The Cost-Effectiveness of Seizure Dogs for Persons Living With Severe Refractory Epilepsy: Results From the EPISODE Study.

OBJECTIVES: The Epilepsy Support Dog Evaluation study was commissioned by the Dutch Ministry of Health, Welfare and Sports to inform a reimbursement decision on seizure dogs. The randomized trial found that seizure dogs reduce seizure frequency and improve health-related quality of life of persons with severe refractory epilepsy (PSREs). This article examined the cost-effectiveness (CE) of adding seizure dogs to usual care for PSREs in The Netherlands. METHODS: A microsimulation model was developed, informed by generalized linear mixed models using patient-level trial data from the Epilepsy Support Dog Evaluation study. The model adopted a 10-year time horizon and took a societal perspective. Seizure frequency was predicted as a function of time with the seizure dog. Patient utilities, caregiver utilities, and costs were predicted as a function of seizure frequency and time with the seizure dog. RESULTS: Quality-adjusted life-years (QALYs) of PSREs with a seizure dog and usual care alone were estimated at 6.28 and 5.65, respectively (Δ 0.63). For caregivers, estimated QALYs were 6.94 and 6.52, respectively (Δ 0.42). Total costs were respectively €228 691 and €226 261 (Δ €2430). Intervention costs were largely offset by savings in informal care and healthcare. The incremental CE ratio was €2314/QALY. Probabilistic sensitivity analysis indicated a 91% probability of seizure dogs being cost-effective at the €50 000/QALY threshold. The incremental CE ratio fell well below this threshold in scenario analyses. CONCLUSIONS: Seizure dogs are likely to be a cost-effective addition to usual care for PSREs in The Netherlands.

Benefits of early highly effective versus escalation treatment strategies in relapsing multiple sclerosis estimated using a treatment-sequence model.

BACKGROUND: Uncertainty about disproportionate impact on health care budgets limits implementation of early highly effective treatment (EHT) in multiple sclerosis (MS). OBJECTIVE: To estimate cost-effectiveness of escalation versus EHT disease-modifying treatment (DMT) sequences. METHODS: Using a health-economic approach, we analysed health benefits (relapse rate reduction, disability prevention), direct/indirect DMT and societal costs of escalation versus EHT DMT sequences. In scenario analyses, we allowed (1) earlier use of alemtuzumab (ALE) and (2) a single retreatment with cladribine (CLA). RESULTS: In our model, we showed that the ratio between costs and quality-adjusted life years (QALYs) for the most cost-effective EHT and escalation sequence results into a similar net health benefit with higher costs and also higher QALYs associated with an EHT versus escalation strategy. Earlier use of ALE is more cost-effective than in later lines, even when aggravating the impact of its side-effects tenfold. Retreatment with CLA was more cost-effective in both escalation and EHT sequences. CONCLUSIONS: Certain EHT sequences are equally cost-effective to escalation sequences and are likely to result in more health at uncertain additional costs. The favourable cost-benefit ratio of CLA and ALE suggests that a wider application of affordable highly effective therapies could promote the cost-effectiveness both EHT and escalation approaches.

Estimating the Prognostic Value of the NTRK Fusion Biomarker for Comparative Effectiveness Research in The Netherlands.

OBJECTIVES: We evaluated the prognostic value of the neurotrophic tyrosine receptor kinase (NTRK) gene fusions by comparing the survival of patients with NTRK+ tumours with patients without NTRK+ tumours. METHODS: We used genomic and clinical registry data from the Center for Personalized Cancer Treatment (CPCT-02) study containing a cohort of cancer patients who were treated in Dutch clinical practice between 2012 and 2020. We performed a propensity score matching analysis, where NTRK+ patients were matched to NTRK- patients in a 1:4 ratio. We subsequently analysed the survival of the matched sample of NTRK+ and NTRK- patients using the Kaplan-Meier method and Cox regression, and performed an analysis of credibility to evaluate the plausibility of our result. RESULTS: Among 3556 patients from the CPCT-02 study with known tumour location, 24 NTRK+ patients were identified. NTRK+ patients were distributed across nine different tumour types: bone/soft tissue, breast, colorectal, head and neck, lung, pancreas, prostate, skin and urinary tract. NTRK fusions involving the NTRK3 gene (46%) and NTRK1 gene (33%) were most common. The survival analysis rendered a hazard ratio (HR) of 1.44 (95% CI 0.81-2.55) for NTRK+ patients. Using the point estimates of three prior studies on the prognostic value of NTRK fusions, our finding that the HR is > 1 was deemed plausible. CONCLUSIONS: NTRK+ patients may have an increased risk of death compared with NTRK- patients. When using historic control data to assess the comparative effectiveness of TRK inhibitors, the prognostic value of the NTRK fusion biomarker should therefore be accounted for.

Effectiveness of Seizure Dogs for People With Severe Refractory Epilepsy: Results From the EPISODE Study.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate whether people living with severe medically refractory epilepsy (PSRE) benefit from a seizure dog. METHODS: An individual-level stepped-wedge randomized controlled trial was conducted. The study was conducted in the Netherlands among adults with daily to weekly seizures. All participants were included simultaneously (on June 1, 2019) while receiving usual care. Then, during the 36-month follow-up, they received a seizure dog in a randomized sequence. Participants kept a seizure diary and completed 3-monthly surveys. Seizure frequency was the primary outcome. Secondary outcomes included seizure-free days, seizure severity, health-related quality of life (HRQoL), and well-being. Data were analyzed using generalized linear mixed modeling (GLMM). The models assumed a delayed intervention effect, starting when the seizure dog reached an advanced stage of training. Effects were calculated as changes per 28-day period with the intervention. RESULTS: Data were collected from 25 participants, of whom 20 crossed over to the intervention condition. The median follow-up was 19 months with usual care and 12 months with the intervention. On average, participants experienced 115 (SD 164) seizures per 28-day period in the usual care condition and 73 (SD 131) seizures in the intervention condition. Seven participants achieved a reduction of 50% or more at the end of follow-up. GLMM indicated a 3.1% decrease in seizure frequency for each consecutive 28-day period with the intervention (0.969, 95% CI 0.960-0.977). Furthermore, an increase in the number of seizure-free days was observed (1.012, 95% CI 1.009, 1.015), but no effect on seizure severity measured with the NHS3. Generic HRQoL scores improved, as reflected in the decrease in EQ-5D-5L utility decrement (0.975, 95% CI 0.954-0.997). Smaller improvements were observed on overall self-rated HRQoL, epilepsy-specific HRQoL, and well-being, measured with the EQ VAS, QOLIE-31-P, and ICECAP-A, respectively. DISCUSSION: Seizure dogs reduce seizure frequency, increase the number of seizure-free days, and improve the quality of life of PSRE. The magnitude of the effect on generic HRQoL indicates that seizure dogs benefit PSRE beyond the impact on seizure frequency alone. Early discontinuation of seizure dog partnerships suggests that this intervention is not suitable for all PSRE and requires further study. TRIAL REGISTRATION INFORMATION: This study was registered in the Dutch Trial Register (NL6682) on November 28, 2017. Participants were enrolled on June 1, 2019. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that seizure dogs are associated with a decrease in seizure frequency in adult patients with medically refractory epilepsy.

Benefits of sphingosine-1-phosphate receptor modulators in relapsing MS estimated with a treatment sequence model.

BACKGROUND: Three sphingosine-1-phosphate receptor (S1PR) modulators are currently available as disease-modifying therapies (DMTs) for relapsing MS in the Netherlands (i.e. fingolimod, ozanimod and ponesimod). We aimed to identify which S1PR modulator yields the highest benefit from a health-economic and societal perspective during a patient's lifespan. METHODS: Incorporating Dutch DMT list prices, we used the ErasmusMC/iMTA MS model to compare DMT sequences, including S1PR modulators and eight other DMT classes, for treatment-naïve patients with relapsing MS in terms of health outcomes (number of lifetime relapses, time to Expanded Disability Status Scale (EDSS) 6, lifetime quality-adjusted life years (QALYs)) and cost-effectiveness (net health benefit (NHB)). We estimated the influence of list price and EDSS progression on cost-effectiveness outcomes. RESULTS: In deterministic and probabilistic analysis, DMT sequences with ponesimod have lower lifetime costs and higher QALYs resulting in a higher average NHB compared to sequences with other S1PR modulators. Ponesimod remains the most cost-effective S1PR modulator when EDSS progression is class-averaged. Given the variable effects on disability progression, list price reductions could make fingolimod but not ozanimod more cost-effective than ponesimod. CONCLUSION: Our model favours ponesimod among the S1PR modulators for the treatment of relapsing MS. This implies that prioritizing ponesimod over other S1PR modulators translates into a more efficacious spending of national healthcare budget without reducing benefit for people with MS. Prioritizing cost-effective choices when counselling patients contributes to affordable and accessible MS care.

Cost-effectiveness of extended DPYD testing before fluoropyrimidine chemotherapy in metastatic breast cancer in the UK.

The aim of this study was to evaluate the cost-effectiveness of ToxNav©, a multivariant genetic test, to screen for DPYD followed by personalized chemotherapy dosing for metastatic breast cancer in the UK compared with no testing followed by standard dose, standard of care. In the main analysis, ToxNav was dominant over standard of care, producing 0.19 additional quality-adjusted life years and savings of £78,000 per patient over a lifetime. The mean additional quality-adjusted life years per person from 1000 simulations was 0.23 savings (95% CI: 0.22-0.24) at £99,000 (95% CI: £95-102,000). Varying input parameters independently by range of 20% was unlikely to change the results in the main analysis. The probabilistic sensitivity analysis showed ~97% probability of the ToxNav strategy to be dominant.

Cost-effectiveness and budget impact analysis of screening strategies for maturity-onset diabetes of the young in three European countries.

Background: Correct diagnosis of maturity-onset diabetes of the young (MODY), which is often misdiagnosed as Type 1 or 2 diabetes, is important for providing appropriate treatment. Materials & Methods: A diabetes model was adapted to Hungary, the Netherlands, and the UK to analyse the cost-effectiveness and budget impact of different screening strategies for MODY with 20 years time horizon. Results: Compared with no screening, screening with the MODY calculator then genetic testing is considered cost-effective with respect to each country's willingness to pay threshold. The addition of autoantibody testing dominated the no screening strategy. The budget impact of the strategies ranges between 0.001 and 0.025% of annual public healthcare spending. Conclusion: The analysed strategies are considered good value for money with potential cost savings in the long term.

Cost-effectiveness of genetic-based screening strategies for maturity-onset diabetes of the young.

Maturity-onset diabetes of the young (MODY) is often misdiagnosed as Type I or II diabetes. This study was designed to assess the cost-effectiveness of MODY screening strategies in Hungary, which included a recent genetic test compared with no routine screening for MODY. A simulation model that combined a decision tree and an individual-level Markov model was constructed to assess the costs per quality-adjusted life year of screening strategies. Stratifying patients based on age and insulin treatment followed by a risk assessment questionnaire, a laboratory test and genetic testing was the most cost-effective strategy, saving EUR 12 and generating 0.0047 quality-adjusted life years gained per screened patient. This screening strategy could be considered for reimbursement, especially in countries with limited resources.

Lessons learned from the application of the HEcoPerMed guidance to three modeling case studies.

Background: The HEcoPerMed consortium developed a methodological guidance for the harmonization and improvement of economic evaluations in personalized medicine. Materials & methods: In three therapeutic areas, health economic models were developed to scrutinize the recommendations of the guidance. Results: Altogether, 20 of the 23 recommendations of the guidance were addressed by the models. Seven recommendations were applied in all studies, six in two of the studies and seven in one of the studies. Recommendations with an essential role on the final conclusions of the analyses were identified in each study. Conclusion: The guidance was found to be best used as a tool to identify and prioritize issues, verify solutions and justify decisions during the economic analysis of personalized interventions.

Cost-effectiveness of alternative NTRK testing strategies in cancer patients followed by histology-independent therapy with entrectinib: an analysis of three European countries.

Aim: To explore variations in the cost-effectiveness of entrectinib across different testing strategies and settings. Methods: Four testing strategies where adult cancer patients received entrectinib if they tested positive for NTRK gene fusions compared with 'no testing' and standard of care (SoC) for all patients were evaluated. Results: Immunohistochemistry for all patients followed by RNA-based next-generation sequencing after a positive result was the optimal strategy in all included countries. However, the incremental net monetary benefit compared with SoC was negative in all countries, ranging between international euros (int€) -206 and -404. In a subgroup analysis with only NTRK-positive patients, the incremental net monetary benefit was int€ 8405 in England, int€ -53,088 in Hungary and int€ 54,372 in The Netherlands. Conclusion: Using the cost-effectiveness thresholds recommended by national guidelines, none of the testing strategies were cost-effective compared with no testing. The implementation of entrectinib is unlikely to become cost-effective in Hungary, due to the large cost difference between the entrectinib and SoC arms, while there might be more potential in England and The Netherlands.

Histology-independent pharmaceuticals are a new phenomenon in cancer care. Most chemotherapies are prescribed based on the tumor's (primary) location, while histology-independent therapies are prescribed based on genetic markers in the tumor DNA. In this study, the added value of the histology-independent treatment entrectinib, which is aimed at cancer patients with so-called NTRK gene fusions, was investigated. Because these patients must be identified before they can be given entrectinib, various strategies for diagnostic testing were considered. An economic model was programmed to gain insight into the costs and health outcomes associated with the different testing strategies. The same analysis was done for three different countries (England, Hungary and The Netherlands) using local data. In all three countries, the health gains from receiving entrectinib may be large for patients with NTRK gene fusions. However, treatment with entrectinib was also much more expensive than standard-care treatment, especially in Hungary. In each of the three countries, all evaluated testing strategies were found to offer a negative net benefit to society (i.e., a net loss). This may be partially explained by the fact that NTRK gene fusions are rare, meaning that a large group of cancer patients has to receive (costly) testing while, subsequently, only a few patients enjoy the benefit of switching to a treatment that is more effective for them (i.e., entrectinib). Nonetheless, in England and Hungary, even if the most accurate test was provided for free, the net benefit to society of implementing entrectinib remained negative. Further changes, such as a reduction in the price of entrectinib, may therefore be needed.

Budget impact and transferability of cost-effectiveness of DPYD testing in metastatic breast cancer in three health systems.

The cost-effectiveness and budget impact of introducing extended DPYD testing prior to fluoropyrimidine-based chemotherapy in metastatic breast cancer patients in the UK, The Netherlands and Hungary were examined. DPYD testing with ToxNav© was cost-effective in all three countries. In the UK and The Netherlands, the ToxNav strategy led to more quality-adjusted life years and fewer costs to the health systems compared with no genetic testing and standard dosing of capecitabine/5-fluorouracil. In Hungary, the ToxNav strategy produced more quality-adjusted life years at a higher cost compared with no testing and standard dose. The ToxNav strategy was found to offer budget savings in the UK and in The Netherlands, while in Hungary it resulted in additional budget costs.

Financial incentives to promote personalized medicine in Europe: an overview and guidance for implementation.

The implementation of adequate financing and reimbursement of personalized medicine (PM) in Europe is still turbulent. The views and experience of stakeholders about barriers in financing and reimbursing PM and potential solutions were elicited and supplemented with literature findings to draft a set of recommendations. Key recommendations to overcome the barriers for adequately financing and reimbursing PM in different healthcare systems in Europe included the provision of legal foundations and establishment of large pan-European databases, use of financial-based agreements and regulation of transparency of prices and reimbursement, and creating a business-friendly environment and attractive market for innovation. The recommendations could be used by health authorities for designing a sequence of policy steps to ensure the timely access to beneficial PM.

Health-economic benefits of anti-CD20 treatments in relapsing multiple sclerosis estimated using a treatment-sequence model.

Background: In high-income countries, four anti-CD20 monoclonal antibodies (mAbs) are used or in the pipeline for relapsing MS: ocrelizumab, ofatumumab (both registered), ublituximab (awaiting registration) and rituximab (off-label). List prices differ significantly between registered and off-label drugs. Objective: Comparing differences in benefits between anti-CD20 mAbs from a health-economic and societal perspective. Methods: To reflect lifetime use of DMTs, we used a treatment-sequence model to compare ocrelizumab/ofatumumab and eight other drug classes in terms of health (lifetime relapses, time to Expanded Disability Status Scale [EDSS] 6, lifetime quality-adjusted life years) and cost-effectiveness (net health benefit). To become cost-effective compared to ocrelizumab, we modelled the list price of ublituximab and desired effect on EDSS progression of rituximab. Results: Although drug sequences with ocrelizumab in first- and second-line were more cost-effective than ofatumumab, our probabilistic analysis suggests this outcome was very uncertain. To be more cost-effective than ocrelizumab, ublituximab needs to be about 25% cheaper whilst rituximab needs to equal the effect on disability progression seen with first-line treatments. Conclusions: Our model showed no clear difference in cost-effectiveness between ocrelizumab and ofatumumab. Hence, prescribing the least costly anti-CD20 mAb can democratise MS care without a loss in health benefits.

[The qaly: informing decision-making in health care]. / De qaly: basis voor debat over keuzes in de zorg.

In this 'perspective' article, the pandemic and other examples are used to provide a basic explanation of the quality adjusted life year (QALY), when it can, and when it can't be used. QALYs are intended to compare the population health gains or losses of interventions, regardless of indication area. That information feeds into decision-making that aims to improve societal health outcomes.

Societal Utilities for Cognitive Impairment in Schizophrenia: Developing a Preference-Based Scoring Algorithm Based on the Schizophrenia Cognition Rating Scale.

INTRODUCTION: Loss of cognitive function is a common feature in schizophrenia. However, generic measures of health-related quality of life favored by decision-makers, such as the EQ-5D, are not designed to detect changes in cognitive function. We report the valuation of the Schizophrenia Cognition Rating Scale (SCoRS), a schizophrenia-specific measure of cognitive impairment. METHODS: Expert opinion and psychometric analysis of the SCoRS from clinical trial data was undertaken to select 5 key items from the measure. These items were combined orthogonally to develop health-state vignettes. Vignettes were valued using composite time trade-off (cTTO) in one-on-one video calls. Several econometric models were fitted to the data to estimate disutilities. Performance of EQ-5D- and SCoRS-based utilities were compared in the trial data. RESULTS: The SCoRS items selected for the valuation study represented attention, learning, processing speed, social cognition and memory. Four hundred respondents participated in the valuation study. The best observed health state was valued at 0.855 [standard deviation (SD) = 0.179] and the worst at 0.152 (SD = 0.575). At the most severe levels, 'social cognition' received the largest disutility followed by 'learning' and 'memory'. The final model to estimate utilities had 15 parameters. SCoRS-based utilities were sensitive to change in cognition, but the EQ-5D was not. CONCLUSION: It is feasible to value different dimensions of cognition separately using a validated instrument for proxy assessment. The resulting utilities indicate loss of quality of life due to reduced cognitive functioning.

The Value of Health in a Cost-Effectiveness Analysis: Theory Versus Practice.

A cost-effectiveness analysis has become an important method to inform allocation decisions and reimbursement of new technologies in healthcare. A cost-effectiveness analysis requires a threshold to which the cost effectiveness of a new intervention can be compared. In principle, the threshold ought to reflect opportunity costs of reimbursing a new technology. In this paper, we contrast the practical use of this threshold within a CEA with its theoretical underpinnings. We argue that several assumptions behind the theoretical models underlying this threshold are violated in practice. This implies that a simple application of the decision rules of CEA using a single estimate of the threshold does not necessarily improve population health or societal welfare. Conceptual differences regarding the interpretation of the threshold, widely varying estimates of its value, and an inconsistent use within and outside the healthcare sector are important challenges in informing policy makers on optimal reimbursement decision and setting appropriate healthcare budgets.

In search of a 'pan-European value set'; application for EQ-5D-3L.

OBJECTIVES: Country-specific value sets for the EQ-5D are available which reflect preferences for health states elicited from the general population. This allows the transformation of responses on EQ-5D to health state utility values. Only twelve European countries possess country-specific value sets and no value set reflecting the preferences of Europe exists. We aim to estimate a 'pan-European' value set for the EQ-5D-3L, reflecting the preferences for health states of the European population that could help to evaluate health care from the perspective of the European decision-maker. METHODS: We systematically assessed and compared the methodologies of available EQ-5D-3L time trade-off (TTO) value sets from twelve European countries: Denmark, France, Germany, Hungary, Italy, Netherlands, Poland, Portugal, Romania, Slovenia, Spain and UK. Using their published coefficients, a dataset with utility values for all 243 health states was simulated. Different modelling techniques and model specifications including interaction terms were tested. Model selection was based on goodness-of-fit criteria. We also explored results with application of population size weights. RESULTS: Methodological, procedural and analytical characteristics of the included EQ-5D-3L valuation studies were quite comparable. An OLS based model was the preferred model to represent European preferences. Weighting with population size made little difference. CONCLUSIONS: EQ-5D-3L valuation studies were considered of sufficient comparability to form the basis for a new 'pan-European' value set. The method used allows for an easy update when new national value sets become available.

Cost-Effectiveness Analysis of Treating Patients With NTRK-Positive Cancer With the Histology-Independent Therapy Entrectinib.

OBJECTIVES: This study tackles several challenges of evaluating histology-independent treatments using entrectinib as an example. Histology-independent treatments are provided based on genetic marker(s) of tumors, regardless of the tumor type. We evaluated the lifetime cost-effectiveness of testing all patients for NTRK fusions and treating the positive cases with entrectinib compared with no testing and standard of care (SoC) for all patients. METHODS: The health economic model consisted of a decision tree reflecting the NTRK testing phase followed by a microsimulation model reflecting treatment with either entrectinib or SoC. Efficacy of entrectinib was based on data from basket trials, whereas historical data from NTRK-negative patients were corrected for the prognostic value of NTRK fusions to model SoC. RESULTS: "Testing" (testing for NTRK fusions, with subsequent entrectinib treatment in NTRK-positive patients and SoC in NTRK-negative patients) had higher per-patient quality-adjusted life-years (QALYs) and costs than "No testing" (SoC for all patients), with a difference of 0.0043 and €732, respectively. This corresponded to an incremental cost-effectiveness ratio (ICER) of €169 957/QALY and, using a cost-effectiveness threshold of €80 000/QALY, an incremental net monetary benefit of -€388. When excluding the costs of genetic testing for NTRK fusions, the ICER was reduced to €36 290/QALY and the incremental net monetary benefit increased to €188. CONCLUSIONS: When treatment requires the identification of a genetic marker, the associated costs and effects need to be accounted for. Because of the low prevalence of NTRK fusions, the number needed-to-test to identify patients eligible for entrectinib is large. Excluding the testing phase reduces the ICER substantially.

Future medical and non-medical costs and their impact on the cost-effectiveness of life-prolonging interventions: a comparison of five European countries.

When healthcare interventions prolong life, people consume medical and non-medical goods during the years of life they gain. It has been argued that the costs for medical consumption should be included in cost-effectiveness analyses from both a healthcare and societal perspective, and the costs for non-medical consumption should additionally be included when a societal perspective is applied. Standardized estimates of these so-called future costs are available in only a few countries and the impact of inclusion of these costs is likely to differ between countries. In this paper we present and compare future costs for five European countries and estimate the impact of including these costs on the cost-effectiveness of life-prolonging interventions. As countries differ in the availability of data, we illustrate how both individual- and aggregate-level data sources can be used to construct standardized estimates of future costs. Results show a large variation in costs between countries. The medical costs for the Netherlands, Germany, and the United Kingdom are large compared to Spain and Greece. Non-medical costs are higher in Germany, Spain, and the United Kingdom than in Greece. The impact of including future costs on the ICER similarly varied between countries, ranging from €1000 to €35,000 per QALY gained. The variation between countries in impact on the ICER is largest when considering medical costs and indicate differences in both structure and level of healthcare financing in these countries. Case study analyses were performed in which we highlight the large impact of including future costs on ICER relative to willingness-to-pay thresholds.