FDA advisory panel endorses Pfizer/BioNTech Covid-19 vaccine
A panel of outside experts on Thursday recommended the Food and Drug Administration issue an emergency use authorization to the Covid-19 vaccine being developed by Pfizer and BioNTech, a vaccine that appeared to be highly efficacious in a Phase 3 clinical trial.
The 17-4 vote came after a long day in which members of the Vaccines and Related Biological Products Advisory Committee, or VRBPAC, discussed a wide range of issues related to the vaccine, including concerns about vaccinating people with severe allergies and 16- and 17-year-olds, as well as issues regarding vaccination during pregnancy or lactation.
Although the FDA does not have to follow the panel’s recommendation, it is widely expected to do so.
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The rollout of Covid-19 vaccine could then begin in the United States in a matter of days.
STAT’s coverage of the meeting is below, with updates and analysis posted in reverse chronological order.
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A positive vote, but a missed opportunity
6:30 p.m.: By any account, today’s vote — again, 17 yes, four no, with one abstention — was a resounding thumbs up for granting an emergency use authorization for the Covid-19 vaccine developed by Pfizer and BioNTech.
But to anyone who has followed many FDA advisory meetings, the conclusion of this one was surprising, and not in a good way. The final vote seems to have been influenced by one narrow issue: the inclusion of 16- and 17-year olds in the proposed emergency use authorization. Oddly, the FDA declined to reword the question — something the FDA has done in the past during in-person advisory committee meetings — when some panelists protested the inclusion of people younger than 18.
We don’t really know why the panelists voted as they did, though. Surprisingly, there was no opportunity for them to explain their vote afterward. Such comments are often every bit as important as the actual vote.
The purpose of these committees — and of waiting for them — is to delve into nuance. On that score, too many opportunities were missed.
— Matthew Herper
Coda: We need to talk about the kids
6:20 p.m.: A late afternoon dust up over teenagers may at least partially explain four negative votes and one abstention when VRBPAC members voted on the question of whether the FDA should issue an EUA to allow use of Pfizer’s vaccine in people ages 16 and older.
Several members of the committee expressed serious concerns about including 16- and 17-year-olds in the EUA, saying Pfizer has very little data on the vaccine’s safety in this group. The data package the company filed for its EUA application included only 153 participants 16 and 17 years old. (More recently the company has been vaccinating children as young as 12 years of age, but those data weren’t in the EUA filing.)
“I would support not including them,” Hayley Gans, a professor of pediatrics at Stanford University, said during a section of the overall discussion where multiple members of the committee raised concerns about including that group.
Multiple, but not all.
“We have clear evidence of a benefit. All we have on the other side is theoretical risk,” said Paul Offit, a pediatrician at Children’s Hospital of Philadelphia.
Acting chairman Arnold Monto, a vaccines researcher from the University of Michigan, called on FDA’s Marion Gruber, director of the Office of Vaccines Research and Review, for advice. She said she wanted to hear from the rest of the committee, so Monto called the vote.
Several of the committee members — Gans among them — who had advocated excluding 16- and 17-year-olds ended up voting to recommend approval of vaccine. One, Cody Meissner, a pediatrician at Tufts Children’s Hospital, abstained. There was no call for an explanation of why dissenters voted no — and STAT hasn’t had time yet to reach out to them — but at least one, Archana Chatterjee, vice president for medical affairs at Rosalind Franklin University, had indicated she would have voted to raise the age covered by an EUA to 18 years old.
— Helen Branswell
The vote
5:37 p.m.: After eight-plus hours of data presentations, discussion and debate, today’s Covid vaccine advisory panel finally got down to voting on the penultimate question:
Based on the totality of scientific evidence available, do the benefits of the Pfizer-BioNTech COVID-19 Vaccine outweigh its risks for use in individuals 16 years of age and older?
The results:
17 Yes, 4 No, 1 abstention.
And with that, the FDA will very likely grant an emergency use authorization to the Pfizer/BioNTech Covid vaccine within days, if not sooner.
One thing to watch: There was a lot of disagreement among the panel members about whether the data support the inclusion of people 16-17 years of age in the EUA. Will FDA make changes to the EUA to exclude this group?
— Adam Feuerstein
Pfizer pushes back against “crossover” design for placebo patients
5:05 p.m.: Earlier in the day, there was an enthusiastic presentation of a proposal that tried to allow volunteers who had received placebo to receive the vaccine while minimizing the problems this would present for collecting new data about the vaccine.
The idea, summarized by Helen this morning, is that all volunteers would get two more shots. Those who had received placebo would get the vaccine; those who got the vaccine would get placebo.
But William Gruber, a Pfizer senior vice president, pushed back on this idea. It was, he pointed out, potentially impractical. “44,000 individuals would have to be brought in for two additional visits,” he noted. That means they would need to sign new consent forms. And, if they already suspected they received the vaccine because they noticed aches or chills, they might decide not to come in for those additional visits. Gruber has said previously that he is worried that volunteers will leave the study if they are not offered the vaccine, and that he will not get data from them at all.
In an email earlier today, a Pfizer spokesperson confirmed the company is not currently planning to use the crossover design.
“The participants in our COVID-19 vaccine clinical trial are courageous volunteers who have made a personal and important choice to help make a difference during this pandemic,” Pfizer said in a statement. “We also believe that we have an ethical duty to create a pathway within the study for interested, eligible participants in the placebo group to have access to the vaccine as regulatory authorities make decisions about authorization or approval of the vaccine candidate around the world.”
Pfizer added: “In turn, we have developed a protocol amendment that is subject to input from and alignment with regulatory authorities but is designed so that all interested participants 16 years and older in the placebo group would have the option to receive the vaccine at scheduled timepoints in the study.”
— Matthew Herper
What do we do about vaccinating people with severe allergies?
4:29 pm: A big question has emerged around the Pfizer-BioNTech vaccine: Two people in the U.K who received the vaccine had severe allergic reactions requiring treatment, leading regulators there to advise that people with severe allergies should not get the vaccine for the time being.
Paul Offit, the noted vaccinologist from Children’s Hospital of Philadelphia and a panelist at today’s meeting, pointed out that this is a potentially big problem. It means that tens of millions of Americans, by his count, could be too afraid to get the vaccine because they have a medical history of severe allergy. Offit was clear that he did not think this should stand in the way of an EUA, but he said that Pfizer and BioNTech needed to do a study in people with a history of common allergies and asked the FDA what it planned to do.
“This issue is not going to die until we have better data,” Offit said.
Marion Gruber, director of the office of vaccines research and review at the FDA, said that the FDA had note of this possibility even before the two cases in the U.K. Weeks ago, she said, language was added to a draft EUA warning that people who had an allergy to any of the vaccine’s components should not get it, and that equipment for dealing with a severe allergic reaction should be available wherever the vaccine is administered.
Gruber also said that an independent analysis by the FDA had pointed to the possibility of some volunteers in the trial potentially having allergic reactions that researchers had not caught, although all of those would have been minor, by definition.
But Offit pointed out that with this vaccine, which he said had one of the longest chemical names he’d ever seen, patients would have trouble identifying potential allergens from the ingredients list. He also clarified that his main worry, perhaps caused by years of discussions with people who were vaccine hesitant, was as much about people’s fears as the vaccine’s characteristics.
“I’m talking about perception more than reality,” Offit said. “With those two statements out there, that people with severe allergic reactions shouldn’t get the vaccine, we just really need to offer people some solace.”
— Matthew Herper
Showtime!
3:50 p.m.: The meeting, which is currently running about 40 minutes behind schedule, is about to get down to brass tacks.
The session in which members will discuss what they’ve heard and vote on whether the FDA should issue an emergency use authorization for Pfizer’s Covid vaccine begins now.
If you want to check the meeting out yourself, it’s streaming here.
— Helen Branswell
During Pfizer presentation, anxiety and excitement commingle
2:55 p.m.: In a sense, Pfizer’s presentation to the VRBPAC was a victory lap, as Kathrin Jansen, the company’s head of vaccine research, took a moment to explain how an mRNA vaccine mimics the body’s normal immune response. A piece of mRNA is shepherded into a cell by a coating of fat, called a lipid nanoparticle. It does not, likely, get all the way to the nucleus, where the DNA is, so the mRNA is unlikely to ever have a long-term effect. But it makes a protein that is part of the virus, without any risk of viral infection.
Amid all the science, though, Jansen emphasized that vaccines may be “the only way to return to normal lives.”
The presentation conveyed both the tremendous potential and the impressive results that Pfizer and its partner BioNTech have demonstrated so far and some nagging questions. One of these has to do with whether the vaccine prevents severe cases of Covid-19 or hospitalizations. Pfizer simply has fewer of these severe cases in its trial than does Moderna, which is presenting results at an FDA panel meeting in a week. And one case logged as severe disease was in the vaccine group.
William Gruber, the Pfizer executive who presented the company’s data, described lots of alternative ways of cutting these data aimed at calming any nerves. First, he noted, this one case only counted as severe for one reason — a brief drop in blood oxygen levels. And, using different definitions of severe disease from the one favored by the FDA, there were more cases in the placebo group and they did worse.
But at least one panelist seemed to have a different question: Do we even need to use two doses? Juan Gea-Banacloche, a Mayo Clinic epidemiologist, asked how confident Pfizer is that the second dose is even needed. Pfizer replied, basically, that there isn’t enough evidence to conclude a vaccine would give the same long-term protection as two doses.
Pfizer also leaked out some news related to when we’ll have answers to some important vaccine questions. Data on how well the vaccine protects against asymptomatic infection — that is, Covid-19 cases with no symptoms — is expected early next year. And, as Helen noted earlier, preclinical studies aimed at understanding potential development toxicities could deliver preliminary results in mid-December, which could mean within days.
— Matthew Herper
Some news on vaccination during pregnancy or lactation
1:55 p.m.: As Covid-19 vaccine rollout nears, a key question has been: Should pregnant and lactating people be vaccinated? There are no data on which to base an answer, but some may be on the way.
The FDA told vaccine manufacturers they had to do what are called DART studies — that’s short for developmental and reproductive toxicity studies — before they could conduct clinical trials to test if these vaccines are safe to use in pregnancy and during breastfeeding. DART studies are done in animals, looking to see if there are any signs a vaccine might hurt a developing fetus or pose a threat to the pregnancy.
None of the vaccine manufacturers near the front of the vaccine pipeline has completed DART studies. But on Thursday, Pfizer told the VRBPAC meeting it expects preliminary results from its DART studies in Wistar rats by mid-December — in other words, within days.
The company will still have to do trials in people who are pregnant and lactating before the FDA would agree to specifically authorize the vaccine for these populations. But experts on the issue of drug and vaccine testing during pregnancy have urged the agency not to close the door to use in these groups in the meantime. In an opinion piece published Wednesday in STAT, they argued that the FDA should allow the vaccine to be offered to pregnant and lactating people, and let them decide whether they want to be vaccinated.
Vaccination in the United States could begin within days, and health care workers are at the front of the line. About 75% of health care workers are women and a large portion of them are of child-bearing age. The CDC estimates that at any given time, about 330,000 health care workers are either pregnant or lactating.
— Helen Branswell
Public hearing elevates vaccine hesitancy issue
1:45 pm: Vaccine hesitancy was on full display during the one-hour open public hearing, as multiple speakers raised concerns about the safety of the Pfizer/BioNTech vaccine and the legitimacy of granting early authorization based on limited data.
The skeptical comments, some of which veered uncomfortably close to dangerous conspiracy theories, underscore the challenge facing vaccine makers and public health officials in convincing Americans to get vaccinated against Covid-19.
One speaker, who described herself as a mother of a child who she said was “injured” by routine childhood vaccinations, urged the FDA to disclose all the ingredients that go into the Covid vaccine, including “aborted fetal cells” — a false claim.
Another speaker, a pediatrician from Florida who said he does not require his patients to get routine vaccines, highlighted potential safety risks that some people might experience if they get vaccinated.
Several other speakers voiced concerns that the clinical trial conducted by Pfizer and BioNTech was rushed, or that certain participant groups, particularly people of color, were underrepresented in the clinical database. The 44,000-patient clinical trial enrolled a diverse patient population in terms of race and ethnicity, age, and underlying health conditions. About 26% of participants were identified as Latino and 10% as Black, with the study evenly split between men and women.
To be clear, these panels are not meant to be coronations of clinical data without anyone asking appropriately probing questions. But these days, distinguishing healthy skepticism from damaging anti-vaccine tropes is increasingly difficult. The FDA wants to encourage transparency in the review process to enhance vaccine confidence, but by doing so, it also opens up the possibility of amplifying people with the opposite agenda.
Sidney Wolfe, founder and senior advisor of Public Citizen’s Health Research Group, gave testimony during the open public hearing, expressing his support for the emergency use authorization of the Pfizer/BioNTech Covid vaccine. Wolfe is notorious for opposing almost every new drug that comes in front of the FDA, so his support shows that even perma-skeptics can be convinced that vaccine makers are doing something right.
— Adam Feuerstein
Trying to solve a sticky wicket
12:15 p.m.: The morning’s session concluded with a fascinating presentation on a really tricky topic.
A major dilemma facing the FDA has been the question of whether participants in the placebo arms of vaccine trials ought to be offered vaccine when an EUA is issued.
Some of the manufacturers — notably Pfizer — want to give their placebo recipients vaccine. The FDA wants the trials to generate as much placebo-controlled data for as long as possible, because once the placebo groups are unblinded and vaccinated, important opportunities to collect data are lost forever.
The VRBPAC panel heard an interesting compromise proposal at the end of the morning session from Steven Goodman, associate dean of clinical and translational research at the Stanford University School of Medicine.
Goodman said ethically, the companies are not required to vaccinate the people in their placebo arms, though from a practical point of view, they could lose participants anyway when people in the trial become eligible to be vaccinated. And he said that vaccinating all placebo recipients after the issuance of an EUA would allow trial volunteers to “jump the queue” — get vaccinated before other people of their age or risk group.
The proposed compromise would be to vaccinate placebo recipients, but maintain the blinding. What that would mean would be that when people in a trial were eligible to get vaccine where they lived, they would be vaccinated. If someone had received placebo shots originally, they’d be given vaccine. If someone had received vaccine doses, they’d get placebo shots. They would not be told what their original status was — but all would be confident that they had received vaccine.
“As soon as they can get it outside their trial than this would kick in,” Goodman said. “I don’t think we have that special obligation to give them the vaccine early.”
This approach would remove the motivation for people who are in trials to withdraw as vaccine starts to roll out across the country, he said. And while vaccinating the placebo arm would result in some loss of data — for instance, the ability to continue to compare safety data long term — it would allow the trials to continue to gather comparative data on issues like the durability of the immune response generated by the vaccine.
On the question of whether placebo-controlled vaccine trials can continue once one vaccine has received an EUA, Goodman said in times of limited vaccine supplies it would still be ethical, but might become increasingly infeasible as supplies increase and more and more people have access to vaccines.
— Helen Branswell
How do you monitor a vaccine’s safety and efficacy after it is authorized?
11 a.m.: The big question when a vaccine is tested in 30,000 people and then given to 30 (or 300?) million is how one knows if it is as safe and effective as it initially appeared.
Part of the answer is to conduct more clinical trials, but it’s also necessary to conduct observational studies that can capture how well the vaccine is working in the real world. The plans for doing this were presented by Nancy Messonnier of the Centers for Disease Control and Prevention, who became well known for her prescient public remarks early in the pandemic.
On safety: the CDC is stitching together a number of large databases that will allow it to track adverse events and try to determine if those are side effects of the vaccine. These include the Vaccine Adverse Events Reporting System, run by the CDC and the FDA, but also other databases including the CDC’s V-safe and VSD databases, and databases from the Department of Veterans Affairs, Department of Defense, and Genesis Healthcare, a database in long-term care facilities run with Brown University.
And how do you track efficacy without a clinical trial? That will be done in much the same way that the efficacy of flu vaccines is tracked, by comparing whether people who test positive for Covid-19 got the vaccine at a different rate than those who test negative. This will start with a study among healthcare workers to check that the vaccine’s overall efficacy is what is currently expected, followed by studies in severely affected or hospitalized patients, the elderly and those in long-term care facilities, and those with key underlying conditions, among other groups. Messonnier said that U.S. safety monitoring will be coordinated with international efforts to do the same, including those of the World Health Organization.
— Matthew Herper
How many vaccine EUAs can the FDA grant?
9:50 a.m.: Here’s an interesting question: If the FDA approves one Covid-19 vaccine, would that make it impossible to grant emergency use authorizations to future ones?
Panelist Jeannette Lee, a biostatistician from the University of Arkansas, raised the issue after an FDA official outlined the rules governing EUAs. Among them is a provision saying that an EUA is warranted when there’s no adequate, approved product for a particular indication. When it comes to Covid-19, wouldn’t that suggest that once the FDA grants full approval to a first vaccine, it would be precluded from bestowing EUAs on the ones to come?
The answer is no, according to Doran Fink, deputy director of the FDA’s vaccine division. If an approved product is available only in limited supply — as is certain to be the case with the first approved Covid-19 vaccine — the FDA can still grant EUAs to investigational products.
That means that we’ll be tuning into meetings like this on a regular basis for the months to come. But, if the U.S. meets its goals of securing hundreds of millions of vaccine doses by the summer, it also means that the next generation of Covid-19 vaccines might have to go through the FDA’s standard, non-EUA process.
— Damian Garde
NEJM editorial: Vaccine is a ‘triumph’
9:30 a.m.: As today’s FDA panel gets underway, one of the invited experts — and a voting member of the panel — has already expressed his opinion that the Pfizer/BioNTech Covid vaccine is a “triumph.”
Eric Rubin, an immunologist at the Harvard T.H. Chan School of Public Health, co-authored a laudatory editorial about the vaccine, published this morning in the New England Journal of Medicine. While highlighting minor issues with the clinical trial design, the vaccine results are “impressive enough to hold up in any conceivable analysis,” Rubin wrote.
He adds:
“This is a triumph. Most vaccines have taken decades to develop, but this one is likely to move from conception to large-scale implementation within a year. The sequence of the virus that led to the development of the specific antiviral RNA sequence required to design the vaccine didn’t become known until it had been determined and widely disseminated by the Chinese Center for Disease Control and Prevention in January 2020. There is a lot of credit to go around: to the scientists who shared data and who developed the underlying methods and implemented them to create a vaccine, to the clinical trialists who performed high-quality work in the setting of a health emergency, to the thousands of participants who volunteered to take part in the trial, and to the governments that helped create performance standards and a market for the vaccine. And all this stands as a template for the many other Covid-19 vaccines currently in development, some of which have already completed their phase 3 trials.”
The Phase 3 trial results from Pfizer/BioNTech were also published in NEJM this morning.
— Adam Feuerstein
Here we go!
9 a.m.: The meeting has just been called to order. It is streaming here, if you are interested in checking in.
The virtual audience for this meeting is expected to be large, and global. The world is watching how U.S. agencies are evaluating the effectiveness and safety of Covid-19 vaccines and how it’s thinking about prioritizing vaccine allocation.
How do we know? Well, nearly 32,000 computers in more than 66 countries and most parts of the United States were streaming the Dec. 1 meeting of the Advisory Committee on Immunization Practices, an expert panel that helps the Centers for Disease Control and Prevention assess vaccines and prioritize their use. It is not common that an ACIP meeting would garner that much attention.
During that meeting, ACIP members voted to recommend health care workers and residents of nursing homes get first access to Covid vaccines when supplies are limited.
The VRBPAC audience will likely be larger. The FDA is considered the gold standard for regulatory agencies. It is the only one that requires companies applying to bring a drug or vaccine to market to supply its raw data, which the agency’s scientists recalculate to ensure that the claims being made by the drug or vaccine sponsor are supported by the evidence.
Pro tip: If you’re wondering how long after today’s meeting it will take for FDA to decide on Pfizer’s emergency use authorization application, this afternoon’s discussion will be critical. Norman Baylor, a former director of FDA’s office of vaccines research and review, said Wednesday that if it seems like the committee members agree with the positive tone of the FDA’s review of the vaccine and vote unanimously to recommend an EUA be granted, things could move very rapidly.
If however, VRBPAC members — who have been poring over the Pfizer data in preparation for the meeting — raise a bunch of red flags, there could be delays, said Baylor, who is now president and CEO of Biologics Consulting.
— Helen Branswell
The FDA’s questions — and the placebo problem
8:45 a.m.: The FDA has posted the questions that the panel will be charged with discussing. The big one, the voting question, is no surprise:
“Based on the totality of scientific evidence available, do the benefits of the Pfizer-BioNTech COVID-19 Vaccine outweigh its risks for use in individuals 16 years of age and older?”
It would be a big surprise if the panel doesn’t vote positively, although I’d expect discussion about the meaning of each “yes.”
In addition to the voting question, there are two discussion questions:
1. “Please discuss any gaps in plans described today and in the briefing documents for further evaluation of vaccine safety and effectiveness in populations who receive the Pfizer-BioNTech Vaccine under an EUA.”
2. “Pfizer has proposed a plan for continuation of blinded, placebo-controlled follow-up in ongoing trials if the vaccine were made available under EUA. Please discuss Pfizer’s plan, including how loss of blinded, placebo-controlled follow-up in ongoing trials should be addressed.”
I want to focus a bit on the second. This is going to be a big issue for all of the vaccine studies. Volunteers in these clinical trials generally expect that even if they were randomly assigned to get the placebo, they’ll be switched to the vaccine once it is effective. Experts, in particular the ones on the VRBPAC panel, generally want to hold off the moment when placebo patients get the vaccine for as long as possible. Once it comes, the ability to compare the vaccine to a placebo to determine efficacy and side effects is lost.
But there’s another problem, which is that once a vaccine is available, patients may try to get it outside the trial, which is even worse from the perspective of getting good data than switching them over. A month ago STAT obtained a Pfizer memo saying that the company’s plan was to switch patients over as soon as they were eligible to receive the vaccine. There will be a lot more discussion of that plan all day, with time specifically allotted to this issue at 10:50.
— Matthew Herper
VRBPAC’s agenda
6 a.m.: Good day, folks. In honor of what promises to be an historic day, a crowd of us here at STAT— Matt, Adam, Damian and I — will be monitoring and live-blogging on the day’s discussions.
For starters, let’s introduce you to the committee members. The FDA has a very strict conflict of interest policy for VRBPAC members. Anyone involved in any of the Covid-19 clinical trials — even a member who works at a university that is a trial site — is “conflicted out,” which means that temporary replacements who are equally stringently vetted are named in their place.
The early part of the meeting, which begins at 9 a.m. EST, is about setting the table for the discussion that will follow. It includes discussion of what is happening in the U.S. outbreak right now, the plans for monitoring for adverse events potentially triggered by vaccination, as well as a presentation on distribution.
At or about 10:50 a.m. EST (VRBPAC discussions can run long) there will be an important discussion about what steps can be taken to ensure that issuing EUAs for some vaccines don’t interfere with the efforts to run placebo-controlled trials on others that are behind them in the pipeline. This is a thorny but critical issue.
After an early lunch, Pfizer will make a presentation on the vaccine. Then the FDA will make a presentation, which will lay out for committee members what issues the agency wants their advice on and what questions it wants them to answer by holding votes.
Then, starting at 3:10 p.m. EST (or thereabouts), the committee members will begin their deliberations. That’s crunch time.
— Helen Branswell
The context
The Covid-19 pandemic is raging around the world but most especially in the United States, which has the highest number of cases and deaths of any country on the planet. More than 15.3 million Americans have been diagnosed with Covid-19 and more than 288,000 have died.
The country has invested billions of dollars into fast-tracking development and production of Covid vaccines through a military-led project called Operation Warp Speed. While vaccines have been developed at an exceptional pace, there’s been a steady decline in the estimates of how quickly Americans will be vaccinated. Operation Warp Speed currently estimates it will have enough vaccine for 20 million people by the end of December — though vaccines in warehouses and vaccines in arms are two different things.
The administration now estimates that every American who wants to be vaccinated will be able to access vaccine by the end of the second quarter of 2021. Thursday’s hearing starts that process.
— Helen Branswell
*** This article has been archived for your research. The original version from STAT can be found here ***
