The U.S. Food and Drug Administration (FDA) initially declined to review Moderna's application for its new messenger RNA (mRNA) seasonal flu vaccine, citing issues with the clinical trial design. However, following discussions with Moderna and an amendment to the application, the FDA has reversed its decision and agreed to proceed with the review.
Initial Refusal: Clinical Trial Design Concerns
On February 3, the FDA issued a "refuse to file" letter to Moderna regarding its mRNA flu vaccine application. The agency's primary concern centered on the design of Moderna's clinical trials, specifically for participants aged 65 and older.
The FDA stated that the trial compared Moderna's vaccine to a standard-dose flu shot in this demographic, rather than to a high-dose flu vaccine, which is generally recommended for older adults.
Vinay Prasad, director of the FDA’s Center for Biologics Evaluation and Research (CBER), indicated in a letter that the trial lacked an "adequate and well controlled" design and that the control group did not receive "the best-available standard of care."
Andrew Nixon, a spokesperson for the U.S. Department of Health and Human Services (HHS), asserted that Moderna "refused to follow very clear FDA guidance" and "exposed participants age 65 and over to increased risk of severe illness."
Moderna's Defense and Dialogue
Moderna maintained that the FDA had provided frequent input throughout its multi-year research and development process and had not objected to the study design until the initial refusal.
A Moderna spokesperson affirmed it was an "FDA-approved trial design" and cited communications from CBER in April 2024, which stated that while using a standard dose influenza vaccine in the control group would be "acceptable," CBER "recommend[ed] you use a vaccine preferentially recommended for use in older adults."
Moderna also noted that the consent form, which trial participants signed, reflected a plan that FDA officials had previously agreed to. The company also submitted data indicating its shot generated more antibodies than the higher-dose alternative for seniors.
Sources familiar with the matter indicated that the decision to initially refuse the application came from Vinay Prasad, rather than from senior career staff who reportedly supported allowing the review to proceed, an action described as unusual.
FDA Reversal and the Path Forward
Following a meeting between Moderna and the FDA, Moderna amended its application. The FDA subsequently accepted the amended application for review.
As part of this agreement, Moderna has committed to conducting a confirmatory study in older adults comparing its mRNA vaccine to a high-dose flu shot. This study is planned to take place after potential market authorization of the mRNA vaccine.
Moderna has invested over $1 billion in the development of its mRNA flu shot, including up to $750 million from Blackstone. The company anticipates that the new vaccine could be available for the next flu season, pending FDA approval.
Broader Implications for Vaccine Development
The situation has prompted discussions among experts regarding regulatory clarity and its potential impact on vaccine development. Some experts have expressed concerns that regulatory uncertainty could deter pharmaceutical companies from investing in and developing new vaccines, particularly those utilizing mRNA technology.
Michael Osterholm, director of the University of Minnesota’s Center for Infectious Disease Research and Policy, stated that the FDA appeared to have reversed its established process.
Others have questioned whether new vaccines necessarily need to be superior to all existing options to provide value, suggesting benefits such as addressing allergies or diversifying supply chains. Some experts also noted the FDA could have approved the vaccine for the 50-65 age group exclusively.
HHS spokesperson Andrew Nixon dismissed concerns that mRNA and other vaccines are being targeted by officials as "baseless." The HHS had also announced a policy requiring new vaccines to be compared to placebos instead of existing vaccines, a policy some argue deviates from current standards of care.
Scientists and industry experts have highlighted the potential benefits of mRNA flu vaccines, including their utility for individuals with egg allergies and the technology's flexibility in adapting to flu mutations and responding to pandemics, emphasizing its significance for public health. Regulatory stability is considered crucial for continued investment in such advancements.