Assessment of novel technologies in healthcare - off-label use of drugs and the ethics of implementation and distribution of COVID-19 vaccines

Vivian Iida Avelino-Silva Mario Thadeu Leme de Barros FilhoClass 8 FICSAE Working GroupAbout the authors

New health technologies, such as new medications, products, equipment, and vaccines, are constantly produced. The traditional development of new health technologies is a lenghty and high-cost process, including pre-clinical development phases (in vitro and animal model studies) and clinical trials, traditionally divided into phases 1, 2 and 3. The registry of novel technologies must be required at the National Health Surveillance Agency (Anvisa - Agência Nacional de Vigilância Sanitária), only after the conclusion of clinical trials. The agency has a technical team responsible for evaluating and determining whether or not the novel technology can be introduced in the Brazilian market.(11. Brasil. Ministério da Saúde. Agência Nacional de Vigilância Sanitária (ANVISA). Registro de novos medicamentos: saiba o que é preciso. Brasília (DF): ANVISA; 2018.)

Nonetheless, the effective incorporation of novel technologies in clinical practice also depends on demonstrating that they will in fact benefit both patients and the society. Health Technology Assessment (HTA) consists of a multistep analyses based on scientific evidence, implemented as an essential criterion for decisions about the incorporation of novel health technologies in the context of the Public Health System (SUS - Sistema Único de Saúde), since the ratification of Act 12,401, of April 28th, 2011.(22. Brasil. Ministério da Saúde. Secretaria de Ciência, Tecnologia e Insumos Estratégicos. Departamento de Gestão e Incorporação de Tecnologias em Saúde. Entendendo a Incorporação de Tecnologias em Saúde no SUS : como se envolver. Brasília (DF): Ministério da Saúde; 2016 [citado 2021 Jun 22]. Disponível em: https://bvsms.saude.gov.br/bvs/publicacoes/entendendo_incorporacao_tecnologias_sus_envolver.pdf
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Health Technology Assessment is a decision-making tool, based on unbiased and transparent deliberations regarding the following aspects:

  • Clinical: evaluation of safety, efficacy, effectiveness, clinical indications, and target population, considering the burden of the disease and its social impacts.

  • Economic: evaluation of economic studies (studies on cost, cost-effectiveness, cost-utility, and cost-benefit) and impact on budget.

  • Patient-related: evaluation of characteristics and social impact of the disease, importance and benefits of technologies already implemented, patient demands that are currently overlooked, convenience, public perception and acceptance of the new technology, and ethical issues related to the implementation of the novel technology.

  • Organizational: evaluation of the feasibility for widespread use, capacity-building of professionals, optimized allocation of resources, monitoring of results, and sustainability of the new health technology.

The HTA process is employed in several countries with similar principles, but adapted to the local context, as a tool to support decisions made by health managers. In Brazil, the National Committee for Health Technology Incorporation in the SUS (CONITEC - Comissão Nacional de Incorporação de Tecnologias), a technical agency of health policy, uses the HTA as a strategy to help the Ministry of Health in evaluating the implementation of novel technologies at SUS.(33. Comissão Nacional de Incorporação de Tecnologias no Sistema Único de Saúde (CONITEC). A comissão. São Paulo: CONITEC; 2021 [citado 2021 Jun 22]. Disponível em: http://conitec.gov.br/entenda-a-conitec-2
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,44. Comissão Nacional de Incorporação de Tecnologias no SUS, Secretaria de Ciência, Tecnologia e Insumos Estratégicos, Ministério da Saúde. Uso off label: erro ou necessidade? Rev Saude Publica. 2012;46(2):398-9.)

The participation of the civil society in the HTA process is anticipated and encouraged, aiming to add pieces of information about the impacts of the disease, limitations imposed to quality of life, and expectations concerning the benefits associated with new technologies as compared to available interventions. Information gathered from patients and caregivers improve the overall understanding and implementation of novel technologies, considering the health-related preferences of the target population. It is particularly important to have the civil society participating in the discussion about HTA. There are four main mechanisms for including public participation in discussions concerning the incorporation of new health technologies, as follows: public consultations; court hearings; surveys; and participation in plenary sessions. It is also worth mentioning that the engagement of the civil society can also occur by the mere access to information, research, analyses, and recommendations published by CONITEC and available for the general public.(22. Brasil. Ministério da Saúde. Secretaria de Ciência, Tecnologia e Insumos Estratégicos. Departamento de Gestão e Incorporação de Tecnologias em Saúde. Entendendo a Incorporação de Tecnologias em Saúde no SUS : como se envolver. Brasília (DF): Ministério da Saúde; 2016 [citado 2021 Jun 22]. Disponível em: https://bvsms.saude.gov.br/bvs/publicacoes/entendendo_incorporacao_tecnologias_sus_envolver.pdf
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Assessment of new health technologies in the context of off-label use and repurposing of drugs for treatment and prevention of COVID-19

Some medications are used for purposes that are not described in the package insert; therefore, they are not analyzed in controlled studies, neither submitted to evaluation by regulatory processes, such as HTA, or official agencies, such as CONITEC, the National Health Agency (ANS - Agência Nacional de Saúde) and Anvisa. This practice is generally known as off-label use.(55. Agência Nacional de Vigilância Sanitária (ANVISA). Como a Anvisa vê o uso off label de medicamentos. Brasília (DF): ANVISA; 2005 [citado 2021 Jun 22]. Disponível em: http://antigo.anvisa.gov.br/en_US/resultado-de-busca?p_p_id=101&p_p_lifecycle=0&p_p_state=maximized&p_p_mode=view&p_p_col_id=column-1&p_p_col_count=1&_101_struts_action=%2Fasset_publisher%2Fview_content&_101_assetEntryId=352702&_101_type=content&_101_grou
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) The off-label use of medications or other medical technologies must be differentiated from repurposed or repositioned use, in which medications that are already approved are submitted to a rigorous and systematic process of analysis, aiming to identify compounds that might be applied to other conditions, such as emerging or rare diseases, for which no specific treatment is available.(66. Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, et al. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov. 2019;18(1):41-58. Review.) Drug repurposing has advantages relatively to the traditional development of new medicines, since repurposed drugs have often undergone safety studies, and can be implemented faster, with lower financial investments. The initial identification of candidate compounds for repurposing can be conducted by experimental or computational methods, which identify molecules more likely to act in targets of interest. Another option is to select candidate compounds that have phenotypical or functional characteristics similar to the drugs already used for that specific purpose.(66. Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, et al. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov. 2019;18(1):41-58. Review.)

While repurposing of drugs implies the demonstration of efficacy in clinical trials, off-label use can be indicated by a physician, who simply believes the patient will benefit from that medication. In the case of medicines sold over the counter, off-label use can be decided by the patients themselves, not requiring medical prescriptions. Off-label use of medications may imply risks not only for patients but also for physicians, due to the lack of clinical studies or approval of the new purpose of the drug by Anvisa, leaving them with no legal support. Moreover, off-label prescription exempts the pharmaceutical industry from legal and judicial responsibilities if adverse reactions occur, since this use is not described in the package insert.(77. Aniceto DL. ANVISA e o uso off-label de medicamentos: as relações entre evidência e regulação [dissertação]. Fortaleza (CE): Universidade Federal do Ceará, Faculdade de Medicina; 2019. 70 f. [citado 2021 Jun 22]. Disponível em: http://www.repositorio.ufc.br/bitstream/riufc/49579/1/2019_dis_dlfpaniceto.pdf
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The search for therapeutic interventions for the coronavirus disease 2019 (COVID-19) has been non-stop since the beginning of the pandemic. Several medications have been used off-label for treatment and prevention of COVID-19, based on reports of effect against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in in vitro studies, or human studies with major methodological limitations.(88. World Health Organization (WHO). Off-label use of medicines for COVID-19. Geneva: WHO; 2020 [cited 2021 June 22]. Available from: https://www.who.int/news-room/commentaries/detail/off-label-use-of-medicines-for-covid-19
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9. Kalil AC. Treating COVID-19-off-label drug use, compassionate use, and randomized clinical trials during pandemics. JAMA. 2020;323(19):1897-8.

10. Alpern JD, Gertner E. Off-label therapies for covid-19-are we all in this together? Clin Pharmacol Ther. 2020;108(2):182-4.
-1111. Paumgartten FJ, Oliveira AC. Off label, compassionate and irrational use of medicines in Covid-19 pandemic, health consequences and ethical issues.. Cien Saude Colet. 2020;25(9):3413-9.) A few months after the pandemic began, controlled clinical trials were published,(1212. WHO Solidarity Trial Consortium, Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, Abdool Karim Q, Alejandria MM, Hernández García C, Kieny MP, Malekzadeh R, Murthy S, Reddy KS, Roses Periago M, Abi Hanna P, Ader F, Al-Bader AM, Alhasawi A, Allum E, Alotaibi A, Alvarez-Moreno CA, Appadoo S, Asiri A, Aukrust P, Barratt-Due A, Bellani S, Branca M, Cappel-Porter HB, Cerrato N, Chow TS, Como N, Eustace J, García PJ, Godbole S, Gotuzzo E, Griskevicius L, Hamra R, Hassan M, Hassany M, Hutton D, Irmansyah I, Jancoriene L, Kirwan J, Kumar S, Lennon P, Lopardo G, Lydon P, Magrini N, Maguire T, Manevska S, Manuel O, McGinty S, Medina MT, Mesa Rubio ML, Miranda-Montoya MC, Nel J, Nunes EP, Perola M, Portolés A, Rasmin MR, Raza A, Rees H, Reges PP, Rogers CA, Salami K, Salvadori MI, Sinani N, Sterne JA, Stevanovikj M, Tacconelli E, Tikkinen KA, Trelle S, Zaid H, Røttingen JA, Swaminathan S. Repurposed antiviral drugs for Covid-19 - interim WHO solidarity trial results. N Engl J Med. 2021;384(6):497-511.

13. Self WH, Semler MW, Leither LM, Casey JD, Angus DC, Brower RG, Chang SY, Collins SP, Eppensteiner JC, Filbin MR, Files DC, Gibbs KW, Ginde AA, Gong MN, Harrell FE Jr, Hayden DL, Hough CL, Johnson NJ, Khan A, Lindsell CJ, Matthay MA, Moss M, Park PK, Rice TW, Robinson BR, Schoenfeld DA, Shapiro NI, Steingrub JS, Ulysse CA, Weissman A, Yealy DM, Thompson BT, Brown SM; National Heart, Lung, and Blood Institute PETAL Clinical Trials Network, Steingrub J, Smithline H, Tiru B, Tidswell M, Kozikowski L, Thornton-Thompson S, De Souza L, Hou P, Baron R, Massaro A, Aisiku I, Fredenburgh L, Seethala R, Johnsky L, Riker R, Seder D, May T, Baumann M, Eldridge A, Lord C, Shapiro N, Talmor D, O’Mara T, Kirk C, Harrison K, Kurt L, Schermerhorn M, Banner-Goodspeed V, Boyle K, Dubosh N, Filbin M, Hibbert K, Parry B, Lavin-Parsons K, Pulido N, Lilley B, Lodenstein C, Margolin J, Brait K, Jones A, Galbraith J, Peacock R, Nandi U, Wachs T, Matthay M, Liu K, Kangelaris K, Wang R, Calfee C, Yee K, Hendey G, Chang S, Lim G, Qadir N, Tam A, Beutler R, Levitt J, Wilson J, Rogers A, Vojnik R, Roque J, Albertson T, Chenoweth J, Adams J, Pearson S, Juarez M, Almasri E, Fayed M, Hughes A, Hillard S, Huebinger R, Wang H, Vidales E, Patel B, Ginde A, Moss M, Baduashvili A, McKeehan J, Finck L, Higgins C, Howell M, Douglas I, Haukoos J, Hiller T, Lyle C, Cupelo A, Caruso E, Camacho C, Gravitz S, Finigan J, Griesmer C, Park P, Hyzy R, Nelson K, McDonough K, Olbrich N, Williams M, Kapoor R, Nash J, Willig M, Ford H, Gardner-Gray J, Ramesh M, Moses M, Ng Gong M, Aboodi M, Asghar A, Amosu O, Torres M, Kaur S, Chen JT, Hope A, Lopez B, Rosales K, Young You J, Mosier J, Hypes C, Natt B, Borg B, Salvagio Campbell E, Hite RD, Hudock K, Cresie A, Alhasan F, Gomez-Arroyo J, Duggal A, Mehkri O, Hastings A, Sahoo D, Abi Fadel F, Gole S, Shaner V, Wimer A, Meli Y, King A, Terndrup T, Exline M, Pannu S, Robart E, Karow S, Hough C, Robinson B, Johnson N, Henning D, Campo M, Gundel S, Seghal S, Katsandres S, Dean S, Khan A, Krol O, Jouzestani M, Huynh P, Weissman A, Yealy D, Scholl D, Adams P, McVerry B, Huang D, Angus D, Schooler J, Moore S, Files C, Miller C, Gibbs K, LaRose M, Flores L, Koehler L, Morse C, Sanders J, Langford C, Nanney K, MdalaGausi M, Yeboah P, Morris P, Sturgill J, Seif S, Cassity E, Dhar S, de Wit M, Mason J, Goodwin A, Hall G, Grady A, Chamberlain A, Brown S, Bledsoe J, Leither L, Peltan I, Starr N, Fergus M, Aston V, Montgomery Q, Smith R, Merrill M, Brown K, Armbruster B, Harris E, Middleton E, Paine R, Johnson S, Barrios M, Eppensteiner J, Limkakeng A, McGowan L, Porter T, Bouffler A, Leahy JC, deBoisblanc B, Lammi M, Happel K, Lauto P, Self W, Casey J, Semler M, Collins S, Harrell F, Lindsell C, Rice T, Stubblefield W, Gray C, Johnson J, Roth M, Hays M, Torr D, Zakaria A, Schoenfeld D, Thompson T, Hayden D, Ringwood N, Oldmixon C, Ulysse C, Morse R, Muzikansky A, Fitzgerald L, Whitaker S, Lagakos A, Brower R, Reineck L, Aggarwal N, Bienstock K, Freemer M, Maclawiw M, Weinmann G, Morrison L, Gillespie M, Kryscio R, Brodie D, Zareba W, Rompalo A, Boeckh M, Parsons P, Christie J, Hall J, Horton N, Zoloth L, Dickert N, Diercks D. Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: a Randomized Clinical Trial. JAMA. 2020;324(21):2165-76.

14. Ulrich RJ, Troxel AB, Carmody E, Eapen J, Bäcker M, DeHovitz JA, et al. Treating COVID-19 with hydroxychloroquine (TEACH): a multicenter, double-blind randomized controlled trial in hospitalized patients. Open forum Infect Dis. 2020;7(10):ofaa446.

15. Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020;369:m1849.

16. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A Trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. N Engl J Med. 2020;382(19):1787-99.

17. RECOVERY Collaborative Group. Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2020;396(10259):1345-52.
-1818. Rosenberg ES, Dufort EM, Udo T, Wilberschied LA, Kumar J, Tesoriero J, et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State. JAMA. 2020;323(24):2493-502.) subsidizing the publication of guidelines that contraindicated the use of a large number of these medications.(1919. National Institutes of Health (NHI). Coronavirus disease 2019 (COVID-19) treatment guidelines. Geneva: WHO; 2021 [cited 2021 June 22]. Available from: https://www.covid19treatmentguidelines.nih.gov/
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20. Bhimraj A, Morgan RL, Shumaker AH, Lavergne V, Baden L, Cheng VC, et al. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19. Infect Dis Soc Am. 2020 Apr 27:ciaa478. doi: 10.1093/cid/ciaa478. Epub ahead of print.
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-2121. World Health Organization (WHO). COVID-19 clinical management: living guidance 25 January 2021. Geneva: WHO; 2021 [cited 2021 June 21]. Available from: https://apps.who.int/iris/handle/10665/33882.
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) However, many of these drugs are still being prescribed, despite the evidence of futility from several studies.(2222. Belayneh A. Off-label use of chloroquine and hydroxychloroquine for COVID-19 treatment in Africa Against WHO recommendation. Res Rep Trop Med. 2020;11:61-72. Review.) The widespread use of such medications has several harmful consequences, including the occurrence of adverse events;(2323. Beyzarov E, Chen Y, Julg R, Naim K, Shah J, Gregory WW, et al. Global safety database summary of COVID-19-related drug utilization-safety surveillance: a sponsor’s perspective. Drug Saf. 2021;44(1):95-105.)a disproportionate consumption leading to supply shortage;(2424. Fernandes N. Falta de cloroquina causa internação de pacientes com lúpus. São Paulo: R7 notícias; 2020 jun 20 [atualizado 2020 Jun 8; citado 2020 Jun 4]. Disponível em: https://noticias.r7.com/saude/falta-de-cloroquina-causa-internacao-de-pacientes-com-lupus-08062020
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,2525. Beatriz R. Susam afirma que cloroquina está em falta para pacientes que fazem uso contínuo do medicamento. G1 AM. Amazonas: G1 AM; 2020 Abr 17 [citado 2021 Jun 21]. Disponível em: https://g1.globo.com/am/amazonas/noticia/2020/04/17/susam-afirma-que-cloroquina-esta-em-falta-para-pacientes-que-fazem-uso-continuo-do-medicamento.ghtml
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) higher prices in the market;(2626. Sobrinho WP. Com alta na procura, preço dispara e cloroquina some das farmácias. São Paulo; 2020 Mai 26 [citado 2021 Jul 22]. Disponível em: https://noticias.uol.com.br/saude/ultimas-noticias/redacao/2020/05/26/com-alta-na-procura-preco-dispara-e-cloroquina-some-das-farmacias.htm
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) and development of antimicrobial resistance, in the case of extensive use of antibiotics for such purpose.(2727. Afshinnekoo E, Bhattacharya C, Burguete-García A, Castro-Nallar E, Deng Y, Desnues C, Dias-Neto E, Elhaik E, Iraola G, Jang S, Łabaj PP, Mason CE, Nagarajan N, Poulsen M, Prithiviraj B, Siam R, Shi T, Suzuki H, Werner J, Zambrano MM, Bhattacharyya M; MetaSUB Consortium. COVID-19 drug practices risk antimicrobial resistance evolution. Lancet Microbe. 2021;2(4):e135-6.) Moreover, the benefits of HTA, including technical, economic, and operational deliberations, and the participation of the civil society, are not applied for off-label use of medications. Finally, persisting on the off-label prescription of medications for treatment and prevention of COVID-19, even after the demonstration of their inefficacy, no longer stands as an exercise of medical autonomy, but could be legally characterized as medical error.(77. Aniceto DL. ANVISA e o uso off-label de medicamentos: as relações entre evidência e regulação [dissertação]. Fortaleza (CE): Universidade Federal do Ceará, Faculdade de Medicina; 2019. 70 f. [citado 2021 Jun 22]. Disponível em: http://www.repositorio.ufc.br/bitstream/riufc/49579/1/2019_dis_dlfpaniceto.pdf
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Applications of new health technology assessment: ethical aspects of the implementation of COVID-19 vaccines

Among the new health technologies developed for COVID-19, vaccines are arguably the most important strategy to control the pandemic, and have been implemented in Brazil based on a HTA process.(2828. Comissão Nacional de Incorporação de Tecnologias no Sistema Único de Saúde (CONITEC). Tecnologias para tratamento da COVID-19 são pauta de reunião extraodinária da CONITEC. São Paulo: CONITEC; 2021 [citado 2021 Jun 22]. Disponível em: http://conitec.gov.br/tecnologias-para-tratamento-da-covid-19-sao-pauta-de-reuniao-extraodinaria-da-conitec
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) Despite the current robust evidence on safety,(2929. Anand P, Stahel VP. Review the safety of Covid-19 mRNA vaccines: a review. Patient Saf Surg. 2021;15(1):20. Erratum in: Patient Saf Surg. 2021;15(1):22. Review.

30. Menni C, Klaser K, May A, Polidori L, Capdevila J, Louca P, et al. Vaccine side-effects and SARS-CoV-2 infection after vaccination in users of the COVID Symptom Study app in the UK: a prospective observational study. Lancet Infect Dis. 2021;21(7):939-49.

31. Frenck Jr. RW, Klein NP, Kitchin N, Gurtman A, Absalon J, Lockhart S, Perez JL, Walter EB, Senders S, Bailey R, Swanson KA, Ma H, Xu X, Koury K, Kalina WV, Cooper D, Jennings T, Brandon DM, Thomas SJ, Türeci Ö, Tresnan DB, Mather S, Dormitzer PR, Şahin U, Jansen KU, Gruber WC; C4591001 Clinical Trial Group. Safety, Immunogenicity, and Efficacy of the BNT162b2 Covid-19 Vaccine in Adolescents. N Engl J Med. 2021;385(3):239-50.

32. Voysey M, Clemens SA, Madhi SA, Weckx LY, Folegatti PM, Aley PK, Angus B, Baillie VL, Barnabas SL, Bhorat QE, Bibi S, Briner C, Cicconi P, Collins AM, Colin-Jones R, Cutland CL, Darton TC, Dheda K, Duncan CJ, Emary KR, Ewer KJ, Fairlie L, Faust SN, Feng S, Ferreira DM, Finn A, Goodman AL, Green CM, Green CA, Heath PT, Hill C, Hill H, Hirsch I, Hodgson SH, Izu A, Jackson S, Jenkin D, Joe CC, Kerridge S, Koen A, Kwatra G, Lazarus R, Lawrie AM, Lelliott A, Libri V, Lillie PJ, Mallory R, Mendes AV, Milan EP, Minassian AM, McGregor A, Morrison H, Mujadidi YF, Nana A, O’Reilly PJ, Padayachee SD, Pittella A, Plested E, Pollock KM, Ramasamy MN, Rhead S, Schwarzbold AV, Singh N, Smith A, Song R, Snape MD, Sprinz E, Sutherland RK, Tarrant R, Thomson EC, Török ME, Toshner M, Turner DPJ, Vekemans J, Villafana TL, Watson ME, Williams CJ, Douglas AD, Hill AV, Lambe T, Gilbert SC, Pollard AJ; Oxford COVID Vaccine Trial Group. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 2021;397(10269):99-111. Erratum in: Lancet. 2021;397(10269):98.

33. Sadoff J, Gray G, Vandebosch A, Cárdenas V, Shukarev G, Grinsztejn B, Goepfert PA, Truyers C, Fennema H, Spiessens B, Offergeld K, Scheper G, Taylor KL, Robb ML, Treanor J, Barouch DH, Stoddard J, Ryser MF, Marovich MA, Neuzil KM, Corey L, Cauwenberghs N, Tanner T, Hardt K, Ruiz-Guiñazú J, Le Gars M, Schuitemaker H, Van Hoof J, Struyf F, Douoguih M; ENSEMBLE Study Group. Safety and efficacy of single-dose Ad26.COV2. S vaccine against Covid-19. N Engl J Med. 2021;384(23):2187-2201.

34. Zhang Y, Zeng G, Pan H, Li C, Hu Y, Chu K, et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis. 2021;21(2):181-92.

35. Zhu FC, Guan XH, Li YH, Huang JY, Jiang T, Hou LH, et al. Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2020;396(10249):479-88.
-3636. Ella R, Vadrevu KM, Jogdand H, Prasad S, Reddy S, Sarangi V, et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: a double-blind, randomised, phase 1 trial. Lancet Infect Dis. 2021;21(5):637-46. Erratum in: Lancet Infect Dis. 2021;21(4):e81.) efficacy,(3131. Frenck Jr. RW, Klein NP, Kitchin N, Gurtman A, Absalon J, Lockhart S, Perez JL, Walter EB, Senders S, Bailey R, Swanson KA, Ma H, Xu X, Koury K, Kalina WV, Cooper D, Jennings T, Brandon DM, Thomas SJ, Türeci Ö, Tresnan DB, Mather S, Dormitzer PR, Şahin U, Jansen KU, Gruber WC; C4591001 Clinical Trial Group. Safety, Immunogenicity, and Efficacy of the BNT162b2 Covid-19 Vaccine in Adolescents. N Engl J Med. 2021;385(3):239-50.,3232. Voysey M, Clemens SA, Madhi SA, Weckx LY, Folegatti PM, Aley PK, Angus B, Baillie VL, Barnabas SL, Bhorat QE, Bibi S, Briner C, Cicconi P, Collins AM, Colin-Jones R, Cutland CL, Darton TC, Dheda K, Duncan CJ, Emary KR, Ewer KJ, Fairlie L, Faust SN, Feng S, Ferreira DM, Finn A, Goodman AL, Green CM, Green CA, Heath PT, Hill C, Hill H, Hirsch I, Hodgson SH, Izu A, Jackson S, Jenkin D, Joe CC, Kerridge S, Koen A, Kwatra G, Lazarus R, Lawrie AM, Lelliott A, Libri V, Lillie PJ, Mallory R, Mendes AV, Milan EP, Minassian AM, McGregor A, Morrison H, Mujadidi YF, Nana A, O’Reilly PJ, Padayachee SD, Pittella A, Plested E, Pollock KM, Ramasamy MN, Rhead S, Schwarzbold AV, Singh N, Smith A, Song R, Snape MD, Sprinz E, Sutherland RK, Tarrant R, Thomson EC, Török ME, Toshner M, Turner DPJ, Vekemans J, Villafana TL, Watson ME, Williams CJ, Douglas AD, Hill AV, Lambe T, Gilbert SC, Pollard AJ; Oxford COVID Vaccine Trial Group. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 2021;397(10269):99-111. Erratum in: Lancet. 2021;397(10269):98.,3535. Zhu FC, Guan XH, Li YH, Huang JY, Jiang T, Hou LH, et al. Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2020;396(10249):479-88.,3737. Voysey M, Costa Clemens SA, Madhi SA, Weckx LY, Folegatti PM, Aley PK, Angus B, Baillie VL, Barnabas SL, Bhorat QE, Bibi S, Briner C, Cicconi P, Clutterbuck EA, Collins AM, Cutland CL, Darton TC, Dheda K, Dold C, Duncan CJ, Emary KR, Ewer KJ, Flaxman A, Fairlie L, Faust SN, Feng S, Ferreira DM, Finn A, Galiza E, Goodman AL, Green CM, Green CA, Greenland M, Hill C, Hill HC, Hirsch I, Izu A, Jenkin D, Joe CC, Kerridge S, Koen A, Kwatra G, Lazarus R, Libri V, Lillie PJ, Marchevsky NG, Marshall RP, Mendes AV, Milan EP, Minassian AM, McGregor A, Mujadidi YF, Nana A, Padayachee SD, Phillips DJ, Pittella A, Plested E, Pollock KM, Ramasamy MN, Ritchie AJ, Robinson H, Schwarzbold AV, Smith A, Song R, Snape MD, Sprinz E, Sutherland RK, Thomson EC, Török ME, Toshner M, Turner DP, Vekemans J, Villafana TL, White T, Williams CJ, Douglas AD, Hill AV, Lambe T, Gilbert SC, Pollard AJ; Oxford COVID Vaccine Trial Group. Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials. Lancet. 2021;397(10277):881-91. Erratum in: Lancet. 2021;397(10277):880.,3838. Logunov DY, Dolzhikova IV, Shcheblyakov DV, Tukhvatulin AI, Zubkova OV, Dzharullaeva AS, Kovyrshina AV, Lubenets NL, Grousova DM, Erokhova AS, Botikov AG, Izhaeva FM, Popova O, Ozharovskaya TA, Esmagambetov IB, Favorskaya IA, Zrelkin DI, Voronina DV, Shcherbinin DN, Semikhin AS, Simakova YV, Tokarskaya EA, Egorova DA, Shmarov MM, Nikitenko NA, Gushchin VA, Smolyarchuk EA, Zyryanov SK, Borisevich SV, Naroditsky BS, Gintsburg AL; Gam-COVID-Vac Vaccine Trial Group. Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. Lancet. 2021;397(10275):671-81. Erratum in: Lancet. 2021;397(10275):670.) effectiveness(3030. Menni C, Klaser K, May A, Polidori L, Capdevila J, Louca P, et al. Vaccine side-effects and SARS-CoV-2 infection after vaccination in users of the COVID Symptom Study app in the UK: a prospective observational study. Lancet Infect Dis. 2021;21(7):939-49.,3333. Sadoff J, Gray G, Vandebosch A, Cárdenas V, Shukarev G, Grinsztejn B, Goepfert PA, Truyers C, Fennema H, Spiessens B, Offergeld K, Scheper G, Taylor KL, Robb ML, Treanor J, Barouch DH, Stoddard J, Ryser MF, Marovich MA, Neuzil KM, Corey L, Cauwenberghs N, Tanner T, Hardt K, Ruiz-Guiñazú J, Le Gars M, Schuitemaker H, Van Hoof J, Struyf F, Douoguih M; ENSEMBLE Study Group. Safety and efficacy of single-dose Ad26.COV2. S vaccine against Covid-19. N Engl J Med. 2021;384(23):2187-2201.,3939. Tenforde MW, Olson SM, Self WH, Talbot HK, Lindsell CJ, Steingrub JS, Shapiro NI, Ginde AA, Douin DJ, Prekker ME, Brown SM, Peltan ID, Gong MN, Mohamed A, Khan A, Exline MC, Files DC, Gibbs KW, Stubblefield WB, Casey JD, Rice TW, Grijalva CG, Hager DN, Shehu A, Qadir N, Chang SY, Wilson JG, Gaglani M, Murthy K, Calhoun N, Monto AS, Martin ET, Malani A, Zimmerman RK, Silveira FP, Middleton DB, Zhu Y, Wyatt D, Stephenson M, Baughman A, Womack KN, Hart KW, Kobayashi M, Verani JR, Patel MM; IVY Network; HAIVEN Investigators. Effectiveness of Pfizer-BioNTech and Moderna Vaccines Against COVID-19 among hospitalized adults aged ≥65 years - United States, January-March 2021. MMWR Morb Mortal Wkly Rep. 2021;70(18):674-9.,4040. Vasileiou E, Simpson CR, Shi T, Kerr S, Agrawal U, Akbari A, et al. Interim findings from first-dose mass COVID-19 vaccination roll-out and COVID-19 hospital admissions in Scotland: a national prospective cohort study. Lancet. 2021;397(10285):1646-57.) and cost-effectiveness(4141. Kohli M, Maschio M, Becker D, Weinstein MC. The potential public health and economic value of a hypothetical COVID-19 vaccine in the United States: use of cost-effectiveness modeling to inform vaccination prioritization. Vaccine. 2021;39(7):1157-64.,4242. Siedner MJ, Alba C, Fitzmaurice KP, Gilbert RF, Scott JA, Shebl FM, et al. Cost-effectiveness of COVID-19 vaccination in low- and middle-income countries. medRxiv. 2021 Jan 1;2021.04.28.21256237. Available from: http://medrxiv.org/content/early/2021/05/02/2021.04.28.21256237.abstract
http://medrxiv.org/content/early/2021/05...
)of COVID-19 vaccines, some operational and ethical aspects related to the incorporation of these new health technologies, such as distribution strategies and priority groups, should be considered with caution.(4343. Wouters OJ, Shadlen KC, Salcher-Konrad M, Pollard AJ, Larson HJ, Teerawattananon Y, et al. Challenges in ensuring global access to COVID-19 vaccines: production, affordability, allocation, and deployment. Lancet. 2021;397(10278):1023-34. Review.)

Although COVID-19 vaccines have been rapidly developed by different manufacturers, the number of doses is still much beyond the required volume to immunize the world population. It has been necessary to allocate resources giving priority to certain places and population groups.(4343. Wouters OJ, Shadlen KC, Salcher-Konrad M, Pollard AJ, Larson HJ, Teerawattananon Y, et al. Challenges in ensuring global access to COVID-19 vaccines: production, affordability, allocation, and deployment. Lancet. 2021;397(10278):1023-34. Review.)Furthermore, compliance to vaccine recommendations has not been uniform in the population. Hence, implementing COVID-19 vaccines has raised important ethical discussions.(4444. Jecker NS, Wightman AG, Diekema DS. Vaccine ethics: an ethical framework for global distribution of COVID-19 vaccines. J Med Ethics. 2021 Feb 16:medethics-2020-107036.)

Access to COVID-19 vaccines has been effective and quick in high-income countries when compared to more deprived regions.(4343. Wouters OJ, Shadlen KC, Salcher-Konrad M, Pollard AJ, Larson HJ, Teerawattananon Y, et al. Challenges in ensuring global access to COVID-19 vaccines: production, affordability, allocation, and deployment. Lancet. 2021;397(10278):1023-34. Review.) The United States, Canada, United Kingdom, and Israel, were the first countries to reserve large batches of vaccines, taking advantage of their higher purchasing and negotiation capacity.(4343. Wouters OJ, Shadlen KC, Salcher-Konrad M, Pollard AJ, Larson HJ, Teerawattananon Y, et al. Challenges in ensuring global access to COVID-19 vaccines: production, affordability, allocation, and deployment. Lancet. 2021;397(10278):1023-34. Review.,4545. Mathieu E, Ritchie H, Ortiz-Ospina E, Roser M, Hasell J, Appel C, et al. A global database of COVID-19 vaccinations. Nat Hum Behav. 2021;5(7):947-53. Erratum in: Nat Hum Behav. 2021 Jun 17.) According to this market-based system, low-income countries have had access to a reduced number of COVID-19 vaccine batches. According to the World Health Organization (WHO), ten countries concentrate approximately 75% of all COVID-19 vaccines worldwide.(4646. Estadão. Época Negócios. Dez países concentram 75% das vacinas aplicadas no mundo, indica OMS. São Paulo: Época Negócios; 2021 Jan 27 [citado 2021 Jun 21]. Disponível em: https://epocanegocios.globo.com./Mundo/noticia/2021/01/epoca-negocios-dez-paises-concentram-75-das-vacinas-aplicadas-no-mundo-indica-oms.html
https://epocanegocios.globo.com./Mundo/n...
) Tedros Adhanom, general director of WHO, declared “the world is on the brink of a catastrophic moral failure – and the price of this failure will be paid with lives and livelihoods in the world’s poorest countries”.(4747. BBC New Brasil. Vacinas contra covid: a advertência da OMS sobre “fracasso moral catastrófico” da distribuição de imunizantes. São Paulo: BBC News Brasil; 2021 Jan 19 [citado 2021 Jun 21]. Disponível em: https://www.bbc.com/portuguese/internacional-55716829
https://www.bbc.com/portuguese/internaci...
)

This inequity in the distribution of COVID-19 vaccines has relevant practical implications. While there is no international mobilization for the distribution of doses to more deprived countries, with more cases of the disease and excessive number of avoidable deaths, one could anticipate the persistence of the pandemic, due to the emergence and spread of new variants of the virus.(4848. Sah P, Vilches TN, Moghadas SM, Fitzpatrick MC, Singer BH, Hotez PJ, et al. Accelerated vaccine rollout is imperative to mitigate highly transmissible COVID-19 variants. EClinicalMedicine. 2021;35:100865.) In addition, countries with delayed implementation of the vaccine will also suffer from greater impact to the health system and increased need of non-pharmacological measures, such as physical distancing, trade restrictions, and closing of schools, with repercussions that amplify the social and economic abyss in relation to richer countries.(4343. Wouters OJ, Shadlen KC, Salcher-Konrad M, Pollard AJ, Larson HJ, Teerawattananon Y, et al. Challenges in ensuring global access to COVID-19 vaccines: production, affordability, allocation, and deployment. Lancet. 2021;397(10278):1023-34. Review.)

Another ethical aspect of implementing COVID-19 vaccines has been the priority given to certain population groups in the vaccination strategy. Ethical considerations include the principles of Utility (allocation of resources aiming to maximize benefits and reduce drawbacks); Justice (prioritizing individuals and communities who are underprivileged or at higher risk of negative outcomes); as well as giving priority to workers directly involved in patient care.(4444. Jecker NS, Wightman AG, Diekema DS. Vaccine ethics: an ethical framework for global distribution of COVID-19 vaccines. J Med Ethics. 2021 Feb 16:medethics-2020-107036.,4949. World Health Organization (WHO). Ethics and COVID-19: resource allocation and priority-setting. Geneva: WHO; 2020 [cited 2021 June 22]. Available from: https://www.who.int/blueprint/priority-diseases/key-action/EthicsCOVID-19resourceallocation.pdf
https://www.who.int/blueprint/priority-d...
)In Brazil, the priority groups, as outlined in the National Operationalization Plan for COVID-19 Vaccination,(5050. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Imunização e Doenças Transmissíveis. Coordenação-Geral do Programa Nacional de Imunizações. Plano Nacional de Operacionalização da Vacinação Contra a COVID-19. Brasília (DF): Ministério da Saúde; 2021 [citado 2021 Jun 22]. Disponível em: https://www.gov.br/saude/pt-br/media/pdf/2021/marco/23/plano-nacional-de-vacinacao-covid-19-de-2021
https://www.gov.br/saude/pt-br/media/pdf...
) included healthcare workers, indigenous and quilombolas, older persons (in descending age order) and, more recently, people with underlying medical conditions associated to poorer outcomes in COVID-19. Although apparently suitable, we believe the vaccination strategy should not aggravate the social inequalities in our society, and highlight several ethical issues related to priority groups for COVID-19 vaccines in Brazil.

Healthcare workers included those with technical training or university degree; however, unskilled and less qualified workers or those with no formal employment, such as maintenance and security workers, were not uniformly included in the priority group for vaccination, despite delivering direct care to patients. This fact underlined and aggravated inequalities, since it is a benefit that once again excluded the victims of precarious work conditions.

Although indigenous and quilombolas have been included as priority groups for vaccination, marginalized and socially excluded populations may distrust the government actions, due to the historic lack of support by the State, or even the exploitation experience;(5151. Razai MS, Osama T, McKechnie DG, Majeed A. Covid-19 vaccine hesitancy among ethnic minority groups. BMJ. 2021;372:n513.,5252. Khan MS, Ali SA, Adelaine A, Karan A. Rethinking vaccine hesitancy among minority groups. Lancet. 2021;397(10288):1863-5.) the estimated vaccine coverage with two doses among indigenous peoples in Brazil varied between 42% and 93%.(5353. Brasil. Ministério da Saúde. Imunização Indígena | COVID-19. Brasília (DF): Ministério da Saúde; 2021 [citado 2021 Jun 22]. Disponível em: https://qsprod.saude.gov.br/extensions/imunizacao_indigena/imunizacao_indigena.html
https://qsprod.saude.gov.br/extensions/i...
) Furthermore, the paucity of actions informing about the safety and importance of vaccination for these populations may have had a significant impact in the low vaccine coverage in these groups.(5454. Varella D, Maleronka M, Mendonça S. População indígena: como as fake news atrapalham a vacinação? [video]. São Paulo; 2021 Mar 19 [apresentação 3, 12 min]. Disponível em: https://drauziovarella.uol.com.br/videos/linha-de-frente/populacao-indigena-como-as-fake-news-atrapalham-a-vacinacao/
https://drauziovarella.uol.com.br/videos...
)

Setting priority to older adults based on a descending age order places a paramount importance on age. In fact, this criteria could be better characterized by other factors, such as frailty.(5555. Aliberti MJ, Szlejf C, Avelino-Silva VI, Suemoto CK, Apolinario D, Dias MB, Garcez FB, Trindade CB, Amaral JR, de Melo LR, de Aguiar RC, Coelho PH, Hojaij NH, Saraiva MD, da Silva NOT, Jacob-Filho W, Avelino-Silva TJ; COVID HCFMUSP Study Group. COVID-19 is not over and age is not enough: Using frailty for prognostication in hospitalized patients. J Am Geriatr Soc. 2021;69(5):1116-27.) Moreover, in Brazil and other countries, ageing is a privilege of white individuals of more favored social brackets.(5656. Singer P. The Ethics of Prioritizing COVID-19 Vaccination. Geneva: Gavi; 2021 Jan 21 [cited 2021 June 21]. Available from: https://www.gavi.org/vaccineswork/ethics-prioritizing-covid-19-vaccination?gclid=Cj0KCQjw--GFBhDeARIsACH_kdYSo25N-8AcgNt3BI-H65eC5Y1BW48v6yre_924DT_vysIEh5SXTRoaAuQOEALw_wcB
https://www.gavi.org/vaccineswork/ethics...
)

Several studies have demonstrated that black and pardo people are at a greater risk of death following COVID-19,(5757. Sze S, Pan D, Nevill CR, Gray LJ, Martin CA, Nazareth J, et al. Ethnicity and clinical outcomes in COVID-19: A systematic review and meta-analysis. EClinicalMedicine. 2020;29:100630.

58. Li SL, Pereira RH, Prete CA Jr, Zarebski AE, Emanuel L, Alves PJ, et al. Higher risk of death from COVID-19 in low-income and non-White populations of São Paulo, Brazil. BMJ Glob Health. 2021;6(4):e004959.
-5959. Rocha SQ, Avelino-Silva VI, Tancredi MV, Jamal LF, Ferreira PR, Tayra A, Ferreira PM, Carvalhanas T, Domingues CS, Souza RA, Gianna MC, Kalichman AO, Leite OH, Souza TN, Gomes E Costa DA, Furtado JJ, Costa AF; HIV-COVID/SP Study Group. COVID-19 and HIV/AIDS in a cohort study in Sao Paulo, Brazil: outcomes and disparities by race and schooling. AIDS Care. 2021 Jun 4:1-7. doi: 10.1080/09540121.2021.1936444. Epub ahead of print.
https://doi.org/10.1080/09540121.2021.19...
) but the vaccination plan did not give priority to individuals according to race/skin color. Additionally, individuals with worse housing and sanitation conditions, and less likely to comply with the recommendations of physical distancing, were not prioritized in the vaccination strategy.

Finally, in view of the growing movement of vaccine hesitancy,(4343. Wouters OJ, Shadlen KC, Salcher-Konrad M, Pollard AJ, Larson HJ, Teerawattananon Y, et al. Challenges in ensuring global access to COVID-19 vaccines: production, affordability, allocation, and deployment. Lancet. 2021;397(10278):1023-34. Review.)the implementation of mandatory vaccination for COVID-19 has been discussed in some contexts.(6060. World Health Organization (WHO). COVID-19 and mandatory vaccination: ethical considerations and caveats. Geneva: WHO; 2021 [cited 2021 June 22]. Available from: https://www.who.int/publications/i/item/WHO-2019-nCoV-Policy-brief-Mandatory-vaccination-2021.1
https://www.who.int/publications/i/item/...

61. Graeber D, Schmidt-Petri C, Schröder C. Attitudes on voluntary and mandatory vaccination against COVID-19: evidence from Germany. PLoS One. 2021;16(5):e0248372.

62. Wise J. Covid-19: Is the UK heading towards mandatory vaccination of healthcare workers? BMJ. 2021;373:n1056.
-6363. McCoy T. Should a coronavirus vaccine be mandatory? In Brazil’s most populous state, it will be. London: The Washington Post; 2020 [cited 2021 June 22]. Available from: https://www.washingtonpost.com/world/the_americas/virus-mandatory-vaccine-brazil-bolsonaro/2020/12/06/31767b4a-33e5-11eb-8d38-6aea1adb3839_story.html
https://www.washingtonpost.com/world/the...
) Ethical considerations concerning this debate include the principles of autonomy and individual freedom, as opposed to solidarity and collective well-being. However, one of the most important characteristics of fundamental rights is that no single right is absolute. In other words, refusing a vaccine is an individual right, but this action may cause losses to society by hindering or delaying collective benefits, such as herd immunity and reductions of overloads in health facilities, or by posing risks to susceptible persons. In a pandemic, it must be understood that the individual and collective interests are mixed, since the individual will be protected only when the collectivity is safe. The general understanding of rights and duties as an exercise of civility must be reconsidered to effectively support the social interest as an extent of the individual interest. Solidarity is relevant and must receive cooperative consideration. No one is safe in an epidemic while being alone. Protection or prevention actions must have a collective nature. We must promote a balance between freedom and social solidarity.

Policies of compulsory vaccination often accept exemptions (for instance, medical contraindications or religious restrictions) and do not involve direct punishment or criminal implications against individuals; however, these policies may enforce restrictions in activities, such as attending schools, carrying out certain professional activities(6464. Gur-Arie R, Jamrozik E, Kingori P. No jab, no job? Ethical Issues in Mandatory COVID-19 Vaccination of Healthcare Personnel. BMJ Global Health. 20211;6(2):e004877.) or traveling. Before implementing compulsory vaccines, it is essential to employ all possible strategies of information and persuasion; to guarantee enough supplies for vaccination; and to address if the compulsory use will be proportionally corroborated by the expected benefit (that is, the number of individuals vaccinated with this strategy justifies the achieved collective good). It is paramount to consider that policies of compulsory use can trigger negative reactions, hindering the trust of the population in government actions, and even the compliance with other public health measures.(6060. World Health Organization (WHO). COVID-19 and mandatory vaccination: ethical considerations and caveats. Geneva: WHO; 2021 [cited 2021 June 22]. Available from: https://www.who.int/publications/i/item/WHO-2019-nCoV-Policy-brief-Mandatory-vaccination-2021.1
https://www.who.int/publications/i/item/...
)

The COVID-19 pandemic shed light on the importance of assessing new health technologies as a strategy to implement medications and vaccines in clinical practice and at SUS. In a pandemic characterized by a high burden of cases and deaths, as well as intense social impact, the ethical perspective is crucial and must guide the evaluation of clinical, economic, organizational, and social aspects of HTA. Any political measure is doomed to failure if scientific and health processes are not respected and understood, and this fact emphasizes the importance of assessing new health technologies. Solidarity must be understood as a shared practice that allows each individual to assume costs and tasks, facing challenges that are relevant to the whole society . It is worth mentioning that individual health depends on the cooperation in collective health, based on transparency and trust. We must give room to the rebirth of a society guided by “us” rather than “me”.

ACKNOWLEDGMENT

We acknowledge Carlos Augusto Rossetti, Gabriel Acca Barreira, Giulia Fanhani de Castro and Gabriela de Carvalho Ferreira for helping with management of references and english translation.

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Publication Dates

  • Publication in this collection
    05 Jan 2022
  • Date of issue
    2021
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