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.

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.

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.

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.

Estimating Quality of Life Decrements in Oncology Using Time to Death.

OBJECTIVES: The estimation of lifetime quality-adjusted life-years (QALYs) requires the extrapolation of both length and quality of life (QoL). The extrapolation of QoL has received little attention in the literature. Here we explore the predictive value of "time to death" (TTD) for extrapolating QoL in oncology. METHODS: We used QoL and survival data from the Patient Reported Outcomes Following Initial Treatment and Long-Term Evaluation of Survivorship registry, which is linked to The Netherlands Cancer Registry. QoL was assessed with EQ-5D and SF-6D. We tested the relationship between TTD and QoL using linear, 2-part, and beta regression models. Incremental QALYs were compared using the TTD approach and an annual age-related disutility approach using artificial survival data with varying mortality rates. RESULTS: A total of 6 samples with >100 patients each were used for the analysis. A declining pattern in QoL was observed when patients were closer to death, confirming the predictive value of TTD for QoL. The declining pattern in QoL was most pronounced when QoL was measured with SF-6D. Proximity to death had a larger impact on QoL than age. Incremental QALYs were higher using the TTD approach than annual age-related disutility, ranging from +0.139 to +0.00003 depending on mortality rates. CONCLUSIONS: TTD is a predictor variable for QoL. Using TTD allows cost-effectiveness models that lack QoL data to extrapolate morbidity using overall survival estimates. The TTD approach generates more incremental QALYs than an annual age-related disutility, most notably for longer survival periods.

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.

Correcting for discounting and loss aversion in composite time trade-off.

Time trade-off utilities have been suggested to be biased upwards. This bias is a result of the method being applied assuming linear utility of life duration, which is violated when individuals discount future life years or are loss averse for health. Applying a "corrective approach", that is, measuring individuals' discount function and loss aversion and correcting time trade-off utilities for these individual characteristics, may reduce this bias in utilities. Earlier work has developed this approach for time trade-off in a student sample. In this study, the corrective approach was extended to composite time trade-off (cTTO) methodology, which enabled correcting utilities for health states worse than dead. In digital interviews a sample of 150 members of the general public completed cTTO tasks for six health states, and afterward they completed measurements of loss aversion and discounting. cTTO utilities were corrected using these measurements under multiple specifications. Respondents were also asked to reflect on and adjust their cTTO utilities directly. Our results show considerable loss aversion and both positive and negative discounting were prevalent. As predicted, correction generally resulted in lower utilities. This was in accordance with the direction of adjustments made by respondents themselves.

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.

Burden of Providing Informal Care for Patients with Atrial Fibrillation.

OBJECTIVES: Patients with atrial fibrillation (AF) have rapid and irregular heart rates, increasing the risk of comorbidities and mortality. Next to formal medical care, many patients receive informal care from their social environment. The objective of this study was to examine the well-being and economic burden of providing informal care to patients with AF in the UK, Italy, and Germany. METHODS: Caregivers of patients with AF completed an online survey based on the iMTA Valuation of Informal Care Questionnaire, with questions about their caregiving situation, perceived burden of caregiving, and absence from work due to health problems resulting from caregiving. Care-related quality-of-life utilities were calculated using the Care-related Quality of Life instrument and associated tariffs. Societal costs of caregiving were calculated based on the proxy good method. RESULTS: A total of 585 caregivers participated in this study. On average, caregivers provided 33 hours of informal care per week to patients (SD 29 hours). On a scale from 0 to 10, their self-rated burden was 5.4. The average Care-related Quality of Life utility was 72. Caregivers primarily indicated problems with daily activities, mental health, and physical health. Still, the vast majority of caregivers (87%) derived fulfillment from providing care. Weekly societal costs of caregiving were on average €636. Comorbidities contributed substantially to the caregiver time and burden. CONCLUSIONS: Caring for a patient with AF is associated with substantial objective and subjective burden, but also provides fulfillment from being able to care for a loved one.

Performance of the EQ-5D-5L Plus Respiratory Bolt-On in the Birmingham Chronic Obstructive Pulmonary Disease Cohort Study.

OBJECTIVES: A respiratory bolt-on dimension for the EQ-5D-5L has recently been developed and valued by the general public. This study aimed to validate the EQ-5D-5L plus respiratory dimension (EQ-5D-5L+R) in a large group of patients with chronic obstructive pulmonary disease (COPD). METHODS: Validation was undertaken with data from the Birmingham COPD Cohort Study, a longitudinal UK study of COPD primary care patients. Data on the EQ-5D-5L+R were collected from 1008 responding participants during a follow-up questionnaire in 2017 and combined with (previously collected) data on patient and disease characteristics. Descriptive and correlation analyses were performed on the EQ-5D-5L+R dimensions and utilities, in relation to COPD characteristics and compared with the EQ-5D-5L without respiratory dimension. Multivariate regression models were estimated to test whether regression coefficients of clinical characteristics differed between the EQ-5D-5L+R utility and the EQ-5D-5L utility. RESULTS: Correlation coefficients for the EQ-5D-5L+R utility with COPD parameters were slightly higher than the EQ-5D-5L utility. Both instruments displayed discriminant validity but analyses in clinical subgroups of patients showed larger absolute differences in utilities for the EQ-5D-5L+R. In the multivariate analyses, only the coefficient for the COPD Assessment Test score was higher for the model using the EQ-5D-5L+R utility as outcome. CONCLUSIONS: This study showed that the addition of a respiratory domain to the EQ-5D-5L led to small improvements in the instrument's performance. Comparability of the EQ-5D across diseases, currently considered one of its strengths, would have to be traded off against a modest improvement in utility difference when adding the respiratory dimension.

Good Days and Bad Days: Measuring Health-Related Quality of Life in People With Epilepsy.

OBJECTIVES: Cost-effectiveness analyses typically require measurement of health-related quality of life (HRQoL) to estimate quality-adjusted life-years. Challenges with measuring HRQoL arise in the context of episodic conditions if patients are less likely-or even unable-to complete surveys when having disease symptoms. This article explored whether HRQoL measured at regular time intervals adequately reflects the HRQoL of people with epilepsy (PWE). METHODS: Follow-up data from the Epilepsy Support Dog Evaluation study on the (cost-)effectiveness of seizure dogs were used in which HRQoL is measured in 25 PWE with the EQ-5D at baseline and every 3 months thereafter. Seizure count is recorded daily using a seizure diary. Regression models were employed to explore whether PWE were more likely to complete the HRQoL survey on a good day (ie, when seizures are absent or low in frequency compared with other days) and to provide an estimate of the impact of reporting HRQoL on a good day on EQ-5D utility scores. RESULTS: A total of 111 HRQoL measurements were included in the analyses. Regression analyses indicated that the day of reporting HRQoL was associated with a lower seizure count (P<.05) and that a lower seizure count was associated with a higher EQ-5D utility score (P<.05). CONCLUSIONS: When HRQoL is measured at regular time intervals, PWE seem more likely to complete these surveys on good days. Consequently, HRQoL might be overestimated in this population. This could lead to underestimation of the effectiveness of treatment and to biased estimates of cost-effectiveness.

Distributional consequences of including survivor costs in economic evaluations.

Medical interventions that increase life expectancy of patients result in additional consumption of non-medical goods and services in 'added life years'. This paper focuses on the distributional consequences across socio-economic groups of including these costs in cost effectiveness analysis. In that context, it also highlights the role of remaining quality of life and household economies of scale. Data from a Dutch household spending survey was used to estimate non-medical consumption and household size by age and educational attainment. Estimates of non-medical consumption and household size were combined with life tables to estimate what the impact of including non-medical survivor costs would be on the incremental cost effectiveness ratio (ICER) of preventing a death at a certain age. Results show that including non-medical survivor costs increases estimated ICERs most strongly when interventions are targeted at the higher educated. Adjusting for household size (lower educated people less often live additional life years in multi-person households) and quality of life (lower educated people on average spend added life years in poorer health) mitigates this difference. Ignoring costs of non-medical consumption in economic evaluations implicitly favors interventions targeted at the higher educated and thus potentially amplifies socio-economic inequalities in health.

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

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

A cost-effectiveness threshold based on the marginal returns of cardiovascular hospital spending.

Traditionally, threshold levels of cost-effectiveness have been derived from willingness-to-pay studies, indicating the consumption value of health (v-thresholds). However, it has been argued that v-thresholds need to be supplemented by so-called k-thresholds, which are based on the marginal returns to health care. The objective of this research is to estimate a k-threshold based on the marginal returns to cardiovascular disease (CVD) hospital care in the Netherlands. To estimate a k-threshold for hospital care on CVD, we proceed in two steps: First, we estimate the impact of hospital spending on mortality using a Bayesian regression modelling framework, using data on CVD mortality and CVD hospital spending by age and gender for the period 1994-2010. Second, we use life tables in combination with quality of life data to convert these estimates into a k-threshold expressed in euros per quality-adjusted life year gained. Our base case estimate resulted in an estimate of 41,000 per quality-adjusted life year gained. In our sensitivity analyses, we illustrated how the incorporation of prior evidence into the estimation pushes estimates downwards. We conclude that our base case estimate of the k-threshold may serve as a benchmark value for decision making in the Netherlands as well as for future research regarding k-thresholds.

Cost Effectiveness of the Angiotensin Receptor Neprilysin Inhibitor Sacubitril/Valsartan for Patients with Chronic Heart Failure and Reduced Ejection Fraction in the Netherlands: A Country Adaptation Analysis Under the Former and Current Dutch Pharmacoeconomic Guidelines.

OBJECTIVES: To describe the adaptation of a global health economic model to determine whether treatment with the angiotensin receptor neprilysin inhibitor LCZ696 is cost effective compared with the angiotensin-converting enzyme inhibitor enalapril in adult patients with chronic heart failure with reduced left ventricular ejection fraction in the Netherlands; and to explore the effect of performing the cost-effectiveness analyses according to the new pharmacoeconomic Dutch guidelines (updated during the submission process of LCZ696), which require a value-of-information analysis and the inclusion of indirect medical costs of life-years gained. METHODS: We adapted a UK model to reflect the societal perspective in the Netherlands by including travel expenses, productivity loss, informal care costs, and indirect medical costs during the life-years gained and performed a preliminary value-of-information analysis. RESULTS: The incremental cost-effectiveness ratio obtained was €17,600 per quality-adjusted life-year (QALY) gained. This was robust to changes in most structural assumptions and across different subgroups of patients. Probability sensitivity analysis results showed that the probability that LCZ696 is cost-effective at a €50,000 per QALY threshold is 99.8%, with a population expected value of perfect information of €297,128. On including indirect medical costs of life-years gained, the incremental cost-effectiveness ratio was €26,491 per QALY gained, and LCZ696 was 99.46% cost effective at €50,000 per QALY, with a population expected value of perfect information of €2,849,647. CONCLUSIONS: LCZ696 is cost effective compared with enalapril under the former and current Dutch guidelines. However, the (monetary) consequences of making a wrong decision were considerably different in both scenarios.

Are Health State Valuations from the General Public Biased? A Test of Health State Reference Dependency Using Self-assessed Health and an Efficient Discrete Choice Experiment.

Health state valuations of patients and non-patients are not the same, whereas health state values obtained from general population samples are a weighted average of both. The latter constitutes an often-overlooked source of bias. This study investigates the resulting bias and tests for the impact of reference dependency on health state valuations using an efficient discrete choice experiment administered to a Dutch nationally representative sample of 788 respondents. A Bayesian discrete choice experiment design consisting of eight sets of 24 (matched pairwise) choice tasks was developed, with each set providing full identification of the included parameters. Mixed logit models were used to estimate health state preferences with respondents' own health included as an additional predictor. Our results indicate that respondents with impaired health worse than or equal to the health state levels under evaluation have approximately 30% smaller health state decrements. This confirms that reference dependency can be observed in general population samples and affirms the relevance of prospect theory in health state valuations. At the same time, the limited number of respondents with severe health impairments does not appear to bias social tariffs as obtained from general population samples. Copyright © 2016 John Wiley & Sons, Ltd.

Dutch Tariff for the Five-Level Version of EQ-5D.

BACKGROUND: In 2009, a new version of the EuroQol five-dimensional questionnaire (EQ-5D) was introduced with five rather than three answer levels per dimension. This instrument is known as the EQ-5D-5L. To make the EQ-5D-5L suitable for use in economic evaluations, societal values need to be attached to all 3125 health states. OBJECTIVES: To derive a Dutch tariff for the EQ-5D-5L. METHODS: Health state values were elicited during face-to-face interviews in a general population sample stratified for age, sex, and education, using composite time trade-off (cTTO) and a discrete choice experiment (DCE). Data were modeled using ordinary least squares and tobit regression (for cTTO) and a multinomial conditional logit model (for DCE). Model performance was evaluated on the basis of internal consistency, parsimony, goodness of fit, handling of left-censored values, and theoretical considerations. RESULTS: A representative sample (N = 1003) of the Dutch population participated in the valuation study. Data of 979 and 992 respondents were included in the analysis of the cTTO and the DCE, respectively. The cTTO data were left-censored at -1. The tobit model was considered the preferred model for the tariff on the basis of its handling of the censored nature of the data, which was confirmed through comparison with the DCE data. The predicted values for the EQ-5D-5L ranged from -0.446 to 1. CONCLUSIONS: This study established a Dutch tariff for the EQ-5D-5L on the basis of cTTO. The values represent the preferences of the Dutch population. The tariff can be used to estimate the impact of health care interventions on quality of life, for example, in context of economic evaluations.

Testing mapping algorithms of the cancer-specific EORTC QLQ-C30 onto EQ-5D in malignant mesothelioma.

BACKGROUND: In order to estimate utilities for cancer studies where the EQ-5D was not used, the EORTC QLQ-C30 can be used to estimate EQ-5D using existing mapping algorithms. Several mapping algorithms exist for this transformation, however, algorithms tend to lose accuracy in patients in poor health states. The aim of this study was to test all existing mapping algorithms of QLQ-C30 onto EQ-5D, in a dataset of patients with malignant pleural mesothelioma, an invariably fatal malignancy where no previous mapping estimation has been published. METHODS: Health related quality of life (HRQoL) data where both the EQ-5D and QLQ-C30 were used simultaneously was obtained from the UK-based prospective observational SWAMP (South West Area Mesothelioma and Pemetrexed) trial. In the original trial 73 patients with pleural mesothelioma were offered palliative chemotherapy and their HRQoL was assessed across five time points. This data was used to test the nine available mapping algorithms found in the literature, comparing predicted against observed EQ-5D values. The ability of algorithms to predict the mean, minimise error and detect clinically significant differences was assessed. RESULTS: The dataset had a total of 250 observations across 5 timepoints. The linear regression mapping algorithms tested generally performed poorly, over-estimating the predicted compared to observed EQ-5D values, especially when observed EQ-5D was below 0.5. The best performing algorithm used a response mapping method and predicted the mean EQ-5D with accuracy with an average root mean squared error of 0.17 (Standard Deviation; 0.22). This algorithm reliably discriminated between clinically distinct subgroups seen in the primary dataset. CONCLUSIONS: This study tested mapping algorithms in a population with poor health states, where they have been previously shown to perform poorly. Further research into EQ-5D estimation should be directed at response mapping methods given its superior performance in this study.

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.