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.

How microsimulation translates outcome estimates to patient lifetime event occurrence in the setting of heart valve disease.

Treatment decisions in healthcare often carry lifelong consequences that can be challenging to foresee. As such, tools that visualize and estimate outcome after different lifetime treatment strategies are lacking and urgently needed to support clinical decision-making in the setting of rapidly evolving healthcare systems, with increasingly numerous potential treatments. In this regard, microsimulation models may prove to be valuable additions to current risk-prediction models. Notable advantages of microsimulation encompass input from multiple data sources, the ability to move beyond time-to-first-event analysis, accounting for multiple types of events and generating projections of lifelong outcomes. This review aims to clarify the concept of microsimulation, also known as individualized state-transition models, and help clinicians better understand its potential in clinical decision-making. A practical example of a patient with heart valve disease is used to illustrate key components of microsimulation models, such as health states, transition probabilities, input parameters (e.g. evidence-based risks of events) and various aspects of mortality. Finally, this review focuses on future efforts needed in microsimulation to allow for increasing patient-tailoring of the models by extending the general structure with patient-specific prediction models and translating them to meaningful, user-friendly tools that may be used by both clinician and patient to support clinical decision-making.

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 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.

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 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.

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.

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.

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.

Ultrasonographic measurements of the prostate gland in castrated adult dogs.

BACKGROUND: The dimensions of the prostatic gland in castrated adult dogs, as assessed by ultrasonography, is currently not yet reported in veterinary literature. The current study was aimed at reporting the prostatic dimensions in castrated dogs and investigate the relationship between the dogs' body weight and prostate size. A second aim of the study was to investigate whether there was a relationship between the dogs' age and prostate dimensions. A prospective, single-centre, observational study was conducted and 72 privately owned, adult, male castrated dogs with a range of breeds and ages met the final inclusion criteria. The subjects were divided into three categories based on body weight. RESULTS: A Kruskal-Wallis test found prostatic length and prostatic depth in the longitudinal orientation to be significantly different among the 3 categories (P < 0.005), with an increase in both prostatic length and prostatic depth with increasing body weight. Linear regression of the data set provided comprehensive formulas calculating prostatic length and depth based on the body weight of the dog (r2 of 0.69 and 0.53 for prostatic length and depth respectively). Kendall's Tau rank test showed no correlation between dogs' age and prostate dimensions (P > 0.100). CONCLUSIONS: The current study is the first to provide a comprehensive, weight-based reference for the canine prostate gland of castrated dogs when assessed on ultrasonography.

Costs of Persons with Dementia Living in Nursing Homes in The Netherlands.

BACKGROUND: Disease modifying treatments (DMTs) currently under development for Alzheimer's disease, have the potential to prevent or postpone institutionalization and more expensive care and might delay institutionalization of persons with dementia. OBJECTIVE: The current study estimates costs of living in a nursing home for persons with dementia in the Netherlands to help inform economic evaluations of future DMTs. METHODS: Data were collected during semi-structured interviews with healthcare professionals and from the financial administration of a healthcare organization with several nursing homes. Personnel costs were calculated using a bottom-up approach by valuing the time estimates. Non-personnel costs were calculated using information from the financial administration of the healthcare organization. RESULTS: Total costs of a person with dementia per 24 hours, including both care staff and other healthcare providers, were € 151 for small-scale living wards and € 147 for independent living wards. Non-personnel costs were € 37 per day. CONCLUSION: This study provides Dutch estimates for total healthcare costs per day for institutionalized persons with dementia. These cost estimates can be used in cost-effectiveness analyses for future DMTs in dementia.

Effectiveness and Cost-Effectiveness of 360 Disease-Modifying Treatment Escalation Sequences in Multiple Sclerosis.

OBJECTIVES: The rapid expansion in treatment options for relapsing-remitting multiple sclerosis (RRMS) of the past decade requires clinical decision making on the sequential prescription of these treatments. Here, we compare 360 treatment escalation sequences for patients with RRMS in terms of health outcomes and societal costs in The Netherlands. METHODS: We use a microsimulation model with a societal perspective, developed in collaboration with MS neurologists, to estimate the effectiveness and cost-effectiveness of 360 treatment sequences starting with first-line therapies in RRMS. This model integrated data on disease progression, disease-modifying treatment efficacy, clinical decision rules, age-dependent relapse rates, quality of life, healthcare, and societal costs. RESULTS: Costs and health outcomes were overlapping among different treatment escalation sequences. In our model for RRMS treatment, optimal lifetime health outcomes (20.24 ± 1.43 quality-adjusted life-years [QALYs], 6.11 ± 0.30 relapses) were achieved with the sequence peginterferon-dimethyl fumarate-ocrelizumab-natalizumab-alemtuzumab. The most cost-effective sequence (peginterferon-glatiramer acetate-ocrelizumab-cladribine-alemtuzumab) yielded numerically worse health outcomes per patient (19.59 ± 1.43 QALYs, 6.64 ± 0.43 relapses), but resulted in €98 127 ± €19 134 less costs than the most effective treatment sequence. CONCLUSIONS: Effectiveness estimates of treatments have overlapping confidence intervals but the treatment sequence that yields most QALYs is not the most cost-effective option, also when taking uncertainty into account. It is important that neurologists are aware of cost constraints and its relationship with prescription behavior, but treatment decisions should be individually tailored.

Financing and Reimbursement Models for Personalised Medicine: A Systematic Review to Identify Current Models and Future Options.

BACKGROUND: The number of healthcare interventions described as 'personalised medicine' (PM) is increasing rapidly. As healthcare systems struggle to decide whether to fund PM innovations, it is unclear what models for financing and reimbursement are appropriate to apply in this context. OBJECTIVE: To review financing and reimbursement models for PM, summarise their key characteristics, and describe whether they can influence the development and uptake of PM. METHODS: A literature review was conducted in Medline, Embase, Web of Science, and Econlit to identify studies published in English between 2009 and 2021, and reviews published before 2009. Grey literature was identified through Google Scholar, Google and subject-specific webpages. Articles that described financing and reimbursement of PM, and financing of non-PM were included. Data were extracted and synthesised narratively to report on the models, as well as facilitators, incentives, barriers and disincentives that could influence PM development and uptake. RESULTS: One hundred and fifty-three papers were included. Research and development of PM was financed through both public and private sources and reimbursed largely through traditional models such as single fees, Diagnosis-Related Groups, and bundled payments. Financial-based reimbursement, including rebates and price-volume agreements, was mainly applied to targeted therapies. Performance-based reimbursement was identified mainly for gene and targeted therapies, and some companion diagnostics. Gene therapy manufacturers offered outcome-based rebates for treatment failure for interventions including Luxturna®, Kymriah®, Yescarta®, Zynteglo®, Zolgensma® and Strimvelis®, and coverage with evidence development for Kymriah® and Yescarta®. Targeted testing with OncotypeDX® was granted value-based reimbursement through initial coverage with evidence development. The main barriers and disincentives to PM financing and reimbursement were the lack of strong links between stakeholders and the lack of demonstrable benefit and value of PM. CONCLUSIONS: Public-private financing agreements and performance-based reimbursement models could help facilitate the development and uptake of PM interventions with proven clinical benefit.

Being Transparent About Brilliant Failures: An Attempt to Use Real-World Data in a Disease Model for Patients with Castration-Resistant Prostate Cancer.

BACKGROUND: Real-world disease models spanning multiple treatment lines can provide insight into the (cost) effectiveness of treatment sequences in clinical practice. OBJECTIVE: Our objective was to explore whether a disease model based solely on real-world data (RWD) could be used to estimate the effectiveness of treatments for patients with castration-resistant prostate cancer (CRPC) that could then be suitably used in a cost-effectiveness analysis. METHODS: We developed a patient-level simulation model using patient-level data from the Dutch CAPRI registry as input parameters. Time to event (TTE) and overall survival (OS) were estimated with multivariate regression models, and type of event (i.e., next treatment or death) was estimated with multivariate logistic regression models. To test internal validity, TTE and OS from the simulation model were compared with the observed outcomes in the registry. RESULTS: Although patient characteristics and survival outcomes of the simulated data were comparable to those in the observed data (median OS 20.6 vs. 19.8 months, respectively), the disease model was less accurate in estimating differences between treatments (median OS simulated vs. observed population: 18.6 vs. 17.9 [abiraterone acetate plus prednisone], 24.0 vs. 25.0 [enzalutamide], 20.2 vs. 18.7 [docetaxel], and 20.0 vs. 23.8 months [radium-223]). CONCLUSIONS: Overall, the disease model accurately approximated the observed data in the total CRPC population. However, the disease model was unable to predict differences in survival between treatments due to unobserved differences. Therefore, the model is not suitable for cost-effectiveness analysis of CRPC treatment. Using a combination of RWD and data from randomised controlled trials to estimate treatment effectiveness may improve the model.

The Net Benefit of Personalized Medicine: A Systematic Literature Review and Regression Analysis.

OBJECTIVES: Amidst conflicting expectations about the benefits of personalized medicine (PM) and the potentially high implementation costs, we reviewed the available evidence on the cost-effectiveness of PM relative to non-PM. METHODS: We conducted a systematic literature review of economic evaluations of PM and extracted data, including incremental quality-adjusted life-years (ΔQALYs) and incremental costs (Δcosts). ΔQALYs and Δcosts were combined with estimates of national cost-effectiveness thresholds to calculate incremental net monetary benefit (ΔNMB). Regression analyses were performed with these variables as dependent variables and PM intervention characteristics as independent variables. Random intercepts were used to cluster studies according to country. RESULTS: Of 4774 studies reviewed, 128 were selected, providing cost-effectiveness data for 279 PM interventions. Most studies were set in the United States (48%) and the United Kingdom (16%) and adopted a healthcare perspective (82%). Cancer treatments (60%) and pharmaceutical interventions (72%) occurred frequently. Prognostic tests (19%) and tests to identify (non)responders (37%) were least and most common, respectively. Industry sponsorship occurred in 32%. Median ΔQALYs, Δcosts, and ΔNMB per individual were 0.03, Int$575, and Int$18, respectively. We found large heterogeneity in cost-effectiveness. Regression analysis showed that gene therapies were associated with higher ΔQALYs than other interventions. PM interventions for neoplasms brought higher ΔNMB than PM interventions for other conditions. Nonetheless, average ΔNMB in the 'neoplasm' group was found to be negative. CONCLUSIONS: PM brings improvements in health but often at a high cost, resulting in 0 to negative ΔNMB on average. Pricing policies may be needed to reduce the costs of interventions with negative ΔNMB.

The Potential Impact of Digital Biomarkers in Multiple Sclerosis in The Netherlands: An Early Health Technology Assessment of MS Sherpa.

(1) Background: Monitoring of Multiple Sclerosis (MS) with eHealth interventions or digital biomarkers provides added value to the current care path. Evidence in the literature is currently scarce. MS sherpa is an eHealth intervention with digital biomarkers, aimed at monitoring symptom progression and disease activity. To show the added value of digital biomarker-based eHealth interventions to the MS care path, an early Health Technology Assessment (eHTA) was performed, with MS sherpa as an example, to assess the potential impact on treatment switches. (2) Methods: The eHTA was performed according to the Dutch guidelines for health economic evaluations. A decision analytic MS model was used to estimate the costs and benefits of MS standard care with and without use of MS sherpa, expressed in incremental cost-effectiveness ratios (ICERs) from both societal and health care perspectives. The efficacy of MS sherpa on early detection of active disease and the initiation of a treatment switch were modeled for a range of assumed efficacy (5%, 10%, 15%, 20%). (3) Results: From a societal perspective, for the efficacy of 15% or 20%, MS sherpa became dominant, which means cost-saving compared to the standard of care. MS sherpa is cost-effective in the 5% and 10% scenarios (ICERs EUR 14,535 and EUR 4069, respectively). From the health care perspective, all scenarios were cost-effective. Sensitivity analysis showed that increasing the efficacy of MS sherpa in detecting active disease early leading to treatment switches be the most impactful factor in the MS model. (4) Conclusions: The results indicate the potential of eHealth interventions to be cost-effective or even cost-saving in the MS care path. As such, digital biomarker-based eHealth interventions, like MS sherpa, are promising cost-effective solutions in optimizing MS disease management for people with MS, by detecting active disease early and helping neurologists in decisions on treatment switch.

Modeling the Cost-Utility of Treatment Sequences for Multiple Sclerosis.

OBJECTIVES: Most patients with multiple sclerosis (MS) switch between disease-modifying therapies (DMTs) during their lifetime. Our aim was to develop an MS cost-utility model that takes treatment switching into account to provide a more realistic estimate of treatment benefit than previous models that assume lifetime use of 1 DMT. METHODS: A treatment sequence model using a microsimulation framework with a lifetime time horizon and a societal perspective was developed in R. Clinical plausibility and decision rules for switching were defined in consultation with Dutch MS neurologists. The ability of DMTs to prevent relapses and delay disease progression was modeled by applying DMT-specific estimates derived from a network meta-analysis of randomized controlled trials to natural history data. A total of 2 treatment strategies were compared: a first-line DMT sequence (peginterferon-glatiramer-teriflunomide-interferon-beta-dimethyl fumarate) and an escalation DMT sequence (peginterferon-glatiramer-ocrelizumab-natalizumab-alemtuzumab). Scenario analyses explored impact of alternative sources of natural history data, societal versus healthcare perspective, and condition-specific versus generic utilities. Predicted short-term switches (<5 years) were externally validated with Dutch claims data on DMT use. RESULTS: Short-term switches predicted by the model compared well with Dutch claims data. Transition from relapsing-remitting MS to secondary progressive MS was delayed by the escalation sequence (24.7 vs 20.3 years on first-line sequence). Model results were sensitive to utility values and medical resource consumption was a large driver of uncertainty. CONCLUSIONS: This microsimulation model overcomes the limitation of previous models by modeling treatment sequences. Because it better reflects clinical reality, it facilitates incorporating cost-utility information in clinical guidelines.