From the WebMD Archives

Sept. 25, 2020 -- Time and again, regulators, drug companies, and politicians have assured that any COVID vaccine approved for use in the U.S. will be safe.

In a Sept. 23 hearing before the Senate Committee on Health, Education, Labor and Pensions, FDA Commissioner Stephen Hahn, MD, promised Americans that the “FDA will not authorize or approve any COVID-19 vaccine before it has met the agency’s rigorous expectations for safety and effectiveness.” Major drug makers have collectively pledged that they will not apply for approval until the safety and effectiveness of their vaccines have been demonstrated in large clinical studies.

But there may be a catch.

Built into the design of the phase III trials are plans to see how effective the vaccines are as the studies go along. If a vaccine is clearly more effective than the placebo during one of these tests, the drug maker could choose to apply for a swift OK from the FDA under an emergency use authorization (EUA). If the agency gives the vaccine that green light, that creates a dilemma.

If an experimental therapy is shown to be of great benefit, it has long been considered unethical to deprive people who are enrolled in the placebo arm of a clinical trial of the choice to get that protection.

But that could compromise the collection of further safety data, says Grace Lee, MD, a professor of pediatric infectious diseases at Stanford University. She is leading the technical safety assessment of COVID-19 vaccines for the CDC’s Advisory Committee on Immunization Practices. It will be ACIP’s job to review the safety information available for the vaccines and make recommendations -- based on what’s known -- about their use in the general public.

Lee and other public health experts are worried that an early EUA would end the placebo section of the trials, and they would lose a critical source of comparison, making it more difficult to understand whether a vaccine may cause serious side effects.

The FDA has not spelled out what should happen to the placebo arms of vaccine clinical trials if the vaccine is given an EUA.

Lee says she’s hopeful the FDA will hold the line, because “if they don’t, then it comes to us, and it’s going to be a really difficult position to be in.”

“I do feel like just waiting a little bit longer for all that safety data to come is in absolutely worth it. Just doubling the amount of safety data we could have is huge,” she says.

Other experts are pushing for more safety data, too. Eric Topol, MD,  a cardiologist at Scripps Research Translational Institute in California and editor-in-chief of Medscape, was one of 60 physicians and experts to send a letter on Friday to the drug company Pfizer urging them to delay seeking the FDA's nod until all trial participants had been monitored for at least two months. "We respectfully urge you to abide by this rigorous safety standard," they wrote. "There is too much at stake."

Vaccines are extraordinarily safe and one of the great successes of modern medicine. Since the year 2000, the World Health Organization estimates, the measles vaccine alone has saved more than 17 million lives. Serious side effects linked to approved vaccines are very rare. Serious allergic reactions for example, are thought to occur in 1 or 2 people for every million doses of vaccine given.

But vaccines are also not without some risk. Understanding that risk is important, especially for vaccines that use new technologies -- as some now being developed do.

“The great vaccinologist who created new vaccines -- Maurice Hilleman -- always said, and he created a whole series of vaccines that are now in use, he said he was always worried until the first 3 million doses had been administered,” says William Schaffner, MD, an infectious disease specialist at Vanderbilt University in Nashville. “You always have to worry that something unexpected might come up.”

In placebo-controlled studies, investigators enroll people who meet a set of pre-specified criteria. That study population is then randomly split into two groups -- one that gets the experimental therapy and the “placebo group,” which gets a lookalike, but inactive, treatment. Neither the study participants, nor the people who interact with them, know which group they were sorted into. The idea is to create two closely matched pools of people that researchers can then carefully compare to tease out any differences.

If the group that got the active vaccine has less COVID-19 than the group that got the placebo, that shows the vaccine is effective. But the placebo group also plays a critical role in finding out whether or not a new vaccine is safe. Losing the comparison group would mean that any further safety information would come from clinical observations, meaning that it would be harder to tease out whether the adverse event was a side effect of vaccination or could have been caused by something else, like a person’s lifestyle or age.

Lee says she’s hopeful the FDA will lay out more explicit safety standards for an EUA, and those may indeed be on the way.

The Washington Post  reported this week that new FDA guidelines under review by the White House would require vaccine manufacturers seeking an EUA to follow all clinical trial participants for a median time of at least 2 months after they’ve had their second dose. Two months of follow-up data would make it unlikely the companies would have enough data to apply to the FDA until mid-November, after the election.

But 2 months of data is just a fraction of the information the trials were designed to collect. The Pfizer trial, for example, was planned to run for 2 years.

Pfizer’s CEO, Albert Bourla, DVM, PhD, has said as recently as Sept. 13, on the news program Face the Nation, that its trial was seeing enough COVID-19 cases to apply for approval by late October.

Those statements have concerned Tom Frieden, MD, former head of the CDC who is now CEO of the nonprofit Resolve to Save Lives. “If you stop early for cases, you’re not going to play out the full time looking for adverse events.”

“It’s cutting corners,” he says.

“This is a new type of vaccination. We’ve never given people mRNA vaccines,” Frieden says. “We think it’s a great technology. We really hope it’s going to work and be safe and effective, but if all you look at is efficacy, and in fact all you look at is efficacy overall, you’re not going to potentially have the answer to: ‘Does it work for older people? Does it work in different race, ethnicity groups? And is it safe?’”

In response to questions about its plans to seek an EUA, a spokesperson for Pfizer emailed a statement to WebMD saying that the late-stage clinical trials now underway were designed to test the safety and efficacy of the vaccine “as fast as possible.” The company also says the study would continue after any regulatory approval is given “to characterize its long-term performance.”

But it’s not clear if that means the placebo group would continue. The company didn’t answer a specific question about whether it had determined what would happen with the placebo group.

The need for transparency in evaluations of vaccine safety has never been more pressing. Parents reluctant to vaccinate their children have fueled recent resurgences in preventable diseases like measles and whooping cough. Recent U.S. polls show most people said they would wait to get a vaccine against COVID-19, potentially delaying community protection against the virus.

In its guidance to vaccine manufacturers issued last June, the FDA wrote: “Efficacy trials should include contingency plans for continued follow-up … in the event that a safe and effective vaccine becomes available. … In that case, discussion with the agency may be necessary to address ethical arguments to break the blind and offer vaccine to placebo recipients.”

If placebo groups are lost, Lee says, she’s worried it will be harder to find out about longer-term adverse events.

One particularly difficult complication to tease out is something called vaccine-associated enhanced respiratory disease, or VAERD. In VAERD, vaccination makes the disease worse. Tweaking the wrong part of the immune system can cause it to overreact when it sees the virus, and make the illness much worse.

This happened in 1962 with the first vaccine designed to protect infants and toddlers against respiratory syncytial virus, or RSV. That vaccine was initially tested in 1962 in a pilot study of 54 children. In that study, 10 out of 21 immunized children who caught the virus got very severe disease. There was no placebo group in that study, and when the researchers reviewed the results, they said an unusually severe season was behind the extreme cases.

Four years later, researchers tested the same vaccine again in four different studies. This time, they used placebo groups. Again, vaccinated children became very ill. In one study, 80% of vaccinated children were hospitalized, compared to just 5% of children in the control group. Two of them died. The differences were clear.

In mouse studies, some experimental vaccines against SARS, the original cousin to the virus that causes COVID-19, showed evidence of vaccine enhanced disease.

“That's the one example of an outcome where if we lose our blinding on the trials, I really don't know how he would figure out if VAERD was a potential adverse event,” Lee says. “VAERD looks like coronavirus disease,” she says. “If somebody gets COVID, you’re not going to know is it because they got COVID and they had a bad outcome, or is it because they got COVID and they had vaccine and their immune response is kind of over-responding to the COVID?

“The only way we’ll know that is through a clinical trial.”

Show Sources

Grace Lee, MD, professor of pediatric infectious diseases, Lucile Salter Packard Children’s Hospital, Stanford University, Stanford, CA.

William Schaffner, MD, professor, preventive medicine, health policy, infectious diseases, Vanderbilt University Medical Center, Nashville.

Tom Frieden, MD, president and CEO, Resolve to Save Lives, New York City.

Hearing, U.S. Senate Committee on Health, Education, Labor and Pensions: “COVID-19: An Update on the Federal Response,” Sept. 23, 2020.

CDC: Advisory Committee on Immunization Practices meeting webcast, Sept. 22, 2020.

FDA: “Development and Licensure of Vaccines to Prevent COVID-19: Guidance for Industry,” June 2020.

Pfizer, study protocol, phase 1/2/3 SARS-COV-2 RNA vaccine candidates, accessed Sept. 25, 2020.

News release, Pfizer, Sept. 8, 2020.

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