The U.S. now has two COVID-19 vaccines that are safe and effective enough for the public.
On Dec. 18, the Food and Drug Administration issued an emergency use authorization (EUA) for a COVID-19 vaccine made by Moderna, a biotech company based in Massachusetts.
The decision followed an overwhelming 20 to zero vote, with one abstention, in favor or authorizing the vaccine by an FDA vaccine advisory committee on Dec. 17.
“This evening the FDA granted the second emergency use authorization for a COVID-19 vaccine,” Dr. Stephen Hahn, commissioner of the FDA, said during a media briefing announcing the decision. “This is another crucial step in the fight against a global pandemic causing vast numbers of hospitalizations and deaths in the United States every day. The transparency around our review of the Moderna COVID-19 vaccine should reassure the public that this vaccine met the FDA’s rigorous standards for quality, safety and efficacy. As with any decision made by the FDA this authorization was fixed solely by science and data.”
Last week, the agency issued the first EUA for a COVID-19 vaccine to Pfizer-BioNTech on Dec. 11. The two vaccines use the same technology, based on the genetic material mRNA, and in trials showed similar efficacy in protecting against COVID-19 disease. The U.S. is the first country to begin distributing two COVID-19 vaccines.
In its EUA for the Moderna shot, the FDA, as it did with the Pfizer-BioNTech vaccine, added a warning to providers that people with known allergies to components of the vaccine should not get the shot; a handful of reports of allergic reactions, some of them severe, have occurred in people who have been vaccinated with the Pfizer shot so far.
Dr. Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, said it will be possible to get a better idea of which component of the vaccine might be generating the allergic reactions as more people are vaccinated with the two different shots; for example, if people also develop similar allergic reactions to the Moderna vaccine, the culprit may be common pharmacological ingredients used in both shots. “We just don’t know yet,” said Marks.
With two vaccines, the government’s Operation Warp Speed program will come closer to meeting its promised goal of shipping about 20 million doses around the country by the end of the year. Both Pfizer-BioNTech and Moderna began manufacturing their vaccines before receiving authorization in order to meet the U.S.’ ambitious distribution goal.
During a day-long meeting on Dec. 17 in which Moderna scientists made their case for an EUA, and FDA scientists presented their analysis of the company’s safety and effectiveness data, an independent panel of vaccine, infectious disease and ethics experts parsed the data and asked detailed questions about the existing data and Moderna’s plans for continued testing of its vaccine.
Moderna executives presented data from the company’s Phase 3 study of the vaccine, which involved more than 30,000 people and included participants from a number of groups at higher risk of COVID-19, like those over age 65; people from certain racial and ethnic groups; and those with underlying health conditions. The results showed that the vaccine was 94.1% effective in protecting against COVID-19 disease, and was 100% effective in protecting people from severe COVID-19, defined as requiring hospitalization or supplemental oxygen support. In the study, 30 people developed severe disease—and all 30 had received the placebo shot, not the vaccine.
Even though Moderna’s vaccine is now authorized, it’s still not approved, which means that the company will need to continue monitoring for effectiveness and side effects among participants in its ongoing study. The same is true of Pfizer and BioNTech, which began shipping their vaccines last week.
One question that the FDA authorization of the Moderna and Pfizer-BioNTech vaccines raises is whether study participants who were given a placebo should now get the actual shot. Pfizer has sent a letter to doctors leading its studies in the U.S. informing them that the company will allow people to learn if they received placebo in the study when they become eligible for vaccination in the government’s phased immunization program, which prioritizes health care workers and people living in long term care facilities, and then moves to essential workers, the elderly, and people with underlying health conditions before finally including the rest of the population. Whenever the study volunteers become eligible to receive the vaccine under this phased system, they will be allowed to get vaccinated if they wish under the study, or leave the study and get vaccinated on their own.
But continuing those studies, in which people are currently randomly assigned to either receive the vaccine or a placebo, will be critical for fully understanding not only how safe and effective the vaccines are, but for learning more about how long the immunity the shots provide lasts, and whether they actually protect people from getting infected with the COVID-19 virus in the first place. For now, the studies show that the vaccines protect people against getting especially sick with the disease. If people in the placebo group are allowed to learn their status and get vaccinated, that could weaken the strength of the study since the placebo group serves as a control to compare the vaccine’s safety and efficacy.
So Moderna has proposed a different plan: anyone in the company’s trial who wants to learn of their status can request to become “unblinded.” On Dec. 17, the FDA’s vaccine advisory committee spent a good part of the day delving into the question of how to maintain the integrity of those studies if the volunteers demand to know their status and then decide to drop out if they find out they were assigned to the placebo group.
Last week, during the committee meeting on the Pfizer-BioNTech vaccine, Dr. Steven Goodman, associate dean for clinical and translational research at Stanford University, proposed that the companies allow people to switch from their current group to the other—vaccinated people would receive the placebo, and people who had been given the placebo would receive the real vaccine. The participants and the study researchers would remain blinded to what each participant was receiving, which would help to maintain the validity of the data in determining how effective vaccines are, what side effects they might have, and how durable the protection against COVID-19 might be.
Pfizer decided instead to allow its study participants to learn their placebo or vaccine status when they became eligible for vaccination and receive the vaccine if they were in the placebo group and remain in the trial, or leave the study. But panel members discussing the Moderna data pointed out that each state may have different policies about when different groups will be eligible for vaccination, and that could complicate the unblinding process and potentially mean people in some states would be vaccinated before others even if, for example, they all have underlying health conditions.
Moderna proposed that people in the placebo group be allowed to get vaccinated, presumably any time after the EUA is issued and even if they aren’t in the priority groups intended to receive shots at the time, and then continue in the study so researchers can still monitor them for effectiveness, safety and other important measures. Dr. Lindsey Baden, associate professor of medicine at Brigham and Women’s Hospital and one of the scientists overseeing the Moderna trial suggested that as more vaccines are given an EUA and thus made available for people outside of the study settings, ongoing trials should not remain blinded. He also noted that Goodman’s proposal to keep both vaccinated and placebo volunteers blinded may no longer be feasible. “We need to consider volunteers; viewpoints on fairness, equity, trust, and larger societal interest,” he said, noting that already, since last week’s EUA of the Pfizer vaccine, “We have seen a substantial dropout…that undermines the data integrity and what can be learned. We must be proactive and provide the best choice to participants to remain in the study and ensure that the ask of them is reasonable and respectful and ensure that they are treated fairly.”
Ultimately, the majority of the panel supported the proposal made by Moderna. While such a design would dilute the placebo group and potentially weaken the power of the study on important questions about safety and efficacy, that loss doesn’t outweigh the benefits of giving more people protection against COVID-19. In addition, as Captain Amanda Cohn, chief medical officer for the National Center for Immunizations and Respiratory Diseases at the U.S. Centers for Disease Control and Prevention, noted, there may be additional studies that can be done to collect such data, even if they aren’t of the ideal gold standard quality that a placebo controlled trial would provide.
Marks said the FDA is continuing discussions with Moderna about how to move forward with the placebo group in the trial.
The committee also analyzed the data on potential allergic and anaphylactic reactions to the Moderna vaccine. The FDA noted that “no anaphylactic or severe hypersensitivity reactions with close temporal relation to the vaccine” were reported in the Moderna studies, but that the agency and the company are continuing to monitor for any potential cases as more people get vaccinated.
The EUA for the Moderna shot is important for many state and local health officials, since the Moderna vaccine can be stored at close to normal freezer temperatures, while the Pfizer-BioNTech vaccine requires ultra-cold freezers that reach -70°C. Some counties have been waiting for Moderna’s EUA to place their vaccine orders.
With two authorized vaccines, the big question now for the FDA is how to evaluate the next vaccines, from companies including AstraZeneca, Johnson & Johnson and Sanofi/GlaxoSmithKline, on safety and efficacy. Will the effectiveness of the Pfizer and Moderna shots, at around 94%, be the new standard against which the upcoming vaccines will be compared, instead of placebo? How will companies continue to convince people to enroll in clinical trials if participants will have a 50% chance of receiving a placebo when they could, if they don’t join the study, get vaccinated with an effective vaccine at their local pharmacy?
Answering these questions is also critical for Pfizer-BioNTech and Moderna to reach their next regulatory goal: obtaining full licensure, and not just emergency use, for their vaccines. A formal approval requires strong scientific evidence, similar to what has already been generated from the shots from placebo controlled studies, of safety and efficacy, but for longer time periods. “We will be working with companies over the next couple of months on what data will be needed to support a license application and what can be done,” said Marion Gruber, director of the Office of Vaccines Research and Review at the FDA’s Center for Biological Evaluation and Research. “Not only clinical data, but also manufacturing information and facilities information will be critical deciding factors for when we are able to move to accepting a [licensing] application.”
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Contributor: Alice Park