Multiplier Effects and Compensation Mechanisms for Inclusion in Health Economic Evaluation: A Systematic Review.

BACKGROUND: Compensation mechanisms and multiplier effects may affect productivity losses due to illness, disability, or premature death of individuals. Hence, they are important in estimating productivity losses and productivity costs in the context of economic evaluations of health interventions. This paper presents a systematic literature review of papers focusing on compensation mechanisms and multiplier effects, as well as whether and how they are included in health economic evaluations. METHODS: The systematic literature search was performed covering EconLit and PubMed. A data-extraction form was developed focusing on compensation mechanisms and multiplier effects. RESULTS: A total of 26 studies were included. Of these, 15 were empirical studies, three studies were methodological studies, two studies combined methodological research with empirical research, four were critical reviews, one study was a critical review combined with methodological research, and one study was a cost-benefit analysis. No uniform definition of compensation mechanisms and multiplier effects was identified. The terminology used to describe compensation mechanisms and multiplier effects varied as well. While the included studies suggest that both multipliers as well as compensation mechanisms substantially impact productivity cost estimates, the available evidence is scarce. Moreover, the generalizability as well as validity of assumptions underlying the calculations are unclear. Available measurement methods for compensation mechanisms and multiplier effects differ in approaches and are hardly validated. CONCLUSION: While our review suggests that compensation mechanisms and multiplier effects may have a significant impact on productivity losses and costs, much remains unclear about their features, valid measurement, and correct valuation. This hampers their current inclusion in economic evaluation, and therefore, more research into both phenomena remains warranted.

Economic Evaluation of a Tumour-Agnostic Therapy: Dutch Economic Value of Larotrectinib in TRK Fusion-Positive Cancers.

BACKGROUND: Larotrectinib is the first tumour-agnostic therapy that has been approved by the European Medicines Agency. Tumour-agnostic therapies are indicated for a multitude of tumour types. The economic models supporting reimbursement submissions of tumour-agnostic therapies are complex because of the multitude of indications per model. OBJECTIVE: The objective of this paper was to evaluate the cost effectiveness of larotrectinib compared with standard of care in patients with cancer with tropomyosin receptor kinase fusion-positive tumour types in the Netherlands. METHODS: A previously constructed cost-effectiveness model with a partitioned survival approach was adapted to the Dutch setting, simulating costs and effects of treatment in patients with tropomyosin receptor kinase fusion-positive cancer. The cost-effectiveness model conducts a naïve comparison of larotrectinib to a weighted comparator standard-of-care arm. Dutch specific resource use and costs were implemented and inflated to reflect 2019 euros. The analysis includes a lifetime horizon and a societal perspective. RESULTS: Larotrectinib versus Dutch standard of care resulted in 5.61 incremental (QALYs) and €232,260 incremental costs, leading to an incremental cost-effectivenes ratio of €41,424/QALY. The probabilistic sensitivity analysis reveals a 88% chance of larotrectinib being cost effective compared with the pooled comparator standard-of-care arm at the applicable €80,000/QALY willingness-to-pay threshold in the Netherlands. CONCLUSIONS: The incremental cost-effectivenes ratio was well below the applicable threshold for diseases with a high burden of disease in the Netherlands (€80,000). At this threshold, larotrectinib was estimated to be a cost-effective treatment for patients with tropomyosin receptor kinase fusion-positive cancer compared with current standard of care in the Netherlands.

Measurement Instruments of Productivity Loss of Paid and Unpaid Work: A Systematic Review and Assessment of Suitability for Health Economic Evaluations From a Societal Perspective.

OBJECTIVES: This study aimed (1) to perform a systematic literature review of instruments for measuring productivity loss of paid and unpaid work and (2) to assess the suitability (in terms of identification, measurement, and valuation) of these instruments for use in health economic evaluations from a societal perspective. METHODS: Articles published from 2018 were sourced from PubMed/Medline, PsycInfo, Embase, and Econlit. Using 2 separate search strategies, eligible economic evaluations and validation studies were selected and unique measurement instruments identified. A data-extraction form was developed by studying previous literature and consulting an international panel of experts in the field of productivity costs. This data-extraction form was applied to assess the suitability of instruments for use in economic evaluations. RESULTS: A total of 5982 articles were retrieved from the databases, of which 99 economic evaluations and 9 validation studies were included in the review. A total of 42 unique measurement instruments were identified. Nine instruments provided quantified measures of absenteeism, presenteeism, and unpaid work. Five instruments supplied the necessary information to enable the use of at least 1 common valuation method. The Health and Labour Questionnaire-Short Form, Health and Labour Questionnaire, and Institute for Medical Technology Assessment Productivity Cost Questionnaire met both criteria. Nevertheless, the developers replaced the Health and Labour Questionnaire-Short Form and Health and Labour Questionnaire by the more recently developed Institute for Medical Technology Assessment Productivity Cost Questionnaire. CONCLUSIONS: Although many instruments for measuring productivity loss were identified, most were not suitable for capturing productivity changes for economic evaluations from a societal perspective. Future research can benefit from this study by making an informed instrument choice for the measurement of productivity loss of paid and unpaid work.

Concerns, quality of life, access to care and productivity of the general population during the first 8 weeks of the coronavirus lockdown in Belgium and the Netherlands.

BACKGROUND: The COVID-19 pandemic has a disruptive impact on our society. We therefore conducted a population survey to describe: 1) stress, concerns and quality of life 2) access to healthcare and cancelled/delayed healthcare and 3) productivity during the first 8 weeks of the coronavirus lockdown in the general population. METHODS: An online cross-sectional survey was conducted in a representative sample after 8 weeks of the coronavirus lockdown in Belgium and the Netherlands. The survey included a series of three validated questionnaires about quality of life delayed/cancelled medical care and productivity loss using validated questionnaires. RESULTS: In total, 2099 Belgian and 2058 Dutch respondents completed the survey with a mean age of 46.4 and 42.0 years, respectively. Half of the respondents were female in both countries. A small proportion tested positive for COVID-19, 1.4% vs 4.7%, respectively. The majority of respondents with a medical condition was worried about their current health state due to the pandemic (53%) vs (63%), respectively. Respondents experienced postponed/cancelled care (26%) and were concerned about the availability of medication (32%) for both countries. Productivity losses due to the COVID-19 restrictions were calculated in absenteeism (36%) and presenteeism (30%) for Belgium, and (19%) and (35%) for the Netherlands. Most concerns and productivity losses were reported by respondents with children < 12 years, respondents aged 18-35 and respondents with an (expected) COVID-19 infection. CONCLUSIONS: This study describes stress, quality of life, medical resource loss and productivity losses in Belgium and the Netherlands after 8 weeks of coronavirus lockdown. The results underline the burden on society.

Correction to: Cost Effectiveness of Cladribine Tablets for the Treatment of Relapsing-Remitting Multiple Sclerosis in The Netherlands.

The second author's name should be "Maria De Francesco" rather than "Maria de Fransesco".

The burden of amputation in patients with peripheral arterial disease in the Netherlands.

INTRODUCTION: Peripheral arterial disease (PAD) can lead to severe cases of critical limb ischemia (CLI), which in turn might lead to amputation. Amputation can have substantial consequences for patients. This publication aims to give a better understanding of the amputation-related burden in patients with PAD in the Netherlands. EVIDENCE ACQUISITION: A systematic review and grey literature searches were conducted followed by qualitative interviews with a multidisciplinary team of clinical experts in amputation. Subsequently, IQVIA's Dutch hospital claims data were analyzed. EVIDENCE SYNTHESIS: Twenty-seven publications were identified. Dutch claims data identified claims for 2328 patients after amputation for PAD. Data for the following topics were found: incidence, mortality, complications, mobility, daily functioning, quality of life, utilities, length of stay (LoS), costs, and resource use. Annually, 90% of the 3300 amputations carried out in the Netherlands were due to vascular disease. One-year mortality in patients with an amputation ranged from 49.6% (above-the-knee amputation) to 9% (specialized care). Patients' quality of life was substantially affected and utility of post-major amputation for PAD was 0.54. LoS after amputation varied from 11.4 (general rehabilitation) to 53.4 days (amputation of the leg). Total budget incurred based on frequently claimed DBC's from Dutch claims data in patients with PAD undergoing an amputation over 2012 to 2016 was € 136,651,374. Mean cost per patient was € 17,821. CONCLUSIONS: Amputation leads to substantial burden in patients with PAD in the Netherlands. Identified results give a better understanding of the specific Dutch burden of amputation.

Cost Effectiveness of Cladribine Tablets for the Treatment of Relapsing-Remitting Multiple Sclerosis in The Netherlands.

BACKGROUND: Cladribine tablets have recently become available in The Netherlands for patients with relapsing-remitting multiple sclerosis (RRMS) as a disease-modifying agent that reduces the frequency and severity of relapses and delays disability progression. OBJECTIVE: The aim of this study was to evaluate the cost effectiveness of cladribine tablets, compared with alternative options, in the treatment of RRMS patients with high disease activity (HDA) and patients with rapidly evolving severe (RES) MS in The Netherlands. METHODS: A Markov model was developed simulating the costs and effects of RRMS treatment. For HDA, alemtuzumab and fingolimod were used as comparators; natalizumab was used for the RES subpopulation. The analysis included a societal perspective and a value-of-information (VOI) analysis. RESULTS: For the HDA subpopulation, treatment with cladribine tablets was the cost-effective (dominant) strategy compared with alemtuzumab and fingolimod, with 50.9% and 98.2%, respectively, probability of being cost effective at a threshold of €50,000/QALY gained and a net monetary benefit (NMB) of €10,866 and €151,115, respectively. For the RES subpopulation, treatment with cladribine tablets dominated treatment with natalizumab, with 94.1% probability of being cost effective at a threshold of €50,000/QALY gained and an NMB of €122,986. Note that these outcomes are driven by the lower costs of cladribine tablets. Efficacy differences were small, very uncertain, and likely not clinically meaningful. The probabilistic sensitivity analyses showed significant overlap in the credible intervals for total lifetime QALY outcomes and costs of cladribine tablets and all relevant comparators. The population-level VOI amounted to €19,295,441. CONCLUSIONS: The base-case analysis shows that treatment of RRMS with cladribine tablets is cost effective versus alemtuzumab and fingolimod in HDA patients, and cost effective versus natalizumab in RES patients, at a threshold of €50,000. Driven by the lower costs, cladribine tablets were cost effective (dominant) in all base-case analyses. However, given that outcomes are based on indirect comparisons and post hoc subgroup analysis, as well as the uncertainty surrounding the outcomes, the results presented in this paper should be interpreted with caution.

Health state utilities for infertility and subfertility.

BACKGROUND: Health state utility values allow for comparison of treatments across different diseases. Utility values for fertility-impaired health states are currently unavailable. Such values are necessary in order to determine the relative costs-effectiveness of fertility treatments. METHODS: This study aimed to determine utility weights for infertile and subfertile health states. In addition, it explored the Dutch general population's opinions regarding the inclusion of infertility treatments in the Dutch health insurers' basic benefit package. An online questionnaire was designed to determine the health-related quality of life values of six fertility-impaired health states. The study population consisted of a representative sample of the Dutch adult population. Respondents were asked to evaluate the health states through direct health valuation methods, i.e. the Visual Analogue Scale (VAS) and the Time Trade-Off (TTO) method. In addition, respondents were asked about their opinions regarding reimbursement of fertility-related treatments. RESULTS: The respondents' (n = 767) VAS scores ranged from 0.640 to 0.796. TTO utility values ranged from 0.792 to 0.868. Primary infertility and subfertility was valued lower than secondary infertility and subfertility. In total, 92% of the respondents stated that fertility treatments should be fully or partially reimbursed by the health insurance basic benefit package. CONCLUSIONS: Having fertility problems results in substantial disutilities according to the viewpoint of the Dutch general population. The results make it possible to compare the value for money of infertility treatment to that of treatments in other disease areas. There is strong support among the general population for reimbursing fertility treatments through the Dutch basic benefit package.

Measurement and evaluation of quality of life and well-being in individuals having or having had fertility problems: a systematic review.

OBJECTIVES: The aims of this study were: (1) to identify which measurement instruments are used in practice to assess the quality of life or well-being of individuals with and without (sub)fertility; (2) to describe the design and outcomes of studies comparing quality of life or well-being of individuals with and without fertility problems; and (3) to determine which of the outcomes of the identified studies could be used in cost-utility studies. METHODS: A systematic literature review was performed of studies published before July 2018, using multiple databases. Included studies investigated (health-related) quality of life or well-being of individuals with fertility problems. The applied instruments were assessed, as were the outcomes and suitability for use in cost-utility studies. RESULTS: Twenty-six studies met the inclusion criteria. Twelve distinct instruments of measurement were applied: two generic quality-of-life instruments, five generic well-being instruments and five disease-specific instruments. Most studies found negative associations in one or more domains assessing fertility problems and quality of life or well-being. However, two studies found the opposite. None of the studies reported outcomes relevant for cost-utility studies. CONCLUSION: Quality of life and well-being related to having fertility problems are regularly studied. However, the reported information is not suitable for use in cost-utility studies. There is a clear need for studies investigating the impact of fertility problems on quality of life in a way that outcomes can be compared across studies and disease areas.

Healthcare utilization and costs of multiple sclerosis patients in the Netherlands: a healthcare claims database study.

AIM: To investigate the incidence and prevalence and healthcare costs of multiple sclerosis (MS) in the Netherlands by using healthcare claims data. MATERIALS & METHODS: A claims database was analyzed including 26% of the Dutch population. RESULTS: Average prevalence of MS in the Netherlands was 88 per 100,000 inhabitants (males 48, 127 females) and incidence nine per 100,000. Yearly per patient medication costs were highest in the year after the first MS claim and then decreased. Hospital costs were 30% higher in the first year of MS claims than after 3 years of MS claims. The patients often used co-medication, such as antidepressants and antibiotics. CONCLUSION: Dutch incidence and cost estimates based on claims were consistent with previous estimates. Prevalence estimates were somewhat higher. Drug and hospital costs were highest shortly after the diagnosis. Healthcare consumption related to comorbidities was in-line with the previously reported comorbidity estimates.

New findings from the time trade-off for income approach to elicit willingness to pay for a quality adjusted life year.

In this paper we empirically investigate how to appropriately model utility of wealth and health. We use a recently proposed alternative approach to value willingness to pay (WTP) for health, making use of trade-offs between income and life years or quality of life, which we extend to allow for a more realistic multiplicative utility function over health and money. Moreover, we show how reference-dependency can be incorporated into this model and derive its predictions for WTP elicitation. We propose three experimental elicitation procedures and test these in a feasibility study, analysing the responses under different assumptions about the discount rate. Several interesting results are reported: first, the data are highly skewed, but if we trim the 5% lowest and highest values, we obtain plausible WTP estimates. Second, the results differ considerably between procedures, indicating that WTP estimates are sensitive to the assumed utility function. Third, respondents appear to be loss averse for both health and money, which is consistent with assumptions from prospect theory. Finally, our results also indicate that respondents are more willing to trade quality of life than life years.

Altruistic Preferences in Time Tradeoff: Consideration of Effects on Others in Health State Valuations.

Whether respondents incorporate altruistic preferences in time tradeoff (TTO) exercises remains understudied. We present an extended quality-adjusted life-year model incorporating altruism. We derive that altruism may affect TTO values in 2 directions. First, "longevity altruists" may wish to prolong life for the sake of their loved ones (to avoid being missed). Second, "quality-of-life altruists" may have a preference to avoid bad health states resulting in being a burden to loved ones. The existence and influence of these preferences in a TTO were empirically confirmed in a sample of 1690 respondents from the general public. We classified respondents as "longevity altruists" or "quality-of-life altruists" based on their reasoning behind inclusion of loved ones in their TTO responses. In line with expectations, longevity altruists traded fewer years than quality-of-life altruists. Nonaltruists gave intermediate values.

Exploring a new method for deriving the monetary value of a QALY.

Several studies have sought to determine the monetary value of health gains expressed as quality adjusted life years (QALYs) gained, predominantly using willingness to pay approaches. However, willingness to pay has a number of recognized problems, most notably its insensitivity to scope. This paper presents an alternative approach to estimate the monetary value of a QALY, which is based on the time trade-off method. Moreover, it presents the results of an online study conducted in the Netherlands exploring the feasibility of this novel approach. The results seem promising, but also highlight a number of methodological problems with this approach, most notably nontrading and the elicitation of negative values. Additional research is necessary to try to overcome these problems and to determine the potential of this new approach.

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.

Unpaid work in health economic evaluations.

Given its societal importance, unpaid work should be included in economic evaluations of health care technology aiming to take a societal perspective. However, in practice this does not often appear to be the case. This paper provides an overview of the current place of unpaid work in economic evaluations in theory and in practice. It does so first by summarizing recommendations regarding the inclusion of unpaid labor reported in health economic textbooks and national guidelines for economic evaluations. In total, three prominent health economic text-books were studied and 28 national health economic guidelines. The paper, moreover, provides an overview of the instruments available to measure lost unpaid labor and reports on a review of the place of unpaid labor in applied economic evaluations in the area of rheumatoid arthritis. The review was conducted by examining methodology of evaluations published between 1 March 2008 and 1 March 2013. The results of this study show that little guidance is offered regarding the inclusion of unpaid labor in economic evaluations in textbooks and guidelines. The review identified five productivity costs instruments including questions about unpaid work and 33 economic evaluations of treatments for rheumatoid arthritis of which only one included unpaid work. The results indicate that unpaid work is rarely included in applied economic evaluations of treatments for rheumatoid arthritis, despite this disease expecting to be associated with lost unpaid work. Given the strong effects of certain diseases and treatments on the ability to perform unpaid work, unpaid work currently receives less attention in economic evaluations than it deserves.

The iMTA Productivity Cost Questionnaire: A Standardized Instrument for Measuring and Valuing Health-Related Productivity Losses.

BACKGROUND: Productivity losses often contribute significantly to the total costs in economic evaluations adopting a societal perspective. Currently, no consensus exists on the measurement and valuation of productivity losses. OBJECTIVE: We aimed to develop a standardized instrument for measuring and valuing productivity losses. METHODS: A group of researchers with extensive experience in measuring and valuing productivity losses designed an instrument suitable for self-completion, building on preknowledge and evidence on validity. The instrument was designed to cover all domains of productivity losses, thus allowing quantification and valuation of all productivity losses. A feasibility study was performed to check the questionnaire's consistency and intelligibility. RESULTS: The iMTA Productivity Cost Questionnaire (iPCQ) includes three modules measuring productivity losses of paid work due to 1) absenteeism and 2) presenteeism and productivity losses related to 3) unpaid work. Questions for measuring absenteeism and presenteeism were derived from existing validated questionnaires. Because validated measures of losses of unpaid work are scarce, the questions of this module were newly developed. To enhance the instrument's feasibility, simple language was used. The feasibility study included 195 respondents (response rate 80%) older than 18 years. Seven percent (n = 13) identified problems while filling in the iPCQ, including problems with the questionnaire's instructions and routing (n = 6) and wording (n = 2). Five respondents experienced difficulties in estimating the time that would be needed for other people to make up for lost unpaid work. CONCLUSIONS: Most modules of the iPCQ are based on validated questions derived from previously available instruments. The instrument is understandable for most of the general public.

Does including informal care in economic evaluations matter? A systematic review of inclusion and impact of informal care in cost-effectiveness studies.

BACKGROUND: Informal care makes an important contribution to societal welfare. However, it may involve substantial time costs and can have a considerable negative effect on the health and well-being of informal caregivers. These costs and effects of informal caregiving are often excluded in economic evaluations of healthcare interventions. The impact of this exclusion on the outcomes of these evaluations is largely unknown. OBJECTIVES: This study aimed to explore the inclusion of informal care in economic evaluations and the potential impact of the costs and effects of informal caregiving on cost-effectiveness outcomes. METHODS: A systematic review was conducted to identify economic evaluations of interventions in four distinct disease areas where informal care is potentially important: Alzheimer's disease, metastatic colorectal cancer, Parkinson's disease and rheumatoid arthritis. It was recorded how often economic evaluations included informal caregiving. Next, for the studies including informal care, the impact on cost-effectiveness outcomes was determined by removing informal care costs and effects of the cost-effectiveness calculations and recalculating the outcomes. The new cost-effectiveness outcomes were then compared with the original reported outcomes. RESULTS: The study identified 100 economic evaluations investigating interventions targeted at Alzheimer's disease (n = 25), metastatic colorectal cancer (n = 24), Parkinson's disease (n = 8) and rheumatoid arthritis (n = 43). Twenty-three of these evaluations (23 %) included costs and/or effects of informal caregiving: 64 % of the Alzheimer's disease studies, 0 % of the metastatic colorectal cancer studies, 13 % of Parkinson's disease studies and 14 % of rheumatoid arthritis studies. When informal care was included, this mostly concerned time costs. Studies rarely included both costs and effects. The effect of including or excluding informal care costs or effects on cost-effectiveness outcomes in most studies was modest, but in some studies the impact was strong. CONCLUSION: Most economic evaluations in the area of Alzheimer's disease include costs and/or effects related to informal caregiving. However, in other disease areas where informal caregiving is common it seems that the majority of economic evaluations ignore informal caregiving. The inclusion of informal care can have a strong impact on cost-effectiveness outcomes. Future economic evaluations should therefore consider the relevance of informal care in the context of their study, and either include these costs and effects or justify why they were excluded.

How to estimate productivity costs in economic evaluations.

Productivity costs are frequently omitted from economic evaluations, despite their often strong impact on cost-effectiveness outcomes. This neglect may be partly explained by the lack of standardization regarding the methodology of estimating productivity costs. This paper aims to contribute to standardization of productivity cost methodology by offering practical guidance on how to estimate productivity costs in economic evaluations. The paper discusses the identification, measurement and valuation of productivity losses. It is recommended to include not only productivity losses related to absenteeism from and reduced productivity at paid work, but also those related to unpaid work. Hence, it is recommended to use a measurement instrument including questions about both paid and unpaid productivity, such as the iMTA Productivity Cost Questionnaire (iPCQ) or the Valuation of Lost Productivity (VOLP). We indicate how to apply the friction cost and the human capital approach and give practical guidance on deriving final cost estimates.

Predicting productivity based on EQ-5D: an explorative study.

BACKGROUND: Productivity costs are often ignored in economic evaluations. In order to facilitate productivity cost inclusion, it has been suggested to estimate productivity costs indirectly using quality of life data. OBJECTIVE: This study aimed to derive and validate an algorithm for predicting productivity losses on the basis of quality-of-life data using the EQ-5D-3L. METHODS: A large representative sample of the Dutch general public (n = 1,100) was asked in a web-based questionnaire to state their expected level of productivity in terms of absenteeism and presenteeism for multiple EQ-5D health states. Based on these data, two generalized estimating equations (GEE) models were constructed: (1) a model predicting levels of absenteeism and (2) a model predicting presenteeism. The models were validated by comparing model predictions with conventionally measured productivity within a group of low back pain patients. RESULTS: Predicted absenteeism levels based on EQ-5D health state closely resembled conventionally measured absenteeism levels. Productivity losses related to presenteeism seemed somewhat overestimated by our prediction model. Measured and predicted productivity were moderately but highly significantly correlated. CONCLUSIONS: Overall, it appears possible to make reasonable productivity predictions based on EQ-5D data. Further exploration and validation of prediction algorithms remains necessary, however, especially for presenteeism.

Economic evaluations in European reimbursement submission guidelines: current status and comparisons.

This study aimed to review European national health-economic (HE) guidelines and to identify recent developments in guideline recommendations by comparing the findings with those of a review published in 2001. Guidelines were identified by searching websites of the Internal Society for Pharmacoeconomics and Outcomes Research (ISPOR) and government health insurance agencies, and by a literature review. National guidelines showed broad consistency in ranking clinical data sources and choice of comparators for HE analysis, but varied in recommended costs to be included, methods related to cost calculation and discounting. Many European countries have developed or revised national HE guidelines. The recommendations in these guidelines differ in some key aspects, limiting transferability of outcomes of HE evaluations.