On February 3, the Food and Drug Administration’s (FDA’s) Center for Biologics Evaluation and Research (CBER) issued Moderna a refusal-to-file letter for its mRNA influenza vaccine, mRNA-1010. Two weeks later, under mounting pressure from the scientific community and the pharmaceutical industry, yesterday the agency reversed itself and agreed to review the application.
The reversal is welcome. But the episode—and the reasoning behind the original refusal—deserve close examination, because the damage to regulatory credibility is not so easily undone.
Flimsy rationale
The refusal letter, signed personally by CBER Director Vinay Prasad, MD, MPH, did not cite safety concerns. It did not cite efficacy concerns. It cited one thing: the choice of comparator in Moderna’s pivotal phase 3 trial.
The sole objection was that Moderna compared mRNA-1010 to a licensed standard-dose influenza vaccine rather than a high-dose or adjuvanted formulation — the products preferentially recommended for adults 65 and older. Prasad’s letter stated that the comparator “does not reflect the best-available standard of care,” and therefore the trial did not meet the FDA’s definition of an “adequate and well-controlled” study.
This rationale does not withstand scrutiny.
Moderna’s BLA submission included two phase 3 studies enrolling a total of 43,808 participants. The pivotal efficacy trial (P304) was a randomized, observer-blind study of 40,805 adults aged 50 and older conducted across 11 countries. It compared mRNA-1010 to a licensed standard-dose influenza vaccine and demonstrated a 26.6% relative vaccine efficacy (rVE) against confirmed influenza (95% confidence interval [CI], 16.7% to 35.4%), with consistent results in adults 65 and older (27.4% rVE) and efficacy against each circulating strain.
This rationale does not withstand scrutiny.
A second phase 3 trial (P303 part C) directly compared mRNA-1010 to a licensed high-dose influenza vaccine in adults 65 and older, measuring immunogenicity. mRNA-1010 demonstrated statistical superiority over the high-dose vaccine. Both studies met all prespecified primary end points. Both study designs were reviewed by FDA prior to initiation.
To restate this clearly: Moderna tested its vaccine against the standard-dose comparator the FDA agreed to and demonstrated superiority. Then it tested against the high-dose comparator Prasad says should have been used and demonstrated superiority again. The FDA refused to review any of it.
Striking departure from regulatory norms
The regulatory timeline makes the decision more difficult to defend. In April 2024, Moderna submitted the phase 3 study protocol to CBER for a pre-trial consultation. CBER responded in writing that using a standard-dose comparator was “acceptable,” while recommending—but not requiring—a high-dose comparator for the 65-and-older subgroup. The agency placed no clinical hold and raised no objections before the trial began enrolling in September 2024.
In August 2025, following the trial’s successful completion, Moderna held a pre-submission meeting with CBER. The agency flagged the comparator as a “significant issue during review” and requested supportive analyses, which Moderna provided—including the P303 part C high-dose comparator data. At no point did CBER indicate it would refuse to review the file.
Then, on February 3, 2026, it did exactly that.
In a background press briefing, a senior FDA official defended the decision with striking language: “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.” The suggestion that a company running a trial under an FDA-approved design was “rigging” the study is a remarkable departure from regulatory norms.
A shifting benchmark
It also raises an uncomfortable question about the products Prasad now considers the gold standard. Fluzone High-Dose—the high-dose vaccine Prasad believes should have been the comparator—was itself licensed on the basis of a pivotal trial comparing it to a standard-dose vaccine. It demonstrated 24.2% rVE against lab-confirmed influenza versus standard-dose and met FDA requirements for superiority.
Fluad, the adjuvanted influenza vaccine, was similarly evaluated against an unadjuvanted standard-dose comparator and approved under accelerated approval based on immunogenicity.
As Moderna has pointed out, the P304 trial design mirrors the approach these products used to gain their own approvals. Prasad is applying a standard retroactively that the vaccines he considers the benchmark did not themselves have to meet.
Demonstrating superiority over a licensed product is an established and legitimate pathway to approval.
The evidence base for high-dose superiority in older adults, while meaningful, is also less definitive than the refusal letter implies. Two large randomized controlled trials comparing high-dose to standard-dose influenza vaccines in adults 65 and older were published in the New England Journal of Medicine in August 2025.
The Danish DANFLU-2 trial randomized 332,438 participants across three influenza seasons. Its primary end point—hospitalization for influenza or pneumonia—showed no statistically significant benefit for the high-dose vaccine (rVE, 5.9%, 95.2% CI, −2.1% to 13.4%, P = 0.14). High-dose did reduce influenza-specific hospitalization (rVE, 43.6%) but missed the composite end point the trial was designed to test. The companion GALFLU trial in Spain, enrolling 133,882 participants, found a 23.7% rVE against the same composite endpoint—but it fell short of its prespecified threshold for confirmatory hypothesis testing, so the results were reported descriptively.
None of this means high-dose vaccines don’t work or don’t have advantages for older adults. Our own systematic review of respiratory virus vaccines, published in the New England Journal of Medicine in October 2025, found that high-dose formulations were associated with added benefit in adults 65 and older compared to standard-dose products. But “added benefit” and “the only acceptable comparator for licensure” are very different claims.
Standard-dose influenza vaccines reduce hospitalization, medically attended illness, and death. They remain licensed and widely administered. Millions of US adults, including those 65 and older, receive standard-dose influenza vaccines each season. Demonstrating superiority over a licensed product is an established and legitimate pathway to approval.
Far-reaching implications
The implications of this decision extend well beyond one application. In late January, Moderna announced it would not invest in new late-stage vaccine trials in the United States, citing regulatory uncertainty. The company has discontinued multiple mRNA vaccine programs.
When asked whether the anti-vaccine climate would affect Moderna’s vaccine development, CEO Stéphane Bancel, MBA, Meng, answered: “100%.” Pfizer, which is developing its own mRNA influenza vaccine, is watching the regulatory landscape closely. Venture capital investors have reportedly described vaccines as “radioactive.”
This is the chilling effect in real time. The mRNA platform—the technology that enabled the fastest vaccine development in history during the COVID-19 pandemic, developed in the United States with substantial public investment—is being driven out of the country not because the science has failed, but because the regulatory environment has become unpredictable.
Strong, predictable, science-based regulation protects the public.
mRNA-1010 is under active review in the European Union, Canada, and Australia. If the path to licensure in this country becomes untenable while international regulators proceed with standard reviews, the consequences for American innovation and pandemic preparedness are serious. mRNA vaccines can be manufactured faster than egg-based or cell-based platforms, with closer strain matching to circulating viruses—an advantage not captured in any single season’s efficacy data but essential when the next pandemic strain emerges.
Strong, predictable, science-based regulation protects the public. A refuse-to-file letter—for a vaccine with no identified safety or efficacy concerns, tested under an FDA-approved trial design, supported by data showing superiority over both standard-dose and high-dose comparators, and submitted through a pathway that prior vaccines used to gain the very approvals Prasad now demands as the benchmark—does not meet that standard. The scientific and medical community should push back forcefully and clearly.
Dr. Scott is a clinical associate professor of infectious diseases at Stanford University School of Medicine, a co-author of “Updated Evidence for Covid-19, RSV, and Influenza Vaccines for 2025-2026” in the New England Journal of Medicine, and is co-lead of a comprehensive database of approximately 1,700 randomized controlled trials of vaccines.
The opinions voiced in CIDRAP Op-Ed pieces are the authors’ own and do not necessarily represent the official position of CIDRAP.
