The Food and Drug Administration’s decision to give full approval to the Pfizer Covid vaccine was only a few hours old last week when groups on Facebook lit up with questions. The move changed the vaccine’s availability in the marketplace, triggered business and military vaccine mandates, and may have altered its acceptability to vaccine-hesitant people.
But that was only for people 16 years old and up. For teens 12 to 15, the FDA left the Pfizer formula under emergency authorization. For children younger than 12, it kept the vaccine entirely off-limits until the conclusion of kids’ clinical trials, which are now due sometime in late fall. That immediately ignited debate among parents about whether they could find a way to get younger kids the shot, as well as whether they should.
“My child is almost the size of a 12-year-old,” began one thread in a private group. “I’m calling my pediatrician tomorrow,” began another. A third person floated a rumor: Someone took their child to a pharmacy and accidentally wrote the wrong birthdate on the vaccine paperwork.
Parents weren’t the only ones talking. Online circles of physicians and scientists fired up just as fast, arguing the ethics of administering the vaccine outside the bounds of the approval—through a process called “off-label” prescribing—versus waiting for data and for the FDA to rule. Off-label use, or prescribing a drug for a purpose or in a population not studied during its approval process, is legal to do, and it is especially common in pediatric medicine, since many older drugs still on the market were never studied in children.
But this case is trickier than normal, as online disagreements made clear. “We need more knowledge here, but kids are dying in this once-in-century catastrophe. I support off-label use in children under 12,” a pediatric infectious disease specialist in Minnesota posted on Twitter, while one in Indiana countered: “I’m eager for kids (under) 12 to get a Covid-19 vaccine, but feel we must have the Phase III data and an FDA EUA or approval first.”
A week later the chatter hasn’t died down, and there isn’t much more clarity. The Advisory Committee on Immunization Practices, the outside committee that advises the Centers for Disease Control and Prevention on new drugs, met Monday but did not discuss child vaccination. Meanwhile, CDC data released last week made clear that, as more adults get vaccinated, children account for a larger proportion of those falling ill. And some are becoming seriously ill: Almost one-third of 12- to 17-year-olds who have developed Covid since March 2020 have required intensive care, the agency reported, and 5 percent of those needed to be put on ventilators.
With schools opening, mask-wearing unenforced (and in many places forbidden), and the Delta variant cresting everywhere, the question of being able to vaccinate kids feels like a synecdoche for the whole Covid response: a landscape of unclear risk in which policy is insufficient to clarify how much danger people—or their kids—are in.
The vaccine approval for adults but not for children leaves pediatricians and pharmacists in an uncomfortable position. Their professional obligation to be gatekeepers—to decline to order a drug or honor a prescription if they do not think it is justified—feels at odds with their professional goals of keeping patients healthy and safe. Saying no to worried parents is “not only hard, it’s heartbreaking,” says Hina J. Talib, a pediatrician and adolescent medicine specialist at the Children’s Hospital at Montefiore in the Bronx. “Because we are the ones, as pediatricians, who consistently have been trying our best to put kids first in this pandemic. And it’s certainly tempting to us as parents as well. We want to protect children, so we want to protect our children too.”
An Instagram page Talib started during the pandemic, TeenHealthDoc, has almost 45,000 followers. Immediately after the FDA approval, she asked her followers how many parents would want to seek an off-label vaccine dose for children too young to qualify. Sixty percent of those responding told her they would. Talib has been urging them, as sympathetically as she can, to hold on. “We know this feels like a letdown for parents who have been so anxiously waiting,” she says. “It’s important to say that the data is coming. It is around the corner.”
Here’s where the data actually is: Last December, the FDA granted emergency use authorizations for both mRNA vaccines, the Pfizer formula and the one made by Moderna. In May, the agency extended the emergency use authorization for the Pfizer vaccine down to 12-year-olds, and in June, Moderna submitted data asking the agency to authorize its formula from 17 years down to 12. Last week, the FDA gave the Pfizer vaccine full approval for the initial age range covered by the EUA: 16 and up. Two days later, Moderna filed the paperwork to request the same.
While all that was happening, both companies were rolling out clinical trials to test the efficacy and safety of their vaccines in younger kids, with the goal of eventually vaccinating children as young as 6 months. Pfizer began its studies in March; Moderna’s launched in August. But in July, the FDA asked both companies to enroll more children, to quantify the occurrence of a rare heart inflammation that has shown up in younger recipients.
That request likely pushed emergency authorization back to late 2021 for Pfizer’s formula, and possibly 2022 for the Moderna version, with full approval to follow later. (The trial timeline of the J&J shot, the third US vaccine—which did not receive emergency authorization until the end of February—is far behind these two.) On Sunday’s Face the Nation, former FDA commissioner Scott Gottlieb estimated that vaccine authorization (not full approval) for 5- to 11-year-olds might not occur until early December, with authorization for the younger cohorts coming early next year.
So, on paper, none of these vaccines are available to children younger than 12. And yet: The FDA regulates drugs, but it does not assert control over the practice of medicine. Once a drug is approved, physicians are allowed to decide whether to deploy it for disease states or age ranges that were not specified in any FDA paperwork. And nothing prevents parents from asking for it.
But immediately after the FDA decision last week, federal and medical authorities asked doctors not to exercise their discretion for the Covid vaccine. FDA commissioner Janet Woodcock cautioned against off-label use in the same media briefing in which she announced the approval: It “would not be appropriate,” she said. The same day, the American Association of Pediatrics said in a statement that it “strongly discourages” off-label use and wants physicians to wait for the FDA.
This isn’t merely a question of legality. Though interim phase-by-phase data has not been published, researchers say the ongoing child clinical trials have shown some adverse effects in young recipients. They are eager to pin down the frequency and risk before the shots are widely distributed.
“We know from the clinical trials of the vaccine for children that it can produce a fair amount of immediate side effects—fevers and flu-like symptoms—which are easily resolved, but are more likely to occur and may actually be a little more severe in kids,” says Yvonne Maldonado, a pediatrician and professor at Stanford University School of Medicine and principal investigator of its trial site for the Pfizer vaccine. “So we don’t want children to get vaccinated off-label with a vaccine that hasn’t been completely studied in them yet.”
A difficult reality, though, is that many medications are already used off-label in children; before 2003, when legislation changed the licensing rules, there was no requirement that drugs be tested in kids before being prescribed to them. A 2019 study found that physicians used medications off-label for kids during almost one in five outpatient visits, most commonly antibiotics, though other classes were prescribed off-label as well. Such frequent use poses challenges for physicians and pharmacists under pressure to prove that Covid is different.
“In other cases of off-label prescribing of medications approved for adults, pediatric use happens very gradually, generally one case report at a time, until there is a sufficient knowledge base to either halt or expand usage in kids,” Shannon Manzi, an assistant professor of pediatrics and director of safety and quality in Harvard Medical School’s Department of Pharmacy, told WIRED by email. “If many thousands of children receive the vaccine all at once, without time for sufficient review of the data from the vaccine manufacturer trials in kids, we have lost that ability to ensure efficacy and detect any issues before it reaches the general population.”
Yet, Manzi wrote, pharmacists are already feeling pressure to dispense the vaccine. Ashley Duty, the pharmacy manager at Children’s Mercy Hospital in Kansas City, Missouri, said the same. “When we heard that the FDA was going to approve the Pfizer vaccine, our team started a conversation and made sure we were going to be united on this,” she said. “The sentiment I’ve heard from everyone I have talked to is that we do feel the pressure—but we don’t feel comfortable expanding upon what was approved and going any lower than age 12. Because we’re still in the middle of the pediatric studies to determine the best dose.”
The Pfizer trial design splits children under 12 into three age ranges—6 to 23 months, 2 years to just under 5, and then 5 through 11 years old—and assigns a different dose to each group based on their average age, size, and the likely maturity of their immune systems. Those doses have been made public, and in some of the social chatter last week, clinicians posted them again, as a hedge against anyone trying to use the vaccine off-label making a mistake. “The first thing is to make sure they use the right dose, because if you use the adult dose people will have too many side effects,” says David Boulware, an adult infectious disease physician and professor at University of Minnesota Medical School. “Hopefully, if people use the vaccine off-label, they are going to use the same dose being studied in the Phase III pediatric trials.”
Obtaining the vaccine off-label might not be as easy as it sounds. For one thing, the child doses are tiny, as low as 3 micrograms. That dosage isn’t individually prepackaged; it has to be drawn up from a vial. Working ad hoc from the vaccine vials now in use, it would be easy to be imprecise and draw up a too-large dose, says Michael Ganio, who is senior director of pharmacy practice and quality at the American Society of Health-System Pharmacists. Once the vaccine is fully approved, that’s expected to change, with a different formula or diluted version available for kids. But it’s an obstacle now.
Another obstacle: the unique way in which the Covid vaccines are distributed. They are still under the control of the federal government, which pays for them, so obtaining them on behalf of a hospital pharmacy or medical office is not as simple as asking a medical-products distributor for a delivery. Entities that dispense the vaccines signed commitments with the CDC in advance about how they will distribute them. Breaking those could have professional repercussions. In fact, during Monday’s ACIP meeting, there was an unscheduled addition to the agenda: a brief talk by a CDC staff member who, without specifying which recipients he was discussing, warned that using the vaccine off-label could keep providers from being reimbursed, make them legally liable for vaccine-injury claims, and endanger their permission from the CDC to keep delivering the vaccine.
It also isn’t clear how much demand there will be. Last week’s outpouring on social media suggested lots—but CDC data published last week shows that only 32 percent of the 12- to 17-year-olds now eligible for the shots have received both doses; 42.4 percent have received one dose. Granted, teens have only been eligible since May. Still, that doesn’t suggest parents everywhere are breaking down doctors’ doors.
But even the possibility of some off-label use worries vaccine researchers—not just because it risks side effects, but because negative publicity about those side effects could harm people’s willingness to get their kids vaccinated once federal approval arrives.
“If there were some specific safety concerns that were to emerge, in the long term those could be very difficult to address, and may do a lot of harm in terms of vaccine uptake and confidence,” says Florence Bourgeois, an associate professor of pediatrics at Harvard Medical School who studies pediatric drug development. “Having the controlled trials and FDA review and official approval will allow for a more controlled rollout and evidence generation that can keep pace with the interest the public has in maintaining confidence in the vaccine.”
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