建立一個評估創新醫療科技是否具價值的機制，並將評估結果作為公共政策制定或管理的依據，牽涉的範圍包括產業、科技、醫學、管理、經濟、民眾等面向，影響的層面不僅只政府及人民的需求，還可能涉及產業界龐大的商業利益與競爭壓力，甚至影響未來的科技進展走向，不同面向之利害關係人及各參與群體的立場或理念往往不同，甚至敏感對立，各種可控制及不可控制的因果關聯也極為複雜。除相關的利害關係人群體間因立場不一致，可能產生衝突而影響政策之可行性外，還面臨各方對醫療科技評估角色、相關制度規劃及執行模式等制度建立之要素是否有共識、研究能力及科學基礎是否足夠、基礎環境是否已完備等，都是制度能否建立及有效運作之影響變因。 本研究針對我國建立醫療科技評估之政策可行性，及連帶牽動之制度架構規劃與執行運作設計等面向之相關影響變數，進行不同利害關係人群體間之意見分析，以深入訪談政府單位、學者專家及產業界代表的方式，探討我國發展HTA制度之最主要的爭議點，並參酌國際經驗，提出我國如何平順進行醫療科技評估之建議。 自訪談中發現台灣發展HTA最可能面對的問題為產業界對此政策的疑慮和反彈壓力；各利害團體間對HTA角色、定位、評估方法、判斷標準及研究報告如何使用之認知與共識；制度面的完整規劃及運作；HTA對中小型企業可能造成的衝擊；本土資料缺乏、人才不足、及使用者對HTA報告沒有信心等。 因此本研究將依據研究發現與討論，嘗試自我國建立HTA之政策可行性、發展HTA之法規環境、HTA執行模式及相關運作規劃等面向，提出研究結論與可行建議： 研究結論 壹、針對我國建立HTA之政策可行性的探討： 由國際各區域的HTA發展情形可知HTA已為國際趨勢，雖然產業界與政府及學者專家對我國是否有必要發展HTA機制有二極的看法，本研究經研討後認為政府有義務介入新醫療科技的發展和使用，以確保民眾獲得及使用醫療資源的可近性與可靠性，再加上HTA方法學可協助提供充分且可靠的資訊，協助並增進決策制定的品質，因此國內有建立HTA機制的必要性與需要性，目前亦為國內開始推動HTA的適合時機。 貳、針對我國發展HTA之法規環境及HTA執行模式之探討： 推動HTA機制須否設立法源及明確的法規，本研究經研討後認為初始的推動過程中，以行政命令的方式推動會較有效率，但當最後社會共識形成，國內環境成熟後，建立法源依據對推動及落實仍有其需要性，因為包括相關研究如何公開及如何使用，都會涉及到權利義務，一旦研究內容有所爭議，也才較具裁量的空間及效力。至於立法的方式，單獨立法或初期附屬在一個法之下，或初期以軟性方式描述，隨著國內的HTA報告之參考性逐漸被認可及能產生效應，再階段性演進為硬性規範，都是可行的方式。 而在執行模式的探討上，由研究結果可知，科學、透明、公正，具有公信力，是各界對HTA報告之最重要的要求，至於執行單位，則不限政府單位設立的財團法人、學術界、社團學會、研究中心或產業界等都可以執行。至於HTA機制與目前決策委員會間角色功能的探討，因為科學能提供的是有限證據，仍需要各領域專家就其經驗提供實務意見，政策單位再考量其特定的政策或政治目的，將科學證據、實務經驗與政治考量結合，進行最後的決策。觀諸國際經驗，大多數以國家力量執行HTA的國家，雖然都已設立具法律依據、獨立的科學專責機構執行HTA的評估或研究，但是中央政策單位仍會組織相關的委員會進行督導或審議。因此，以專家委員會協助決策制定的機制在短時間內是不會改變的方式，HTA評估機制也無法完全取代專家經驗。 參、對於我國HTA運作規劃之探討： 1. 研究能力 相對於我國有已建置之健保資料庫，各國也都面臨研究所需之資訊不足的問題，因此國際各國的HTA機制除了專職的評估或研究人員外，也聘請了許多的專家顧問或外審人力，整個機制中也含括許多的專家委員會，及與學研界間之合作管道；而除了各國本身的機制外，國際間也成立了許多的HTA合作網絡及跨國的HTA學會，以期增進針對HTA相關知識與經驗之合作研究及資訊分享。國內除善用國際資源及建立與學研單位間的合作管道外，我國機制中若能由政府投資經費並出面協調與整合相關的HTA組織，含括學界、醫界及HTA機構共同進行整合性應用研究，甚至將相關需求以國際競標的方式，請國際專家來幫忙，則可望各界均有機會自實案中逐步學習與累積相關研究實力。由政府投資經費進行整合性應用研究的好處是可避免學界依靠廠商的捐款或補助進行研究，而使HTA的研究成果失去公正客觀。除相關機制的建立外，研究人員可嘗試於已建置的健保資料庫取得抽樣資料，依不同狀況建立假說，進行不同可能性的模型推估。 至於需否制定政策誘因，以激發產業界願意投入，共同產生國內目前不足的本土流行病學資料或新科技適當使用的指引規範。自研究中之訪談結果顯示，雖然目前政策單位已就如何訂立鼓勵政策進行相關可行性設計，但若能先將制度的透明度及一致性做好，產業界能預期效果，自動就會投入，且若政策重視好的本土數據，並能在決策上看到效果及影響，則學術界、學會等自然也會願意付出行動，各方面能量就會很快的啟動。 2. 研究執行 國內執行HTA研究，不需要開發自我的方法學，因為國際公認的方法學已經過演進，能接受挑戰，且研究結果較能被國際標準認同。 由於進行一個HTA評估需耗費相當的人力、時間、金錢，在資源有限的情形下，HTA資源的運用需有其優先順序之安排；觀諸國際經驗，各國的HTA機制對於研究議題的產出也有不同的方式，若自新藥是否納入給付之層面而言，我國與國際各國類似，工作計畫單純來自政府委託評估的個案。但對於醫療照護領域相關之公共政策議題的研究，我國尚未發展出民眾及基層醫療人員參與提出健康照護相關議題之機制，是否朝更開放透明的全民社會參與的機制進行設計，因涉及整個運作流程的效率問題，可由政策主管單位視需要性進行研議。但研究結果完成後應有周延的檢討，且對於現行使用中的科技也應有定期檢視的機制。 3. 政策運行方式 建議建構溝通平台，邀集各界討論及溝通，進行各方面意見的整合，使產業界去敏感性並願意尋求合作利基。溝通平台的發起及召集者，應由政策主導單位擔任。各項法令的定義及標準的設立，主政機構能連動可用資源及最終期望能達到的目標進行整體的策略思考，避免因片段的決策，衍生其他額外問題，同時盡量避免過多模糊的空間，以使產業界為其產品進行策略規劃時能有清楚明確的依據，並能預期可能結果。 / Perspectives from industry, technology, medicine, management, economics and people are essential to the establishing of an innovative health technology assessment (HTA) mechanism for the purpose to placing the assessment results as a basis of public policy decision-making. The impacts of an innovative HTA mechanism were not only occurred to the government and people's needs but also to huge commercial interests and competitions, and even to the future progression of science & technology of a country. Different stakeholders might have different thoughts and standpoints and these conflicts might lead to the failure of a HTA mechanism at the end. In addition to that roles of HTA, consensus on important components for planning & executing models, capabilities of research & groundwork of science, infrastructure etc. all are influencing factors to the establishment and the successful operation of a HTA mechanism of a country. The purposes of the study were to explore the policy possibility and the factors connected to the system planning and operation design of HTA mechanism in Taiwan. Comprehensive literature review and in-deep interviews to the experts from government, academia and industry affiliates were executed to discover the most critical points. A potential HTA mechanism in Taiwan has been projected after the considerations of global experiences and the study findings. Study revealed that the most important issue of the HTA mechanism in Taiwan was the nervousness and the opposition from the industry. In addition to that consensus has not been reached on the roles, position, methods of assessment, criteria of judgment, and even the usage of reports of the HTA. How to establish a comprehensive planning and operation system, potential impacts of HTA to small and medium enterprises in Taiwan, lack of domestic data, insufficient person of talent, and no confidence to the HTA reports from the users etc. were all important factors exposed by this study and have to be resolved in the future. Conclusion of the study was provided as below: 1. Aspect of the policy possibility: Although there existed different opinions on the HTA mechanism in Taiwan among industry, government and academia the necessity and essentiality of HTA mechanism were recognized and currently was a suitable time to endorse such a mechanism in Taiwan. However under current situations where consensus not reached for the roles of HTA, lack of persons with talents and experiences the most practical ways in this early beginning stage were to cultivate people and to go through learning process. By following the acceptance of HTA report and the appearance of important issues concerned by the society roles and directions of the HTA in Taiwan would be consolidated. Why and how to bridge HTA results to policy decision-making was under discussion and construction presently. Nevertheless purely scientific assessment was emphasized to maintain its entirely objective standpoint of the HTA. Otherwise bias or policy leading will happened and the accountability of the HTA in Taiwan will be lost. 2. Aspect of the regulation envirement:Whether explicit law and regulation wanted for the endorsement of HTA mechanism had debates with different thoughts and rationales. Study revealed that affecting with political order has been the most efficiency way presently. However in the long run law or regulation will be desired as the HTA environment been established and society consensus been attained. Considering the modes of legislation on matter single legislation, attended to current law, or graduated from soft guidance to consolidated law all were sufficient. 3. Aspect of the executing model: The most significant requirements to HTA executing models and HTA reports were scientific, transparency, justice and accountability. SOPs of HTA research were recommended to set up as the environment of HTA conduction in Taiwan been matured. Accreditation mechanism applied to HTA researcher and HTA institution was also suggested. Field experts to provide professional opinions were crucial owing to the limitation of scientific evidences. For the positioning of HTA experiences from experts will not be wholly replaced by the HTA mechanism, therefore by using experts committee to help for decision making will not be changed in short time. 4. Aspect of the operation planning: In front of shortage of data and expertise in Taiwan one recommendation was to retrieve data from the national health insurance database while models can be explored under different assumptions. Different levels of assessment reports may have their levels of value for references. As experience and capability increased, related database built up and as time moving forward the deficiency of data can be enhanced. In addition to that networking with research institutes domestically and internationally was essential seeing that the extension of resources. Government should lead to coordinate and to integrate related HTA organizations and to invest money for the research of the integration. Incentive scheme to related parities was not suggested right away. More important facets were the transparency and the consistence of the system. If the final consequences of the HTA in Taiwan are predictable and then the industry will have their input. And if good research can be acknowledged by the policy and the impacts on the decision-making can be recognized then the academia and related associations will have their actions. After all powers from different sources will be initialed. It was not necessary to determine self-owned HTA methodology in Taiwan but just followed the global standards because HTA methodologies have developed for a period of time and by this way the results found in Taiwan can be accepted globally. HTA assessment is resources consuming while lots of human resources, time and money required. Since resources are scare the utilization of HTA resources should has its priority setting. A mechanism to have people or basic health care workers to provide health care issues was not been developed in Taiwan. Considering the efficiency of operation whether to design a more transparency mechanism with whole society participation can be considered by the authorities according to the demands in the future. Comprehensive evaluation to the HTA results and routinely assessment to the technologies in uses were also recommended. Plate-form of communication was suggested to construct to invite related parties for discussion and for connection. If opinions can be integrated and the susceptibility from industry can be released then a cooperation foundation can be built. To initial and to chair of the plate-form should be the responsibilities of the authorities. Comprehensive strategic planning including definition of the regulations, establishment of the guidance was critical to the authorities to avoid pieces of decision-making, surprised problems and too much uncertain room occurred. By this way the industry will have unambiguous basis with predictable outcomes to make strategic planning for their innovative medicinal products.

HTA et Institutions: 3 réseaux internationaux d'HTA permettent aux agences de collaborer afin de réduire la consommation de ressources des agences au niveau global et améliorer l'efficience de l'HTA. L'Economie des réseaux enseigne sur l'importance d'une taille minimale, la structure en 3 couches informationnelles, les risques d'engouement ou d'inertie pour un standard donné et les enjeux de qualité - du fait de la structuration en réseau HTA et laboratoires : les consultations précoces des agences d'HTA sont un outil de minimisation du risque pour les laboratoires. Du point de vue des agences, l'activité peut être développée de façon concurrentielle, selon les leçons de l'Economie Industrielle / HTA and institutions: 3 international networks of HTA agencies aim at increasing the efficiency of HTA globally. The theories of Network Economics provide tools to describe and analyse issues around the optimal size of the networks, the informational structure, the risks of early standard adoption of inertia and quality deficiencies.HTA and companies: early advice provided by HTA agencies to pharmaceutical firms in a means for companies to mitigate risks. From the agencies perspective this activity could be developped in a competitive fashion according to the theories of industrial econmics

This report is aimed at those who are interested in data analysis and data blending. Decision making is crucial for an organization to succeed in today’s market. Data analysis is an important support activity in decision making and is applied in many industries, for example healthcare. For many years data analysts have worked on structured data in small volumes, with traditional methods such as spreadsheet. As new data sources emerged, such as social media, data is generated in higher volume, velocity and variety [1]. The traditional methods data analysts apply are no longer capable of handling this situation. Hence scientists and engineers have developed a new technology called data blending. Data blending is the process of merging, sorting, joining and combining all the useful data into a functional dataset [2]. Some of the well-known data blending platforms include Datawatch, Microsoft Power Query for Excel, IBM DataWorks and Alteryx [3]. Synergus AB is a consulting company engaged in health economics, market access and Health Technology Assessment (HTA) [4]. The company does analysis for their clients. Unfortunately the way they work is not efficient. New tools and methods need to be applied in the company. The company has decided to apply data blending in their daily work. My task in this project was to build datasets for analysis and create workflows for future use with a data blending platform. For my interest, I did a research on data blending to understand how this new technology works. During the project I have worked with four data sources. These were Microsoft Excel worksheet, CSV file, MS Access database and JSON file. I built datasets the company needs. I also preceded a case study on data blending process. I focused on the three steps of data handling, namely input, process and output. After the project, I reached a conclusion that data blending offers better performance and functionality. It is easy to learn and use, too. / Denna rapport vänder sig till de som är intresserad av data analys och datahantering. Belsut fattande är avgörande för en organisation att lyckas i dagens marknad. Data analys är en viktig stöd inom beslutfattande och tillämpas i många industrier, till exempel hälsovård. I många år har data analyster arbetat med strukturerad data i små volymer, med traditionella arbetsmetoder såsom kalkyblad. Med nya data källor uppstått, såsom sociala media, data är genererad i högre volym, högre hastighet och högre variation. De traditionella metoder data analyster använder är inte längre kapabla av att hantera denna situation. Därför har vetenskapsmän och ingenjörer utvecklat ett ny teknologi kallad datahantering. Datahantering är en process för att sammanfoga, sortera och kombinera all värdeful data till en funktionell dataset. Några av de välkända datahanteringsplatformer inkluderar Datawatch, Microsoft Power Query for Excel, IBM DataWorks and Alteryx. Synergus AB är ett konsultföretag engagerad inom hälsoekonomi, marknad tillträde, och Health Technology Assessment (HTA). Företaget gör analys för deras kunder. Tyvärr är de arbetsmetoder inom företaget inte effektiv. Nya verktyg och metoder måste tillämpas inom företaget. Synergus AB har beslutat att tillämpa datahantering i deras dagliga arbete. Mitt uppdrag i detta projekt var att bygga dataset för analys och skapa arbetsflöde för framtida användning med en datahanteringsplatform. För mitt eget intresse, jag utförde en studie av datahantering för att förstå hur denna nya teknologi fungerar. Under projektet har jag arbetat med fyra data källor. De var Microsft Excel kalkylblad, CSV fil, MS Access databas och JSON fil. Jag byggde dataset företaget behöver. Jag också utförde ett fall studie om datahanteringsprocess. Jag fokuserade mig på de tre steg inom datahantering, nämligen inmatning, bearbetning och utmatning. Efter projektet kom jag till en slutsats att datahantering erjuder bättre prestanda och funktionelitet. Det är också lätt att lära sig och använda.

To fill a gap in the literature and to better inform decision making in oncology, this doctoral thesis investigates the role and impact of analytical methods in the economic evaluation of oncology medications through three main chapters which have been recently published. Chapter 2 presents a systematic literature survey of published economic evaluations in oncology over a 10-year period in order to identify, examine, and describe analytical methods that have been utilized (published in Pharmacoeconomics Open in 2021). This chapter demonstrated that greater detail in reporting of extrapolation methods, statistical techniques, and validation procedures is needed in order to conform with best practices outlined in existing economic evaluation guidelines. Chapter 3 complements the work of chapter 2 but takes a different perspective through an examination of the methods reported in economic evaluations published by HTA agencies in Canada, the UK, and Australia (published in Current Oncology in 2022). This chapter revealed significant reporting discrepancies across the agencies and concluded that common standards for reporting the results of HTAs should be implemented. Building on chapters 2 and 3, chapter 4 provides a model-based health technology re-assessment of an oncology drug approved on the basis of interim trial data using recently published long-term follow up data (published in Current Oncology in 2023). The findings from this chapter highlight the importance of transparency in the reporting of methods, the impact of using a life-cycle approach to HTA, and demonstrate the existence of a tradeoff between clinical/economic uncertainty and the value of the incremental cost-effectiveness ratio (ICER). The final chapter provides the overall conclusions of the research and presents avenues for future research. / Thesis / Doctor of Philosophy (PhD)

The motivation to avoid punishment, or to pursue reward can result in certain behavioral tendencies. It is known that individuals with higher sensitivity towards reward can express traits of extrovertedness, openness to novel situations, and a general appetite for feeling good. Individuals on the other side of the spectrum tend to show a pessimistic attitude towards approaching novel situations. As a consequence, individuals with a higher tendency of approaching novel situations ought to find themselves in risky situations more frequently than individuals who would rather avoid novel situations. Looking at this from a human factors perspective, it becomes apparent that a tendency to approach situations with a lack of conflict monitoring can produce risks, but simeltaneously, disinterest in approaching a risky situation can lead to crisis events. In other words, whilst individuals with a sensitivity towards reward might have a proclivity for producing a crisis, they might also have a higher chance of solving a crisis. In order to solve unexpected crisis events, it is necessary to be able to improvise. In the experiment of this current thesis, individuals were assessed for their sensitivity towards reward and punishment, and following this, the individuals were assessed in improvisational skills. Motivation behavior and improvisation skills were investigated to see if there is a correlation between them. The purpose of this thesis was to present a multidisciplinary literature account for the relevant subjects by tying together aspects of cognition, cognitive neuroscience, human factors, and psychology, and to provide experimental data about the mentioned correlation. The present experiment showed that there is a significant correlation between sensitivity towards reward and improvisation skills. Additionally, it was also found that system-level factors i.e pre-implemented elements by a designer/organization might not facilitate improvisational performance, but this significant result did not appear in the expected manner. Future directions of research on this subject should focus on five mainpoints (1) replication of investigating the relationship between personality styles and improvisation with different methodologies, (2) investigating the mechanisms leading to the emergence of this relationship, (3) approach the subject mainly from a cognitive-neuroscientific standpoint, but complement with a multiple disciplinary approach (4) use the results within the disciplines of human factors, safety, and resilience, and (5) take data into consideration for e.g. future accident preventions policies.

A Avaliação de Tecnologias em Saúde (ATS) é investigada neste trabalho como uma forma de minimizar as consequências da excessiva judicialização do direito à saúde, ao vincular o conhecimento científico à tomada de decisão, já que pondera riscos, benefícios, custos e impactos referentes à ética e equidade, no estudo de uma determinada tecnologia. O direito ao acesso a medicamentos é apenas uma faceta do direito à saúde, considerando a abrangência de seu conceito. Todavia, a assistência farmacêutica é hoje uma das áreas mais problemáticas e assíduas no debate sobre o direito à saúde, motivo pelo qual o foco deste estudo são as avaliações das tecnologias medicamentosas. Um dos fatores mais relevantes no incremento dos custos em saúde é a utilização de tecnologias cada vez mais caras e de uso específico, cuja inovação, nessa área, tende a ser cumulativa, e não substitutiva. Daí a importância de políticas públicas eficazes em saúde, que consigam gerir as tecnologias de modo a cumprir os princípios de universalidade, equidade e integralidade do SUS. Este trabalho é orientado pela interdisciplinaridade inerente ao estudo dos direitos humanos, pautando-se em pesquisas teóricas e documentais que demonstram tanto a evolução do direito à saúde no ordenamento jurídico brasileiro, quanto a contextualização e a afirmação da ATS como pressuposto à incorporação de tecnologias no SUS e auxiliar na tomada de decisões, possuindo um papel fundamental como fator de justiça social e instrumento de garantia dos direitos humanos. / The Health Technology Assessment (HTA) is studied as a way of minimizing the consequences of the excessive judicialization of the right to health when taking decisions is linked to the scientific knowledge. It weighs risks, benefits, costs and impacts referred to ethics and equity in the study of a certain technology. The right of access to medicines is only a tiny part of the right to health considering the scope of its concept. However, the pharmacy assistance is currently one of the most problem and constant subject presents in debates about the right to health, reason why the focus of this study are the evaluations of medicines technologies. One of the most relevant fact in the increasing of costs in health is the using of technologies increasingly expensive and specific, which innovation tend to be cumulative and not substitutive. That is the importance of effective public policies in health, which are able to manage the technologies in a way of compliance with universality, equity and integrality principles of SUS. This work is oriented by the intrinsic interdisciplinarity of the human rights studies and guided by theoretical and documental researches that demonstrate the evolution of the right to health in Brazilian legal system and the contextualization and predication of HTA as an important point to be considered when incorporating technologies in SUS and taking decisions, having an important role as a factor of social justice and human rights guaranties.

A Avaliação Tecnológica em Saúde (ATS) é uma sistemática que avalia os impactos clínicos, sociais e econômicos das tecnologias em saúde e tem como finalidade auxiliar os gestores na tomada de decisão quanto ao desenvolvimento, incorporação e descontinuação destas tecnologias. Agências de ATS têm destacado a importância da existência de métodos que visem padronizar e implantar esta sistemática em diferentes contextos. Assim, o objetivo geral desta tese é propor procedimentos para apoiar a avaliação tecnológica de equipamentos médico-hospitalares, por meio de uma pesquisa construtiva (Constructive Research) aplicada à terapia de hemodiálise. Os procedimentos propostos compõem um modelo adaptado do EuroScan, modelo desenvolvido por agências Europeias e indicado como boa prática pelo Ministério da Saúde do Brasil. Também são procedimentos ajustados às necessidades de pesquisadores de centros regionais de avaliação de equipamentos médico-hospitalares. Inicialmente, foi desenvolvida uma coleta de dados sobre os problemas de desenvolvimento e incorporação das tecnologias da saúde por meio de duas fontes: uma revisão sistemática de literatura sobre oportunidades de melhorias do EuroScan no mundo e discussões com pesquisadores no país. A partir destas investigações foi proposto um modelo preliminar de ATS, aplicado para o domínio Operacional e de Inovação na hemodiálise. Finalmente a aplicação foi validada e examinada por especialistas para a geração de um modelo final. Os principais procedimentos resultantes foram: (i) validação da relevância das avaliações para novos desenvolvimentos e incorporações tecnológicas do ponto de vista de diferentes especialistas, integrando diferentes áreas do conhecimento na ATS; (ii) operação de Observatórios Tecnológicos, auxiliando na definição das tecnologias e domínios a serem avaliadas; (iii) definição de técnicas para análise dos domínios de ATS, como o uso de séries temporais e o Technology Roadmap (TRM) para previsões sobre o futuro das inovações e o uso das dimensões da usabilidade e de incidentes críticos de riscos para os aspectos operacionais; e (iv) integração das diretrizes de ATS no Brasil em um único modelo, amparando pesquisadores não relacionados a saúde na compreensão sobre ATS e no desenvolvimento ágil de novos estudos tanto para equipamentos emergentes como em uso. Já a avaliação dos domínios selecionados para a hemodiálise resultou: (i) na identificação de um crescimento médio anual de 7% dos indicadores da terapia; (ii) no diagnóstico de usabilidade de máquinas eficazes, porém com possibilidades de gerarem maior satisfação aos usuários quanto: ao espaço entre elas, a redução dos desperdícios de água e materiais, aos planos de manutenção para evitar temperaturas elevadas, a capacitação visando mais atenção e treinamento para tarefas de apoio e aos aspectos de display (realimentação de dados e visualização); e (iii) na consolidação entre profissionais sobre um futuro promissor, para os próximos 10 anos no Brasil, da assistência homecare com máquinas de hemodiálise portáteis, mais seguras e sustentáveis. / The Health Technology Assessment (HTA) is a systematic evaluation of clinical, social and economic impacts of health technologies aiming to assist managers in the decision making process related to the development, consolidation and discontinuation of these technologies. HTA agencies have been highlighting the importance of methods to standardize and apply this systematic evaluation in different contexts. Thus, the general objective of this thesis is to propose procedures to support the technology assessment of medical-hospital equipment through a constructive research applied to hemodialysis therapy. The proposed procedures compose a EuroScan adapted model, which was developed by European agencies and is recommended as a good practice by the Brazilian Ministry of Health, and also are procedures adjusted to the needs of researchers in regional centers of medical equipment assessment. Initially, a data collection on the problems of developing and incorporating health technologies was carried out using two sources: a systematic review of the literature on opportunities to improve the EuroScan around the world and discussions with Brazilian researchers. Based on these investigations, it was proposed a preliminary HTA model applied to the hemodialysis’ Operational and Innovation domain. The application of the model was reviewed and evaluated by experts to produce a final version. The main resulting procedures were: (i) to validate the importance of assessments for new technological developments and incorporations considering the point of view of different experts from diverse knowledge areas; (ii) to operate Technological Observatories, assisting to define the technologies and domains to be evaluated; (iii) to set techniques for the analysis of HTA domains such as the use of time series and the Technology Roadmap (TRM) to make predictions about the future of innovations and the use of usability dimensions and critical incidents of risks to the operational aspects; and (iv) to integrate HTA Brazilian guidelines in a single model, supporting researchers not related to health in the understanding of HTA and fast development of new studies for both emerging and in use equipment. The assessment of the domains selected for hemodialysis led to: (i) the identification of an annual growth in therapy indicators (7% in average); (ii) the usability diagnosis of efficient machines, however with the potential to generate greater user satisfaction considering: distance between machines, reduction in the waste of water and materials, maintenance plans to avoid high temperatures, training aiming more attention to supporting tasks as well as focus on display aspects (data feedback and visualization); and (iii) the consolidation among professionals of a future, for the next 10 years in Brazil, based on homecare with portable machines, safer and more sustainable.

Dans les régions de fortes endémicités, 70-80% des carcinomes hépatocellulaires sont induits par le VHB. Bien qu’un vaccin prophylactique très efficace existe, il n’est d’aucune utilité pour les 250 millions de personnes chroniquement infectées. Les traitements actuels pour contrôler l'infection chronique par le VHB montrent des limites et le besoin de nouvelles thérapies se fait ressentir. La Polo-like kinase-1 (PLK1), qui joue un rôle essentiel dans la mitose et est surexprimée dans de nombreux cancers, représente une cible prometteuse. Outre son rôle lors de la division cellulaire, PLK1 est impliquée dans la régulation de l'expression des gènes en interphase. Il a été montré que la protéine X du VHB (HBx) active PLK1 dans des modèles de cellules murines. Cependant, il restait à déterminer si PLK1 jouait un rôle au niveau de la réplication du VHB dans des hépatocytes quiescents. Des études récentes ont mis en évidence un lien positif entre l'activation de PLK1 et la réplication du VHB. Le but de ce projet de thèse a été d'étudier le(s) mécanisme(s) par le(s)quel(s) PLK1 jouait un rôle positif sur la réplication virale, avec pour objectif futur d'explorer l’inhibition de PLK1 comme cible antivirale. L'interaction entre PLK1 et la réplication du VHB a d'abord été décrite à l'aide du modèle HepAD38. Dans ce contexte, l'ADN viral est intégré dans le génome hôte, sous le contrôle d'un système d'expression Tet-off. La transcription de l'ARN prégénomique (pgRNA), à la base de la réplication virale, est initiée par la suppression de tétracycline. Dans ce contexte, l'augmentation de l'expression de PLK1 est corrélée avec la régulation négative de deux protéines; SUZ12 et ZNF198, faisant partie de complexes de remodelage de la chromatine. L'inhibition de PLK1 bloque la réplication du VHB, en agissant au niveau de la transcription virale. D'autre part, dans les modèles de réplication du VHB qui miment au mieux une infection, comprenant les hépatocytes primaires humains (PHH) et les cellules non transformées/différenciées HepaRG (dHepaRG), où le VHB se réplique dans des cellules quiescentes, nous avons mis en évidence que: 1) L'inhibition pharmacologique de PLK1 bloque la réplication virale, semblablement en perturbant l’encapsidation du pgRNA via une interaction avec la protéine core du VHB (HBc). 2) Un knocking-down de PLK1 en utilisant des ARN interférents délivrés par nanoparticules lipidiques résulte en une forte baisse de la production de pgRNA et dans la sécrétion des antigènes HBeAg/HBsAg, sans impact sur la viabilité cellulaire. Ce projet a donc permis la preuve de concept que PLK1 pouvait être une cible thérapeutique afin de controler la réplication du VHB. De plus, grâce à la technologie de délivrance par nanoparticules lipidiques d’ARN interférents, nous avons pu cibler spécifiquement les hépatocytes, augmentant de ce fait la spécificité et l’efficacité de nos traitements. Un travail sur la compréhension précise des méchanismes cellulaires impliqués permettra de mieux cerner cette interaction hôte/virus afin de poursuivre le développement de stratégies antivirales innovantes portant sur l’inhibition de PLK1. De manière significative, l'inhibition de PLK1 est non toxique pour les cellules quiescentes par rapport à des cellules cancéreuses à fort taux réplicatif, ce qui fait de PLK1 une cible thérapeutique attrayante. Des inhibiteurs spécifiques sont déjà en essais cliniques pour certains cancers (e.g., Volasertib pour le traitement de la leucémie myéloïde aiguë) et pourraient servir de thérapie bimodale dans le cadre de patients infectés par le VHB, en inhibant la réplication virale, ainsi qu’en prévenant l'émergence de cellules néoplasiques. L'inhibition de la PLK1 est une approche antivirale innovante, qui, en combinaison avec les thérapies actuelles de type IFN-α ou analogues nucléotidiques offre de grandes promesses pour endiguer l'infection chronique par le VHB mais également prévenir les événements carcinogéniques / In highly HBV endemic regions, 70-80% of hepatocellular carcinoma cases are attributable to this virus. Despite the existence of an HBV vaccine, the World Health Organization estimates 240 million individuals are chronically infected with HBV worldwide. Current antiviral treatments to control chronic HBV infections, and consequently reduce the incidence of liver cancer, are ineffective. New and effective therapies are needed not only for fighting the virus but also to prevent HCC emergence or progression. The polo-like-kinase 1 (PLK1), which plays pivotal roles in mitosis and is over-expressed in many human cancers, represents a promising druggable target in oncology. Beside its role during cell division, PLK1 is also thought to be involved in gene expression regulation during interphase. It was shown that the X protein (HBx) could activate PLK1 in murine cell transformation models. Yet it remained to be determined whether PLK1 could also play a role for HBV replication in non-dividing hepatocytes. Our, and collaborators, recent studies have identified a positive link between PLK1 activation and HBV replication. The goal of this thesis project was to investigate the mechanism(s) by which PLK1 exerts a positive effect on HBV replication, with the future goal of exploring PLK1 as an antiviral target. The interplay between PLK1 and HBV replication was firstly described using the HepAD38 cellular model of HBV replication. In this context, the HBV DNA is stably integrated into the host genome, under control of a Tet-off expression system. Transcription of HBV pregenomic RNA (pgRNA), the template of viral replication, is initiated by tetracycline removal. It has been shown that in HBV-replicating HepAD38 cells, increased PLK1 expression correlates with down-regulation of two proteins that are components of chromatin modifying complexes; SUZ12 protein of the PRC2 complex, and ZNF198 of the LSD1-CoREST-HDAC1 complex. PLK1 inhibition was described to inhibit HBV replication by reducing viral transcription. How PLK1 regulates HBV transcription remains unknown. On the other hand, in HBV replication models that resemble physiologic HBV infection, comprised of Primary Human Hepatocytes (PHH) and non-transformed/differentiated HepaRG cells (dHepaRG), where HBV replicates in non-transformed and non-dividing cells, thus enabling the study of the inter-phasic role of PLK1, irrespective of its well-established cell division implication, we have demonstrated that: 1) A pharmacological inhibition of PLK1 suppressed HBV replication by a different mechanism, likely targeting the packaging of pgRNA by the HBV core antigen (HBc). 2) Knocking-down PLK1 using siRNA delivered by lipid nanoparticles (LNP siPLK1) results in a strong drop of HBV DNAs, RNAs and HBe/HBsAg secretion without affecting the cell viability. This thesis project brought the proof of concept that PLK1 could be a drug target in HBV infection. Furthermore, the use of LNP allowed us to improve the delivery of siPLK1 to hepatocytes. Significantly, PLK1 inhibition is not toxic to quiescent cells in comparison to fast growing cancer cells, rendering PLK1 an attractive therapy target. High level of viremia in chronic HBV patients is a risk factor for progression to liver cancer. PLK1 specific inhibitors are already in clinical trials for other types of cancer (e.g., acute myeloid leukaemia) and could serve as bimodal therapy in HBV infected patients, by inhibiting virus replication as well as preventing emergence and spreading of neoplastic cells. This project was part of a full-working group of experts and thus, has beneficiated of a strong support. The proximity of the oncology-specialized hospital, the Centre Léon Bérard provided us with fresh hepatic biopsy [etc...]

A Avaliação Tecnológica em Saúde (ATS) é uma sistemática que avalia os impactos clínicos, sociais e econômicos das tecnologias em saúde e tem como finalidade auxiliar os gestores na tomada de decisão quanto ao desenvolvimento, incorporação e descontinuação destas tecnologias. Agências de ATS têm destacado a importância da existência de métodos que visem padronizar e implantar esta sistemática em diferentes contextos. Assim, o objetivo geral desta tese é propor procedimentos para apoiar a avaliação tecnológica de equipamentos médico-hospitalares, por meio de uma pesquisa construtiva (Constructive Research) aplicada à terapia de hemodiálise. Os procedimentos propostos compõem um modelo adaptado do EuroScan, modelo desenvolvido por agências Europeias e indicado como boa prática pelo Ministério da Saúde do Brasil. Também são procedimentos ajustados às necessidades de pesquisadores de centros regionais de avaliação de equipamentos médico-hospitalares. Inicialmente, foi desenvolvida uma coleta de dados sobre os problemas de desenvolvimento e incorporação das tecnologias da saúde por meio de duas fontes: uma revisão sistemática de literatura sobre oportunidades de melhorias do EuroScan no mundo e discussões com pesquisadores no país. A partir destas investigações foi proposto um modelo preliminar de ATS, aplicado para o domínio Operacional e de Inovação na hemodiálise. Finalmente a aplicação foi validada e examinada por especialistas para a geração de um modelo final. Os principais procedimentos resultantes foram: (i) validação da relevância das avaliações para novos desenvolvimentos e incorporações tecnológicas do ponto de vista de diferentes especialistas, integrando diferentes áreas do conhecimento na ATS; (ii) operação de Observatórios Tecnológicos, auxiliando na definição das tecnologias e domínios a serem avaliadas; (iii) definição de técnicas para análise dos domínios de ATS, como o uso de séries temporais e o Technology Roadmap (TRM) para previsões sobre o futuro das inovações e o uso das dimensões da usabilidade e de incidentes críticos de riscos para os aspectos operacionais; e (iv) integração das diretrizes de ATS no Brasil em um único modelo, amparando pesquisadores não relacionados a saúde na compreensão sobre ATS e no desenvolvimento ágil de novos estudos tanto para equipamentos emergentes como em uso. Já a avaliação dos domínios selecionados para a hemodiálise resultou: (i) na identificação de um crescimento médio anual de 7% dos indicadores da terapia; (ii) no diagnóstico de usabilidade de máquinas eficazes, porém com possibilidades de gerarem maior satisfação aos usuários quanto: ao espaço entre elas, a redução dos desperdícios de água e materiais, aos planos de manutenção para evitar temperaturas elevadas, a capacitação visando mais atenção e treinamento para tarefas de apoio e aos aspectos de display (realimentação de dados e visualização); e (iii) na consolidação entre profissionais sobre um futuro promissor, para os próximos 10 anos no Brasil, da assistência homecare com máquinas de hemodiálise portáteis, mais seguras e sustentáveis. / The Health Technology Assessment (HTA) is a systematic evaluation of clinical, social and economic impacts of health technologies aiming to assist managers in the decision making process related to the development, consolidation and discontinuation of these technologies. HTA agencies have been highlighting the importance of methods to standardize and apply this systematic evaluation in different contexts. Thus, the general objective of this thesis is to propose procedures to support the technology assessment of medical-hospital equipment through a constructive research applied to hemodialysis therapy. The proposed procedures compose a EuroScan adapted model, which was developed by European agencies and is recommended as a good practice by the Brazilian Ministry of Health, and also are procedures adjusted to the needs of researchers in regional centers of medical equipment assessment. Initially, a data collection on the problems of developing and incorporating health technologies was carried out using two sources: a systematic review of the literature on opportunities to improve the EuroScan around the world and discussions with Brazilian researchers. Based on these investigations, it was proposed a preliminary HTA model applied to the hemodialysis’ Operational and Innovation domain. The application of the model was reviewed and evaluated by experts to produce a final version. The main resulting procedures were: (i) to validate the importance of assessments for new technological developments and incorporations considering the point of view of different experts from diverse knowledge areas; (ii) to operate Technological Observatories, assisting to define the technologies and domains to be evaluated; (iii) to set techniques for the analysis of HTA domains such as the use of time series and the Technology Roadmap (TRM) to make predictions about the future of innovations and the use of usability dimensions and critical incidents of risks to the operational aspects; and (iv) to integrate HTA Brazilian guidelines in a single model, supporting researchers not related to health in the understanding of HTA and fast development of new studies for both emerging and in use equipment. The assessment of the domains selected for hemodialysis led to: (i) the identification of an annual growth in therapy indicators (7% in average); (ii) the usability diagnosis of efficient machines, however with the potential to generate greater user satisfaction considering: distance between machines, reduction in the waste of water and materials, maintenance plans to avoid high temperatures, training aiming more attention to supporting tasks as well as focus on display aspects (data feedback and visualization); and (iii) the consolidation among professionals of a future, for the next 10 years in Brazil, based on homecare with portable machines, safer and more sustainable.

Vid rökdykning i stora byggnader har rökdykare problem med desorientering, stora avstånd och lokalisering av branden. Detta arbete utforskar användbarheten och rollen av en brandrobot, FUMO, vid rökdykning i industrilokaler och underjordiska parkeringshus. Genom att intervjua brandmän med erfarenhet av rökdykning har en hierarkisk uppgiftsanalys (HTA) genomförts och HTA-diagram har tagits fram för hur rökdykning i underjordiska parkeringshus och industrilokaler ser ut idag. Baserat på dessa HTA-diagram har nya analyser genomförts som har resulterat i kompletterade HTA-diagram som beskriver hur en rökdykningsprocess som inkluderar FUMO kan se ut. Resultatet visar att FUMO kan genom utforskning och lokalisering av branden innan rökdykarpar går in, bidra med en säkrare arbetsmiljö för rökdykarna. / When smoke diving in large buildings, firefighters struggle with disorientation, vast distances and locating the fire itself. This thesis explores the usability and role of a surveillance robot, FUMO, when smoke diving in industries and underground parking lots. By interviewing firefighters and conducting a hierarchical task analysis (HTA) on smoke diving in both underground parking lots and industries, it has been found that FUMO in its basic module can aid firefighters in planning and locating a fire. Based on the HTA describing the current work process of smoke diving, two iterations were conducted to create an HTA with part-goals allocated to FUMO for each environment. These HTA shows how FUMO can be integrated in the current work process of the firefighters. By exploring the environment and locating the fire before the smoke divers are sent in, FUMO can contribute to a safer work environment for the smoke divers.