Moderna Says FDA Refusal to Review mRNA Flu Vaccine Contradicts Federal Rules, Prior Guidance Leave a comment

Moderna’s messenger RNA influenza vaccine succeeded in two pivotal clinical trials, but the Food and Drug Administration is refusing to even review the application seeking regulatory approval, telling the company that the comparator in the studies — an FDA-approved vaccine — is insufficient.

The FDA’s refuse-to-file letter did not identify any safety or efficacy concerns for the vaccine, mRNA-1010, Moderna said after Tuesday’s market close. The agency told the company that the vaccine lacked an adequate and well-controlled study and the comparator does not reflect standard of care.

Refuse-to-file letters inform a company that an application lacks information for the agency to conduct a review. While the issue may be resolved by submitting additional data, it can also mean the agency wants a company to conduct another clinical trial. Refuse-to-file letters are considered confidential communication between the FDA and a company, and are not typically made public. But Moderna took the unusual step of posting this letter to its website. It was signed by Vinayak Prasad, director of the FDA’s Center for Biologics Evaluation and Research (CBER).

“CBER does not consider the application to contain a trial ‘adequate and well controlled’ and the application is therefore, on its face, inadequate for review,” Prasad wrote in the letter dated Feb. 3. “This is because your control arm does not reflect the best-available standard of care in the United States at the time of the study. I note that this determination is consistent with FDA’s advice given to you prior to your study.”

Moderna’s mRNA-1010 is a seasonal flu vaccine that uses mRNA to get the body’s protein-making machinery to code for hemagglutinin, a protein on the surface of the influenza virus. This protein triggers a protective immune response. The company’s submission for the vaccine candidate was based on Phase 3 studies whose designs were reviewed by the FDA before their start.

Moderna noted that the federal rules that call for adequate and well-controlled clinical trials make no reference to a comparator reflecting “the best-available standard of care.” According to the company, the FDA’s 2024 written guidance stated the agency agreed a licensed standard dose influenza vaccine would be an acceptable comparator for the pivotal study, but “we recommend you use a vaccine preferentially recommended for use in older adults by the ACIP [Advisory Committee on Immunization Practices] (i.e., Fluzone HD, Fluad or Flublok) for participants >65 years of age in the study.” The Centers for Disease Control and Prevention recommends high-dose flu vaccines for older adults because immune responses typically diminish with age, putting this age group at higher risk.

The Moderna flu vaccine met pre-specified efficacy goals for the study, named P303. The comparator in this study was GSK’s Fluarix, a standard-dose quadrivalent influenza vaccine. One cohort in this study enrolled participants age 65 and older and compared the Moderna vaccine to Fluzone, a high-dose influenza vaccine marketed by Sanofi.

Moderna said the agency’s written feedback asked that supportive analysis on the comparator be included in the application seeking regulatory approval. The company said it provided this information, including data from a separate Phase 3 trial, P304. This study compared mRNA-1010 to Fluarix, whose FDA approval covers adults age 65 and holder. Moderna said many other countries do not preferentially recommend high-dose influenza vaccines over standard-dose flu vaccines for those age 65 and older. The company added that based on the FDA’s prior feedback, there was no indication the agency would refuse to review the application.

“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,” Moderna CEO Stéphane Bancel said in a prepared statement. “We look forward to engaging with CBER to understand the path forward as quickly as possible so that America’s seniors, and those with underlying conditions, continue to have access to American-made innovations.”

The Trump administration’s justifications for some of its health policies has been to bring the U.S. in line with other countries. When the CDC cut the list of recommended vaccinations from 17 to 11 last month, the agency said the move makes the U.S. consistent with peer nations. That was also one of the justifications for the FDA changing its Covid-19 recommendations, emphasizing vaccination for older adults and at-risk groups. In an article published in the New England Journal of Medicine last May, Prasad and FDA Commissioner Marty Makary pointed out this approach is consistent with Europe and other high-income nations.

Like other manufacturers of Covid-19 vaccines, Moderna has been dealing with declining revenue from these shots amid falling vaccination rates. But the Trump administration’s policy shifts effectively shrink the market for Moderna’s top source of revenue, putting pressure on the company to grow revenue from other products. Some of these efforts have been also been stymied by the Trump administration. Last year, the Department of Health and Human Services terminated Moderna’s $590 million contract to develop a vaccine for avian influenza.

Moderna’s flu vaccine is currently under regulatory review in Europe, Canada, and Australia, and the company plans submissions in more countries this year. But securing U.S. approval will be key for meeting revenue goals. Investment bank William Blair had projected mRNA-1010 sales could top $1 billion in what is a $5 billion annual market. Moderna is also developing mRNA-1083, a Covid-19/influenza combination vaccine. In a Wednesday research note, William Blair analyst Myles Minter wrote that the refuse-to-file letter for mRNA-1010 casts doubt on the future of the combination shot.

“We remain curious as to the specific control arm CBER is requesting, particularly given its stated preference for placebo-controlled studies in its previously published Covid-19 vaccine guidance,” Minter said. “Moderna’s quotations taken from FDA meeting minutes acquired prior to the Phase 3 program initiation suggest the company did utilize a recommended comparator vaccine in the P303 and P304 studies and appear to directly contradict Vinayak Prasad’s statement in the RTF letter that his ‘determination is consistent with FDA’s advice given to you prior to your study.”

Moderna has requested a meeting with the FDA to discuss the refuse-to-file letter.

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