A play-by-play of the FDA's meeting on Pfizer's vaccine for kids

Tuesday, October 26, 2021

Source: Biopharma Dive

Just over 220 million people have received at least one coronavirus vaccine dose in the U.S., about two-thirds of the country's population. But for children younger than 12, none of the three available vaccines are authorized for use, a gap that's hindered progress in knocking down COVID-19 cases, frustrated parents and upended fall returns to school.

On Tuesday, outside advisers to the Food and Drug Administration met to review Pfizer's application to authorize its vaccine for kids aged 5 to 11 years old. A daylong meeting led to a 17-0 vote, with one abstention, that the vaccine's benefits outweigh its risks in the age group.

An FDA authorization could soon follow, which would make tens of millions of children newly eligible for vaccination.

BioPharma Dive tracked the meeting and reported on the discussion here. The most recent entries are listed first.

UPDATED 4:16 pm
The vote is in

Pfizer’s coronavirus vaccine should soon be available for kids as young as 5.

Though several committee members struggled with their decision — with some pushing for authorization in a more limited group of kids — the group ultimately felt the benefits of vaccination outweighed the risks. Some wanted to make sure parents have the option to get their children vaccinated. Others felt the benefits of preventing the proven, worst effects of COVID-19 offset concerns of myocarditis.

The final vote was 17 to 0, with Kurilla abstaining. — Ben Fidler

4:02 pm
A longer interval between doses?

Pfizer's Gruber gave an interesting response to a question from panelist Michael Kurilla on the possibility of spacing out dosing intervals. The current three-week interval that's been the norm for Pfizer's vaccine series seems to be "suboptimal, at least in terms of durability of the antibody response," Kurilla remarked, alluding to the waning antibody levels shown in clinical trials and used to bolster vaccine developers' cases for booster doses.

Gruber said at the onset of the pandemic, the priority was to provide protection in a short interval of time, which is why the three-week dosing interval was ideal. However, he said that could change in the future, particularly looking at the youngest populations.

"It may be advisable and probably will as we get particularly in that first year of life to look at longer intervals as part of a routine immunization series," Gruber said.

Data on what that longer interval of time would be is not available yet, Gruber clarified. — Shoshana Dubnow

3:55 pm
A 'tougher' question than anticipated

For several panelists, authorizing Pfizer's vaccine in kids is not as clear-cut as FDA reviewers made it appear to be in briefing documents. Multiple experts doubted the benefits of vaccinating given the high rates of asymptomatic infections observed in young kids and the correspondingly low hospitalization rates. Some also questioned the shot's effects on transmission in the face of newer variants, like delta, that are tougher to thwart.

Moreover, the FDA's risk-benefit models were largely based on the state of the pandemic in early September, the peak of the most recent wave. Panelists also struggled with the unclear risk of myocarditis.

"This is a much tougher one than we had expected coming into it," said Rubin. "The data show that the vaccine works and is safe. And yet we're worried about a side effect that we can't measure yet. We see a benefit that isn't the same as it is in older age groups."

Rubin, along with James Hildreth, CEO of Meharry Medical College, suggested they'd be more comfortable authorizing the shot for a smaller group of more vulnerable children. Marks, the FDA's top vaccine reviewer, indicated that might be a possibility if the initial vote fails. But a majority of committee members currently appear to support clearance.

"We know enough," said Paul Offit, pediatrics professor at the Children's Hospital of Philadelphia. "We certainly know that there are many children 5 to 11 who are susceptible to this disease. And on myocarditis, it's reassuring that [the dose for children] is a lower dose and that the myocarditis rate in teens is lower than in 20 year olds." — Jonathan Gardner

3:15 pm
The safest estimate

Multiple committee members questioned the FDA's statistical models, wondering how likely they are to predict what will happen should the shot be authorized.

Meissner, for example, noted the hospitalization rate for children has declined significantly as cases have fallen. Kurilla wondered whether the FDA accounted for the waning potency seen in adults. Eric Rubin asked whether there is a specific group of children who are most vulnerable. And Hildreth questioned whether the most appropriate scenario to use is the one in which infections are low, given the current trajectory of the pandemic.

"If the trends continue the way they're going, the emergency for children is not what we might think," he said.

Agency reviewers, however, said their estimates were conservative. They overestimated the likelihood of myocarditis, for instance, and assumed a vaccine efficacy rate of 70% against symptomatic COVID-19 and 80% versus hospitalization — below what Pfizer reported in clinical trials. Havers, of the CDC, said that roughly a third of hospitalized kids were previously healthy, making it difficult to identify a subgroup most likely to benefit.

And committee chair Arnold Monto warned committee members of being too optimistic about the decline in cases. "We've assumed that we were on the descending slope of the curve previously and got caught flat footed," he said. — Ben Fidler

2:00 pm
A quick break and open public hearing

Panelists ran out of time to scrutinize the FDA's presentation before a scheduled lunch break and open hearing for the public to comment. The discussion will pick back up at 2:10 pm. — Ben Fidler

12:51 pm
The worst-case scenario

Pictured below is the one scenario in which, according to FDA scientists, kids would be more likely to be hospitalized from vaccine-triggered myocarditis than COVID-19. In this statistical model, infection and COVID-19 hospitalization rates are about 5% and 10%, respectively, of what they were in mid-September.

FDA vaccine reviewers still believe the benefits of vaccination would be worth the risk in this case, however, because of an impact on milder infections and disease transmission. — Ben Fidler

A screenshot of a chart shared by Food and Drug Administration scientists at an Oct. 26 meeting of the Vaccine and Blood Related Products advisory committee.
Ben Fidler / BioPharma Dive; slide from FDA
12:22 pm
Challenging Pfizer

In laying out Pfizer's case, Bill Gruber, a company executive in vaccine R&D, drew on the company's efficacy results as well as statistical models from FDA scientists that appear to favor its shot. But committee members challenged a few of those assertions in a possible prelude to the voting discussion later this afternoon.

Kurilla, for instance, asked for evidence showing Pfizer's shot reduces the spread of asymptomatic infections in kids, a proxy for whether the vaccine can reduce transmission. And James Hildreth, a professor of internal medicine at Meharry Medical College, pointed to the one FDA model in which there were more hospitalizations from myocarditis than COVID-19 — a scenario with very low case rates. In that scenario, the benefits of vaccination "clearly don't" outweigh the risks, Hildreth said.

Pfizer didn't track asymptomatic infections in its trial, so it's unclear how many of those cases were missed, or the extent to which transmission would be slowed if kids are vaccinated. But Gruber said a "great deal of real-world evidence" shows vaccination can reduce transmission among adults, so it's fair to expect similar results in children given the immune response the shot appears to generate.

As for Hildreth's question, Gruber countered that other societal benefits — like protecting vulnerable groups and keeping schools open — would make up for the risk of hospitalizations from myocarditis. That being said, "there's every reason to believe that the rate [of infections] will not be at the nadir" upon authorization, he added. — Ben Fidler

12:11 pm
Weighing myocarditis, the 'principal concern' of the day

Looming over the panelists today is the risk of myocarditis, an inflammation of the heart that — in rare but still significant cases — has been linked to Pfizer's and Moderna's coronavirus vaccines, particularly in younger men and teenagers.

Matthew Oster, a cardiologist and CDC go-to for all things myocarditis and pericarditis, presented data on the infection and what's known about the condition in younger age groups.

Oster said after receiving a vaccine, the observed impacts of myocarditis are less severe than in other age groups, though the data to back that up is still preliminary. He later explained "testosterone and hormones" might play a role in the lower rates for kids between 5 and 11.

"Not all myocarditis is the same," he said. "There may be some similarities in presentation with some or in acute outcomes with others. It's hard to do straight comparisons."

Cody Meissner, a pediatric professor at Tufts University School of Medicine, characterized the discussion as "the principal concern that people have regarding use of these mRNA vaccines in children."

Making matters more complex is the fact that myocarditis is also a complication of COVID-19 in some cases.

Asked about later-onset side effects from coronavirus infection, Oster said for adults, there can be minor lasting effects, but most "everything else is normal." Younger children, by comparison, could do well but have slight indications of scarring in an MRI.

"Their exercise test can be normal ... everything else can be normal, and all we have is this little signal that you see in the MRI that compared to prior MRIs isn't as impressive," he said.

Oster also took the opportunity to respond to questions about multisystem inflammatory syndrome, or MIS-C, in children; a condition associated with the coronavirus where body parts such as the heart, lungs, kidneys, brain, skin or eyes can become inflamed. He said there is "not a big signal" of MIS-C associated with vaccination yet, at least in the 12 and older age group. — Shoshana Dubnow

10:55 am
More details on the coronavirus' impact on children

A Centers for Disease Control and Prevention presentation drilled more deeply into the number of positive COVID-19 cases and hospitalizations in children, as well as the ripple effect those infections can have on society.

Fiona Havers, a medical officer with the CDC's COVID-19, noted that for every reported COVID-19 case between May and June, there were 6.2 infections in people aged 17 and younger, compared with 2.4 in the general population. The highest share of positive cases was observed in 5- to 11-year-olds, for which 42% of all tests turned up positive, she said.

The virus' spread in younger people led to hospitalization rates that climbed through the summer and reached their highest point of the pandemic in September. Those instances were more common among Black, Hispanic, and Native American and Alaska Native children than in White children, Havers said.

All told, hospitalization rates from COVID-19 now match those of the pre-pandemic flu seasons 2017-18 and 2018-19. Hospital stays are longer for COVID-19 patients, and rates of intensive care unit admissions, breathing support and death match or exceed that of flu. With 66 deaths recorded in the 12 months ended Oct. 2, COVID-19 would be the eighth-leading cause of death in that age group if compared to the pre-pandemic world of 2019, Havers said.

Infections can affect children who don't get sick, too: In the first two months of the 2021-22 school year, 2,000 schools closed due to outbreaks, affecting more than 1 million students. — Jonathan Gardner

10:15 am
A winter warning

Doran Fink, the deputy clinical director of the FDA's vaccine review team, acknowledged the uncertainty committee members have previously displayed when discussing the prospect of vaccinating children.

Recalling a June discussion, Fink noted that several panelists pushed for larger clinical tests to properly assess the pros and cons of vaccination. But even bigger studies would leave unanswered questions, Fink said.

"No matter what size of the safety database, there will always be uncertainties regarding benefits and risks," including the potential risk of heart inflammation, he said.

But Fink reminded the committee of what could happen if authorization is delayed. Younger children now account for 40% of pediatric COVID-19 cases, an uptick largely due to the highly transmissible delta variant.

And though cases are declining, they could spike again in the winter, with much of the population still unvaccinated and people forced to go inside more often. — Shoshana Dubnow

9:55 am
A stark reminder of the coronavirus' cost

Peter Marks, the director of the FDA's vaccine review office, gave an overview of the coronavirus' impact on children. Despite being less vulnerable to COVID-19 than adults, kids are "far from spared" from potential harm, he said.

There have been over 1.9 million infections and more than 8,300 hospitalizations in kids between 5 to 11 years old since the virus began spreading, according to Marks. Close to 100 children in that age range have died from COVID-19, making the disease one of the top 10 causes of death for 5- to 11-year-olds during the pandemic.

Marks also noted the public divisiveness around potential mandates in schools should Pfizer's vaccine win authorization. The meeting is purely on scientific data, not a referendum on vaccine mandates, he emphasized.

"I ask that we keep our discourse today civil and focus on the science related to this issue, so that we can get through a productive discussion," Marks said. — Shoshana Dubnow

8:30 am
The meeting begins

Arnold Monto, an epidemiologist who has chaired the FDA's advisory committee through reviews of each coronavirus vaccine, opened the meeting. He will preside over the day of presentations ahead, attempting to keep members on schedule while hearing from health officials and company representatives.

After introductions, CDC scientists will give an overview on the epidemiology of coronavirus vaccines in kids, followed by a presentation specifically on safety risks, such as myocarditis, that panelists are likely to focus on.

William Gruber, head of vaccine clinical research and development at Pfizer, will present on behalf of the drugmaker. The FDA's presentation will follow his before the meeting breaks for lunch.

The most important part of the meeting starts at 2:55 pm, when the committee will directly debate whether to recommend Pfizer's shot for use in young children. Sometime before 5:00 pm, a vote will be held on the following question: "Based on the totality of scientific evidence available, do the benefits of the Pfizer-BioNTech COVID-19 Vaccine when administered as a 2-dose series ... outweigh its risks for use in children 5-11 years of age?" — Shoshana Dubnow

What do we know about Pfizer's vaccine in kids?

Pfizer is seeking authorization of a two-shot regimen using doses two-thirds smaller than what's been given to teenagers and adults.

In clinical testing, Pfizer has shown the smaller dose may be as potent in kids as the larger one is in older individuals. The immune responses generated in the vaccinated children enrolled in Pfizer's trial were comparable to those in 16- to 25-year-olds, according to the company's data.

Documents published last week indicated those results translated to protection from COVID-19 as well, with only three vaccinated participants testing positive during the trial compared to 16 who were given placebo. That equated to efficacy of about 91% versus symptomatic disease, although the small number of cases involved mean the true number may be anywhere from 67% to 98%.

The shot appears safe in children too. The most common side effects reported in testing were mild pain, swelling and redness. Swelling of the lymph nodes was also more frequent in vaccine recipients. No instances of myocarditis — a top concern of the FDA and its panelists — were observed in testing, though the study was too small to properly detect it.

But there are important questions we don't yet know the answer to. Follow-up from the trial is limited, for instance, so it's not clear whether the vaccine's effectiveness in kids is as durable as in adults. There were also no cases of COVID-19 among children who had previously been infected, making conclusions in that group more difficult to draw. And while it's plausible that younger kids may have a lower risk of myocarditis, as Pfizer argues, it's not proven.

Pfizer plans to run further studies that could help answer those questions, however. — Ben Fidler

Which advisers to pay attention to

Throughout the different FDA meetings on vaccine authorizations and booster shots, a number of committee members have made their positions well known. Some have favored more aggressive rollouts, arguing that doing so could more quickly break chains of transmission. Others have been more cautious, noting the goals of vaccination are to turn COVID-19 into a mild, manageable disease.

The more cautious committee members have been hesitant to vaccinate or boost younger people without clear-cut evidence. Michael Kurilla, for instance, voted against the initial authorization of Pfizer's vaccine last year because of thin supporting evidence in 16- and 17-year-olds. Paul Offit and Cody Meissner opposed the use of boosters in the general population. At the hearing on Moderna's application to authorize additional shots, Meissner was adamant the risk-benefit ratio for young children needed to be clear before shots were authorized for that group, citing the myocarditis rates observed in real-world use.

All three have been outspoken at each hearing and could have significant sway over the outcome. — Ben Fidler

Which way is the FDA leaning?

The documents the FDA posts before an advisory meeting can offer important clues as to how staff scientists view the data the committee has been tasked to debate. Those documents can appear negative even when they aren't, because they are meant to provide panelists with an unbiased, critical view of clinical results.

The clear support from agency staff for Pfizer's vaccine in children, then, was notable. The bulk of the briefing document discussed statistical models used to evaluate whether the benefits of vaccination were worth the risks in 5- to 11-year-olds. Of chief concern is a type of heart inflammation called myocarditis that's been associated in rare cases with Pfizer's vaccine, particularly in adolescents and younger men.

FDA scientists laid out a variety of scenarios using different assumptions of COVID-19 case rates and levels of vaccine effectiveness. In nearly all of them, vaccination "clearly outweigh[ed]" the risk of myocarditis, staff scientists said. That includes when infection rates are low, which could be convincing for panelists weighing declining case counts across the U.S.

Advisory committees don't always agree with the FDA's take, and vice versa. But absent a surprisingly negative vote — or a call by committee members to narrow an authorization to specific groups — it is difficult to envision the agency rejecting Pfizer's request outright. — Ben Fidler

What would a positive recommendation mean?

A majority vote supporting use of Pfizer's vaccine in younger kids does not guarantee the FDA will follow.

But, if previous meetings involving coronavirus vaccines are any indication, it's likely a positive vote will lead to the agency authorizing Pfizer's shot for the youngest group of Americans to date.

An OK would open the door for vaccinations to begin in the nearly 28 million kids ages 5 to 11 estimated to be in the U.S. An advisory committee for the Centers for Disease Control and Prevention is scheduled to meet on Nov. 2 and 3 to issue its own recommendation for the age group, potentially refining who would be eligible further.

Making matters urgent for regulators, the delta variant and its resulting effect on cases, hospitalizations and deaths, remains a significant concern for public health officials. Many outside experts hope an authorization in kids could help curb outbreaks in schools — something that would be welcome relief for parents and educators around the country.

The Biden administration has already released its plan for vaccinating young kids, indicating distribution and administration of the vaccine will be channeled through pediatricians' offices, children's hospitals, schools and community clinics. Along with a smaller dose, vaccines designated for kids would come in tailored packaging with smaller needles. —

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