The FDA Was Right to Reject Moderna's New Flu Shot — And the Reason Why Goes Deeper Than You Think
Moderna is moving through the FDA approval process for mRNA-1010, their new mRNA-based annual influenza vaccine. The FDA recently issued a “refuse to file” — meaning the submitted studies were deemed inadequate and not “well-controlled.” Having reviewed the publicly available data, the FDA not only made the right call, but the full story is more damning than that headline, because it exposes a foundational problem with how flu vaccines get approved in this country.
Moderna Picked the Weakest Possible Opponent and Chose this Regulatory Pathway
The foundation of any vaccine trial is choosing a fair comparator. For adults over 65, ACIP recommends three specific flu vaccines: high-dose Fluzone, Flublok, or Fluad. These recommendations exist because studies going back to 2014 showed these vaccines meaningfully outperform standard-dose shots in older adults — by 24% relative risk reduction for HD Fluzone (DiazGranados et al., NEJM 2014) and 43% for Flublok (Dunkle et al., NEJM 2017). Moderna chose neither. Instead, they compared mRNA-1010 against Fluarix — a standard-dose vaccine that ACIP explicitly does not prefer for adults over 65. The FDA had actually advised Moderna before the trial to use an ACIP-recommended comparator — or at minimum, to inform participants that better options existed. Moderna declined.
Everyone losing their mind about FDA conventions not being followed also won’t tell you that Moderna also chose not to pursue a SPA (Special Protocol Assessment) that would have made FDA guidance binding. A SPA is a formal, FDA-directed process where sponsors and the FDA reach a binding agreement on the design, endpoints, and analysis of trials before they begin. If regulatory certainty was what Moderna (or others) wanted, go get a SPA. Again, Moderna chose not to do so.
Here’s What Makes the Fluarix Choice as Comparator Even Worse
Most people have naturally assumed the Glaxo Smithkline manufactured Fluarix is a well-proven vaccine with solid efficacy data across all ages. The actual regulatory history tells a very different story.
Fluarix was first approved in the US in 2005 under accelerated approval
— based purely on antibody titers, not demonstrated protection from flu. Accelerated approval is indicative of the FDA accepting a lower bar than it ordinarily does because of some compelling reason. Fluarix didn’t receive traditional approval based on actual clinical efficacy until October 2009 — four years after it was already being administered to millions of Americans. It was also the first vaccine ever approved via the accelerated approval pathway. The traditional approval efficacy trial enrolled 7,652 adults aged 18–64 and showed an overall vaccine efficacy of 66.9%. That sounds impressive. But when you break it down by age, the picture collapses:
Adults 18–49: efficacy 73.4% (95% CI: 59.3–82.8) — 35 cases in 3,602 Fluarix recipients vs. 66 in 1,810 placebo
Adults 50–64: efficacy 13.8% (95% CI: -137.0 to 66.3) — 14 cases in 1,501 Fluarix recipients vs. 8 in 739 placebo
The trial was never powered to detect a difference in older adults, and the label itself states the clinical significance of the 50–64 result is unknown. The entire demonstrated efficacy of Fluarix was carried by younger adults. So this is the key point : In the age group Moderna was specifically targeting — 50 and older — Fluarix has never been shown to clinically be effective.
So this is the key point : In the age group Moderna was specifically targeting — 50 and older — Fluarix has never been shown to clinically be effective.
For adults over 65, the situation is even more striking. GSK (maker of FluArix) never ran a placebo-controlled efficacy trial in this age group. Approval for the elderly rested entirely on a 606-person immunogenicity study showing antibody non-inferiority versus another standard-dose vaccine — not vs. placebo, not on actual flu prevention outcomes. Those antibody thresholds were themselves derived from studies in younger adults, where immune responses are more robust.
So to summarize the comparator Moderna chose: a vaccine with some demonstrated clinical efficacy in younger people (< 50 years old) approved for the > 50 year old crowd based on antibody surrogates. There was no placebo-controlled efficacy trial in adults over 65, and a confidence interval in the 50–64 subgroup was so wide the vaccine may not work at all in that population.
Moderna’s Data Reveal Problems: The Efficacy Numbers Don’t Justify the Side Effects
Even against this weak comparator, mRNA-1010 showed only a ~0.75% absolute risk reduction and 26.6% relative vaccine efficacy in the per-protocol analysis. A cross-trial comparison by Dr. Anil Makam makes the stakes concrete. Per 1,000 vaccinated, mRNA-1010 and HD Fluzone prevent roughly the same number of flu cases. But the side effect burden is dramatically different:
mRNA-1010: 200 people per 1,000 experience flu-like symptoms vs. 50 for HD Fluzone
mRNA-1010: 20 people per 1,000 have activity-limiting Grade 3 reactions vs. 5 for HD Fluzone
That’s four times the side effect burden for the same efficacy. As Dr. Makam notes, in a meaningful minority of mRNA-1010 recipients, the vaccine produces an activity-limiting syndrome that resembles the very illness the trial was designed to prevent.
In response to the charge that Moderna never compared their product to a stronger product, the pro-Moderna crowd always responds with a small immunogenicity trial that showed non-inferiority of their product compared to Fluzone. But buried in that trial that did show immunologic equivalence of the new Moderna offering (as mentioned before, not well clinically validated) is a concerning result.
A Red Flag : A Death Deemed Attributable to the Product
There were 5 deaths (0.4%) in the mRNA-1010 arm, 1 (0.1%) in the Fluarix QIV comparator arm, and 1 in the Fluzone HD arm. The only death attributed to a study drug by an independent investigator was in the mRNA-1010 arm (Moderna disagreed). This was out of ~1200 patients. This signal alone raises some serious questions about this platform that demands a serious conversation about how we ensure the product is safe to go into millions of American arms.
The Public Health Consequence Nobody Is Talking About
If approved and widely distributed, millions of Americans will receive this vaccine without ever being asked which flu shot they want — that’s simply not how flu vaccine administration works in practice. Many will experience what feels like a bad flu reaction, blame “the flu shot,” and decline future vaccination. The net effect may be to erode, not enhance, population-level flu protection.
Moderna Responds to the FDA
Most objective observers would agree the FDA was well within its authority to refuse this application and had a valid reason to do so. Whether they should have registered their concern in another way is a different discussion that FDA insiders and those who cover the FDA have a very strong opinion on. They have forwarded a chaos narrative at the nation’s health protector which I believe is hyperbolic. What we do know is that Moderna asked for and was granted a Type A meeting which resulted in negotiations between t two parties that resulted in the agency agreeing to formally review the mRNA-1010 biologics license application, potentially positioning the vaccine for the 2026–2027 flu season.
In exchange for the FDA moving the regulatory process forward, Moderna agreed to a split regulatory strategy: full approval for adults 50–64, based on the existing trial data, and accelerated approval for adults 65 and older, contingent on a required post-marketing study in that population. (Moderna press release, February 18, 2026).
The outcome concedes the core argument at heart of the FDA concerns that prompted the Refuse To File letter - the serious concerns over efficacy of the vaccine in the 65+ population. The resolution for this age group is to receive only accelerated approval, with a commitment to run a larger confirmatory RCT in this population. In other words, the agency is acknowledging through its own framework that the existing data is not sufficient to support full approval in elderly adults. That is not a vindication of Moderna’s trial design. It is a workaround.
Given what I’ve seen with regards to Fluarix clinical data, I think full approval for the 50–64 cohort is still questionable, but if you accept the framework of Fluarix being an approved on the market comparator flu vaccine, the decision is defensible and should make the hounds hung up on process happy (yeah right).
But the 65+ pathway remains on much shakier ground. Accelerated approval was designed for serious or life-threatening conditions where early access outweighs uncertainty of efficacy or safety concerns. Whether seasonal influenza in otherwise healthy older adults clears that bar — particularly when better-studied alternatives already exist — is an open question that the FDA is punting on.
Moderna and biotech is lucky Vinay Prasad is CBER head, because this random cardiologist somewhere in Philadelphia would have been a lot harsher in large part because the story here is bigger than just Moderna. The Fluarix comparator problem reveals a fundamental problem: the regulatory framework for approving flu vaccines in older adults has historically relied on antibody surrogates with very poor clinical validation data for that population. Moderna appears to have exploited that gap deliberately because they probably have seen that FluArix is somehow on the market as an approved therapeutic despite the weak clinical data that supports it.
Moderna is doing exactly what they are supposed to do - maximize future revenue and shareholder value. The reaction to the FDA noticing this loophole and attempting to close it is troubling to say the least. The pressure campaign sparked by Moderna’s unusual step to publicly release the FDA refusal letter was intense and withering. I don’t know if that campaign had any impact on the deal made between the FDA and Moderna to advance their vaccine, but it certainly does not engender good feelings towards Moderna and the FDA insiders who mounted the campaign while sidestepping the very real and good questions that were posed about the march to approval based on a comparison to the really weak Fluarix.
Speaking as someone who very much wants effective vaccines, and therapeutics available for patients and loved ones - whether our flu vaccine approval standard is rigorous enough for populations that need protection most, and whether the regulatory process is sufficiently free of pressure from product manufacturers are questions the medical community and wider public need to take seriously.
Anish Koka is a Cardiologist who writes about medicine and health care policy. He also cohosts a weekly podcast called The Doctors Lounge. @anish_koka
Sources:
HD Fluzone 24% RRR:
Flublok 43% RRR:
Fluarix approval history:
Fluarix age subgroup efficacy:
Fluarix elderly immunogenicity data:
ACIP recommendations:
mRNA-1010 vs HD Fluzone side effect comparison:
After reading your excellent summary, one is left to wonder how in the Sam Hill Fluarix is allowed to remain on the market when it is clearly an inferior product for the 50-65 population? I’m a weirdo because when I go to my doctor’s office or pharmacy for my flu vaccination, I ask for the box insert before acquiescing to the shot. But my educated guess is that I’m not like most people. If a 55-year old is trying to do the right thing and get their annual flu shot to stay healthy and they get a shot with no demonstrated efficacy in their age range, they are paying for the equivalent of a placebo (to put it in the most extreme way). That is unethical in the extreme.
"Most objective observers would agree the FDA was well within its authority to refuse this application and had a valid reason to do so."
No - "Objective observers" with any experience with FDA CDER, CBER or CDRH would not agree. The trial protocol had been extensively discussed with the CBER review division, which stated the design, including comparator choice, was acceptable before the study began.
The refusal to file was inconsistent with those prior communications. There were no new safety or efficacy issues.
Borrowing from someone else's comment - Neither federal regulations for pivotal efficacy trials design nor any FDA’s own Guidance for Industry, refer to the use of "best-available standard of care” in selecting comparator vaccines. Prasad has been there for about 10 months and they've not announced they're drafting a new Guidance document specifying "most effective approved comparator," for vaccine efficacy trials, or overall, across therapeutic areas
"Best available comparator" was December POLICY CHANGE BY TWEET and opinion piece. FDA never even released this monumentally important "Black Friday memo," though it has leaked. That's not how legitimate regulatory agencies operate.
SPA requests are submitted WELL before pivotal studies begin (often as part of EOP2 planning). Moderna had pre-trial feedback covering all trial design elements to FDA’s satisfaction. Sponsors generally prioritize SPA requests for novel or genuinely uncertain trial designs, rather than for large vaccine trials that follow standard regulatory expectations.
Companies rely on written minutes and pre-Phase 3 consultation meetings instead of the SPA process, especially when FDA feedback appears clear and the trial follows well-established clinical endpoints and comparators.
Also, regarding yesterday's comment, there's no publicly available information that your contention (from yesterday), "the former CBER head override staff’s concerns ... and even intervened to quash a warning about COVID mRNA vaccine myocarditis."