Evaluation of the regulatory preparedness for health threats and health crisis

Tese de mestrado, Regulação e Avaliação do Medicamento e Produtos de Saúde, 2020, Universidade de Lisboa, Faculdade de Farmácia.Num mundo global e interconectado, as doenças infeciosas de âmbito internacional são inevitáveis e imprevisíveis, atingindo as comunidades de forma devastadora. Quando ameaças de saúde pública (re)emergem, o sistema de saúde pública trabalha para mitigar seu impacto, reduzir o número de mortes e a morbilidade associada. Dentro dos sistemas de saúde pública, o sistema regulamentar tem um papel crítico na resposta a estas ameaças, com pressão para o desenvolvimento e acesso a medicamentos, vacinas e testes de diagnóstico o mais rapidamente possível. Neste contexto, é importante compreender a forma como o sistema regulamentar está preparado, como pode acelerar a avaliação e a disponibilização de soluções terapêuticas, e identificar oportunidades de melhoria. Este trabalho apresenta uma análise minuciosa do desempenho do sistema regulamentar nas recentes crises da saúde do Ébola, seguida pela identificação dos mecanismos atuais implementados pelas principais Autoridades Regulamentares e possíveis oportunidades de melhoria. O surto de 2014-2016 na África Ocidental, o maior e mais mortífero surto de Ébola até ao presente, marcou um ponto de viragem na capacidade de preparação e resposta global e regulamentar. Os esforços conjugados de vários stakeholders levaram ao desenvolvimento acelerado de vacinas e medicamentos para o Ébola, num contexto catastrófico. No entanto, este surto expôs também fraquezas na capacidade de resposta rápida e efetiva dos sistemas regulamentares às ameaças de saúde pública. Durante o surto, apenas um ensaio clínico foi capaz de reunir dados suficientes para avaliar a eficácia de uma vacina, e várias dúvidas sobre segurança, tolerabilidade ou imunogenicidade ficaram sem resposta. Como consequência, muitas lições foram discutidas e tidas em conta posteriormente, com destaque para a inclusão da investigação clínica nos planos para futuras crises de saúde e maior integração nas respostas às epidemias. Com base nessas lições, a resposta ao segundo maior surto de Ébola, dois anos depois, foi rápida, mais organizada e melhor coordenada, culminando na aprovação da primeira vacina contra o Ébola (um marco na capacidade de preparação em saúde pública). A análise da resposta aos surtos de Ébola demonstrou a implementação bem-sucedida de mecanismos regulamentares diversificados, que promoveram o desenvolvimento, o acesso antecipado e a avaliação rápida de medicamentos, vacinas e testes de diagnóstico, incluindo revisão prioritária, autorização condicional de introdução no mercado e revisões contínuas. Esta análise também mostrou a flexibilidade do sistema regulamentar, a sua capacidade de resposta e capacidade de adotar soluções inovadoras, mantendo os padrões de qualidade, segurança e eficácia. Existem algumas oportunidades de melhoria no atual quadro regulamentar, incluindo uma coordenação mais centralizada, melhor capacidade regulamentar e harmonização nos países em desenvolvimento, maior transparência e comunicação mais clara. Apesar disso, o sistema regulamentar parece capaz e adequado para lidar positivamente com atuais e futuras crises de saúde pública. Não obstante não poder impedir a sua ocorrência, pode minimizar os seus impactos e proteger a saúde global.In a globalized and highly interconnected world, infectious diseases of international concern are inevitable and unpredictable, hitting communities in devastating ways. When public health threats (re-)emerge, the public health system works towards mitigating their impact, reduce the death toll and any associated morbidity. Within it, the regulatory system has a critical role in responding to such threats, with pressure being applied to the development and access to medicinal products, vaccines and diagnostic tests as quickly as possible. In this context, it is important to understand how the regulatory system is prepared, how it can accelerate the assessment and availability of therapeutic solutions and identify possible opportunities for improvement. This work presents a thorough analysis of the regulatory system’s performance in recent Ebola health crises, followed by the identification of the current mechanisms put in place by the main Regulatory Authorities and possible opportunities for improvement. The 2014-2016 West African Outbreak, the largest and deadliest Ebola outbreak in history so far, marked a turning point in regulatory and global health preparedness. Efforts across multiple stakeholders led to the accelerated development of Ebola virus vaccines and medicinal products, in a catastrophic environment. However, this outbreak also exposed weaknesses in the worldwide regulatory systems’ capacity to respond rapidly and effectively to health threats. Only one vaccine clinical trial was able to gather enough data to assess efficacy during the outbreak, and several doubts on safety, tolerability or immunogenicity were left unanswered. Consequently, important lessons were discussed and considered thereafter, mainly the inclusion of clinical research in the plans for future health crisis and further integration in epidemic responses. Based on these lessons, the response to the second largest Ebola outbreak, two years later, was swift, more organized and better coordinated, culminating in the approval of the first vaccine against Ebola (a landmark moment in public health preparedness). The analysis of the response to the Ebola outbreaks demonstrated the successful implementation of diversified regulatory mechanisms that fostered the development, early access and expedite assessment of medicinal products, vaccines and diagnostic tests, including priority review, conditional marketing authorization and rolling reviews. It also showcased the regulatory system’s flexibility, response capacity and ability to embrace innovative solutions, while keeping the standards of quality, safety and efficacy. Some opportunities for improvement exist within the current regulatory framework, including a more centralized coordination, better regulatory capacity and harmonization in low and middle-income countries, transparency and clearer communication. Despite these, the regulatory system seems capable and adequate to positively address both current and future public health crisis. It cannot stop them from occurring, but it can minimize their impact and protect our global health

The Brazilian consensus for the diagnosis and treatment of hyperthyroidism: recommendations by the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism

INTRODUCTION: Hyperthyroidism is characterized by increased synthesis and release of thyroid hormones by the thyroid gland. Thyrotoxicosis refers to the clinical syndrome resulting from excessive circulating thyroid hormones, secondary to hyperthyroidism or due to other causes. This article describes evidence-based guidelines for the clinical management of thyrotoxicosis. OBJECTIVE: This consensus, developed by Brazilian experts and sponsored by the Department of Thyroid Brazilian Society of Endocrinology and Metabolism, aims to address the management, diagnosis and treatment of patients with thyrotoxicosis, according to the most recent evidence from the literature and appropriate for the clinical reality of Brazil. MATERIALS AND METHODS: After structuring clinical questions, search for evidence was made available in the literature, initially in the database MedLine, PubMed and Embase databases and subsequently in SciELO - Lilacs. The strength of evidence was evaluated by Oxford classification system was established from the study design used, considering the best available evidence for each question. RESULTS: We have defined 13 questions about the initial clinical approach for the diagnosis and treatment that resulted in 53 recommendations, including the etiology, treatment with antithyroid drugs, radioactive iodine and surgery. We also addressed hyperthyroidism in children, teenagers or pregnant patients, and management of hyperthyroidism in patients with Graves' ophthalmopathy and various other causes of thyrotoxicosis. CONCLUSIONS: The clinical diagnosis of hyperthyroidism usually offers no difficulty and should be made with measurements of serum TSH and thyroid hormones. The treatment can be performed with antithyroid drugs, surgery or administration of radioactive iodine according to the etiology of thyrotoxicosis, local availability of methods and preferences of the attending physician and patient.INTRODUÇÃO: O hipertireoidismo é caracterizado pelo aumento da síntese e liberação dos hormônios tireoidianos pela glândula tireoide. A tireotoxicose refere-se à síndrome clínica decorrente do excesso de hormônios tireoidianos circulantes, secundário ao hipertireoidismo ou não. Este artigo descreve diretrizes baseadas em evidências clínicas para o manejo da tireotoxicose. OBJETIVO: O presente consenso, elaborado por especialistas brasileiros e patrocinado pelo Departamento de Tireoide da Sociedade Brasileira de Endocrinologia e Metabologia, visa abordar o manejo, diagnóstico e tratamento dos pacientes com tireotoxicose, de acordo com as evidências mais recentes da literatura e adequadas para a realidade clínica do país. MATERIAIS E MÉTODOS: Após estruturação das questões clínicas, foi realizada busca das evidências disponíveis na literatura, inicialmente na base de dados do MedLine-PubMed e posteriormente nas bases Embase e SciELO - Lilacs. A força das evidências, avaliada pelo sistema de classificação de Oxford, foi estabelecida a partir do desenho de estudo utilizado, considerando-se a melhor evidência disponível para cada questão. RESULTADOS: Foram definidas 13 questões sobre a abordagem clínica inicial visando ao diagnóstico e ao tratamento que resultaram em 53 recomendações, incluindo investigação etiológica, tratamento com drogas antitireoidianas, iodo radioativo e cirurgia. Foram abordados ainda o hipertireoidismo em crianças, adolescentes ou pacientes grávidas e o manejo do hipertireoidismo em pacientes com oftalmopatia de Graves e com outras causas diversas de tireotoxicose. CONCLUSÕES: O diagnóstico clínico do hipertireoidismo, geralmente, não oferece dificuldade e a confirmação diagnóstica deverá ser feita com as dosagens das concentrações séricas de TSH e hormônios tireoidianos. O tratamento pode ser realizado com drogas antitireoidianas, administração de radioiodoterapia ou cirurgia de acordo com a etiologia da tireotoxicose, as características clínicas, disponibilidade local de métodos e preferências do médico-assistente e paciente.20523

Patient‐centered digital biomarkers for allergic respiratory diseases and asthma: The ARIA‐EAACI approach – ARIA‐EAACI Task Force Report

Biomarkers for the diagnosis, treatment and follow-up of patients with rhinitis and/ or asthma are urgently needed. Although some biologic biomarkers exist in specialist care for asthma, they cannot be largely used in primary care. There are no validated biomarkers in rhinitis or allergen immunotherapy (AIT) that can be used in clinical practice. The digital transformation of health and health care (including mHealth) places the patient at the center of the health system and is likely to optimize the practice of allergy. Allergic Rhinitis and its Impact on Asthma (ARIA) and EAACI (European Academy of Allergy and Clinical Immunology) developed a Task Force aimed at proposing patient-reported outcome measures (PROMs) as digital biomarkers that can be easily used for different purposes in rhinitis and asthma. It first defined control digital biomarkers that should make a bridge between clinical practice, randomized controlled trials, observational real-life studies and allergen challenges. Using the MASK-air app as a model, a daily electronic combined symptom-medication score for allergic diseases (CSMS) or for asthma (e-DASTHMA), combined with a monthly control questionnaire, was embedded in a strategy similar to the diabetes approach for disease control. To mimic real-life, it secondly proposed quality-of- life digital biomarkers including daily EQ-5D visual analogue scales and the bi-weekly RhinAsthma Patient Perspective (RAAP). The potential implications for the management of allergic respiratory diseases were proposed.info:eu-repo/semantics/publishedVersio

Pervasive gaps in Amazonian ecological research

Biodiversity loss is one of the main challenges of our time,1,2 and attempts to address it require a clear un derstanding of how ecological communities respond to environmental change across time and space.3,4 While the increasing availability of global databases on ecological communities has advanced our knowledge of biodiversity sensitivity to environmental changes,5–7 vast areas of the tropics remain understudied.8–11 In the American tropics, Amazonia stands out as the world’s most diverse rainforest and the primary source of Neotropical biodiversity,12 but it remains among the least known forests in America and is often underrepre sented in biodiversity databases.13–15 To worsen this situation, human-induced modifications16,17 may elim inate pieces of the Amazon’s biodiversity puzzle before we can use them to understand how ecological com munities are responding. To increase generalization and applicability of biodiversity knowledge,18,19 it is thus crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple or ganism groups in a machine learning model framework to map the research probability across the Brazilian Amazonia, while identifying the region’s vulnerability to environmental change. 15%–18% of the most ne glected areas in ecological research are expected to experience severe climate or land use changes by 2050. This means that unless we take immediate action, we will not be able to establish their current status, much less monitor how it is changing and what is being lostinfo:eu-repo/semantics/publishedVersio

Photography-based taxonomy is inadequate, unnecessary, and potentially harmful for biological sciences

The question whether taxonomic descriptions naming new animal species without type specimen(s) deposited in collections should be accepted for publication by scientific journals and allowed by the Code has already been discussed in Zootaxa (Dubois & Nemésio 2007; Donegan 2008, 2009; Nemésio 2009a–b; Dubois 2009; Gentile & Snell 2009; Minelli 2009; Cianferoni & Bartolozzi 2016; Amorim et al. 2016). This question was again raised in a letter supported by 35 signatories published in the journal Nature (Pape et al. 2016) on 15 September 2016. On 25 September 2016, the following rebuttal (strictly limited to 300 words as per the editorial rules of Nature) was submitted to Nature, which on 18 October 2016 refused to publish it. As we think this problem is a very important one for zoological taxonomy, this text is published here exactly as submitted to Nature, followed by the list of the 493 taxonomists and collection-based researchers who signed it in the short time span from 20 September to 6 October 2016

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Pervasive gaps in Amazonian ecological research

Biodiversity loss is one of the main challenges of our time,1,2 and attempts to address it require a clear understanding of how ecological communities respond to environmental change across time and space.3,4 While the increasing availability of global databases on ecological communities has advanced our knowledge of biodiversity sensitivity to environmental changes,5,6,7 vast areas of the tropics remain understudied.8,9,10,11 In the American tropics, Amazonia stands out as the world's most diverse rainforest and the primary source of Neotropical biodiversity,12 but it remains among the least known forests in America and is often underrepresented in biodiversity databases.13,14,15 To worsen this situation, human-induced modifications16,17 may eliminate pieces of the Amazon's biodiversity puzzle before we can use them to understand how ecological communities are responding. To increase generalization and applicability of biodiversity knowledge,18,19 it is thus crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple organism groups in a machine learning model framework to map the research probability across the Brazilian Amazonia, while identifying the region's vulnerability to environmental change. 15%–18% of the most neglected areas in ecological research are expected to experience severe climate or land use changes by 2050. This means that unless we take immediate action, we will not be able to establish their current status, much less monitor how it is changing and what is being lost