Researchers in all countries where trials have been initiated are currently considering the ethical issue of placebo groups and then mass vaccination. The Russian Ministry of Health has announced that it will no longer recruit volunteers for clinical trials of the “Sputnik V” vaccine – despite the fact that efficacy studies of the drug have not yet been completed. Officially, the developers of the Gamaleya Research Center explain this decision by the fact that “Sputnik” study volunteers cannot participate in the country’s mass vaccination campaign, even if they are among the first to receive the vaccine. Thus, volunteers who received a placebo instead of a real vaccine are at risk of infection, which is unacceptable in the conditions of a pandemic. As a result, the “Sputnik” trial recruited nine thousand fewer volunteers than originally planned, calling it a “change in the format of the study.”
The Russian BBC service is trying to find out whether this can be considered a success of the drug – or, on the contrary, it means that the trials have actually failed? In the Russian Direct Investment Fund (RDIF), which finances “Sputnik V”, it was clarified that more than 23,250 people received the vaccine, while 7,750 people received a placebo. “The acquired group of research participants will allow a thorough study of the safety profile and preventive efficacy of the vaccine over a long period of time,” the Ministry of Health said. Speaking on Wednesday, December 23, the head of the Gamaleya Research Center for Epidemiology and Microbiology, Alexander Gintsburg, noted that many of those who received a placebo during the trials took an antibody test and then received the vaccine.
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Podcast Advertising This means that the placebo group in the trial has become smaller – and apparently even the researchers themselves cannot determine who among those who received the placebo were tested for the presence of antibodies and received the vaccine. The proportions of participants in the trial are changing, which may affect the results. The BBC has written to the Department of Health seeking clarification on these issues and is awaiting a response.
This situation raises an important ethical question: should participants in the placebo group have the right to be vaccinated once the vaccine has been approved and civil vaccination has begun, or should they remain in the placebo group without protection in the interest of research and for the benefit of society? Despite the “change in format” of the research, there are no plans to disclose who received the vaccine and who received the placebo, according to the Ministry of Health. They noted that the observation of the volunteers will continue according to the protocol, with the placebo group being maintained for at least six months. However, any participant in the clinical trial has the right to withdraw at any time.
The reasons for stopping the recruitment of volunteers for the placebo group were explained by Alexander Gintsburg, the head of the Gamaleya Center. He stated that “everything is proven there” and “the pandemic is ongoing and the placebo is not good at all”. How to interpret his words? Preliminary results of the effectiveness of “Sputnik” were published at the end of November – a week after the second injection, it was evaluated at a level of 91.4%, and after 21 days – at a level of 95%. However, all we have are press releases, and there is currently no scientific evidence to confirm Gintsburg’s words. The interim data from the research was promised to be published “in one of the leading international peer-reviewed medical journals” – but this has not yet happened. The same is true for the Pfizer and BioNTech vaccine, which is already licensed and in use in the UK and approved for emergency use in the US, and for the Moderna vaccine. The press secretary of the Russian Foundation for Advanced Studies (RFPI), Arseny Palagin, told the BBC that the publication is planned “soon” and that the timeframe depends on expert assessment.
“Due to the fact that mass vaccination was announced in parallel with the study, those who believe they are in the placebo group rushed to get vaccinated – which means they started dropping out of the study,” explains Svetlana Zavidova, the director of the Association of Organizations for Clinical Trials (AOKI). The vaccination rules state that volunteers who have received a placebo cannot be vaccinated yet. “The original goal of the study will definitely not be achieved,” she believes. “The placebo group is already shrinking to 7.5 thousand people, and it is unknown how many of them will ‘escape’ by the end of the trial,” she says. The endpoint of the study was initially set to determine the percentage of people infected within six months of the first dose. “Most participants will not reach this point before then,” says the expert. Scientists will get some numbers, but the reliability of these results will suffer, notes Zavidova.
“The situation is not new; in Russia, when scientists invent something, they convince themselves that it works, and they consider all clinical trials as “annoying obstacles” on the way to patients,” says Ilya Yasny, head of scientific expertise at the venture pharmaceutical fund Inbio Ventures. “Although global practice shows that you can be very wrong in this regard.” “Since Sputnik V has already been received by many people, there have not been many reports of adverse reactions, and antibodies seem to be produced, they probably felt they had enough evidence of safety and efficacy,” says Yasny.
Experts believe that the exclusion of the placebo group from the vaccine that has been put into circulation will undermine confidence in the research. “The propaganda attack on Sputnik was so strong that fewer people than expected participated in clinical trials,” explains Dmitry Kulish, a professor at the Center for Innovation and Entrepreneurship at the Skolkovo Institute of Science and Technology. “A significant number of Russians do not believe in the Sputnik vaccine, and I partly blame the propaganda machine of the United States and Europe for this situation.” “As far as I understand the statistics of clinical trials of vaccines, the difference between 30 thousand and 40 thousand is not so significant,” the expert says. Kulish notes that he himself is participating in the research and keeping track of what happens during the trials. According to him, no more than 500 people have participated in the study. “I can assure you that these few hundred people who left the study have no effect on the coefficient of [statistical reliability],” he says confidently.
Kulish claims that there were also people who dropped out of the studies conducted by Pfizer and Moderna, but the companies did not officially disclose this information. Doctor-infectionist Valery Beznosenko from the “Medical Center in Kolomenskoye”, who participated in the trials of “Sputnik” and with 95% probability received a placebo (no antibodies appeared), said in an interview with the BBC that he does not intend to be vaccinated. “I have never done it this way, knowing that there is a 5 percent chance that the vaccine administered will not work,” he says. That chance exists if there are antibodies to the adenovirus and vector neutralization occurs. When asked how he feels about being unprotected as a doctor, Beznosenko says he was prepared for such a scenario: “I immediately made a decision for myself that regardless of whether I receive the vaccine or a placebo, I will take all necessary epidemiological precautions.
“In the West, vaccine trials go through independent committees that make recommendations to researchers and sponsors about interim results,” says Stephen Evans, professor of virology at the London School of Hygiene and Tropical Medicine, in an interview with the BBC. In Russia, this role is played by the Ministry of Health. “If the availability of the vaccine in Russia is such that anyone can obtain it outside the trial, it is understandable that enrollment will have to be stopped, but the researchers will continue to follow the individuals,” Evans explains. “Expanding the study population in a clinical trial means extending the timeline of the trial itself,” Beznozenko explains. According to him, vaccine researchers do not want to extend the timeline. On the other hand, reducing the number of participants from the previously announced number undermines confidence in the clinical trial itself, the doctor acknowledges.
The double-blind, randomized, placebo-controlled trial is considered the “gold standard” in scientific research. Dividing people into two groups, one receiving the vaccine and the other (the control) receiving a placebo, while no one, including the scientists, knows who is in which group, provides the most reliable results. In such a study, participants are randomly assigned regardless of any characteristics. It is believed that this eliminates the influence of any characteristic, such as age or gender. Debates about the ethics of conducting placebo-controlled trials in the presence of a safe vaccine have been going on for a long time.
In 2013, the World Health Organization (WHO) formulated its position on this issue. According to the WHO, if there is no vaccine for the disease, then the most common scenario for the trial will be a placebo-controlled trial. By the end of the summer, when the third phase of “Sputnik” research began, the vaccine had already been registered, but had not yet entered mass distribution. According to WHO experts, the use of a placebo is acceptable if there is no effective vaccine and if the vaccine under investigation is intended for the vaccination of the population in which the vaccine is to be tested. According to the WHO, the use of placebos is “clearly unacceptable” when an effective (or partially effective) and safe vaccine is available and accessible to the health system of the country in which the trials are conducted, and when there is a risk that participants will not be able to receive the investigational vaccine – a risk that cannot be adequately mitigated. “Sometimes the use of placebo may be justified even in cases when the administration of placebo to volunteers instead of a developed vaccine with proven efficacy (or delayed administration of such a vaccine) may increase the level of risk,” – believes the WHO. Thus, according to WHO standards, the “Sputnik” vaccine should have been studied with a placebo group at the beginning of the trials. However, with the start of mass vaccination (which can only be called mass in Moscow), more and more questions arise about the ethics of recruiting volunteers who might end up in the placebo group.
“On the one hand, research must be conducted in the interests of other people, and on the other hand, the interests of the participants must not be violated,” explains Ilya Yasny. “The inclusion of a placebo group in vaccine clinical trials was a fundamentally unusual and risky decision by the Russian regulator [Ministry of Health], according to Dmitry Kulish.” According to him, vaccine clinical trials are usually conducted without a placebo group because “by giving a placebo to a patient, we are putting their life at risk”. “And since in vaccine trials it is usually very easy to understand whether he is in the placebo group or not, we are subjecting him to severe moral and ethical torture, and this is very unethical,” says the expert.
“Stephen Evans, Professor of Virology, believes that the early cessation of recruitment of volunteers alone will not affect the WHO’s assessment. It will be more important to demonstrate that all research procedures were conducted according to scientific standards. According to Dmitry Kulish, the vaccine meets WHO requirements. Ilya Yasny disagrees and believes that “Sputnik” does not meet Western standards even in preclinical trials. “With such a protocol as Sputnik’s, we should not expect reliable results, because the evaluation is very subjective,” he explains. All the vaccine research was not conducted in accordance with modern scientific methods, says Yasny. According to him, Turkey, in rejecting the Russian vaccine, specifically referred to the fact that the results of preclinical studies were not conducted in accordance with proper laboratory practice. ” These rules are accepted and obligatory for us, but we do not have laboratories that can carry out the full cycle of such research,” explains the expert.
If the data provided by the vaccine’s developers is in order, experts believe it could be approved by the WHO. “To make a vaccine that would be approved in the West, everything would have to be done from scratch, from animal testing to production and clinical trials,” Yasny says. “They will definitely never approve it in its current form in Europe and the U.S.,” he believes. Kulish says that during the preclinical trials, the data from “Sputnik” did not meet the standards of the European Medicines Agency (EMA) because several, according to the expert, “meaningless” tests required in Europe were not performed in Russia. “According to my information, these tests are not required by the WHO,” the expert said. Currently, the use of “Sputnik” has been approved only in Belarus and Argentina. The latter recently announced the start of mass vaccination. Head of RDIF Kirill Dmitriev reported that on October 22 RDIF submitted an application for approval of the drug to the EMA. The “Sputnik” manufacturers are still discussing the possibilities of cooperation with the EMA, the agency’s press service reported on December 11. Experts believe that the joint development of a combined vaccine with the British company Astrazeneca could improve the situation and increase confidence in the Russian vaccine. On December 11, the company announced that it would conduct a study to assess the safety and immunogenicity of the combined use of the AZD1222 and “Sputnik” vaccines. Both vaccines are based on adenoviral vectors into which the spike protein of the virus is inserted, a new technology that has never been used on this scale before.
“It is really unethical to keep a placebo group when there is a vaccine that is considered effective,” agrees Ilya Yasny.
“This is a big problem worldwide, and Pfizer is currently considering options on how to continue the trial and collect long-term patient information,” he says. The expert points out that it would take at least six months to evaluate this information.
“The U.S. FDA insisted on conducting vaccine research with a placebo group,” Kulish explains, “and since the [Sputnik developers’] goal is to show that ‘Sputnik’ is identical to U.S. and British vaccines, the Russian regulator agreed.”
The problem with the placebo group, he said, also arose in Pfizer’s vaccine research in Germany – where study participants realized from their symptoms that they were receiving a placebo and asked what to do if they were not protected. “It is widely believed that the placebo problem led the FDA to grant an unprecedented early approval of vaccines that violated all of its previous rules,” says Kulish.
Recently, experts recommended that the FDA approve the use of Moderna’s vaccine in the United States. Pfizer’s vaccine has already been approved for emergency use in the country, and the company promises to produce 50 million doses this year.
The American company Moderna has proposed to “unblind” the trial and offer the vaccine to those who received a placebo. The investigators will have to get permission from the regulatory authorities to do this. Pfizer has already requested permission from the FDA to stop the blinded study and allow volunteers who received a placebo to receive the vaccine.
There is a catch, writes Science. Given the limited number of vaccine doses available, authorities in the United States and other countries require that the most vulnerable populations be vaccinated first. Pfizer plans to follow this rule by initially “unblinding” only volunteers from priority groups. AstraZeneca in the UK plans to do the same with its placebo groups.
“Three of my staff are participating in the Oxford trial (in collaboration with AstraZeneca – BBC). They have been promised that as soon as the blind trial is unblinded, they will be informed immediately and given priority access to the vaccine,” said Professor Brendan Wren, a virology expert at the London School of Hygiene and Tropical Medicine, in an interview with the BBC.
Participants in randomized controlled trials must be informed that the trial is being conducted for the benefit of society, not for their personal gain, said Steven Goodman, M.D., vice chair of the Department of Clinical and Translational Research and professor of epidemiology, population health, and medicine at Stanford University.
If participants are deprived of the vaccine in the name of science and society, he added, many will lose faith in research or withdraw from it, refusing to observe themselves. They may want to be vaccinated with another available vaccine – and nothing is known about the safety and efficacy of vaccine combinations, Goodman said.
“The trial organizers should not restrict the ability of a participant in the placebo group to be vaccinated if they have access to the vaccine. This participant can also independently ‘unblind’ himself by taking a test,” Goodman noted.
Ethical decision-making is complicated by the fact that the context of the situation changes rapidly and depends on the amount of data available on the effectiveness of the vaccine and its accessibility to individuals, the scientist explained. According to him, the choice is not between a ‘right’ and a ‘wrong’ decision, but between different ‘right’ options, each of which may have a different moral-ethical basis.