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This study maps the conceptual structure of health technology assessment (HTA) research with the aim of contributing to a better understanding of this research stream. A bibliometric analysis of 1,198 HTA articles retrieved from the Web of Science database was conducted. The analysis of descriptive performance indicators identified the main traits of the scientific debate about the HTA in terms of publications, productive countries, and sources. A co-word analysis was performed by adopting social network analysis tools to map the conceptual structure of the dataset. The results highlight the growing academic interest in the research topic, especially in recent years. The results revealed that HTA is a widely known term and represents the reference paradigm for assessment in healthcare technologies. This paper contributes to the field by providing an examination of the current state of the art of HTA research and identifying possible future research directions. This study differs from existing studies because it involved a conceptual analysis of the scientific literature using macro keywords.

Resource modeling aims to explicitly quantify the effects of adopting new health care technologies in settings with capacity-related constraints. The aim of this analysis was to use resource modeling to explore the effects of the uptake of first-line treatment with daratumumab on wait lists and wait times in patients with untreated multiple myeloma. Two formulations were compared: the standard IV formulation (DARA-IV) and a recently approved SC formulation (DARA-SC).First, semi-structured interviews at six oncologic centers were used to retrieve data on the management of patients given a DARA-IV regimen. Second, a discrete event simulation (DES) model was built to estimate the effects on resource consumption, wait lists, and wait times in scenarios with different incident numbers of patients treated with either DARA-IV or DARA-SC.In all of the simulated scenarios with more incident patients initiated on first-line treatment with DARA-IV, the actual capacity of infusion chairs was not enough to meet the demand, leading to increases in wait times and wait lists. In the highest-demand scenario, 17 more infusion chairs per center would be required to avoid such increases. Treatment with DARA-SC would allow centers to meet the demand with their actual capacity.DES modeling can effectively be used to formally explore the effects of different formulations on the use of limited resources, wait lists, and wait times at the facility level. Based on the findings from this analysis, DARA-SC may free up resources and prevent short- and long-term costs to infusion centers.

Please note that the scope of this Deliverable has been extended following feedback from the reviewers and the title “Health Economics Models for Genomics in Healthcare - Recommendations for the application of Health Technology Assessment and Health Economics to genomics in the framework of the 1+MG Initiative” best describes the Deliverable after the introduced changes. The B1MG Work Package 5 (WP5) has among its tasks one dedicated to address health economics aspects of the adoption of genomics in health-care. As a result of the activities performed by the WP5 is this deliverable that tries to contribute to the discussions about a sustainable implementation of genomics in the European countries providing recommendations about Health Technology Assessment and Health Economics and their application to genomics. It is necessary to clarify that the HTA concept includes Health Economics as one of the essential domains to be evaluated. In order to elaborate this document the WP5 has organised a workshop entitled “Health Technology Assessment and Health Economics of Genomics in Health-care: Key Issues for Implementation”. The workshop was organised with the objective of providing insights and facilitating discussion on experiences of national genome initiatives and/or relevant projects from Canada, France, the Netherlands and the United Kingdom. A total of 218 participants from 40 different countries were registered, mainly from academia, governmental organisations and industry. Researchers from ISCIII, Lygature and INSA coordinated the elaboration of this deliverable that is based on the experiences shared and lessons learned in the workshop and during the preparation of the workshop. This activity has been useful to identify some key challenges for a successful application of the HTA methods to genomics. In addition the activity has served to develop a series of key recommendations, some related to the role of HTA in genomics, others with methodology and others about opportunities for international collaboration.&nbsp

Introduction: The incidence of foot fractures is increasing. These types of fractures represent the most expensive group of diagnoses in the emergency department. Next to this, the need for economic evaluation studies is growing fast. The aim of this article is to provide healthcare professionals with an introduction to economic evaluation studies in the field of foot fractures.Types of economic evaluation studies: Four types of economic evaluation studies exist: cost-minimization analysis (CMA), cost-benefit analysis (CBA), cost-effectiveness analysis (CEA), and cost-utility analysis (CUA). An economic evaluation study can be either trial- or model-based.Cost assessment: When assessing costs in an economic evaluation study, three steps need to be made: identification of costs, measurement of costs, and valuation of costs.Perspective of analysis: Two main perspectives exist in economic evaluation studies. When using a healthcare perspective, only the potential costs and benefits of an intervention for the healthcare sector are included. The societal perspective includes all potential costs, including societal costs.Synthesis of costs and effects and uncertainty analysis: The level of cost-effectiveness can be objectively expressed using the incremental cost-effectiveness ratio (ICER). This measure can be plotted in a cost-effectiveness plane and can be compared with existing regional ceiling ratios.Conclusion: Although this article is not a guideline for economic evaluations, we do want to present five tips to consider when performing an economic evaluation. Firstly, when measuring resource use, consult the Database of Instruments for Resource Use Measurements (DIRUM) to find an appropriate instrument. Secondly, when measuring utility values, use the EuroQol questionnaire if possible. Thirdly, when setting up an economic evaluation study, consult the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) database for the appropriate pharmacoeconomic guidelines. Fourthly, consult international guidelines to decide which study design is most appropriate. Finally, when performing an economic evaluation, consult a heath technology assessment (HTA) specialist from the start to ensure methodological quality. (C) 2022 The Author(s). Published by Elsevier Ltd.

Introduction: Industrial accidents are among the major problems of today's societies. Studies on accidents indicated that the most important cause of their occurrence was the human factor. Therefore, the purpose of this study was to identify and evaluate human error in the operation of furnace using the human event analysis technique in a petrochemical industry. Methods: This was a qualitative and cross-sectional study which was analyzed by directly observing the activities, interviewing the analysis, and reviewing the documents and instructions, tasks and sub-tasks by Hierarchical task analysis (HTA) method, and the results were provided in HTA charts. In the next step, according to Technique for Human Error Analysis (ATHEANA) instructions, the relevant worksheet was completed. Results: The results indicated that coil breakage or precision instrument connections, improper bypassing of pressure in the paths to rotate the furnace to the atmosphere, or process and leakage of gas lines, flanges and valves whose probability of defect was 0.20, 0.14 and 0.13, respectively, had the highest probability of error. The probability of human error in the operation of the furnace was calculated to be 0.63. Conclusion: Applying corrective measures such as: selecting skilled people, holding training courses, routine monitoring of temperature, pressure measuring equipment, etc. for proper operation of the apparatus and visual monitoring of all furnace parts, including valves, are some of the things with which the likelihood of human error in the operation of the furnaces was reduced.

L’utilizzo di valutazioni economiche in ambito sanitario ha assunto nel corso degli anni un ruolo di crescente importanza, alla luce dell’esigenza di fornire informazioni utili ai decision-maker nel difficile ruolo di continuare a garantire l’innovazione in contesti di risorse scarse all’interno di un sistema universalistico. I modelli decisionali, siano essi alberi decisionali o modelli di Markov, sono strumenti che dimostrano di rispondere il più delle volte alle esigenze di simulare il decorso di una patologia e l’effetto dei trattamenti su di esso, producendo stime su outcome finali e costi nel lungo termine che alimentano indicatori di costo-efficacia/costo-utilità, utilizzati, seppur con logiche differenti, da diverse agenzie di HTA per definire il valore economico di una nuova tecnologia e supportare le negoziazioni di prezzo. Oltre ai modelli di costo-efficacia/utilità, i più semplici modelli di impatto sul budget trovano notevole spazio in questo contesto, fornendo informazioni cruciali rispetto la sostenibilità del sistema.Anche in Italia tali valutazioni sono considerate nei processi di valutazione dei farmaci da parte di AIFA che le analizza e le utilizza all’interno delle istruttorie sottoposte al Comitato Prezzi e Rimborso (CPR) per la definizione delle condizioni di prezzo e rimborso dei farmaci. Tali valutazioni sono inoltre particolarmente raccomandate in quegli ambiti decisionali particolarmente complessi, quali ad esempio il caso di farmaci orfani/per malattie rare.Al fine di leggere come la valutazione economica viene effettivamente utilizzata nei contesti valutativi l’accesso in Italia, è stato pertanto presentato in questo lavoro il caso specifico dell’atrofia muscolare spinale e del medicinale risdiplam, come ambito esemplificativo di una malattia rara in cui l’innovazione è entrata in modo prepotente negli ultimi anni e dove pertanto i decisori si sono trovati (e tuttora si trovano) a dover valutare attentamente gli impatti sia da un punto di vista clinico che da un punto di vista organizzativo ed economico, in una logica HTA.Il lavoro svolto ha riguardato lo sviluppo di tre tipologie di analisi diverse la cui sola lettura integrata permette di avere un quadro complessivo degli elementi di efficienza allocativa e di impatto di sostenibilità richiesti da AIFA per le sue valutazioni di accesso ai farmaci. La prima analisi effettuata è stata una analisi di costo-utilità in pazienti con SMA 1, in cui il nuovo medicinale ha dimostrato un profilo favorevole, con un indicatore di costo/QALY guadagnato di circa 43.000 € nello scenario lifetime, che rientra all'interno delle soglie di accettabilità comunemente definite. Negli scenari a 5 e 10 anni, risdiplam si è dimostrato cost saving rispetto all'alternativa. La seconda valutazione effettuata è stata una analisi di costo-minimizzazione in pazienti con SMA 2 e 3, in cui si è evidenziata una convenienza economica di circa 160.000 € su 10 anni, considerando i costi sia farmacologici che di somministrazione. Infine è stata realizzata una analisi di impatto sul budget in cui, a seguito dell'introduzione di risdiplam nel mercato, non si stima un impatto di spesa incrementale in virtù di una riduzione dei costi nella SMA 1 e 3 che compensa l'aumento atteso nella SMA 2. La lettura integrata dei risultati dei tre modelli sviluppati, trova profonda coerenza nell’avere negoziato una nuova terapia con dei range di costo-utilità coerenti con quelli correntemente citati in altri paesi e dei parametri di impatto finanziario compatibili con le esigenze di non aggravare ulteriormente sul SSN. The use of economic assessments in the health sector has assumed a role of increasing importance over the years, in light of the need to provide useful information to decision-makers in the difficult role of continuing to guarantee innovation in contexts of scarce resources, in a universalistic system. Decision models, both decision trees or Markov models, are tools that demonstrate that they most often respond to the need to simulate the course of a disease and the effect of treatments on it, producing estimates on final outcomes and costs in the long term that feed cost-effectiveness / cost-utility indicators, used, albeit with different logics, by various HTA agencies to define the economic value of a new technology and support price negotiations. In addition to cost-effectiveness / utility models, the simplest budget impact models find considerable space in this context, providing crucial information regarding the sustainability of the system. AIFA which analyzes and uses them within the investigations submitted to the Price and Reimbursement Committee (CPR) for the definition of the price and reimbursement conditions for drugs. These evaluations are also particularly recommended in those particularly complex decision-making areas, such as the case of orphan drugs / for rare diseases. in this work, the specific case of spinal muscular atrophy and the medicinal product risdiplam, as an example of a rare disease in which disruptive innovation has entered in recent years and where therefore the decision-makers have found themselves (and still are) to have to carefully evaluate the impacts both from a clinical point of view and from an organizational and economic point of view, in an HTA logic. The work carried out involved the development of three different types of analyzes whose integrated reading alone allows for an overall picture of the elements of allocative efficiency and sustainability impact required by AIFA for its evaluations of access to drugs. The first analysis performed was a cost-utility analysis in patients with SMA 1, in which the new drug demonstrated a favorable profile, with a cost / QALY indicator gained of approximately € 43,000 in the lifetime scenario, which falls within commonly defined acceptability thresholds. In the 5 and 10 year scenarios, risdiplam proved to be cost saving compared to the alternative. The second evaluation carried out was a cost-minimization analysis in patients with SMA 2 and 3, which showed an economic convenience of about € 160,000 over 10 years, considering both pharmacological and administration costs. Finally, a budget impact analysis was carried out in which, following the introduction of risdiplam in the market, an incremental spending impact is not estimated due to a cost reduction in SMA 1 and 3 which offsets the expected increase in SMA 2. The integrated reading of the results of the three models developed finds profound coherence in having negotiated a new therapy with cost-utility ranges consistent with those currently cited in other countries and financial impact parameters compatible with the further aggravate on the NHS.

Highly mechanized forestry operations are essential for efficient timber harvesting. Therefore, the skills of harvester operators appear to be key to productive and sustainable use of the machines. Recent research has revealed a knowledge deficit regarding the work practices of forest machine operators. This urges systematic research into forestry machine handling and a corresponding refinement of analytical methods. Current analyses of operator tasks in forestry are less formalized and focus predominantly on machine efficiency and overall performance, but not so much on the human-related conditions of work performance and workload. Therefore, the objective of this paper is to introduce hierarchical task analysis (HTA) into forestry science. HTA is a versatile, formalized human-factors method that can be used to describe the work objectives of forest machine operators. HTA is suitable, for example, for describing (in)efficient work practices and thus as a basis for designing machine operator training and for systematically evaluating assistive technologies. The task analyses in this paper draw on a recently published empirical approach to analyzing work practices, workflows, and machine operator behavior for optimal human–machine collaboration in forestry application research. Specifically, the main work methods of clearcutting and thinning stand in European forestry were considered, with examples from Scandinavian and German method application. The process of HTA is described and a prototypical approach to HTA for both working methods provided. As a result, this work could show that a single work practice affects operator goals within different work elements and sets out how inefficient work practices can be described in terms of operator goals. With the introduction and exemplary application of HTA, a structured task definition in human-centered approaches is encouraged to analyze work practices, workflows, and machine operator behavior for optimal human–machine collaboration in forestry application research.

Introdução: As doenças cardiovasculares (CV) são um problema de saúde pública nas sociedades modernas, representando a hipertensão arterial (HTA) um dos principais fatores de risco, com consequente morbilidade e mortalidade associadas. Os métodos de avaliação da pressão arterial (PA) evoluíram nas últimas décadas, com uma maior acessibilidade e facilidade de utilização para a maioria da população, com a auto-medição da PA em ambulatório (AMPA) a ter um papel fundamental. Seria assim expectável a sua maior utilização na prática clínica a nível do diagnóstico, monitorização, tratamento e prognóstico da PA, sendo mais representativa dos valores reais da PA no dia-a-dia, comparativamente à PA de consultório. O uso da AMPA tem ganho uma importância e popularidade crescente como método complementar e até preferencial, pois permite uma avaliação longitudinal com uma reprodutibilidade superior. Estudos recentes mostram um valor preditivo superior na previsão da morbimortalidade CV. A AMPA fornece vários parâmetros com informação crucial para a tomada de decisões, entre os quais: PA sistólica (PAS), PA diastólica (PAD), pressão de pulso (PP), frequência cardíaca (FC) e variabilidade tensional. Objetivos: Rever a evidência científica sobre a utilização da AMPA e dos seus parâmetros: PAS, PAD, FC, PP e variabilidade PAS na previsão de eventos CV futuros. Orientar e melhorar a leitura da AMPA, com a valorização dos diferentes parâmetros como a PP, a variabilidade tensional (medida pelo coeficiente de variação) e a percentagem de valores acima do valor de corte (equivalente à carga da monitorização ambulatória da pressão arterial - MAPA). Métodos: Pesquisa bibliográfica de artigos originais, revisões sistemáticas e metanálises publicadas entre 1995 e 2020 nas bases de dados: Pubmed® e Google Scholar® utilizando os termos “HBPM”, “pulse pressure”, “variability of blood pressure” e “heart rate”. Resultados: Validação científica dos diferentes parâmetros como preditores de eventos cardiovasculares futuros: a maioria da literatura baseia-se em medições da PA através da MAPA ou de consultório e, poucos utilizando a AMPA. Sobre a AMPA: valores de PAS e PAD mostraram relação com eventos CV futuros. PP e a variabilidade são ainda pouco estudados. PP, PAD e PAS medidas pela AMPA, foram fortemente correlacionadas com hipertrofia ventricular esquerda (HVE). A variabilidade tensional obtida pela AMPA foi também alvo de estudos na previsão de eventos CV, com uma grande relação com acidentes vasculares cerebrais. No entanto, esta relação com eventos cardíacos e outros eventos CV ainda não foi estabelecida. Este estudo realizado no Japão apontou algumas limitações, dado que nesta população, a relação entre a HTA e os eventos vasculares cerebrais está bem estabelecida e é superior aos eventos cardíacos. Conclusões: A relação entre PA (obtida em consultório e MAPA) e eventos CV está bem estabelecida. Sem evidência clínica suficiente sobre a utilização e valorização de parâmetros como a PP, FC, variabilidade da PAS e “carga” obtidos através da AMPA. AMPA é um método com grande potencial de informação a ser aplicado na prática clínica do dia-a-dia.

This is a registration of a protocol for a scoping review on strategies for training and involving laypeople in health technology assessment.

Source at https://www.fhi.no/. Vi har utarbeidet en fullstendig metodevurdering av kirurgi med sutur sammenlignet med ikke-kirurgisk behandling ved degenerativ fulltykkelse rotatorcuff-ruptur. Vi inkluderte fem randomiserte og 18 ikke-randomiserte studier. Vi sammenstilte studiene i metaanalyser og vurderte tilliten til effektestimatene med GRADE-tilnærmingen. For pasienter med ruptur i én sene gir kirurgi liten eller ingen klinisk relevant forskjell i smerte, nattesmerte, funksjon, pasienttilfredshet og helserelatert livskvalitet sammenlignet med ikke-kirurgisk behandling ved ett år (GRADE: middels til lav). For pasienter med ruptur i én eller to sener gir kirurgi litt høyere pasienttilfredshet, men liten eller ingen klinisk relevant forskjell i smerte, nattesmerte, funksjon og helserelatert livskvalitet sammenlignet med ikke-kirurgisk behandling ved ett år (GRADE: middels til lav). Re-ruptur / manglende tilheling forekom hos mellom 5 % og 35 % seks måneder til ti år etter kirurgi og økt rupturstørrelse hos 59 % etter ti år ved ikke-kirurgisk behandling (GRADE: ikke vurdert). Det ble rapportert få alvorlige uønskede hendelser, men kunnskapsgrunnlaget her er tynt og vi er usikre på absolutt risiko. Den helseøkonomiske hovedanalysen viste at kirurgi er det mest kostbare alternativet, med en kostnadsforskjell på ca 36 000 kroner og en forventet akkumulert forskjell i effekt over fem år på 0,09 QALYs. Dette gir en IKER på 389 035 kroner per QALY. • Potensielle årlige kostnadsbesparelser ved å velge kun ikke-kirurgisk behandling framfor kirurgi kan utgjøre inntil 81 millioner kroner. Estimatet er usikkert, og vil antakelig være noe lavere siden kirurgi vil være et behandlingsalternativ for enkelte pasienter.

Introduction: Human error plays a significant role in the occurrence of industrial accidents. Displacement and unloading operations are operations in which the occurrence of human error may lead to plenty of human and financial losses. The present study aimed to investigate the possibility of human error occurrence in overhead crane operators in a Steel Company in Hormozgan, Iran. Material & Methods: This cross-sectional and descriptive study was conducted using the Standardized Plant Analysis Risk-Human Reliability Analysis (SPAR-H) technique. In this study, the job tasks of overhead crane operators were firstly analyzed using the hierarchical task analysis (HTA) technique. Subsequently, the probability of human error in job tasks was assessed using the SPAR-H technique. (Ethic code: IR.ACECR.JDM.REC.1399.005) Findings: Generally, five main tasks and 16 sub-tasks have been analyzed in this study. The highest probability of error was related to the three sub-tasks of longitudinal motion, transverse motion, and high and low motion (0.3975). The lowest probability of error was under the duty of recording shift reports, transmitting information orally, and writing (0.05). The results of this study clearly showed the effect of interdependence on increasing the probability of error occurrence. Discussion & Conclusion: Based on the results of the present study, some preventive measures were proposed to reduce the possibility of human error, including identifying and controlling job stressors, correcting the ergonomic status of crane cabins, preparing work instructions, as well as training and monitoring their proper implementation.

Objectives: The aim of this study was to determine the role of the patient’s point of view when assessing health technologies as well as the patients’ willingness to participate in this process in our country. Methods: A pilot study included 165 patients across Bulgaria recruited from December 2019 to March 2020. Appropriate descriptive and statistical methods were used. Results: The patient’s point of view was an essential element in HTA. Patients in Bulgaria have the desire and willingness to share their personal experience with institutions, but insufficient knowledge of the process hinders their full participation in HTA. Our results showed that the need for higher awareness in the field and familiarity with HTA methodology are critical factors for the inclusion of patients in the HTA procedures in Bulgaria. Conclusion: This study was one of the few ones focused on the impact of patient participation in HTA in Bulgaria. The patient’s role in the development of medical technology must be recognized and considered a critical factor in the future of HTA.

Protocol for a scoping review of factors that facilitate or limit the consideration of economic evaluations in clinical practice guidelines (CPG). Funded by ZonMW, project number: 859002001

Background. Common mental health disorders such as depression and anxiety have severe negative impact on mental wellbeing, quality of life and social and work-related functioning. E-Mental health (eMH) services such as Internet-based Cognitive Behaviour Therapy (iCBT), are proven to be effective in treating common mental health disorders. However, eMH services do not enter routine care as expected and their uptake in practice remains low, slow and costly. The difference between what is known and what is delivered in routine care, is one of the most critical issues in achieving effective, sustainable, and equitable mental health care. This dissertation aimed to contribute to understanding and reducing the research-to-practice gap in clinical mental health care. This thesis focussed on five research questions related to: decision-making in implementing eMH services, a taxonomy of barrier, characterisation of organisational implementation climate, the validity of NoMAD as an instrument to measure and monitor implementation outcomes, and the effectiveness of a toolkit for developing and applying tailored implementation strategies for implementing eMH services. Various methods were applied, including systematic reviews of existing literature, qualitative research using a concept mapping approach, a psychometric Confirmatory Factor Analysis, and an implementation effectiveness trial employing a Stepped Wedge cluster randomised study design with Linear Mixed Modelling with repeated measures. A substantial part of the research was carried out in an international context. Main findings. Implementation is preceded by a decision-making process. Various Health Technology Assessment (HTA) frameworks are adapted and used to assess various aspects of eMH services and by that, support systematic and evidence-informed decision making. In general, outcomes and instruments are not specified by the framework potentially limiting the applicability and comparability of assessments. Once the decision has been made, a logical next step is to identify the barriers that hinder implementation of the eMH service in routine care. Three barriers were reported most frequently in the scientific literature: (1) acceptance of patients and professionals, (2) appropriateness of the eMH service and specifically in relation to the therapeutic interaction, and (3) technological aspects of eMH services, including interoperability with other digital technologies. Focussing on the organisational context, a explorative study showed that organisational implementation is a relevant factor in implementing eMH services in routine care. Important elements include roles and skills of implementers, implementation targets, and the availability of a dedicated implementation team. Moreover, the implementation climate within a mental health care organisation not only is a (set of) static determinants, it can also be shaped in such way that the implementation of eMH services can be improved. To determine whether an implementation strategy is effective, reliable and valid measurement instruments are required. The Confirmatory Factor Analysis (CFA) reported in Chapter 5, confirmed the validity of the Normalization MeAsure Development Questionnaire (NoMAD) in samples of Dutch mental health service providers. NoMAD is theory-based and supports implementers in monitoring progress, and to compare outcomes of implementation strategies. One-size-fits-all implementation strategies most likely do not exist. Implementation takes place in a context and faces barriers that vary considerably from setting to setting and from time to time. Chapter 6 reports the effectiveness of a self-guided online toolkit (the ItFits-toolkit) that supports implementers in developing, applying and monitoring tailored implementation strategies for eMH services. Conclusions. The work presented in this dissertation touches upon four major topics relevant to implementing eMH services in practice: technology assessment and decision making, identifying barriers to implementation, measuring implementation outcomes, and developing effective implementation strategies that are matched to the local situation. It is possible to move from identifying barriers to developing and applying effective implementation strategies for eMH services that are tailored to the local context.

Background. Common mental health disorders such as depression and anxiety have severe negative impact on mental wellbeing, quality of life and social and work-related functioning. E-Mental health (eMH) services such as Internet-based Cognitive Behaviour Therapy (iCBT), are proven to be effective in treating common mental health disorders. However, eMH services do not enter routine care as expected and their uptake in practice remains low, slow and costly. The difference between what is known and what is delivered in routine care, is one of the most critical issues in achieving effective, sustainable, and equitable mental health care. This dissertation aimed to contribute to understanding and reducing the research-to-practice gap in clinical mental health care. This thesis focussed on five research questions related to: decision-making in implementing eMH services, a taxonomy of barrier, characterisation of organisational implementation climate, the validity of NoMAD as an instrument to measure and monitor implementation outcomes, and the effectiveness of a toolkit for developing and applying tailored implementation strategies for implementing eMH services. Various methods were applied, including systematic reviews of existing literature, qualitative research using a concept mapping approach, a psychometric Confirmatory Factor Analysis, and an implementation effectiveness trial employing a Stepped Wedge cluster randomised study design with Linear Mixed Modelling with repeated measures. A substantial part of the research was carried out in an international context. Main findings. Implementation is preceded by a decision-making process. Various Health Technology Assessment (HTA) frameworks are adapted and used to assess various aspects of eMH services and by that, support systematic and evidence-informed decision making. In general, outcomes and instruments are not specified by the framework potentially limiting the applicability and comparability of assessments. Once the decision has been made, a logical next step is to identify the barriers that hinder implementation of the eMH service in routine care. Three barriers were reported most frequently in the scientific literature: (1) acceptance of patients and professionals, (2) appropriateness of the eMH service and specifically in relation to the therapeutic interaction, and (3) technological aspects of eMH services, including interoperability with other digital technologies. Focussing on the organisational context, a explorative study showed that organisational implementation is a relevant factor in implementing eMH services in routine care. Important elements include roles and skills of implementers, implementation targets, and the availability of a dedicated implementation team. Moreover, the implementation climate within a mental health care organisation not only is a (set of) static determinants, it can also be shaped in such way that the implementation of eMH services can be improved. To determine whether an implementation strategy is effective, reliable and valid measurement instruments are required. The Confirmatory Factor Analysis (CFA) reported in Chapter 5, confirmed the validity of the Normalization MeAsure Development Questionnaire (NoMAD) in samples of Dutch mental health service providers. NoMAD is theory-based and supports implementers in monitoring progress, and to compare outcomes of implementation strategies. One-size-fits-all implementation strategies most likely do not exist. Implementation takes place in a context and faces barriers that vary considerably from setting to setting and from time to time. Chapter 6 reports the effectiveness of a self-guided online toolkit (the ItFits-toolkit) that supports implementers in developing, applying and monitoring tailored implementation strategies for eMH services. Conclusions. The work presented in this dissertation touches upon four major topics relevant to implementing eMH services in practice: technology assessment and decision making, identifying barriers to implementation, measuring implementation outcomes, and developing effective implementation strategies that are matched to the local situation. It is possible to move from identifying barriers to developing and applying effective implementation strategies for eMH services that are tailored to the local context.

By using a case-study on a fall-prediction device for elderly patients with orthostatic hypotension we aim to demonstrate how the MAFEIP tool, developed as part of the European Innovation Programme on Active and Healthy Ageing (EIP on AHA), can be used to inform manufacturers on their product development based on a cost-effectiveness criterion. Secondly, we critically appraise the tool and suggest further improvements that may be needed for a larger-scale adoption of MAFEIP within and beside the EIP on AHA initiative. The model was implemented using the MAFEIP tool. Within the tool one way sensitivity analyses were performed to assess the robustness of the model against the relative effectiveness of the fall-prevention device at different price levels. The MAFEIP tool was applied to a novel fall-prediction device and used to estimate the expected cost-effectiveness and perform threshold analysis. In our case study, the device produced estimated gains of 0.035 QALYs per patient and incremental costs of £ 518 (incremental cost-effectiveness ratio £14,719). Based on the one-way sensitivity analysis, the maximum achievable price at a willingness to pay threshold of £20,000 per QALY is estimated close to £900. The MAFEIP allows to quickly create early economic models, and to explore model uncertainty by performing deterministic sensitivity analysis for single parameters. However, the integration within the MAFEIP of common analytical tools such as probabilistic sensitivity analysis and Value of information would greatly contribute to its relevance for evaluating innovative technologies within and beside the EIP on AHA initiative.

Objectives A recent debate in health economics and outcomes research community identified option value as one of the elements warranting consideration in the assessment of medical technologies. To conduct a scoping review of contributions on option value in the healthcare sector and identify relevant conceptual aspects and methods used to incorporate it in standard economic evaluations. Methods A systematic search was conducted up to July 2020 to identify contributions from electronic bibliographic database and gray literature. Data on the proposed definitions of option value, theoretical implications of its use in economic evaluations, and methods used to estimate it were extracted and analyzed. Results We found 57 eligible studies. Three different definitions emerged: insurance value, real option value, and option value of survival. Focusing on the latter (24 studies), we analyzed in depth 8 empirical applications across 7 therapeutic areas. The most relevant methodological challenges were on the perspective used in economic evaluations and how to robustly manage forecasting uncertainty, update cost-effectiveness thresholds, and avoid double-counting issues. For empirical studies assessing the total value of the technology, including option value, estimates ranged from +7% to +469% of its conventional value. Conclusions This review synthesizes theoretical and empirical aspects on option value of healthcare technologies and proposes a terminology to distinguish 3 different concepts identified. Future work should focus primarily on agreeing on whether option value should be included in economic evaluations and, if so, on developing and validating reliable methods for its ex-ante estimation.

Rapid evaluation of health technology on the safety and efficacy of Atezolizumab for hepatocellular carcinoma compared to standard therapy for use in Central America and other immunotherapies.

Scoping review about Hospital-Based Health Technology Assessment

Differing contexts have greatly influenced HTA development in various countries, with considerable effort recently made by international HTA networks (e.g., EUnetHTA) and the European Union (EU) to make HTA a more coherent, equal, and efficient process. Medical devices (MDs) present particular challenges for HTA because of frequent, rapid innovation, outcomes influenced by end-user competence, dynamic pricing and often low-quality scientific evidence. Our objective is to describe the development, structure and governance of a National HTA Program for MDs (PNHTADM) in Italy, a highly participatory, stakeholder-engaged, evidence-based process to reform a fragmented system of appraisal and approval. Based largely on EUnetHTA methods, the resulting process delineates a standardized system for proposing MDs by any stakeholders, accrediting HTA producers, setting criteria for prioritization and appraisals, and innovatively linking recommendations with coverage, reimbursement and procurement of MDs. Expected benefits include reduced disparities in pricing and reimbursement policies and improved access to new technologies across 21 regional healthcare systems in Italy's decentralized, universal system, complete with provisions to require additional evidence collection and centrally monitor diffusion. Though devised for Italy, the design, resources and underlying analysis provide a framework for other nations seeking to consolidate HTA initiatives, particularly in light of new EU regulation.

Background Health Technology Assessment (HTA), which can support public drug reimbursement decisions will play a core function in the planned national Pharmacare program in Canada. To address existing barriers to the use of HTA, these must be ranked in order of priority. The goal of this study was to access the relative importance of known facilitators and barriers to the use of HTA in the context of the Canadian health care system, with attention to differences between regions and stakeholder groups. Methods We used the best-worst scaling object case approach to elicit a quantitative ranking of a list of 20 facilitators and 22 barriers. A sample of 68 Canadian HTA stakeholders, including members of expert committees, decision/policymakers, researchers/academics, and others participated in the study. Their task was to identify the most important and the least important item in 12 sub-sets of five facilitators and 14 sub-sets of five barriers. Findings Relative Importance Scores derived via hierarchical Bayes analysis revealed relations, engagement, and contact between stakeholders as most important on both the barrier and facilitator sides. Other top-ranked facilitators included the availably of credible and relevant research. Other top-ranked barriers included inconsistencies in the evidence and limited generalizability. The availability of HTA guidelines did not rank highly on either side. The main limitation of the study was the challenge with reaching the relevant respondents; this was mitigated by involving the national HTA agency in the research. Conclusion Canadian stakeholders consider the relationships within the HTA network among the most important. Policies should focus on strengthening these relationships. Future research should focus on the connectivity and distribution of knowledge and power within the HTA network.

Objectives: Italy was the first European country to introduce universal vaccination of adolescents, for both males and females, against Human Papilloma Virus (HPV) starting in 2017 with the NIP 2017–2019′s release. However, vaccine coverage rates (VCRs) among adolescents have shown a precarious take-off since the NIP’s release, and this situation worsened due to the impact of the COVID-19 pandemic in 2020. The aim of this work is to estimate the epidemiological and economic impact of drops in VCRs due to the pandemic on those generations that missed the vaccination appointment and to discuss alternative scenarios in light of the national data. Methods: Through an analysis of the official ministerial HPV vaccination reports, a model was developed to estimate the number of 12-year-old males and females who were not vaccinated against HPV during the period 2017–2021. Based on previously published models that estimate the incidence and the economic impact of HPV-related diseases in Italy, a new model was developed to estimate the impact of the aggregated HPV VCRs achieved in Italy between 2017 and 2021. Results: Overall, in 2021, 723,375 girls and 1,011,906 boys born between 2005 and 2009 were not vaccinated against HPV in Italy (42% and 52% of these cohorts, respectively). As compared with the 95% target provided by the Italian NIP, between 505,000 and 634,000 girls will not be protected against a large number of HPV-related diseases. For boys, the number of the unvaccinated population compared to the applicable target is over 615,000 in the ‘best case scenario’ and over 749,000 in the ‘worst case scenario’. Overall, between 1.1 and 1.3 million young adolescents born between 2005 and 2009 will not be protected against HPV-related diseases over their lifetime with expected lifetime costs of non-vaccination that will be over EUR 905 million. If the 95% optimal VCRs were achieved, the model estimates a cost reduction equal to EUR 529 million, the net of the costs incurred to implement the vaccination program. Conclusion: Suboptimal vaccination coverage represents a missed opportunity, not only because of the increased burden of HPV-related diseases, but also in terms of economic loss. Thus, reaching national HPV immunization goals is a public health priority.

Due to uncertainty regarding the potential impact of unmeasured confounding, health technology assessment (HTA) agencies often disregard evidence from nonrandomized studies when considering new technologies. Quantitative bias analysis (QBA) methods provide a means to quantify this uncertainty but have not been widely used in the HTA setting, particularly in the context of cost–effectiveness modelling (CEM). This study demonstrated the application of an aggregate and patient-level QBA approach to quantify and adjust for unmeasured confounding in a simulated nonrandomized comparison of survival outcomes. Application of the QBA output within a CEM through deterministic and probabilistic sensitivity analyses and under different scenarios of knowledge of an unmeasured confounder demonstrates the potential value of QBA in HTA.

Evidence generated from nonrandomized studies (NRS) is increasingly submitted to health technology assessment (HTA) agencies. Unmeasured confounding is a primary concern with this type of evidence, as it may result in biased treatment effect estimates, which has led to much criticism of NRS by HTA agencies. Quantitative bias analyses are a group of methods that have been developed in the epidemiological literature to quantify the impact of unmeasured confounding and adjust effect estimates from NRS. Key considerations for application in HTA proposed in this article reflect the need to balance methodological complexity with ease of application and interpretation, and the need to ensure the methods fit within the existing frameworks used to assess nonrandomized evidence by HTA bodies.

Introduction: The correct measurement of blood pressure (BP) is essential for the diagnosis and approach of blood hypertension. The way to appropriately perform this measurement is described in the “Guidelines for the Management of Arterial Hypertension 2018” from the European Society of Cardiology. This work pretends to highlight the importance of performing three blood pressure measurements during the evaluation of each patient and also analyse the differences between the two blood pressure measurements underwent in the consultation. Objetive: To analyse the difference between the first and second BP measurements in the office, in patients following a specialized HTA hospital consultation.Methods: This is a retrospective study, corresponding to two years of follow-up of 149 patients in a hypertension consultation, between the years of 2017 and 2018. Sociodemographic data and blood pressure measurements were collected. Data were processed using SPSS version 23.0. Central tendency and dispersion values for continuous variables are presented as means and standard deviations. Results: The mean age of the participants was 55±16 years, with 53% of the male patients. In each patient, 2.4±0.5 blood pressure measurements were performed in each consultation. The differences between the systolic blood pressure and diastolic blood pressure values from the first and second measurements were 26.0±6.0mmHg for systolic blood pressure (pvalue

Background and aims: There is an alarming delay in Europe for anticancer medicines becoming accessible for children. Following a paediatric European Union marketing authorisation, national Health Technology Assessment (HTA) agencies evaluate effectiveness, and safety of medicines to support decision on their cost and reimbursement. This study (a SIOPE Access to Medicines project) aimed to evaluate how these HTA evaluations take place for anticancer medicines indicated for paediatric use in Europe and to explore where the delays for market access originate. Methods: We obtained HTA reports from the public domain for nine European countries for blinatumomab, dinutuximab beta and tisagenlecleucel. We evaluated the time elapsed between marketing authorisation for a paediatric indication and a national HTA decision and the nature of the decision. Results: Out of 23 HTA decisions (four countries without blinatumomab report), 18 were positive, two with restrictions, three negative. For blinatumomab, tisagenlecleucel and dinutuximab beta, the median time to an HTA decision after regulatory approval for paediatric use was 353 days (range 193–751), 141 days (range 77–517) and 515 days (range 0–780), respectively, with variability between countries. Dinutuximab beta and tisagenlecleucel were first introduced in children, but did not result in shorter time to HTA decision. For blinatumomab, marketing authorisation followed 1008 days after the indication in adults, with HTA applications submitted a median of 167 days later, and a recommendation after 145 days. Conclusions: This study reveals ample variability in HTA decision making in nine European Union countries. Collaboration and alignment of required evidence is needed to facilitate robust scientific HTA assessments, also considering methodological challenges in paediatric oncology.

Lucrezia Ferrario,1 Fabrizio Schettini,1 Elisabetta Garagiola,1 Adriana Cecchi,2 Lucia Lugoboni,3 Paolo Serra,4 Emanuele Porazzi,1 Emanuela Foglia1 1Carlo Cattaneo – LIUC University and LIUC Business School, Castellanza, Italy; 2ARCS – Azienda Regionale di Coordinamento per la Salute, Udine, Italy; 3Bee Care, Lugano, Switzerland; 4Brotzu Hospital, Cagliari, ItalyCorrespondence: Lucrezia FerrarioCarlo Cattaneo – LIUC University and LIUC Business School, Corso Matteotti 22, Castellanza, VA 21053, ItalyTel +39 033 1572504Fax +39 033 1572513Email lferrario@liuc.itPurpose: To evaluate the incremental benefits concerning the implementation of closed-system medical devices for the preparation and administration of chemotherapy agents (integrated or not with traceable workflow), within an Italian clinical practice, in which the use of such technologies is not standardized.Methodology: Four Scenarios, implying different levels of technologies introduction, were analyzed, based on the presence and/or absence of closed systems and traceable workflow, in the preparation and in the administration phase. A literature review was conducted, in order to retrieve efficacy and safety measures. Economic and organizational benefits, assuming a hospitals perspective, were assessed by means of health-economics tools, considering 27,660 (± 695.86) drugs on average prepared, on an annual basis, by 12 hospitals involved. The typology of medical devices and other devices/equipment used, the human resources involved, and the time spent for the preparation and administration phases were collected.Results: Literature stated that the introduction of advanced technologies (CSTDs in the preparation phase, closed-system in the administration phase, both integrated by a traceable workflow) could: i) decrease surface contamination (12.24% vs 26.39%, P< 0.001) and ii) improve the capability to identify dosage errors (7% vs 0.096%, P< 0.05). The above technologies presented the best trade-off between cost sustained and efficacy gained. Despite marginal investments (ranging from +1% to +6%) being required for their acquisition, an organizational saving equal to more than 1,000 working hours emerged, which could be spent on other hospital activities.Conclusion: The implementation of closed systems, integrated with a traceable workflow grounding on gravimetric control, may be considered a valid technological alternative within the investigated setting. The marginal incremental costs could be absorbed already in the first year after their introduction, in particular, because of the potential time saving in using closed systems in both the preparation and administration phases, demonstrating the sustainability and feasibility of such advanced technologies.Keywords: closed-system medical device, chemotherapy agents, safety, economic evaluation, HTA, organisational benefits

Lucrezia Ferrario,1 Fabrizio Schettini,1 Elisabetta Garagiola,1 Adriana Cecchi,2 Lucia Lugoboni,3 Paolo Serra,4 Emanuele Porazzi,1 Emanuela Foglia1 1Carlo Cattaneo – LIUC University and LIUC Business School, Castellanza, Italy; 2ARCS – Azienda Regionale di Coordinamento per la Salute, Udine, Italy; 3Bee Care, Lugano, Switzerland; 4Brotzu Hospital, Cagliari, ItalyCorrespondence: Lucrezia FerrarioCarlo Cattaneo – LIUC University and LIUC Business School, Corso Matteotti 22, Castellanza, VA 21053, ItalyTel +39 033 1572504Fax +39 033 1572513Email lferrario@liuc.itPurpose: To evaluate the incremental benefits concerning the implementation of closed-system medical devices for the preparation and administration of chemotherapy agents (integrated or not with traceable workflow), within an Italian clinical practice, in which the use of such technologies is not standardized.Methodology: Four Scenarios, implying different levels of technologies introduction, were analyzed, based on the presence and/or absence of closed systems and traceable workflow, in the preparation and in the administration phase. A literature review was conducted, in order to retrieve efficacy and safety measures. Economic and organizational benefits, assuming a hospitals perspective, were assessed by means of health-economics tools, considering 27,660 (± 695.86) drugs on average prepared, on an annual basis, by 12 hospitals involved. The typology of medical devices and other devices/equipment used, the human resources involved, and the time spent for the preparation and administration phases were collected.Results: Literature stated that the introduction of advanced technologies (CSTDs in the preparation phase, closed-system in the administration phase, both integrated by a traceable workflow) could: i) decrease surface contamination (12.24% vs 26.39%, P< 0.001) and ii) improve the capability to identify dosage errors (7% vs 0.096%, P< 0.05). The above technologies presented the best trade-off between cost sustained and efficacy gained. Despite marginal investments (ranging from +1% to +6%) being required for their acquisition, an organizational saving equal to more than 1,000 working hours emerged, which could be spent on other hospital activities.Conclusion: The implementation of closed systems, integrated with a traceable workflow grounding on gravimetric control, may be considered a valid technological alternative within the investigated setting. The marginal incremental costs could be absorbed already in the first year after their introduction, in particular, because of the potential time saving in using closed systems in both the preparation and administration phases, demonstrating the sustainability and feasibility of such advanced technologies.Keywords: closed-system medical device, chemotherapy agents, safety, economic evaluation, HTA, organisational benefits

Introduction The use of oral FTC/TDF for pre-exposure prophylaxis (PrEP) among high-risk people without HIV is emerging as an innovative strategy to decrease HIV epidemic. The study aims at evaluating the implications related to PrEP introduction, from a multidimensional point of view, with particular attention to the sustainability of its implementation. Methods To achieve this objective a Health Technology Assessment was conducted, within 35 Italian Infectious Disease Departments. Data were collected from literature review and using validated questionnaires and literature evidence. The introduction of PrEP (applied as “add-on” and “substitute” prevention strategy) into the clinical practice was compared with a baseline scenario (use of condoms among men who have sex with men and serodiscordant couples, and the use of Needle Syringe Programme among injection drugs users). Results Despite the improvement in patients’ quality of life, PrEP would generate a decrease of patient safety, and an increase in staff workflow, with investment in medical supplies and training courses. PrEP would lead to significant economic investments both for the NHS, and for citizens (40% and 2,377% respectively) if used as an add-on strategy, assuming FTC/TDF patent cost. With the off-patent drug, the NHS would benefit from an advantage (37%) and a shrink of the patients’ expenditure emerged (+682%). More economic resources are required if PrEP is applied as a substitute strategy, considering both the patent (NHS: 212%; citizens: 3,423%) and the off-patent drug (NHS: 73%; citizens: 1,077%). Conclusions The most cost-containing strategy would be the use of PrEP, as an add-on strategy, assuming the off-patent drugs, even if safety and organisational aspects would be deeply considered., Journal of Preventive Medicine and Hygiene, Vol. 61 No. 3 (2020): 2020613

Chakrapani Balijepalli,1 Lakshmi Gullapalli,1 Eric Druyts,1 Kevin Yan,1 Kamal Desai,1 Stephane Barakat,2 Jason Locklin2 1Pharmalytics Group, Vancouver, British Columbia, Canada; 2Alexion Pharmaceuticals, Vaughan, Ontario, CanadaCorrespondence: Chakrapani Balijepalli Email chak.balijepalli@pharmalyticsgroup.comAbstract: Orphan drugs have high acquisition costs and when standard health technology assessment (HTA) approaches are used to assess their cost-effectiveness, they often appear not cost-effective. The Canadian Patented Medicine Review Board (PMPRB), through new regulations, will apply HTA assessment results from the Canadian Agency for Drugs and Technologies in Health (CADTH) and Institut national d’excellence en santé et en services sociaux (INESSS) when setting the maximum price that can be charged for Category I patented medicines (treatments with an annual cost exceeding 150% of GDP per capita of Canada or with expected annual market size >$50M). Through these regulations, PMPRB has also established a willingness-to-pay threshold of CAD$200,000 or CAD$150,000 per quality adjusted life year (QALY) for medications with a prevalence of no more than 1 in 2000 across all approved indications. We reviewed the orphan drug submissions made to CADTH’s Common Drug Review (CDR) January 2015–May 2020 to understand how the methodology of assessing cost-effectiveness of orphan drugs has guided pricing in Canada. A total of 35 orphan drug submissions were assessed by CDR in this period, none of which met the willingness-to-pay threshold of CAD$50,000 per QALY. Only one drug met the CAD$200,000 per QALY for Therapeutic Criteria Level I, and two drugs met CAD$150,000 per QALY for other Therapeutic Criteria Levels proposed by PMPRB. Price reductions of 32– 99% were recommended for treatments that were approved in order to be listed for reimbursement. This review showed that the new PMPRB regulations could be creating challenges for manufacturers of rare disease treatments to meet Canadian pricing regulations. These regulations may jeopardize the launch of new medicines and limit opportunities to add to the development of real-world evidence of orphan drugs, which can be used in reimbursement approaches such as pay-for-performance.Keywords: orphan drugs, rare diseases, CADTH, QALY, HTA

Orphan drugs have high acquisition costs and when standard health technology assessment (HTA) approaches are used to assess their cost-effectiveness, they often appear not cost-effective. The Canadian Patented Medicine Review Board (PMPRB), through new regulations, will apply HTA assessment results from the Canadian Agency for Drugs and Technologies in Health (CADTH) and Institut national d’excellence en santé et en services sociaux (INESSS) when setting the maximum price that can be charged for Category I patented medicines (treatments with an annual cost exceeding 150% of GDP per capita of Canada or with expected annual market size >$50M). Through these regulations, PMPRB has also established a willingness-to-pay threshold of CAD$200,000 or CAD$150,000 per quality adjusted life year (QALY) for medications with a prevalence of no more than 1 in 2000 across all approved indications. We reviewed the orphan drug submissions made to CADTH’s Common Drug Review (CDR) January 2015–May 2020 to understand how the methodology of assessing cost-effectiveness of orphan drugs has guided pricing in Canada. A total of 35 orphan drug submissions were assessed by CDR in this period, none of which met the willingness-to-pay threshold of CAD$50,000 per QALY. Only one drug met the CAD$200,000 per QALY for Therapeutic Criteria Level I, and two drugs met CAD$150,000 per QALY for other Therapeutic Criteria Levels proposed by PMPRB. Price reductions of 32–99% were recommended for treatments that were approved in order to be listed for reimbursement. This review showed that the new PMPRB regulations could be creating challenges for manufacturers of rare disease treatments to meet Canadian pricing regulations. These regulations may jeopardize the launch of new medicines and limit opportunities to add to the development of real-world evidence of orphan drugs, which can be used in reimbursement approaches such as pay-for-performance.

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

L’attività di ricerca durante il dottorato è stata focalizzata su una valutazione di HTA per uno nuovo farmaco per il trattamento dello scompenso cardiaco. Una prima analisi farmaco-economica era stata condotta prima dell’immissione in commercio per dimostrarne la costo-efficacia, utilizzando i dati degli studi clinici randomizzati e i tariffari nazionali ed è parte del lavoro svolto durante il primo anno di dottorato. Successivamente sono state svolte due nuove analisi, che hanno l’obiettivo di dimostrare come la tecnologia farmaceutica, una volta immessa nel mercato, sia ancora costo-efficace e quale sia il suo impatto sul budget del Servizio Sanitario Nazionale. Sono stati utilizzati in questo caso come dati di efficacia quelli di real life e per i costi i tariffari nazionali. L’analisi di impatto sul budget consente di ottenere stime sulla sostenibilità economica delle tecnologie sanitarie. L’analisi ha l’obiettivo di valutare l’impatto finanziario sul Servizio Sanitario Nazionale (SSN) italiano legato all’utilizzo di sacubitril/valsartan come terapia per lo scompenso cardiaco nei pazienti di classe NYHA II e III con frazione di eiezione ridotta (FE

Digital health and mobile medical apps (MMAs) have shown great promise in transforming health care, but their adoption in clinical care has been unsatisfactory, and regulatory guidance and coverage decisions have been lacking or incomplete. A multidimensional assessment framework for regulatory, policymaking, health technology assessment, and coverage purposes based on the MMA lifecycle is needed. A targeted review of relevant policy documents from international sources was conducted to map current MMA assessment frameworks, to formulate 10 recommendations, subsequently shared amongst an expert panel of key stakeholders. Recommendations go beyond economic dimensions such as cost and economic evaluation and also include MMA development and update, classification and evidentiary requirements, performance and maintenance monitoring, usability testing, clinical evidence requirements, safety and security, equity considerations, organizational assessment, and additional outcome domains (patient empowerment and environmental impact). The COVID-19 pandemic greatly expanded the use of MMAs, but temporary policies governing their use and oversight need consolidation through well-developed frameworks to support decision-makers, producers and introduction into clinical care processes, especially in light of the strong international, cross-border character of MMAs, the new EU medical device and health technology assessment regulations, and the Next Generation EU funding earmarked for health digitalization.

Objectives To conduct a formative evaluation of applying the VALIDATE approach in practice by (i) assessing how students appreciated the e-learning course, (ii) exploring how, for what purposes and with what outcomes the acquired VALIDATE competences subsequently were used in internships in different institutional contexts, and how this was shaped by these contexts, and (iii) what this shows on real-world use of VALIDATE. Methods Comparative discussion of experiences of applying the VALIDATE approach via a semistructured survey and oral feedback from e-course students; final reports on internships in health technology assessment (HTA) practice, followed by semistructured interviews with interns and supervisors to complement and interpret results. Results All students considered the VALIDATE approach an enlightening and important addition to current HTA knowledge, especially regarding understanding the relation between empirical analysis and normative inquiry, identifying policy relevant questions and using the method of reconstructing interpretive frames for scoping. The latter appeared intellectually challenging and requiring some prior HTA knowledge. The use the VALIDATE approach in practice shows that interns productively redefined the HTA problem, based on appreciation of different stakeholders’ definition of the issue; they experienced constraints from retrieving all relevant perspectives from existing literature as well as from institutional rules and routines. Conclusions Some challenges in applying the VALIDATE approach deserve attention for its future use: currently used research approaches often assume a problem as “given”; and the data needed on different perspectives is often not reported in scientific literature. Finally, data gathering on and evaluation of value dimensions was experienced as challenging.

Key message Obstructive sleep apnea (OSA) is a sleep disorder characterized by frequent interruption in breathing (apnoea) due to the narrowing or closure of the soft pharyngeal tissue while asleep. This is a risk factor for cardiovascular, neurological, and metabolic conditions. Current clinical practice involves treatment with continuous positive airway pressure (CPAP) during sleep. Many patients have a low tolerance for CPAP treatment, and the compliance rate can be as low as 50%. Hypoglossal nerve stimulation (HNS) is a possible alternative for patients who do not tolerate CPAP. The method, which is illustrated in this rapid HTA, keeps the airways open by stimulating the hypoglossal nerve during sleep. Effect and safety: An HTA published by EUnetHTA in June 2020 included one randomized controlled trial (n = 46) and seven uncontrolled studies. The effect of hypoglossal nerve stimulation in the treatment of obstructive sleep apnea is generally very uncertain. Several relevant studies are expected to publish results in 2022 and 2023. Severity: Severity is not calculated as this rapid HTA does not include a health economic assessment of cost-effectiveness. Costs: The equipment costs are estimated at NOK 270,000 per patient. The clinical experts estimate that the first year will be 100 relevant patients but expect the use to increase with 25-30 percent each year. In such a scenario, the total annual costs for equipment will be estimated at NOK 27 million in the first year and NOK 72 million in year five. This estimate does not include cost related to the surgical procedures. Hovedbudskap Obstruktiv søvnapne (OSA) er en søvnforstyrrelse karakterisert ved hyppige pusteforstyrrelser under søvn fordi faryngalt vev kollapser. Dette utgjør en risikofaktor for kardiovaskulære, nevrologiske og metabolske tilstander. Gjeldende klinisk praksis innebærer behandling med kontinuerlig positive luftveistrykk (CPAP) gjennom en mask under søvn. Mange pasienter har lav toleranse for behandling med CPAP, og etterlevelsesandelen kan være så lav som 50%. Hypoglossal nervestimulering (HNS) er et mulig alternativ til pasienter som ikke tolererer CPAP. Metoden, som belyses i denne forenklede metodevurderingen, holder luftveiene åpne ved å stimulere den hypoglossale nerven under søvn. Effekt og sikkerhet: En metodevurdering utgitt av EUnetHTA i juni 2020 omfattet èn randomisert kontrollert studie (n=46) og sju ukontrollerte studier. Effekten av hypoglossal nervestimulering i behandling av obstruktivt søvnapné er gjennomgående svært usikker. Det pågår flere relevante studier som forventes å publisere resultater i 2022 og 2023. Alvorlighet: Alvorlighetsgrad er ikke beregnet ettersom dette er en forenklet metodevurdering uten helseøkonomisk vurdering av kostnadseffektivitet. Kostnader: Prisen for utstyret estimeres til NOK 270 000 per pasient. Fagekspertene anslår at det første år vil være 100 aktuelle pasienter, men regner med en årlig økning på 25-30 prosent. De totale årlige kostnadene for utstyr vil i et slikt scenario estimeres til 27 MNOK første år og 72 MNOK i år fem. Denne kostnaden omfatter ikke kirurgiske kostnader som er nødvendig for å operere inn utstyret.

Three directly acting antivirals (DAAs) demonstrated substantial reduction in COVID-19 hospitalizations and deaths in clinical trials. However, these agents did not completely prevent severe illness and are associated with cases of rebound illness and viral shedding. Combination regimens can enhance antiviral potency, reduce the emergence of drug-resistant variants, and lower the dose of each component in the combination. Concurrently targeting virus entry and virus replication offers opportunities to discover synergistic drug combinations. While combination antiviral drug treatments are standard for chronic RNA virus infections, no antiviral combination therapy has been approved for SARS-CoV-2. Here, we demonstrate that combining host-targeting antivirals (HTAs) that target TMPRSS2 and hence SARS-CoV-2 entry, with the DAA molnupiravir, which targets SARS-CoV-2 replication, synergistically suppresses SARS-CoV-2 infection in Calu-3 lung epithelial cells. Strong synergy was observed when molnupiravir, an oral drug, was combined with three TMPRSS2 (HTA) oral or inhaled inhibitors: camostat, avoralstat, or nafamostat. The combination of camostat plus molnupiravir was also effective against the beta and delta variants of concern. The pyrimidine biosynthesis inhibitor brequinar combined with molnupiravir also conferred robust synergistic inhibition. These HTA+DAA combinations had similar potency to the synergistic all-DAA combination of molnupiravir plus nirmatrelvir, the protease inhibitor found in paxlovid. Pharmacodynamic modeling allowed estimates of antiviral potency at all possible concentrations of each agent within plausible therapeutic ranges, suggesting possible in vivo efficacy. The triple combination of camostat, brequinar, and molnupiravir further increased antiviral potency. These findings support the development of HTA+DAA combinations for pandemic response and preparedness. IMPORTANCE Imagine a future viral pandemic where if you test positive for the new virus, you can quickly take some medicines at home for a few days so that you do not get too sick. To date, only single drugs have been approved for outpatient use against SARS-CoV-2, and we are learning that these have some limitations and may succumb to drug resistance. Here, we show that combinations of two oral drugs are better than the single ones in blocking SARS-CoV-2, and we use mathematical modeling to show that these drug combinations are likely to work in people. We also show that a combination of three oral drugs works even better at eradicating the virus. Our findings therefore bode well for the development of oral drug cocktails for at home use at the first sign of an infection by a coronavirus or other emerging viral pathogens.

Område for helsetjenester, Folkehelseinstituttet, fikk i oppdrag av Bestillerforum for nye metoder å lage en forenklet metodevurdering om kombinasjon av abirateron og docetaxel i behandlingen av nydiagnostisert prostatakreft med spredning. Etter å ha gjennomført et systematisk litteratursøk viste det seg at bare fantes én studie som tilfredsstilte inklusjonskriteriene, og vi har derfor valg å presentere resultatene som en svært forenklet formidlingssak. Notatet er relevant for norske klinikere og beslutningstakere.

Hintergrund: Dieser Health Technology Assessment (HTA)-Bericht untersucht die Beschäftigungstherapie für Patienten mit kognitiven Beeinträchtigungen aufgrund von Schädigungen des zentralen Nervensystems im Erwachsenenalter. Schädigungen des zentralen Nervensystems können im Erwachsenenalter zum Beispiel durch Schlaganfall, Trauma, Tumoren oder chronische Krankheiten entstehen. Nach Schädigung des zentralen Nervensystems treten neben physischen Einschränkungen auch kognitive Einschränkungen auf. Am häufigsten wird eine Ergotherapie bei neurologischen Diagnosen verordnet, darunter auch Schlaganfall und Schädel-Hirn-Trauma. Die Anzahl der Schlaganfalldiagnosen in deutschen Krankenhäusern betrug 2018 351 Fälle pro 100 000 Einwohner, die Anzahl der Fälle von Schädel-Hirn-Trauma betrug im selben Jahr 343 Fälle pro 100 000. Die Ergotherapie stellt eine Intervention zur Verbesserung und Stützung von Alltagsfunktionen und Handlungsfähigkeit mit dem Ziel der Verbesserung von Teilhabe und Lebensqualität im individuellen Alltag und Lebenskontext dar. Sie setzt gezielt individuell sinnvolle Tätigkeiten als Behandlungsmaßnahme ein, um Einschränkungen zu reduzieren und die selbstständige Handlungsfähigkeit zu verbessern. Daneben umfasst die Ergotherapie das Training spezifischer Funktionen, kompensatorische Maßnahmen sowie Beratung zur Anpassung der Lebensumgebung. Bei Schädigungen des zentralen Nervensystems sind die vorrangig verordneten Heilmittel die sensomotorisch-perzeptive Behandlung, die motorisch-funktionelle Behandlung sowie die neuropsychologisch orientierte Behandlung beziehungsweise das Hirnleistungstraining. Der vorliegende HTA-Bericht untersucht die medizinische Wirksamkeit, Kosteneffektivität sowie patientenbezogene, soziale und ethische Aspekte der Ergotherapie bei Personen mit kognitiven Störungen. Personen mit mittlerer oder schwerer Demenz sind aus der Betrachtung ausgeschlossen. Fragestellungen: Im Rahmen dieses HTA-Berichts werden die folgenden vier Fragestellungen bearbeitet: 1. Wie effektiv sind ergotherapeutische Interventionen bei Personen mit kognitiven Einschränkungen hinsichtlich der Verbesserung oder des Erhalts der kognitiven Fähigkeiten, einer Verbesserung der Selbstständigkeit, Verbesserung der Selbstbestimmung sowie der gesundheitsbezogenen Lebensqualität bei stationärer Versorgung in sozialen Einrichtungen beziehungsweise in der ambulanten Versorgung? 2. Verändert sich durch den Einsatz von Ergotherapie der stationäre oder ambulante Pflege- und Betreuungsaufwand für Personen mit kognitiven Einschränkungen? Sind ergotherapeutische Interventionen im Rahmen der stationären oder ambulanten Versorgung von Personen mit kognitiven Einschränkungen kosteneffektiv? 3. Welche spezifischen Patienten- und sozialen Aspekte sind beim Einsatz von Ergotherapie im Rahmen der Betreuung von Personen mit kognitiven Einschränkungen zu berücksichtigen? 4. Welche ethischen Aspekte auf individueller, gesellschaftlicher und berufsethischer Ebene sind bei der Anwendung der Ergotherapie bei Patienten und Patientinnen mit kognitiven Störungen zu berücksichtigen? Methodik: Für diesen HTA-Bericht wurden systematische Overviews - das sind systematische Übersichtsarbeiten von systematischen Übersichtsarbeiten - zur medizinischen Wirksamkeit, zu Kosten und zur Kosteneffektivität, zu Patienten- und sozialen Aspekten sowie zu ethischen Aspekten der Ergotherapie bei Personen mit kognitiven Defiziten nach Schädigung des zentralen Nervensystems im Erwachsenenalter im Vergleich zu keiner Ergotherapie durchgeführt. Zusätzlich wurden ergänzend in einem explorativen Überblick die Effekte verschiedener ergotherapeutischer Maßnahmen mit und ohne kognitive Komponenten im Vergleich dargestellt. Datengrundlage waren ausschließlich die eingeschlossenen systematischen Übersichtsarbeiten, auf Primärstudien wurde nicht zurückgegriffen. Ergebnisse: Zur Bewertung der medizinischen Wirksamkeit wurden in den vorliegenden HTA-Bericht insgesamt neun systematische Übersichtsarbeiten zu insgesamt 45 randomisierten Studien eingeschlossen. Zur Bewertung von Kosten und Kosteneffektivität konnte keine systematische Übersichtsarbeit identifiziert werden. Zur Bewertung von Patienten- und sozialen Aspekten wurden fünf systematische Übersichtsarbeiten zu insgesamt 104 Studien, zur ethischen Bewertung neun Dokumente eingeschlossen. Dieses systematische Overview fasst die Evidenz zur medizinischen Wirksamkeit der Ergotherapie bei kognitiven Einschränkungen aus publizierten systematischen Übersichtsarbeiten indikationsübergreifend zusammen. Die vorliegende Evidenz beruht auf klinischen Studien mit Personen nach Schlaganfall, mit erworbenen Hirnverletzungen, mit Parkinson-Krankheit und mit Multipler Sklerose. Primär wird in diesem Overview die medizinische Wirksamkeit der Ergotherapie im Unterschied zu keiner Ergotherapie verglichen. Für diesen Vergleich wurden fünf systematische Reviews zu insgesamt 20 RCT mit 1316 Personen eingeschlossen. Kleine statistisch signifikante positive Effekte wurden für die Zielgrößen „generelle kognitive Funktion“, Standardised Mean Difference (SMD) Cohen’s d = 0,16 (95 %-Konfidenzintervall [KI]: 0,03; 0,29) und die „Aktivitäten des täglichen Lebens“, SMD Cohen‘s d = 0,19 (95 %-KI: 0,01; 0,37) berichtet, sowie ein nicht-quantifizierter positiver Effekt auf die Zielgrößen gesundheitsbezogene Lebensqualität und Verhaltenskontrolle. Für einzelne Komponenten der Kognition (Konzeptbildung, Planung, Flexibilität) und Zielgrößen der Wahrnehmung ließ sich kein Effekt belegen. Die Vertrauenswürdigkeit der Evidenz für alle Zielgrößen ist gering. Dies beruht auf einem hohen Verzerrungsrisiko oder einem Fehlen der Information zum Verzerrungsrisiko. Zudem gab es Mängel in den angewendeten statistischen Verfahren der Metaanalysen, die zu einer möglichen Überschätzung der Präzision führen. In den ergänzenden Darstellungen zu den Vergleichen Ergotherapie mit kognitiver Komponente gegenüber Ergotherapie ohne kognitiver Komponente (sieben systematische Übersichtsarbeiten zu insgesamt sieben randomisierten Studien mit 407 Personen) beziehungsweise unterschiedlicher Formen der Ergotherapie mit kognitiver Komponente (fünf systematische Übersichtsarbeiten mit 20 RCT mit insgesamt 853 Personen) ließen sich anhand der verfügbaren Evidenz keine positiven Effekte nachweisen. Die Vertrauenswürdigkeit der Evidenz wurde nicht bewertet. Es wurden keine geeigneten systematischen Übersichtsarbeiten zur Bewertung der Kosten oder Kosteneffektivität zur vorliegenden Fragestellung identifiziert. Somit konnten diese Zielgrößen nicht bewertet werden. Zur Bewertung von Patienten- und sozialen Aspekten wurden fünf systematische Übersichtsarbeiten mit Personen mit Schlaganfall oder Schädel-Hirn-Trauma ohne Spezifizierung hinsichtlich kognitiver Defizite oder Studien mit deren Angehörigen eingeschlossen. Patienten und Patientinnen nach Schlaganfall oder Schädel-Hirn-Trauma sowie betreuende Angehörigen scheinen während der Rehabilitation und nach der Entlassung bestimmte Phasen von Verlust, Diskontinuität, Neubewertung und Neuanpassung zu durchlaufen. Ein entscheidender Einschnitt stellt die Entlassung nach Hause dar. Die Rückgewinnung einer aktiven, selbstbestimmenden Rolle ist ein Prozess, der den Therapeuten und Therapeutinnen abverlangt, das richtige Maß an Unterstützung von Patienten und Patientinnen sowie Angehörigen zu finden. Patientinnen und Patienten in den Studien wünschten sich individuelle und ausreichende Informationen zur Ursache der Krankheit, dem individuellen Fortschritt, der Bewertung des Behandlungsplans und Entscheidungen über Entlassung und Nachbehandlung. Sie wünschten sich, dass ihren psychosozialen Bedürfnissen mehr Aufmerksamkeit gewidmet würde. Angehörige in den Studien wollten als Stakeholder im Genesungsprozess des Patienten verstanden und einbezogen werden und auch die dazu benötigten Informationen vom Fachpersonal erhalten. Aus den Berufskodizes ergotherapeutischer Berufsverbände ließen sich ethische Prinzipien und Problemlösungsmodelle zu ethischen Konflikten entnehmen, die sich an den vier Prinzipien biomedizinischer Ethik orientieren; dies sind Respekt der Autonomie, Nicht-Schaden, Fürsorge und Gerechtigkeit. Diese Prinzipien wurden teils um weitere Prinzipien wie Nutzen, Integrität sowie Kollegialität und Professionalität ergänzt. Zu spezifischen ethischen Aspekten der Ergotherapie bei kognitiven Defiziten wurden drei systematische Übersichtsarbeiten identifiziert, denen 16 ethische Aspekte entnommen werden konnten. Zentrales Thema der ethischen Analyse stellt die Einschränkung der Autonomie von Patienten und Patientinnen durch die Folgen der Krankheit sowie daraus resultierende Spannungen mit den und für die Therapeutinnen und Therapeuten. Speziell kognitive Einschränkungen und eine eingeschränkte Wahrnehmung der eigenen Defizite können auch die Entscheidungsfähigkeit betreffen. Dies stellt besonders für Fachpersonal aus der Ergotherapie eine Herausforderung dar, weil die klientenzentrierte Zielsetzung ein zentraler professioneller Standard des beruflichen Selbstverständnisses der Ergotherapie ist. Schlussfolgerungen und Empfehlungen: Auf Grundlage dieses systematische Overviews kann nicht sicher belegt werden, dass die Ergotherapie bei kognitiven Einschränkungen für erwachsene Patienten und Patientinnen mit Verletzungen des zentralen Nervensystems eine wirksame Therapie im Vergleich zu keiner Ergotherapie darstellt. Die vorliegende Evidenz zeigt einen kleinen positiven Effekt auf die kognitive Funktionsfähigkeit, die Funktionsfähigkeit bei Aktivitäten des täglichen Lebens und auf die gesundheitsbezogene Lebensqualität. Die Vertrauenswürdigkeit der Evidenz ist jedoch, soweit durch die Overview-Methodik nachvollziehbar, gering. Andererseits kann die Wirksamkeit der Beschäftigungstherapie auch nicht ausgeschlossen werden, da die meisten der eingeschlossenen Studien eine relativ kleine Stichprobengröße und eine begrenzte „power“ haben, so dass kleinere Effekte möglicherweise nicht nachgewiesen werden können. Zudem lässt die klinische Heterogenität von Studienpopulationen, Interventionen und Vergleichsinterventionen eine hohe Varianz der Effekte erwarten. Da keine der eingeschlossenen Studien in den Gesundheitssystemen des deutschsprachigen Raums durchgeführt wurden, erscheint zudem die Übertragbarkeit fraglich. Basierend auf diesen Ergebnissen empfehlen wir die Fortführung der Forschung zur Ergotherapie in randomisierten klinischen Studien mit patientenrelevanten Endpunkten und mit ausreichender Fallzahl. Dabei sollte die Form der untersuchten Ergotherapie genau definiert und beschrieben werden und es sollte auf die Vergleichbarkeit von Begleittherapien in Interventions- und Kontrollgruppe geachtet werden. Wir empfehlen zudem die Durchführung und Registrierung gut geplanter Beobachtungsstudien in der Versorgungsroutine. Für solche Studien ist bei der Studienplanung eine entsprechende Erhebung von potenziellen Confoundern zu berücksichtigen, für die in der Analyse adjustiert werden kann. Bei zukünftigen Studien sollten auch gesundheitsökonomische Komponenten zum Ressourcenverbrauch und zu Kosten integriert werden. In qualitativen Studien zu Patienten- und sozialen Aspekten aus dem nordeuropäischen und angelsächsischen Raum haben Patienten und Patientinnen sowie Angehörige die Phasen, die nach Erkrankung durchlebt werden, geschildert und Wünsche nach besserer Kommunikation und stärker klientenzentrierten Rehabilitationsmaßnahmen geäußert, von denen angenommen werden könnte, dass sie auch im deutschsprachigen Raum geteilt werden. Die geäußerten Wünsche stimmen überdies mit dem Verständnis von klientenzentrierter Behandlung in der Ergotherapie überein. Deshalb sollte neben einer Verifizierung der Bedürfnisse von Patienten, Patientinnen und Angehörigen während und nach der Rehabilitation durch entsprechende Befragungen im deutschsprachigen Raum, auch Untersuchungen durchgeführt werden, was die Umsetzung einer klientenzentrierten Therapie bei Patienten und Patientinnen mit kognitiven Defiziten nach neurologischen Erkrankungen des zentralen Nervensystems behindert und welche Maßnahmen sie fördern könnten. Im vorliegenden Bericht konnten zwar einige Lösungsmodelle für ethische Konflikte und auch 16 ethische Aspekte identifiziert werden. Aber es lagen nur wenige systematische Übersichtsarbeiten zu ethischen Aspekten aus Perspektive von Patientinnen und Patienten, Angehörigen und dem Fachpersonal vor, die auf empirischen Primärstudien basierten. Daher sollte eine systematische Übersichtsarbeit zu Primärstudien zu ethischen Aspekten in der ergotherapeutischen Therapie bei Personen mit kognitiven Defiziten, deren Angehörigen und dem Fachpersonal durchgeführt werden. Gegebenenfalls könnte man hier auch Studien einschließen, die sich allgemein mit der Rehabilitation kognitiver Defizite bei den eingeschlossenen Indikationen befassen, weil anzunehmen ist, dass viele ethische Aspekte auf die Ergotherapie übertragbar sind.

Innledning I 2020 forekom preeklampsi (svangerskapsforgiftning) i 2,6 % av svangerskapene i Norge. Preeklampsi medfører økt risiko for tidlig fødsel og for sykelighet og død hos mor og barn. I dag vurderes risiko for preeklampsi på grunnlag av ulike karakteristika ved den gravide, samt historikk fra eventuelle tidligere svangerskap. Den prediktive nøyaktigheten av dagens vurdering er begrenset og gir ikke optimalt grunnlag for å identifisere kvinner med høy risiko for preeklampsi senere i svangerskapet. Screening med bedret prediksjon av risiko for preeklampsi gjennomført i uke 11-14 kan gi mulighet for mer hensiktsmessig forebygging av tidlig innsettende preeklampsi som må forløses før uke 37 av svangerskapet (preterm preeklampsi). Forutsetninger for effektiv forebygging er oppstart med lavdose acetylsalisylsyre (ASA) før uke 16 av svangerskapet. Dette er i henhold til den reviderte Veilederen i fødselshjelp (1) som anbefaler inntak av lavdose ASA fra uke 12 uke og frem til fødsel (dersom 75 mg/dag) eller til uke 36 (dersom 150 mg/dag) hos kvinner med høy risiko for preeklampsi. Oppstart etter uke 16 er ikke anbefalt fordi dette har vist ikke å ha forebyggende effekt, og fordi alle medikamenter, inkludert ASA, medfører mulig risiko for bivirkninger. Metode Vi utførte en systematisk kunnskapsoppsummering for • å undersøke prediktiv nøyaktighet av screening med den foreslåtte algoritmen som grunnlag for å beregne individuell risiko for preeklampsi • å vurdere den kliniske effekten av forebyggende behandling med ASA på forekomsten av preeklampsi for gravide kvinner identifisert med høy risiko for preeklampsi basert på den foreslåtte algoritmen. Vi vurderte også økonomiske og organisatoriske aspekter av å innføre det foreslåtte tiltaket i spesialisthelsetjenesten. Vi brukte PICOS-rammeverk (populasjon, intervensjon, sammenligning, utfall, studiedesign) for å identifisere studier som kunne være relevante for metodevurderingen, ett rammeverk for studier av prediktiv nøyaktighet og et annet for effekt av forebygging av preeklampsi med ASA. Vi søkte først etter systematiske oversikter og så etter primærstudier som kunne dekke problemstillingene. Etter inklusjon vurderte vi metodisk kvalitet og risiko for systematiske skjevheter i primærstudiene. Utfallsmål for prediktiv nøyaktighet var algoritmens evne til å predikere høy risiko for preeklampsi med forløsning

Introduction: Hereditary angioedema (HAE) is a rare genetic disease that impairs quality of life and could be life-threatening. The aim of this study was to apply a multicriteria decision analysis to assess the value of three long-term prophylactic (LIP) therapies for HAE in Spain. Methods: A multidisciplinary committee of 10 experts assessed the value of lanadelumab (subcutaneous use), C1-inhibitor (C1-INH; intravenous), and danazol (orally), using placebo as comparator. We followed the EVIDEM methodology that considers a set of 13 quantitative criteria. The overall estimated value of each intervention was obtained combining the weighting of each criterion with the scoring of each intervention in each criterion. We used two alternative weighting methods: hierarchical point allocation (HPA) and direct rating scale (DRS). A reevaluation of weightings and scores was performed. Results: Lanadelumab obtained higher mean scores than C1-INH and danazol in all criteria, except for the cost of the intervention and clinical practice guidelines. Under the HPA method, the estimated values were 0.51 (95% confidence interval [CI]: 0.44-0.58) for lanadelumab, 0.47 (95%CI: 0.41-0.53) for C1-INH, and 0.31 (95%CI: 0.240.39) for danazol. Similar results were obtained with the DRS method: 0.51 (95%CI: 0.42-0.60), 0.47 (95%CI: 0.40-0.54), and 0.27 (95%CI: 0.18-0.37), respectively. The comparative cost of the intervention was the only criterion that contributed negatively to the values of lanadelumab and C1-INH. For danazol, four criteria contributed negatively, mainly comparative safety. Conclusion: Lanadelumab was assessed as a high-value intervention, better than C1-INH and substantially better than danazol for LTP treatment of HAE.

Hovedbudskap Postoperative sårinfeksjoner fører til økt sykelighet og dødelighet. Ventilasjonssystem i operasjonsstuer er én av mange faktorer som kan påvirke infeksjonsforekomst. Hvilket ventilasjonssystem som er best på å forebygge infeksjoner i operasjonssår har vært diskutert i mange år. Vi har utarbeidet en forenklet metodevurdering for å undersøke effekten av laminær ventilasjon (LAF) på infeksjonsforekomst. Vi inkluderte til sammen 22 observasjonsstudier. Alle studiene hadde moderat eller alvorlig risiko for systematiske skjevheter. Det var også upresise effektestimater og til dels manglende samsvar på tvers av de inkluderte studiene. I sammenligningen av LAF med konvensjonell ventilasjon, fant vi at: • Det var ingen forskjell i forekomst av alvorlige infeksjoner ved alle typer kirurgi og ved ortopedisk protesekirurgi (GRADE: lav tillit) • Det var ingen forskjell i forekomst av alle infeksjoner ved alle typer kirurgi og ved ortopedisk protesekirurgi (GRADE: svært lav tillit) • Vi fant ingen studier som ga tilstrekkelig informasjon om effekten på dødelighet De samlede merkostnadene for én operasjonsstue ved LAF i nybygg anslås til å være i størrelsesorden NOK 41 000 per år ved avskrivning over en 30-årsperiode eller 77 000 per år ved avskrivning over en 10-årsperiode. Det er usikkerhet knyttet til anslaget. Key messages Surgical site infections are associated with increased morbidity and mortality. The role of the operating theatre ventilation system in preventing surgical site infections has been discussed for decades. We conducted a health technology assessment to evaluate the efficacy of laminar airflow (LAF) in reducing surgical site infections. We included 22 observational studies. All studies were at moderate or serious risk of bias. The effect estimates were imprecise, and there were somewhat lack of consistency of the results across the included studies. For the comparison of LAF with conventional ventilation, we found that: • There were no difference in rates of serious surgical site infections (SSI) in all types of surgery and in joint prosthesis surgery (GRADE: low certainty) • There were no difference in rates of all SSIs in all types of surgery and in joint prosthesis surgery (GRADE: very low certainty) • We found no studies that provide sufficient information on the effect on mortality • We estimated the additional annual costs for one opeating theathre with LAF to be NOK 41 000 discounted over a 30-day period and 77 000 discounted over a 10-year period. The estimate is associated with uncertainty.

BackgroundHealth Technology Assessment (HTA) is a multidisciplinary process that synthesizes, with a systematic, transparent, impartial and robust methodological approach, the main information on the medical, economic, ethical and social implications of the use and dissemination of a health technology. Its aim is to support decision-makers in identifying safe, effective, patient-centered and best-value health policies, in order to promote an equitable, efficient, and high-quality health system. Given the continued application of innovative technologies into clinical practice, healthcare professionals need to be able to adequately evaluate these technologies using evidence-based approaches such as HTA. Therefore, the implementation of training in HTA is crucial. The aim of this study was to investigate existing HTA training initiatives for healthcare professionals provided by international HTA agencies and organizations around the world.MethodsFrom March to November 2020, the websites of HTA agencies and organizations belonging to the European network for HTA (EUnetHTA) and to the International Network of Agencies for HTA (INAHTA), and the website of the HTA International (HTAi), were explored for identifying the HTA training initiatives directed to healthcare professionals. In addition, we screened the training initiatives proposed at European level by EUnetHTA as part of its Joint Actions and conducted in collaboration with its public-private partners. Specific keywords were searched in English and adapted to French, Portuguese, Spanish, Italian and German. Data extraction of the retrieved training initiatives was conducted from November 2020 to February 2021 and considered the following information: agency, country, website, coordinator, type of initiative, target, topic, main contents, and language.ResultsOut of 124 agencies/organizations/EUnetHTA public-private partners screened, only 21 provided training initiatives for healthcare professionals. A total of 55 training initiatives were analyzed, 85.5% of which were delivered at the European level and 14.5% at the international level. The countries with a greater number of courses were: Austria, Argentina, Spain, Portugal, and the United Kingdom. Twenty-one training initiatives focused on HTA application and methodology while 34 on specific HTA domains, particularly on the economic one. The technologies covered were mainly drugs.ConclusionsOur study revealed a limited number of HTA training programs targeting healthcare professionals. HTA supports the decision-making processes concerning the use and application of health technologies with scientific evidence. Indeed, training of healthcare professionals in this field should be a key driver in implementing evidence-based healthcare choices and through rigorous methodological approaches such as HTA, in order to ensure proper health governance and value-based application of technological innovations in clinical practice. Therefore, capacity building of healthcare professionals in this area should be enhanced by using appropriate and effective training initiatives and educational strategies.

Adequate methods are urgently needed to guarantee the good practice of health technology assessment (HTA) for technologies with novel properties. The aim of the study was to construct a conceptual framework to help understand the innovation of HTA methods (IHTAM). The construction of the IHTAM framework was based on two scoping reviews, one on the current practice of innovating methods, that is existing HTA frameworks, and one on theoretical foundations for innovating methods outside the HTA discipline. Both aimed to identify and synthesize concepts of innovation (i.e., innovation processes and roles of stakeholders in innovation). Using these concepts, the framework was developed in iterative brainstorming sessions and subsequent discussions with representatives from various stakeholder groups. The framework was constructed based on twenty documents on innovating HTA frameworks and fourteen guidelines from three scientific disciplines. It includes a generic innovation process consisting of three phases (“Identification,” “Development,” and “Implementation”) and nine subphases. In the framework, three roles that HTA stakeholders can play in innovation (“Developers,” “Practitioners,” and “Beneficiaries”) are defined, and a process on how the stakeholders innovate HTA methods is included. The IHTAM framework visualizes systematically which elements and stakeholders are important to the development and implementation of novel HTA methods. The framework could be used by all stakeholders involved in HTA innovation to learn how to engage dynamically and collaborate effectively throughout the innovation process. HTA stakeholders in practice have welcomed the framework, though additional testing of its applicability and acceptance is essential.

Ο σακχαρώδης διαβήτης είναι μια ετερογενής μεταβολική ασθένεια, που χαρακτηρίζεται από πολυάριθμους τύπους, καθένας από τους οποίους έχει ξεχωριστή παθοφυσιολογική βάση, αλλά μερικές φορές εμφανίζεται ως κατάσταση με επικαλυπτόμενα και δύσκολα διαφοροποιήσιμα χαρακτηριστικά. Είναι ζωτικής σημασίας για την προστασία των διαβητικών ατόμων από την έκθεση σε πιθανές επιζήμιες συνέπειες ακατάλληλων, ανεπαρκών ή περιττών φαρμακολογικών θεραπειών, οι οποίες συχνά καθυστερούν την επιδιωκόμενη πρόγνωση και παρατείνουν τη διάρκεια της υπεργλυκαιμικής έκθεσης. Η μακροχρόνια υπεργλυκαιμία, με τη σειρά της, έχει συχνά συνδεθεί με αυξημένο κίνδυνο μικροαγγειακών και μακροαγγειακών επιπλοκών του διαβήτη, οι οποίες υποβαθμίζουν την ποιότητα ζωής και συμβάλλουν κυρίως στη νοσηρότητα και τη θνησιμότητα που σχετίζεται με τον διαβήτη. Ένας τρόπος θεραπείας του σακχαρώδους διαβήτη τύπου 2 αποτελεί η θεραπεία με το ενέσιμο σκεύασμα Suliqua. Ένα σημαντικό ζήτημα που ανακύπτει όσον αφορά την κυκλοφορία του σκευάσματος αποτελεί η συμπερίληψή του στον θετικό κατάλογο αποζημιούμενων φαρμακευτικών προϊόντων. Από έρευνες που έχουν γίνει έχουν διαφανεί ότι η θεραπευτική αποτελεσματικότητα του Xultophy, κύριου ανταγωνιστή του Suliqua στην γραμμή θεραπείας όπου τα δύο αυτά φάρμακα έχουν ενταχθεί, είναι μεγαλύτερη από αυτή του Suliqua όσον αφορά τον έλεγχο της γλυκόζης και τη διατήρηση ενός υγιούς σωματικού βάρους και την επιρροή του στα καρδιαγγειακά αποτελέσματα σε άτομα με προϋπάρχουσα καρδιαγγειακή νόσο. Ωστόσο, με βάση στοιχεία που συγκεντρώθηκαν στην Ελλάδα, έχει γίνει σύσταση για την ενσωμάτωσή του Suliqua στα κατάλληλα στάδια του θεραπευτικού σχήματος για τον διαβήτη τύπου 2. Εφόσον βέβαια έρευνες δείχνουν πως το Suliqua υπερτερεί της βασικής ινσουλίνης glargine στα παραπάνω, έχοντας συγκρίσιμη ασφάλεια στη χρήση, και καλύτερη συμμόρφωση σε σύγκριση με τη θεραπεία με τα μεμονωμένα συστατικά του συνδυαστικού σχήματος, υπάρχουν ασθενείς οι οποίοι θα επωφελούνταν από τη χρήση του σκευάσματος εφόσον τηρηθούν οι προϋποθέσεις ώστε να αποζημιωθεί., Diabetes mellitus is a metabolic illness with several subtypes, each having its own pathophysiological foundation, but sometimes overlapping and difficult to distinguish characteristics. Each kind of diabetes is treated and managed differently, although the ailment itself is identical. All of this emphasizes the need of accurately diagnosing each form of diabetes and understanding their pathophysiology. Inappropriate, insufficient, or unneeded pharmacological therapies can delay the targeted prognosis and extend the length of hyperglycemic exposure. A proper and quick molecular diagnostic may assist analyze the risk of diabetes, anticipate the illness, and early discover persons at risk. family members' disorder Prognostic molecular/genetic testing and preventative treatment may help. Intensive nutrition modifications, physical activity, avoiding the sedentary lifestyle, and weight management are paramount to the prevention and management of diabetes. Suliqua injections constitutes a therapy for type 2 diabetes. Inclusion on the list of positive compensations is a marketing problem other drastic substances like Xultophy is more effective than Suliqua in controlling glucose and maintaining healthy weight, according to research. Suliqua is inferior than Xultophy for pre-existing cardiovascular disease patients. Cardiovascular safety tests on both products' separate components show this (GLP1 agonists). According the data gathered from the studies of the individual constituents of the formulation, it is proposed that Suliqua should be included into the proper phases of type 2 diabetes therapy. Although it falls behind comparable medications in glycemic management, weight change, and cardiovascular impact, it could still be of use as an intermediate treatment between basic insulin and combinations of insulin/GLP1 agonists, for patients that do not have elevated cardiovascular risk, with the prerequisite of its price be adjusted accordingly in order for it to be reimbursed.

Los precios de los fármacos oncológicos están creciendo de manera muy pronunciada y junto a un aumento considerable de la incidencia de esta patología, hacen que sea necesario abordar el tema de la asequibilidad, equidad y calidad del cuidado de la salud en cáncer si no queremos que los diferentes sistemas nacionales de salud entren en bancarrota. Se han generado muchas iniciativas cuyo objetivo es evaluar el beneficio clínico de las intervenciones y así, se financien aquellas intervenciones que aporten un mayor valor tanto para los pacientes oncológicos como para la sociedad en general. Esta tesis realiza un análisis de las diferentes herramientas e iniciativas puestas en marcha por los sistemas nacionales de salud y por las organizaciones internacionales oncológicas (ESMO, ASCO, NCCN, ICER, Drug Abacus), para ver si son concordantes con sus resultados y estimaciones. Evidenciándose que, utilizadas a nivel de los fármacos para una misma indicación terapéutica, sólo son coherentes a la hora de discernir las opciones terapéuticas de “escaso valor”, no siendo concluyentes a la hora de determinar las que aportan un “mayor valor”. Para la inclusión de las terapias oncológicas en los petitorios hospitalarios, la evaluación que ofrecen estas herramientas no se correlaciona con la decisión de la comisión hospitalaria, con una mayoría de fármacos aprobados con una valoración de beneficio clínico no significativamente relevante. Aplicadas a nivel nacional, los fármacos considerados de “alto valor” presentan una media de precio similar a los de “bajo valor”, constatándose que el beneficio clínico no va asociado al precio de las terapias. Tampoco hay correlación entre las evaluaciones que arrojan estas herramientas y las aprobaciones por las agencias reguladoras (EMA y FDA), con sólo un tercio de los fármacos aprobados cumpliendo los umbrales de beneficio clínico significativo; Incrementándose escasamente hasta la mitad de ellos, en el periodo post-comercialización. Por otro lado, los MCDAs presentan mayor consistencia en sus resultados, pero al compararlos con los que ofrecen el resto de las herramientas como la de ESMO y ASCO, aparecen divergencias en sus valoraciones. Evidenciándose la importancia de considerar todos los aspectos “críticos” de una intervención oncológica. Actualmente no hay una uniformidad en la valoración de las terapias oncológicas que nos permita discernir con claridad las que aportan un mayor de las que no lo aportan, del mismo modo, la industria farmacéutica no está ofreciendo precios de fármacos oncológicos en línea ni con el beneficio clínico que aportan ni con la renta de cada uno de los países, dificultando el objetivo de conseguir un cuidado de salud oncológico sostenible, asequible y de calidad. Cancer drugs prices are growing very sharply and together with a considerable increase in the incidence of this pathology, make it necessary to address the issue of affordability, equity and quality of health care in cancer if we do not want the different national health systems to go bankrupt. Many initiatives have been generated whose objective is to evaluate the clinical benefit of the interventions and thus, those interventions that provide greater value for both cancer patients and society in general are financed. This thesis makes an analysis of the different tools and initiatives implemented by national health systems and international oncological organizations (ESMO, ASCO, NCCN, ICER, Drug Abacus), to see if they are consistent with their results and estimates. Evidencing that, used at the level of drugs for the same therapeutic indication, they are only coherent when it comes to discerning therapeutic options of "low value", not being conclusive when determining those that provide a "greater value". For the inclusion of oncological therapies in hospital requests, the evaluation offered by these tools does not correlate with the decision of the hospital commission, with the majority of approved drugs with a clinical benefit assessment not significantly relevant. Applied at the national level, the drugs considered of "high value" have an average price similar to those of "low value", finding that the clinical benefit is not associated with the price of the therapies. There is also no correlation between the evaluations of these tools and the approvals by regulatory agencies (EMA and FDA), with only one-third of the drugs approved meeting the thresholds of significant clinical benefit; Increasing scarcely to half of them, in the post-marketing period. On the other hand, the MCDAs present greater consistency in their results, but when compared with those offered by the rest of the tools such as ESMO and ASCO, divergences appear in their valuations. Evidencing the importance of considering all the "critical" aspects of an oncological intervention. Currently there is no uniformity in the assessment of oncological therapies that allows us to clearly discern those that provide a greater than those that do not, in the same way, the pharmaceutical industry is not offering prices of oncological drugs online or with the clinical benefit they provide or with the income of each of the countries, hindering the goal of achieving sustainable, affordable and quality cancer health care