The US Food and Drug Administration’s (FDA’s) Center for Biologics Evaluation and Research (CBER) is refusing to review Moderna’s application for approval of a new flu vaccine. The decision comes after the FDA previously indicated support for the company’s phase 3 trial of its mRNA flu vaccine.  

Moderna’s study included more than 40,000 adults age 50 and up and was intended to help the company get approval to use the vaccine in that age-group. In a press release, Moderna said the FDA determined that the company’s study was not “adequate and well-controlled” because the comparable vaccine used in the trial did not represent the “best-available standard of care” in the United States at the time of the study. 

Neither federal rules for how drug studies must be designed, nor the FDA’s own guidance for flu vaccines, refer to the use of “best-available standard of care” in selecting comparator vaccines. Previous correspondence from the FDA to Moderna expressed a preference for the company to use a higher-dose vaccine for older adults as a comparator but stated, “We agree it would be acceptable to use a licensed standard dose influenza vaccine as the comparator in your Phase 3 study.”

The study followed a well-established framework for flu vaccine trials, according to virologist Angela Rasmussen, PhD, of the University of Saskatchewan in Canada. “The trial design they used is essentially the trial design that every single flu vaccine has used,” she tells CIDRAP news. 

Refusal could undermine confidence in FDA

In an interview with The New York Times, Moderna’s president Stephen Hoge, MD, expressed surprise and confusion about the decision, noting the FDA’s earlier support for the company’s study plan. The company’s mRNA vaccine has been accepted for review in the European Union, Canada, and Australia. Moderna has requested a meeting with the FDA to understand the basis for their refusal.

“This decision by CBER, which did not identify any safety or efficacy concerns with our product, does not further our shared goal of enhancing America’s leadership in developing innovative medicines,” Stephane Bancel, MBA, Moderna CEO, said in the release. “It should not be controversial to conduct a comprehensive review of a flu vaccine submission that uses an FDA-approved vaccine as a comparator in a study that was discussed and agreed on with CBER prior to starting.”

Vaccine companies generally work with clear, well-established expectations of the kinds of studies considered acceptable by the FDA, Peter Hotez, MD, PhD, of Baylor College of Medicine, tells CIDRAP News. 

“There was a commitment,” he said, adding that to “string Moderna along and all of a sudden say, nope, we’re not going to even review it” risks undermining confidence in FDA processes. The decision, Hotez warned, could “have an immediate chilling effect on the vaccine industry.” Vaccine makers may start to reassess whether to invest in US-based vaccine development if regulatory expectations shift late in the process. 

The FDA “changed their mind,” about whether Moderna could use a standard-dose flu shot in the trial, Paul Offit, MD, director of the Vaccine Education Center at Children’s Hospital of Philadelphia, said, “which is really not fair.”

The refusal has broader implications, too, specifically when it comes to US biosecurity. Hotez says the federal government appears to be stepping back from biothreat preparedness across multiple domains, including future pandemics. The federal government has “no plan for what they’re going to do to stockpile vaccines” for future flu, coronavirus, or other catastrophic respiratory infections, he says. 

CBER director overruled career scientists

Reporting today from STAT suggests that the decision to refuse Moderna’s application was not unanimous. Sources told STAT that Vinay Prasad, MD, director of CBER, overruled career scientists who had been preparing to move forward with a formal review. 

A US Department of Health and Human Services (HHS) spokesperson disputed that characterization, saying there was a “diverse set of conclusions” among staff.

In a background press briefing today about the decision, a senior FDA official defended the refusal as an ethical necessity, arguing that Moderna failed to use the appropriate standard-of-care comparator for adults 65 and older. “You can either do what’s right and give seniors the standard of care that protects them the best. Or you can kind of rig the study so that it makes your product look better,” said the official, who spoke on background. ““It’s bad behavior in my opinion. It’s morally problematic. It borders on putting profits ahead of patients.”

The official also characterized the decision as procedural rather than substantive, emphasizing that “a refusal to file is not a rejection of the drug.” 

Throughout the press conference, the official repeatedly described the agency’s prior position as a “strong recommendation” and says it was “pretty clear” that FDA recommended using a high-dose comparator in seniors. He did not say the FDA formally required that design as a condition of proceeding with the trial.

Rasmussen said the Moderna decision, if Prasad made it unilaterally, fits a broader pattern. “It’s not the first time he’s done it,” she said, referring to earlier instances in which Prasad overruled internal FDA experts. Last summer, she noted, he “basically overruled two different internal FDA expert panels” related to COVID vaccines.

In a statement emailed to reporters after the press conference, HHS spokesperson Andrew Nixon said, “The FDA rejected Moderna’s application for filing because the company refused to follow very clear FDA guidance from 2024 to test its product in a clinical trial against a CDC-recommended flu vaccine to compare safety and efficacy.”

HHS leadership skeptical of mRNA technology

In the press conference, the senior FDA official also drew a distinction between traditional flu vaccines and Moderna’s mRNA platform, calling the latter “an entirely novel platform” that warrants heightened scrutiny. 

HHS Secretary Robert F. Kennedy Jr. has criticized mRNA technology and has moved to scale back federal support for certain vaccine initiatives. During the COVID-19 pandemic, mRNA vaccines developed by Moderna and Pfizer were deployed widely and credited with preventing severe disease and death. The technology was recognized with the 2023 Nobel Prize in Medicine.

Since taking office, Kennedy, a vocal vaccine skeptic, has terminated hundreds of millions of dollars’ worth of grants aimed at developing mRNA technology. 

mRNA technology may allow more precise flu vaccines

Moderna’s flu vaccine had been positioned as an alternative to egg-based influenza vaccines, which can be less precisely matched to circulating strains and require months of production time. 

“We have a lot of options for flu vaccination in this country right now. The challenge is that many of those options require production in eggs and that requires a reasonably long timeline to get that done,” Robert Hopkins Jr., MD, medical director for the National Foundation for Infectious Diseases, said. 

The option of having a messenger RNA-based flu vaccine “would give us a great deal more ability to modify our vaccines on a shorter timeline if needed,” says Hopkins. “This year is the perfect situation. We chose flu vaccine strains in March or April, then this new variant of H3n2 emerged in Europe in June. If that had happened and we’d had an mRNA vaccine available, there would have been a potential that we could have had an updated vaccine that’s much more targeted to this newly emergent strain.”