Influenza virus vaccine, quadrivalent(GlaxoSmithKline Plc)

Caught in the crossfire of the US's tumultuous and controversial vaccine policy overhaul, Moderna is the latest drugmaker stunned by a negative decision from the FDA that seemed to contradict earlier feedback. The biotech said Tuesday it received a refusal-to-file (RTF) letter from the FDA's Center for Biologics Evaluation and Research (CBER) after using a priority review voucher to speed along its regulatory filing for mRNA-based influenza vaccine candidate mRNA-1010, submitted in January.The letter, signed by CBER Director Vinay Prasad, did not identify any issues with mRNA-1010's safety or efficacy. Instead, the FDA's decision not to review the vaccine's application was based on the company's use of a licensed seasonal flu vaccine comparator in clinical studies. "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 company release.According to Moderna, the letter cited the lack of an "adequate and well-controlled" study with a comparator arm that "does not reflect the best-available standard of care." However, the biotech argued that the RTF letter was "inconsistent with previous written communications from CBER," pointing to feedback it received on its Phase III study protocol.In an April 2024 note, CBER wrote that "it would be acceptable to use a licensed standard dose influenza vaccine as the comparator," though it recommended the drugmaker instead use a vaccine recommended for adults ages 65 and up by the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices (ACIP), such as Fluzone HD, Fluad or Flublok. The agency concluded that if Moderna proceeded "with using a standard dose influenza vaccine comparator in participants ≥65 years of age, we agree with your plan to include statements in the Informed Consent Form." According to the drugmaker, CBER did not flag any issues with the study protocol before it was launched in September 2024 — but did so after the Phase III efficacy trial had finished and met its agreed-upon primary endpoints. In the study, which recruited 40,817 participants aged 50 and older, mRNA-1010 achieved a relative vaccine efficacy against influenza illness of 26.6% compared to Fluarix, a flu shot marketed by GSK.Following a pre-submission meeting with CBER in August 2025, Moderna said the agency requested that supportive analyses on the comparator be included in the submission, noting that it would be a "significant issue during review of your BLA." The drugmaker did so, and also shared data from a separate Phase III trial that evaluated mRNA-1010's safety and immunogenicity against a licensed high-dose influenza vaccine. In that trial, the mRNA shot demonstrated superior seroconversion rates and geometric mean titre ratios against all strains included in the vaccine."At no time in the pre-submission written feedback or meeting did CBER indicate that it would refuse to review the file," Moderna said. It has requested a Type A meeting with CBER "to understand the basis for the RTF letter." The drugmaker noted that regulators in the EU, Canada and Australia have all accepted its mRNA-1010 application for review, and more global submissions are expected this year. Vaccines in the crosshairs The RTF letter is the latest setback for Moderna since the US began reworking its vaccine policies under the direction of Health and Human Services (HHS) Secretary Robert F. Kennedy Jr., who has shepherded stricter vaccine development guidelines and an overhaul of the CDC's childhood vaccine schedule (see – ViewPoints: 'It's only going to get worse' — Offit's 2026 vaccine outlook).Amidst the flurry of changes in the past year, mRNA technology in particular has come under fire. In August, HHS cancelled funding for 22 mRNA vaccine programmes, including Moderna's experimental mRNA-based bird flu jab. At the time, Kennedy said the wind-down of agency support for the technology was because "the data show these vaccines fail to protect effectively against upper respiratory infections like COVID and flu," though he did not provide any data to support his claim.Increased scrutiny on mRNA-based vaccines also prompted Moderna last year to withdraw its FDA application for mRNA-1083, a combination influenza/COVID-19 candidate, based on a request for additional Phase III flu efficacy data. The biotech had planned to submit a filing for the combo vaccine once the review for mRNA-1010 was under way. Fellow vaccine developer Pfizer also has an mRNA flu shot in late-stage development, though it's unclear whether it will also be hit with an RTF letter. In a Phase III trial, the pharma's jab demonstrated superiority over Fluzone on the study's primary endpoint of relative efficacy.FDA about-faceOutside of the vaccine landscape, other drugmakers have raised concerns with unexpected FDA rejections on products that succeeded in pivotal testing. Most recently, Regenxbio's Hunter syndrome gene therapy received a complete response letter (CRL), though the company asserted on Monday that it had addressed all issues raised "through the submission of additional data and responses to numerous information requests."Regenxbio and Moderna are part of a growing cohort of companies who have called out inconsistent feedback from the FDA.Sanofi's tolebrutinib was rebuffed by the FDA late last year in what it called a "significant and meaningful change in direction from the feedback the agency previously provided." Similarly, Corcept Therapeutics' relacorilant was rejected in December in what the company called a "surprise and disappointment" in the face of a pivotal trial that had met its primary endpoint.For a breakdown on other high-profile rejections from the agency last year — including those handed down to Ultragenyx Pharmaceuticals, Capricor Therapeutics, Atara Biotherapeutics and Replimune — see Vital Signs: The FDA's 2025 report card.

Analysts note that the FDA’s refusal to review mRNA-1010 could impact Moderna’s capacity to break even in 2028. Image credit: MargJohnsonVA via ShutterStock.com. The US Food and Drug Administration (FDA) has refused to review Moderna’s seasonal influenza jab, mRNA-1010, as the shifting vaccine landscape within the country continues to prove volatile for pharma companies. The FDA sent a refusal-to-file (RTF) notice to Moderna, which was signed by the Center for Biologics Evaluation and Research (CBER) director, Vinay Prasad. In the letter, the CBER cites the lack of an “adequate and well-controlled” study within Moderna’s biologics license application (BLA) for mRNA-1010 – leading the agency to deem the vaccine unsuitable for review. Moderna’s investigational vaccine uses the same underlying mRNA technology as its marketed Covid-19 jab Spikevax, which the FDA approved in 2022. The modality works by instructing cells to produce specific proteins that can recognise and fight pathogens. This decision primarily revolves around the FDA’s belief that the control arm used in the study “does not reflect the best-available standard of care” (SoC) within the US at the time of the Phase III trial (NCT05415462). As per ClinicalTrials.gov, Moderna opted to use GSK’s marketed quadrivalent jab, Fluarix Tetra as the comparator in its registrational study. Fluarix Tetra, also known as Fluarix Quadrivalent, is an FDA-approved influenza vaccine. The FDA shun sent Moderna’s stock sliding 10.5% from $41.99 at market close on 10 February to $37.60 at opening on 11 February. Moderna has a market cap of $14.7bn. Moderna rebuts FDA stance on mRNA-1010 In a 10 February statement addressing the RTF, Moderna refuted the FDA’s claims, noting: “Neither the relevant regulation, 21 C.F.R. § 314.126, covering adequate and well-controlled studies, nor the FDA’s guidance for industry on seasonal influenza vaccines contain any reference to the use of a comparator reflecting the best-available SoC”. GlobalData Strategic Intelligence US Tariffs are shifting - will you react or anticipate? Don’t let policy changes catch you off guard. Stay proactive with real-time data and expert analysis. By GlobalData Learn more about Strategic Intelligence Moderna also stated that the letter is “inconsistent” with what the agency told the drugmaker in April 2024 and August 2025. The company claimed that the department did not issue any feedback on the Phase III trial’s adequacy at protocol submission or study initiation. Moderna’s CEO Stéphane Bancel said: “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.” The Massachusetts-based pharma has requested a Type A meeting with the FDA to review next steps for mRNA-1010. Currently, there are no publicly available references to a specific SoC vaccine option for influenza prevention available either on the FDA or the Centers for Disease Control’s (CDC) websites. The FDA currently authorises the use of 26 influenza vaccines across different age ranges and viral strains. Moderna feels effect of mRNA sidelining In a research note reacting to Moderna’s application rejection, Citi analysts stated that the agency’s shift in approach is “not unexpected” within the evolving regulatory environment. While Moderna has requested a Type A meeting with the FDA, the analysts note that maintaining a vaccine-focused business leaves the company “highly exposed to volatility.” mRNA-based vaccines have firmly been under the regulatory spotlight in the US under the Trump administration, leading to the deprioritisation of their development by US Health Secretary, Robert F Kennedy Junior (RFK Jr). This is largely due to concerns around their efficacy and safety. The vaccines have been the subject of notable federal funding cuts – triggering a further knock-on impact on venture financing . Outside of the infectious disease area, cancer vaccine developers are also feeling the strain as the Trump administration looks to distance public health reliance away from mRNA technologies. Within the FDA, CBER lead Vinay Prasad has also been a vocal critic of mRNA vaccines. Previously, he called the wider decision to deprioritise mRNA vaccine technology research “wise”, citing long-term safety and better alternatives. William Blair analyst Myles Minter separately stated that the RTF marks a “substantial hit to the probability of success for mRNA-1010, and in turn mRNA-1083’s (combo flu/COVID vaccine) US approvability”. In a LinkedIn post , Julien Willard, head of research & investments at royalty investment firm BioPalace, highlighted the increasing importance of addressing political risks in investment memos. “The FDA letter to Moderna illustrates why every investment memo must explicitly address political risks, not only policy-related ones; especially when the underlying asset operates in politically sensitive domains such as sexual health and vaccines,” Willard stated.