TARGETING SCIENCEThe FDA Refused to Review a Flu Vaccine, Contrary to Evidence. Now the Agency Reversed Itself
Strong, predictable, science-based regulation protects the public. A refuse-to-file letter—for a vaccine with no identified safety or efficacy concerns; tested under an FDA-approved trial design; supported by data showing superiority over both standard-dose and high-dose comparators; and submitted through a pathway that prior vaccines used to gain the very approvals Vinay Prasad, Director of the Center for Biologics Evaluation and Research (CBER) now demands as the benchmark—does not meet that standard.
On February 3, the Food and Drug Administration’s (FDA’s) Center for Biologics Evaluation and Research (CBER) issued Moderna a refusal-to-file letter for its mRNA influenza vaccine, mRNA-1010. Two weeks later, under mounting pressure from the scientific community and the pharmaceutical industry, yesterday the agency reversed itself and agreed to review the application.
The reversal is welcome. But the episode—and the reasoning behind the original refusal—deserve close examination, because the damage to regulatory credibility is not so easily undone.
Flimsy Rationale
The refusal letter, signed personally by CBER Director Vinay Prasad, MD, MPH, did not cite safety concerns. It did not cite efficacy concerns. It cited one thing: the choice of comparator in Moderna’s pivotal phase 3 trial.
The sole objection was that Moderna compared mRNA-1010 to a licensed standard-dose influenza vaccine rather than a high-dose or adjuvanted formulation — the products preferentially recommended for adults 65 and older. Prasad’s letter stated that the comparator “does not reflect the best-available standard of care,” and therefore the trial did not meet the FDA’s definition of an “adequate and well-controlled” study.
This rationale does not withstand scrutiny.
Moderna’s BLA submission included two phase 3 studies enrolling a total of 43,808 participants. The pivotal efficacy trial (P304) was a randomized, observer-blind study of 40,805 adults aged 50 and older conducted across 11 countries. It compared mRNA-1010 to a licensed standard-dose influenza vaccine and demonstrated a 26.6% relative vaccine efficacy (rVE) against confirmed influenza (95% confidence interval [CI], 16.7% to 35.4%), with consistent results in adults 65 and older (27.4% rVE) and efficacy against each circulating strain.
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“This rationale does not withstand scrutiny.”
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A second phase 3 trial (P303 part C) directly compared mRNA-1010 to a licensed high-dose influenza vaccine in adults 65 and older, measuring immunogenicity. mRNA-1010 demonstrated statistical superiority over the high-dose vaccine. Both studies met all prespecified primary end points. Both study designs were reviewed by FDA prior to initiation.
To restate this clearly: Moderna tested its vaccine against the standard-dose comparator the FDA agreed to and demonstrated superiority. Then it tested against the high-dose comparator Prasad says should have been used and demonstrated superiority again. The FDA refused to review any of it.
