FDA refuses to review Moderna’s application for mRNA flu vaccine, company says

By Meg Tirrell, Adam Cancryn, CNN

(CNN) — The US Food and Drug Administration has refused to accept an application from Moderna to review its first mRNA seasonal flu vaccine, the company said Tuesday, in another setback for the technology that’s been a target of some Trump administration health officials.

The agency told Moderna that its application didn’t contain an “adequate and well-controlled” trial because the control arm didn’t reflect the “best-available standard of care in the United States at the time of the study,” according to a letter dated February 3 that Moderna posted online. It didn’t identify any safety or efficacy concerns, the company said.

Moderna said that the refusal was inconsistent with previous feedback from the agency and that it had requested a meeting with FDA officials to understand how to proceed.

“The complete stunner here is at no point in any of this did anybody say that it was not adequate” to run its clinical trial the way it had discussed with the agency, Moderna’s president, Dr. Stephen Hoge, told CNN on Tuesday.

Some US Department of Health and Human Services officials disagreed with that assessment. In a call Wednesday with reporters, 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.”

It’s rare for the FDA to issue a “refuse-to-file” letter; a 2021 study of almost 2,500 applications submitted to the agency found that only 4% received such letters.

Moderna used a standard-dose seasonal flu vaccine called Fluarix as a comparator in a 40,700-person clinical trial to demonstrate the experimental mRNA vaccine’s safety and efficacy. The company said the FDA had agreed with that plan in April 2024 but suggested it also include data comparing its vaccine with an approved high-dose flu vaccine for people over 65, which the company said it did.

Moderna added that as recently as August, in a meeting before it submitted its application for approval of the vaccine, the FDA suggested that it would review the filing and assess issues with the comparator during that process. The agency did note that there could be a “significant issue” with the data “during review” of the application, according to written feedback that Moderna shared.

But last week, the agency refused to do the review at all, according to the letter. It was signed by Dr. Vinay Prasad, director of the FDA’s Center for Biologics Evaluation and Research, which oversees vaccine regulation.

Nixon said Wednesday that HHS holds that “Moderna exposed participants age 65 and over to increased risk of severe illness by giving them a substandard of care against the recommendation of FDA scientists. The most protective flu shots for seniors are a subset of high-dose flu shots recommended by the CDC Advisory Committee on Immunization Practices, which would have served as the proper control in this study.”

A spokesperson for Moderna said Wednesday, “The FDA reviewed and cleared the trial design as adequate before the study began 18 months ago. The industry depends on clear, transparent rules that are applied consistently in order to make the long-term investments that benefit Americans.”

The decision not to accept Moderna’s application came over the objection of some career staffers charged with reviewing the new flu vaccine, two people familiar with the matter told CNN. That included Dr. David Kaslow, who heads the FDA’s vaccine office, who had argued in favor of advancing the application. Kaslow declined to sign the agency’s official refusal letter, according to one of the people familiar with the matter, prompting Prasad to take the highly unusual step of putting his name on the decision.

A senior FDA official speaking on the condition of anonymity told reporters Wednesday that “there was a healthy scientific debate” internally, but they pointed out that during the previous administration, FDA staffers had “made a strong recommendation to use the appropriate flu shot as the control group in the over-65 population.”

Moderna is one of three manufacturers in the US of approved Covid-19 vaccines, along with Pfizer and Novavax. Moderna and Pfizer’s vaccines use mRNA technology. Pfizer also has mRNA-based flu vaccines in development.

Although the record-speed development of mRNA-based Covid-19 vaccines during the pandemic was a chief accomplishment of Trump’s first term, his second administration has withdrawn support for mRNA technology in infectious diseases. HHS canceled 22 projects worth about $500 million focused on mRNA vaccine development in August, with HHS Secretary Robert F. Kennedy Jr. claiming against evidence that “these vaccines fail to protect effectively against upper respiratory infections like COVID and flu.”

The senior FDA official said Kennedy “was not directly or indirectly involved” with the decision to not accept Moderna’s flu vaccine application. The official said they have “been hopeful that mRNA technology would have some spinoff platform benefits outside of infectious diseases, but it just hasn’t panned out yet.”

Moderna is also working on mRNA approaches to multiple kinds of cancer.

Covid-19 vaccines are estimated to have saved millions of lives. The hope behind applying mRNA technology to seasonal flu vaccines is that it could improve how well they work, enable tailoring for geographic regions where different strains are circulating and lead to combinations with Covid-19 vaccines so people would need only one shot for protection against both viruses.

With currently approved technology, experts select flu strains for each fall’s seasonal vaccines during the preceding February. Hoge pointed out that mRNA vaccines can be manufactured much faster; for Covid-19 vaccines, he said, the design is decided in May or June, for shipping by August.

Choosing the strains closer to the start of flu season could potentially lead to a better match with circulating viruses, “and better matching equals, usually, better protection,” Hoge said.

Moderna’s Phase 3 study showed in results reported in June that the mRNA-based flu shot produced efficacy that was about 27% higher than Fluarix in adults 50 and older. A separate trial that assessed safety and immune response included the comparison with a high-dose flu vaccine for people 65 and older and showed superiority, Moderna said.

Immune response is assessed in the laboratory by analyzing blood samples of people who’ve been vaccinated, while efficacy assessments typically involve seeing how well a vaccine protects against cases of the disease.

Moderna had been awaiting the start of the review of its flu shot before it moved its experimental combination flu and Covid-19 mRNA vaccine into the FDA review process, Hoge said. That’s now on hold as the company awaits a meeting and further guidance from the agency.

Meanwhile, the combination vaccine is moving forward in other countries.

“We do expect that our first approval will be … probably in Europe, and this year,” Hoge said. “So that’ll be a milestone event.”

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