Abstract
The Covid-19 pandemic challenges research institutions with the urgent need of responding to the morbidity and mortality caused by the virus. This study aimed to overview studies with humans on this disease in the first three months of 2020, in Brazil. Official data of the population and research protocols on Covid-19, distributed by Brazilian states, supported this temporal analysis. The incidence of the virus has grown exponentially, especially in the North and Northeast regions. Despite the discrete, slow, and asymmetric diffusion of studies, they are concentrated in the Southeast, and few clinical trials have entered Phase II. The geographical distribution of research ethics committees, higher education institutions, investments in science and technology, health centers and hospitals generate state vulnerabilities when addressing the disease. Close longitudinal follow-up should be carried out in the face of regional inequities, to defend bioethical principles and human life.
Keywords:
Coronavirus; Sars virus; Bioethics; Human experimentation; Clinical trial
Resumo
A pandemia de covid-19 desafia instituições de pesquisa pela urgência de responder à morbimortalidade provocada pelo vírus. O objetivo deste estudo foi traçar panorama das pesquisas com humanos sobre essa doença no primeiro trimestre de 2020 no Brasil. Dados oficiais de saúde da população e de protocolos de pesquisa sobre a covid-19, distribuídos por estados brasileiros, subsidiaram a análise temporal. Houve crescimento exponencial da incidência do vírus, principalmente nas regiões Norte e Nordeste, apesar da difusão discreta, lenta e assimétrica das pesquisas, concentradas no Sudeste. Os poucos ensaios clínicos entraram na Fase II. A distribuição geográfica de comitês de ética em pesquisa, instituições de ensino superior, investimentos em ciência e tecnologia e unidades assistenciais básicas e hospitalares gera vulnerabilidades estaduais para enfrentar a doença. Acompanhamento longitudinal atento deve ser realizado diante das iniquidades regionais, em defesa dos preceitos bioéticos e da vida humana.
Palavras-chave:
Coronavírus; Vírus da Sars; Bioética; Experimentação humana; Ensaio clínico
Resumen
La pandemia de covid-19 desafía a las instituciones de investigación en la urgencia de responder a la morbilidad y mortalidad causadas por el virus. El objetivo de este estudio fue esbozar una visión general de la investigación con humanos sobre esta enfermedad en el primer trimestre de 2020 en Brasil. Los datos oficiales sobre salud, población y protocolos de investigación sobre covid-19 distribuidos por la unidad federativa brasileña respaldaron un análisis temporal. Hubo un crecimiento exponencial en la incidencia de covid-19, especialmente en las regiones del Norte y Nordeste, a pesar de la diseminación discreta, lenta y asimétrica de la investigación, concentrada en el Sudeste. Los pocos ensayos clínicos estaban en Fase II. La distribución geográfica de los comités de ética de la investigación, las instituciones de educación superior, las inversiones en ciencia y tecnología y las unidades de atención desde la red básica hasta el hospital identificaron los potenciales y vulnerabilidades estatales para hacer frente a la enfermedad. Se debe llevar a cabo un monitoreo longitudinal atento ante las desigualdades regionales, en defensa de los preceptos bioéticos y de la vida humana.
Palabras clave:
Coronavirus; Virus del SRAS; Bioética; Experimentación humana; Ensayo clínico
With the disease caused by the novel coronavirus (Covid-19), the world faces a public health and civilizing crisis not seen since the Spanish flu of 1918, with a challenging number of contaminations even with the efforts of governments and research institutions11. Angelos P. Surgeons, ethics, and covid-19: early lessons learned. J Am Coll Surg [Internet]. 2020 [acesso 8 jun 2020];230(6):1119-20. DOI: 10.1016/j.jamcollsurg.2020.03.028
https://doi.org/10.1016/j.jamcollsurg.20...
. The global geopolitical scenario in the pandemic intensifies economic and social inequalities, as well as the divergence between countries and the World Health Organization (WHO)22. Arora A, Arora A. Ethics in the age of covid-19. Intern Emerg Med [Internet]. 2020 [acesso 8 jun 2020];889-90. DOI: 10.1007/s11739-020-02368-2
https://doi.org/10.1007/s11739-020-02368...
,33. Hiscott J, Alexandridi M, Muscolini M, Tassone E, Palermo E, Soultsioti M, Zevini A. The global impact of the coronavirus pandemic. Cytokine Growth Factor Rev [Internet]. 2020 [acesso 8 jun 2020];53:1-9. DOI: 10.1016/j.cytogfr.2020.05.010
https://doi.org/10.1016/j.cytogfr.2020.0...
. The U.S. presidential demand, at the beginning of the pandemic, for a rapid Covid-19 vaccine showed discredit in the scientific stages, which require several phases and pre-clinical and clinical studies44. Thorp HH. Do us a favor. Science [Internet]. 2020 [acesso 8 jun 2020];367(6483):1169. DOI: 10.1126/science.abb6502
https://doi.org/10.1126/science.abb6502...
. Accelerated contamination, high morbidity and mortality, and the absence of pharmacological treatment have made social distancing and biosecurity the only effective weapons against Covid-1955. Maciel JAC, Castro-Silva II, Farias MR. Análise inicial da correlação espacial entre a incidência de covid-19 e o desenvolvimento humano nos municípios do estado do Ceará no Brasil. Rev Bras Epidemiol [Internet]. 2020 [acesso 22 jun 2020];23:E200057. DOI: 10.1590/1980-549720200057
https://doi.org/10.1590/1980-54972020005...
.
After three months, the political pressure in Brazil worsened with contradictory discourses on the virus impact, disdain for the high lethality rate of the disease66. Covid-19 in Brazil: “So what?” [editorial]. Lancet [Internet]. 2020 [acesso 23 jun 2020];395(10235):1461. DOI: 10.1016/S0140-6736(20)31095-3
https://doi.org/10.1016/S0140-6736(20)31...
,77. Silva R, Pasti D. Da “gripezinha” ao “e daí?”: as falas de Bolsonaro em cada fase da pandemia. Gazeta [Internet]. Política; 7 jul 2020 [acesso 8 ago 2020]. Disponível: https://bit.ly/2FKMFKZ
https://bit.ly/2FKMFKZ...
and the removal of epidemiological data from official websites88. Rosário M. Covid-19: sites paralelos divulgam dados oficiais apagados pelo governo. Veja [Internet]. Saúde; 8 jun 2020 [acesso 8 jun 2020]. Disponível: https://bit.ly/3j9jH56
https://bit.ly/3j9jH56...
. The public repudiation note of the Brazilian Society for the Advancement of Science, the Brazilian Academy of Sciences and 70 other entities99. Mais de 70 entidades assinam nota contra ocultação de dados de covid-19 pelo governo. Sociedade Brasileira para o Progresso da Ciência [Internet]. 8 jun 2020 [acesso 8 jun 2020]. Disponível: https://bit.ly/3jgW9eH
https://bit.ly/3jgW9eH...
and the actions of state health departments sought to maintain data transparency on alternative websites and reliability for decision-making88. Rosário M. Covid-19: sites paralelos divulgam dados oficiais apagados pelo governo. Veja [Internet]. Saúde; 8 jun 2020 [acesso 8 jun 2020]. Disponível: https://bit.ly/3j9jH56
https://bit.ly/3j9jH56...
. It is important to develop an evidence base to establish better healthcare standards, new interventions, and management guidelines in public health1010. Coelho MTP, Rodrigues JFM, Medina AM, Scalco P, Terribile LC, Vilela B et al. Exponential phase of covid-19 expansion is driven by airport connections. MedRxiv [Internet]. 6 maio 2020 [acesso 8 jun 2020]. DOI: 10.1101/2020.04.02.20050773
https://doi.org/10.1101/2020.04.02.20050...
.
In 2016, WHO published the Guidance for managing ethical issues in infectious disease outbreaks1111. World Health Organization. Guidance for managing ethical issues in infectious disease outbreaks [Internet]. Geneva: WHO; 2016 [acesso 9 nov 2020]. Disponível: https://bit.ly/37x8pp7
https://bit.ly/37x8pp7...
to ensure scientific validity of the rights and safety of participants in studies conducted during outbreaks. The guideline emphasized the moral obligation to conduct timely research, respecting basic ethical principles of studies with human beings1212. Zhang H, Shao F, Gu J, Li L, Wang Y. Ethics committee reviews of applications for research studies at 1 hospital in China during the 2019 novel coronavirus epidemic. JAMA [Internet]. 2020 [acesso 8 jun 2020];323(18):1844-6. DOI: 10.1001/jama.2020.4362
https://doi.org/10.1001/jama.2020.4362...
, such as autonomy, beneficence, non-maleficence and justice1313. World Economic Forum. Code of ethics [Internet]. Geneva: WEF; 2018 [acesso 6 jun 2020]. Disponível: https://bit.ly/3dN4iWX
https://bit.ly/3dN4iWX...
. This principlism is essential for clinical research, and its perception must be parsimonious to avoid misunderstandings in extreme conditions1414. Kirkpatrick JN, Hull SC, Fedson S, Mullen B, Goodlin SJ. Scarce-resource allocating and patient triage during the covid-19 pandemic: JACC review topic of the week. J Am Coll Cardiol [Internet]. 2020 [acesso 8 jun 2020];76(1):85-92. DOI: 10.1016/j.jacc.2020.05.006
https://doi.org/10.1016/j.jacc.2020.05.0...
.
Trials include supervisory processes and can be performed quickly without compromising participants' safety, and randomized clinical trials are considered ideal to support causal inference, despite their epistemic limits to address population health and analyze direct harm or benefits to participants1515. Meagher KM, Cummins NW, Bharucha AE, Badley AD, Chlan LL, Wright RS. Covid-19 ethics and research. Mayo Clin Proc [Internet]. 2020 [acesso 8 jun 2020];95(6):1119-23. DOI: 10.1016/j.mayocp.2020.04.019
https://doi.org/10.1016/j.mayocp.2020.04...
.
Covid-19 studies involve multiple ethical controversies. The placebo arm of research covers individual physical risks, such as additional pain, suffering or death; in the randomization of the active treatment arm, the benefit is uncertain, and unrecognized damage may occur1010. Coelho MTP, Rodrigues JFM, Medina AM, Scalco P, Terribile LC, Vilela B et al. Exponential phase of covid-19 expansion is driven by airport connections. MedRxiv [Internet]. 6 maio 2020 [acesso 8 jun 2020]. DOI: 10.1101/2020.04.02.20050773
https://doi.org/10.1101/2020.04.02.20050...
. Thus, decisions on the prioritization of treatment accentuate discussions in the media and in public debate1616. Herreros B, Gella P, Real de Asua D. Triage during the covid-19 epidemic in Spain: better and worse ethical arguments. J Med Ethics [Internet]. 2020 [acesso 8 jun 2020];46(7):455-8. DOI: 10.1136/medethics-2020-106352
https://doi.org/10.1136/medethics-2020-1...
.
With limited resources in the pandemic, the collective benefit is more important than the individual, even though a patient's request for care must be respected, maintaining his autonomy. The impartial distribution of critical respiratory support care, such as mechanical ventilators, is ruled by values that are not usually considered1717. Rawlings A, Brandt L, Ferreres A, Asbun H, Shadduck P. Ethical considerations for allocation of scarce resources and alterations in surgical care during a pandemic. Surg Endosc [Internet]. 2020 [acesso 8 jun 2020]. DOI: 10.1007/s00464-020-07629-x
https://doi.org/10.1007/s00464-020-07629...
. The protection of justice is under strain, allowing Covid-19 patients with better results to be prioritized over a substantial amount of non-urgent care, which has a negative long-term effect1616. Herreros B, Gella P, Real de Asua D. Triage during the covid-19 epidemic in Spain: better and worse ethical arguments. J Med Ethics [Internet]. 2020 [acesso 8 jun 2020];46(7):455-8. DOI: 10.1136/medethics-2020-106352
https://doi.org/10.1136/medethics-2020-1...
.
Thus, the pandemic challenges healthcare systems with an unprecedented number of critically ill patients. Measures to minimize the gap between needs and resources depend on the reduction of viral transmission and increased treatment capacity, which can be made possible by ethical scientific studies1818. Leclerc T, Donat N, Donat A, Pasquier P, Libert N, Schaeffer E et al. Prioritisation of ICU treatments for critically ill patients in a covid-19 pandemic with scarce resources. Anaesth Crit Care Pain Med [Internet]. 2020 [acesso 8 jun 2020];39(3):333-9. DOI: 10.1016/j.accpm.2020.05.008
https://doi.org/10.1016/j.accpm.2020.05....
. So, this article aimed to trace an initial overview of research on Covid-19 conducted with humans during the first quarter of the pandemic, and potentially innovative factors and assistance to face the disease in Brazil, discussed in the light of current bioethical norms.
Material and methods
This is a quantitative study, with documental analysis of data from the Ministry of Health1919. Comissão Nacional de Ética em Pesquisa. Boletim Ética em Pesquisa: edição especial coronavírus (covid-19): relatório semanal 1 [Internet]. 23 mar 2020 [acesso 6 jun 2020]. Disponível: https://bit.ly/35hIFu3
https://bit.ly/35hIFu3...
–2424. Brasil. Ministério da Saúde. Plataforma Brasil [Internet]. 2020 [acesso 6 jun 2020]. Disponível: https://bit.ly/35Z2gzC
https://bit.ly/35Z2gzC...
, Ministry of Education2525. Brasil. Ministério da Educação. Cadastro Nacional de Cursos e Instituições de Educação Superior: Cadastro e-MEC [Internet]. 2020 [acesso 6 jun 2020]. Disponível: https://bit.ly/38clq7K
https://bit.ly/38clq7K...
and Ministry of Science, Technology and Innovations2626. Brasil. Ministério da Ciência, Tecnologia e Inovações. Recursos aplicados: governos estaduais: 2.3.4 Brasil: dispêndios dos governos estaduais em ciência e tecnologia (C&T) por região, unidade da federação e atividade, 2000-2017 [Internet]. 2019 [acesso 6 jun 2020]. Disponível: https://bit.ly/3kXsybT
https://bit.ly/3kXsybT...
available between March and May 2020, during the first three months of the Covid-19 pandemic in Brazil. Since official and secondary data are used, the bioethical principles of the National Health Council Resolution (CNS) 510/20162727. Conselho Nacional de Saúde. Resolução CNS n° 510, de 7 de abril de 2016. Dispõe sobre as normas aplicáveis a pesquisas em ciências humanas e sociais cujos procedimentos metodológicos envolvam a utilização de dados diretamente obtidos com os participantes ou de informações identificáveis ou que possam acarretar riscos maiores do que os existentes na vida cotidiana. Diário Oficial da União [Internet]. Brasília, n° 98, p. 44, 24 maio 2016 [acesso 29 maio 2020]. Seção 1. Disponível: https://bit.ly/3l0NVJb
https://bit.ly/3l0NVJb...
were adopted.
To measure in the country the impact of the disease and studies with humans in progress, research protocols and the subcategory of clinical trials approved in each state was associated with the Covid-19 incidence coefficient, obtained at different periods. The monthly public data provided by the Ministry of Health was collected from the epidemiological bulletins of the National Committee of Ethics in Research (Conep), in three periods: T1 (bulletin 1, of March 23rd, 2020 or 13th epidemiological week)1919. Comissão Nacional de Ética em Pesquisa. Boletim Ética em Pesquisa: edição especial coronavírus (covid-19): relatório semanal 1 [Internet]. 23 mar 2020 [acesso 6 jun 2020]. Disponível: https://bit.ly/35hIFu3
https://bit.ly/35hIFu3...
, T2 (bulletin 10, of April 24th, 2020 or 17th epidemiological week)2020. Comissão Nacional de Ética em Pesquisa. Boletim Ética em Pesquisa: edição especial coronavírus (covid-19): relatório semanal 10 [Internet]. 24 abr 2020 [acesso 6 jun 2020]. Disponível: https://bit.ly/2FP5tc2
https://bit.ly/2FP5tc2...
and T3 (bulletin 19, of May 26th, 2020 or 22nd epidemiological week)2121. Comissão Nacional de Ética em Pesquisa. Boletim Ética em Pesquisa: edição especial coronavírus (covid-19): relatório semanal 19 [Internet]. 26 maio 2020 [acesso 6 jun 2020]. Disponível: https://bit.ly/2T9JTBR
https://bit.ly/2T9JTBR...
.
To determine the Covid-19 incidence coefficient in each state and in the country, the number of confirmed cases2222. Brasil. Ministério da Saúde. Coronavírus Brasil [Internet]. 2020 [acesso 29 maio 2020]. Disponível: https://bit.ly/2HhtitI
https://bit.ly/2HhtitI...
was divided by the resident population2323. Brasil. Ministério da Saúde. Datasus: Tabnet [Internet]. 2020 [acesso 29 maio 2020]. Disponível: https://bit.ly/3dPX58D
https://bit.ly/3dPX58D...
and multiplied by the population base of 100,000 inhabitants. Simple descriptive analysis was used for the absolute frequency of the number of research protocols and clinical trials approved in each state and in Brazil1919. Comissão Nacional de Ética em Pesquisa. Boletim Ética em Pesquisa: edição especial coronavírus (covid-19): relatório semanal 1 [Internet]. 23 mar 2020 [acesso 6 jun 2020]. Disponível: https://bit.ly/35hIFu3
https://bit.ly/35hIFu3...
–2121. Comissão Nacional de Ética em Pesquisa. Boletim Ética em Pesquisa: edição especial coronavírus (covid-19): relatório semanal 19 [Internet]. 26 maio 2020 [acesso 6 jun 2020]. Disponível: https://bit.ly/2T9JTBR
https://bit.ly/2T9JTBR...
.
The clinical trials registered in T32121. Comissão Nacional de Ética em Pesquisa. Boletim Ética em Pesquisa: edição especial coronavírus (covid-19): relatório semanal 19 [Internet]. 26 maio 2020 [acesso 6 jun 2020]. Disponível: https://bit.ly/2T9JTBR
https://bit.ly/2T9JTBR...
and detailed at Plataforma Brasil2424. Brasil. Ministério da Saúde. Plataforma Brasil [Internet]. 2020 [acesso 6 jun 2020]. Disponível: https://bit.ly/35Z2gzC
https://bit.ly/35Z2gzC...
(Brazil Platform) were categorized according to protocol title, number of participating centers and number of volunteers in Phase I (initial phase, with healthy volunteers, in tens), Phase II (pilot therapeutic study, with target population, in hundreds), Phase III (expanded therapeutic or large randomized studies, multicenter studies, with hundreds to thousands of participants) or Phase IV (post-registration study, pharmacovigilance, with thousands to millions of participants). The relative frequency of clinical trial phases was expressed as a percentage in Figure 1.
To relate this scenario to the infrastructure to fight the virus of each state, two analysis groups were formulated: Category 1, research and innovation; and category 2, research and assistance. The first counted the absolute frequency of research ethics committees (CEP) registered at Plataforma Brasil2424. Brasil. Ministério da Saúde. Plataforma Brasil [Internet]. 2020 [acesso 6 jun 2020]. Disponível: https://bit.ly/35Z2gzC
https://bit.ly/35Z2gzC...
, higher education institutions active in the electronic register of the Ministry of Education2525. Brasil. Ministério da Educação. Cadastro Nacional de Cursos e Instituições de Educação Superior: Cadastro e-MEC [Internet]. 2020 [acesso 6 jun 2020]. Disponível: https://bit.ly/38clq7K
https://bit.ly/38clq7K...
and the coefficient of investments in science and technology (S&T). This indicator was calculated by the amount of million reais invested in S&T, referring to research, development, scientific activities and related techniques, invested in the last year by the Ministry of Science, Technology and Innovations2626. Brasil. Ministério da Ciência, Tecnologia e Inovações. Recursos aplicados: governos estaduais: 2.3.4 Brasil: dispêndios dos governos estaduais em ciência e tecnologia (C&T) por região, unidade da federação e atividade, 2000-2017 [Internet]. 2019 [acesso 6 jun 2020]. Disponível: https://bit.ly/3kXsybT
https://bit.ly/3kXsybT...
, divided by the resident population2323. Brasil. Ministério da Saúde. Datasus: Tabnet [Internet]. 2020 [acesso 29 maio 2020]. Disponível: https://bit.ly/3dPX58D
https://bit.ly/3dPX58D...
and multiplied by the population base of 100,000 inhabitants. Category 2 recorded data released by the Ministry of Health regarding the absolute frequency of public testing laboratories2222. Brasil. Ministério da Saúde. Coronavírus Brasil [Internet]. 2020 [acesso 29 maio 2020]. Disponível: https://bit.ly/2HhtitI
https://bit.ly/2HhtitI...
, family health teams2323. Brasil. Ministério da Saúde. Datasus: Tabnet [Internet]. 2020 [acesso 29 maio 2020]. Disponível: https://bit.ly/3dPX58D
https://bit.ly/3dPX58D...
and public reference hospitals2222. Brasil. Ministério da Saúde. Coronavírus Brasil [Internet]. 2020 [acesso 29 maio 2020]. Disponível: https://bit.ly/2HhtitI
https://bit.ly/2HhtitI...
. Simple descriptive analysis was adopted for absolute data.
Results
Table 1 shows that the Covid-19 incidence coefficient increased exponentially during the first quarter of the pandemic throughout Brazil, especially in the North and Northeast regions. This was accompanied by a slight increase in the number of research protocols on the disease, and approved clinical trials corresponded to a small portion of the total in Brazil (18.4%), mostly in São Paulo.
Covid-19 incidence coefficient, research protocols and clinical trials approved in the first trimester of the pandemic, by Brazilian state
According to Figure 1, of the 64 clinical trials approved until May 2020, 69% were in Phase II, with no authorized national research in Phase IV. It is important to highlight that a study in São Paulo was completely suspended and another study in Amazonas was partially suspended, due to a higher dose arm, after the approval of protocols.
Table 2 presents information on research with human beings related to innovation or assistance. Family health teams are fundamental for the first care of suspected Covid-19 cases, and their number exceeds that of other specialized diagnostic or treatment units in all states. The North region presented the smallest amount of family health teams, and the Southeast region the largest number of higher education institutions, research ethics committees, and investment coefficient in S&T, being an innovation center in the fight against Covid-19.
Physical and financial resources involved in research, innovation, and assistance, by federated units and in the country
Discussion
Research with human beings in Brazil during the pandemic is essential to generate data on the disease and should be based on the ethical principles of CNS Resolution 466/20122828. Conselho Nacional de Saúde. Resolução CNS n° 466, de 12 de dezembro de 2012. Aprova diretrizes e normas regulamentadoras de pesquisas envolvendo seres humanos. Diário Oficial da União [Internet]. Brasília, n° 12, p. 59, 13 jun 2013 [acesso 29 maio 2020]. Seção 1. Disponível: https://bit.ly/3esS2LS
https://bit.ly/3esS2LS...
. Other norms in force are continuously improving2929. Gouy CML, Porto TF, Penido C. Avaliação de ensaios clínicos no Brasil: histórico e atualidades. Rev. bioét. (Impr.) [Internet]. 2018 [acesso 29 maio 2020];26(3):350-9. DOI: 10.1590/1983-80422018263254
https://doi.org/10.1590/1983-80422018263...
and have a lot to contribute. For example, CNS Resolution 510/20162727. Conselho Nacional de Saúde. Resolução CNS n° 510, de 7 de abril de 2016. Dispõe sobre as normas aplicáveis a pesquisas em ciências humanas e sociais cujos procedimentos metodológicos envolvam a utilização de dados diretamente obtidos com os participantes ou de informações identificáveis ou que possam acarretar riscos maiores do que os existentes na vida cotidiana. Diário Oficial da União [Internet]. Brasília, n° 98, p. 44, 24 maio 2016 [acesso 29 maio 2020]. Seção 1. Disponível: https://bit.ly/3l0NVJb
https://bit.ly/3l0NVJb...
for humanities research, CNS Resolution 553/20173030. Conselho Nacional de Saúde. Resolução CNS n° 553, de 9 de agosto de 2017. Aprova a atualização da Carta dos Direitos e Deveres da Pessoa Usuária da Saúde. Diário Oficial da União [Internet]. Brasília, n° 10, p. 41-4, 15 jan 2018 [acesso 29 maio 2020]. Seção 1. Disponível: https://bit.ly/34YM9CR
https://bit.ly/34YM9CR...
, addressing patients’ rights and duties, and CNS Carta Circular 166/20183131. Conselho Nacional de Saúde. Carta circular CNS n° 166, de 12 de junho de 2018 [Internet]. Brasília: Ministério da Saúde; 21 jun 2018 [acesso 26 jun 2020]. Disponível: https://bit.ly/3kTy2Em
https://bit.ly/3kTy2Em...
, with a code of conducts for case reports. In addition, CNS Resolution 580/20183232. Conselho Nacional de Saúde. Resolução CNS n° 580, de 22 de março de 2018. Regulamenta o disposto no item XIII.4 da Resolução CNS n° 466, de 12 de dezembro de 2012, que estabelece que as especificidades éticas das pesquisas de interesse estratégico para o Sistema Único de Saúde (SUS) serão contempladas em resolução específica, e dá outras providências. Diário Oficial da União [Internet]. Brasília, n° 135, p. 55, 16 jul 2018 [acesso 29 maio 2020]. Seção 1. Disponível: https://bit.ly/3erWgmJ
https://bit.ly/3erWgmJ...
discusses research of strategic interest to the Unified Health System (SUS) and CNS Resolution 588/20183333. Conselho Nacional de Saúde. Resolução CNS n° 588, de 12 de julho de 2018. Institui a Política Nacional de Vigilância em Saúde. Diário Oficial da União [Internet]. Brasília, n° 155, p. 87-90, 13 ago 2018 [acesso 29 maio 2020]. Seção 1. Disponível: https://bit.ly/2JBy6ei
https://bit.ly/2JBy6ei...
presents the National Health Surveillance Policy.
The maximum representations of autonomy in clinical studies are the informed consent form and the consent form – a similar document for minors or legally incapable people2828. Conselho Nacional de Saúde. Resolução CNS n° 466, de 12 de dezembro de 2012. Aprova diretrizes e normas regulamentadoras de pesquisas envolvendo seres humanos. Diário Oficial da União [Internet]. Brasília, n° 12, p. 59, 13 jun 2013 [acesso 29 maio 2020]. Seção 1. Disponível: https://bit.ly/3esS2LS
https://bit.ly/3esS2LS...
. In times of social isolation, a major strategy for mitigating Covid-19 in the Brazilian territory3434. Costa GS, Cota W, Ferreira SC. Metapopulation modeling of covid-19 advancing into the countryside: an analysis of mitigation strategies for Brazil. MedRxiv [Internet]. 13 maio 2020 [acesso 29 maio 2020]. DOI: 10.1101/2020.05.06.20093492
https://doi.org/10.1101/2020.05.06.20093...
, obtaining physical signature from participants becomes more difficult, but even surveys with remote data collection must electronically attest their approval or justify their absence, in the case of secondary data3535. Williamson E, Walker AJ, Bhaskaran K, Bacon S, Bates C, Morton CE et al. OpenSAFELY: factors associated with covid-19-related hospital death in the linked electronic health records of 17 million adult NHS patients. MedRxiv [Internet]. 7 maio 2020 [acesso 29 maio 2020]. DOI: 10.1101/2020.05.06.20092999
https://doi.org/10.1101/2020.05.06.20092...
,3636. Speich B, Schur N, Gryaznov D, Von Niederhäusern B, Hemkens LG, Schandelmaier S et al. Resource use, costs, and approval times for planning and preparing a randomized clinical trial before and after the implementation of the new Swiss human research legislation. PLoS ONE [Internet]. 2019 [acesso 29 maio 2020];14(1):e0210669. DOI: 10.1371/journal.pone.0210669
https://doi.org/10.1371/journal.pone.021...
.
Non-maleficence is the idea of not exposing individuals to harm. This reinforces the necessary caution in clinical and Phase II studies, which are still scarce in Brazil, unlike places with a higher history of outbreaks, such as China, where intervention research prevails1212. Zhang H, Shao F, Gu J, Li L, Wang Y. Ethics committee reviews of applications for research studies at 1 hospital in China during the 2019 novel coronavirus epidemic. JAMA [Internet]. 2020 [acesso 8 jun 2020];323(18):1844-6. DOI: 10.1001/jama.2020.4362
https://doi.org/10.1001/jama.2020.4362...
. So far, no pharmacological risk-free agent has been approved at all stages for treating the virus, but fatal adverse effects have been reported in patients using test drugs3737. Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for covid-19. N Engl J Med [Internet]. 2020 [acesso 29 maio 2020];383:517-25. DOI: 10.1056/NEJMoa2016638.X
https://doi.org/10.1056/NEJMoa2016638.X...
–4040. Rana DRSJB, Dulal S. Therapeutic application of chloroquine and hydroxychloroquine in clinical trials for covid-19: a systematic review. MedRxiv [Internet]. 10 abr 2020 [acesso 29 maio 2020]. DOI: 10.1101/2020.03.22.20040964
https://doi.org/10.1101/2020.03.22.20040...
. Even so, the Brazilian Ministry of Health allowed the use of hydroxychloroquine and chloroquine for critically ill patients4141. Entenda a liberação de cloroquina e hidroxicloroquina. Agência Nacional de Vigilância Sanitária [Internet]. Novo coronavírus; 31 mar 2020 [acesso 8 jun 2020]. Disponível: https://bit.ly/32geeUf
https://bit.ly/32geeUf...
.
The controversy extended to the international scientific sphere, as a study published in The Lancet4242. Mehra MR, Desai SS, Ruschitzka F, Patel AN. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of covid-19: a multinational registry analysis. Lancet [Internet]. 2020 [acesso 29 maio 2020]. DOI: 10.1016/S0140-6736(20)31180-6
https://doi.org/10.1016/S0140-6736(20)31...
mistakenly concluded that these drugs were effective. However, the own editors of the journal4343. The Lancet Editors. Expression of concern: hydroxychloroquine or chloroquine with or without a macrolide for treatment of covid-19: a multinational registry analysis. Lancet [Internet]. 2020 [acesso 29 maio 2020];395(10240):E102. DOI: 10.1016/S0140-6736(20)31290-3
https://doi.org/10.1016/S0140-6736(20)31...
and 120 scientists4444. Watson J, Adler A, Agweyu A, Prieto-Alhambra D, Amaravadi R, Anaya J-M et al. Concerns regarding the statistical analysis and data integrity [Internet]. 2020 [acesso 6 jun 2020]. Disponível: https://bit.ly/2U0vEzP
https://bit.ly/2U0vEzP...
from 26 countries – mostly Asian, European and African, a few from Oceania and the Americas, and none from Brazil – spoke out against the false results of the article. Thirteen days after publication, the authors of the article apologized4545. Mehra MR, Ruschitzka F, Patel AN. Retraction: hydroxychloroquine or chloroquine with or without a macrolide for treatment of covid-19: a multinational registry analysis. Lancet [Internet]. 2020 [acesso 29 maio 2020];395(10240):1820. DOI: 10.1016/S0140-6736(20)31324-6
https://doi.org/10.1016/S0140-6736(20)31...
, showing that this period of intense global academic debate on the reliability and repercussion of research is important for protecting participants.
The incidence coefficient presented in this study refutes the pandemic denial4646. Covid-19: a human rights checklist. Human Rights Watch [Internet]. 2020 [acesso 12 jun 2020]. Disponível: https://bit.ly/2IaSQJ0
https://bit.ly/2IaSQJ0...
, proving it is a serious public health issue, and that clinical research can assist the population directly or indirectly2828. Conselho Nacional de Saúde. Resolução CNS n° 466, de 12 de dezembro de 2012. Aprova diretrizes e normas regulamentadoras de pesquisas envolvendo seres humanos. Diário Oficial da União [Internet]. Brasília, n° 12, p. 59, 13 jun 2013 [acesso 29 maio 2020]. Seção 1. Disponível: https://bit.ly/3esS2LS
https://bit.ly/3esS2LS...
. But the lack of clear benefits in research protocols on the disease can create conflicts when risks are high, as observed in China in proposals for the use of Interferon Alfa and traditional medicine, or when the level of biosafety is inadequate1212. Zhang H, Shao F, Gu J, Li L, Wang Y. Ethics committee reviews of applications for research studies at 1 hospital in China during the 2019 novel coronavirus epidemic. JAMA [Internet]. 2020 [acesso 8 jun 2020];323(18):1844-6. DOI: 10.1001/jama.2020.4362
https://doi.org/10.1001/jama.2020.4362...
.
Main decisions based on clinical trials should be entrusted to physicians and experienced teams, who will apply all available resources22. Arora A, Arora A. Ethics in the age of covid-19. Intern Emerg Med [Internet]. 2020 [acesso 8 jun 2020];889-90. DOI: 10.1007/s11739-020-02368-2
https://doi.org/10.1007/s11739-020-02368...
. In the pandemic, given the high risk of contamination, individual rights of hospitalized patients with Covid-19 are limited, as well as funeral arrangements or necropsy. These measures should be understood as exceptional conditions4747. Calmon M. Considerations of coronavirus (covid-19) impact and the management of the dead in Brazil. Forensic Sci Int [Internet]. 2020 [acesso 29 maio 2020];100110. DOI: 10.1016/j.fsir.2020.100110
https://doi.org/10.1016/j.fsir.2020.1001...
, and new research on the efficacy of medicines, personal protective and supportive equipment can justify practical changes that benefit patients2828. Conselho Nacional de Saúde. Resolução CNS n° 466, de 12 de dezembro de 2012. Aprova diretrizes e normas regulamentadoras de pesquisas envolvendo seres humanos. Diário Oficial da União [Internet]. Brasília, n° 12, p. 59, 13 jun 2013 [acesso 29 maio 2020]. Seção 1. Disponível: https://bit.ly/3esS2LS
https://bit.ly/3esS2LS...
,3030. Conselho Nacional de Saúde. Resolução CNS n° 553, de 9 de agosto de 2017. Aprova a atualização da Carta dos Direitos e Deveres da Pessoa Usuária da Saúde. Diário Oficial da União [Internet]. Brasília, n° 10, p. 41-4, 15 jan 2018 [acesso 29 maio 2020]. Seção 1. Disponível: https://bit.ly/34YM9CR
https://bit.ly/34YM9CR...
,3232. Conselho Nacional de Saúde. Resolução CNS n° 580, de 22 de março de 2018. Regulamenta o disposto no item XIII.4 da Resolução CNS n° 466, de 12 de dezembro de 2012, que estabelece que as especificidades éticas das pesquisas de interesse estratégico para o Sistema Único de Saúde (SUS) serão contempladas em resolução específica, e dá outras providências. Diário Oficial da União [Internet]. Brasília, n° 135, p. 55, 16 jul 2018 [acesso 29 maio 2020]. Seção 1. Disponível: https://bit.ly/3erWgmJ
https://bit.ly/3erWgmJ...
,3333. Conselho Nacional de Saúde. Resolução CNS n° 588, de 12 de julho de 2018. Institui a Política Nacional de Vigilância em Saúde. Diário Oficial da União [Internet]. Brasília, n° 155, p. 87-90, 13 ago 2018 [acesso 29 maio 2020]. Seção 1. Disponível: https://bit.ly/2JBy6ei
https://bit.ly/2JBy6ei...
.
We emphasize the timid advance of research protocols in Brazil and the importance of continuous investments in S&T, since the scarcity of resources can cause difficult decisions related to beneficence and non-maleficence1616. Herreros B, Gella P, Real de Asua D. Triage during the covid-19 epidemic in Spain: better and worse ethical arguments. J Med Ethics [Internet]. 2020 [acesso 8 jun 2020];46(7):455-8. DOI: 10.1136/medethics-2020-106352
https://doi.org/10.1136/medethics-2020-1...
. The asymmetric distributions of investments, research centers, and assistance verified in this study are inequities in the fight against Covid-19 in Brazil. The country has become one of the epicenters of the disease, whose geographical distribution is marked by interiorization55. Maciel JAC, Castro-Silva II, Farias MR. Análise inicial da correlação espacial entre a incidência de covid-19 e o desenvolvimento humano nos municípios do estado do Ceará no Brasil. Rev Bras Epidemiol [Internet]. 2020 [acesso 22 jun 2020];23:E200057. DOI: 10.1590/1980-549720200057
https://doi.org/10.1590/1980-54972020005...
, with metropolitan regions spreading the virus to poorer cities in the countryside4848. Cota W. Monitoring the number of covid-19 cases and deaths in Brazil at municipal and federative units level. SciELO Preprints [Internet]. 2020 [acesso 29 maio 2020];e362. DOI: 10.1590/SciELOPreprints.362
https://doi.org/10.1590/SciELOPreprints....
.
The North region was affected later, but the incidence of Covid-19 was high and alarming, with higher risk of healthcare collapse3434. Costa GS, Cota W, Ferreira SC. Metapopulation modeling of covid-19 advancing into the countryside: an analysis of mitigation strategies for Brazil. MedRxiv [Internet]. 13 maio 2020 [acesso 29 maio 2020]. DOI: 10.1101/2020.05.06.20093492
https://doi.org/10.1101/2020.05.06.20093...
,4848. Cota W. Monitoring the number of covid-19 cases and deaths in Brazil at municipal and federative units level. SciELO Preprints [Internet]. 2020 [acesso 29 maio 2020];e362. DOI: 10.1590/SciELOPreprints.362
https://doi.org/10.1590/SciELOPreprints....
, which corroborates the findings of this study. Access to different SUS services is a universal and integral right of patients3030. Conselho Nacional de Saúde. Resolução CNS n° 553, de 9 de agosto de 2017. Aprova a atualização da Carta dos Direitos e Deveres da Pessoa Usuária da Saúde. Diário Oficial da União [Internet]. Brasília, n° 10, p. 41-4, 15 jan 2018 [acesso 29 maio 2020]. Seção 1. Disponível: https://bit.ly/34YM9CR
https://bit.ly/34YM9CR...
and it must be preserved, regardless of personal decisions to participate in research3232. Conselho Nacional de Saúde. Resolução CNS n° 580, de 22 de março de 2018. Regulamenta o disposto no item XIII.4 da Resolução CNS n° 466, de 12 de dezembro de 2012, que estabelece que as especificidades éticas das pesquisas de interesse estratégico para o Sistema Único de Saúde (SUS) serão contempladas em resolução específica, e dá outras providências. Diário Oficial da União [Internet]. Brasília, n° 135, p. 55, 16 jul 2018 [acesso 29 maio 2020]. Seção 1. Disponível: https://bit.ly/3erWgmJ
https://bit.ly/3erWgmJ...
. Protocols of public health emergencies or with territories or people in situations of great risk or vulnerability3333. Conselho Nacional de Saúde. Resolução CNS n° 588, de 12 de julho de 2018. Institui a Política Nacional de Vigilância em Saúde. Diário Oficial da União [Internet]. Brasília, n° 155, p. 87-90, 13 ago 2018 [acesso 29 maio 2020]. Seção 1. Disponível: https://bit.ly/2JBy6ei
https://bit.ly/2JBy6ei...
require special and urgent analysis, primarily aiming to reduce social and health inequalities3232. Conselho Nacional de Saúde. Resolução CNS n° 580, de 22 de março de 2018. Regulamenta o disposto no item XIII.4 da Resolução CNS n° 466, de 12 de dezembro de 2012, que estabelece que as especificidades éticas das pesquisas de interesse estratégico para o Sistema Único de Saúde (SUS) serão contempladas em resolução específica, e dá outras providências. Diário Oficial da União [Internet]. Brasília, n° 135, p. 55, 16 jul 2018 [acesso 29 maio 2020]. Seção 1. Disponível: https://bit.ly/3erWgmJ
https://bit.ly/3erWgmJ...
,3333. Conselho Nacional de Saúde. Resolução CNS n° 588, de 12 de julho de 2018. Institui a Política Nacional de Vigilância em Saúde. Diário Oficial da União [Internet]. Brasília, n° 155, p. 87-90, 13 ago 2018 [acesso 29 maio 2020]. Seção 1. Disponível: https://bit.ly/2JBy6ei
https://bit.ly/2JBy6ei...
.
Budget forecasting is an important item in care surveys in SUS3232. Conselho Nacional de Saúde. Resolução CNS n° 580, de 22 de março de 2018. Regulamenta o disposto no item XIII.4 da Resolução CNS n° 466, de 12 de dezembro de 2012, que estabelece que as especificidades éticas das pesquisas de interesse estratégico para o Sistema Único de Saúde (SUS) serão contempladas em resolução específica, e dá outras providências. Diário Oficial da União [Internet]. Brasília, n° 135, p. 55, 16 jul 2018 [acesso 29 maio 2020]. Seção 1. Disponível: https://bit.ly/3erWgmJ
https://bit.ly/3erWgmJ...
and health surveillance3333. Conselho Nacional de Saúde. Resolução CNS n° 588, de 12 de julho de 2018. Institui a Política Nacional de Vigilância em Saúde. Diário Oficial da União [Internet]. Brasília, n° 155, p. 87-90, 13 ago 2018 [acesso 29 maio 2020]. Seção 1. Disponível: https://bit.ly/2JBy6ei
https://bit.ly/2JBy6ei...
, which legitimizes the discussion about resource sustainability for the well-being of the Brazilian population. Covid-19 creates extremely difficult dilemmas for health professionals, and no isolated algorithm can give complete guidance or relieve the medical burden of individual evaluation, which must weigh between beneficence and justice in particular situations4949. Hulsbergen AFC, Eijkholt MM, Balak N, Brennum J, Bolger C, Boher A-M et al. Ethical triage during the covid-19 pandemic: a toolkit for neurosurgical resource allocation. Acta Neurochir [Internet]. 2020 [acesso 29 maio 2020];162:1485-90. DOI: 10.1007/s00701-020-04375-w
https://doi.org/10.1007/s00701-020-04375...
.
The recognition of ethical appreciation in public health emergencies generates greater articulation between research institutions, health systems and the community, to prioritize research that improves the well-being and reduces mortality in the short term, especially in contexts of overcrowded hospitals22. Arora A, Arora A. Ethics in the age of covid-19. Intern Emerg Med [Internet]. 2020 [acesso 8 jun 2020];889-90. DOI: 10.1007/s11739-020-02368-2
https://doi.org/10.1007/s11739-020-02368...
,4949. Hulsbergen AFC, Eijkholt MM, Balak N, Brennum J, Bolger C, Boher A-M et al. Ethical triage during the covid-19 pandemic: a toolkit for neurosurgical resource allocation. Acta Neurochir [Internet]. 2020 [acesso 29 maio 2020];162:1485-90. DOI: 10.1007/s00701-020-04375-w
https://doi.org/10.1007/s00701-020-04375...
.
The speed of the evaluation of research on Covid-19 may be positive, as verified by ethics committees in China, where monthly collegiate meetings became almost daily, and decisions began to be released in 2.13 days, on average, with 1.81 more days in case of new submissions during the pandemic1212. Zhang H, Shao F, Gu J, Li L, Wang Y. Ethics committee reviews of applications for research studies at 1 hospital in China during the 2019 novel coronavirus epidemic. JAMA [Internet]. 2020 [acesso 8 jun 2020];323(18):1844-6. DOI: 10.1001/jama.2020.4362
https://doi.org/10.1001/jama.2020.4362...
. This pattern is much more dynamic than in Brazil, where the average CEP deadline for decisions is 30 days and for Conep is 60 days2929. Gouy CML, Porto TF, Penido C. Avaliação de ensaios clínicos no Brasil: histórico e atualidades. Rev. bioét. (Impr.) [Internet]. 2018 [acesso 29 maio 2020];26(3):350-9. DOI: 10.1590/1983-80422018263254
https://doi.org/10.1590/1983-80422018263...
.
A multinational study involving Germany, Italy, Spain, France, the United Kingdom, Belgium, the Netherlands, Austria, Denmark, and Sweden showed that each of these countries receives more than 200 clinical trials of drugs per year, mainly in Phase III5050. Dombernowsky T, Hædersdal M, Lassen U, Thomsen SF. Development in the number of clinical trial applications in Western Europe from 2007 to 2015: retrospective study of data from national competent authorities. BMJ Open [Internet]. 2017 [acesso 29 maio 2020];7(7):e015579. DOI: 10.1136/bmjopen-2016-015579
https://doi.org/10.1136/bmjopen-2016-015...
. The fluctuations over the years were attributed to political influences and commercial sponsorship in Western Europe, with a 4% decrease in proposals between 2007 and 2011, stagnation between 2012 and 2013, and an 10% increase between 2014 and 20155050. Dombernowsky T, Hædersdal M, Lassen U, Thomsen SF. Development in the number of clinical trial applications in Western Europe from 2007 to 2015: retrospective study of data from national competent authorities. BMJ Open [Internet]. 2017 [acesso 29 maio 2020];7(7):e015579. DOI: 10.1136/bmjopen-2016-015579
https://doi.org/10.1136/bmjopen-2016-015...
. In Switzerland, randomized clinical trials cost, on average, US$ 72,000, with different approval intervals when comparing research ethics committees (from 82 to 92 days) and the Swissmedic regulatory agency (27 to 49 days)3636. Speich B, Schur N, Gryaznov D, Von Niederhäusern B, Hemkens LG, Schandelmaier S et al. Resource use, costs, and approval times for planning and preparing a randomized clinical trial before and after the implementation of the new Swiss human research legislation. PLoS ONE [Internet]. 2019 [acesso 29 maio 2020];14(1):e0210669. DOI: 10.1371/journal.pone.0210669
https://doi.org/10.1371/journal.pone.021...
.
In Brazil, these trials depend heavily on the infrastructure of participating centers, and multicentric participation is recommended for lower costs. To develop a new drug, a dossier of clinical development is analyzed in parallel by the CEP/Conep system and regulatory bodies of the National Health Surveillance Agency (Anvisa). Only after the approval of both, the study can begin.
The Anvisa manifestation period varies from 180 days for Phases I or II, or 90 days for the others. Time is relevant in these studies, but it is necessary to consider the safety of volunteers, to guard good research practices2929. Gouy CML, Porto TF, Penido C. Avaliação de ensaios clínicos no Brasil: histórico e atualidades. Rev. bioét. (Impr.) [Internet]. 2018 [acesso 29 maio 2020];26(3):350-9. DOI: 10.1590/1983-80422018263254
https://doi.org/10.1590/1983-80422018263...
. These considerations impact national research on Covid-19, which mostly test chloroquine and hydroxychloroquine, in addition to other therapeutic forms, such as the association with azithromycin, lopinavir/ritonavir, nitazoxanide, eculizumab, tocilizumab, sarilumab, ivermectin, convalescent plasma and mesenchymal stem cells2121. Comissão Nacional de Ética em Pesquisa. Boletim Ética em Pesquisa: edição especial coronavírus (covid-19): relatório semanal 19 [Internet]. 26 maio 2020 [acesso 6 jun 2020]. Disponível: https://bit.ly/2T9JTBR
https://bit.ly/2T9JTBR...
.
Suspensions of ongoing trials in Brazil, even in a sample universe that is still small and recent, reinforce the ethics debate during the studies. The “Brazilian way,” a cultural construct used as a strategy to solve problems, cannot overlook scientific criteria and the commitment to research quality in the country5151. Farias SA. The Brazilian little way in academia. BAR Braz Adm Rev [Internet]. 2018 [acesso 29 maio 2020];15(1):e180035. DOI: 10.1590/1807-7692bar2018180035
https://doi.org/10.1590/1807-7692bar2018...
.
In this sense, cunning or métis, which refers to ancient Greek thought, arises in the encounter with new challenges, and its flexible psychodynamics reminds us that new operational tactics are always present in human production, but should not disqualify or subvert the quality of knowledge5252. Silva JTA, Muniz HP. Considerações sobre a métis, a inteligência astuciosa. Mnemosine [Internet]. 2017 [acesso 29 maio 2020];13(2):309-31. Disponível: https://bit.ly/3l65Azg
https://bit.ly/3l65Azg...
. Considering the immediate search for results during the pandemic, the researcher's role in protecting patients and volunteers against significant risks or damages should be recognized. If damages occur, they should be communicated to research ethics committees for the readjustment or suspension of the study2828. Conselho Nacional de Saúde. Resolução CNS n° 466, de 12 de dezembro de 2012. Aprova diretrizes e normas regulamentadoras de pesquisas envolvendo seres humanos. Diário Oficial da União [Internet]. Brasília, n° 12, p. 59, 13 jun 2013 [acesso 29 maio 2020]. Seção 1. Disponível: https://bit.ly/3esS2LS
https://bit.ly/3esS2LS...
.
The limitation of this study is related to the short time interval analyzed, the first trimester of the 2020 pandemic. However, the initial panorama of research with human beings and the dimensioning of S&T resources in Brazil contribute to decision-making in the fight against the disease.
Final considerations
Despite the exponential growth of Covid-19, initial research with humans in Brazil had a discrete, slow, and asymmetric diffusion in the states, with most clinical trials in Phase II. The geographical distribution of resources and assistance generates advances and vulnerabilities in coping with the disease. Close longitudinal follow-up should be carried out in the face of regional inequities, to defend bioethical principles and human life.
Referências
-
1Angelos P. Surgeons, ethics, and covid-19: early lessons learned. J Am Coll Surg [Internet]. 2020 [acesso 8 jun 2020];230(6):1119-20. DOI: 10.1016/j.jamcollsurg.2020.03.028
» https://doi.org/10.1016/j.jamcollsurg.2020.03.028 -
2Arora A, Arora A. Ethics in the age of covid-19. Intern Emerg Med [Internet]. 2020 [acesso 8 jun 2020];889-90. DOI: 10.1007/s11739-020-02368-2
» https://doi.org/10.1007/s11739-020-02368-2 -
3Hiscott J, Alexandridi M, Muscolini M, Tassone E, Palermo E, Soultsioti M, Zevini A. The global impact of the coronavirus pandemic. Cytokine Growth Factor Rev [Internet]. 2020 [acesso 8 jun 2020];53:1-9. DOI: 10.1016/j.cytogfr.2020.05.010
» https://doi.org/10.1016/j.cytogfr.2020.05.010 -
4Thorp HH. Do us a favor. Science [Internet]. 2020 [acesso 8 jun 2020];367(6483):1169. DOI: 10.1126/science.abb6502
» https://doi.org/10.1126/science.abb6502 -
5Maciel JAC, Castro-Silva II, Farias MR. Análise inicial da correlação espacial entre a incidência de covid-19 e o desenvolvimento humano nos municípios do estado do Ceará no Brasil. Rev Bras Epidemiol [Internet]. 2020 [acesso 22 jun 2020];23:E200057. DOI: 10.1590/1980-549720200057
» https://doi.org/10.1590/1980-549720200057 -
6Covid-19 in Brazil: “So what?” [editorial]. Lancet [Internet]. 2020 [acesso 23 jun 2020];395(10235):1461. DOI: 10.1016/S0140-6736(20)31095-3
» https://doi.org/10.1016/S0140-6736(20)31095-3 -
7Silva R, Pasti D. Da “gripezinha” ao “e daí?”: as falas de Bolsonaro em cada fase da pandemia. Gazeta [Internet]. Política; 7 jul 2020 [acesso 8 ago 2020]. Disponível: https://bit.ly/2FKMFKZ
» https://bit.ly/2FKMFKZ -
8Rosário M. Covid-19: sites paralelos divulgam dados oficiais apagados pelo governo. Veja [Internet]. Saúde; 8 jun 2020 [acesso 8 jun 2020]. Disponível: https://bit.ly/3j9jH56
» https://bit.ly/3j9jH56 -
9Mais de 70 entidades assinam nota contra ocultação de dados de covid-19 pelo governo. Sociedade Brasileira para o Progresso da Ciência [Internet]. 8 jun 2020 [acesso 8 jun 2020]. Disponível: https://bit.ly/3jgW9eH
» https://bit.ly/3jgW9eH -
10Coelho MTP, Rodrigues JFM, Medina AM, Scalco P, Terribile LC, Vilela B et al Exponential phase of covid-19 expansion is driven by airport connections. MedRxiv [Internet]. 6 maio 2020 [acesso 8 jun 2020]. DOI: 10.1101/2020.04.02.20050773
» https://doi.org/10.1101/2020.04.02.20050773 -
11World Health Organization. Guidance for managing ethical issues in infectious disease outbreaks [Internet]. Geneva: WHO; 2016 [acesso 9 nov 2020]. Disponível: https://bit.ly/37x8pp7
» https://bit.ly/37x8pp7 -
12Zhang H, Shao F, Gu J, Li L, Wang Y. Ethics committee reviews of applications for research studies at 1 hospital in China during the 2019 novel coronavirus epidemic. JAMA [Internet]. 2020 [acesso 8 jun 2020];323(18):1844-6. DOI: 10.1001/jama.2020.4362
» https://doi.org/10.1001/jama.2020.4362 -
13World Economic Forum. Code of ethics [Internet]. Geneva: WEF; 2018 [acesso 6 jun 2020]. Disponível: https://bit.ly/3dN4iWX
» https://bit.ly/3dN4iWX -
14Kirkpatrick JN, Hull SC, Fedson S, Mullen B, Goodlin SJ. Scarce-resource allocating and patient triage during the covid-19 pandemic: JACC review topic of the week. J Am Coll Cardiol [Internet]. 2020 [acesso 8 jun 2020];76(1):85-92. DOI: 10.1016/j.jacc.2020.05.006
» https://doi.org/10.1016/j.jacc.2020.05.006 -
15Meagher KM, Cummins NW, Bharucha AE, Badley AD, Chlan LL, Wright RS. Covid-19 ethics and research. Mayo Clin Proc [Internet]. 2020 [acesso 8 jun 2020];95(6):1119-23. DOI: 10.1016/j.mayocp.2020.04.019
» https://doi.org/10.1016/j.mayocp.2020.04.019 -
16Herreros B, Gella P, Real de Asua D. Triage during the covid-19 epidemic in Spain: better and worse ethical arguments. J Med Ethics [Internet]. 2020 [acesso 8 jun 2020];46(7):455-8. DOI: 10.1136/medethics-2020-106352
» https://doi.org/10.1136/medethics-2020-106352 -
17Rawlings A, Brandt L, Ferreres A, Asbun H, Shadduck P. Ethical considerations for allocation of scarce resources and alterations in surgical care during a pandemic. Surg Endosc [Internet]. 2020 [acesso 8 jun 2020]. DOI: 10.1007/s00464-020-07629-x
» https://doi.org/10.1007/s00464-020-07629-x -
18Leclerc T, Donat N, Donat A, Pasquier P, Libert N, Schaeffer E et al Prioritisation of ICU treatments for critically ill patients in a covid-19 pandemic with scarce resources. Anaesth Crit Care Pain Med [Internet]. 2020 [acesso 8 jun 2020];39(3):333-9. DOI: 10.1016/j.accpm.2020.05.008
» https://doi.org/10.1016/j.accpm.2020.05.008 -
19Comissão Nacional de Ética em Pesquisa. Boletim Ética em Pesquisa: edição especial coronavírus (covid-19): relatório semanal 1 [Internet]. 23 mar 2020 [acesso 6 jun 2020]. Disponível: https://bit.ly/35hIFu3
» https://bit.ly/35hIFu3 -
20Comissão Nacional de Ética em Pesquisa. Boletim Ética em Pesquisa: edição especial coronavírus (covid-19): relatório semanal 10 [Internet]. 24 abr 2020 [acesso 6 jun 2020]. Disponível: https://bit.ly/2FP5tc2
» https://bit.ly/2FP5tc2 -
21Comissão Nacional de Ética em Pesquisa. Boletim Ética em Pesquisa: edição especial coronavírus (covid-19): relatório semanal 19 [Internet]. 26 maio 2020 [acesso 6 jun 2020]. Disponível: https://bit.ly/2T9JTBR
» https://bit.ly/2T9JTBR -
22Brasil. Ministério da Saúde. Coronavírus Brasil [Internet]. 2020 [acesso 29 maio 2020]. Disponível: https://bit.ly/2HhtitI
» https://bit.ly/2HhtitI -
23Brasil. Ministério da Saúde. Datasus: Tabnet [Internet]. 2020 [acesso 29 maio 2020]. Disponível: https://bit.ly/3dPX58D
» https://bit.ly/3dPX58D -
24Brasil. Ministério da Saúde. Plataforma Brasil [Internet]. 2020 [acesso 6 jun 2020]. Disponível: https://bit.ly/35Z2gzC
» https://bit.ly/35Z2gzC -
25Brasil. Ministério da Educação. Cadastro Nacional de Cursos e Instituições de Educação Superior: Cadastro e-MEC [Internet]. 2020 [acesso 6 jun 2020]. Disponível: https://bit.ly/38clq7K
» https://bit.ly/38clq7K -
26Brasil. Ministério da Ciência, Tecnologia e Inovações. Recursos aplicados: governos estaduais: 2.3.4 Brasil: dispêndios dos governos estaduais em ciência e tecnologia (C&T) por região, unidade da federação e atividade, 2000-2017 [Internet]. 2019 [acesso 6 jun 2020]. Disponível: https://bit.ly/3kXsybT
» https://bit.ly/3kXsybT -
27Conselho Nacional de Saúde. Resolução CNS n° 510, de 7 de abril de 2016. Dispõe sobre as normas aplicáveis a pesquisas em ciências humanas e sociais cujos procedimentos metodológicos envolvam a utilização de dados diretamente obtidos com os participantes ou de informações identificáveis ou que possam acarretar riscos maiores do que os existentes na vida cotidiana. Diário Oficial da União [Internet]. Brasília, n° 98, p. 44, 24 maio 2016 [acesso 29 maio 2020]. Seção 1. Disponível: https://bit.ly/3l0NVJb
» https://bit.ly/3l0NVJb -
28Conselho Nacional de Saúde. Resolução CNS n° 466, de 12 de dezembro de 2012. Aprova diretrizes e normas regulamentadoras de pesquisas envolvendo seres humanos. Diário Oficial da União [Internet]. Brasília, n° 12, p. 59, 13 jun 2013 [acesso 29 maio 2020]. Seção 1. Disponível: https://bit.ly/3esS2LS
» https://bit.ly/3esS2LS -
29Gouy CML, Porto TF, Penido C. Avaliação de ensaios clínicos no Brasil: histórico e atualidades. Rev. bioét. (Impr.) [Internet]. 2018 [acesso 29 maio 2020];26(3):350-9. DOI: 10.1590/1983-80422018263254
» https://doi.org/10.1590/1983-80422018263254 -
30Conselho Nacional de Saúde. Resolução CNS n° 553, de 9 de agosto de 2017. Aprova a atualização da Carta dos Direitos e Deveres da Pessoa Usuária da Saúde. Diário Oficial da União [Internet]. Brasília, n° 10, p. 41-4, 15 jan 2018 [acesso 29 maio 2020]. Seção 1. Disponível: https://bit.ly/34YM9CR
» https://bit.ly/34YM9CR -
31Conselho Nacional de Saúde. Carta circular CNS n° 166, de 12 de junho de 2018 [Internet]. Brasília: Ministério da Saúde; 21 jun 2018 [acesso 26 jun 2020]. Disponível: https://bit.ly/3kTy2Em
» https://bit.ly/3kTy2Em -
32Conselho Nacional de Saúde. Resolução CNS n° 580, de 22 de março de 2018. Regulamenta o disposto no item XIII.4 da Resolução CNS n° 466, de 12 de dezembro de 2012, que estabelece que as especificidades éticas das pesquisas de interesse estratégico para o Sistema Único de Saúde (SUS) serão contempladas em resolução específica, e dá outras providências. Diário Oficial da União [Internet]. Brasília, n° 135, p. 55, 16 jul 2018 [acesso 29 maio 2020]. Seção 1. Disponível: https://bit.ly/3erWgmJ
» https://bit.ly/3erWgmJ -
33Conselho Nacional de Saúde. Resolução CNS n° 588, de 12 de julho de 2018. Institui a Política Nacional de Vigilância em Saúde. Diário Oficial da União [Internet]. Brasília, n° 155, p. 87-90, 13 ago 2018 [acesso 29 maio 2020]. Seção 1. Disponível: https://bit.ly/2JBy6ei
» https://bit.ly/2JBy6ei -
34Costa GS, Cota W, Ferreira SC. Metapopulation modeling of covid-19 advancing into the countryside: an analysis of mitigation strategies for Brazil. MedRxiv [Internet]. 13 maio 2020 [acesso 29 maio 2020]. DOI: 10.1101/2020.05.06.20093492
» https://doi.org/10.1101/2020.05.06.20093492 -
35Williamson E, Walker AJ, Bhaskaran K, Bacon S, Bates C, Morton CE et al OpenSAFELY: factors associated with covid-19-related hospital death in the linked electronic health records of 17 million adult NHS patients. MedRxiv [Internet]. 7 maio 2020 [acesso 29 maio 2020]. DOI: 10.1101/2020.05.06.20092999
» https://doi.org/10.1101/2020.05.06.20092999 -
36Speich B, Schur N, Gryaznov D, Von Niederhäusern B, Hemkens LG, Schandelmaier S et al Resource use, costs, and approval times for planning and preparing a randomized clinical trial before and after the implementation of the new Swiss human research legislation. PLoS ONE [Internet]. 2019 [acesso 29 maio 2020];14(1):e0210669. DOI: 10.1371/journal.pone.0210669
» https://doi.org/10.1371/journal.pone.0210669 -
37Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC et al A randomized trial of hydroxychloroquine as postexposure prophylaxis for covid-19. N Engl J Med [Internet]. 2020 [acesso 29 maio 2020];383:517-25. DOI: 10.1056/NEJMoa2016638.X
» https://doi.org/10.1056/NEJMoa2016638.X -
38Lane JCE, Weaver J, Kostka K, Duarte-Salles T, Abrahao MTF, Alghoul H et al Safety of hydroxychloroquine, alone and in combination with azithromycin, in light of rapid wide-spread use for covid-19: a multinational, network cohort and self-controlled case series study. MedRxiv [Internet]. 31 maio 2020 [acesso 8 jun 2020]. DOI: 10.1101/2020.04.08.20054551
» https://doi.org/10.1101/2020.04.08.20054551 -
39Borba MGS, Val FA, Sampaio VS, Alexandre MAA, Melo GC, Brito M et al Chloroquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (Sars-CoV-2) infection: preliminary safety results of a randomized, double-blinded, phase IIb clinical trial (CloroCovid-19 Study). MedRxiv [Internet]. 16 abr 2020 [acesso 29 maio 2020]. DOI: 10.1101/2020.04.07.20056424
» https://doi.org/10.1101/2020.04.07.20056424 -
40Rana DRSJB, Dulal S. Therapeutic application of chloroquine and hydroxychloroquine in clinical trials for covid-19: a systematic review. MedRxiv [Internet]. 10 abr 2020 [acesso 29 maio 2020]. DOI: 10.1101/2020.03.22.20040964
» https://doi.org/10.1101/2020.03.22.20040964 -
41Entenda a liberação de cloroquina e hidroxicloroquina. Agência Nacional de Vigilância Sanitária [Internet]. Novo coronavírus; 31 mar 2020 [acesso 8 jun 2020]. Disponível: https://bit.ly/32geeUf
» https://bit.ly/32geeUf -
42Mehra MR, Desai SS, Ruschitzka F, Patel AN. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of covid-19: a multinational registry analysis. Lancet [Internet]. 2020 [acesso 29 maio 2020]. DOI: 10.1016/S0140-6736(20)31180-6
» https://doi.org/10.1016/S0140-6736(20)31180-6 -
43The Lancet Editors. Expression of concern: hydroxychloroquine or chloroquine with or without a macrolide for treatment of covid-19: a multinational registry analysis. Lancet [Internet]. 2020 [acesso 29 maio 2020];395(10240):E102. DOI: 10.1016/S0140-6736(20)31290-3
» https://doi.org/10.1016/S0140-6736(20)31290-3 -
44Watson J, Adler A, Agweyu A, Prieto-Alhambra D, Amaravadi R, Anaya J-M et al Concerns regarding the statistical analysis and data integrity [Internet]. 2020 [acesso 6 jun 2020]. Disponível: https://bit.ly/2U0vEzP
» https://bit.ly/2U0vEzP -
45Mehra MR, Ruschitzka F, Patel AN. Retraction: hydroxychloroquine or chloroquine with or without a macrolide for treatment of covid-19: a multinational registry analysis. Lancet [Internet]. 2020 [acesso 29 maio 2020];395(10240):1820. DOI: 10.1016/S0140-6736(20)31324-6
» https://doi.org/10.1016/S0140-6736(20)31324-6 -
46Covid-19: a human rights checklist. Human Rights Watch [Internet]. 2020 [acesso 12 jun 2020]. Disponível: https://bit.ly/2IaSQJ0
» https://bit.ly/2IaSQJ0 -
47Calmon M. Considerations of coronavirus (covid-19) impact and the management of the dead in Brazil. Forensic Sci Int [Internet]. 2020 [acesso 29 maio 2020];100110. DOI: 10.1016/j.fsir.2020.100110
» https://doi.org/10.1016/j.fsir.2020.100110 -
48Cota W. Monitoring the number of covid-19 cases and deaths in Brazil at municipal and federative units level. SciELO Preprints [Internet]. 2020 [acesso 29 maio 2020];e362. DOI: 10.1590/SciELOPreprints.362
» https://doi.org/10.1590/SciELOPreprints.362 -
49Hulsbergen AFC, Eijkholt MM, Balak N, Brennum J, Bolger C, Boher A-M et al Ethical triage during the covid-19 pandemic: a toolkit for neurosurgical resource allocation. Acta Neurochir [Internet]. 2020 [acesso 29 maio 2020];162:1485-90. DOI: 10.1007/s00701-020-04375-w
» https://doi.org/10.1007/s00701-020-04375-w -
50Dombernowsky T, Hædersdal M, Lassen U, Thomsen SF. Development in the number of clinical trial applications in Western Europe from 2007 to 2015: retrospective study of data from national competent authorities. BMJ Open [Internet]. 2017 [acesso 29 maio 2020];7(7):e015579. DOI: 10.1136/bmjopen-2016-015579
» https://doi.org/10.1136/bmjopen-2016-015579 -
51Farias SA. The Brazilian little way in academia. BAR Braz Adm Rev [Internet]. 2018 [acesso 29 maio 2020];15(1):e180035. DOI: 10.1590/1807-7692bar2018180035
» https://doi.org/10.1590/1807-7692bar2018180035 -
52Silva JTA, Muniz HP. Considerações sobre a métis, a inteligência astuciosa. Mnemosine [Internet]. 2017 [acesso 29 maio 2020];13(2):309-31. Disponível: https://bit.ly/3l65Azg
» https://bit.ly/3l65Azg
Publication Dates
-
Publication in this collection
20 Jan 2021 -
Date of issue
Oct-Dec 2020
History
-
Received
13 June 2020 -
Reviewed
24 Sept 2020 -
Accepted
01 Oct 2020