and costs were based on Brazilian-specific sources. Costs and health outcomes were both discounted by 5% annually in line with Brazilian guidelines. The robustness of the results was evaluated through extensive sensitivity analysis and scenario analyses., Results: When comparing the matched versus unmatched OS, PFS, and TTD curves there was no noteworthy difference. NIVO + IPI was associated with cost savings (R$ 350,232), higher LYs (5.54 vs. 4.61), and QALYs (4.74 vs. 3.76) versus PEM + AXI, resulting in NIVO + IPI dominating PEM + AXI. Key model drivers were the treatment duration for PEM, NIVO, and AXI. NIVO + IPI remained dominant in all scenario analyses, which indicated that model results were robust to alternative modelling inputs or assumptions., Conclusions: This analysis shows that NIVO + IPI is estimated to be a life-extending and potentially cost-saving 1 L treatment option when compared with PEM + AXI for intermediate/poor-risk a RCC patients in the Brazilian private healthcare system.

Aims: Existing treatment-sequence models for psoriasis are limited by lines of treatments included. We sought to more accurately capture the patient experience with an increasing number of treatments while maintaining the complexity and transparency of current models., Materials and Methods: We adapted a standard treatment-sequence model for psoriasis with two lines of active treatments followed by best supportive care (BSC). The first line was used to model the targeted treatments for comparison (Biologic A or B). The second line was used potentially to model all treatments (excluding the first-line treatment) before BSC, termed the basket of biologics (BoB). First-line treatment and the BoB were modeled with an induction and maintenance phase. The BoB efficacy was assumed to be the average of all treatments included and the BoB annual discontinuation rate was based on the number of treatments included and their individual annual discontinuation rate. A varying number of treatments in the BoB were tested (1, 5, 10). Model inputs were from published literature., Results: In our example, when the number of treatments in the BoB increased from 1 to 10, the annual discontinuation rate of the BoB dropped from 16.5% to 1.2%. Time on BoB increased from 4.16 to 19.16 years and the time on BSC decreased from 28.28 to 13.29 years. Total costs and quality-adjusted life years increased with an increasing number of treatments in the BoB., Limitations: The properties of the BoB were simplified in order to maintain the transparency of the model. Results may differ if individual treatments in the BoB are modeled line by line., Conclusions: Modification with the BoB allows a greater number of treatments within the model, providing a closer reflection of clinical reality, and has implications for evaluation of the long-term cost-effectiveness of psoriasis treatments.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is a significant health and economic burden in the United States. Treatments include chemoimmunotherapy, such as obinutuzumab (G) plus chlorambucil (Clb) or bendamustine plus rituximab (BR), and chemotherapy-free regimens incorporating oral targeted therapies such as ibrutinib (Ibr), acalabrutinib (Acala), or venetoclax (Ven). Most chemotherapy-free regimens require continuous treatment to progression, while Ven plus G (VenG) is given for a fixed duration of 12 months, based on the CLL14 trial that led to its approval. Fixed-duration VenG has the potential for cost savings compared with treat-to-progression chemotherapy-free regimens. OBJECTIVE: To evaluate the cost-effectiveness of 12 months fixed-duration VenG in first-line treatment of unfit patients with CLL from a US health care payer perspective compared with GClb, BR, Ibr, Ibr + G, Ibr + R, Acala, and Acala + G. METHODS: A partitioned survival model was developed with 3 health states: progression-free survival (PFS), postprogression survival, and dead. The patient population, as based on the CLL14 trial, comprised previously untreated unfit patients with CLL (mean age 71.1 years, 33.1% female). The distribution of patients in each health state over time was estimated using extrapolated PFS and overall survival (OS) curves for VenG and GClb, based on CLL14 data 2 or more years after treatment cessation. PFS and OS for the other comparators were estimated using hazard ratios vs VenG, based on a network metaanalysis. Adverse events, utility values, and costs were obtained from published literature. The model estimated life-years gained, quality-adjusted life-years (QALYs) gained, and costs. The time horizon was 20 years, with a cycle time of 28 days. Outcomes and costs were discounted at 3.0% per year, and costs were estimated from a US health care payer perspective. One-way and probabilistic sensitivity analyses were conducted. RESULTS: In this cross-trial analysis of unfit CLL patients, in the base case, VenG had lower projected total costs than all comparators investigated. VenG also had larger projected health benefits (more QALYs gained) than GClb, BR, Ibr, and Ibr + R. VenG was therefore more effective and less costly than these comparators (dominant). Ibr + G, Acala, and Acala + G showed higher QALYs gained vs VenG (0.022, 0.672, and 0.961, respectively), and substantially higher projected costs vs VenG ($1,488,400, $1,579,737, and $1,656,154, respectively). Thus, Ibr + G, Acala, and Acala + G would cost more than $1,000,000 per QALY gained vs VenG. At the commonly used willingness-to-pay threshold of $150,000 per QALY gained, Ibr + G, Acala, and Acala + G were not cost-effective compared with VenG. CONCLUSIONS: Fixed-duration VenG for 12 months is a cost-effective first-line treatment option for unfit CLL patients compared with other available options and provides value for money to US health care payers at a threshold of $150,000 per QALY gained. Future studies with longer trial follow-up and more mature survival data may help to confirm longer-term cost benefits of VenG. DISCLOSURES: Genentech Inc. and AbbVie provided financial support for this study. Genentech Inc., AbbVie, and Pharmerit - An OPEN Health Company participated in the design, study conduct, analysis, and interpretation of data, as well as the writing, review, and approval of the manuscript. Venetoclax is being developed in a collaboration between Genentech Inc. and AbbVie. Ravelo and Shapouri are employed by Genentech Inc. and have ownership interests. Manzoor and Sail are employed by AbbVie and have ownership interests. Chatterjee, van de Wetering, and Qendri, employees of Pharmerit - An OPEN Health Company, received consultancy fees from AbbVie. Davids has received consultancy fees from AbbVie, AstraZeneca, Eli Lilly, Genentech Inc., Janssen, MEI Pharma, Novartis, Pharmacyclics, and Verastem; research funding from Ascentage Pharma, Genentech Inc., MEI Pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, and Verastem; and has served on board of directors or advisory committees for AbbVie, Adaptive Biotechnologies, AstraZeneca, BeiGene, Eli Lilly, Genentech Inc., Janssen, Pharmacyclics, TG Therapeutics, and Verastem. This study was presented as a poster at ASH 61st Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL.

Aim: To analyse the cost-effectiveness of MEP with standard of care (SoC) versus other anti-IL-5 therapies approved for the treatment of severe eosinophilic asthma (SEA) patients, within the Spanish National Health System (NHS) perspective., Methods: A Markov model with a 4-week cycle length was used to compare MEP with BEN and RES as therapies added to SoC in the management of SEA, in terms of cost per QALY gained and incremental cost-effectiveness ratio (ICER). Costs (€2019) were obtained from public sources, while utilities and transition probabilities were retrieved from literature, e.g. network meta-analysis. Continuation criteria for biological treatment and reduction of oral corticosteroids (OCS) was set at 50% minimum reduction of exacerbation rate. Adverse events related to chronic OCS use included diabetes, osteoporosis, cataracts, acute myocardial infarct, and peptic ulcer. The analysis was performed over a 5-year time horizon from the National Healthcare System (NHCS) perspective, with a yearly discount rate of 3% applied to both costs and QALYs. Probabilistic sensitivity analysis and univariate deterministic sensitivity analysis were performed to address uncertainty around the cost-effectiveness results., Results: On top of SoC, the model indicates that MEP is dominant (lower cost, higher benefit) compared to BEN and RES: For BEN and RES, respectively, treatment with MEP had a point estimate of 0.076 and 0.075 additional QALYs, and savings of €3,173.47 and €7,772.95 per patient. The findings were robust to variation as estimated using sensitivity analysis., Conclusions: MEP is a cost-effective treatment in comparison with BEN and RES added to SoC for patients with SEA in the Spanish setting.

Background: In the UK, the standard of care for patients with multiple myeloma who received ≥2 prior treatments is lenalidomide plus dexamethasone (LEN + DEX) and pomalidomide plus DEX (POM + DEX) (in Wales only). Recently, panobinostat plus bortezomib and DEX (PAN + BTZ + DEX) was licensed in this setting. The current study assessed the progression-free survival (PFS) and overall survival (OS) outcomes with PAN + BTZ + DEX versus LEN + DEX (primary comparator) and POM + DEX (exploratory comparator)., Methods: Since an anchor-based indirect treatment comparison was not feasible, the matching-adjusted indirect treatment comparison approach was used. To compare the survival outcomes, patient-level data were generated for the comparators utilizing published Kaplan-Meier survival estimates. The use of approximated patient-level data and matched data for PAN + BTZ + DEX allowed the use of Cox proportional hazards models and the assessment of the proportional hazards assumption. In cases where there was evidence that the proportional hazards assumption was violated, time-dependent hazard ratios (HRs) were estimated. Median and mean values for PFS and OS were predicted., Results: For both PFS and OS, the proportional hazards assumption was not satisfied, therefore time-dependent HRs were estimated. Using time-dependent HRs, the mean PFS was estimated to be 11.83 months for PAN + BTZ + DEX and 10.96 months for LEN + DEX. The corresponding mean OS estimates were 30.73 and 27.76 months, respectively. Comparisons with POM + DEX were affected by large uncertainty and did not allow making robust inferences., Conclusions: To our knowledge, this is the first study that combined matching-adjusted indirect treatment comparison with time-dependent HRs to address changing patterns in the HR. The results suggest that treatment with PAN + BTZ + DEX and LEN + DEX are associated with similar mean PFS and OS in the third-line treatment setting of multiple myeloma.

Background: Timely provision of information on the cost-effectiveness of innovations in health care becomes more and more important, resulting in increasing pressure on researchers to provide proof of cost-effectiveness in a short time frame. However, most of these innovations require considerable time and effort to optimally implement leading to a biased "steady state" cost-effectiveness outcome. As decision makers in health care predominantly have a short-term focus, the discrepancy between short-term study outcomes and long-term cost-effectiveness may very well lead to misguided decisions about the adoption of innovations in health care., Methods: Factors such as learning effects, capacity constraints, and delayed time to benefit are all related to a short-run timeframe and result in inefficiencies during the implementation of an innovation. These factors and the mechanisms by which they influence the cost-effectiveness outcome are explained for three different types of healthcare innovations., Results: As standard cost-effectiveness analysis assumes costs and effects to behave constant and representative for an innovation's entire economic lifetime, resulting cost-effectiveness outcomes might give a biased, and often overly pessimistic, reflection of the actual cost-effectiveness of an innovation. This is further amplified by the fact that short-run inefficiencies are most prevalent and impactful during an innovation's earliest stage of operation., Conclusions: This study advocates to carefully take into account the different factors contributing to lag-time bias in the design and analysis of cost-effectiveness studies, and to communicate potential biases due to short-run inefficiencies to all stakeholders involved in the decision making process.

Cost-effectiveness analysis has become a widely accepted tool for decision making in health care. The standard textbook cost-effectiveness analysis focuses on whether to make the switch from an old or common practice technology to an innovative technology, and in doing so, it takes a global perspective. In this article, we are interested in a local perspective, and we look at the questions of whether and when the switch from old to new should be made. A new approach to cost-effectiveness from a local (e.g., a hospital) perspective, by means of a mathematical model for cost-effectiveness that explicitly incorporates time, is proposed. A decision rule is derived for establishing whether a new technology should be adopted, as well as a general rule for establishing when it pays to postpone adoption by 1 more period, and a set of decision rules that can be used to determine the optimal timing of adoption. Finally, a simple example is presented to illustrate our model and how it leads to optimal decision making in a number of cases.

This paper examines the short run inefficiencies that arise during gradual implementation of a new cost-effective technology in healthcare. These inefficiencies arise when health gains associated with the new technology cannot be obtained immediately because the new technology does not yet supply all patients, and when there is overcapacity for the old technology in the short run because the supply of care is divided among two mutually exclusive technologies. Such efficiency losses are not taken into account in standard textbook cost-effectiveness analysis in which a steady state is presented where costs and effects are assumed to be unchanging over time. A model is constructed to quantify such short run inefficiencies as well as to inform the decision maker about the optimal implementation pattern for the new technology. The model operates by integrating the incremental net benefit equations for both the period of co-existence of mutually exclusive technologies and the period after complete substitution of the old technology. It takes into account the rate of implementation of the new technology, depreciation of capital of the old technology as well as the demand curves for both technologies. The model is applied to the real world case of converting from screen film to digital mammography in the Netherlands.

Objective: This article provides a systematic and critical review of the evolving methods and applications of value of information (VOI) in academia and practice and discusses where future research needs to be directed., Methods: Published VOI studies were identified by conducting a computerized search on Scopus and ISI Web of Science from 1980 until December 2011 using pre-specified search terms. Only full-text papers that outlined and discussed VOI methods for medical decision making, and studies that applied VOI and explicitly discussed the results with a view to informing healthcare decision makers, were included. The included papers were divided into methodological and applied papers, based on the aim of the study., Results: A total of 118 papers were included of which 50 % (n = 59) are methodological. A rapidly accumulating literature base on VOI from 1999 onwards for methodological papers and from 2005 onwards for applied papers is observed. Expected value of sample information (EVSI) is the preferred method of VOI to inform decision making regarding specific future studies, but real-life applications of EVSI remain scarce. Methodological challenges to VOI are numerous and include the high computational demands, dealing with non-linear models and interdependency between parameters, estimations of effective time horizons and patient populations, and structural uncertainties., Conclusion: VOI analysis receives increasing attention in both the methodological and the applied literature bases, but challenges to applying VOI in real-life decision making remain. For many technical and methodological challenges to VOI analytic solutions have been proposed in the literature, including leaner methods for VOI. Further research should also focus on the needs of decision makers regarding VOI.

Important assumptions that underlie cost-effectiveness analysis (CEA) are that production technologies are convex and that production processes always perform at constant returns to scale. However, in the short run these assumptions are likely to be violated. Therefore, CEAs might overestimate cost-effectiveness in the short run. To come up with a more precise cost-effectiveness outcome, we present a model that is able to correct the long-run incremental net benefit (INB) for short-run inefficiencies. This provides decision makers with a more realistic view of the expected efficiency gains. This model starts by determining the initial efficiency losses inflicted by inflexible resources. Then the model is made dynamic in order to adjust the efficiency losses by allowing for refilling and writing off freed capacity. Finally, the model calculates the length of the short-run time frame in which such efficiency losses exist, and a correction term with which the usual long-run INB should be adjusted to account for short-run inefficiencies. The model is applied to two cases: dialysis and digitizing a radiography department. The dialysis case shows moderate short-run efficiency losses while in the radiography case short-run efficiency losses are sufficiently large to cause a switch in cost-effectiveness from favorable to inefficient in the short run., (Copyright © 2011 John Wiley & Sons, Ltd.)

To detect Bovine Virus Diarrhoea Virus (BVDV)-specific antibodies in cattle serum, plasma and bulk milk, a simple, reliable and rapid blocking ELISA ("Ceditest") has been developed using two monoclonal antibodies ("WB112" and "WB103") directed to different highly conserved epitopes on the non-structural peptide NS3 of pestiviruses. The test can be performed at high reproducibility using undiluted samples. In testing 1000 field serum samples, the ELISA showed a specificity and a sensitivity relative to the virus neutralization test of 99% and 98%, respectively. The blocking ELISA is able to detect specific antibodies in serum obtained 12 days after an acute infection and in serum of vaccinated and challenged animals. A frequency distribution diagram, obtained by testing almost 1800 random Dutch field serum samples, showed a clear separation between a negative population (maximum frequency of the % inhibition at -5%) and a positive population (maximum frequency of the % inhibition at 95%). Based on these data, the prevalence of seropositive animals was 65% (95% confidence interval: 63%-67%). By exchanging plasma- and bulk milk samples between two laboratories (The Netherlands and Denmark), a good overall agreement was found between results obtained with the Ceditest and those obtained with the Danish blocking ELISA as used in the Danish BVDV eradication programme. The results indicate that BVDV infections can reliably be diagnosed by the Ceditest ELISA and that the test is suitable for use in large scale screening and eradication programmes.

Fourteen synthetic peptides corresponding to previously mapped antigenic sites in VP2 of canine parvovirus (CPV) were used for immunization of rabbits to identify antiviral properties favourable for inclusion into a vaccine. Most antipeptide antisera obtained were reactive with viral protein, and with one of them it was possible to locate the hypothetical amino terminus of VP3 within positions 15-31 of VP2. Virus-neutralizing antibodies were only obtained with two overlapping 15-mer peptides corresponding in sequence to the amino terminus of VP2 (MSDGAVQPDGGQPAVRNERAT). Antibodies in the neutralizing sera bound most strongly to amino acids of the sequence DGGQPAV within the N-terminus of VP2, indicating that efforts to develop a synthetic vaccine against CVP should be focused on this stretch of amino acids. The two peptides induced long-lasting immunity (at least 8 months) using either Freund's adjuvant or aluminium hydroxide plus Quil A. Thus, this approach delineated the exact peptide sequence useful for vaccines applied to the amino-terminal region of VP2. These findings in experimental animals form a solid basis for exploration of a synthetic peptide vaccine against parvovirus infection in dogs, minks or cats.