Aspectos éticos, legais e tendências no desenvolvimento de ensaios clínicos no Brasil

Dissertação (mestrado)—Universidade de Brasília, Faculdade de Ciência da Saúde, Programa de Pós-Graduação em Ciência da Saúde, 2014.Introdução: A pesquisa de novos medicamentos é uma estratégia importante para o desenvolvimento científico e tecnológico da nação e o conhecimento da realidade da pesquisa clínica brasileira é relevante para a tomada de decisão na construção da Política Nacional de Ciência, Tecnologia e Inovação em Saúde. Objetivos: Analisar o perfil de ensaios clínicos de bases de dados do Sistema de Controle de Pesquisa Clínica (SCPC) e da Plataforma Internacional para registro de ensaios Clínicos da Organização Mundial da Saúde (WHO International Clinical Trials Registry Platform - ICTRP) e pesquisas envolvendo seres humanos do Sistema Nacional sobre Ética em Pesquisa – SISNEP. Ainda, analisar registro de medicamentos do Sistema de Produtos e Serviços sob Vigilância Sanitária (Datavisa) da Anvisa. Métodos: As bases da dados utilizadas: (i) Sistema de Controle de Pesquisa Clínica (SCPC) da Agência Nacional de Vigilância Sanitária – Anvisa no período de 2007 a 2012; (ii) Sistema Nacional sobre Ética em Pesquisa – SISNEP no período de 2007 a 2012; (iii) Plataforma Internacional para registro de ensaios Clínicos da Organização Mundial da Saúde (WHO International Clinical Trials Registry Platform - ICTRP), no período de 2011 a 2012; (iv) Sistema de Produtos e Serviços sob Vigilância Sanitária – Datavisa, no período de 2010 a 2012. Os aspectos avaliados: patrocinadores, insumos farmacêuticos estudados, doenças estudadas, número de projetos de pesquisa aprovados pelos Comitês de Ética em Pesquisa (CEP). A tabulação dos dados dos ensaios clínicos do SCPC e ICTRP foi realizada em planilha Excel, utilizando o recurso de tabela dinâmica. Para os dados dos estudos do SISNEP foi utilizado IBM SPSS® (Statistical Package for Social Sciences) versão 15.0 para descrição das frequências absolutas e relativas. Resultados: Os dados obtidos SISNEP mostram um aumento do número de projetos de pesquisa envolvendo seres humanos aprovados por Comitês de Ética em Pesquisa (CEP’s) no Brasil. Em 2007 e 2011 foram aprovados, respectivamente, 18.160 e 125.743 projetos. Aproximadamente 50% dos CEP’s estão na região sudeste. Já 27% dos CEP’s estão concentrados no Estado de São Paulo. No Brasil a maioria dos estudos aprovados pela Anvisa é de cooperação estrangeira, envolvendo medicamentos sintéticos e sem participação de Organizações Representativas de Pesquisa Clínica (ORPC’s). As doenças mais frequentemente estudadas são o diabetes mellitus tipo 2 (DM2) e a neoplasia maligna da mama. O DM2 foi mais estudado nos Estados de São Paulo, Rio Grande do Sul e Ceará. Já a neoplasia maligna da mama foi mais estudada em São Paulo, Rio Janeiro e Rio Grande Sul. As pesquisas nacionais envolvem mais frequentemente doenças associadas à baixa mortalidade, como asma e varizes, ao passo que pesquisas de cooperação estrangeira abordam doenças associadas a maior mortalidade como as neoplasias malignas. As doenças consideradas negligenciadas ainda são pouco estudadas. Grande parte dos novos medicamentos registrados pela Anvisa não foi estudada na população Brasileira. A indústria nacional ainda é insipiente em inovação e está mais voltada ao desenvolvimento de medicamentos fitoterápicos. Conclusão: O desenvolvimento das inovações radicais e incrementais possui expressiva participação estrangeira. Nos testes de novos insumos farmacêuticos ativos, a população brasileira geralmente não é selecionada para participação nos ensaios clínicos. Os registros desses medicamentos pela Anvisa acontece com os dados de outras populações. A validade externa, que é a capacidade de generalização dos dados para a população geral, é um aspecto importante a ser avaliado na análise de solicitação de registro. A capacidade de inovação do Brasil na área farmacêutica ainda é insipiente.Introduction: The search for new drugs is an important strategy for scientific and technological development of the nation and the knowledge of the reality of Brazilian clinical research is relevant to decision making in the construction of the National Policy on Science, Technology and Innovation in Health. Objectives: To analyze the profile of clinical trials approved by the Brazilian Health Surveillance Agency (ANVISA) and the clinical trials registered in the International Registry Platform for Clinical Trials of the World Health Organization (WHO International Clinical Trials Registry Platform - ICTRP. Moreover, to analyze data from research projects approved by the Research Ethics Committee in National Research Ethics System (SISNEP) and to analyze drugs registered by Anvisa from Products and Services System in Health Surveillance – Datavisa. Methods: The database used: (i) Clinical Research Control System (SCPC) - ANVISA in the period 2007-2012; (ii) National System of Research Ethics - SISNEP the period 2007-2012; (iii) International Platform for registration Clinical trials of the World Health Organization (WHO International Clinical Trials Registry Platform - ICTRP) in the period 2011-2012; (iv) Products and Services System in Health Surveillance – Datavisa, in the period 2010- 2012. The aspects evaluated were sponsors, studied drugs and diseases, number of research projects approved by the Research Ethics Committee (CEP). The tabulation of data from clinical trials of SCPC and ICTRP was performed on an Excel spreadsheet, using the PivotTable feature. To study data SISNEP the IBM ® SPSS (Statistical Package for Social Sciences) version 15.0 for description of absolute and relative frequencies were used. Results: The data obtained from the National Research Ethics System (SISNEP) show an increase in the number of research projects involving Human Subjects approved by Research Ethics Committee (CER's) in Brazil. In 2007 and 2011 were approved 18,160 and 125,743 projects, respectively.. Approximately 50% of CER’s are in the Southeast. Already 27% of CER’s are concentrated in São Paulo. In Brazil the majority of studies approved by ANVISA is foreign cooperation, involving synthetic drug and without participation of Contract Research Organizations (CRO's). The most studied diseases were diabetes mellitus type II and malignant neoplasm of breast. The diabetes mellitus type II has been more studied in the States of São Paulo, Rio Grande do Sul and Ceará. Malignant neoplasm of the breast has been more studied in São Paulo, Rio de Janeiro and Rio Grande do Sul. National research study more diseases with low mortality, like asthma, varicose veins and other. Foreign cooperation research study more diseases with high mortality such as neoplasms. Neglected diseases are still poorly studied in Brazil. Many of the new drugs registered by Anvisa has not been studied in the Brazilian population. National Industry is more conducive to the development of herbal medicines. Conclusion: The development of radical and incremental innovations has significant foreign participation. In tests of new drugs, the Brazilian population is generally not selected for participation in clinical trials. The registry of these drugs by Anvisa happens with data from other populations. External validity, which is the ability to generalize the data to the general population, it is important aspect to be evaluated in the registry request. The innovativeness of Brazil in the pharmaceutical area is still incipient

National governance and excess mortality due to COVID-19 in 213 countries: a retrospective analysis and perspectives on future pandemics

Background: National governance may have influenced the response of institutions to the Covid-19 pandemic, being a key factor in preparing for the next pandemics. The objective was to analyze the association between excess mortality due to COVID-19 (daily and cumulative per 100 thousand people) and national governance indicators in 213 countries. // Method: Multiple linear regression models using secondary data from large international datasets that are in the public domain were performed. Governance indicators corresponded to six dimensions: (i) Voice and Accountability; (ii) Political Stability and Absence of Violence/Terrorism; (iii) Government Effectiveness; (iv) Regulatory Quality; (v) Rule of Law and (vi) Control of Corruption. The statistical analysis consisted of adjusting a multiple linear regression model. Excess mortality due to COVID-19 was adjusted for potential confounding factors (demographic, environmental, health, economic, and ethnic variables). // Results: The indicators Control of Corruption, Government Effectiveness, Regulatory Quality and Rule of Law had a significant inverse association (p < 0.0001) with the estimated excess mortality in 2020, 2021 and 2022. Furthermore, the governance indicators had a direct significant association (p < 0.0001) with the vaccination variables (People_fully_vaccinated; Delivered population; The total number of vaccination doses administered per 100 people at the country level), except for the variables Vaccination policies and Administration of first dose, which were inversely associated. In countries with better governance, COVID-19 vaccination was initiated earlier. // Conclusion: Better national governance indicators were associated with lower excess mortality due to COVID-19 and faster administration of the first dose of the COVID-19 vaccine

Tendências, implicações éticas e regulatórias da globalização de ensaios clínicos com novos medicamentos em países das Américas, Ásia, África e Europa.

Tese (Doutorado)—Universidade de Brasília, Faculdade de Ciências da Saúde, 2018.Introdução: A migração de ensaios clínicos de regiões de países ricos para regiões menos desenvolvidas como os países de renda média baixa e renda baixa envolve benefícios, pois permite acesso a tratamentos experimentais inovadores aos pacientes, atração de investimentos para os centros de pesquisa e a possibilidade de harmonização de procedimentos. Por outro lado, esses estudos têm migrado para regiões com desigualdades sociais, econômicas e de saúde expressivas, onde há risco de violações dos direitos dos participantes. Objetivo: Analisar tendências relativas a participação de populações vulneráveis em ensaios clínicos, aos planos de acesso pós-estudo e aos tipos de câncer investigados nos ensaios clínicos em países das Américas, Europa, Ásia e África, classificados pelo nível de desenvolvimento, no período de 2009 a 2017. Métodos: Estudo analítico, retrospectivo e de coleta de dados em bases: (i) Sistema de Controle de Pesquisa Clínica (SCPC) da Agência Nacional de Vigilância Sanitária (Anvisa), (ii) Sistema de Produtos e Serviços sob Vigilância Sanitária - Datavisa (Anvisa) e (iii) Plataforma Internacional de Registro de Ensaios Clínicos (International Clinical Trials Registry Platform, ICTRP). Resultados: Nos ensaios clínicos globais, conduzidos em diversos países, os pacientes incapazes de dar consentimento pessoalmente têm 11,4 vezes mais chances de serem pacientes vulneráveis do que pacientes que são capazes, e que pacientes em países de renda média-alta têm 1,7 vezes mais chances de serem pacientes vulneráveis do que pacientes de países de alta renda quando participam de ensaios clínicos globais. Entre os países selecionados na pesquisa, o fornecimento de medicamentos pós-estudo é obrigatório apenas na Argentina, no Brasil, no Chile, na Finlândia e no Peru. Os ensaios clínicos sem planos de acesso pós-estudo e que envolveram populações vulneráveis foram mais concentrados em países de renda média alta (25%) e renda média baixa (24%) em comparação aos países de renda alta (20%). Na região da América Latina e do Caribe, as doenças negligenciadas, como a doença de Chagas e a dengue, representaram 1% do total de estudos. Houve uma tendência de ensaios clínicos envolvendo câncer de mama e pulmão em países com menor nível de desenvolvimento. Por outro lado, os cânceres de colo de útero, de estômago e de fígado, apesar do impacto na saúde das populações dos países de renda média baixa, foram pouco estudados. Conclusões: Os ensaios clínicos têm migrado para países onde os participantes podem ter seus direitos violados. Esses participantes têm ajudado a desenvolver os novos medicamentos, a partir de sua participação nos estudos, mas o acesso ao medicamento experimental após o encerramento dos estudos pode não ser garantido. Isso porque apenas em poucos países esse acesso pós-estudo é regulamentado. Isso pode ser mais grave em países com populações vulneráveis, onde os indivíduos não conseguem proteger seus interesses e o paciente corre o risco de sofrer danos devido a descontinuação permanente do tratamento. Os países precisam aprimorar e fortalecer seus mecanismos de controle ético e regulatório, considerando os riscos envolvidos na migração de ensaios clínicos.Introduction: The migration of clinical trials from rich countries to less-developed regions, such as lower middle-income and low-income countries, involves benefits, as it allows access to innovative experimental treatments for the patients, attracts investment to research centers, and raises the possibility of standardizing procedures. On the other hand, these studies have migrated to regions with significant social, economic and health inequalities, where there is a risk that the participants’ rights will be violated. Objective: To analyze tendencies related to the participation of vulnerable populations in clinical trials, to post-trial access plans and to the types of cancer investigated in clinical trials in countries in the Americas, Asia, Africa and Europe, classified by level of development, in the period 2009 – 2017. Methods: Analytical and retrospective study, based on data collection from the following bases: (i) the Clinical Research Control System (Sistema de Controle de Pesquisa Clínica - SCPC) of the Brazilian Health Regulatory Agency (Anvisa), (ii) the Products and Services Subject to Health Surveillance System (Sistema de Produtos e Serviços sob Vigilância Sanitária (Datavisa) of the Anvisa and (iii) the International Clinical Trials Registry Platform (ICTRP). Results: In the global clinical trials, conducted in various countries, patients unable to give consent personally are 11.4 times more likely to be vulnerable patients than are patients who are able; patients in upper-middle income countries are 1.7 times more likely to be vulnerable patients than are patients from high income countries when they participate in global clinical trials. Among the countries selected in the study, it is obligatory to provide drugs after the study only in Argentina, Brazil, Chile, Finland and Peru. The clinical trials lacking post-trial access plans and involving vulnerable populations were concentrated more heavily in upper-middle income countries (25%) and lower middle-income countries (24%), in comparison with high income countries (20%). In the region of Latin America and the Caribbean, the neglected diseases, such as Chagas’ disease and dengue, represented 1% of the total number of studies. There was a tendency for clinical trials involving breast and lung cancer to be conducted in countries with lower levels of development. On the other hand, cancers of the cervix, stomach and liver, in spite of their impact on the health of the populations of lower middle-income countries, were studied little. Conclusions: Clinical trials have migrated to countries where the participants’ rights may be violated. These participants have helped to develop the new drugs, based on their participation in the study; however, access to the experimental drug after the termination of the trial may not be guaranteed. This is because post-trial access is regulated in only a small number of countries. This may be a more serious issue in countries with vulnerable populations, where individuals are unable to protect their interests, and where the patient runs the risk of being harmed due to the permanent discontinuation of the treatment. Countries need to improve and strengthen their mechanisms for ethical and regulatory control, taking into account the risks involved in the migration of clinical trials

National governance and excess mortality due to COVID-19 in 213 countries: a retrospective analysis and perspectives on future pandemics

Abstract Background National governance may have influenced the response of institutions to the Covid-19 pandemic, being a key factor in preparing for the next pandemics. The objective was to analyze the association between excess mortality due to COVID-19 (daily and cumulative per 100 thousand people) and national governance indicators in 213 countries. Method Multiple linear regression models using secondary data from large international datasets that are in the public domain were performed. Governance indicators corresponded to six dimensions: (i) Voice and Accountability; (ii) Political Stability and Absence of Violence/Terrorism; (iii) Government Effectiveness; (iv) Regulatory Quality; (v) Rule of Law and (vi) Control of Corruption. The statistical analysis consisted of adjusting a multiple linear regression model. Excess mortality due to COVID-19 was adjusted for potential confounding factors (demographic, environmental, health, economic, and ethnic variables). Results The indicators Control of Corruption, Government Effectiveness, Regulatory Quality and Rule of Law had a significant inverse association (p < 0.0001) with the estimated excess mortality in 2020, 2021 and 2022. Furthermore, the governance indicators had a direct significant association (p < 0.0001) with the vaccination variables (People_fully_vaccinated; Delivered population; The total number of vaccination doses administered per 100 people at the country level), except for the variables Vaccination policies and Administration of first dose, which were inversely associated. In countries with better governance, COVID-19 vaccination was initiated earlier. Conclusion Better national governance indicators were associated with lower excess mortality due to COVID-19 and faster administration of the first dose of the COVID-19 vaccine

Trends in research involving human beings in Brazil

Developing countries have experienced a dramatic increase in the number of clinical studies in the last decades. The aim of this study was to describe 1) the number of clinical trials submitted to the Brazilian Health Surveillance Agency (Agência Nacional de Vigilância Sanitária, Anvisa) from 2007 to 2012 and the number of human-subject research projects approved by research ethics committees (RECs) and the National Research Ethics Committee (Comissão Nacional de Ética em Pesquisa, CONEP) in Brazil from 2007 to 2011 and 2) the diseases most frequently studied in Brazilian states in clinical trials approved in the country from 2009 to 2012, based on information from an Anvisa databank. Two databases were used: 1) the National Information System on Research Ethics Involving Human Beings (Sistema Nacional de Informação Sobre Ética em Pesquisa envolvendo Seres Humanos, SISNEP) and 2) Anvisa's Clinical Research Control System (Sistema de Controle de Pesquisa Clínica, SCPC). Data from the SCPC indicated an increase of 32.7% in the number of clinical trials submitted to Anvisa, and data from the SISNEP showed an increase of 69.9% in those approved by RECs and CONEP (from 18 160 in 2007 to 30 860 in 2011). Type 2 diabetes (26.0%) and breast cancer (20.5%)-related to the main causes of mortality in Brazil-were the two most frequently studied diseases. The so-called “neglected diseases,” such as dengue fever, were among the least studied diseases in approved clinical trials, despite their significant impact on social, economic, and health indicators in Brazil. Overall, the data indicated 1) a clear trend toward more research involving human beings in Brazil, 2) good correspondence between diseases most studied in clinical trials approved by Anvisa and the main causes of death in Brazil, and 3) a low level of attention to neglected diseases, an issue that should be considered in setting future research priorities, given their socioeconomic and health effects

Incentives and challenges related to technological research and innovation within the Unified Health System in the Federal District of Brazil

Submitted by Jaqueline Ferreira de Souza ([email protected]) on 2020-03-16T13:17:24Z No. of bitstreams: 2 ve_Maria_Novaes_etal_por.pdf: 283808 bytes, checksum: 7c924f7666568141760fcf0ae7c61016 (MD5) ve_Maria_Novaes_etal_eng.pdf: 277323 bytes, checksum: 6a2d89535284d779a3d19b8816498f60 (MD5)Approved for entry into archive by Jaqueline Ferreira de Souza ([email protected]) on 2020-03-18T14:19:35Z (GMT) No. of bitstreams: 2 ve_Maria_Novaes_etal_por.pdf: 283808 bytes, checksum: 7c924f7666568141760fcf0ae7c61016 (MD5) ve_Maria_Novaes_etal_eng.pdf: 277323 bytes, checksum: 6a2d89535284d779a3d19b8816498f60 (MD5)Made available in DSpace on 2020-03-18T14:19:35Z (GMT). No. of bitstreams: 2 ve_Maria_Novaes_etal_por.pdf: 283808 bytes, checksum: 7c924f7666568141760fcf0ae7c61016 (MD5) ve_Maria_Novaes_etal_eng.pdf: 277323 bytes, checksum: 6a2d89535284d779a3d19b8816498f60 (MD5) Previous issue date: 2019Fundação de Ensino e Pesquisa em Ciências de Saúde. Escola Superior de Ciências da Saúde. Coordenação de Pesquisa e Comunicação Científica. Brasília, DF, Brasil.Fundação Oswaldo Cruz. Fiocruz Brasília. Brasília, DF, Brasil.Fundação Oswaldo Cruz. Fiocruz Brasília. Brasília, DF, Brasil.Agência Nacional de Vigilância Sanitária. Coordenação de Pesquisa Clínica em Medicamentos e Produtos Biológicos. Brasília, DF, Brasil.Fundação de Ensino e Pesquisa em Ciências de Saúde. Escola Superior de Ciências da Saúde. Coordenação de Pesquisa e Comunicação Científica. Brasília, DF, Brasil.Fundação de Ensino e Pesquisa em Ciências de Saúde. Escola Superior de Ciências da Saúde. Coordenação de Pesquisa e Comunicação Científica. Brasília, DF, Brasil.Ministério da Saúde. Departamento de Ciência e Tecnologia. Brasília, DF, Brasil.O objetivo deste trabalho foi analisar o perfil das pesquisas científicas financiadas no Distrito Federal provenientes das chamadas públicas do Programa Pesquisa para o SUS: Gestão Compartilhada em Saúde (PPSUS/DF) e Programa de Fomento a Pesquisa Científica da ESCS/FEPECS, no período de 2008 a 2017. O estudo é analítico e documental, abrangendo o universo das pesquisas financiadas nesses dois Programas. As variáveis foram: ano, título, tema de pesquisa da Agenda Nacional de Prioridades de Pesquisas em Saúde (ANPPS), setor de aplicação, instituição e valor financiado. No período de 2008 a 2017, 73 projetos foram financiados pelos cinco editais do PPSUS/ DF. O valor total foi de aproximadamente oito milhões de reais. Em relação à ESCS/FEPECS, entre 2008 a 2017, foram financiados 85 projetos pelos dez editais lançados. O valor total foi de 2,3 milhões de reais. Concluiu-se que o perfil das pesquisas científicas permitiu uma análise crítica das temáticas dos projetos. Recomenda-se que os próximos editais adotem como prioridade de pesquisa as três principais causas de óbitos, o processo de organização e avaliação de linhas de cuidados, serviços de saúde e redes de atenção.This article analyzes the profile of research conducted in the Federal District of Brazil funded through public calls for proposals issued by the Research for the SUS Program: shared health management/Federal District (PPSUS/DF) and a research support program run by the Superior School of Health Sciences, maintained by the Health Sciences Teaching and Research Foundation (ESCS/FEPECS, acronym in Portuguese). A document analysis was undertaken of all research funded by the PPSUS/DF and ESCS/FEPECS's Research Support Program between 2008 and 2017 using the following variables: year, title, research themes of the National Agenda for Health Research Priorities (ANPPS, acronym in Portuguese), implementing organization, area of application of research, and amount of funding. PPSUS/DF funded 73 projects with a total investment of approximately R$8 million, while ESCS/FEPECS funded 85 projects with a total investment of R$2.3 million. This study provides a critical analysis of the research themes supported by ESCS/FEPECS and PPSUS/DF between 2008 and 2017. It is recommended that future calls for proposals should prioritize the three leading causes of death in the Federal District and the organization and evaluation of healthcare services

Research Priorities and Resource Allocation in the Investigation of New Drugs for Cancer in Least Developed Countries

Cancer incidence has increased significantly in low- and middle-income countries. The priorities of international health research are not always aligned with the global burden of cancer. This study aims to analyze global tendencies in clinical trials in oncology and discuss research priorities and resource allocation in the investigation of new drugs for cancers that significantly affect the least developed countries. This was a retrospective and analytical study that included data collected from the World Health Organization’s International Clinical Trials Registry Platform (ICTRP) in 2014. According to our results, there was a tendency for clinical trials involving breast and lung cancer to be conducted in countries with a lower level of economic development. On the other hand, cervical, stomach, and liver cancer, despite the significant burden that these place on middle- and low-income countries, were studied little among the countries selected. In conclusion, the organizations that most fund research to develop new drugs for cancer treatment continue to show little interest in prioritizing resources to fund research for certain types of cancer such as those of the cervix, stomach, and liver, which have a significant impact in low- and middle-income countries