Clinicians' Views on Therapeutic Outcomes of Systemic Interventions and on the Ability of the EQ-5D to Capture these Outcomes.

BACKGROUND: Systemic interventions focus on improvements of interactions between clients and their environments, and are increasingly used to treat adolescents with problems of substance use and delinquency. Clients' progress may include broad and non-medical effects. When performing economic evaluations of these interventions, the common outcome of costs per quality adjusted life year (cost/QALY) may not capture all of these effects. AIMS OF THE STUDY: The current study is an explorative study. It aims to investigate which outcomes clinicians consider relevant to the therapeutic success of systemic interventions and whether these, according to them, are sufficiently captured by the EQ-5D instrument. METHODS: Semi-structured interviews were performed with seven clinicians at two mental health institutions in the Netherlands. Clinicians were asked to list the most relevant outcomes of systemic interventions. They were asked whether they considered the EQ-5D dimensions to sufficiently capture these outcomes or if they missed aspects or outcome domains. RESULTS: The clinicians mentioned several broad effects relevant for the evaluation of systemic interventions. These were aspects of family functioning, parental functioning, social competencies, school attendance, etc. They considered several EQ-5D dimensions relevant (i.e. in particular 'usual activities' and 'anxiety/depression'), yet they indicated that the instrument lacked systemic dimensions (i.e. family relations and relations with others) and addiction-related aspects. DISCUSSION: The interviewed clinicians considered several dimensions of the EQ-5D useful in evaluating effects of systemic interventions, yet they expressed the need to add additional dimensions particularly relevant to systemic aspects to the instrument when performing economic evaluations of systemic interventions. The explorative analysis was limited by the small number of interviewed clinicians. Furthermore, a relatively high proportion of clinicians were specialized in Multidimensional Family Therapy, a type of systemic intervention particularly used to treat adolescents with substance use disorders and related problems. Hence the importance of addiction-related improvements may have been over-emphasized in this group of respondents. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE: Practical implications of the current study may be the need for enhancements of the current health economic methodology for evaluating systemic interventions as to capture additional aspects specifically relevant to these interventions. This may lead to different choices in the use of instruments for the evaluation of treatment progress and success in clinical practice. IMPLICATIONS FOR HEALTH POLICIES: By improving the health economic toolkit to evaluate systemic interventions one may provide policy recommendations in line with the therapeutic goals of the interventions. IMPLICATIONS FOR FURTHER RESEARCH: Further research could be directed at investigating the suitability of other available instruments than the EQ-5D for economic evaluations of systemic interventions.

A noticeable difference? Productivity costs related to paid and unpaid work in economic evaluations on expensive drugs.

Productivity costs can strongly impact cost-effectiveness outcomes. This study investigated the impact in the context of expensive hospital drugs. This study aimed to: (1) investigate the effect of productivity costs on cost-effectiveness outcomes, (2) determine whether economic evaluations of expensive drugs commonly include productivity costs related to paid and unpaid work, and (3) explore potential reasons for excluding productivity costs from the economic evaluation. We conducted a systematic literature review to identify economic evaluations of 33 expensive drugs. We analysed whether evaluations included productivity costs and whether inclusion or exclusion was related to the study population's age, health and national health economic guidelines. The impact on cost-effectiveness outcomes was assessed in studies that included productivity costs. Of 249 identified economic evaluations of expensive drugs, 22 (9 %) included productivity costs related to paid work. One study included unpaid productivity. Mostly, productivity cost exclusion could not be explained by the study population's age and health status, but national guidelines appeared influential. Productivity costs proved often highly influential. This study indicates that productivity costs in economic evaluations of expensive hospital drugs are commonly and inconsistently ignored in economic evaluations. This warrants caution in interpreting and comparing the results of these evaluations.

Cost comparison of two implantable cardiac monitors in two different settings: Reveal XT in a catheterization laboratory vs. Reveal LINQ in a procedure room.

AIMS: Implantable cardiac monitors (ICMs) are used for long-term heart rhythm monitoring, e.g. to diagnose unexplained syncope or for detection of suspected atrial and ventricular arrhythmias. The newest ICM, Reveal LINQ™ (Medtronic Inc.), is miniaturized and inserted with a specific insertion tool kit. The procedure is therefore minimally invasive and can be moved from catheterization laboratory (cath lab) to a less resource intensive setting. This study aims to assess the change in procedure costs when performed outside the cath lab. METHODS AND RESULTS: A bottom-up costing methodology was used. Data were collected from interviews with physicians, cath lab managers, and financial controllers. Hospitals in the Netherlands, France, and the UK were included in this study. The cost comparison of a Reveal XT implantation in a cath lab setting vs. a Reveal LINQ insertion outside a cath lab resulted in an estimated reduction of €662 for the UK, €682 for the Netherlands, and €781 for France. These cost savings were primarily realized through fewer staff, less equipment, and overhead costs. The net effect on savings depends on the price differential between these two technologies. The patient care pathway can be improved due to the possibility to move the procedure out of the cath lab. CONCLUSION: Inserting the miniaturized version of the ICM is simpler and faster, and the procedure can take place outside the cath lab in a less resource intensive environment. Hospitals save resources when the higher price of the Reveal LINQ does not outweigh these savings.

A conceptual disease model for adult Pompe disease.

BACKGROUND: Studies in orphan diseases are, by nature, confronted with small patient populations, meaning that randomized controlled trials will have limited statistical power. In order to estimate the effectiveness of treatments in orphan diseases and extrapolate effects into the future, alternative models might be needed. The purpose of this study is to develop a conceptual disease model for Pompe disease in adults (an orphan disease). This conceptual model describes the associations between the most important levels of health concepts for Pompe disease in adults, from biological parameters via physiological parameters, symptoms and functional indicators to health perceptions and final health outcomes as measured in terms of health-related quality of life. METHODS: The structure of the Wilson-Cleary health outcomes model was used as a blueprint, and filled with clinically relevant aspects for Pompe disease based on literature and expert opinion. Multiple observations per patient from a Dutch cohort study in untreated patients were used to quantify the relationships between the different levels of health concepts in the model by means of regression analyses. RESULTS: Enzyme activity, muscle strength, respiratory function, fatigue, level of handicap, general health perceptions, mental and physical component scales and utility described the different levels of health concepts in the Wilson-Cleary model for Pompe disease. Regression analyses showed that functional status was affected by fatigue, muscle strength and respiratory function. Health perceptions were affected by handicap. In turn, self-reported quality of life was affected by health perceptions. CONCLUSIONS: We conceptualized a disease model that incorporated the mechanisms believed to be responsible for impaired quality of life in Pompe disease. The model provides a comprehensive overview of various aspects of Pompe disease in adults, which can be useful for both clinicians and policymakers to support their multi-faceted decision making.

Value of Information Analysis Applied to the Economic Evaluation of Interventions Aimed at Reducing Juvenile Delinquency: An Illustration.

OBJECTIVES: To investigate whether a value of information analysis, commonly applied in health care evaluations, is feasible and meaningful in the field of crime prevention. METHODS: Interventions aimed at reducing juvenile delinquency are increasingly being evaluated according to their cost-effectiveness. Results of cost-effectiveness models are subject to uncertainty in their cost and effect estimates. Further research can reduce that parameter uncertainty. The value of such further research can be estimated using a value of information analysis, as illustrated in the current study. We built upon an earlier published cost-effectiveness model that demonstrated the comparison of two interventions aimed at reducing juvenile delinquency. Outcomes were presented as costs per criminal activity free year. RESULTS: At a societal willingness-to-pay of €71,700 per criminal activity free year, further research to eliminate parameter uncertainty was valued at €176 million. Therefore, in this illustrative analysis, the value of information analysis determined that society should be willing to spend a maximum of €176 million in reducing decision uncertainty in the cost-effectiveness of the two interventions. Moreover, the results suggest that reducing uncertainty in some specific model parameters might be more valuable than in others. CONCLUSIONS: Using a value of information framework to assess the value of conducting further research in the field of crime prevention proved to be feasible. The results were meaningful and can be interpreted according to health care evaluation studies. This analysis can be helpful in justifying additional research funds to further inform the reimbursement decision in regard to interventions for juvenile delinquents.

Access to orphan drugs in western Europe: can more systematic policymaking really help to avoid different decisions about the same drug?

When the Scottish government recently launched a £21 million fund to provide patients with rare diseases access to treatment, Alex Neill, the Scottish Health Secretary, stated that 'it was only right that Scottish patients with rare conditions had access to innovative medicines which were clinically justified, and that they were not disadvantaged due to the very high cost of these treatments'. This statement raises questions about the criteria that play a role in reimbursement decisions on orphan drugs. This editorial examines the criteria that were used in the decisions about the reimbursement of an orphan drug for Pompe disease and explores methods to improve the transparency and consistency of reimbursement decisions for orphan drugs in general.

Orphan drugs expenditure in the Netherlands in the period 2006-2012.

BACKGROUND: The relatively low budget impact of orphan drugs is often used as an argument in reimbursement decisions. However, overall, the budget impact of orphan drugs can still be substantial. In this study, we assess the uptake and budget impact of orphan drugs in the Netherlands. METHODS: We examined the number of orphan drugs, the number of patients and budget impact of orphan drugs in the Netherlands in the period 2006 to 2012, both for inpatient and outpatient orphan drugs. Budget impact was provided in absolute numbers and relative to total pharmaceutical spending. RESULTS: The number of orphan drugs and patients treated increased substantially over the period studied. Overall, budget impact increased substantially over a period of six years, both in absolute terms (326% increase) as well as relative to total pharmaceutical spending (278% increase). Growth rates decreased over time. In 2012, 17% of available drugs had an individual budget impact of more than €10 million per year. CONCLUSIONS: Individual budget impact of orphan drugs is often limited, although exceptions exist. However, in total, the budget impact of orphan drugs is considerable and has grown substantially over the years. This could potentially influence reimbursement decisions for orphan drugs in the future.

Cost-effectiveness of enzyme replacement therapy with alglucosidase alfa in classic-infantile patients with Pompe disease.

BACKGROUND: Infantile Pompe disease is a rare metabolic disease. Patients generally do not survive the first year of life. Enzyme replacement therapy (ERT) has proven to have substantial effects on survival in infantile Pompe disease. However, the costs of therapy are very high. In this paper, we assess the cost-effectiveness of enzyme replacement therapy in infantile Pompe disease. METHODS: A patient simulation model was used to compare costs and effects of ERT with costs of effects of supportive therapy (ST). The model was filled with data on survival, quality of life and costs. For both arms of the model, data on survival were obtained from international literature. In addition, survival as observed among 20 classic-infantile Dutch patients, who all received ERT, was used. Quality of life was measured using the EQ-5D and assumed to be the same in both treatment groups. Costs included the costs of ERT (which depend on a child's weight), infusions, costs of other health care utilization, and informal care. A lifetime time horizon was used, with 6-month time cycles. RESULTS: Life expectancy was significantly longer in the ERT group than in the ST group. On average, ST receiving patients were modelled not to survive the first half year of life; whereas the life expectancy in the ERT patients was modelled to be almost 14 years. Lifetime incremental QALYs were 6.8. Incremental costs were estimated to be € 7.0 million, which primarily consisted of treatment costs (95%). The incremental costs per QALY were estimated to be € 1.0 million (range sensitivity analyses: € 0.3 million - € 1.3 million). The incremental cost per life year gained was estimated to be € 0.5 million. CONCLUSIONS: The incremental costs per QALY ratio is far above the conventional threshold values. Results from univariate and probabilistic sensitivity analyses showed the robustness of the results.

How work impairments and reduced work ability are associated with health care use in workers with musculoskeletal disorders, cardiovascular disorders or mental disorders.

PURPOSE: The aim of this study was to explore how work impairments and work ability are associated with health care use by workers with musculoskeletal disorders (MSD), cardiovascular disorders (CVD), or mental disorders (MD). METHODS: In this cross-sectional study, subjects with MSD (n = 2,074), CVD (n = 714), and MD (n = 443) were selected among health care workers in 12 Dutch organizations. Using an online questionnaire, data were collected on individual characteristics, health behaviors, work impairments, work ability, and consultation of a general practitioner (GP), physiotherapist, specialist, or psychologist in the past year. Univariate and multivariate logistic regression analyses were performed to explore the associations of work impairments and work ability with health care use. RESULTS: Lower work ability was associated with a higher likelihood of consulting any health care provider among workers with common disorders (OR 1.05-1.45). Among workers with MSD work impairments increased the likelihood of consulting a GP (OR 1.55), specialist (OR 2.05), and physical therapist (OR 1.98). Among workers with CVD work impairments increased the likelihood of consulting a specialist (OR 1.94) and physical therapist (OR 2.73). Among workers with MD work impairments increased the likelihood of consulting a specialist (OR 1.79) and psychologist (OR 1.82). CONCLUSION: Work impairments and reduced work ability were associated with health care use among workers with MSD, CVD, or MD. These findings suggest that addressing work-related problems in workers with common disorders may contribute in reducing health care needs.

Systematic review of available evidence on 11 high-priced inpatient orphan drugs.

BACKGROUND: Attention for Evidence Based Medicine (EBM) is growing, but evidence for orphan drugs is argued to be limited and inferior. This study systematically reviews the available evidence on clinical effectiveness, cost-effectiveness and budget impact for orphan drugs. METHODS: A systematic review was performed in PubMed, Embase, NHS EED and HTA databases for 11 inpatient orphan drugs listed on the Dutch policy rule on orphan drugs. For included studies, we determined the type of study and various study characteristics. RESULTS: A total of 338 studies met all inclusion criteria. Almost all studies (96%) focused on clinical effectiveness of the drug. Of these studies, most studies were case studies (41%) or observational studies (39%). However, for all orphan diseases at least one experimental or quasi-experimental study was found, and a randomized clinical trial was available for 60% of the orphan drugs. Eight studies described the cost-effectiveness of an orphan drug; an equal number described an orphan drug's budget impact. CONCLUSIONS: Despite the often heard claim that RCTs are not feasible for orphan drugs, we found that an RCT was available in 60% of orphan drugs investigated. Cost-effectiveness and budget impact analyses for orphan drugs are seldom published.

The impact of informal care for patients with Pompe disease: an application of the CarerQol instrument.

BACKGROUND: Patients with Pompe disease, a rare progressive neuromuscular disorder, receive a considerable amount of informal care. In this study, we examined the impact of providing informal care to patients with Pompe disease. METHODS: Caregivers were administered various instruments, which measured the (impact of) informal care in the context of Pompe disease. Patients' quality of life and use of a wheelchair and respiratory support were used to investigate the impact of disease severity on the burden and well-being of caregivers. RESULTS: Of all Dutch patients with Pompe disease, 88 indicated to receive informal care, of which 67 (76%; 67 caregivers) participated in this study. On average, caregivers provided 17.7 hours of informal care per week. Higher disease burden was associated with more hours of informal care. Caregivers experienced burden due to caregiving. Half of the informal caregivers reported mental health problems and problems with daily activities due to providing informal care. Physical health problems occurred in 40% of informal caregivers. Caregiver burden was higher for patients with a lower quality of life and for wheelchair dependent patients. Burden was not associated with respiratory support. Caregivers reported deriving personal fulfillment from caregiving and, on average, would become unhappier if someone else were to take over their care activities. CONCLUSIONS: The provision of informal care causes burden to caregivers. However, caregivers also value caring for their loved ones themselves. The study may help physicians and policy makers to design measures to support informal caregivers.

Framework for modelling the cost-effectiveness of systemic interventions aimed to reduce youth delinquency.

BACKGROUND: Many interventions initiated within and financed from the health care sector are not necessarily primarily aimed at improving health. This poses important questions regarding the operationalisation of economic evaluations in such contexts. AIMS OF THE STUDY: We investigated whether assessing cost-effectiveness using state-of-the-art methods commonly applied in health care evaluations is feasible and meaningful when evaluating interventions aimed at reducing youth delinquency. METHODS: A probabilistic Markov model was constructed to create a framework for the assessment of the cost-effectiveness of systemic interventions in delinquent youth. For illustrative purposes, Functional Family Therapy (FFT), a systemic intervention aimed at improving family functioning and, primarily, reducing delinquent activity in youths, was compared to Treatment as Usual (TAU). "Criminal activity free years" (CAFYs) were introduced as central outcome measure. Criminal activity may e.g. be based on police contacts or committed crimes. In absence of extensive data and for illustrative purposes the current study based criminal activity on available literature on recidivism. Furthermore, a literature search was performed to deduce the model's structure and parameters. RESULTS: Common cost-effectiveness methodology could be applied to interventions for youth delinquency. Model characteristics and parameters were derived from literature and ongoing trial data. The model resulted in an estimate of incremental costs/CAFY and included long-term effects. Illustrative model results point towards dominance of FFT compared to TAU. DISCUSSION: Using a probabilistic model and the CAFY outcome measure to assess cost-effectiveness of systemic interventions aimed to reduce delinquency is feasible. However, the model structure is limited to three states and the CAFY measure was defined rather crude. Moreover, as the model parameters are retrieved from literature the model results are illustrative in the absence of empirical data. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE: The current model provides a framework to assess the cost-effectiveness of systemic interventions, while taking into account parameter uncertainty and long-term effectiveness. IMPLICATIONS FOR HEALTH POLICIES: The framework of the model could be used to assess the cost-effectiveness of systemic interventions alongside (clinical) trial data. Consequently, it is suitable to inform reimbursement decisions, since the value for money of systemic interventions can be demonstrated using a decision analytic model. IMPLICATIONS FOR FURTHER RESEARCH: Future research could be focussed on testing the current model based on extensive empirical data, improving the outcome measure and finding appropriate values for that outcome.

Burden of illness of Pompe disease in patients only receiving supportive care.

BACKGROUND: Pompe disease is an orphan disease for which enzyme replacement therapy (ERT) recently became available. This study aims to estimate all relevant aspects of burden of illness--societal costs, use of home care and informal care, productivity losses, and losses in health-related quality of life (HRQoL)--for adult Pompe patients only receiving supportive care. METHODS: We collected data on all relevant aspects of burden of illness via a questionnaire. We applied a societal perspective in calculating costs. The EQ-5D was used to estimate HRQoL. RESULTS: Eighty adult patients (87% of the total Dutch adult Pompe population) completed a questionnaire. Disease severity ranged from mild to severe. Total annual costs were estimated at 22,475 (range 0-169,539) per adult Pompe patient. Patients on average received 8 h of home care and 19 h of informal care per week. Eighty-five percent of the patients received informal care from one or more caregivers; 40% had stopped working due to their disease; another 20% had reduced their working hours. HRQoL for Pompe patients who only received supportive care was estimated at 0.72, 17% lower than the Dutch population at large. CONCLUSIONS: Adult Pompe disease is associated with a considerable burden of illness at both the societal and patient levels. The disease leads to substantial costs and dependency on medical devices, home care, and informal care, and has a high impact on the patient's social network. In addition, patients are limited in their ability to work and have significantly reduced HRQoL.

Cost-consequence analysis of remifentanil-based analgo-sedation vs. conventional analgesia and sedation for patients on mechanical ventilation in the Netherlands.

INTRODUCTION: Hospitals are increasingly forced to consider the economics of technology use. We estimated the incremental cost-consequences of remifentanil-based analgo-sedation (RS) vs. conventional analgesia and sedation (CS) in patients requiring mechanical ventilation (MV) in the intensive care unit (ICU), using a modelling approach. METHODS: A Markov model was developed to describe patient flow in the ICU. The hourly probabilities to move from one state to another were derived from UltiSAFE, a Dutch clinical study involving ICU patients with an expected MV-time of two to three days requiring analgesia and sedation. Study medication was either: CS (morphine or fentanyl combined with propofol, midazolam or lorazepam) or: RS (remifentanil, combined with propofol when required). Study drug costs were derived from the trial, whereas all other ICU costs were estimated separately in a Dutch micro-costing study. All costs were measured from the hospital perspective (price level of 2006). Patients were followed in the model for 28 days. We also studied the sub-population where weaning had started within 72 hours. RESULTS: The average total 28-day costs were €15,626 with RS versus €17,100 with CS, meaning a difference in costs of €1474 (95% CI -2163, 5110). The average length-of-stay (LOS) in the ICU was 7.6 days in the RS group versus 8.5 days in the CS group (difference 1.0, 95% CI -0.7, 2.6), while the average MV time was 5.0 days for RS versus 6.0 days for CS. Similar differences were found in the subgroup analysis. CONCLUSIONS: Compared to CS, RS significantly decreases the overall costs in the ICU. TRIAL REGISTRATION: Clinicaltrials.gov NCT00158873.

The cost utility of solifenacin in the treatment of overactive bladder.

OBJECTIVES: Overactive bladder may cause significant discomfort to patients. The standard therapy for overactive bladder includes behavioural therapy and sometimes medication. Recently, a new medication (solifenacin 5 and 10 mg) was developed for treatment of overactive bladder. The objective of this study was to assess the cost utility of solifenacin 5 and 10 mg for overactive bladder. METHODS: We developed a Markov model to estimate the cost per quality adjusted life years (QALY) over a period of 12-months. Model parameters were based on randomized clinical trials for solifenacin 5 and 10 mg. Data on utility scores were taken from the literature. RESULTS: The incremental cost per QALY for solifenacin 5 mg and solifenacin 10 mg compared with placebo were 17,602 pounds and 24,464 pounds respectively. Sensitivity analyses showed that these results were robust to changes of relevant input data. CONCLUSION: Solifenacin 5 and 10 mg are cost-effective treatments in patients with overactive bladder.

A detailed cost analysis of in vitro fertilization and intracytoplasmic sperm injection treatment.

OBJECTIVE: To provide detailed information about costs of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) treatment stages and to estimate the cost per IVF and ICSI treatment cycle and ongoing pregnancy. DESIGN: Descriptive micro-costing study. SETTING: Four Dutch IVF centers. PATIENT(S): Women undergoing their first treatment cycle with IVF or ICSI. INTERVENTION(S): IVF or ICSI. MAIN OUTCOME MEASURE(S): Costs per treatment stage, per cycle started, and for ongoing pregnancy. RESULT(S): Average costs of IVF and ICSI hormonal stimulation were euro 1630 and euro 1585; the costs of oocyte retrieval were euro 500 and euro 725, respectively. The cost of embryo transfer was euro 185. Costs per IVF and ICSI cycle started were euro 2381 and euro 2578, respectively. Costs per ongoing pregnancy were euro 10,482 and euro 10,036, respectively. CONCLUSION(S): Hormonal stimulation covered the main part of the costs per cycle (on average 68% and 61% for IVF and ICSI, respectively) due to the relatively high cost of medication. The costs of medication increased with increasing age of the women, irrespective of the type of treatment (IVF or ICSI). Fertilization costs (IVF laboratory) constituted 12% and 20% of the total costs of IVF and ICSI. The total cost per ICSI cycle was 8.3% higher than IVF.