Concerns raised yesterday by an advisory group to the U.S. Food and Drug Administration (FDA) may once again tap the brakes on Operation Warp Speed, the U.S. government’s $10.8 billion push to rapidly move candidate COVID-19 vaccines from concept to communities.
As new U.S. cases of the pandemic coronavirus set a daily high of more than 75,000, FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) held a 9-hour virtual meeting to discuss a regulatory pathway that could permit the widescale use of a COVID-19 vaccine that has only minimal evidence of safety and efficacy. A so-called emergency use authorization (EUA) could use preliminary data from vaccine efficacy trials now underway to shave many months off the standard approval process, and FDA wanted VRBPAC to weigh in about the wisdom of taking this shortcut. The hearing, live-streamed on YouTube, drew intense interest, and some of the committee members—a mix of academics, consumer representatives, and government scientists—had an unsettling but clear message to FDA: Hold your horses.
Several VRBPAC members worried an EUA could contribute to the public’s growing hesitancy toward COVID-19 vaccines by fueling the perception that FDA was compromising its famously high standards. Sheldon Toubman, an attorney on the committee who represents consumers, flat out urged FDA not to issue an EUA for a COVID-19 vaccine, arguing that the agency should stick to the traditional approval process. “There’s only one chance to do this right,” Toubman said. “And if we do it wrong, then we’re done for, it’ll be years. Because there’s already a serious problem with a lack of trust, and the [lack of] trust will become so severe at that point, we won’t be able to dig out of it.”
The committee also discussed the possibility that an early authorization of a vaccine could disrupt many of the COVID-19 vaccine efficacy trials now underway, derailing attempts to obtain the most robust—and convincing—safety and efficacy data. And several members worried FDA’s most recent guidance for vaccine companies that might seek an EUA still does not have stringent enough safety criteria.
Four candidate vaccines selected by Operation Warp Speed now are in efficacy trials, which are comparing the incidence of COVID-19 disease in at least 30,000 participants who blindly receive either a vaccine or a placebo. They are designed to end when they have about 150 cases of symptomatic disease, but independent monitoring boards will tell investigators whether a vaccine looks like it’s working at 50 cases and again at 100 cases. FDA guidance issued in June says the agency will consider issuing an EUA for a vaccine if it shows at least 50% efficacy at any of these analyses.
FDA has committed to seeking VRBPAC’s feedback if a COVID-19 vaccine company does request an EUA. Doran Fink, deputy director of FDA’s vaccine division, cautioned the committee that permitting the use of a weakly effective COVID-19 vaccine could do more harm than good—and not only because of its impact on trials of other candidates. “It could do so by providing a false sense of security that interferes with measures to reduce [COVID-19] transmission,” Fink cautioned, citing effective nonmedical interventions such as wearing masks and social distancing.
Researchers from the Reagan-Udall Foundation, a nonprofit set up by Congress to “advance the mission of the FDA,” told the committee about sobering findings from its COVID-19 Vaccine Confidence Project, which underscored misgivings held by people in underrepresented communities and “frontline workers” in service, retail, and health care settings. Some people interviewed “would want to wait months, or even years, before choosing to receive a vaccine” because of widespread distrust of government and the health care system itself, the foundation researchers noted. The country’s racial and ethnic disparities also played a role, especially given the infamous Tuskegee experiment in which Black men were denied syphilis treatment so researchers could better understand the disease. “The more they study me, the more they know how to get rid of me,” one interviewee told the researchers.
President Donald Trump repeatedly pushed for a COVID-19 vaccine EUA before the 3 November elections, but FDA effectively removed that possibility earlier this month when it issued a second guidance that added a safety stipulation: Two months must have passed after at least half the people in the trial have received all doses of the vaccine, in order to see whether side effects emerge over time. Several committee members and public commenters contended that 2 months was not long enough, however, and urged FDA to extend this to at least 6 months.
Committee member Paul Offit, a vaccine researcher at the Children’s Hospital of Philadelphia, noted that EUAs already issued for COVID-19 treatments have created confusion about how early approval might be granted to a vaccine. Under pressure from the Trump administration, FDA issued EUAs for hydroxychloroquine and convalescent plasma based on the standard that they “may be effective”—a “very low bar” that did not require convincing efficacy data from a randomized, controlled trial. Neither treatment actually works, Offit asserted, adding that those EUAs tainted the validity of the process. “I think we have a language problem,” said Offit, who argued for renaming the process. A vaccine EUA, in contrast, requires evidence of efficacy and at least some safety assurances, which is much closer to the full approval process.
FDA explicitly asked the committee for guidance on what the meeting’s chair, epidemiologist Arnold Monto of the University of Michigan School of Public Health, referred to as “a very thorny issue”: whether an EUA for a COVID-19 vaccine could undermine efforts to assess the safety and efficacy of that product and other candidates as well. Before the meeting, Pfizer, which has one of the candidates furthest along in efficacy trials, put the dilemma in sharp focus in a letter it submitted to FDA.
If FDA granted the company an EUA, a senior vice president for the company wrote, Pfizer would want FDA’s approval to give those in the placebo arm its vaccine—a step that would then compromise the ability of the 2-year study to continue to gather comparative safety and efficacy data of the vaccine and the placebo. A representative from Moderna, which also has a candidate that’s far along in efficacy trials, told the committee that “participants are beginning to ask when they will know if they receive study vaccine or placebo.”
“Once a decision is made to unblind an ongoing placebo-controlled trial, that decision cannot be walked back,” Fink noted, stressing that future data from the control arm “is lost forever.”
The FDA representatives suggested a way out of the dilemma: Instead of receiving an EUA, a vaccine could be approved for “expanded access,” which would limit its use to select populations at high risk of COVID-19. This pathway typically is reserved to allow the use of experimental treatments in patients who have life-threatening conditions, but it has been used before for vaccines, such as one for meningitis B in college students. Because access to the vaccine would be limited, the approach has the advantage of allowing efficacy trials to continue.
Offit suggested after the meeting that to keep collecting vital vaccine efficacy data from trials, FDA may well need to use a mechanism like expanded access—or create a new one—that’s somewhere in between an EUA and full approval. “They just don’t have a lot of leeway right now,” Offit said.