On Thursday, a committee of advisers to the Food and Drug Administration met for the second time in as many weeks to review an experimental coronavirus vaccine.
The panel last week endorsed Pfizer and BioNTech's shot, clearing the way for the regulator to issue a historic emergency authorization the next day, and this week convened to review Moderna's candidate.
Both vaccines were found in large trials of tens of thousands of volunteers to be strongly effective, preventing COVID-19 in nearly all participants who received them. FDA scientists affirmed the companies' claims in their own reviews, issuing detailed analysis of Pfizer and BioNTech's data last week and of Moderna's this Tuesday.
BioPharma Dive tracked the day-long meeting and reported on the discussion here. The most recent entries are listed first.
Updated 5:42 pm
As with last week's vote, this one also had some last-minute drama. Panelist Michael Kurilla, a director at the NIH's National Center for Advancing Translational Sciences, raised concerns about how the positive vote on Pfizer and BioNTech's vaccine was portrayed as supportive of a full approval, rather than an emergency use authorization.
Kurilla pushed the FDA to rephrase the question to include "emergency use" language, but the committee and FDA officials declined. That left Kurilla as the only expert to abstain from voting.
"I'm very uncomfortable with the language in the midst of pandemic and with limited supply available, a blanket statement for 18 and older is too broad," he said, pointing to the possibility of using expanded access trials to achieve the same goals as an EUA.
A. Oveta Fuller, who had voted against recommending Pfizer and BioNTech's shot, supported Moderna's vaccine this week. She echoed Kurilla's concerns, however. "I did not think the EUA was the way to go, but since the train has left the station, I appreciate that Moderna has given us a big, transparent and thorough study," Fuller said.
As a final word, Chairman Arnold Monto urged observers not to draw too many conclusions from differing vote tallies between the two meetings.
"I don't think anybody should interpret the difference in the vote as pointing one way or another," he said. "Academics have a way of going into details." — Jonathan Gardner
A second coronavirus vaccine is almost surely on the way.
The committee voted 20-0 to authorize Moderna's shot for emergency use in adults 18 years or older.
Michael Kurilla, of the National Institutes of Health, abstained.
The panel's support should lead to an imminent, positive decision from the FDA. The agency authorized Pfizer and BioNTech's shot the day after an endorsement from the same group of advisers last week.
Stay tuned for more details on the discussion. — Ben Fidler
In the afternoon, committee members continued to grapple with an issue that's been a subject of debate in both this and last week's meetings: What should be done with the volunteers who got a placebo?
Panelists weren't asked to vote on what Moderna should do. Marion Gruber, director of the FDA's vaccines review office, said that the agency declined to turn the discussion into a vote after being pressed to do so by panel members.
Nonetheless, the consensus of the committee was clear: A blinded crossover would be the best way for Moderna to accrue critical information about its vaccine, but it isn't realistic. A deadly pandemic is raging. A second vaccine will likely be available imminently, and there's a good chance volunteers will leave the trial if they're less likely to get it. If a blinded crossover were to be done, it should have been carried out from the start, the panelists agreed.
"I think we have given the FDA a sense of our wish that we could do a crossover blinded design, but the realization that that may be impossible," said committee chair Arnold Monto.
Though it wasn't unanimous, a majority of committee members instead believed that an open-label crossover design was Moderna's best available option — though exactly when placebo participants should get vaccinated was still a matter of debate. — Ben Fidler
Late-stage results from Moderna, as well as Pfizer and BioNTech, make clear that antibodies that neutralize the coronavirus offer some level of protection against COVID-19. But it's still uncertain what the threshold is for that protection. A better understanding of the correlation between the two could help speed the development of other vaccines.
Moderna's Jacqueline Miller indicated the company could have that type of information "in the coming months. "The company has collected routine blood samples throughout the trial, and will continue to over time with the help of the National Institutes of Health.
By analyzing everyones' immune responses over time and comparing them to "breakthrough" cases when a vaccinated patient contracts disease, Moderna and NIH hope to pull together an analysis that could help vaccine researchers. — Ben Fidler
Advisory committee members continued to express concern about allergic reactions to Pfizer and BioNTech's vaccine, and the Moderna representatives were asked their share of questions during the morning and early afternoon portions of the meeting.
Responding to one query, Jacqueline Miller, head of Moderna's infectious disease therapy development, said the reports of allergic reactions prompted them to take a look at clinical trials of their other experimental vaccines to see if any had previously occurred. Among 1,700 volunteers given eight other Moderna vaccines using the same mRNA platform, there was only one case, in a woman with soy allergies who had a reaction a month after vaccination.
Responding to another question, chief medical officer Tal Zaks said he doubted the mRNA component could stimulate an allergic response because it's something found in the body. Several components of the Moderna lipid nanoparticle encasing the mRNA differ from BioNTech's, which could end up giving it a different side effect profile, Zaks added.
He also doubted Pfizer and BioNTech's shorter dosing interval of three weeks would make a difference compared with Moderna's four weeks, because some of the volunteers got the Moderna vaccine up to three days early and up to seven days late. — Jonathan Gardner
A quick break before the committee returns at 2:00 pm for the FDA's presentation. The committee will then discuss and vote through the remainder of the afternoon.
The committee has already discussed if and when trial volunteers who received a placebo should get a vaccine. But the issue still hasn't been decided, and has wide-ranging implications not just for Pfizer and Moderna, but other vaccine trials, too. Quickly "unblinding" the trials could make it harder to tell how long the vaccines remain protective, or to accrue other crucial information.
"The reason we're coming back to this question is because it's important," the FDA's Doran Fink said.
Pfizer and BioNTech want to vaccinate placebo participants when they request a shot and CDC guidelines say they're eligible. Moderna aims to proactively obtain consent and immediately vaccinate placebo volunteers. They'd get access to supply reserved for clinical trials, not commercial use, chief medical officer Tal Zaks said at the meeting.
Lindesy Baden, a physician at Brigham and Women's Hospital and an investigator in the study, added that they've seen more volunteers drop out of the trial since authorization of Pfizer's vaccine last week.
An alternative option prominently being discussed is called the "blinded crossover." Under this scenario, all placebo participants would get the vaccine, and vice versa, but none would know which they received and when. It's a way to vaccinate all volunteers, while still maintaining some of the trial's integrity.
Multiple panelists expressed support for the idea. Cody Meissner, an infectious disease expert at Tufts University School of Medicine, for instance, said the design would help evaluate any “long-term complications” between vaccinated and unvaccinated groups.
But, like Pfizer last week, some were concerned whether a blinded crossover is possible. Vaccine side effects may make it clear when volunteers get the real shot. Participants would have to get more periodic blood draws, and those tests would have to be tightly synchronized between the two groups. As time goes on, more participants will be eligible for vaccination, making it less likely they would continue to go through trial protocols to get a vaccine. — Ben Fidler
Sharp-eyed pharmacists administering some of the first doses of Pfizer and BioNTech's vaccine following last week's authorization noticed the vials contain more than the five doses they're supposed to hold.
Extra drug product in vials, or "overfill," is common with injectable medicines, but with supplies of Pfizer's vaccine extremely short, the revelation there may be six or even seven doses in each vial was met with some surprise.
Doran Fink of the FDA noted Thursday that, per instructions for the vaccine, 1.8 mL of diluents are supposed to be added to the 0.45 mL of vaccine in each vial. As each doses is 0.3 mL, it's "not entirely unexpected" there would be more than five doses, Fink said.
The FDA has reportedly told state health officials the extra doses can be used, rather than discarded as is usual practice with overfill.
But the issue raised alarm bells for at least one committee member, who had asked Fink whether the extra doses changed the FDA's confidence in Pfizer's manufacturing process.
"We do feel confident that we have enough information to justify issuing an EUA for this vaccine," said Fink. — Ned Pagliarulo
Doran Fink, a deputy director for the FDA division that oversees vaccines, made a point to address reports of allergic reactions observed in four healthcare workers who received Pfizer and BioNTech's vaccine following authorization in the U.K. and U.S.
Fink predicted there "may be additional reports," but noted the cases are being found through established vaccine safety surveillance systems that are "working exactly as designed."
"While the totality of data at this time continue to support vaccinations under the Pfizer EUA, without new restrictions, these cases underscore the need to remain vigilant during the early phase of the vaccination campaign," Fink said. "We will do the same for Moderna if [its vaccine is] authorized."
The FDA is currently working with Pfizer to update the prescribing information for its shot and to draw more attention to the need for monitoring immediately after vaccination. Prescribing information for the vaccine already warns against administering to people with a history of severe allergies, and cautions medical staff to have treatment on hand in case of emergency.
Fink said the agency doesn't have enough information yet to make any new recommendations. — Ben Fidler
Today's meeting builds to a single question, on which advisory committee members will be asked to vote yes or no: "Based on the totality of scientific evidence available, do the benefits of the Moderna COVID-19 vaccine outweigh its risks for use in individuals 18 years of age and older?"
Restricting an authorization to people 18 and over could result in a slightly different vote outcome. Last week, the FDA asked to authorize the Pfizer and BioNTech vaccine for people 16 and older, a question on which four of the 22 panel members voted no.
Two of them, David Kim from the Department of Health and Human Services and Archana Chatterjee from Rosalind Franklin University, said they voted no because they didn't believe there was enough data to support authorization in the 16- and 17-year-olds. Moderna's Phase 3 trial didn't enroll anybody under age 18, so that will not be debated.
A third no vote came from Oveta Fuller of the University of Michigan, who believes the Pfizer and BioNTech vaccine should be used in expanded access trials to gain more data. She could make the same argument this week, too.— Jonathan Gardner
Like last week, Arnold Monto, a professor and epidemiologist at the University of Michigan, is leading Thursday's meeting.
The first two presentations in the morning are repeats from last week — going over the FDA's emergency use authorization process and questions around running a placebo-controlled clinical trial after an authorization. But the FDA has built in more time for Q&A following each presentation this time around, perhaps taking to heart criticism last week's meeting was rushed.
Moderna's chief medical officer, Tal Zaks, will present his company's data before lunch, after which an open public hearing will follow.
The FDA's presentation begins at 2 pm, while the real meat of the committee's discussion will happen between 3:10 pm and 5:15 pm.
Last week, the experts ran out of time after their vote and the meeting adjourned without any being able to explain their votes. Watch the clock today to see if this time around they get more time to discuss. — Ned Pagliarulo
The FDA has been concerned the public will be hesitant to receive a vaccine tested in the fastest development effort in history. The regulator has responded by attempting to make its vaccine reviews transparent. A crucial part of that plan involves holding and broadcasting advisory committee meetings for each emergency authorization application. The result: two meetings, seven days apart, for two similar shots.
Thursday's meeting, however, may not be just a repeat of last week. Moderna's vaccine appears to have a slightly different profile than Pfizer and BioNTech's, most notably a perhaps more pronounced slate of side effects. (More on that in the next section.)
One side effect in particular, a type of facial paralysis known as Bell's palsy, was observed in a few participants in both Pfizer's and Moderna's trials, and will likely feature in the day's discussion.
Another emerging issue is whether one dose of vaccine, rather than two, could be effective and should be more formally tested, given Moderna's and Pfizer's limited supplies.
With rollout of Pfizer's vaccine now underway, committee experts may ask about four cases of allergic reactions reported among some of the first people to get the shot, and whether there is any reason to believe the same issue may occur with Moderna's.
Panelists last week also ran out of time discussing a number of critical topics, including questions of when trial participants who originally received placebo should get vaccinated and how companies should adjust their studies when an authorized vaccine is more widely available. The same points could come up again Thursday. — Ben Fidler
In many important ways, the two shots are very similar.
Both consist of genetic sequences that encode for virus proteins, rather than the virus itself, to teach the immune system to recognize and fight the coronavirus. Both appear to be similarly and strongly effective at preventing COVID-19 across age, race, ethnicity or gender. And while we don't know yet if either can slow or stop transmission of the virus, data are expected from each developer soon.
But there are differences, too. Moderna's shot uses a higher dose of mRNA than Pfizer's and appears to be slightly less tolerable, with vaccination leading to higher rates of side effects like pain, chills and fever — particularly after the second dose.
Moderna's two-shot regimen is spaced four weeks apart, compared to three for Pfizer. And Moderna's vaccine can also be stored at warmer temperatures than Pfizer's, and stays stable in a standard refrigerator for longer.
Additionally, Moderna is seeking emergency clearance for its vaccine in adults 18 and older, while Pfizer's FDA authorization included 16 and 17 year olds. — Ben Fidler
Not even the most bullish optimist would have predicted as 2020 dawned that Moderna would have a medicine on the cusp of regulatory clearance by the end of the year. The scale of the pandemic, along with the government and investor resources put toward combating it, has changed that outlook considerably.
Authorization of Moderna's vaccine would bring further validation of its messenger RNA technology, which is similar to what's used in Pfizer's and BioNTech's shot and has proven more potent than expected in testing against the coronavirus.
Moderna hopes to use mRNA in preventive vaccines for other infectious diseases, as well as drugs for cancer and rare disorders. Lessons learned from the past year of development could help those hopes along.
An authorization could also give Moderna a place on national immunization schedules. Looking ahead, CEO Stéphane Bancel has proposed a combined vaccine to fight several respiratory viruses, including influenza and coronavirus.
More broadly, an authorization would cement Moderna's place in the national spotlight and give real backing to the company's ballooning market valuation. — Jonathan Gardner