A senior US Food and Drug Administration (FDA) official says Moderna’s clinical trial on a new, potentially more effective flu vaccine was a “brazen failure” and that the FDA is now calling it into question.
The FDA unexpectedly refused to consider Moderna’s application for a flu shot based on messenger RNA (mRNA) technology in a decision that experts say is already having a chilling effect on vaccine development.
Officials say the issue is the design of the study, in which control group participants over the age of 65 should have received a high-dose flu shot instead of a standard flu shot.
Outside experts say the reasons seem to go deeper.
“It’s all pretext and obfuscation when the real agenda is rejecting conventional science and serving a predetermined anti-vaccine agenda,” said Richard Hughes IV, a partner with Epstein Becker Green and law professor at George Washington University.
Dorit Reiss, professor of law at UC Law San Francisco, said “personally humiliating a company is not a legitimate reason to refuse to review a submission”, and the refusal needs to “address substantive reasons”. Angela Rasmussen, an American virologist at the Vaccine and Infectious Disease Organization at the University of Saskatchewan, says “they’re just coming up with reasons to not approve mRNA anything, and they’re going to eventually do it to all these vaccines”.
Andrew Nixon, a spokesperson for the US Department of Health and Human Services, said the concerns that mRNA and other vaccines are being targeted by officials were “baseless”.
The senior FDA official who asked not to be named in a press conference with journalists on Wednesday said that the “brazen failure of Moderna” to design the study differently “raises significant ethical concerns”.
Even the way the FDA is communicating about the issue raises alarm, Reiss said.
“Not identifying yourself tells me you are unwilling to stand behind the decision because you know it is weak, flawed and untenable – politically motivated, not substantially valid,” she said. “Being anonymous here is a coward’s act, and shows the government knows it has no case.”
The vaccine application was rejected because it did not have an “adequate and well controlled” trial, with the control group lacking “the best-available standard of care in the United States at the time of the study”, according to a letter signed by Vinay Prasad, director of the FDA’s Center for Biologics Evaluation and Research (CBER).
Moderna says the FDA frequently weighed in on their process, and never objected to the study until now.
“This was an FDA-approved trial design,” said Chris Ridley, spokesperson for Moderna.
When the Guardian asked whether the FDA approved the design, the official didn’t answer directly, confirming that the FDA gave a “a recommendation in writing” to include a high-dose vaccine for older participants, “but of course, they did say if they don’t follow the recommendation, it’s important for patients to have informed consent”.
At other points in the press briefing, however, the official characterized the FDA’s stance in stronger terms.
“We told you not to run it in over 65,” the official said of its directive to Moderna. “You didn’t do what we told you, so go back to the drawing board.”
In April 2024, Moderna said, CBER told the company in writing that “while we agree it would be acceptable to use a licensed standard dose influenza vaccine” in the control group, “we recommend you use a vaccine preferentially recommended for use in older adults”, such as a high-dose vaccine. Such a move “may help inform ACIP’s recommendation for the use of your vaccine in the older adult population”, the FDA said, according to Moderna.
The Advisory Committee on Immunization Practices (ACIP) and CDC recommend the higher-dose vaccines when possible, though standard vaccines are recommended if higher doses aren’t available.
Moderna included information about the decision to use the standard flu shot for all ages in the consent form that all trial participants signed, a plan with which FDA officials agreed, according to Moderna. It’s highly unlikely that the FDA told Moderna not to proceed on a trial like this and the company did so, Hughes said.
“It’s too risky for a manufacturer to simply run roughshod over agency guidance and continue down a path that very clearly is not in line with what was agreed to with the agency. What is more likely is that this FDA turned the tables at the 11th hour,” he said.
The FDA last year only approved Covid shots from Novavax and Pfizer for certain groups of people. And instead of adding a warning label for a new Chikungunya vaccine after serious side effects were observed, the FDA revoked the license entirely, Hughes pointed out.
In the Moderna decision, Prasad overrode agency scientists who recommended review of the application, including a memo from David Kaslow, director of the vaccine office, according to Stat News. The FDA official who refused to be named on Wednesday dismissed the reporting as “gossip in the hallways of the FDA” from “a disgruntled person getting disproportionate coverage by reaching out and telling their version of the story”.
Prasad’s tenure at the FDA has been tumultuous. He was fired from the FDA in July before being reinstated, and the Wall Street Journal on Wednesday reported that there are allegations of verbal and sexual harassment from Prasad at the agency.
Moderna could change its application to consider the vaccine for people from the ages of 50 and 64, the official said.
“It is entirely feasible that if they come back, maybe even show some humility and [say] that: ‘Yes, we didn’t follow your recommendation, these are the data we have, and let’s just take a look at the 50 to 65 [sic] group, where there’s a little more equipoise,’ then the review team could say: ‘We’ll consider that cohort,’” they said.
Moderna did add a group of participants over the age of 65 who received the high-dose vaccine in the trial. But the FDA said that evidence wasn’t robust enough to be considered for approval.
“They looked at immediate antibody response,” the official said. “People have been critical of using an antibody surrogate when you have the real-world outcome that is measurable.” Antibody responses are frequently used in vaccine trials, especially for flu vaccines.
Nixon, the HHS spokesperson, said: “Moderna exposed participants age 65 and over to increased risk of severe illness by giving them a substandard of care against the recommendation of FDA scientists.”
Rasmussen didn’t find these arguments compelling: “It just seems like they couldn’t really find anything that suggested that there would be a problem in the overall trial, so you focus on the older people.”
The HHS announced last year that all new vaccines must be compared to placebos instead of existing vaccines, which would violate current standards of care.
“Changing your position mid-stream is a problem for companies,” Reiss said. “This really will deter companies from doing vaccine trials. We need better and more influenza vaccines, not less.”
The Moderna decision is having “a huge chilling effect, because no other manufacturers are going to want to make those kinds of investments”, Rasmussen said. “If you don’t have access to the US market, you can’t viably do business.”
An mRNA flu vaccine would be extremely useful for people with egg allergies, and mRNA is also a more flexible way to respond to flu mutations and even pandemics, Rasmussen said: “It’s something that’s hugely important for public health.”
