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Background: The COVID-19 pandemic has given rise to an increasing number of patients with 'long COVID'. Long COVID is the persistence of symptoms for weeks or months after an infection by SARS-CoV-2. It often impacts on the professional life of affected people., Aims: The aim of this study is to understand the experiences and needs of people with long COVID in relation to their return to work., Methods: A qualitative study, combining individual interviews and online forum discussions, was performed early 2021, as part of a larger mixed method study on the needs of long COVID patients in Belgium., Results: One hundred and thirty-four people participated in the study. Participants described various clinical symptoms precluding their return to work. They also face sceptical reactions from employers and colleagues and a lack of support from the social welfare system to facilitate their return to work. These barriers have various impacts, including psychological ones, likely to compromise the professional future of long COVID patients., Conclusions: While the analysis of patients' experiences shows variation in long COVID patients' experiences with return to work, it may help occupational physicians and healthcare practitioners to better take up their crucial role in the return to work of long COVID patients, including raising employers' and colleagues' awareness of the specific difficulties related to long COVID., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Patients have unique insights and are (in-)directly affected by each decision taken throughout the life cycle of medicinal products. Patient preference studies (PPS) assess what matters most to patients, how much, and what trade-offs patients are willing to make. IMI PREFER was a six-year European public-private partnership under the Innovative Medicines Initiative that developed recommendations on how to assess and use PPS in medical product decision-making, including in the regulatory evaluation of medicinal products. This paper aims to summarize findings and recommendations from IMI PREFER regarding i) PPS applications in regulatory evaluation, ii) when and how to consult with regulators on PPS, iii) how to reflect PPS in regulatory communication and iv) barriers and open questions for PPS in regulatory decision-making. Methods: PREFER performed six literature reviews, 143 interviews and eight focus group discussions with regulators, patient representatives, industry representatives, Health Technology Assessment bodies, payers, academics, and clincians between October 2016 and May 2022. Results: i) With respect to PPS applications, prior to the conduct of clinical trials of medicinal products, PPS could inform regulators' understanding of patients' unmet needs and relevant endpoints during horizon scanning activities and scientific advice. During the evaluation of a marketing authorization application, PPS could inform: a) the assessment of whether a product meets an unmet need, b) whether patient-relevant clinical trial endpoints and outcomes were studied, c) the understanding of patient-relevant effect sizes and acceptable trade-offs, and d) the identification of key (un-)favorable effects and uncertainties. ii) With respect to consulting with regulators on PPS, PPS researchers should ideally have early discussions with regulators (e.g., during scientific advice) on the PPS design and research questions. iii) Regarding external PPS communication, PPS could be reflected in the assessment report and product information (e.g., the European Public Assessment Report and the Summary of Product Characteristics). iv) Barriers relevant to the use of PPS in regulatory evaluation include a lack of PPS use cases and demonstrated impact on regulatory decision-making, and need for (financial) incentives, guidance and quality criteria for implementing PPS results in regulatory decision-making. Open questions concerning regulatory PPS use include: a) should a product independent broad approach to the design of PPS be taken and/or a product-specific one, b) who should optimally be financing, designing, conducting, and coordinating PPS, c) when (within and/or outside clinical trials) to perform PPS, and d) how can PPS use best be operationalized in regulatory decisions. Conclusion: PPS have high potential to inform regulators on key unmet needs, endpoints, benefits, and risks that matter most to patients and their acceptable trade-offs. Regulatory guidelines, templates and checklists, together with incentives are needed to foster structural and transparent PPS submission and evaluation in regulatory decision-making. More PPS case studies should be conducted and submitted for regulatory assessment to enable regulatory discussion and increase regulators' experience with PPS implementation and communication in regulatory evaluations., Competing Interests: CW was employed by the Evidera, Inc. IC works for a publicly funded research agency performing HTA. IS was employed by the stockholder of Bayer AG. BL was employed by the Janssen Research and Development, LLC. He is a stockholder in Johnson & Johnson and a portfolio that at times includes other pharmaceutical and health care-related companies. MM was employed by the stockholder of Novartis Pharma AG, Swizterland. EK was employed by the stockholder of Johnson and Johnson. CP was employed by the Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Inc., Rahway, NJ, United States (MSD) and stockholder. TH was employed by the Takeda Pharmaceutical, United States. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Janssens, Barbier, Muller, Cleemput, Stoeckert, Whichello, Levitan, Hammad, Girvalaki, Ventura, Bywall, Pinto, Schoefs, Katz, Kihlbom and Huys.)

Background: After almost 2 years of fighting against SARS-CoV-2 pandemic, the number of patients enduring persistent symptoms long after acute infection is a matter of concern. This set of symptoms was referred to as "long COVID", and it was defined more recently as "Post COVID-19 condition" by the World health Organization (WHO). Although studies have revealed that long COVID can manifest whatever the severity of inaugural illness, the underlying pathophysiology is still enigmatic., Aim: To conduct a comprehensive review to address the putative pathophysiology underlying the persisting symptoms of long COVID., Method: We searched 11 bibliographic databases (Cochrane Library, JBI EBP Database, Medline, Embase, PsycInfo, CINHAL, Ovid Nursing Database, Journals@Ovid, SciLit, EuropePMC, and CoronaCentral). We selected studies that put forward hypotheses on the pathophysiology, as well as those that encompassed long COVID patients in their research investigation., Results: A total of 98 articles were included in the systematic review, 54 of which exclusively addressed hypotheses on pathophysiology, while 44 involved COVID patients. Studies that included patients displayed heterogeneity with respect to the severity of initial illness, timing of analysis, or presence of a control group. Although long COVID likely results from long-term organ damage due to acute-phase infection, specific mechanisms following the initial illness could contribute to the later symptoms possibly affecting many organs. As such, autonomic nervous system damage could account for many symptoms without clear evidence of organ damage. Immune dysregulation, auto-immunity, endothelial dysfunction, occult viral persistence, as well as coagulation activation are the main underlying pathophysiological mechanisms so far., Conclusion: Evidence on why persistent symptoms occur is still limited, and available studies are heterogeneous. Apart from long-term organ damage, many hints suggest that specific mechanisms following acute illness could be involved in long COVID symptoms. KEY MESSAGESLong-COVID is a multisystem disease that develops regardless of the initial disease severity. Its clinical spectrum comprises a wide range of symptoms.The mechanisms underlying its pathophysiology are still unclear. Although organ damage from the acute infection phase likely accounts for symptoms, specific long-lasting inflammatory mechanisms have been proposed, as well.Existing studies involving Long-COVID patients are highly heterogeneous, as they include patients with various COVID-19 severity levels and different time frame analysis, as well.

Objective: This study aimed to establish a Belgian EQ-5D-5L value set based on the preferences of the adult Belgian general population., Methods: The most recent EuroQol Valuation Technology (EQ-VT 2.1) protocol for EQ-5D-5L valuation studies was followed. Computer-assisted personal interviews were carried out in a representative sample of the adult Belgian population. Potential respondents were randomly selected from the National Register using a multistage, stratified, cluster sampling with unequal probability design. Each respondent valued 10 or 11 health states using composite time trade-off (cTTO) and 14 health states in seven paired choice tasks using a discrete choice experiment (DCE). Different model specifications were explored and assessed based on logical consistency, goodness of fit, predictive accuracy and theoretical considerations., Results: A total of 892 respondents were included in the analyses. The sample was representative of the Belgian adult population in terms of age, sex, region of residence, educational attainment, labour market status, self-assessed health status and health-related quality of life (HRQoL). The preferred model specification was a hybrid (DCE and cTTO data combined) multiplicative eight-coefficient model with intercept random effects and correction for heteroskedasticity. Values range from - 0.532 to 1. Loss of HRQoL is highest in the dimension pain/discomfort, closely followed by anxiety/depression., Conclusions: This study developed a Belgian EQ-5D-5L value set, based on the preferences of the Belgian adult general population. It provides opportunities for future clinical and economic evaluations in healthcare, for the measurement of patient-reported outcomes and for population health assessments., (© 2022. The Author(s).)

Purpose: Health-related quality of life outcomes are increasingly used to monitor population health and health inequalities and to assess the (cost-) effectiveness of health interventions. The EQ-5D-5L has been included in the Belgian Health Interview Survey, providing a new source of population-based self-perceived health status information. This study aims to estimate Belgian population norms for the EQ-5D-5L by sex, age, and region and to analyze its association with educational attainment., Methods: The BHIS 2018 provided EQ-5D-5L data for a nationally representative sample of the Belgian population. The dimension scores and index values were analyzed using logistic and linear regressions, respectively, accounting for the survey design., Results: More than half of respondents reported problems of pain/discomfort, while over a quarter reported problems of anxiety/depression. The average index value was 0.84. Women reported more problems on all dimensions, but particularly on anxiety/depression and pain/discomfort, resulting in significantly lower index values. Problems with mobility, self-care, and usual activities showed a sharp increase after the age of 80 years. Consequently, index values decreased significantly by age. Lower education was associated with a higher prevalence of problems for all dimensions except anxiety/depression and with a significantly lower index value., Conclusion: This paper presents the first nationally representative Belgian population norms using the EQ-5D-5L. Inclusion of the EQ-5D in future surveys will allow monitoring over time of self-reported health, disease burden, and health inequalities., (© 2021. The Author(s).)

Introduction: After contracting COVID-19, many people have continued to experience various symptoms for several weeks and months, even after a mild acute phase. These people with ‘long COVID’ faced difficulties when confronted with the healthcare system., Purpose of Research: In order to better understand their experience, we supplemented the information obtained in an online survey with a mixed qualitative approach based on 33 individual interviews and discussions with 101 participants in a forum in March 2021., Results: Several shortcomings were identified in the contacts of ‘long’ COVID patients with the health care system, such as the lack of listening or empathy of some health care professionals, the lack of a systematic or proactive approach during the diagnostic assessment, or the lack of interdisciplinary coordination. Patients feel misunderstood and are forced to develop their own strategies, whether for diagnosis or treatment. Patients’ discomfort has led them to question the value of medicine and to resort to unconventional therapies to alleviate their symptoms, sometimes at great cost., Conclusions: Better informing the medical profession about the manifestation of the disease and the possible treatments, including the possibilities of reimbursement, would raise awareness and give them the tools to respond to the needs of ‘ long’ COVID patients. A comprehensive assessment of the patient through an “interdisciplinary assessment” seems necessary.

Objectives: The objective of this study was to map the PI culture at KCE in the context of the development of organization-wide supported position statements about PI., Methods: A nominal group technique was used to measure the PI culture at KCE. Arguments for and against PI and conditions for PI in different phases of the HTA process were collected. A literature review and interviews fed the draft position statements, for which support was assessed by means of a two-round Delphi process., Results: Arguments in favor of PI in HTA related to the relevance of the scope, expertise with data collection, bringing in fresh ideas for study design, access to survey participants, validation of data analyses, adherence to recommendations. Disadvantages and risks included the lack of scientific knowledge of involved patients, resources requirements, conflicts of interest, and heterogeneity within patient populations. Conditions for meaningful PI referred to measures mitigating the identified disadvantages. Eighteen position statements supported by KCE could be formulated., Conclusion: The KCE culture seems predominantly positive toward PI, although attitudes vary between HTA researchers. KCE recognizes the potential value of PI in HTA, but considers the level of involvement to be contingent on the topic and phase in the HTA process.

Background: Patient preference (PP) information is not effectively integrated in decision-making throughout the medical product lifecycle (MPLC), despite having the potential to improve patients' healthcare options. A first step requires an understanding of existing processes and decision-points to know how to incorporate PP information in order to improve patient-centric decision-making., Objectives: The aims were to: 1) identify the decision-making processes and decision-points throughout the MPLC for industry, regulatory authorities, and reimbursement/HTA, and 2) determine which decision-points can potentially include PP information., Methods: A scoping literature review was conducted using five scientific databases. Semi-structured interviews were conducted with representatives from seven European countries and the US, including industry (n = 24), regulatory authorities (n = 23), reimbursement/HTA (n = 23). Finally, validation meetings with key stakeholders (n = 11) were conducted., Results: Six critical decision-points were identified for industry decision-making, three for regulatory decision-making, and six for reimbursement/HTA decision-making. Stakeholder groups agreed that PP information is not systematically integrated, either as obligatory information or pre-set criteria, but would benefit all the listed decision-points in the future., Conclusion: Currently, PP information is not considered as obligatory information to submit for any of the MPLC decision-points. However, PP information is considered an important component by most stakeholders to inform future decision-making across the MPLC. The integration of PP information into 15 identified decision-points needs continued discussion and collaboration between stakeholders., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate the strengths and weaknesses of managed entry agreements (MEAs) in Belgium., Methods: All Belgian MEAs signed between 2010 and 2015 (n = 71) were studied, including the re-evaluations of 16 reimbursement requests for which the initial MEA had ended. The analysis was supported by the findings from a systematic literature review and structured interviews with Belgian stakeholders., Results: The current application of MEAs provides the short-term advantage of getting a positive reimbursement decision with lower confidential prices. However, it is not clear whether the negotiated prices are in line with the added value of the interventions. Furthermore, the contracts do not provide incentives for manufacturers to gather evidence or to set public prices at an acceptable level., Conclusions: Based on our analysis of the Belgian MEAs and discussions with Belgian stakeholders, an overview of various issues and pitfalls related to the current application of the system is given. Recommendations are made related to providing correct incentives to deliver good evidence, establishing a correct link between identified uncertainties/problems and the type and content of the MEA, reducing the risk of making the system non-transparent, the importance of international collaboration, etc. in order to optimize the potential of this system. These recommendations are addressed to both the Belgian policymakers and stakeholders in other countries making use of MEAs., Competing Interests: Declaration of Competing Interest We have no relevant interests to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: To investigate stakeholder perspectives on how patient preference studies (PPS) should be designed and conducted to allow for inclusion of patient preferences in decision-making along the medical product life cycle (MPLC), and how patient preferences can be used in such decision-making. Methods: Two literature reviews and semi-structured interviews (n = 143) with healthcare stakeholders in Europe and the US were conducted; results of these informed the design of focus group guides. Eight focus groups were conducted with European patients, industry representatives and regulators, and with US regulators and European/Canadian health technology assessment (HTA) representatives. Focus groups were analyzed thematically using NVivo. Results: Stakeholder perspectives on how PPS should be designed and conducted were as follows: 1) study design should be informed by the research questions and patient population; 2) preferred treatment attributes and levels, as well as trade-offs among attributes and levels should be investigated; 3) the patient sample and method should match the MPLC phase; 4) different stakeholders should collaborate; and 5) results from PPS should be shared with relevant stakeholders. The value of patient preferences in decision-making was found to increase with the level of patient preference sensitivity of decisions on medical products. Stakeholders mentioned that patient preferences are hardly used in current decision-making. Potential applications for patient preferences across industry, regulatory and HTA processes were identified. Four applications seemed most promising for systematic integration of patient preferences: 1) benefit-risk assessment by industry and regulators at the marketing-authorization phase; 2) assessment of major contribution to patient care by European regulators; 3) cost-effectiveness analysis; and 4) multi criteria decision analysis in HTA. Conclusions: The value of patient preferences for decision-making depends on the level of collaboration across stakeholders; the match between the research question, MPLC phase, sample, and preference method used in PPS; and the sensitivity of the decision regarding a medical product to patient preferences. Promising applications for patient preferences should be further explored with stakeholders to optimize their inclusion in decision-making., (Copyright © 2019 van Overbeeke, Janssens, Whichello, Schölin Bywall, Sharpe, Nikolenko, Phillips, Guiddi, Pravettoni, Vergani, Marton, Cleemput, Simoens, Kübler, Juhaeri, Levitan, de Bekker-Grob, Veldwijk and Huys.)

Objective: Recent years have witnessed an increased interest in the use of multicriteria decision analysis (MCDA) to support health technology assessment (HTA) agencies for setting healthcare priorities. However, its implementation to date has been criticized for being "entirely mechanistic," ignoring opportunity costs, and not following best practice guidelines. This article provides guidance on the use of MCDA in this context., Methods: The present study was based on a systematic review and consensus development. We developed a typology of MCDA studies and good implementation practice. We reviewed 36 studies over the period 1990 to 2018 on their compliance with good practice and developed recommendations. We reached consensus among authors over the course of several review rounds., Results: We identified 3 MCDA study types: qualitative MCDA, quantitative MCDA, and MCDA with decision rules. The types perform differently in terms of quality, consistency, and transparency of recommendations on healthcare priorities. We advise HTA agencies to always include a deliberative component. Agencies should, at a minimum, undertake qualitative MCDA. The use of quantitative MCDA has additional benefits but also poses design challenges. MCDA with decision rules, used by HTA agencies in The Netherlands and the United Kingdom and typically referred to as structured deliberation, has the potential to further improve the formulation of recommendations but has not yet been subjected to broad experimentation and evaluation., Conclusion: MCDA holds large potential to support HTA agencies in setting healthcare priorities, but its implementation needs to be improved., (Copyright © 2019 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Background: The inclusion of patient preferences (PP) in the medical product life cycle is a topic of growing interest to stakeholders such as academics, Health Technology Assessment (HTA) bodies, reimbursement agencies, industry, patients, physicians and regulators. This review aimed to understand the potential roles, reasons for using PP and the expectations, concerns and requirements associated with PP in industry processes, regulatory benefit-risk assessment (BRA) and marketing authorization (MA), and HTA and reimbursement decision-making., Methods: A systematic review of peer-reviewed and grey literature published between January 2011 and March 2018 was performed. Consulted databases were EconLit, Embase, Guidelines International Network, PsycINFO and PubMed. A two-step strategy was used to select literature. Literature was analyzed using NVivo (QSR international)., Results: From 1015 initially identified documents, 72 were included. Most were written from an academic perspective (61%) and focused on PP in BRA/MA and/or HTA/reimbursement (73%). Using PP to improve understanding of patients' valuations of treatment outcomes, patients' benefit-risk trade-offs and preference heterogeneity were roles identified in all three decision-making contexts. Reasons for using PP relate to the unique insights and position of patients and the positive effect of including PP on the quality of the decision-making process. Concerns shared across decision-making contexts included methodological questions concerning the validity, reliability and cognitive burden of preference methods. In order to use PP, general, operational and quality requirements were identified, including recognition of the importance of PP and ensuring patient understanding in PP studies., Conclusions: Despite the array of opportunities and added value of using PP throughout the different steps of the MPLC identified in this review, their inclusion in decision-making is hampered by methodological challenges and lack of specific guidance on how to tackle these challenges when undertaking PP studies. To support the development of such guidance, more best practice PP studies and PP studies investigating the methodological issues identified in this review are critically needed.

Background: Patient preferences (PP), which are investigated in PP studies using qualitative or quantitative methods, are a growing area of interest to the following stakeholders involved in the medical product lifecycle: academics, health technology assessment bodies, payers, industry, patients, physicians, and regulators. However, the use of PP in decisions along the medical product lifecycle remains limited. As the adoption of PP heavily relies on these stakeholders, knowledge of their perceptions of PP is critical., Objective: This study aimed to characterize stakeholders' attitudes, needs, and concerns with respect to PP in decision making along the medical product lifecycle., Methods: Semi-structured interviews (n = 143) were conducted with academics (n = 24), health technology assessment/payer representatives (n = 24), industry representatives (n = 24), patients, caregivers and patient representatives (n = 24), physicians (n = 24), and regulators (n = 23) from seven European countries and the USA. Interviews were conducted between April and August 2017. The framework method was used to organize the data and identify themes and key findings in each interviewed stakeholder group., Results: Interviewees reported being unfamiliar (43%), moderately familiar (42%), or very familiar (15%) with preference methods and studies. Interviewees across stakeholder groups generally supported the idea of using PP in the medical product lifecycle but expressed mixed opinions about the feasibility and impact of using PP in decision making. Interviewees from all stakeholder groups stressed the importance of increasing stakeholders' understanding of the concept of PP and preference methods and ensuring patients' understanding of the questions asked in PP studies. Key concerns and needs in each interviewed stakeholder group were as follows: (1) academics: investigating the validity, reliability, reproducibility, and generalizability of preference methods; (2) health technology assessment/payer representatives: developing quality criteria for evaluating PP studies and gaining insights into how to weigh them in reimbursement/payer decision making; (3) industry representatives: obtaining guidance on PP studies and recognition on the importance of PP from decision makers; (4) patients, caregivers, and patient representatives: providing an incentive and adequate information towards patients when participating in PP studies; (5) physicians: avoiding bias as a result of commercial agendas in PP studies and clarifying how to deal with subjective and emotional elements when measuring PP; and (6) regulators: avoiding the misuse of PP study results to overrule the traditional efficacy and safety criteria used for marketing authorization and obtaining robust PP study results., Conclusions: Despite the interest all interviewed stakeholder groups reported in PP, the effective use of PP in decision making across the medical product lifecycle is currently hampered by a lack of standardization and consensus on how to both measure and use PP.

Objectives: Patient preference information (PPI) is gaining recognition among the pharmaceutical industry, regulatory authorities, and health technology assessment (HTA) bodies/payers for use in assessments and decision-making along the medical product lifecycle (MPLC). This study aimed to identify factors and situations that influence the value of patient preference studies (PPS) in decision-making along the MPLC according to different stakeholders. Methods: Semi-structured interviews (n = 143) were conducted with six different stakeholder groups (physicians, academics, industry representatives, regulators, HTA/payer representatives, and a combined group of patients, caregivers, and patient representatives) from seven European countries (the United Kingdom, Sweden, Italy, Romania, Germany, France, and the Netherlands) and the United States. Framework analysis was performed using NVivo 11 software. Results: Fifteen factors affecting the value of PPS in the MPLC were identified. These are related to: study organization (expertise, financial resources, study duration, ethics and good practices, patient centeredness), study design (examining patient and/or other preferences, ensuring representativeness, matching method to research question, matching method to MPLC stage, validity and reliability, cognitive burden, patient education, attribute development), and study conduct (patients' ability/willingness to participate and preference heterogeneity). Three types of situations affecting the use of PPS results were identified (stakeholder acceptance, market situations, and clinical situations). Conclusion: The factors and situation types affecting the value of PPS, as identified in this study, need to be considered when designing and conducting PPS in order to promote the integration of PPI into decision-making along the MPLC., (Copyright © 2019 Whichello, van Overbeeke, Janssens, Schölin Bywall, Russo, Veldwijk, Cleemput, Juhaeri, Levitan, Kübler, Smith, Hermann, Englbrecht, Hueber, Comanescu, Harding, Simoens, Huys and de Bekker-Grob.)

Industry, regulators, health technology assessment (HTA) bodies, and payers are exploring the use of patient preferences in their decision-making processes. In general, experience in conducting and assessing patient preference studies is limited. Here, we performed a systematic literature search and review to identify factors and situations influencing the value of patient preference studies, as well as applications throughout the medical product lifecyle. Factors and situations identified in 113 publications related to the organization, design, and conduct of studies, and to communication and use of results. Although current use of patient preferences is limited, we identified possible applications in discovery, clinical development, marketing authorization, HTA, and postmarketing phases., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background. Multi-criteria decision analysis can improve the legitimacy of health care reimbursement decisions by taking societal preferences into account when weighting decision criteria. This study measures the relative importance of health care coverage criteria according to the Belgian general public and policy makers. Criteria are structured into three domains: therapeutic need, societal need, and new treatments' added value. Methods. A sample of 4,288 citizens and 161 policy makers performed a discrete choice experiment. Data were analyzed using multinomial logistic regression analysis. Level-independent criteria weights were determined using the log-likelihood method. Results. Both the general public and policy makers gave the highest weight to quality of life in the appraisal of therapeutic need (0.43 and 0.53, respectively). The general public judged life expectancy (0.14) as less important than inconvenience of current treatment (0.43), unlike decision makers (0.32 and 0.15). The general public gave more weight to "impact of a disease on public expenditures" (0.65) than to "prevalence of the disease" (0.56) when appraising societal need, whereas decision makers' weights were 0.44 and 0.56, respectively. When appraising added value, the general public gave similar weights to "impact on quality of life" and "impact on prevalence" (0.37 and 0.36), whereas decision makers judged "impact on quality of life" (0.39) more important than "impact on prevalence" (0.29). Both gave the lowest weight to impact on life expectancy (0.14 and 0.21). Limitations. Comparisons between the general public and policy makers should be treated with caution because the policy makers' sample size was small. Conclusion. Societal preferences can be measured and used as decision criteria weights in multi-criteria decision analysis. This cannot replace deliberation but can improve the transparency of health care coverage decision processes., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article, (© The Author(s) 2018.)

Early temporary reimbursement (ETR) schemes for new interventions targeting high unmet needs are increasingly applied in pharmaceutical policy. Crucial for these schemes is the assessment of unmet healthcare needs of patients and society. This study develops and tests a multi-criteria decision approach (MCDA) for assessing therapeutic and societal needs. The Belgian unmet needs commission, responsible for creating a list of unmet needs for the ETR programme, has tested this methodology to assess the needs in eight health conditions. For therapeutic need, three criteria were included (impact of the condition on quality of life and on life expectancy and inconvenience of current treatment); for societal need two criteria (condition-related healthcare expenditures per patient, prevalence). The results show that the proposed MCDA is feasible and acceptable for the unmet needs commission. Clear definitions of the criteria and regular repetition of these is needed to avoid variable interpretation of the criteria by the commission members. Quality assessment of the evidence is desired. Rankings resulting from the application have face validity. Considering therapeutic need separately from societal need is considered appropriate. Policy makers should consider the use of MCDA in assessing healthcare needs. MCDA improves the transparency and accountability of the decision making processes and is practical and feasible., (Copyright © 2018 Elsevier B.V. All rights reserved.)

In 2010 the Belgian government introduced a low cost administrative procedure for compensating medical injuries to overcome the major shortcomings of the existing tort system. This paper examines, for the first time, to what extent this reform had an impact on physician specialists' defensive practices and what are the relevant determinants affecting physicians' clinical decision making. Based on a survey of 508 physicians, we find evidence of a relatively modest increase in defensive practices among physicians in various specialties. In general, 14% of the respondents, who were aware of the reform, reported to have increased their overall defensive behaviour, while respectively 18 and 13% altered their assurance and avoidance behaviour. Commonly used physician characteristics, such as claims experience and gender, have a similar impact on defensive medicine as documented in existing literature. Furthermore, the determinant physician's access to an incident reporting system is found to have a significant impact on most of the defensive medicine measures. Health care institutions may therefore play an important role in controlling and reducing physicians' defensive practices.

Objectives: Tackling ethical dilemmas faced by reimbursement decision makers requires deeper understanding of values on which health technology assessment (HTA) agencies are founded and how trade-offs are made. This was explored in this study including the case of rare disease., Methods: Representatives from eight HTA explored values on which institutions are founded using a narrative approach and reflective multicriteria (developed from EVIDEM, criteria derived from ethical imperatives of health care). Trade-offs between criteria and the impact of incorporating defined priorities (including for rare diseases) were explored through a quantitative values elicitation exercise., Results: Participants reported a diversity of substantive and procedural values with a common emphasis on scientific excellence, stakeholder involvement, independence, and transparency. Examining the ethical imperatives behind EVIDEM criteria was found to be useful to further explore substantive values. Most criteria were deemed to reflect institutions' values, while 70 percent of the criteria were reported by at least half of participants to be considered formally by their institutions. The quantitative values elicitation highlighted the difficulty to balance imperatives of "alleviating or preventing patient suffering," "serving the whole population equitably," "upholding healthcare system sustainability," and "making decisions informed by evidence and context" but may help share the ethical reasoning behind decisions. Incorporating "Priorities" (including for rare diseases) helped reveal trade-offs from other criteria and their underlying ethical imperatives., Conclusions: Reflective multicriteria are useful to explore substantive values of HTAs, reflect how these values and their ethical underpinnings can be operationalized into criteria, and explore the ethical reasoning at the heart of the healthcare debate.

In the context of pharmaceutical care, policy-makers repeatedly face the challenge of balancing patient access to effective medicines with affordability and rising costs. With the aim of guiding the health policy discourse towards questions that are important to actual and potential patients, this study investigates a broad range of regulatory measures, spanning marketing authorization to generic substitution and resulting price levels in a sample of 16 European health systems (Austria, Belgium, Denmark, England, Finland, France, Germany, Greece, Ireland, Italy, the Netherlands, Poland, Portugal, Scotland, Spain and Sweden). All countries employ a mix of regulatory mechanisms to contain pharmaceutical expenditure and ensure quality and efficiency in pharmaceutical care, albeit with varying configurations and rigour. This variation also influences the extent of publicly financed pharmaceutical costs. Overall, observed differences in pharmaceutical expenditure should be interpreted in conjunction with the differing volume and composition of consumption and price levels, as well as dispensation practices and their impact on measurement of pharmaceutical costs. No definitive evidence has yet been produced on the effects of different cost-containment measures on patient outcomes. Depending on the foremost policy concerns in each country, different levers will have to be used to enable the delivery of appropriate care at affordable prices., (World Health Organization 2016 (acting as the host organization for, and secretariat of, the European Observatory on Health Systems and Policies).)

Background: The prevalence of cancer increases every year, leading to a growing population of patients and survivors in need for care. To achieve good quality care, a patient-centered approach is essential. Correct and timely detection of needs throughout the different stages of the care trajectory is crucial and can be supported by the use of screening and assessment in a stepped-care approach. The Cancer Rehabilitation Evaluation System (CARES) is a valuable and comprehensive quality of life and needs assessment instrument. For use in Flemish research and clinical practice, the CARES tool was translated for the Dutch-speaking part of Belgium (Flanders) from its original English format. This protocol paper describes the translation and revalidation of this Flemish CARES version., Methods: After forward-backward translation of the CARES into Flemish we aim to recruit 150 adult cancer patients with a primary cancer diagnosis (stage I, II or III) for validation. In this study with a combination of qualitative and a quantitative approach, qualitative data will be collected through focus groups and supplemented by two phases of quantitative data collection: i) an initial patient survey containing questions on socio-demographic and medical data, the CARES and seven concurrent instruments; and ii) a second survey administered after 1 week containing the CARES and supplementary questions to explore their impressions on the content and the feasibility of the CARES., Discussion: With this extensive data collection process, psychometric validity of the Flemish CARES can be tested thoroughly using classical test theory. Internal consistency of summary scales, test-retest reliability, content validity, construct validity, concurrent validity and feasibility of the instrument will be examined. If the Flemish CARES version is found reliable, valid and feasible, it will be used in future research and clinical practice. Comprehensive assessment with the CARES in a stepped-care approach can facilitate timely identification of cancer patients' psychosocial concerns and care needs so it can contribute to efficient provision of patient-centered quality care., Trial Registration: ClinicalTrials.gov: NCT02282696 (July 16, 2014).

Objective: The objective of this review is to obtain a better understanding of the user-related barriers against, and facilitators for, the implementation of surgical safety checklists., Methods: We searched MEDLINE for articles describing stakeholders' perspectives regarding, and experiences with, the implementation of surgical safety checklists. The quality of the papers was assessed by means of the Qualitative Assessment and Review Instrument. Thematic synthesis was used to integrate the emergent descriptive themes into overall analytical themes., Results: The synthesis of 18 qualitative studies indicated that implementation requires change in the workflow of healthcare professionals as well as in their perception of the checklist and the perception of patient safety in general. The factors impeding or advancing the required change concentrated around the checklist, the implementation process and the local context. We found that the required safety checks disrupt operating theatre staffs' routines. Furthermore, conflicting priorities and different perspectives and motives of stakeholders complicate checklist implementation. When approaching the checklist as a simple technical intervention, the expectation of cooperation between surgeons, anaesthetists and nurses is often not addressed, reducing the checklist to a tick-off exercise., Conclusions: The complex reality in which the checklist needs to be implemented requires an approach that includes more than eliminating barriers and supporting facilitating factors. Implementation leaders must facilitate team learning to foster the mutual understanding of perspectives and motivations, and the realignment of routines. This paper provides a pragmatic overview of the user-related barriers and facilitators upon which theories, hypothesising potential change strategies and interactions, can be developed and tested empirically., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: In systems with public health insurance, coverage decisions should reflect social values. Deliberation among stakeholders could achieve this goal, but rarely involves patients and citizens directly., Objectives: This study aimed at evaluating the acceptability, and the perceived benefits and risks, of public and patient involvement (PPI) in coverage decision making to Belgian stakeholders., Methods: A two-round Delphi survey was conducted among all stakeholder groups. The survey was constructed on the basis of interviews with 10 key stakeholders and a review of the literature on participation models. Consensus was defined as 65% or more of the respondents agreeing with a statement and less than 15% disagreeing. Eighty stakeholders participated in both rounds. They were defined as the Delphi panel., Results: Belgian stakeholders are open toward PPI in coverage decision processes. Benefits are expected to exceed risks. The preferred model for involvement is to consult citizens or patients, within the existing decision-making structures and at specific milestones in the process. Consulting citizens and patients is a higher level of involvement than merely informing them and a lower level than letting them participate actively. Consultation involves asking nonbinding advice on (parts of) the decision problem. According to the Delphi panel, the benefits of PPI could be increasing awareness among members of the general public and patients about the challenges and costs of health care, and enriched decision processes with expertise by experience from patients. Potential risks include subjectivity, insufficient resources to participate and weigh on the process, difficulties in finding effective ways to express a collective opinion, the risk of manipulation, and lobbying or power games of other stakeholders., Conclusions: PPI in coverage decision-making processes is acceptable to Belgian stakeholders, be it in different ways for different types of decisions. Benefits are expected to outweigh risks., (Copyright © 2015 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Objectives: To develop methodological guidelines for budget impact analysis submitted to the Belgian health authorities as part of a reimbursement request., Methods: A review of the literature was performed and provided the basis for preliminary budget impact guidelines. These guidelines were improved after discussion with health economists from the Belgian Health Care Knowledge Centre (KCE) and different Belgian stakeholders from both government and industry. Preliminary guidelines were also discussed in a workshop with health economists from The German Institute for Quality and Efficiency in Healthcare. Finally, the guidelines were also externally validated by three external experts., Results: The guidelines give explicit guidance for the following components of a budget impact analysis: perspective of the evaluation, target population, comparator, costs, time horizon, modeling, handling uncertainty and discount rate. Special attention is given to handling varying target population sizes over time, applying a time horizon up to the steady state instead of short-term predictions, and similarities and differences between budget impact analysis and economic evaluations., Conclusion: The guidelines provide a framework for both researchers and assessors to set up budget impact analyses that are transparent, relevant, of high quality and apply a consistent methodology. This might improve the extent to which such evaluations can reliably and consistently be used in the reimbursement decision making process.

Around the world, governments are faced with spiralling health care expenditures. This raises the need for further insight in the determinants of these expenditures. Existing literature focuses primarily on income, ageing, health care financing and supply variables. This paper includes medical malpractice system characteristics as determinants of health spending in OECD countries. Estimates from our regression models suggest that no-fault schemes for medical injuries with decoupling of deterrence and compensation reduce health expenditures per capita by 0.11%. Furthermore, countries that introduced a no-fault system without decoupling of deterrence and compensation are found to have higher (+0.06%) health care spending., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: It is unclear which items of the WHO surgical safety checklist are most -crucial for producing its associated benefits. Thoughtless modification, especially removing items, can therefore potentially lead to reduced effectiveness of the instrument. This study describes the modifications made by Belgian hospitals., Methods: An online survey was used to find out which checklists are used. An expert panel conducted a content-driven evaluation of the retrieved checklists by verifying the presence of the WHO items and evaluating any modifications made., Results: All hospitals participating in the survey (n=36) reported the use of a surgical safety checklist. Based on self-report, 69.4% (n=25) of hospitals reported to use all WHO items. The expert panel determined that 17.1% (n=6) of checklists included all WHO items. Inclusion ranged from 7 to 22 items (mean=16.6, Std. Dev.=4.48). Detailing on the functional parts of the checklist, 48.6% (n=17) of checklists contained all sign-in items, 25.7% (n=9) contained all time-out items and 37.1% (n=13) enclosed all sign-out items. Sixty percent (n=21) of checklists added items not -mentioned in the original WHO checklist., Conclusions: The modifications made to the WHO checklist vary between hospitals. Only a small number of hospitals included all 22 WHO items. It is unknown whether these modified checklists will be equally effective in decreasing the number of postoperative complications, including mortality. More detailed recommendations and guidance regarding the modification of the WHO surgical checklist is required., (Copyright© Acta Chirurgica Belgica.)

Background: Health-related quality of life (HRQoL) is an important endpoint of many healthcare interventions. This study develops guidance on how to select appropriate HRQoL measures for inclusion in a clinical trial, given the purposes of the HRQoL measurement., Methods: The guidance is based on a systematic literature review, discussions with members of the European Network for Health Technology Assessment (EUnetHTA) and two rounds of public consultation., Results: A set of twelve recommendations was developed, addressing the requirements for HRQoL data for relative effectiveness assessment, for cost-utility analyses and for informing clinical decision making. Recommendations relate to the choice of the type of measure as well as to aspects such as measurement frequency, target population and presentation., Conclusions: The purpose and context of HRQoL measurement is crucial for the relevance of the data obtained with a specific HRQoL measure. It is recommended to always include a generic HRQoL instrument in clinical trials to cover a wide range of possible future uses of the HRQoL data.

Objectives: The aim of this study was to present the updated methodological guidelines for economic evaluations of healthcare interventions (drugs, medical devices, and other interventions) in Belgium., Methods: The update of the guidelines was performed by three Belgian health economists following feedback from users of the former guidelines and personal experience. The updated guidelines were discussed with a multidisciplinary team consisting of other health economists, assessors of reimbursement request files, representatives of Belgian databases and representatives of the drugs and medical devices industry. The final document was validated by three external validators that were not involved in the previous discussions., Results: The guidelines give methodological guidance for the following components of an economic evaluation: literature review, perspective of the evaluation, definition of the target population, choice of the comparator, analytic technique and study design, calculation of costs, valuation of outcomes, definition of the time horizon, modeling, handling uncertainty and discounting. We present a reference case that can be considered as the minimal requirement for Belgian economic evaluations of health interventions., Conclusions: These guidelines will improve the methodological quality, transparency and uniformity of the economic evaluations performed in Belgium. The guidelines will also provide support to the researchers and assessors performing or evaluating economic evaluations.

Background: Although value issues are increasingly addressed in health technology assessment (HTA) reports, HTA is still seen as a scientific endeavor and sometimes contrasted with value judgments, which are considered arbitrary and unscientific. This article aims at illustrating how numerous value judgments are at play in the HTA process, and why it is important to acknowledge and address value judgments., Methods: A panel of experts involved in HTA, including ethicists, scrutinized the HTA process with regard to implicit value judgments. It was analyzed whether these value judgments undermine the accountability of HTA results. The final results were obtained after several rounds of deliberation., Results: Value judgments are identified before the assessment when identifying and selecting health technologies to assess, and as part of assessment. They are at play in the processes of deciding on how to select, frame, present, summarize or synthesize information in systematic reviews. Also, in economic analysis, value judgments are ubiquitous. Addressing the ethical, legal, and social issues of a given health technology involves moral, legal, and social value judgments by definition. So do the appraisal and the decision-making process., Conclusions: HTA by and large is a process of value judgments. However, the preponderance of value judgments does not render HTA biased or flawed. On the contrary they are basic elements of the HTA process. Acknowledging and explicitly addressing value judgments may improve the accountability of HTA.

Background: A framework for collaborative production and sharing of HTA information, the HTA Core Model, was originally developed within EUnetHTA in 2006-08. In this paper, we describe the further development of the Model to allow implementation and utilization of the Model online. The aim was to capture a generic HTA process that would allow effective use of the HTA Core Model and resulting HTA information while at the same time not interfering with HTA agencies' internal processes., Methods: The work was coordinated by a development team in Finland, supported by an international expert group. Two pilot testing rounds were organized among EUnetHTA agencies and two extensive core HTA projects tested the tool in a real setting. The final work was also formally validated by a group of HTA agencies., Results: The HTA Core Model Online--available at http://www.corehta.info--is a web site hosting a) a tool to allow electronic utilization of the HTA Core Model and b) a database of produced HTA information. While access to the HTA information is free to all, the production features are currently available to EUnetHTA member agencies only. A policy was crafted to steer the use of the Model and produced information., Conclusions: We have successfully enabled electronic use of the HTA Core Model and agreed on a policy for its utilization. The system is already being used in subsequent HTA projects within EUnetHTA Joint Action 2. Identified shortcomings and further needs will be addressed in subsequent development.

Objectives: Clinical endpoints are defined as valid measures of clinical benefit or harm due to treatment, that describe the impact of treatment on how a patient feels, functions, and survives. The choice of endpoints and the manner in which they are reported have a major impact on the relative effectiveness assessment (REA) of pharmaceuticals. The aim of this article is to describe the guideline development process and the key findings that set a framework for appropriate use of endpoints in REAs in Europe., Methods: A multi-health technology assessment (HTA)-agency collaborative process in EUnetHTA JA1 was used to scope, draft, and finalize methodological guidelines for REA in Europe., Results: Patient-relevant clinical endpoints can be broadly categorized into: mortality, morbidity and health-related quality of life. A clinical endpoint is a main symptom or sign of a disease that is clinically relevant, valid, reproducible and responsive to change. Preference is for long-term or final endpoints whenever possible. Surrogate endpoints may be used when there is compelling evidence of a clear and consistent correlation of treatment effects on the surrogate and final outcome of interest., Conclusions: The relevance and hierarchy of the different types of clinical endpoints depend on the research question, disease, and the treatment investigated. Not only the primary endpoint, but also other relevant endpoints are assessed in comparison to adequate comparator(s). This simultaneous assessment of all relevant endpoints is a hallmark of REA.

Surgical safety checklists aim to improve patient safety by prompting the attention of the surgical team towards critical steps during the operation. The checklist's items are aimed to improve compliance with proven interventions, and to facilitate multidisciplinary communication and teamwork. Based on the current literature, corroborated by systematic reviews and meta-analysis, surgical safety checklists have a positive impact on communication and reduce postoperative complications including mortality. However, despite their effectiveness, the implementation of these checklists is not straightforward. Several determinants leading to behaviour were checklists are checked but not properly executed have been highlighted. As surgical safety checklists are in essence complex sociological interventions, they must be implemented accordingly. Key factors for the implementation of these checklists have been suggested in the literature, although, the most profound way of implementation remains unclear., (Copyright© Acta Chirurgica Belgica.)

Background: The World Health Organization (WHO) surgical safety checklist (SSC) was introduced to improve the safety of surgical procedures. This systematic review evaluated current evidence regarding the effectiveness of this checklist in reducing postoperative complications., Methods: The Cochrane Library, MEDLINE, Embase and CINAHL were searched using predefined inclusion criteria. The systematic review included all original articles reporting a quantitative measure of the effect of the WHO SSC on postoperative complications. Data were extracted for postoperative complications reported in at least two studies. A meta-analysis was conducted to quantify the effect of the WHO SSC on any complication, surgical-site infection (SSI) and mortality. Yule's Q contingency coefficient was used as a measure of the association between effectiveness and adherence with the checklist., Results: Seven of 723 studies identified met the inclusion criteria. There was marked methodological heterogeneity among studies. The impact on six clinical outcomes was reported in at least two studies. A meta-analysis was performed for three main outcomes (any complication, mortality and SSI). Risk ratios for any complication, mortality and SSI were 0·59 (95 per cent confidence interval 0·47 to 0·74), 0·77 (0·60 to 0·98) and 0·57 (0·41 to 0·79) respectively. There was a strong correlation between a significant decrease in postoperative complications and adherence to aspects of care embedded in the checklist (Q = 0·82; P = 0·042)., Conclusion: The evidence is highly suggestive of a reduction in postoperative complications and mortality following implementation of the WHO SSC, but cannot be regarded as definitive in the absence of higher-quality studies., (© 2014 BJS Society Ltd. Published by John Wiley & Sons Ltd.)

Background: Ethics has been part of health technology assessment (HTA) from its beginning in the 1970s, and is currently part of HTA definitions. Several methods in ethics have been used in HTA. Some approaches have been developed especially for HTA, such as the Socratic approach, which has been used for a wide range of health technologies. The Socratic approach is used in several ways, and there is a need for harmonization to promote its usability and the transferability of its results. Accordingly, the objective of this study was to stimulate experts in ethics and HTA to revise the Socratic approach., Methods: Based on the current literature and experiences in applying methods in ethics, a panel of ethics experts involved in HTA critically analyzed the limitations of the Socratic approach during a face-to-face workshop. On the basis of this analysis a revision of the Socratic approach was agreed on after deliberation in several rounds through e-mail correspondence., Results: Several limitations with the Socratic approach are identified and addressed in the revised version which consists of a procedure of six steps, 7 main questions and thirty-three explanatory and guiding questions. The revised approach has a broader scope and provides more guidance than its predecessor. Methods for information retrieval have been elaborated., Conclusion: The presented revision of the Socratic approach is the result of a joint effort of experts in the field of ethics and HTA. Consensus is reached in the expert panel on an approach that is considered to be more clear, comprehensive, and applicable for addressing ethical issues in HTA.

This paper aims to describe, using an evidence-based approach, the importance of and the resources necessary for implementing effective infection prevention and control (IPC) programmes. The intrinsic and explicit values of such strategies are presented from a clinical, health-economic and patient safety perspective. Policy makers and hospital managers are committed to providing comprehensive, accessible, and affordable healthcare of high quality. Changes in the healthcare system over time accompanied with variations in demographics and case-mix have considerably affected the availability, quality and ultimately the safety of healthcare. The main goal of an IPC programme is to prevent and control healthcare-associated infections (HAI). Many patient-, healthcare provider-, and organizational factors are associated with an increased risk for acquiring HAIs and may impact both the quality and outcome of patient care. Evidence has been published in support of having an effective IPC programme. It has been estimated that about one-third of HAIs could be prevented if key elements of the evidence-based recommendations for IPC are adequately introduced and followed. However, several healthcare agencies from over the world have reported deficits in the essential resources and components of current IPC programmes. To meet its main goal, staffing, training, and infrastructure requirements are needed. Nevertheless, and given the economic crisis, policy makers and hospital managers may be tempted to not increase or even to reduce the budget as it consumes resources and does not generate sufficient visible revenue. IPC is a critical issue in patient safety, as HAIs are by far the most common complication affecting admitted patients. The significant clinical and health-economic burden HAIs place on the healthcare system speak to the importance of getting introduced effective IPC programmes., (Copyright © 2013 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: Treatment costs of end-stage renal disease with dialysis are high and vary between dialysis modalities. Public healthcare payers aim at stimulating the use of less expensive dialysis modalities, with maintenance of healthcare quality., Objectives: This study examines the effects of Belgian financial incentive mechanisms for the use of low-cost dialysis treatments., Methods: First, the costs of different dialysis modalities were calculated from the hospital's perspective. Data were obtained through a hospital survey. The balance between costs and revenues was simulated for an average Belgian dialysis programme. Incremental profits were calculated in function of the proportion of patients on alternative dialysis modalities., Results: Hospital haemodialysis is the most expensive modality per patient year, followed by peritoneal dialysis and finally satellite haemodialysis. Under current reimbursement rules mean profits of a dialysis programme are maximal if about 28% of patients are treated with a low-cost dialysis modality. This is only slightly lower than the observed percentage in Belgian dialysis centres in the same period., Conclusions: In Belgium, the financial incentives for the use of low-cost dialysis modalities only had a modest impact due to the continuing profits that could be generated by high-cost dialysis. Profit neutrality is crucial for the success of any financial incentive mechanism for low-cost dialysis modalities., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

What Is Known and Objective: Variations in market uptake of an orphan drug have important implications with respect to access to care and inequality of treatment. Therefore, the aim of this study was to quantify both the sales and volume uptake of orphan drugs in Europe and to assess whether a country's gross domestic product (GDP) and/or health technology assessment (HTA) influences the orphan drugs' market uptake., Methods: We analysed the numbers of orphan drugs launched and the sales and volume uptake for 17 orphan drugs in 23 European countries from 2001 until the beginning of 2010 using the IMS Health database. Countries were clustered based on GDP and the availability of a formal HTA-organization., Results and Discussion: The uptake of orphan drugs varied across European countries. The highest volumes and contributions of orphan drugs in the first year occurred in countries with a high GDP (and implicitly, a higher budget for healthcare), independently of the existence of an HTA-organization. In contrast, in countries with a low GDP, orphan drugs were less available when there was a formal HTA-organization. There, budgetary restrictions can cause the exclusion of less cost-effective orphan drugs., What Is New and Conclusion: We observed substantial variation in the market uptake of orphan drugs. Such variation may have important implications with respect to access to care and inequality of treatment. The uptake of orphan drugs could be promoted through the clinical added value of orphan drugs (CAVOD) project and various conditional pricing and reimbursement mechanisms., (© 2012 Blackwell Publishing Ltd.)

Objectives: The aim of our study is to compare five European drug reimbursement systems, describe similarities and differences, and obtain insight into their strengths and weaknesses and formulate policy recommendations., Methods: We used the analytical Hutton Framework to assess in detail drug reimbursement systems in Austria, Belgium, France, the Netherlands, and Sweden. We investigated policy documents, explored literature, and conducted fifty-seven interviews with relevant stakeholders., Results: All systems aim to balance three main objectives: system sustainability, equity and quality of care. System impact, however, is mainly assessed by drug expenditure. A national reimbursement agency evaluates reimbursement requests on a case-by-case basis. The minister has discretionary power to alter the reimbursement advice in Belgium, France, and the Netherlands. All systems make efforts to increase transparency in the decision-making process but none uses formal hierarchical reimbursement criteria nor applies a cost-effectiveness threshold value. Policies to deal with uncertainty vary: financial risk-sharing by price/volume contracts (France, Belgium) versus coverage with evidence development (Sweden, the Netherlands). Although case-by-case revisions are embedded in some systems for specific groups of drugs, systematic (group) revisions are limited., Conclusions: As shared strengths, all systems have clear objectives reflected in reimbursement criteria and all are prepared to pay for drugs with sufficient added value. However, all systems could improve the transparency of the decision-making process; especially appraisal lacks transparency. Systems could increase the use of (systematic) revisions and could make better use of HTA (among others cost-effectiveness) to obtain value for money and ensure system sustainability.

OBJECTIVES. In a democratic system, decision makers are accountable for the reasonableness of their decisions. This presumes (i) transparency, (ii) relevance of the decision criteria, (iii) revisability of decisions, and (iv) enforcement/regulation. We aim to (i) evaluate the extent to which drug reimbursement decision-making processes in different contexts meet these conditions and (ii) develop, starting from these findings, a framework for improving the transparency and the relevance of used decision criteria. METHODS. We evaluated the Austrian, Belgian, French, Dutch, and Swedish drug reimbursement systems. Based on this evaluation, we developed a framework for improving the transparency of drug reimbursement decision-making processes. It makes explicit the questions often addressed implicitly during decision-making processes as well as criteria for answering each question. RESULTS. Transparency of appraisal processes varies across systems. Justification with explicit criteria is generally limited. Although relevant criteria are similar across systems, their operationalization varies and their role in the appraisal process is not always clear. All systems seem to implicitly address five key questions, relating to (i) the medical, therapeutic, and societal need for treatment; (ii) preparedness to pay for treating the condition as a principle and (iii) for using the treatment under consideration; (iv) preparedness to pay more compared with alternatives; and (v) actual willingness to pay from public resources. CONCLUSIONS. Transparency of the appraisal process can be improved by using an explicit decision framework. Systematic use of such a framework enhances consistency across decisions, allows justification of value judgments, and thus enhances legitimacy of societal decision making.

To examine the cost and cost-effectiveness of the use of point-of-care (POC) devices by the general practitioner (GP), in anticoagulation clinic or by the patient in self-testing (PST) and self-management (PSM), compared with standard laboratory testing to realize international normalized ratio tests for patients on long term anticoagulation therapy. An economic evaluation was performed from the Belgian health care payer's perspective using a Markov model. Outcomes data were derived from a meta-analysis and cost data were derived from claims databases. Several scenarios were tested based on number of tests and GP's contacts and probabilistic sensitivity analysis was used to handle uncertainty. Evidence on the impact of POC on mortality was only found for PSM. Therefore, a cost-effectiveness analysis was performed for PSM and for other strategies, only a cost comparison was done. With an unchanged number of tests, POC is cost-saving compared to laboratory testing (probability > 70%). In scenarios where POC induces more tests, results were different: with 52 tests/year, only PSM kept a probability of remaining cost-saving superior to 50%. Except in the case of 100% of GP consultations maintained and 52 tests/year performed, PSM resulted in significantly more "life years gained" (LYG) than usual care and was on average cost-saving. The organisation of long term oral anticoagulation monitoring should be directed towards PSM and, to a lesser extent, PST for selected and trained patients.

Economic evaluations most often use results from randomised controlled trials (RCTs) to model effectiveness. Inconsiderate application of the absolute treatment effect from RCTs may result in unrealistic estimates of an intervention's benefit for the real-world target population. The baseline risk of events in this target population may differ significantly from the baseline risk in the RCT population. An approach to handle this problem is to combine observational data with evidence from RCTs. Reliable administrative or register data can provide an estimate of the real-world baseline risks. In combination with the relative treatment effect from well-performed RCTs this results in an estimate of the absolute benefit for the relevant target population. Applying this approach, one must remain cautious about the validity of the assumption of a constant relative treatment effect., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Over the past 50 years, medicines have made a huge contribution to improving the health status of populations. However, the level of pharmaceutical innovation varies widely, ranging from breakthrough treatments for life-threatening diseases to minor modifications of medicines that have been on the market for some time. Once innovative medicines approach the market, a system of measuring the level of innovation should be established. This perspective describes the current situation, the challenges and initiatives, and formulates recommendations for a coordinated EU action to measure the level of pharmaceutical innovation. In our opinion, comparative effectiveness research needs to play a central role in measuring the level of pharmaceutical innovation.

This Perspective describes (a) the current situation, (b) challenges and initiatives, (c) and formulates recommendations to valorize and create access to innovative medicines in the EU. We are currently still far away from optimal assessment of value for money in the EU. On the one hand, valorizing innovative medicines involves a local appraisal by health technology assessment (HTA) bodies and competent authorities about the value for money, the budget impact, and the local medical need that can be filled with new medicines. Therefore, local priorities and national health care policy environments should be reflected in the processes and criteria used for assessing value for money and ultimately for reimbursement decisions. On the other hand, a pan-European assessment of both relative effectiveness and medical need (including general ethical and social considerations) should be envisaged in order to feed part of the data needed for the local decisions in an efficient way. This could be the task of the European Medicines Agency, HTA bodies, and competent authorities together.

Background: Orphan medicinal products are designed to diagnose or treat rare diseases that are serious, life threatening or chronically debilitating and that affect 50 or fewer people in every 100 000 in the EU. In Belgium, the Drug Reimbursement Committee (DRC) evaluates reimbursement requests for orphan drugs based on multiple criteria: the therapeutic value, price and proposed reimbursement tariff; the importance of the drug in clinical practice; and the budget impact of the drug., Objectives: This study aimed to assess reimbursement dossiers of orphan drugs in Belgium and to compare them with the clinical evidence submitted to the European Medicines Agency (EMA)., Methods: A qualitative analysis examined all reimbursement dossiers of orphan drugs that were submitted in Belgium between January 2002 and June 2008. The following information was extracted from each dossier: description of the orphan drug; indication; reimbursement status; therapeutic value and needs; budget impact; and number of registered indications. For selected orphan drugs, an in-depth analysis extracted and compared information about the clinical trials, their primary endpoints and results from EMA documents (i.e. the marketing authorization application file, European public assessment report and summary of product characteristics) and the Belgian reimbursement dossiers., Results: Reimbursement was awarded to the majority of orphan drugs. In addition to the official criteria, other negotiable factors, such as price adjustments, employment incentives, patient population restrictions and funding of diagnostic tests by the company, seemed to play a role in the reimbursement decision. Despite the low number of patients, randomized controlled trials were conducted for many orphan drugs. Budget-impact analyses were simplistic and did not consider the impact across multiple indications. Some differences were also observed between the clinical evidence submitted to the EMA and that submitted to the Belgian DRC., Conclusions: In addition to the official criteria, other negotiable factors, such as price adjustments and employment incentives, may play a role in Belgian reimbursement decisions of orphan drugs. Some differences have also been noted between the clinical evidence reported in EMA documents and the evidence included in Belgian reimbursement dossiers of orphan drugs. There appears to be a need for further standardization of Belgian reimbursement applications and for European cooperation in sharing clinical evidence of orphan drugs.