Moderna says FDA's refusal to review mRNA flu vaccine violates federal rules and previous guidance
Moderna's messenger RNA flu vaccine was successful in two pivotal clinical trials, but the U.S. Food and Drug Administration refused to even review the application seeking regulatory approval, telling the company that the comparator in the study (an FDA-approved vaccine) was insufficient.
Moderna said after the close on Tuesday that the FDA's rejection letter did not identify any safety or efficacy issues with its vaccine, mRNA-1010. The agency told the company that the vaccine lacked adequate, well-controlled studies and that the comparators did not reflect the standard of care.
A rejection letter informs a company that the application lacks information for the agency to review. While the issue could be resolved by submitting additional data, it could also mean the agency wants a company to conduct another clinical trial. Refusal to submit letters are considered confidential communications between the FDA and the company and generally are not made public. But Moderna took the unusual step of posting the letter on its website. The agreement was signed by Vinayak Prasad, director of the FDA's Center for Biologics Evaluation and Research (CBER).
“CBER does not believe that the application contains an 'adequate and well-controlled' trial and, therefore, on its face, the application is not suitable for review,” Prasad wrote in the February 3 letter. “This is because your control group did not reflect the best available standard of care in the United States at the time of your study. I note that this decision is consistent with the advice the FDA gave you prior to your study.”
Moderna's mRNA-1010 is a seasonal flu vaccine that uses mRNA to cause the body's protein-making machinery to code for hemagglutinin, a protein on the surface of the flu virus. This protein triggers a protective immune response. The company's submitted vaccine candidate is based on a Phase 3 study whose design was reviewed by the FDA before it began.
Moderna noted that federal rules requiring adequate and well-controlled clinical trials make no mention of comparators that reflect the “best available standard of care.” According to the company, the FDA's 2024 written guidance states that the agency agrees that licensed standard-dose influenza vaccines would be acceptable comparators for pivotal studies, but “we recommend that you use ACIP's priority recommendations for vaccines in older adults. [Advisory Committee on Immunization Practices] (i.e., Fluzone HD, Fluad, or Flublok) for study participants over 65 years of age. “The Centers for Disease Control and Prevention recommends that older adults receive the high-dose flu vaccine because the immune response typically weakens with age, putting people in this age group at higher risk.
The Moderna flu vaccine met the study's prespecified efficacy target, called P303. The comparator in this study was GlaxoSmithKline's Fluarix, a standard-dose quadrivalent influenza vaccine. One cohort of the study enrolled participants ages 65 and older and compared the Moderna vaccine to Fluzone, a high-dose flu vaccine marketed by Sanofi.
Moderna said the agency's written feedback requested that supporting analysis of the comparator be included in applications seeking regulatory approval. The company said it provided this information, including data from a separate Phase 3 trial, P304. The study compared mRNA-1010 to Fluarix, whose FDA approval covers adults 65 and older. Moderna said many other countries are not prioritizing seniors 65 and older in recommending high-dose flu vaccine over standard-dose flu vaccine. The company added that based on previous feedback from the FDA, there was no indication that the agency would refuse to review the application.
“Having discussed and agreed with CBER before a study began, a comprehensive review of a flu vaccine submission using an FDA-approved vaccine as a control should not be controversial,” Moderna CEO Stéphane Bancel said in a prepared statement. “We look forward to working with CBER to understand a path forward as quickly as possible so that America's seniors and people with underlying medical conditions can continue to have access to American-made innovations.”
The Trump administration's rationale for some of its health policies is to bring the United States into line with other countries. When the CDC reduced its list of recommended vaccinations from 17 to 11 last month, the agency said the move brought the U.S. in line with other countries. This is one of the reasons the FDA changed its Covid-19 recommendations to emphasize vaccinating older adults and those at higher risk. In an article published in the New England Journal of Medicine last May, Prasad and FDA Commissioner Marty Makary noted that this approach was consistent with Europe and other high-income countries.
Like other Covid-19 vaccine makers, Moderna has been facing declining revenue from those vaccines as vaccination rates decline. But the Trump administration's policy shifts have effectively narrowed the market for Moderna's biggest source of revenue, putting pressure on the company to increase revenue from other products. Some of those efforts have also been stymied by the Trump administration. Last year, the U.S. Department of Health and Human Services terminated Moderna's $590 million contract to develop a bird flu vaccine.
Moderna's flu vaccine is currently under regulatory review in Europe, Canada and Australia, and the company plans to submit applications in more countries this year. But gaining U.S. approval will be key to hitting revenue targets. Investment banker William Blair expects sales of mRNA-1010 to top $1 billion in a $5 billion annual market. Moderna is also developing mRNA-1083, a combined Covid-19/flu vaccine. In a research note on Wednesday, William Blair analyst Myles Minter wrote that the rejection of the submission for mRNA-1010 casts doubt on the future of the combination shot.
“We remain curious about the specific control groups requested by CBER, especially given its stated preference for placebo-controlled studies in previously released COVID-19 vaccine guidance,” Minter said. “The FDA meeting minutes cited by Moderna, obtained before the launch of the Phase 3 program, indicate that the company did use the recommended comparator vaccine in the P303 and P304 studies, and appear to directly contradict Vinayak Prasad's statement in the RTF letter that his decision was inconsistent with the FDA's Consistent advice given to you before researching.”
Moderna has requested a meeting with the FDA to discuss the rejection letter.
Illustration: appledesign, Getty Images
