Quality, Non-clinical and Clinical Considerations for Biosimilar Monoclonal Antibody Development: EU, WHO, USA, Canada, and BRICS-TM Regulatory Guidelines

Objective: The aim was to critically evaluate well-established regulatory agencies mAb biosimilar guidelines for development and marketing authorization about quality, efficacy and safety and compare to BRICS-TM regulations to identify challenges. Materials and Methods: The current valid guidelines of EMA, WHO, USFDA, BGTD/HC, ICH, and BRICS-TM were obtained from official websites and comparative qualitative review was performed. Results: The review revealed that Health Canada uses mAb specific guidelines from EMA or USFDA when necessary. The BRICS agencies (except Russia) have incorporated some or most of the WHO SBP TRS and related annexes in similar national biotechnological/biological guidelines; however, gaps or insufficient information have been identified. The Russian Federation has issued general product registration guideline/s with very brief information about mAbs. The TMMDA (Turkey) has published an updated biosimilar guideline which parallels those of the EMA and the ones from WHO; however, no mAb specific guidelines are published. COFEPRIS (Mexico) has published a biotechnological/biological product registration guideline with no information about mAb. The SAHPRA biosimilar guideline has an annex on mAbs which focuses on non-clinical and clinical aspects. The comparative evaluation of BRICS-TM agencies indicates a gap pertaining to clarification for physico-chemical characterization, manufacturing process, overages and compatibility requirements between biological substances and excipients specifically on mAbs. In vitro assay requirements seem quite aligned with those of WHO, whereas in vivo studies mostly have disparity in terms of necessity, type of studies as well as design and criteria. Clinical safety and efficacy studies are indicated in emerging regulatory agencies, however detailed information pertaining to design, size of populations, requirements for primary and secondary endpoints, clarity and evaluation criteria differ. In general, BRICS-TM agencies allow extrapolation of indications provided that pre-defined conditions are met. Interchangeability, switching and substitution of biosimilars are not defined in most of BRIC-TM guidelines whereas South Africa, by law, allows neither interchangeability nor substitution. Pediatric research remains questionable across BRICS-TM. Conclusions: EMA, USFDA guidelines are broadly aligned with WHO and in addition, they also contain specific requirements pertaining to their own region. BRICS-TM has considerably less defined mAb specific biosimilar development and comparability parameters in their published guidelines.Peer reviewedFinal Published versio

Revisão dos Procedimentos de Pós-Registro de Medicamentos

O Grupo de Trabalho (GT) de revisão do regulamento técnico para pós-registro de -medicamentos da Anvisa vem trabalhando na desburocratização e celeridade dos procedimentos regulatórios referentes à atualização de dados do medicamento após a obtenção de seu registro. Esses são itens de fundamental importância para o estímulo da produção e da qualidade dos medicamentos comercializados no país. Foi feita uma classificação das modificações pós-registro de medicamentos conforme o risco sanitário, a complexidade de análise e testes farmacotécnicos. A abordagem permitiu eficiência da análise técnica e, uma vez que esses procedimentos tornaram-se mais céleres, houve maior previsibilidade nas ações de pós-registro com a adoção dos novos fluxos e prazos de análiseNúmero de páginas: 08 p.Gestão de ProcessosInovaçãoIniciativa premiada no 13º Concurso Inovação na Gestão Pública Federal sob responsabilidade de Mônica da Luz Carvalho Soares. Ações premiadas no 13º Concurso Inovação na Gestão Pública Federal – 2008Áreas temáticas:Melhoria dos processos de trabalho; Implementação de melhoria contínua; Melhoria dos processos de trabalh

Cartilha de vigilância sanitária: cidadania e controle social. 2. ed.

55p., il. color.Esta cartilha apresenta conceitos, informações, leis e reflexões, de forma abrangente, sobre o tema Vigilância Sanitária e sobre o Sistema Único de Saúde (SUS), chamando a atenção para exemplos da vida cotidiana da população brasileira em que as ações de Vigilância Sanitária devem estar presentes

Projeto Hospitais Sentinela: uma estratégia de vigilância para a pós-comercialização de produtos de saúde

O Projeto Hospitais Sentinela, criado em 2002, é uma experiência inovadora que congrega a Agência Nacional de Vigilância Sanitária, Anvisa, o Sistema Nacional de Vigilância Sanitária, SNVS, o Programa para o Desenvolvimento das Nações Unidas, PNUD, e 180 hospitais escolhidos entre os maiores e mais complexos serviços do país para a criação de uma rede sentinela que objetiva obter informações qualificadas a respeito da qualidade dos produtos e do seu perfil de risco-benefício, tendo em vista o subsídio de ações de regulação de mercado. O projeto também contribui para a melhoria da qualidade da atenção à saúde, por meio da busca ativa, bem como da investigação de eventos adversos nesses serviços e da adoção de medidas para a redução e para o controle de riscos relacionados às tecnologias em saúde, inovadoras ou não. A avaliação de desempenho do projeto revela-se como uma estratégia poderosa e de custo reduzido para a obtenção de informação sobre a qualidade e segurança de produtos sujeitos à vigilância sanitária, bem como para a observação da difusão, uso racional, efetividade, segurança e custo de novas práticas em saúde. Esses aspectos da avaliação de desempenho do projeto possibilita recomendá-la como ferramenta de trabalho para estados e municípios que desejem qualificar a atenção hospitalar em seus territóriosNúmero de páginas: 7 p.InovaçãoIniciativa premiada no 11º Concurso Inovação na Gestão Pública Federal sob responsabilidade de Clarice Alegre Petramale. Ações premiadas no 11º Concurso Inovação na Gestão Pública Federal – 2006. Área temática: arranjos institucionais para coordenação e implementação de políticas pública

Melhoria de gestão com foco no trinômio: pessoas, processos e tecnologia de informação

O trabalho iniciou-se em junho de 2005, na GMEFH1, cuja metodologia se pautava na revisão dos processos de trabalho, levantados a partir de reuniões semanais com um grupo representativo, na definição de papéis e responsabilidades dos colaboradores da área, no desenvolvimento de um sistema de informação que possibilitasse a consolidação dos procedimentos e uniformização de condutas e, por fim, no treinamento de uma prática gestora, com estabelecimento de metas, registro e revisão de procedimentos, bem como o monitoramento de prazos e resultados. O cenário anterior apresentava grande descontrole do fluxo do processo de trabalho, ausência de padrão nos procedimentos, número desconhecido das petições sem análise (passivo), infraestrutura imprópria, subjetividade na análise técnica, inexistência de planejamento estratégico, entre outros. Após a realização do trabalho, foram observados os seguintes resultados: acréscimo significativo da produtividade, apesar da redução do quadro-geral de pessoas (de 38 para 30) e do número de técnicos (de 34 para 23) desempenhando a atividade-fim (análise 100 técnica para concessão de registro de medicamentos); tratamento do passivo com redução de 89% das petições que iriam para a análise; grande diminuição do tempo de resposta ao setor regulado; e padronização nos procedimentos de análise técnica, trazendo uniformidade na conduta técnica, tema recorrentemente requisitado pelo setor reguladoNúmero de páginas: 9 p.InovaçãoIniciativa premiada no 11º Concurso Inovação na Gestão Pública Federal sob responsabilidade de Ana Cláudia Sayeg Freire Murahovschi. Ações premiadas no 11º Concurso Inovação na Gestão Pública Federal – 2006. Áreas temáticas: estabelecimento de padrões de atendimento de serviços; atendimento ao cidadã

Establishing What Constitutes a Healthy Human Gut Microbiome: State of the Science, Regulatory Considerations, and Future Directions.

On December 17, 2018, the North American branch of the International Life Sciences Institute (ILSI North America) convened a workshop "Can We Begin to Define a Healthy Gut Microbiome Through Quantifiable Characteristics?" with >40 invited academic, government, and industry experts in Washington, DC. The workshop objectives were to 1) develop a collective expert assessment of the state of the evidence on the human gut microbiome and associated human health benefits, 2) see if there was sufficient evidence to establish measurable gut microbiome characteristics that could serve as indicators of "health," 3) identify short- and long-term research needs to fully characterize healthy gut microbiome-host relationships, and 4) publish the findings. Conclusions were as follows: 1) mechanistic links of specific changes in gut microbiome structure with function or markers of human health are not yet established; 2) it is not established if dysbiosis is a cause, consequence, or both of changes in human gut epithelial function and disease; 3) microbiome communities are highly individualized, show a high degree of interindividual variation to perturbation, and tend to be stable over years; 4) the complexity of microbiome-host interactions requires a comprehensive, multidisciplinary research agenda to elucidate relationships between gut microbiome and host health; 5) biomarkers and/or surrogate indicators of host function and pathogenic processes based on the microbiome need to be determined and validated, along with normal ranges, using approaches similar to those used to establish biomarkers and/or surrogate indicators based on host metabolic phenotypes; 6) future studies measuring responses to an exposure or intervention need to combine validated microbiome-related biomarkers and/or surrogate indicators with multiomics characterization of the microbiome; and 7) because static genetic sampling misses important short- and long-term microbiome-related dynamic changes to host health, future studies must be powered to account for inter- and intraindividual variation and should use repeated measures within individuals

Sensing of formetanate pesticide in fruits with a boron-doped diamond electrode

This study describes the development of a simple and accurate methodology for carbamate pesticide formetanate (FMT) analysis in fruits based on the use of a boron-diamond doped electrode (BDDE) cathodically pretreated and on the forward component of the current of square-wave voltammetry (SWV). FMT exhibits a well-defined irreversible oxidation process, which reaction mechanism is diffusion-controlled, involves the participation of one electron and is influenced by the electrolyte pH. However, protonation does not participate in the rate-determining step in the redox process. The optimum experimental and voltammetric conditions were pH 7.0 (0.04 mol L−1 Britton-Robinson buffer), pulse potential frequency of 20 s−1, amplitude of the pulse of 25 mV, and height of the potential step of 3 mV. Under the optimum conditions, calibration curve was linear from 4.98 × 10−7 to 1.70 × 10−5 mol L−1 FMT with a limit of detection of 3.7 × 10−7 mol L−1. FMT sensing was performed in different fruits (mango and grape). Recoveries ranged from 95.2 ± 2.8 to 104.0 ± 3.5% for mango and 96.5 ± 2.5 to 105.2 ± 3.5% for grape proving the accuracy and precision of the electroanalytical methodology. The attained data validated the applicability of the developed approach for FMT quantification in fruits.info:eu-repo/semantics/publishedVersio

Acute hepatitis C virus infection assessment among chronic hemodialysis patients in the Southwest Parana State, Brazil

BACKGROUND: Chronic hemodialysis patients are at higher risk for acquiring hepatitis C virus (HCV). The prevalence varies among different countries and hemodialysis centers. Although guidelines for a comprehensive infection control program exist, the nosocomial transmission still accounts for the new cases of infection. The aim of this study was analyze the follow up of newly acquired acute hepatitis C cases, during the period from January 2002 to May 2005, in the Hemodialysis Center, located in the Southwest region of Parana State, Brazil and to analyze the effectiveness of the measures to restrain the appearance of new cases of acute hepatitis C. METHODS: Patients were analyzed monthly with anti-HCV tests and ALT measurements. Patients with ALT elevations were monitored for possible acute hepatitis C. RESULTS: During this period, 32 new cases were identified with acute hepatitis C virus infection. Blood screening showed variable ALT levels preceding the anti-HCV seroconversion. HCV RNA viremia by PCR analysis was intermittently and even negative in some cases. Ten out of 32 patients received 1 mcg/kg dose of pegylated interferon alfa-2b treatment for 24 weeks. All dialysis personnel were re-trained to strictly follow the regulations and recommendations regarding infection control, proper methods to clean and disinfect equipment were reviewed and HCV-positive patients were isolated. CONCLUSION: Laboratory tests results showed variable ALT preceding anti-HCV seroconversion and intermittent viremia. The applied recommendations contributed importantly to restrain the appearance of new cases of acute hepatitis C in this center and the last case was diagnosed in May 2004

Consumer Willingness to Pay for Dengue Vaccine (CYD-TDV, Dengvaxia®) in Brazil; Implications for Future Pricing Considerations

Introduction and Objective: Dengue virus is a serious global health problem with an estimated 3.97 billion people at risk for infection worldwide. In December 2015, the first vaccine (CYD-TDV) for dengue prevention was approved in Brazil, developed by Sanofi Pasteur. However, given that the vaccine will potentially be paid via the public health system, information is need regarding consumers’ willingness to pay for the dengue vaccine in the country as well as discussions related to the possible inclusion of this vaccine into the public health system. This was the objective of this research. Methods: We conducted a cross-sectional study with residents of Greater Belo Horizonte, Minas Gerais, about their willingness to pay for the CYD-TDV vaccine. Results: 507 individuals were interviewed. These were mostly female (62.4%) had completed high school (62.17%), were working (74.4%), had private health insurance (64.5%) and did not have dengue (67.4%). The maximum median value of consumers’ willingness to pay for CYD-TDV vaccine is US$33.61 (120.00BRL) for the complete schedule and US$11.20 (40.00BRL) per dose. At the price determined by the Brazil’s regulatory chamber of pharmaceutical products market for the commercialization of Dengvaxia(®) for three doses, only 17% of the population expressed willingness to pay for this vaccine. Conclusion: Brazil is currently one of the largest markets for dengue vaccine and the price established is a key issue. We believe the manufacturer should asses the possibility of lower prices to reach a larger audience among the Brazilian population

International Society of Sports Nutrition Position Stand: Probiotics.

Position statement: The International Society of Sports Nutrition (ISSN) provides an objective and critical review of the mechanisms and use of probiotic supplementation to optimize the health, performance, and recovery of athletes. Based on the current available literature, the conclusions of the ISSN are as follows: 1)Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host (FAO/WHO).2)Probiotic administration has been linked to a multitude of health benefits, with gut and immune health being the most researched applications.3)Despite the existence of shared, core mechanisms for probiotic function, health benefits of probiotics are strain- and dose-dependent.4)Athletes have varying gut microbiota compositions that appear to reflect the activity level of the host in comparison to sedentary people, with the differences linked primarily to the volume of exercise and amount of protein consumption. Whether differences in gut microbiota composition affect probiotic efficacy is unknown.5)The main function of the gut is to digest food and absorb nutrients. In athletic populations, certain probiotics strains can increase absorption of key nutrients such as amino acids from protein, and affect the pharmacology and physiological properties of multiple food components.6)Immune depression in athletes worsens with excessive training load, psychological stress, disturbed sleep, and environmental extremes, all of which can contribute to an increased risk of respiratory tract infections. In certain situations, including exposure to crowds, foreign travel and poor hygiene at home, and training or competition venues, athletes' exposure to pathogens may be elevated leading to increased rates of infections. Approximately 70% of the immune system is located in the gut and probiotic supplementation has been shown to promote a healthy immune response. In an athletic population, specific probiotic strains can reduce the number of episodes, severity and duration of upper respiratory tract infections.7)Intense, prolonged exercise, especially in the heat, has been shown to increase gut permeability which potentially can result in systemic toxemia. Specific probiotic strains can improve the integrity of the gut-barrier function in athletes.8)Administration of selected anti-inflammatory probiotic strains have been linked to improved recovery from muscle-damaging exercise.9)The minimal effective dose and method of administration (potency per serving, single vs. split dose, delivery form) of a specific probiotic strain depends on validation studies for this particular strain. Products that contain probiotics must include the genus, species, and strain of each live microorganism on its label as well as the total estimated quantity of each probiotic strain at the end of the product's shelf life, as measured by colony forming units (CFU) or live cells.10)Preclinical and early human research has shown potential probiotic benefits relevant to an athletic population that include improved body composition and lean body mass, normalizing age-related declines in testosterone levels, reductions in cortisol levels indicating improved responses to a physical or mental stressor, reduction of exercise-induced lactate, and increased neurotransmitter synthesis, cognition and mood. However, these potential benefits require validation in more rigorous human studies and in an athletic population