Challenges and opportunities for access to Advanced Therapy Medicinal Products in Brazil.

BACKGROUND AIMS: The marketing authorization of Advanced Therapy Medicinal Products (ATMPs) in Brazil is recent. The features of these therapies impose specialized regulatory action and are consequently challenging for developers. The goal of this study was to identify the industry's experience in clinical development, marketing authorization and access to ATMPs through the Unified Health System (SUS, acronym in Portuguese), from a regulatory perspective. METHODS: A survey containing structured questions was conducted among research participants who work at companies that commercialize ATMPs. A descriptive analysis was performed. RESULTS: We invited 15 foreign pharmaceutical companies, of which 10 agreed to participate. Overall, participants assessed that Brazil has a well-established regulatory system, especially the sanitary registration by the National Health Surveillance Agency (Anvisa), which ensures the quality, safety, and efficacy of the products. The Agency's good interaction with the regulated sector, the harmonization of sanitary and ethical assessment systems with other countries, and the analysis time in the biosafety assessment of Genetically Modified Organisms (GMOs) stand out as positive in industry's evaluation. On the other hand, it is important to advance the pricing regulation for these products since Brazilian regulations do not establish specific criteria for ATMP. One of the biggest challenges is the difficulty for the SUS in reimbursing these very high-cost therapies, especially using current Health Technology Assessment (HTA) methods. CONCLUSIONS: Considering the increasing number of approvals of cell and gene therapies in Brazil in the coming years, a close dialogue between the industry and the public sector is recommended to advance regulatory improvements (pricing and HTA). Additionally, the construction of policies to promote the national Health Economic-Industrial Complex, based on a mission-oriented vision that encourages innovative models of financing, especially those that consider risk-sharing and co-financing technologies, will help provide the population with universal, equitable and sustainable access to ATMP in the SUS.

Landscape of Brazilian research and development public funding in advanced therapies: lessons learned and a roadmap for middle-income economies.

BACKGROUND AIMS: Advanced therapy medicinal products (ATMPs) have reached the forefront of biotechnological innovation, partly due to public funders' efforts in the early stages of research and development (R&D). Data on investment in R&D of ATMPs are recognized as scarce, particularly in developing countries. Because of the numerous peculiarities of the Brazilian health system and the science and technology (S&T) system, the country is a good example for the evaluation of public investments in R&D of ATMPs. The aim of this study is to analyze the evolution of investments made by the Ministry of Health (MoH) of Brazil and partners in the ATMP field between 2004 and 2020. METHODS: A descriptive analysis was performed based on secondary data. The analysis was based on S&T and innovation research and support for research infrastructure in the field. The database was stratified by year of funding, ATMP type, type of study or research infrastructure project, amount invested in the project, targeted disease for which clinical trials in ATMPs were developed and financing sector (health, education, S&T and economic). RESULTS: The investments coordinated by MoH (61.5%) in partnership with the S&T, education and economic sectors (38.5%) consisted of Int$137.35 million in 282 ATMP projects. Funding included S&T and innovation research (67% of the total amount) and projects to implement or maintain infrastructure in selected research centers (32.98%). With regard to global convergence, cell therapy was the type of ATMP that most benefited from public investment, totaling 82.23% of the total funding in the analyzed period. Cardiology (29%) and neurology (21%) were the main focus of clinical trials. Following the global trend of public sector R&D funding, the number of basic and pre-clinical research projects represented 78.06% of the total number of projects. CONCLUSIONS: Despite the need to implement improvements in ATMP R&D financing policy in Brazil, the country has made important steps in the field and can serve as a benchmark for other countries with socioeconomic similarities. Among the main lessons are the prioritization of research aligned with the health needs of the population, cross-sector articulation by the health policymaker to coordinate R&D efforts of the sector and formulation of a specific sector policy (Programa Genomas Brasil, the Brazilian National Program of Genomic and Precision Medicine) to promote knowledge translation.

Acordo de Compartilhamento de Risco: projeto-piloto no Sistema Único de Saúde / Risk Sharing Agreement: a pilot project in the Brazilian Unified Health System

O Acordo de Compartilhamento de Risco é definido como um acordo no qual o Estado concorda em oferecer acesso temporário a um novo medicamento, enquanto a indústria farmacêutica aceita receber pelo produto conforme o desempenho do medicamento em reais condições de uso. A partilha de risco depende, necessariamente, da coleta de evidências adicionais, que podem se referir aos benefícios terapêuticos ou ao volume de pacientes, conforme avaliação de seu uso na prática. Os autores descreveram a experiência do projeto-piloto de Acordo de Compartilhamento de Risco no Sistema Único de Saúde.

Risk Sharing Agreement is defined as an agreement in which the State agrees to offer temporary access to a new drug, while the pharmaceutical industry accepts to receive the product according to the performance of the drug in real conditions of use. Risk sharing necessarily depends on the collection of additional evidence that may refer to the therapeutic benefits or the volume of patients, according to the assessment of its use in practice. The authors described the experience of the pilot project of a Risk Sharing Agreement in the Unified Health System.

Risk Sharing Agreement: a pilot project in the Brazilian Unified Health System

Risk Sharing Agreement is defined as an agreement in which the State agrees to offer temporary access to a new drug, while the pharmaceutical industry accepts to receive the product according to the performance of the drug in real conditions of use. Risk sharing necessarily depends on the collection of additional evidence that may refer to the therapeutic benefits or the volume of patients, according to the assessment of its use in practice. The authors described the experience of the pilot project of a Risk Sharing Agreement in the Unified Health System.

Pharmacological therapies for patients with human coronavirus infections: a rapid systematic review. / Terapia medicamentosa para infecções por coronavírus em humanos: revisão sistemática rápida.

This work aimed to evaluate the effects of drug therapies for coronavirus infections. Rapid systematic review with search in the MEDLINE, EMBASE, Cochrane, BVS, Global Index Medicus, Medrix, bioRxiv, Clinicaltrials.gov and International Clinical Trials Registry Platform databases. Thirty-six studies evaluating alternative drugs against SARS, SARS-CoV-2 and MERS were included. Most of the included studies were conducted in China with an observational design for the treatment of COVID-19. The most studied treatments were with antimalarials and antivirals. In antimalarial, the meta-analysis of two studies with 180 participants did not identify the benefit of hydroxychloroquine concerning the negative viral load via real-time polymerase chain reaction, and the use of antivirals compared to standard care was similar regarding outcomes. The available scientific evidence is preliminary and of low methodological quality, which suggests caution when interpreting its results. Research that evaluates comparative efficacy in randomized, controlled clinical trials, with adequate follow-up time and with the methods properly disclosed and subject to scientific peer review is required. A periodic update of this review is recommended.

Terapia medicamentosa para infecções por coronavírus em humanos: revisão sistemática rápida / Pharmacological therapies for patients with human coronavirus infections: a rapid systematic review

Resumo O objetivo deste trabalho foi avaliar efeitos de tratamentos medicamentosos para infecções por coronavírus. Revisão sistemática rápida com buscas nas bases MEDLINE, EMBASE, Cochrane, BVS, Global Index Medicus, Medrix, bioRxiv, Clinicaltrials.gov e International Clinical Trials Registry Platform. Foram incluídos 36 estudos avaliando alternativas medicamentosas contra SARS, SARS-CoV-2 e MERS. A maioria dos estudos incluídos foi conduzida na China com delineamento observacional para tratamento da COVID-19. Os tratamentos mais estudados foram antimaláricos e antivirais. Nos antimaláricos, a metanálise de dois estudos com 180 participantes não identificou benefício da hidroxicloroquina em relação à negativação da carga viral via reação em cadeia de polimerase em tempo real e o uso de antivirais comparado ao cuidado padrão foi similar em relação aos desfechos. As evidências científicas disponíveis são preliminares e de baixa qualidade metodológica, o que sugere cautela na interpretação dos dados. Pesquisas que avaliem a eficácia comparativa em ensaios clínicos randomizados, controlados, com tempo de acompanhamento adequado e com os métodos devidamente divulgados e sujeitos à revisão científica por pares são necessárias. Recomenda-se atualização periódica da presente revisão.

Abstract This work aimed to evaluate the effects of drug therapies for coronavirus infections. Rapid systematic review with search in the MEDLINE, EMBASE, Cochrane, BVS, Global Index Medicus, Medrix, bioRxiv, Clinicaltrials.gov and International Clinical Trials Registry Platform databases. Thirty-six studies evaluating alternative drugs against SARS, SARS-CoV-2 and MERS were included. Most of the included studies were conducted in China with an observational design for the treatment of COVID-19. The most studied treatments were with antimalarials and antivirals. In antimalarial, the meta-analysis of two studies with 180 participants did not identify the benefit of hydroxychloroquine concerning the negative viral load via real-time polymerase chain reaction, and the use of antivirals compared to standard care was similar regarding outcomes. The available scientific evidence is preliminary and of low methodological quality, which suggests caution when interpreting its results. Research that evaluates comparative efficacy in randomized, controlled clinical trials, with adequate follow-up time and with the methods properly disclosed and subject to scientific peer review is required. A periodic update of this review is recommended.

Revisão Rápida para informar a Política Nacional de Medicamentos Biológicos no SUS / Rapid review to inform the National Policy on Biological Medicines in SUS

Contexto: O gasto elevado com medicamentos biológicos ameaça a sustentabilidade dos serviços de saúde. O objetivo da presente revisão rápida foi embasar a discussão da Política Nacional de Medicamentos Biológicos no âmbito do Sistema Único de Saúde (SUS), por meio da identificação de barreiras de acesso a esses medicamentos. Metodologia: Revisão rápida da literatura nas fontes de informação Medline via PubMed, EMBASE, Biblioteca Cochrane e Center for Review and Dissemination (CRD). Resultados: Foram incluídos nove estudos com delineamento transversal. No contexto do usuário, as barreiras foram a falta de conhecimento sobre o medicamento, a distância entre a moradia e o serviço de saúde, os longos períodos de espera por atendimento e a passividade sobre decisão de tratamento.

Programa Pesquisa para o sus(PPsus): contribuições para aciência, tecnologia e inovação emsaúde no estado do Paraná / Research Program for sus (PPsus): contributions for science, technology, and health innovation in the state of Paraná

O Programa Pesquisa para o Sistema Único de Saúde: gestão compartilhada em saúde (PPSUS) é uma iniciativa de descentralização de fomento à pesquisa em saúde para promover o desenvolvimento científico e tecnológico de cada unidade federativa brasileira. Este artigo tem por objetivo apresentar os principais indicadores gerenciais e a aplicabilidade para o SUS dos resultados das pesquisas financiadas pelo PPSUS no estado do Paraná.Foram analisados dados de 2004 a 2013 disponíveis na plataforma Pesquisa Saúde do Decit/SCTIE/MS. Os dados quantitativos foram analisados por meio de frequências absolutas e relativa se medidas de tendência central.Os dados qualitativos relativos à aplicabilidade dos resultados para o SUS foram categorizados, descrito se analisados seguindo o método proposto por Minayo para análise de conteúdo. O Paraná participou de cinco edições do PPSUS com 246 projetos financiados, envolvendo R$16.095.000,00 em recursos financeiros. As temáticas de pesquisa mais frequentes estavam relacionadas às doenças não transmissíveis (19,84%)e transmissíveis (18,62%). As pesquisas financiadas concentraram-se em Curitiba, Londrina e Maringá. A aplicabilidade dos resultados das pesquisas no SUS focou a possibilidade de disponibilizar propostas alternativas e/ou melhorias para o apoio terapêutico na assistência à saúde, gerar conhecimento para compreender o processo saúde-doença e subsidiar a formulação das políticas/programas/estratégias e a tomada de decisão. O aumento do aporte de recursos financeiros e do número de projetos de pesquisa financiados indica a ampliação do Programa no estado e os resultados dos estudos apresentam potencial para contribuir para diversas esferas do setor saúde, da assistência à gestão...

The Research Program for the Unified Health System (Sistema Único de Saúde-SUS): Healthcare Shared Management, called PPSUS, is an initiative for decentralization of health research funding to promote scientific and technological development of each Brazilian Federal Unit. This study aims to present the main management indicators and the applicability on SUS of the research results funded by PPSUS in the state of Paraná. Available dataon the platform Pesquisa Saúde of Decit/SCTIE/MS from 2004 to 2013 were analyzed. Quantitative data were analyzed using absolute and relative frequencies and central tendency measures. Qualitative data on the applicability of the results for SUS were classified, described and analyzed by the method proposed by Minayo for content analysis. The state of Paraná participated in five editions of PPSUS with 246 funded projects, involving R$16,095,000.00 in financial resources. The research themes that were more frequently studied were related to non-communicable diseases (19,84%) and communicable diseases (18,62%). The funded researches were concentrated in the cities of Curitiba, Londrina and Maringá. The applicability of research results in SUS focused on the possibility of providing alternative proposals and/or improvements to therapeutic support in health care, generating knowledge to understand the health-disease process,and subsidize the formulation of policies /programs / strategies and decision-taking. The increase in the contribution of financial resources and in the number of funded research projects indicates the expansion of the Programin the state, and the studies results demonstrate potential to contribute to several areas of the health sector, from assistance tomanagement...

Clinical investigations for SUS, the Brazilian public health system.

CONTEXT AND OBJECTIVE: Scientific and technological development is crucial for advancing the Brazilian health system and for promoting quality of life. The way in which the Brazilian Ministry of Health has supported clinical research to provide autonomy, self-sufficiency, competitiveness and innovation for the healthcare industrial production complex, in accordance with the National Policy on Science, Technology and Innovation in Healthcare, was analyzed. DESIGN AND SETTING: Descriptive investigation, based on secondary data, conducted at the Department of Science and Technology, Ministry of Health. METHODS: The Ministry of Health's research management database, PesquisaSaúde, was analyzed from 2002 to 2009, using the key word "clinical research" in the fields "primary sub-agenda" or "secondary sub-agenda". The 368 projects retrieved were sorted into six categories: basic biomedical research, preclinical studies, expanded clinical research, clinical trials, infrastructure support and health technology assessment. From a structured review on "clinical research funding", results from selected countries are presented and discussed. RESULTS: The amount invested was R$ 140 million. The largest number of projects supported "basic biomedical research", while the highest amounts invested were in "clinical trials" and "infrastructure support". The southeastern region had the greatest proportion of projects and financial resources. In some respects, Brazil is ahead of other BRICS countries (Russia, India, China and South Africa), especially with regard to establishing a National Clinical Research Network. CONCLUSION: The Ministry of Health ensured investments to encourage clinical research in Brazil and contributed towards promoting cohesion between investigators, health policies and the healthcare industrial production complex.

Avaliação da toxicidade aguda e potencial neurotóxico do óleo-resina de copaíba (Copaifera reticulata Ducke, Fabaceae) / Assessment of the neurotoxic potential and acute toxicity of copaiba

O óleo-resina de copaíba obtido do gênero Copaifera L., Fabaceae, é largamente utilizado na medicina popular como antiinflamatório, antimicrobiano e antitumoral. Porém, informações sobre seu potencial tóxico são escassos na literatura. O objetivo deste estudo foi estabelecer a toxicidade oral aguda e os possíveis efeitos neurotóxicos relacionados à ingestão do óleo-resina de Copaifera reticulata Ducke, Fabaceae, em ratas Wistar. O estudo foi conduzido com quinze ratas nulíparas distribuídas nos grupos de doses 300 e 2000 mg/kg pc de óleo-resina administrado por gavagem. Os resultados obtidos mostraram que nestas doses não houve sinais clínicos de toxicidade ou neurotoxicidade, alteração no consumo de ração ou alteração no peso corpóreo. A dose letal aguda foi estimada como maior que 2000 mg/kg pc e classificada como categoria 5, segundo o Guia OECD 423. Estes resultados indicam que existe uma relativa margem de segurança para o uso do óleo-resina de copaíba como agente terapêutico, embora estudos toxicológicos adicionais sejam ainda necessários, principalmente com a administração repetida de baixas doses.

Copaiba oil-resin obtained from Copaifera L. genus, Fabaceae, is largely used in popular medicine as antinflammatory, antimicrobial and antitumoral. Information concerning the potential toxicity of this oil is limited in the literature. The goal of this study was to investigate the acute toxicity and the possible neurotoxic effects related to the ingestion of Copaifera reticulata Ducke, Fabaceae, oil-resin using female Wistar rats. Fifteen nulliparous rats were used and distributed in the experimental groups orally exposed to doses of 300 e 2000 mg/kg bw of oil-resin (gavage). No overt clinical signs of toxicity or neurotoxicity, alteration of food consumption or body weight were observed in the animals at the tested doses. The lethal oral toxicity was estimated to be higher than 2000 mg/kg bw, classified as category 5 according to OECD Guide 423. These results indicate that there is a certain safety margin associated with the use of copaiba as therapeutic agent, although additional toxicological studies are still necessary, mainly using repeated low doses.