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”.