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Federal advisers will vote today on whether Pfizer-BioNTech’s COVID-19 vaccine is safe and effective enough to merit an emergency use authorization (EUA).
The US Food and Drug Administration (FDA) has put Pfizer’s application before its Vaccines and Related Biological Products Advisory Committee (VRBPAC), seeking expert feedback on what is likely to be the first COVID-19 vaccine cleared for use in the United States.
New York-based Pifzer developed the vaccine, known as BNT162b2, with Germany’s BioNTech. The FDA has asked VRBPAC to vote on a single question: “Based on the totality of scientific evidence available, do the benefits of the Pfizer-BioNTech COVID-19 Vaccine outweigh its risks for use in individuals 16 years of age and older?” The FDA considers the recommendations of its panels but isn’t bound by them.
During the morning presentations, FDA advisers and scheduled speakers focused on the question of how researchers could continue studies and monitoring of the Pfizer vaccine if it were made widely available under an EUA. The FDA staff has emphasized the need for Pfizer to complete the work necessary for a more extensive regular approval, known as a biologics license application (BLA), for the COVID-19 vaccine, even if it is granted an EUA.
The FDA tasked Steven Goodman, MD, MHS, PhD, of Stanford University with presenting an overview of considerations for continuing a placebo-controlled trial if an unlicensed vaccine becomes available. Once a COVID-19 vaccine becomes available to the public, people who have received placebo in the Pfizer trial should not be allowed to immediately receive the vaccine, Goodman said.
Instead, they could be allowed some deference only in terms of other people who share their risk for COVID-19, Goodman said. Initial supplies of COVID-19 vaccines will be limited, and there are plans to distribute these first to healthcare workers and residents of long-term care facilities, with states likely to then set other ‘priority groups’ such as essential workers.
There could be plans made to allow people who participated in the trials and were in the placebo group to get the COVID-19 vaccine early within these populations, Goodman suggested.
“So in a sense, they jump to the front of their own line,” Goodman said.
An option for trial design with COVID-19 vaccines could be a “blinded crossover,” where all study recipients eventually get the vaccine, he said. He also said there could soon be a demand for tests done comparing experimental COVID-19 vaccines with proven rival treatments.
More than a dozen COVID-19 vaccines have reached advanced stages of testing, including ones developed in Russia and China, according to the World Health Organization (WHO). The two leading candidates for the US market are the Pfizer/BioNTech vaccine and a similar vaccine developed by Moderna and the National Institute of Allergy and Infectious Diseases. The FDA’s VRBPAC will review an EUA application for the Moderna vaccine on December 17. Johnson & Johnson and AstraZeneca are among the other companies with COVID-19 vaccines in testing.
The rapid development of COVID-19 vaccines may make it difficult to continue with placebo-controlled trials, even though such research would be helpful, Goodman said. There isn’t a strong medically based argument against placebo-controlled research in COVID-19, as many people can take steps to reduce their risk for the infection, Goodman said.
“So as long as there are still important things to learn about the vaccine, placebo- controlled trials should not be regarded as unethical,” Goodman said. ” I think, however, they might be infeasible. And that is a big issue, because people may not be willing to either remain in the study or to enroll.”
During the public comment session, a former FDA official spoke of a need for careful consideration of study volunteers’ needs in designing trials of COVID-19 vaccines.
“Reasonable people can disagree over whether study subjects should have priority access to a product whose efficacy they helped demonstrate,” said Peter Lurie, MD, president of the nonprofit Center for Science in the Public Interest. “But we ought to be able to agree on this: No subject who has put their body on the line in a vaccine study should be at a disadvantage in terms of vaccine access as a result of their participation.”
Lurie argued against extended periods of blinded follow-up after authorization of a COVID-19 vaccine. Such a requirement would be “hard to justify ethically, if it is
inconsistent with public health recommendations, particularly with rapidly rising case rates and the reported levels of effectiveness” of the Pfizer vaccine, said Lurie, who served as an associate commissioner at FDA from 2014 to 2017.
Lurie also noted the FDA staff’s identification of what he called “disproportionate numbers of Bell’s Palsy cases (4 in the vaccine groups vs. 0 in the placebo group)” as a matter that should continue to be monitored, including in the postmarketing phase. He raised no objections to the EUA.
Sidney Wolfe, MD, founder and senior adviser to Public Citizen’s Health Research Group, also spoke at the public comment session, citing no objection to an EUA for the Pfizer vaccine. Like Lurie, he urged special consideration of people who have or will receive placebo in COVID-19 vaccine trials.
The Thursday advisory committee on the Pfizer vaccine differed from those held for many other products. The discussion focused more on how to monitor and evaluate the vaccine once approved, while advisory committees sometimes include a detailed look at whether a company has proven that its product works. One of the special advisers serving temporarily on VRBPAC, Eric J. Rubin, MD, PhD, also today published an editorial in The New England Journal of Medicine, titled “SARS-CoV-2 Vaccination — An Ounce (Actually, Much Less) of Prevention.”
In the editorial, Rubin and co-author, Dan L. Longo, MD, called the Pfizer vaccine results seen so far “impressive.”
“In the primary analysis, only 8 cases of Covid-19 were seen in the vaccine group, as compared with 162 in the placebo group, for an overall efficacy of 95% (with a 95% credible interval of 90.3 to 97.6%),” they wrote. “Although the trial does not have the statistical power to assess subgroups, efficacy appeared to be similar in low-risk and high-risk persons, including some from communities that have been disproportionately affected by disease, and in participants older than 55 years of age and those younger than 55.”
Intense Scrutiny
The FDA has come under intense scrutiny this year due in part to the aggressive — and ultimately unrealistic — timelines for COVID-19 treatments promoted by the Trump administration. President Donald Trump several times suggested a COVID-19 vaccine could be approved before the November election. Many concerned physicians and scientists including Medscape Editor-in-Chief Eric Topol, MD, called on FDA staff to fight back against any bid to inappropriately speed the approval process for political reasons.
“Any shortcuts will not only jeopardize the vaccine programs but betray the public trust, which is already fragile about vaccines, and has been made more so by your lack of autonomy from the Trump administration and its overt politicization of the FDA,” Topol wrote in an August open letter to FDA Commissioner Stephen Hahn, MD.
In an October interview with Topol, Hahn noted that there has been some pushback against the idea of an EUA for a COVID-19 vaccine, with some people preferring to wait for a more complete biological license application.
“When you’re talking about a pandemic where people are dying, you want to expedite it as much as possible,” Hahn told Topol in the interview.
On Thursday, Hahn issued a public statement about the VRBPAC meeting. Hahn said the FDA’s “career staff — made up of physicians, biologists, chemists, epidemiologists, statisticians and other professionals — have been working around the clock to thoroughly evaluate the data and information in the EUA request.”
“I can assure you that no vaccine will be authorized for use in the United States until FDA career officials feel confident in allowing their own families to receive it,” Hahn said.
Many clinicians offered their views on the FDA meeting during the day on Twitter.
Robert Wachter, MD, chair of the Department of Medicine at the University of California, San Francisco, who has been a vocal opponent of some of Trump’s public statements on COVID-19, urged state officials to stick with the FDA’s call on the Pfizer vaccine. In a tweet, he noted that officials in California and several other states have called for independent reviews of COVID-19 vaccines.
If such reviews were to delay distribution of vaccines, this would “lead to more harm than good,” Wachter tweeted. “Once FDA says ‘go’, we should go.”
At this point, @US_FDA approval process is highly trustworthy. While 8 states (incl. CA) had vowed to do their own review (when FDA was looking shaky), now if 2nd review causes any delay in vaccine distribution, it'll lead to more harm than good. Once FDA says "go", we should go.
— Bob Wachter (@Bob_Wachter) December 10, 2020