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.

Informal Care Costs According to Age and Proximity to Death to Support Cost-Effectiveness Analyses.

BACKGROUND: Costs of informal care are ignored in many cost-effectiveness analyses (CEAs) conducted from a societal perspective; however, these costs are relevant for lifesaving interventions targeted at the older population. In this study, we estimated informal care costs by age and proximity to death across European regions and showed how these estimates can be included in CEAs. METHODS: We estimated informal care costs by age and proximity to death using generalised linear mixed-effects models. For this, we selected deceased singles from the Survey of Health, Ageing and Retirement, which we grouped by four European regions. We combined the estimates of informal care costs with life tables to illustrate the impact of including informal care costs on the incremental cost-effectiveness ratio (ICER) of a hypothetical intervention that prevents a death at different ages. RESULTS: Informal care use, and hence informal care costs, increase when approaching death and with increasing age. The impact of including informal care costs on the ICER varies between €200 and €17,700 per quality-adjusted life-year gained. The impact increases with age and is stronger for women and in southern European countries. CONCLUSION: Our estimates of informal care costs facilitate including informal care costs in CEAs of life-extending healthcare interventions. Including these costs may influence decisions as it leads to reranking of life-extending interventions compared with interventions improving quality of life.

Burden of illness in people with medically refractory epilepsy who suffer from daily to weekly seizures: 12-month follow-up of participants in the EPISODE study.

Background: A small group of people with epilepsy suffers from frequent seizures despite the available pharmacological and non-pharmacological interventions. The impact of epilepsy on these people extends beyond health-related quality of life (HRQoL), impacting a person's broader well-being and ability to participate in society. This study describes the burden of medically refractory epilepsy in people who suffer from daily to weekly seizures, in terms of HRQoL, well-being, and societal costs. Methods: Data from the EPISODE study on (cost-) effectiveness of seizure dogs for adults with severe medically refractory epilepsy were used, collected in 25 patients during the first 12 months before they were partnered with a certified seizure dog. Data comprised seizure diaries covering 365 days and five three-monthly surveys, including the EQ-5D-5L, QOLIE-31-P, and ICECAP-A to measure HRQoL and well-being. A societal perspective was applied to estimate costs using the iMCQ and iPCQ questionnaires about healthcare use, informal care, and productivity losses. Results: Daily seizure frequency and survey data were collected in 25 patients. A minimum of 114 observations was available for each instrument included in the survey. A total of 80% of participants experienced seizures on three or more days per week, with a median ranging from 1 to 17 seizures per seizure day. The mean EQ-5D-5L utility score was 0.682 (SD 0.235), which is considerably lower than the age-adjusted general population average. The mean QOLIE-31-P and ICECAP-A scores were 55.8 (SD 14.0) and 0.746 (SD 0.172), respectively. The average annual total cost amounted to €39,956 (range €3,804-€132,64). Informal care accounted for the largest share of costs (50%); those who received informal care reported, on average, 26 h per week (SD 30). Conclusions: Severe medically refractory epilepsy is associated with a considerable burden of illness at the patient and societal level. People with this condition have significantly reduced HRQoL and well-being and are limited in their ability to work while having substantial medical costs and a strong dependency on informal care.

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.

Do existing real-world data sources generate suitable evidence for the HTA of medical devices in Europe? Mapping and critical appraisal.

AIM: Technological and computational advancements offer new tools for the collection and analysis of real-world data (RWD). Considering the substantial effort and resources devoted to collecting RWD, a greater return would be achieved if real-world evidence (RWE) was effectively used to support Health Technology Assessment (HTA) and decision making on medical technologies. A useful question is: To what extent are RWD suitable for generating RWE? METHODS: We mapped existing RWD sources in Europe for three case studies: hip and knee arthroplasty, transcatheter aortic valve implantation (TAVI) and mitral valve repair (TMVR), and robotic surgery procedures. We provided a comprehensive assessment of their content and appropriateness for conducting the HTA of medical devices. The identification of RWD sources was performed combining a systematic search on PubMed with gray literature scoping, covering fifteen European countries. RESULTS: We identified seventy-one RWD sources on arthroplasties; ninety-five on TAVI and TMVR; and seventy-seven on robotic procedures. The number, content, and integrity of the sources varied dramatically across countries. Most sources included at least one health outcome (97.5%), with mortality and rehospitalization/reoperation the most common; 80% of sources included resource outcomes, with length of stay the most common, and comparators were available in almost 70% of sources. CONCLUSIONS: RWD sources bear the potential for the HTA of medical devices. The main challenges are data accessibility, a lack of standardization of health and economic outcomes, and inadequate comparators. These findings are crucial to enabling the incorporation of RWD into decision making and represent a readily available tool for getting acquainted with existing information sources.

Validity of Surrogate Endpoints and Their Impact on Coverage Recommendations: A Retrospective Analysis across International Health Technology Assessment Agencies.

BACKGROUND: Surrogate endpoints (i.e., intermediate endpoints intended to predict for patient-centered outcomes) are increasingly common. However, little is known about how surrogate evidence is handled in the context of health technology assessment (HTA). OBJECTIVES: 1) To map methodologies for the validation of surrogate endpoints and 2) to determine their impact on acceptability of surrogates and coverage decisions made by HTA agencies. METHODS: We sought HTA reports where evaluation relied on a surrogate from 8 HTA agencies. We extracted data on the methods applied for surrogate validation. We assessed the level of agreement between agencies and fitted mixed-effects logistic regression models to test the impact of validation approaches on the agency's acceptability of the surrogate endpoint and their coverage recommendation. RESULTS: Of the 124 included reports, 61 (49%) discussed the level of evidence to support the relationship between the surrogate and the patient-centered endpoint, 27 (22%) reported a correlation coefficient/association measure, and 40 (32%) quantified the expected effect on the patient-centered outcome. Overall, the surrogate endpoint was deemed acceptable in 49 (40%) reports (k-coefficient 0.10, P = 0.004). Any consideration of the level of evidence was associated with accepting the surrogate endpoint as valid (odds ratio [OR], 4.60; 95% confidence interval [CI], 1.60-13.18, P = 0.005). However, we did not find strong evidence of an association between accepting the surrogate endpoint and agency coverage recommendation (OR, 0.71; 95% CI, 0.23-2.20; P = 0.55). CONCLUSIONS: Handling of surrogate endpoint evidence in reports varied greatly across HTA agencies, with inconsistent consideration of the level of evidence and statistical validation. Our findings call for careful reconsideration of the issue of surrogacy and the need for harmonization of practices across international HTA agencies.

Surrogate Endpoints in Health Technology Assessment: An International Review of Methodological Guidelines.

In the drive towards faster patient access to treatments, health technology assessment (HTA) agencies are increasingly faced with reliance on evidence from surrogate endpoints, leading to increased decision uncertainty. This study undertook an updated survey of methodological guidance for using surrogate endpoints across international HTA agencies. We reviewed HTA and economic evaluation methods guidance from European, Australian and Canadian HTA agencies. We considered how guidelines addressed the methods for handling surrogate endpoints, including (1) level of evidence, (2) methods of validation, and (3) thresholds of acceptability. Across the 73 HTA agencies surveyed, 29 (40%) had methodological guidelines that made specific reference to consideration of surrogate outcomes. Of the 45 methods documents analysed, the majority [27 (60%)] were non-technology specific, 15 (33%) focused on pharmaceuticals and three (7%) on medical devices. The principles of the European network for Health Technology Assessment (EUnetHTA) guidelines published in 2015 on the handling of surrogate endpoints appear to have been adopted by many European HTA agencies, i.e. preference for final patient-relevant outcomes and reliance on surrogate endpoints with biological plausibility and epidemiological evidence of the association between the surrogate and final endpoint. Only a small number of HTA agencies (UK National Institute for Care and Excellence; the German Institute for Medical Documentation and Information and Institute for Quality and Efficiency in Health Care; the Australian Pharmaceutical Benefits Advisory Committee; and the Canadian Agency for Drugs and Technologies in Health) have developed more detailed prescriptive criteria for the acceptance of surrogate endpoints, e.g. meta-analyses of randomised controlled trials showing strong association between the treatment effect on the surrogate and final outcomes. As the decision uncertainty associated with reliance on surrogate endpoints carries a risk to patients and society, there is a need for HTA agencies to develop more detailed methodological guidance for consistent selection and evaluation of health technologies that lack definitive final patient-relevant outcome evidence at the time of the assessment.

Evaluating the Effectiveness and Cost-Effectiveness of Seizure Dogs in Persons With Medically Refractory Epilepsy in the Netherlands: Study Protocol for a Stepped Wedge Randomized Controlled Trial (EPISODE).

Background: Epilepsy is associated with a high disease burden, impacting the lives of people with epilepsy and their caregivers and family. Persons with medically refractory epilepsy experience the greatest burden, suffering from profound physical, psychological, and social consequences. Anecdotal evidence suggests these persons may benefit from a seizure dog. As the training of a seizure dog is a substantial investment, their accessibility is limited in the absence of collective reimbursement as is seen in the Netherlands. Despite sustained interest in seizure dogs, scientific knowledge on their benefits and costs remains scarce. To substantiate reimbursement decisions stronger evidence is required. The EPISODE study aims to provide this evidence by evaluating the effectiveness and cost-effectiveness of seizure dogs in adults with medically refractory epilepsy. Methods: The study is designed as a stepped wedge randomized controlled trial that compares the use of seizure dogs in addition to usual care, with usual care alone. The study includes adults with epilepsy for whom current treatment options failed to achieve seizure freedom. Seizure frequency of participants should be at least two seizures per week, and the seizures should be associated with a high risk of injury or dysfunction. During the 3 year follow-up period, participants receive a seizure dog in a randomized order. Outcome measures are taken at multiple time points both before and after receiving the seizure dog. Seizure frequency is the primary outcome of the study and will be recorded continuously using a seizure diary. Questionnaires measuring seizure severity, quality of life, well-being, resource use, productivity, social participation, and caregiver burden will be completed at baseline and every 3 months thereafter. The study is designed to include a minimum of 25 participants. Discussion: This protocol describes the first randomized controlled trial on seizure dogs. The study will provide comprehensive data on the effectiveness and cost-effectiveness of seizure dogs in adults with medically refractory epilepsy. Broader benefits of seizure dogs for persons with epilepsy and their caregivers are taken into account, as well as the welfare of the dogs. The findings of the study can be used to inform decision-makers on the reimbursement of seizure dogs.

Ribociclib with an Aromatase Inhibitor for Previously Untreated, HR-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence, as part of the institute's single technology appraisal process, invited the manufacturer of ribociclib (Kisqali®, Novartis) to submit evidence regarding the clinical and cost effectiveness of the drug in combination with an aromatase inhibitor for the treatment of previously untreated, hormone receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced or metastatic breast cancer. Kleijnen Systematic Reviews Ltd and Erasmus University Rotterdam were commissioned as the Evidence Review Group for this submission. The Evidence Review Group reviewed the evidence submitted by the manufacturer, corrected and validated the manufacturer's decision analytic model, and conducted exploratory analyses to assess the robustness and validity of the presented clinical and cost-effectiveness results. This article describes the company submission, the Evidence Review Group assessment and National Institute for Health and Care Excellence subsequent decisions. The main clinical effectiveness evidence was obtained from the MONALEESA-2 trial, a randomised controlled trial comparing ribociclib plus letrozole with placebo plus letrozole. Progression-free survival was significantly longer in the ribociclib group (95% confidence interval, 19.3-not reached) vs. 14.7 months (95% confidence interval 13.0-16.5) in the placebo group. To assess the cost effectiveness of ribociclib in combination with an aromatase inhibitor, the company developed an individual patient-level model using a discrete-event simulation approach in Microsoft® Excel. In the model, simulated patients move through a series of three health states until death, i.e. first-line progression-free survival, second-line progression-free survival and progressive disease. The length of progression-free survival during the first line was informed by the MONALEESA-2 trial. The benefit in progression-free survival in the first line was transferred to a benefit in overall survival assuming full progression-free survival to overall survival surrogacy (because of the immaturity of overall survival data from the MONALEESA-2 trial). Patient-level data from the BOLERO-2 trial, evaluating the addition of everolimus to exemestane in the second-line treatment of postmenopausal HR-positive advanced breast cancer, were used to inform the length of progression-free survival during the second line. Costs included in the model were treatment costs (e.g. technology acquisition costs of first, second, third and/or later line treatments), drug administration costs, monitoring costs and health state costs (including terminal care). Additionally, the costs of adverse events associated with the first-line treatment were incorporated. The Evidence Review Group recalculated the incremental cost-effectiveness ratio using data from a different data cut-off date from the MONALEESA-2 trial and by changing some assumptions (e.g. progression-free survival to overall survival surrogacy approach and post-progression third and/or later line treatment-related costs). After two appraisal committee meetings and a revised base case submitted by the company (including a second enhanced patient access scheme discount), the committee concluded that taking into account the uncertainties in the calculation of the cost effectiveness, there were plausible cost-effectiveness estimates broadly in the range that could be considered as a cost-effective use of National Health Service resources. Therefore, ribociclib was recommended as a treatment option for the first-line treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, contingent on the company providing ribociclib with the discount agreed in the second enhanced patient access scheme.

A cost of illness study of hypoglycaemic events in insulin-treated diabetes in the Netherlands.

OBJECTIVES: Patients with diabetes mellitus are at a risk for hypoglycaemia. Besides the burden of hypoglycaemia for patients, hypoglycaemia poses an economic burden to society. The aim of this study was to calculate the per patient societal costs of hypoglycaemia among patients with type1 diabetes (T1DM) and type 2 diabetes (T2DM) on insulin therapy in the Netherlands. METHODS: To calculate the costs of hypoglycaemia, data from the Global Hypoglycaemia Assessment Tool (HAT) study were used. Dutch patients were selected from the HAT study database and data regarding healthcare resource use, informal care use and productivity losses were combined with Dutch unit costs to calculate the per patient 4-week costs of patients experiencing hypoglycaemia. Besides these 4-week costs, costs per hypoglycaemic event were calculated by dividing the study population total 4-week costs by the total number of events in this period. RESULTS: Mean 4-week total costs of hypoglycaemia amounted to €163 (SD, €870) in T1DM and €134 (SD, €364) in T2DM. While productivity costs were the most important cost driver of hypoglycaemia in patients with T1DM (accounting for 72% of the total costs), costs of hypoglycaemia in patients with T2DM were almost entirely driven by costs within the healthcare sector (accounting for 98% of the total costs). Mean costs of a severe hypoglycaemic event were €828 and €508 in T1DM and T2DM, respectively, whereas mean costs of a non-severe event were almost zero. CONCLUSIONS: This study showed that the economic burden of severe hypoglycaemia is substantial. The prevention of hypoglycaemia could therefore not only reduce the burden for patients, but also the economic burden to society.

Long-term Outcomes in Patients With Multiple Myeloma: A Retrospective Analysis of the Dutch Population-based HAematological Registry for Observational Studies (PHAROS).

Registry data are important for monitoring the impact of new therapies on treatment algorithms and outcomes, and for guiding clinical decision making in multiple myeloma (MM). This observational study analyzed real-world data from patients in the Population-based HAematological Registry for Observational Studies who were treated for symptomatic MM from 2008 to 2013 in the Netherlands. The primary endpoint was overall survival (OS) from initiation of first-line treatment. Secondary endpoints included OS and progression-free survival per treatment line, treatment patterns, and treatment response. Between 2008 and 2013, 917, 583, 283, and 139 patients had initiated first, second, third, and fourth treatment lines, respectively. Thalidomide-based regimens were the most frequently used first-line treatment (66%); bortezomib- and lenalidomide-based regimens were most often used in the second line (41% and 27%, respectively). The median OS (95% confidence interval) ranged from 37.5 months (34.8-41.8 months) in the first line to 9.2 months (6.2-12.3 months) in the fourth line. Univariate analyses showed that survival benefits were most apparent in younger patients (≤65 vs >65 years). These analyses provide important real-world information on treatment patterns and outcomes in patients with MM.

Pomalidomide with Dexamethasone for Treating Relapsed and Refractory Multiple Myeloma Previously Treated with Lenalidomide and Bortezomib: An Evidence Review Group Perspective of an NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE), as part of the institute's single technology appraisal (STA) process, invited the manufacturer of pomalidomide (POM; Imnovid®, Celgene) to submit evidence regarding the clinical and cost effectiveness of the drug in combination with dexamethasone (POM + LoDEX) for the treatment of relapsed and refractory multiple myeloma (RRMM) after at least two regimens including lenalidomide (LEN) and bortezomib (BOR). Kleijnen Systematic Reviews Ltd (KSR) and Erasmus University Rotterdam were commissioned as the Evidence Review Group (ERG) for this submission. The ERG reviewed the evidence submitted by the manufacturer, validated the manufacturer's decision analytic model, and conducted exploratory analyses in order to assess the robustness and validity of the presented clinical and cost-effectiveness results. This paper describes the company submission, the ERG assessment, and NICE's subsequent decisions. The company conducted a systematic review to identify studies comparing POM with comparators outlined in the NICE scope: panobinostat with bortezomib and dexamethasone (PANO + BOR + DEX), bendamustine with thalidomide and dexamethasone (BTD) and conventional chemotherapy (CC). The main clinical effectiveness evidence was obtained from MM-003, a randomized controlled trial (RCT) comparing POM + LoDEX with high-dose dexamethasone (HiDEX; used as a proxy for CC). Additional data from other studies were also used as nonrandomized observational data sources for the indirect treatment comparison of POM + LoDEX with BTD and PANO + BOR + DEX. Covariate or treatment switching adjustment methods were used for each comparison. The model developed in Microsoft® Excel 2010 using a semi-Markov partitioned survival structure, submitted in the original submission to NICE for TA338, was adapted for the present assessment of the cost effectiveness of POM + LoDEX. Updated evidence from the clinical-effectiveness part was used for the survival modelling of progression-free survival and overall survival. For POM + LoDEX, the patient access scheme (PAS) discount was applied to the POM price. Three separate comparisons were conducted for each comparator, each comparison using a different dataset and adjustment methods. The ERG identified and corrected some errors, and the corrected incremental cost-effectiveness ratios (ICERs) for POM + LoDEX versus each comparator were presented: approximately £45,000 per quality-adjusted life-year (QALY) gained versus BTD, savings of approximately £143,000 per QALY lost versus PANO + BOR + DEX, and approximately £49,000 per QALY gained versus CC. The ERG also conducted full incremental analyses, which revealed that CC, POM + LoDEX and PANO + BOR + DEX were on the cost-effectiveness frontier. The committee's decision on the technology under analysis deemed that POM + LoDEX should be recommended as an option for treating multiple myeloma in adults at third or subsequent relapse of treatments including both LEN and BOR, contingent on the company providing POM with the discount agreed in the PAS.

Balancing the Optimal and the Feasible: A Practical Guide for Setting Up Patient Registries for the Collection of Real-World Data for Health Care Decision Making Based on Dutch Experiences.

OBJECTIVES: The aim of this article was to provide practical guidance in setting up patient registries to facilitate real-world data collection for health care decision making. METHODS: This guidance was based on our experiences and involvement in setting up patient registries in oncology in the Netherlands. All aspects were structured according to 1) mission and goals ("the Why"), 2) stakeholders and funding ("the Who"), 3) type and content ("the What"), and 4) identification and recruitment of patients, data handling, and pharmacovigilance ("the How"). RESULTS: The mission of most patient registries is improving patient health by improving the quality of patient care; monitoring and evaluating patient care is often the primary goal ("the Why"). It is important to align the objectives of the registry and agree on a clear and functional governance structure with all stakeholders ("the Who"). There is often a trade off between reliability, validity, and specificity of data elements and feasibility of data collection ("the What"). Patient privacy should be carefully protected, and address (inter-)national and local regulations. Patient registries can reveal unique safety information, but it can be challenging to comply with pharmacovigilance guidelines ("the How"). CONCLUSIONS: It is crucial to set up an efficient patient registry that serves its aims by collecting the right data of the right patient in the right way. It can be expected that patient registries will become the new standard alongside randomized controlled trials due to their unique value.

Cost-effectiveness of obinutuzumab for chronic lymphocytic leukaemia in The Netherlands.

BACKGROUND: Obinutuzumab combined with chlorambucil (GClb) has shown to be superior to rituximab combined with chlorambucil (RClb) and chlorambucil (Clb) in newly diagnosed patients with chronic lymphocytic leukaemia (CLL). This study evaluates the cost-effectiveness per life-year and quality-adjusted life-year (QALY) of GClb compared to RClb, Clb, and ofatumumab plus chlorambucil (OClb) in The Netherlands. METHODS: A Markov model was developed to assess the cost-effectiveness of GClb, RClb, Clb and other treatments in the United Kingdom. A country adaptation was made to estimate the cost-effectiveness of these therapies in The Netherlands using Dutch unit costs and Dutch data sources for background mortality and post-progression survival. RESULTS: An incremental gain of 1.06 and 0.64 QALYs was estimated for GClb compared to Clb and RClb respectively, at additional costs of €23,208 and €7254 per patient. Corresponding incremental cost-effectiveness ratios (ICERs) were €21,823 and €11,344 per QALY. Indirect treatment comparisons showed an incremental gain varying from 0.44 to 0.77 QALYs for GClb compared to OClb and additional costs varying from €7041 to €5028 per patient. The ICER varied from €6556 to €16,180 per QALY. Sensitivity analyses showed the robustness of the results. CONCLUSION: GClb appeared to be a cost-effective treatment strategy compared to RClb, OClb and Clb.

Survival in Patients With Primary Metastatic Renal Cell Carcinoma Treated With Sunitinib With or Without Previous Cytoreductive Nephrectomy: Results From a Population-based Registry.

OBJECTIVE: To evaluate the effect of cytoreductive nephrectomy (CN) on overall survival (OS) in primary metastatic renal cell carcinoma (mRCC) patients treated with first-line sunitinib. PATIENTS AND METHODS: Patients with primary mRCC treated with first-line sunitinib were selected from a Dutch population-based registry. A propensity score was calculated reflecting the probability of a patient undergoing CN prior to sunitinib using a set of known covariates, such as the Memorial Sloan Kettering Cancer Center and International mRCC Database Consortium risk factors. After propensity score matching, differences in OS were analyzed using the Kaplan-Meier method and a multivariable Cox proportional hazards model was used to evaluate the effect of CN on OS. RESULTS: A total of 227 patients met the selection criteria; 74 patients (33%) underwent CN prior to sunitinib. In the matched population, the median OS of patients who underwent CN was 17.9 months compared to 8.8 months for patients treated with sunitinib only. Multivariable analysis showed that CN was an independent predictor of OS (hazard ratio 0.61, 95% confidence interval: 0.41-0.92). A subgroup analysis of patients with a time to targeted therapy of <1 year showed a median OS of 12.7 months for patients treated with CN compared to 8.0 months for patients treated with sunitinib only. The corresponding hazard ratio was 0.67 (95% confidence interval: 0.46-0.98). CONCLUSION: This study suggests that CN may be effective. However, the benefit was modest when correcting for time from diagnosis to sunitinib. One important limitation is the use of a registry (with retrospectively collected data), which made it impossible to correct for unmeasured characteristics that could be associated with treatment choices or survival.

A cost-effectiveness analysis of real-world treatment for elderly patients with multiple myeloma using a full disease model.

OBJECTIVES: To study the impact of novel treatments for elderly (≥66 yr) patients with multiple myeloma (MM) in daily practice by comparing real-world effects [overall survival (OS) and quality-adjusted life years (QALYs)] and costs over time. Also, we calculate cost-effectiveness of treatment sequences commonly prescribed to predict effects and costs if patients had received a different treatment sequence. METHODS: Real-world data including patient and disease characteristics, treatment information and resource use were collected from 1054 elderly patients with MM. Patients received first-line treatment during 2004-2007 (cohort 1) and 2008-2013 (cohort 2). The two cohorts were compared using a patient-level simulation (PLS) model comprising regression models which used patient and disease characteristics to estimate time to next treatment and death. Effects and costs from cohort 2 were compared to 4 commonly prescribed real-world sequences. RESULTS: Utilisation of novel agents was higher for cohort 2 compared to cohort 1. Modelled average OS for cohort 1 was 38 months (median 25) and total costs €44,200. OS for cohort 2 was 42 months (median 28) and total costs €69,017. The model identified potential OS gains if all patients were to be treated using combinations containing thalidomide, lenalidomide and bortezomib in that particular order. This sequence had, compared to real-world treatment, the most favourable incremental cost-effectiveness ratio, €24,618 per life year gained and €34,875 per QALY. CONCLUSIONS: Our patient-level model enabled to study the effects and costs of entire treatment sequences and to compare real-world treatment patterns over time. Increased utilisation of novel agents improved survival and increased costs for real-world patients with MM in the Netherlands.

Which factors may determine the necessary and feasible type of effectiveness evidence? A mixed methods approach to develop an instrument to help coverage decision-makers.

OBJECTIVES: Reimbursement decisions require evidence of effectiveness and, in general, a blinded randomised controlled trial (RCT) is the preferred study design to provide it. However, there are situations where a cohort study, or even patient series, can be deemed acceptable. The aim of this study was to develop an instrument that first examines which study characteristics of a blinded RCT are necessary, and then, if particular characteristics are considered necessary, examines whether these characteristics are feasible. DESIGN: We retrospectively studied 22 interventions from 20 reimbursement reports concerning medical specialist care made by the Dutch National Health Care Institute (ZIN) to identify any factors that influenced the necessity and feasibility of blinded RCTs, and their constituent study characteristics, that is, blinding, randomisation and a control group. A literature review was performed to identify additional factors. Additional expertise was included by interviewing eight experts in epidemiology, medicine and ethics. The resulting instrument was called the FIT instrument (Feasible Information Trajectory), and was prospectively validated using three consecutive reimbursement reports. RESULTS: (Blinded) RCT evidence was lacking in 5 of 11 positive reimbursement decisions and 3 of 11 negative decisions. In the reimbursement reports, we found no empirical evidence supporting situations where a blinded RCT is unnecessary. The literature also revealed few arguments against the necessity of a blinded RCT. In contrast, many factors influencing the feasibility of randomisation, a control group and blinding, were found in the reimbursement reports and the literature; for example, when a patient population is too small or when an intervention is common practice, randomisation will be hindered. CONCLUSIONS: Policy regarding the necessity and feasibility of different types of evidence of effectiveness would benefit from systematic guidance. The FIT instrument has the potential to support transparent, reproducible and well-founded decisions on appropriate evidence of effectiveness in medical specialist care.

Real-world cost-effectiveness of oxaliplatin in stage III colon cancer: a synthesis of clinical trial and daily practice evidence.

OBJECTIVES: Previous cost-effectiveness analyses of oxaliplatin have been based on randomised trials whereas current Dutch policy requires evidence from daily practice. The objective of this study was to examine the real-world cost-effectiveness of oxaliplatin plus fluoropyrimidines (FL) versus FL-only as adjuvant treatment of stage III colon cancer. METHODS: A Markov model was developed to estimate lifetime cost and quality-adjusted life-years from a hospital perspective. The effectiveness of the oxaliplatin arm was modelled by combining published efficacy data from the pivotal clinical registration trial (MOSAIC trial) with real-world (RW) data from a Dutch population-based observational study. RW patients were categorised into "eligible" or "ineligible", depending on whether the patients fulfilled the MOSAIC trial eligibility criteria. Ineligible RW patients (18 %) had a poorer prognosis than eligible RW patients (82 %) and MOSAIC trial patients. The effectiveness of the comparator was modelled using MOSAIC trial results. All cost inputs were based on RW patients and reported in Euro 2012. Cost-effectiveness analyses were performed for four different scenarios: (1) cost-effectiveness analyses based on MOSAIC trial patients; (2) cost-effectiveness analyses using MOSAIC and eligible RW patients; (3) cost-effectiveness analyses using MOSAIC and both eligible and ineligible RW patients, assuming oxaliplatin had an equal effect in ineligible and eligible patients; (4) cost-effectiveness analyses using MOSAIC and both eligible and ineligible RW patients, assuming oxaliplatin had no effect amongst ineligibles. For each scenario, univariate and probabilistic sensitivity analyses were undertaken. RESULTS: MOSAIC trial patients and eligible RW patients treated with oxaliplatin had comparable 2-year disease-free survivals (79.5 vs. 78.4 %). Oxaliplatin showed an incremental QALY gain of 1.02, 1.13, 1.17 and 0.93 and incremental cost of 9,961, 11,055, 9,814 and 11,854 in scenarios 1-4, respectively. The corresponding incremental cost-effectiveness ratios (ICERs) were 9,766, 9,783, 8,388 and 12,746 in scenarios 1-4, respectively. In all scenarios, univariate and probabilistic sensitivity analyses indicated that the ICERs are acceptable and robust under a wide range of model assumptions. CONCLUSIONS: The ICERs of the different scenarios that resulted from combining MOSAIC trial data with data from Dutch daily practice all suggest that FL + oxaliplatin is cost-effective versus FL alone in the adjuvant treatment of colon cancer. This article illustrates how one could design and implement a real-world cost-effectiveness study to yield internally valid results that could also be generalisable.

The economics of improved cancer survival rates: better outcomes, higher costs.

In 2006, over three million new cases of cancer were diagnosed in Europe. This number will increase in the coming years as a result of an aging population and population growth. Advances in the diagnosis and treatment of cancer have resulted in increased survival rates. Simultaneously, increasing costs of screening, diagnosis and the treatment of cancer could threaten the ability to ensure high-quality care and provide access to care for all patients. New genetic tests and biomarkers may help to identify those subtypes of patients that would be most likely to benefit from new cancer drugs. In our opinion, there is still much to gain in cancer diagnosis and treatment but these gains should be worth the costs.

Investigating selection on viruses: a statistical alignment approach.

BACKGROUND: Two problems complicate the study of selection in viral genomes: Firstly, the presence of genes in overlapping reading frames implies that selection in one reading frame can bias our estimates of neutral mutation rates in another reading frame. Secondly, the high mutation rates we are likely to encounter complicate the inference of a reliable alignment of genomes. To address these issues, we develop a model that explicitly models selection in overlapping reading frames. We then integrate this model into a statistical alignment framework, enabling us to estimate selection while explicitly dealing with the uncertainty of individual alignments. We show that in this way we obtain un-biased selection parameters for different genomic regions of interest, and can improve in accuracy compared to using a fixed alignment. RESULTS: We run a series of simulation studies to gauge how well we do in selection estimation, especially in comparison to the use of a fixed alignment. We show that the standard practice of using a ClustalW alignment can lead to considerable biases and that estimation accuracy increases substantially when explicitly integrating over the uncertainty in inferred alignments. We even manage to compete favourably for general evolutionary distances with an alignment produced by GenAl. We subsequently run our method on HIV2 and Hepatitis B sequences. CONCLUSION: We propose that marginalizing over all alignments, as opposed to using a fixed one, should be considered in any parametric inference from divergent sequence data for which the alignments are not known with certainty. Moreover, we discover in HIV2 that double coding regions appear to be under less stringent selection than single coding ones. Additionally, there appears to be evidence for differential selection, where one overlapping reading frame is under positive and the other under negative selection.