The U.S. Food and Drug Administration (FDA) has refused to review Moderna’s application for approval of a new mRNA-based influenza vaccine, the company announced on . The decision, which does not stem from safety or efficacy concerns, centers on the design of Moderna’s clinical trial and the comparator vaccine used to assess its effectiveness.
Moderna’s phase 3 study involved over 40,000 participants aged 50 and older and aimed to demonstrate the vaccine’s efficacy compared to existing influenza vaccines. However, the FDA issued a “refusal-to-file” letter stating that the trial was not “adequate and well-controlled” because the comparator vaccine did not represent the “best-available standard of care” in the United States at the time the study was conducted.
According to Moderna, the FDA’s position is inconsistent with previous guidance. While the agency had expressed a preference for using a high-dose influenza vaccine, particularly for those 65 and older, it had previously indicated that using a standard-dose vaccine as a comparator would be “acceptable.” Moderna proceeded with the study based on this understanding.
The trial design itself, however, aligns with established practices for influenza vaccine trials, according to virologist Angela Rasmussen, PhD, of the University of Saskatchewan. “The trial design they used is essentially the trial design that every single flu vaccine has used,” she stated.
Heightened Scrutiny and Concerns About FDA Processes
The FDA’s decision comes amid increasing scrutiny of vaccines, particularly those utilizing mRNA technology, under the leadership of Health Secretary Robert F. Kennedy Jr. Kennedy has been a vocal critic of mRNA vaccines both before and after assuming his position. This context raises questions about potential political influence on the agency’s regulatory processes.
Stephen Hoge, MD, Moderna’s president, expressed surprise and confusion regarding the FDA’s decision, particularly given the agency’s earlier support for the study plan. Moderna’s mRNA flu vaccine has already been accepted for review in the European Union, Canada, and Australia, highlighting the discrepancy in regulatory approaches.
The refusal to even review the application has sparked concerns about the potential chilling effect on vaccine innovation. Peter Hotez, MD, PhD, of Baylor College of Medicine, warned that this move could undermine confidence in FDA processes and discourage investment in U.S.-based vaccine development. “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.
Paul Offit, MD, director of the Vaccine Education Center at Children’s Hospital of Philadelphia, also criticized the FDA’s change in position, stating, “It’s really not fair.”
Broader Implications for Biosecurity and Pandemic Preparedness
The situation extends beyond a single vaccine application. Hotez expressed concern that the federal government is stepping back from biothreat preparedness, including future pandemic responses. He noted a lack of a clear plan for stockpiling vaccines against potential future influenza pandemics or other respiratory infections.
Internal Disagreements Within the FDA
Reporting from STAT suggests that the decision to refuse Moderna’s application was not unanimous within the FDA. Sources indicated that Vinay Prasad, MD, director of the FDA’s Center for Biologics Evaluation and Research (CBER), overruled career scientists who were prepared to move forward with a formal review.
A spokesperson for the Department of Health and Human Services (HHS) disputed this characterization, stating there was a “diverse set of conclusions” among staff. However, Rasmussen noted that this decision aligns with a broader pattern of Prasad overruling internal FDA experts, citing previous instances related to COVID-19 vaccines.
During a press briefing, 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. The official stated that using the standard-dose flu shot was a deliberate choice to potentially make Moderna’s product appear more effective, characterizing it as “bad behavior” and “morally problematic.” The official emphasized that the refusal to file is not a rejection of the drug itself.
mRNA Technology and Future Vaccine Development
The FDA official also highlighted the novelty of mRNA technology, suggesting it warrants heightened scrutiny. This stance contrasts with the widespread success of mRNA vaccines during the COVID-19 pandemic, a technology that was awarded the 2023 Nobel Prize in Medicine. HHS Secretary Robert F. Kennedy Jr. Has previously expressed skepticism towards mRNA technology and has reduced federal funding for related initiatives.
Moderna’s mRNA flu vaccine offered a potential advantage over traditional egg-based vaccines, which require a lengthy production timeline and may not always be well-matched to circulating influenza strains. Robert Hopkins Jr., MD, medical director for the National Foundation for Infectious Diseases, explained that an mRNA-based vaccine could allow for more rapid adaptation to emerging viral variants. “This year is the perfect situation,” Hopkins said. “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.”
Moderna has requested a meeting with the FDA to discuss the basis for the refusal and hopes to resolve the issue. The outcome of this situation could have significant implications for the future of influenza vaccine development and the broader landscape of vaccine innovation in the United States.
