As doenças raras são epidemiologicamente caracterizadas por ocorrerem entre 0,65-1:1.000 indivíduos. Houve importante incremento no surgimento de tratamentos específicos para muitas destas condições a partir da publicação de legislações específicas em diferentes países (sendo o pioneiro em 1983 nos EUA o chamado 'Orphan Drug Act'). Dentre as doenças que dispõem atualmente de tratamento específico está a Doença de Fabry, uma doença genética classificada erro inato do metabolismo do grupo das doenças Lísossômica se caracterizada pelo acúmulo de glicoesfíngol ipídíos no endotélio vascular, o que ocasiona problemas renais, cardíovasculares e neurológicos. Os problemas renais e cardíovasculares são os responsáveis pela maior morbi-mortalídade entre os portadores da doença. Esta ocorre em homens e mulheres, com manifestações heterogêneas entre indivíduos e diferentes gêneros. O tratamento específ ico da doença é através da chamada Terapia de Reposição Enzimática (TRE) havendo duas opções existentes: a agalsidase alfa e a agalsidase beta. Não há, porém, consenso sobre os resultados da TRE sobre desfechos clínicos relevantes. O alto custo associado a esta terapêutica (cerca de 200 mil dólares/ano/por paciente adulto) é o dificulta o acesso dos pacientes à mesma. Uma das formas se racionalizar a incorporação de tecnologias novas na área de saúde, que se caracteriza empreender uma avaliação objetiva de benefícios e custos associados é a chamada Avaliação de Tecnologias de Saúde. Este conjunto de métodos é cada vez mais empregado para auxiliar ou nortear decisões na área de saúde. Existem, no entanto , dificuldades associadas ao seu emprego no campo das doenças raras. Nossa proposta consiste em tendo como modelo a Doença de Fabry, obter um panorama da situação no Brasil a o acesso a tratamentos de alto custo para doenças raras, e, analisar a aplicabilidade dos princípios da avaliação de tecnologias de saúde no campo das doenças raras, tentando por fim colaborar no aprimoramento do processo de acessibilidade a estes tratamentos. OBJETIVOS Objetivo geral : Avaliar o acesso no Brasil a tratamentos de doenças raras e a aplicabilidade da avaliação de tecnolog ias em saúde no contexto específico destas. Objetivos específicos: 1) Caracterizar as políticas existentes no Brasil em relação ao acesso de medicamentos para doenças raras e avaliar as formas empregadas para este acesso. 2) Colaborar no aprimoramento do processo de incorporação destes tratamentos (de al to custo) no segmento das doenças raras, através da aplicação de principias de 'aval iação de tecnologias em saúde', usando como exemplo a Doença de Fabry. 3) Identificar e propor possíveis estratégias que possam colaborar para uma acessibilidade adequada e justa a tratamentos cl inicamente efetivos no campo das doenças raras. MÉTODOS 1) Foi realizada uma revisão da literatura caracterizando as politicas brasileiras na área de medicamentos e aval iando as formas de acesso utilizadas pelos pacientes; 2) Uma segunda revisão, de caráter sistemático, sobre os efeitos da TRE na DF, foca d a nos efe itos sobre a nefropatia e a cardiopatia (sistemas cujo comprometimento em pacientes com DF causa maior morbi-mortalidade) da doença foi feita. Baseado nos dados obtidos elaborou-se um modelo probabilístico (markoviano) para avaliar o efeito da TRE sobre a nefropatia da DF seguido de aval iação do custo-efetividade. A partir de uma análise destes resultados e da li teratura, foram identificados os aspectos que mais influenciariam a acessibilidade ao tratamento, seguida da elaboração de propostas para auxiliar a incorporação e a acessibil idade a estes tratamentos. RESULTADOS 1) A política de assistência farmacêutica brasileira atual é baseada em elencos de medicamentos divididos em atenção básica e do 'componente especiali zado'. Não existe uma política especifica direcionada aos tratamentos (de alto custo) dos portadores de doenças raras. 2) A revisão empreendida mostrou que dentre os dois sistemas aval iados de forma particular (pela morbi-mortalidade associada) havia mais dados quer sobre história natural , quer sobre efeitos da TRE em relação à nefropatia, tendo sido esta escolh ida então como foco da modelagem . O modelo construido foi capaz de identificar um subgrupo de pacientes com DF que quando tratado com TRE tem redução significativa (diferença absoluta de 10%) na probabilidade de ter progressão da nefropatia (evoluir a estágio dialítico). A despeito dos benefícios observados a análise mostrou ser esta opção não custo-efetiva no contexto existente (custo é superior ao limite preconizado pela OMS de s 3 vezes o PIB per capíta do Brasil). 3) A acessibilidade é ainda um obstáculo ao uso destes medicamentos. O custo é o limitante central da acessibilidade aos tratamentos específicos destas patologias. Atuar em aspectos associados a este e às pol íticas vigentes seriam formas de tentar mudar este cenário. CONCLUSÕES 1) Não há em nosso país políticas que sistematizem o processo de incorporação de tratamentos (de alto custo) para doenças raras. O acesso a estes é disperso, no caso da DF não existe disponibil idade da terapia de reposição enzimática via SUS. 2) A revisão sobre o efeito da TRE na nefropatia mostrou resultados muito heterogêneos. Foi possivel, no entanto, elaborar um modelo avaliando TRE na nefropatia da DM, o qual é o primeiro conhecido utilizando este desfecho especifico e elaborado dentro contexto brasileiro. A despeito de identificado um subgrupo de pacientes que poderia beneficiar-se significativamente com o tratamento especifico a estratégia não foi custo-efetiva para este desfecho. Os custos associados foram o limitante central. Novas opções em termos de efetivação da incorporação destas tecnologias devem ser consideradas. / BACKGROUND. According to the WHO definition rare diseases occur between 0.65-1/1,000 individuals. The U.S. 'Orphan Drug Act' in 1983', the first legislation with incentives for the development of therapies for rare diseases had an impact on the development of treatments for these diseases. Fabry Disease (FD) is a rare genetic disease characterized by accumulation of glycosphingolipids in vascular endothelium leading to systemic dysfunction (renal, cardiovascular, and neurologic disease). This disease has specific treatment available, with two options of recombinant enzymes (alfa or betagalsidase) for enzyme replacement therapy (ERT). There are few controlled trials evaluating their effects, indicating some improvements in neuropathic pain, in heart abnormalities and in globotriaosylceramide (GL-3) levels. Nevertheless most of the clinical benefits of ERT are still unclear. Another aspect is the high cost associated with this treatment which makes it not easily accessible. OBJECTIVES: General Objective: Evaluate access to rare disease treatments in Brazil and the applicability of health technology assessment (HTA) in the context of these diseases. Specific objectives: 1) Evaluate the Brazilian governmental policies for rare diseases treatment and how the access to the treatments is actually done. 2) Evaluate the applicability of health technology assessment (HTA) in the context of rare diseases, using the example of Fabry disease. 3) Identify and propose strategies that could contribute to a fair access to clinically effective treatments for of rare diseases. METHODS: An extensive literature review about the Brazilian policies in the area was performed. In the sequence a systematic review about the subject ERT and FD was conducted. After this, a model estimating the likelihood of nephropathy progression with or without ERT was built, followed by a cost-effectiveness analysis. Another literature review focused in the identification of obstacles to accessibility and possible strategies to overcome them was conducted. RESULTS: 1) There is no specific policy in Brazil regarding high cost drugs for the treatment of rare diseases. 2) ERT appears to slow the progression of nephropathy in the Fonly proteinuria subgroup '. However the cost associated is very high making this option not cost-effective. 3) The accessibility to innovative treatments for rare diseases is not adequate and the high cost of these therapies is a major obstacle to change this scenario. CONCLUSION: There are no policies in Brazil to systematize the access to the specific (high cost) treatments for rare diseases. The model evaluating TRE in FD nephropathy was able to identify benefits for a subgroup of patients. It was the first known model using this specific outcome and built focusing the Brazilian context. However the ERT strategy was not cost-effective for this outcome. The costs associated with these therapies are very high and an important limiting factor to the access. the central. New options should be considered to offer adequate access to the (effective) therapies.

O câncer do colo do útero é o quarto tipo de câncer mais frequente em mulheres em todo mundo. No Brasil, estima-se que cerca de 16 mil novos casos ocorrem por ano. A redução deste tipo de câncer ao longo dos anos deve-se ao rastreamento das lesões intraepiteliais cervicais por meio do exame citológico de Papanicolaou. Em 2014, o Programa Nacional de Imunização (PNI) introduziu a vacina contra o papilomavírus humano (HPV) como prevenção primária deste câncer, uma vez que este vírus é uma causa necessária para o surgimento desta malignidade. A vacinação não substitui o rastreamento, visto que não há proteção contra todos os tipos de HPV de alto risco e nem imunização de toda a população. A incorporação do programa de vacinação interfere nos resultados do programa de rastreamento, pois leva a diminuição dos casos de câncer e lesões precursoras. Desta forma, existe a necessidade de explorar novas estratégias de rastreamento, considerando também outras tecnologias existentes. Objetivo: desenvolver um modelo do tipo Markov para realizar uma análise de custo-efetividade de estratégias de rastreamento do câncer do colo do útero para hipotéticas coortes imunizadas e não imunizadas contra o vírus do HPV no Brasil na perspectiva do Sistema Único de Saúde (SUS). Métodos: A primeira parte é a exploração e avaliação qualitativa de estudos de avaliação econômica sobre estratégias de rastreamento para prevenção do câncer do colo do útero que utilizaram um modelo do tipo Markov feita por meio de uma revisão sistemática. A reunião das várias abordagens utilizadas e das principais características destes modelos poderá auxiliar a construção de um modelo em cenários onde há poucos profissionais capacitados com esta técnica. Baseando-se nesta revisão e nas consultas a especialistas das áreas de ginecologia, virologia e epidemiologia, foi desenvolvido um modelo matemático de análise de decisão estático do tipo Markov que simula a história natural do câncer do colo do útero considerando a imunização contra o HPV. Este modelo simula o seguimento de uma coorte de mulheres, dos 10 anos até o óbito, cujos parâmetros foram estimados a partir de dados secundários (revisão da literatura, sistemas de informação em saúde e inquéritos populacionais) nacionais específicos do rastreamento e calibrados de forma a refletir as condições reais de rastreamento encontradas no Brasil. Resultados: A revisão dos modelos de Markov para avaliação econômica de estratégias de rastreamento do câncer do colo do útero mostrou que a declaração do problema e a descrição das estratégias a serem comparadas foram muito bem relatados. Em contrapartida, os itens de avaliação da incerteza e consistência do modelo e a consistência precisam melhorar o relato. Os resultados obtidos por meio da calibração do modelo se mostraram satisfatórios, pois alcançaram uma boa concordância com os dados empíricos. A análise do caso base sugeriu que a melhor estratégia foi o Teste HPV-DNA como triagem para o encaminhamento da citologia ou da colposcopia, com repetição a cada 5 anos, para mulheres entre 30 e 70 anos. Esta estratégia promove um ganho de 9,5 dias ao longo dos anos e detecta, a cada 100 mil mulheres, 6 casos a mais de câncer e 16 de NIC II/III. A razão de custo-efetividade incremental (RCEI) foi de R$16.056,94 por ano de vida ganho, na perspectiva do sistema de saúde. Conclusão: Estudos futuros devem considerar metodologias que levem em conta a incerteza, a heterogeneidade e a consistência no modelo de decisão e utilizar diretrizes validadas para o relato do estudo / Cervical cancer is the fourth most common cancer in women worldwide. In Brazil, it is estimated that around 16,000 new cases occur per year. The reduction of this type of cancer over the years owes to cervical intraepithelial lesions screening through pap smears. In 2014, the National Immunization Program (NIP) introduced a vaccine against human papillomavirus (HPV) as the primary prevention of this cancer, since this virus is a necessary cause for the onset of this malignancy. Vaccination does not replace screening because there is no protection against all types of high risk HPV nor immunization of the entire population. Incorporation of the vaccination program interferes with the results of the screening program, leading to a decreased number of cancer cases and precursor lesions. In this way, there is a need to explore new screening strategies, also considering other existing technologies. Objective: Determining a Markov based model to perform a cost-effectiveness analysis of cervical cancer screening strategies for hypothetical immunized and non-immunized cohorts against the HPV in Brazil from the perspective of the Unified Health System (UHS). Methods: The first part is a qualitative appraisal and assessment of economic evaluation studies on screening strategies for cervical cancer prevention using a Markov based model done through a systematic review. The combination of different approaches and of the main features of these models can be auxiliary in the construction of a model in scenarios where there are few professionals trained with this technique. Based on this review and consultations with specialists in the areas of gynecology, virology and epidemiology, a Markov model for decision analysis was developed, which simulates the natural history of cervical cancer considering immunization against HPV. This model simulates the follow-up of a cohort of women, from 10 years-old to death, whose parameters were estimated from secondary data, particular to screening and calibrated in order to reflect real screening conditions found in Brazil. Results: A review of Markov models for economic evaluation of cervical cancer screening strategies showed that the report of the problem statement and the description of the compared strategies were well conducted. In contrast, the uncertainties of the model and the consistency were the worst items. The results obtained by calibration of the model were satisfactory, since a good agreement with empirical data was achieved. The baseline case analysis suggested that the best strategy was the HPV-DNA Test as triage for cytology or colposcopy referral, repeated every 5 years, for women between 30 and 70 years-old. This strategy promotes a gain of 9.5 days over the years and detects, every 100,000 women, 6 cases of cancer and 16 of CIN 2/3. The incremental cost-effectiveness ratio (ICER) was R$16,056.94 per life years gained from the health system perspective. Conclusion: Future studies should consider methodologies that take into account uncertainty, heterogeneity and consistency in the decision model and use validated guidelines for the study report

Submitted by Fabiana Gonçalves Pinto (benf@ndc.uff.br) on 2015-12-07T14:06:03Z No. of bitstreams: 1 Luciana Miranda Rodrigues.pdf: 2906831 bytes, checksum: c63fff07e6a85a3c8689b9aadbab96a2 (MD5) / Made available in DSpace on 2015-12-07T14:06:03Z (GMT). No. of bitstreams: 1 Luciana Miranda Rodrigues.pdf: 2906831 bytes, checksum: c63fff07e6a85a3c8689b9aadbab96a2 (MD5) Previous issue date: 2010 / Mestrado Acadêmico em Ciências do Cuidado em Saúde / Este estudo teve como objetivos avaliar a efetividade do hidrogel 2% em pacientes com úlceras de perna; estimar o custo médio do uso do hidrogel 2% num período de 90 dias e comparar o custo do uso do hidrogel 2% em pacientes com úlceras de perna com hidrogéis industrializados disponíveis no mercado nacional. Trata-se de um estudo de intervenção terapêutica, prospectivo, do tipo ensaio clínico não controlado sobre a avaliação do uso do hidrogel 2% produzido na farmácia universitária para o tratamento de feridas em pacientes com úlceras de perna. A amostra constou de 20 voluntários, de ambos os sexos, para 90 dias de tratamento com o hidrogel a 2%, totalizando 250 consultas durante o período de fevereiro a outubro de 2010. Este estudo foi encaminhado ao Comitê de Ética em Pesquisa do Hospital Universitário Antônio Pedro sob o parecer CAAE n0 0154.0.258.000-08 e os termos de consentimento livre e esclarecido e de fotografia encontram-se de acordo com as Resoluções n0 196/96 e 251/97 do Conselho Nacional de Saúde. Do grupo amostral, pôde-se identificar que 62,5% dos voluntários eram predominantemente do sexo feminino. A idade média variou de 60,5 anos ± 11,4 e que 52,25% residiam no município de Niterói. Em relação à análise da evolução clínica das úlceras de perna, pôde-se observar que surgiram dois grupos distintos com relação ao tamanho da área da lesão, sendo estas classificadas no estudo como, área 1 – para lesões com tamanho acima de 100 cm 2 e área 2 – para lesões com tamanho abaixo de 100 cm 2. O tecido de maior prevalência na avaliação inicial foi o tecido de esfacelo que apresentou uma média de 3,75 ± 1,2 de presença no leito da lesão dos voluntários do estudo. Destaca-se ainda, que após 90 dias de tratamento com o hidrogel a 2%, foram observadas alterações teciduais importantes para a cicatrização e/ou redução da área lesional (p=0,0416). A presença do tecido de granulação passa a prevalecer com uma média de 3,12 ± 1,0 e 25% dos voluntários obtiveram cicatrização total (100% de tecido de epitelização). Em relação à análise dos custos do tratamento com o hidrogel a 2% destacou-se inicialmente que o tratamento das úlceras pertencentes à área 1 foi maior que a das úlceras da área 2, sendo esta variação de R$114,40 a R$393,23 (M= R$227,55 e Dp=72). Ao comparar o tratamento das úlceras de perna com hidrogel 2% 100 gramas com outros hidrogéis disponíveis no mercado nos valores proporcionais a 100 gramas observou-se uma diferença significativa (p= 0,0003) para os valores referentes às áreas 1 e 2 em todas as perspectivas estudadas. Os valores variaram de acordo com o tamanho das áreas da lesão. A área 1 teve uma variação de preço de R$ 112,85 a R$ 912,11 nas três esferas estudas e a área 2 variou de R$ 70,75 a R$ 558,88 nas três perspectivas do estudo. Ao analisar os custos e a efetividade do uso dessa terapêutica, verificou-se que o hidrogel a 2% apresenta uma efetividade significante assim como os seus custos, não sendo justificável a sua não utilização nos serviços de saúde. O hidrogel a 2% manipulado magistralmente numa farmácia universitária representa uma alternativa para essa situação, uma vez que promove melhora das taxas de cicatrização, com diminuição do tempo de tratamento dessas úlceras, além de ser um tratamento de baixo custo, se comparado a outros hidrogéis industrializados disponíveis no mercado nacional, trazendo menores gastos para os serviços de saúde e órgãos de financiamento. / This study aimed to evaluate the effectiveness of hydrogel 2% in patients with leg ulcers, estimate the average cost of using the hydrogel 2% within 90 days and compare the cost of the use of hydrogel 2% with others hydrogels industrialized. This is a study of therapeutic intervention, prospective clinical trial, uncontrolled on evaluating use of hydrogel 2% produced in the pharmacy college in the treatment of wounds in patients with leg ulcers. The sample consisted of 20 volunteers of both sexes, during 90 days of treatment with the hydrogel to 2% to 250 consultations during the period from February to October 2010. This study was submitted to Committee on Research Ethics at University Hospital on advice CAAE number 0154.0.258.000-08 and terms of consent and photography are in accordance with Resolutions 196/96 and 251/97 of the National Health Council. Of this sample group, could be identified that 62.5% of the volunteers were predominantly female. The mean age ranged from 11.4 ± 60.5 years and 52.25% lived in Niterói. On the analysis of clinical outcome of leg ulcers, it was observed that emerged two distinct groups with respect to the size of the lesion area, which are classified in this study: area1 - for lesions with a size greater than 100 cm2 and area 2 - for lesions with size below 100 cm2. About these group it was noted that the tissue with the highest prevalence at baseline was the desvitalization tissue that showed presence an average 3.75 ± 1.2 of the wound bed. After 90 days by treatment with hydrogel 2%, it has obtained tissue with an important changes to healing and / or reduction area lesion (p = 0.0416). The granulation tissue presence begins to prevail with an average 3.12 ± 1.0 and 25% these volunteers had total healing (100% epithelization tissue). On the costs analysis with hydrogel 2% treatment it has initially the ulcers belonging area 1 was higher than the second area of ulcers, and this variation was the R$ 114.40 to R$ 393, 23 (mean = R$ 227.55 and dv = 72). When comparing the treatment of leg ulcers with hydrogel 2% 100 grams with other commercially available hydrogels in proportionate amounts to 100 grams there was a significant difference (p = 0.0003) for the values related to areas 1 and 2 in all perspectives studied. The values ranged with the size of the lesion areas. The area 1 had a variation in price from R$ 112.85 to R$ 912.11 and the area 2 ranged from R$ 70.75 to R$ 558.88 on the three perspectives of the study. Analyzed the costs and effectiveness using this therapy, it was found that hydrogel 2% shows a significant efficacy as well as their costs are not justified in not using health services. The hydrogel 2% manipulated in a pharmacy college represents an alternative to this situation, since it promotes improved healing rates, decreased treatment time of these ulcers, as well as being a low-cost treatment, as compared to other hydrogels industrialized in the national sale, bringing lower costs to health services.

La thèse examine les configurations d'acteurs et d'organisations impliquées dans la régulation de l'accès au marché des médicaments en France et en Angleterre, en charge du contrôle scientifique et administratif de la fixation du prix et du remboursement de ces produits. Cette activité s'autonomise de l'appréciation clinique de leur qualité, de leur efficacité et de leur innocuité (dominant la régulation de leur approbation sur le marché) au cours des années 1980. / This thesis examines the configurations of actors and organizations involved in the regulation of the market access for drugs in France and England. Since the mid-1980s, this process has entailed the development of administrative and scientific controls over the fixing of the price and the conditions of reimbursement of these products. These controls have become autonomus from clinical appreciation of their quality, efficacity and safety that dominate approval regulation as a whole.

Cyber attacks by domestic and foreign threat actors are increasing in frequency and sophistication. Cyber adversaries exploit a cybersecurity skill/knowledge gap and an open society, undermining the information security/privacy of citizens and businesses and eroding trust in governments, thus threatening social and political stability. The use of open digital hacking technologies in ethical hacking in higher education and within broader society raises ethical, technical, social, and political challenges for liberal democracies. Programs teaching ethical hacking in higher education are steadily growing but there is a concern that teaching students hacking skills increases crime risk to society by drawing students toward criminal acts. A cybersecurity skill gap undermines the security/viability of business and government institutions. The thesis presents an examination of opportunities and risks involved in using AI powered intelligence gathering/surveillance technologies in ethical hacking teaching practices in Canada. Taking a qualitative exploratory case study approach, technoethical inquiry theory (Bunge-Luppicini) and Weick’s sensemaking model were applied as a sociotechnical theory (STEI-KW) to explore ethical hacking teaching practices in two Canadian universities. In-depth interviews with ethical hacking university experts, industry practitioners, and policy experts, and a document review were conducted. Findings pointed to a skill/knowledge gap in ethical hacking literature regarding the meanings, ethics, values, skills/knowledge, roles and responsibilities, and practices of ethical hacking and ethical hackers which underlies an identity and legitimacy crisis for professional ethical hacking practitioners; and a Teaching vs Practice cybersecurity skill gap in ethical hacking curricula. Two main S&T innovation risk mitigation initiatives were explored: An OSINT Analyst cybersecurity role and associated body of knowledge foundation framework as an interdisciplinary research area, and a networked centre of excellence of ethical hacking communities of practice as a knowledge management and governance/policy innovation approach focusing on the systematization and standardization of an ethical hacking body of knowledge.

Contexte : La pression croissante sur les soins primaires nécessite de développer des approches adaptées pour apprécier la valeur des innovations dans ce domaine et identifier les conditions favorables à leur diffusion, ce qui peut s'avérer difficile, puisque ces innovations sont souvent complexes et de nature organisationnelle. Objectifs : Explorer les arguments de valeur de 10 innovations identifiées comme prometteuses lors des symposiums sur les innovations du Collège québécois des médecins de famille et proposer des pistes pour leur bonification et diffusion. Méthodes : Approche délibérative multidimensionnelle avec un panel diversifié de 12 cliniciens, gestionnaires, patients et citoyens. À partir de données synthétisées par dimension, chaque participant a apprécié le potentiel de valeur des innovations par un score et des arguments justificatifs pour chaque dimension individuellement et suite à une délibération. Le potentiel de valeur moyen a été calculé par innovation, les arguments ont fait l’objet d’une synthèse qualitative. Ces résultats ont informé une seconde délibération visant à identifier des pistes d’amélioration et diffusion qui ont été organisées par analyse thématique. Résultats : Les innovations d’adaptation de l'organisation des soins aux populations vulnérables ont été considérées comme ayant le plus grand potentiel de valeur dans l’ensemble. Les innovations visant l’optimisation des processus cliniques et d’amélioration continue ont reçu des appréciations plus variables. 460 pistes ont été classées en six catégories : objectifs, modalités d’accès, fonctionnement, impacts, gouvernance et contexte externe. Conclusions : L’exploration du potentiel de valeur d’innovations complexes avec une approche délibérative multidimensionnelle permet d’identifier, pour certaines catégories d’innovations en soins primaires, des arguments de valeur communs, et facilite l’identification de pistes d’amélioration et diffusion. / Context: The increasing pressure on primary care calls for the development of appropriate approaches to assess the value of innovations in this field and identify the conditions for their diffusion, which can be difficult, as these innovations are often complex and organizational in nature. Objectives: To explore the value arguments of 10 innovations identified as promising during the Quebec College of Family Physicians' Innovation Symposia and to propose avenues for their improvement and diffusion. Methods: Multidimensional deliberative approach with a diverse panel of 12 clinicians, managers, patients and citizens. Using data synthesized by dimension, each participant assessed the value potential of the innovations by providing a score and supporting arguments for each dimension individually, and following group deliberation. The average value potential was calculated per innovation, and the arguments were qualitatively synthesized. These results informed a second deliberation aimed at identifying avenues for improvement and deployment that were organized by thematic analysis. Results: Innovations aimed at adapting the organization of care for vulnerable populations were considered to have the greatest value potential overall, while interventions aimed at optimizing clinical processes and continuous improvement received more variable appraisals. 460 avenues were categorized into six areas: objectives, access modalities, operations, impacts, governance, and external context. Conclusions: Exploring the value potential of complex innovations with a multidimensional deliberative approach allowed the identification of common value arguments for certain categories of primary care innovations and facilitated the identification of pathways for their improvement and dissemination.

Objectif principal: Il n’est pas démontré que les interventions visant à maîtriser voire modérer la médicamentation de patients atteints d’hypertension peuvent améliorer leur gestion de la maladie. Cette revue systématique propose d’évaluer les programmes de gestion contrôlée de la médicamentation pour l’hypertension, en s’appuyant sur la mesure de l’observance des traitements par les patients (CMGM). Design: Revue systématique. Sources de données: MEDLINE, EMBASE, CENTRAL, résumés de conférences internationales sur l’hypertension et bibliographies des articles pertinents. Méthodes: Des essais contrôlés randomisés (ECR) et des études observationnelles (EO) ont été évalués par 2 réviseurs indépendants. L’évaluation de la qualité (de ce matériel) a été réalisée avec l’aide de l’outil de Cochrane de mesure du risque de biais, et a été estimée selon une échelle à quatre niveaux de qualité Une synthèse narrative des données a été effectuée en raison de l'hétérogénéité importante des études. Résultats: 13 études (8 ECR, 5 EO) de 2150 patients hypertendus ont été prises en compte. Parmi elles, 5 études de CMGM avec l’utilisation de dispositifs électroniques comme seule intervention ont relevé une diminution de la tension artérielle (TA), qui pourrait cependant être expliquée par les biais de mesure. L’amélioration à court terme de la TA sous CMGM dans les interventions complexes a été révélée dans 4 études à qualité faible ou modérée. Dans 4 autres études sur les soins intégrés de qualité supérieure, il n'a pas été possible de distinguer l'impact de la composante CMGM, celle-ci pouvant être compromise par des traitements médicamenteux. L’ensemble des études semble par ailleurs montrer qu’un feed-back régulier au médecin traitant peut être un élément essentiel d’efficacité des traitements CMGM, et peut être facilement assuré par une infirmière ou un pharmacien, grâce à des outils de communication appropriés. Conclusions: Aucune preuve convaincante de l'efficacité des traitements CMGM comme technologie de la santé n’a été établie en raison de designs non-optimaux des études identifiées et des ualités méthodologiques insatisfaisantes de celles-ci. Les recherches futures devraient : suivre les normes de qualité approuvées et les recommandations cliniques actuelles pour le traitement de l'hypertension, inclure des groupes spécifiques de patients avec des problèmes d’attachement aux traitements, et considérer les résultats cliniques et économiques de l'organisation de soins ainsi que les observations rapportées par les patients. / Objective: Whether interventions including measurement and correction of patients’ attitude to antihypertensive medication can improve hypertension management is unclear. The review aims to determine the effectiveness of patient compliance measurement-guided medication management (CMGM) programs in essential hypertension. Design: Systematic review. Data sources: MEDLINE, EMBASE, CENTRAL, hypertension meetings abstracts, and bibliographies of identified articles. Methods: Randomized controlled trials (RCT) and observational studies (OS) were assessed by 2 reviewers independently. Quality assessment was performed with the Cochrane risk of bias tool and evaluated in a four-point continuum. A narrative data synthesis was performed due to significant heterogeneity among studies. Results: 13 studies (8 RCT, 5 OS) involving 2150 hypertensives were included. Five trials of CMGM with electronic devices as a sole intervention suggested decrease in blood pressure (BP) but the result may have been due to bias. Short-term BP improvement under CMGM in complex interventions was revealed in 4 studies of low-to-moderate quality. In 4 integrated care studies of higher quality the impact of CMGM component was not possible to distil and may be compromised by medication regimens. Regular feedback to the treating physician seems to be an essential component of CMGM and may be effectively mediated by a nurse or a pharmacist and via telecommunication. Conclusions: No convincing evidence for the effectiveness of CMGM as a health technology was found due to non-optimal study designs and methodological quality. Future research should follow accepted quality standards and current guidelines for the treatment of hypertension, include specific groups of patients with compliance problems and consider clinical, economic, patient-reported and organizational outcomes.

La littérature abordant les enjeux socio-éthiques et réglementaires associés aux médicaments est relativement abondante, ce qui n’est pas le cas des dispositifs médicaux (DM). Ce dernier secteur couvre une très large diversité de produits qui servent à de multiples applications: diagnostic, traitement, gestion des symptômes de certaines conditions physiques ou psychiatriques, restauration d’une fonction débilitante, chirurgie, etc. À tort, on a tendance à croire que les DM sont réglementés de la même manière que les médicaments, que ce soit pour les exigences concernant leur mise en marché ou des pratiques de surveillance après mise en marché. Or, au cours des dernières années, leur usage élargi, leur impact sur les coûts des soins de santé, et les rappels majeurs dont certains ont fait l’objet ont commencé à inquiéter la communauté médicale et de nombreux chercheurs. Ils interpellent les autorités réglementaires à exercer une plus grande vigilance tant au niveau de l’évaluation des nouveaux DM à risque élevé avant leur mise en marché, que dans les pratiques de surveillance après mise en marché. Une stratégie plus rigoureuse d’évaluation des nouveaux DM permettrait d’assurer un meilleur suivi des risques associés à leur utilisation, de saisir la portée des divers enjeux socio-éthiques découlant de l’utilisation de certains DM, et de préserver la confiance du public. D’emblée, il faut savoir que les autorités nationales n’ont pas pour mandat d’évaluer la portée des enjeux socio-éthiques, ou encore les coûts des DM qui font l’objet d’une demande de mise en marché. Cette évaluation est essentiellement basée sur une analyse des rapports risques-bénéfices générés par l’usage du DM pour une indication donnée. L’évaluation des impacts socio-éthiques et l’analyse coûts-bénéfices relèvent des agences d’Évaluation des technologies de santé (ÉTS). Notre recherche montre que les DM sont non seulement peu fréquemment évalués par les agences d’ÉTS, mais l’examen des enjeux socio-éthiques est trop souvent encore incomplet. En fait, les recommandations des rapports d’ÉTS sont surtout fondées sur une analyse coûts-bénéfices. Or, le secteur des DM à risque élevé est particulièrement problématique. Plusieurs sont non seulement porteurs de risques pour les patients, mais leur utilisation élargie comporte des impacts importants pour les systèmes de santé. Nous croyons que le Principisme, au cœur de l’éthique biomédicale, que ce soit au plan de l’éthique de la recherche que de l’éthique clinique, constitue un outil pour faciliter la reconnaissance et l’examen, particulièrement par les agences d’ÉTS, des enjeux socio-éthiques en jeu au niveau des DM à risque élevé. Également, le Principe de Précaution pourrait aussi servir d’outil, particulièrement au sein des agences nationales de réglementation, pour mieux cerner, reconnaître, analyser et gérer les risques associés à l’évaluation et l’utilisation de ce type de DM. Le Principisme et le Principe de Précaution pourraient servir de repères 1) pour définir les mesures nécessaires pour éliminer les lacunes observées dans pratiques associées aux processus de réglementation, et 2) pour mieux cerner et documenter les enjeux socio-éthiques spécifiques aux DM à risque élevé. / Socio-ethical and regulatory issues about drug development have received substantial coverage in the scientific literature over the years; this has not been the case of medical devices (MD). This latter sector comprises a vast array of products with a multitude of applications: diagnostics, treatment, symptom management for severe physical and psychiatric conditions, restoring physical functioning, surgery, etc. There is a mistaken view that MD are regulated in the same manner as pharmaceutical drugs, whether this be requirements regarding premarket assessment or post-market surveillance. Not only has the extensive use of MD in clinical practice and the resulting impact on healthcare expenditures raised concerns in the scientific and medical communities, but so too have the many recalls for high risk devices in recent years. Regulatory authorities have been challenged to exercise greater vigilance in both the premarket assessment and post-market surveillance of new high risk MD. A more rigorous evaluation strategy for new MD would permit better monitoring of the risks associated with their use, better understanding of the significance of the various socio-ethical issues arising from the use of MD, and thus preserve public confidence. From the outset, it should be noted that national authorities do not have a mandate to assess the significance of socio-ethical issues or the costs associated with the MD that are the subject of an application for marketing approval. This assessment is based primarily on risk-benefit analysis reports generated following the use of MD for a given indication. Evaluation of socioethical impact and cost-benefit analysis are the remit of Health Technology Assessment (HTA) agencies. But research shows that the MD are not only infrequently assessed by HTA agencies, but the consideration of socio-ethical issues is often incomplete; the recommendations of HTA reports are based mostly on a calculation of cost-benefit. However, the high risk MD sector is particularly problematic; many carry risks not only for patients, but their extended use has significant impact on healthcare systems. I argue that Principlism, associated to biomedical ethics, as much to research ethics and clinical ethics, could be adapted to facilitate the recognition and evaluation by HTA agencies of socio-ethical issues involved in high risk MD. The Precautionary Principle could also serve as a tool to help regulatory agencies to enforce understanding, recognition, analysis and management of the risks associated with the use of MD, especially high risk devices. Principlism and the Precautionary Principle could serve as benchmarks to 1) define necessary steps to eliminate gaps observed in the regulatory process, and 2) better understand and document the socio-ethical issues specific to high risk MD.

Introdução: Amplo debate tem associado a incorporação de novas tecnologias para a saúde com os custos crescentes dos sistemas de saúde. Face à dúvidas \"se as novas tecnologias são parte do problema, parte da solução ou as duas coisas\" relativamente à saúde da população e do sistema de saúde, este estudo de caso analisa a incorporação de três inovações no Instituto do Coração, InCor-HC/FMUSP, visando elaborar quais fatores influenciaram a decisão de adoção e exemplificar as metodologias de avaliação de novo medicamento, de procedimento diagnóstico e intervenção cirúrgica. A avaliação das tecnologias para a saúde, ATS, pode auxiliar a constituir algumas propostas de respostas. Metodologia: estudo qualitativo empírico em caso retrospectivo de incorporação de três inovações para assistência de alta complexidade em cardiologia. As metodologias utilizadas consistiram em entrevistas aos tomadores de decisão, revisões sistemáticas da literatura relevante, descritiva ou meta-analítica, e análise de impacto econômico hospitalar. Resultados: O padrão do InCor para a incorporação das inovações funciona como um sistema social criativo, sob uma estratégia prática pluralista, ou seja, utilizam as pesquisas, aprovadas pela Comissão de Ética e Pesquisa do InCor e do HC, que se sucederam e que sucedem em incrementos, verificando e ajustando as informações segundo os resultados obtidos para desenhar novas pesquisas. Os atores construíram conhecimentos e negociaram protocolos de pesquisa, promoveram a capacitação de super-especialistas técnicos, transferindo práticas internacionais e gerando conhecimentos adaptados à realidade do Brasil. A avaliação do medicamento tacrolimus demonstra que se poderia resgatar uma média de 75% das rejeições refratárias às terapias convencionais, proporcionando um custo hospitalar de R$ R$ 102,99 por dia de sobrevida nos 8 adultos e R$ 137,53 nas 13 crianças observadas, comparativamente à R$ 229,00 e R$ 260,00, com ciclosporina, respectivamente. Assim, se evitaria 37% da mortalidade associada à episódios de rejeição nos pacientes com transplante cardíaco e, mesmo no único óbito, o custo hospitalar por dia de sobrevida foi de metade que o custo dos períodos observados nos 32 pacientes sob ciclosporina que foram a óbito. O diagnóstico por angiotomocoronariografia em pacientes com angina atípica e risco moderado permitiria orientar o manejo de até dois terços destes casos evitandose coronariografias invasivas. Isto permitiria aumentar a resolutividade do Departamento de Hemodinâmica de 25% para mais 20% dos casos assim estudados, com economias para o InCor, aumento do acesso e resolutividade, podendo evitar até 2.000 mortes, e com o acréscimo estimado de <10% do valor destas 14% mais angioplastias e 6% mais revascularizações cirúrgicas para o SUS. A ablação cirúrgica tem o potencial de curar >10% das fibrilações atriais refratárias a medicamentos em pacientes com indicação de cirurgia aberta para correção de problemas cardíacos estruturais, evitando morbidade e mortalidade em até 1.000 pacientes por ano, se houver suposição que esta seja utilizada apenas com as cirurgias valvares no âmbito do SUS. Conclusões e discussão: As novas tecnologias estudadas proporcionam benefícios à saúde, mas ainda possuem variados graus de incerteza sobre aspectos de segurança e sobre seu potencial de impacto econômico para os programas assistenciais para o InCor e para o SUS. O InCor e os demais hospitais universitários possuem alta capacidade técnica instalada, onde a estruturação de pesquisas facilita e permite a incorporação de inovações de alta complexidade, sem contudo haver planejamento econômico para os programas de assistência à saúde. O isolamento destes atores, em relação às instâncias gestoras do SUS, permite construções sob visões parciais e imediatistas, permite desenvolvimento de interesses externos e diversos, e, por outro lado, pressiona de maneira desordenada a organização e o sistema de saúde. A integração da capacidade profissional, instalada nos hospitais universitários, dentro do circuito de planejamento de médio e longo prazo para o SUS, avaliando as tecnologias inovadoras comparativamente às estabelecidas para a saúde, com base na epidemiologia local observada, pode permitir uma atualização planejada e contínua dos serviços de saúde, construída sobre bases sólidas de conhecimento científico adaptado à nossa realidade e com o responsável equilíbrio orçamentário. / Introduction: There is an ongoing international debate associating the increasing health care costs with adoption of new health technologies. To aid to ascertain whether new health technologies are part of the problem, part of the solution or both in relation to the health of the population and of the health care system, this case study analyses retrospectively three recent decisions to adopt innovations at the Heart Institute, InCor-HC/FMUSP. In order to provide examples of the application of methods for health technologies assessment, the InCor Board of Directors indicated one innovative drug, a new diagnostic procedure and a recent surgery. Methods: Qualitative, retrospective field evaluation of the three decisions for the highest complexity of care in cardiology. Decision-makers survey, systematic reviews (descriptive or meta-analytic) and hospital economic impact analysis were the methodologies applied to this case. Results: A pattern of new technologies incorporation through incremental research, a strategic and pluralist practice emerged within a creative social system. Approved by the InCor and HC Research Ethics Boards and based on previous research results, successive investigations verified and adjusted the informations and generated additional research. Thus, the decision-makers do build knowledge, negotiate research protocols, promote very technical specialists formation and transfer international practice, inter- and up-grading it to the Brazilian reality. Evaluation of these three innovative technologies results are: - The drug tacrolimus may rescue and resolve an average of 75% of the episodes of rejection refractory to conventional medications. The average hospital cost observed (since conversion from CSA, censored at March the 30th, 2006) was of US$45 or R$102.99 per day of survival in 8 adults and of US$61 or R$137.53 for the 13 children (<18 years of age), compared with R$ 229.00 and R$ 260.00, respectively, in those who remained under cyclosporine treatment. Thus, it could prevent 37% rejection related mortality and bring some economy (even in the single child death observed, the hospital cost per day until death was the half of the cost observed for the 32 cyclosporine treated). - The tomoangiocoronariography diagnosis for patients presenting atypical angina and moderate to low risk of stenosis may orient and modify up to 66% clinical decisions preventing requirement of an invasive procedure. This would increase 20% to the Haemodynamic Department 25% resolutivity, may prevent up to 2000 deaths with an estimated additional 10% of the costs of 14% more angioplasties and 6% increase in surgical coronary bypasses for the health care system. - Surgical ablation has the potential to cure more than 10% of medications refractory atrial fibrillation in patients undergoing open heart surgery for structural corrections. Supposing it is restricted only to the group of patients undergoing valve surgery in the health care system, it could prevent morbidity and mortality for up to 1000 patients. Conclusions and discussion: The new technologies evaluated bring benefits to the health of the patients. Safety concerns and economic impact for the InCor and for the health care system assistance programs require further investigation. InCor and the other university hospitals have enhanced technical capacity installed. The structured research facilitates and allows incorporation of highly complex innovations without planning future programs for care. The isolation of these decision makers from the health care system decision planners allows partial views and immediacies. Such a distance facilitates development of external and diverse interests. These facts, consequently, pressures on the organization and the health care system. The integration of the university hospitals installed professional capacities, within an average and long term health care system plans, making evaluations of the innovative health technologies in comparison with the established ones based on local epidemiology, may permit a planned and continuous actualization of the health services on solid scientific basis adapted to the Brazilian reality and with a responsible financial balance.

Health technology assessment: case study on breast carcinoma treatment in the Czech Republic Bc. Lenka Šlegerová January 4, 2019 Abstract This thesis proposes an original method for assessing total costs of med- ical treatment. It defines the semi-Markov model with four states that are associated with specific costs of the treatment, and not with patients' health statuses. This method is applied to individuals' treatment data drawn from the Czech clinical practice in the treatment of the metastatic HER2+ breast cancer. The aim is to assess the cost-effectiveness of adding medication per- tuzumab to the combination of trastuzumab+docetaxel within first-line therapy and to examine whether using individual data on Czech patients and the economic conditions leads to different results from foreign stud- ies. Furthermore, employing censored data from the clinical practice in the thesis complicates the estimation of patients' overall survival in compari- son to clinical-trials data that form random samples. Therefore, survival functions were not only estimated by the Kaplan-Meier estimator but also using the Cox proportional hazard model and the Accelerated failure time model that both control for the effects of included covariates. The addition of pertuzumab does not result in significantly longer pa- tients'...