2nd generation trials of Covid-19 vaccines still use placebo

The vaccine race is far from over. About 54% of the world has already been immunized with the first wave, but the expansion of the second generation is in full swing. According to the WHO (World Health Organization), there are 326 vaccines in development, of which 132 are in the clinical trials phase.

The good news does not hide an ethical problem. The use of placebo remains the rule among developers, which conflicts with a principle of the Declaration of Helsinki, which deals with research with human beings.

Typically these studies require recruiting volunteers without immunity to Covid-19, which means they have not been vaccinated or infected. In the current context of the pandemic, when the disease remains untreated but vaccines are already available, it is a controversial issue to keep these volunteers on a placebo for months — and at risk.

Of the immunizing agents in clinical trials monitored by the WHO, 40 are in phases 2 or 3, stages in which the product’s efficacy is measured. In this group, 24 have already reported having done tests with placebo, which are faster and cheaper.

In Brazil, where complete vaccination is close to 160 million people, these tests are carried out by national laboratories outsourced by foreign biopharmaceuticals.

Dirceu Greco, a professor at the Faculty of Medicine at UFMG, says that the research model without a placebo has disadvantages that developers prefer not to face.

One of them is the requirement that individuals in the control group be immunized with vaccines on the market, which puts the developer at the cost of making comparisons with an already approved product possible. The requirement to recruit an average of 2.5 times more volunteers to resolve statistical distortions also impacts the budget.

Another constraint in relation to the vaccine already positioned on the market is the transparency rule, says Greco. “The company thinks: I will have to publish the study and it may be that the vaccine from the other laboratory will be better. Even in this sense, the use of a placebo has an advantage, because, when compared to nothing, the vaccine will certainly have some superior effect.”

Apart from these issues, which the researcher defines as marketing, there would be no more justification for the use of a placebo in the pandemic. “The argument that it is complicated to prepare a project is sophistic because there is no availability of vaccines on the market to be the comparator.

SUS contracts with laboratories should facilitate access to vaccines in these situations, the product would not be lost, someone would be immunized.”

The situation brings back the same debate as the HIV pandemic on the so-called exploitation of vulnerability, says Marisa Palacios, professor and director of the Center for Bioethics and Applied Ethics at UFRJ.

Palacios sees no difference between exposing the population of countries without vaccines to the Covid-19 virus and the studies of mother-to-child transmission of HIV carried out in African countries in the 1990s.

“This is not an ethical dilemma. In a dilemma, we don’t know what is good and what is not.” In the current situation, this is clear, says the bioethicist. “It’s an ethical issue.”

In Brazil, at least three of the nine clinical studies authorized by Anvisa use a placebo in the control group: those of COVLP vaccines, by Canadian Medicago; SCB-2019, by Clover, and inactivated against Sars-CoV-2 Cell Vero, by IMCAMS, both Chinese.

The public record is that, in the three cases, 23,600 Brazilians have already been recruited in nine states. THE sheet, Medicago said that recruitment ended in September and that, at the time the study was planned, placebo was the “only realistic option possible.” In September, however, the Brazilian population over 18 years of age was eligible for vaccination.

The drugmaker also said tests on the continent were planned from the start. On July 26, its official Facebook profile reported that, because of ongoing vaccinations in the US, Canada and the UK, the company had suspended testing in those countries and started recruiting in Latin America.

In addition to the lower cost, another argument used in defense of placebo is the need for rapid development of new vaccines. This is the basis of Solidarity Trial Vaccines, a WHO initiative whose purpose is to develop immunizations on a larger scale and in a more agile way.

The program coordinates vaccine efficacy trials in Mali, Colombia and the Philippines, part of them with placebo.

According to the WHO, the STV adopts the placebo in countries with no vaccine available or, when targeted only at the priority population, limits its use to non-priority groups. If there are immunizers for everyone, the comparator for the control group is made with an already authorized vaccine.

Placebo use is now ethical violation, says Covas

Rather than speeding up, placebo trials delayed vaccine production during the pandemic, believes Dimas Covas. In the opinion of the director of the Butantan Institute, the seriousness of the health crisis made it unnecessary to rigorously test effectiveness before December 2020. “It would have been extremely useful if we had a vaccine with 30% effectiveness then.”

Covas, however, is emphatic in stating that, when approved immunizations are available, the use of a placebo in the control group is an ethical violation.

“Alternatives do exist, the one I proposed and then consolidated was the mass vaccination project in Serrana, an attempt to demonstrate the effectiveness of the vaccine in the midst of the pandemic.”

Butanvac, a second-generation immunizer in clinical trials, changed the research model that began to be designed last year. With the advance of vaccination among the population over 18 years of age, Butantan chose to use CoronaVac in the control group.

“First, we demonstrate safety, which is the basics. Second, we compare the immune response,” says Covas.

In comparison studies, new vaccines that demonstrate superior protection in relation to others previously available are approved.