FDA wants 2 months of safety data for Covid-19 vaccines in trials before considering authorization

“Data from Phase 3 studies should include a median follow-up duration of at least two months after completion of the full vaccination regimen to help provide adequate information to assess a vaccine’s benefit-risk profile, including: adverse events; cases of severe COVID-19 disease among study subjects; and cases of COVID-19 occurring during the timeframe when adaptive (rather than innate) and memory immune responses to the vaccine would be responsible for a protective effect,” the FDA said in the guidance.

The two months number should come as no surprise. The FDA has been telling companies for some time, says Dr. Peter Marks, director of the Center for Biologics Evaluation and Research, the FDA division that approves vaccines.

The two vaccines that are furthest along in clinical trials — those being made by Moderna and Pfizer — each require two doses. Moderna’s is being given to volunteers in two doses 28 days apart; Pfizer’s is being delivered in two doses 21 days apart.

The researchers testing the vaccines are then waiting to see how may people eventually become infected with the virus, and whether fewer people who get the real vaccine become infected versus those injected with placebo.

The FDA also wants to wait to ensure that people do not report side effects after that second shot.

“Safety is what keeps me up at night,” Marks said in the JAMA interview. “Because the way we’re going to get over Covid-19 is if we get a vaccine that has 70% or 80% efficacy and we can deploy that to 70 or 80% of the population, we actually have a chance of having herd immunity, and we can be back in restaurants and in banks … and doing what we normally do,” he added.

“It’s only going to happen if people have confidence enough to go get vaccinated and we do have a crisis in vaccine confidence.”

FDA officials have been clear in saying they want to have conversations with vaccine makers, rather than laying down strict rules that must be followed, for providing emergency use authorization for any vaccine.

“In general, FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidance means that something is suggested or recommended, but not required,” the meeting document reads.

The FDA will also hold public meetings of its Vaccines and Related Biological Products Advisory Committee. “That group, the VRBPAC, will then make a recommendation,” NIH’s Collins said during a a vaccine symposium sponsored by Johns Hopkins University and the University of Washington Tuesday.

“FDA will decide whether to accept it — and only then would we be in a circumstance where an emergency use authorization would be approved,” Collins said. “So walking through all those steps, even though I know there’s a great deal of anxiety about mischief here, it would be pretty darn hard for mischief to derail this process.”

Most bad reactions to vaccines come between two and three months after people get them, Marks told the symposium. “For instance, Guillain-Barre, perhaps it’s six weeks, but for transverse myelitis, it’s more like three months,” Marks said.

“We picked two months as something that was reasonably aggressive, yet also somewhat, kind of in the middle,” said Marks “Not too aggressive, not too conservative — in the middle.”

White House resistance?

A senior White House official told CNN the Office of Management and budget had signed off on the guidance. The FDA usually does not seek White House permission to publish guidance, but the Trump administration took a special interest in this case.

Scientists cheered the new FDA guidance as a sign that the regulator was fighting to maintain its independence even under pressure from the White House.

“They’re standing up here. This is really great to see,” Dr. Eric Topol, executive vice president of Scripps Research, said. “It’s really important for the public trust.”

Topol said he thought the White House was forced to back down. “I think they were pinned in a corner and they didn’t have a choice,” Topol said. “Publicly, it would have been horrendous if they had overruled this guidance.”

Dr. Paul Offit of Children’s Hospital of Philadelphia, who will sits on the FDA’s independent vaccine advisory board, noted that those kinds of documents usually come within days of a scheduled meeting — not weeks ahead.

“I think they did that as an end run around the White House. Good for them,” he said.

“Doing things like this makes me feel like the FDA is actually standing up for itself,” Offit added.

Marks has said staff are trying to filter out political arguments as they focus on data from clinical trials involving tens of thousands of volunteers.

The FDA’s requirements for an EUA are less strict than for a full Biologics License Application. The process for an EUA will take weeks, while the process for a BLA takes months, he said.

“That still means that the safety profile of a vaccine that’s going to be deployed in millions of people has to be incredibly clean,” he said. An EUA for a vaccine will be stricter than an EUA would be for a drug designed to rescue sick and dying people, because a vaccine is given to healthy people, so the risk benefit ratio is different.

“We need to have a strong efficacy signal,” he said. If people get vaccinated, they may stop taking other precautions against becoming infected.

“If we tell them it’s got 70% efficacy, they may change their behavior, And if they are going to take their guard down a notch, we better make sure it does what it says it’s supposed to do,” Marks said.

FDA officials have repeatedly said they will not skimp on safety considerations for a coronavirus vaccine even as Trump tries to promise one by Election Day.

There are currently 10 Covid-19 vaccine candidates in late-stage, large clinical trials around the world, according to the World Health Organization. Five candidates in the United States are in advanced Phase 3 trials and two of those have been in Phase 3 trials since late July.