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

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      1 , 1 , Class 8 FICSAE Working Group 1
      Einstein
      Instituto Israelita de Ensino e Pesquisa Albert Einstein

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          Abstract

          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.(1) 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.(2) 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.(3,4) 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.(2) 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.(5) 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.(6) 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.(6) 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.(7) 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.(8-11) A few months after the pandemic began, controlled clinical trials were published,(12-18) subsidizing the publication of guidelines that contraindicated the use of a large number of these medications.(19-21) However, many of these drugs are still being prescribed, despite the evidence of futility from several studies.(22) The widespread use of such medications has several harmful consequences, including the occurrence of adverse events;(23)a disproportionate consumption leading to supply shortage;(24,25) higher prices in the market;(26) and development of antimicrobial resistance, in the case of extensive use of antibiotics for such purpose.(27) 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.(7) 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.(28) Despite the current robust evidence on safety,(29-36) efficacy,(31,32,35,37,38) effectiveness(30,33,39,40) and cost-effectiveness(41,42)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.(43) 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.(43)Furthermore, compliance to vaccine recommendations has not been uniform in the population. Hence, implementing COVID-19 vaccines has raised important ethical discussions.(44) Access to COVID-19 vaccines has been effective and quick in high-income countries when compared to more deprived regions.(43) 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.(43,45) 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.(46) 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”.(47) 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.(48) 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.(43) 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.(44,49)In Brazil, the priority groups, as outlined in the National Operationalization Plan for COVID-19 Vaccination,(50) 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;(51,52) the estimated vaccine coverage with two doses among indigenous peoples in Brazil varied between 42% and 93%.(53) 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.(54) 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.(55) Moreover, in Brazil and other countries, ageing is a privilege of white individuals of more favored social brackets.(56) Several studies have demonstrated that black and pardo people are at a greater risk of death following COVID-19,(57-59) 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,(43)the implementation of mandatory vaccination for COVID-19 has been discussed in some contexts.(60-63) 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(64) 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.(60) 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”.

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          Most cited references65

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          A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19

          Abstract Background No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. Methods We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao 2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao 2) to the fraction of inspired oxygen (Fio 2) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir–ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first. Results A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir–ritonavir group, and 100 to the standard-care group. Treatment with lopinavir–ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.24; 95% confidence interval [CI], 0.90 to 1.72). Mortality at 28 days was similar in the lopinavir–ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, −5.8 percentage points; 95% CI, −17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir–ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir–ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir–ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events. Conclusions In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir–ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.)
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            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

            Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; p interaction =0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. Funding UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D’Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.
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              Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results

              Abstract Background World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs — remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a — in patients hospitalized with coronavirus disease 2019 (Covid-19). Methods We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry. Results At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan–Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P=0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P=0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P=0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P=0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration. Conclusions These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.)
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                Author and article information

                Journal
                Einstein (Sao Paulo)
                Einstein (Sao Paulo)
                eins
                Einstein
                Instituto Israelita de Ensino e Pesquisa Albert Einstein
                1679-4508
                2317-6385
                20 December 2021
                2021
                : 19
                : eED6840
                Affiliations
                [1 ] orgdiv1Faculdade Israelita de Ciências da Saúde Albert Einstein orgnameHospital Israelita Albert Einstein São Paulo SP Brazil originalFaculdade Israelita de Ciências da Saúde Albert Einstein, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.
                [1 ] Brasil original Faculdade Israelita de Ciências da Saúde Albert Einstein, Hospital Israelita Albert Einstein, São Paulo, SP, Brasil.
                Author notes
                Corresponding author: Vivian Iida Avelino-Silva Avenida Professor Francisco Morato, 4.293 – Butantã Zip code: 05521-200 – São Paulo, SP, Brazil Phone: (55 11) 2151-4384 E-mail: vivian.avelino@ 123456einstein.br
                Autor correspondente: Vivian Iida Avelino-Silva Avenida Professor Francisco Morato, 4.293 – Butantã CEP: 05521-200 – São Paulo, SP, Brasil Tel.: (11) 2151-4384 E-mail: vivian.avelino@einstein.br
                Author information
                https://orcid.org/0000-0002-6660-3088
                https://orcid.org/0000-0001-7936-3813
                Article
                00111
                10.31744/einstein_journal/2021ED6840
                8693880
                ecf3648c-4efe-4c0f-932e-896a75e22cf8

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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