Chaotic adcomm sees Pfizer/BioNTech boosters rejected for general population, but recommended for older and high-risk populations
With just days before President Joe Biden’s Covid-19 booster rollout is set to go into effect, an FDA advisory committee appeared on the verge of not recommending boosters for anyone in the US before a last-minute change of wording laid the groundwork for older adults to have access to a third dose.
The FDA’s adcomm on Vaccines and Related Biological Products (VRBPAC) roundly rejected Pfizer/BioNTech booster shots for all individuals older than 16 by a 16-2 vote Friday afternoon. Soon after, however, the agency posed committee members a new question limiting booster use to the 65-and-older population and individuals at high risk of disease due to occupational exposure or comorbidities.
That question, coming roughly 45 minutes after the first, passed through the adcomm with a unanimous 18-0 vote. This vote centered on an emergency use authorization — not the supplemental BLA for which Pfizer had applied.
And at the end of the hearing, CBER director Peter Marks asked the panel to take an “informal poll” on whether health-care workers and others at high risk of “occupational exposure” be included in the EUA. Here, the panel also gave a unanimous 18-0 yes.
After the votes, Pfizer vaccine chief Kathrin Jansen said in a statement that the company would continue to push for boosters in the general population.
“These data, and the larger body of scientific evidence presented at the meeting, underscore our belief that boosters will be a critical tool in the ongoing effort to control the spread of this virus,” Jansen said in an emailed statement to Endpoints News. “We thank the committee for their thoughtful review of the data and will work with the FDA following today’s meeting to address the committee’s questions, as we continue to believe in the benefits of a booster dose for a broader population.”
Several adcomm members noted throughout the discussion period that they’d be open to recommending boosters for smaller high-risk populations, prompting panel chair Arnold Monto to ask Marks for multiple clarifications on the original, broad voting question. The question, released late Thursday night, asked whether or not the safety and efficacy data from Pfizer/BioNTech’s original Phase III study “supported approval” of a booster at least six months after the second dose in those aged 16 and up.
But Monto asked if Marks would allow panel members to consider data from other real-world studies in their votes, to which Marks said the committee would be allowed to consider the “totality of the data.” Then, Monto wanted to know if the question could be modified to allow committee members to vote on a narrower population.
Marks once again answered in the affirmative but, in an extraordinary exchange, received significant pushback from top vaccine official Marion Gruber who noted that Pfizer’s submission covered all individuals older than 16. Gruber, along with another top vaccine staffer, Philip Krause, announced their intent to retire last month after raising concerns with boosters in the Lancet.
Monto then allowed Pfizer to make a five-minute closing statement that was not on the agenda, in which company execs pushed for the committee to vote on the original question.
Observers criticized the FDA in the immediate wake of the first vote, posing what they said was an inflexible question given some data has shown the benefits of boosters outweigh the risk in older populations. Scripps Research director Eric Topol blasted the agency, saying the first question “was set up to fail” in essentially asking for data that are not yet available.
The vote question was set up to fail, calling for a blanket approval for all age 16+ (related to aggressive Pfizer EUA request). How could that possibly be voted for in favor when such broad data do not exist anywhere?
Of course, the vote was 16 to 3 against. pic.twitter.com/8aNB7o2k4E
— Eric Topol (@EricTopol) September 17, 2021
Throughout the afternoon, panelists had expressed severe reservations about recommending boosters for everyone older than 16, particularly given the unknown safety risks in young boys and men with regards to myocarditis. It’s an issue that harkened back to the original vaccine adcomm as well, when panelists took issue with approving vaccines for 16- and 17-year-olds.
“I was struck by the FDA’s comments on the totality of data given there’s more data coming soon on safety for myocarditis,” panel member Hayley Gans said after the first vote. “It feels like a missed opportunity when they consider these [datasets] large enough even when we have data we could have looked at … it feels like we’re making decisions when there’s still data out there.”
After the first vote concluded with a resounding no, FDA officials returned to committee members with a new question. Rather than focus on the entire general population, regulators posed the following question:
Based on the totality of scientific evidence available, including the safety and effectiveness data from clinical trial C4591001, do the known and potential benefits outweigh the known and potential risks of a Pfizer-BioNTech Covid-19 vaccine booster dose administered at least 6 months after completion of the primary series for use in:
a) Individuals 65 years of age and older, and
b) Individuals at high risk of severe Covid-19
It’s here where the majority of panelists seemed to agree, giving the EUA their thumbs up recommendation.
The adcomm started off bright and early at 8:30 a.m. Eastern, with Monto welcoming viewers to the livestream. After a brief introduction he soon handed things off to Marks who, in a striking move, directed panel members to focus conversations on the science rather than concerns over vaccine equity or “operational issues related to a booster campaign.”
Marks’ comments came against the backdrop of Gruber and Krause’s resignations. The two also co-authored an article in the Lancet this week asserting booster doses for the general population are not appropriate at this stage in the pandemic, and Gruber — who spoke during the introduction — noted this would likely be her last adcomm appearance.
Another co-author to that paper, British statistician Jonathan Sterne, gave a presentation early in the session on the topic of “confoundables,” or variables that can introduce or predict both vaccination and Covid-19 outcomes in real-world studies. Sterne’s discussion drew wide praise among observers on social media, raising questions over how difficult it is to determine whether waning vaccine immunity is primarily a result of the shots becoming less effective or the Delta variant’s surge.
Do yourself a favor and look at these awesome slides from Jonathan Sterne presentation at FDA today on interpreting observational vaccine studies. Great presentation and illustrations with opensafely data.https://t.co/M6XVNwOQXX pic.twitter.com/GdIIStGHIK
— Aaron Richterman, MD (@AaronRichterman) September 17, 2021
BOOSTERS: Dr. Jonathan Sterne's slide from VRBPAC on how 2-dose vaccines provide persistent protection from severe disease in studies where delta variant is circulating. For me, the debate on boosters can be divided into 2 lines of research: immunologic & epidemiologic pic.twitter.com/8Tus6B4vls
— Monica Gandhi MD, MPH (@MonicaGandhi9) September 17, 2021
— Dr. Lindsey Nicole Shultz (@lshultz82) September 17, 2021
Sandwiching Sterne were data presentations from the CDC and Israeli health officials, who described how the pandemic had progressed in their countries. The Israeli presentation also included data from real-world studies during the country’s Delta surge, which proved notable given the FDA’s written question to panel members asked solely about Pfizer’s Phase III study.
Soon after came the heavy hitters: Pfizer and the FDA. Much of the arguments asserted here matched up with how they each interpreted the data in the briefing documents released earlier this week. In a minor point of contention during the hearing, Monto cut off Pfizer’s presenter who went over his allotted time when trying to reiterate findings from Israeli studies.
After these presentations and the open comment period, panelists began their Q&A session with Pfizer and the FDA. The first question delivered some fireworks, with Gruber giving Krause the opportunity to question Pfizer on the statistical models used in a real-world study in Israel.
Krause claimed there was a discrepancy between the efficacy Pfizer reported using a specific model, which said efficacy after 8 months fell to 58% to 61%, but numbers calculated through a different mathematical process using cases per person-years resulted in 93% efficacy. These disparate figures, Krause said, came from the same number of cases in a study by California health care company Kaiser Permanente.
When given time to respond, however, Pfizer began experiencing technical difficulties. Execs from the Big Pharma ostensibly had three microphone lines open at the same time, per the adcomm’s technical moderator, prompting an unscheduled break to fix the issue. After the feed returned, Monto moved the panel on to the next question.
Panelists continued peppering Pfizer with questions about the risks of myocarditis in younger patients and whether Pfizer should tailor its booster shots to specific variants. Questions also arose about how Israeli officials have classified severe Covid-19, with the CDC presenter saying they use a looser definition than the United States.
Then things moved to the discussion period when things started to grow more chaotic. Ultimately, the panel landed on recommending an EUA for individuals 65 and older and at high risk for severe Covid-19. The ball now moves back to the FDA’s court, and it’s not immediately clear how long it will take for the agency to make an EUA decision.
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