The U.S. government's most detailed airing of its plans for approval, production and distribution of coronavirus vaccines came Thursday at a marathon meeting of a Food and Drug Administration advisory committee.
Independent experts convened by the FDA debated whether the agency has set an appropriate bar for approving experimental shots, and how research should continue following any emergency clearance that might be granted in the coming months.
Presentations by officials from the National Institutes of Health, the Centers for Disease Control and Prevention and the Biomedical Advanced Research and Development Authority, meanwhile, shed important light on lingering questions about how mass immunization programs will be rolled out. Addressing distribution hurdles and likely vaccine hesitancy among certain groups were a particular focus.
Here are five takeaways from the nearly nine-hour meeting, which is likely only the first of several:
Some experts were reassured by the FDA's standards ...
A large portion of Thursday's meeting was dedicated to detailed explanations by top FDA officials of the standards the agency has set for an emergency clearance or full approval of a coronavirus vaccine.
For some of the committee experts, the presentations seemed to allay their concerns. "I am much more reassured," said H. Cody Meissner, an infectious disease physician at Tufts University, after hearing from regulators.
The agency spelled out approval guidelines in documents released in June and then, despite some controversy, earlier this month.
The requirements for an emergency use authorization, or EUA, have received particular attention, as any early approval would set in motion government plans to vaccinate first tens of millions, then hundreds of millions of people in the U.S. Speed is critical, especially as the pandemic gathers new strength. But waving a vaccine through with limited evidence runs the risk of missing a rarer side effect, or misreading early signs of effectiveness.
Vaccine developers seeking an EUA will need to meet the same efficacy standards as they would to win a full approval. And, before granting an EUA, the FDA will require a median of at least two months of safety follow-up.
"I think we have a language problem," said Paul Offit, director of the Vaccine Education Center at Children's Hospital of Philadelphia, at Thursday's meeting. "This is much much closer to a typical [approval] process than it is to how at least the public or frankly I perceive an EUA process."
Offit contrasted the "relatively high" standard the FDA has set for vaccine EUAs with the agency's controversial authorizations for the malaria pill hydroxychloroquine and blood plasma, the former of which was later revoked.
"I wish we could get rid of the word EUA," he added. The FDA reportedly pushed back on attempts by the White House to do just that, according to an Oct. 13 article in Politico, which said Hahn had rejected an attempt to rebrand a vaccine EUA as "pre-licensure" out of concerns of the appearance of political interference.
... while other committee members weren't so sure.
Some experts on the panel, however, questioned the clinical trial goals companies are using, and debated whether the two-month safety requirement for emergency clearance is sufficient.
"We're talking about platforms that have never been the basis for vaccines, so there could be adverse events we don't know about," said Sheldon Toubman, a Connecticut-based attorney serving as the committee's consumer representative, at the meeting. "Isn't two months a little short?"
FDA officials noted they expect companies that receive an EUA to keep studying their candidates through a full approval, which usually involves at least six months of safety follow-up.
Other committee members were skeptical the Phase 3 trials being run by Pfizer, Moderna, Johnson & Johnson and others would capture important information, such as whether vaccination prevents infection or stops severe COVID-19 from developing.
"I'd like to see how we could actually be measuring infection," said Kathryn Holmes, a professor emerita at the University of Colorado School of Medicine.
Luigi Notarangelo, a top scientist at the National Institutes of Health, argued the endpoints being used were "biased, or skewed" toward measuring whether vaccines are effective in stopping mild disease. Many of the criteria used to define the severity of COVID-19 in study participants, he argued, are subjective and rely on reporting from the volunteers themselves.
The FDA doesn't mandate what goals drug developers choose for their trials, although, under the Trump administration's Operation Warp Speed initiative, there's significantly more coordination between companies and the government.
Measuring success or failure by the prevention of infection or severe disease, meanwhile, could be more challenging.
"If the endpoint of the trial is severe disease, the trials may need to be 10 times as big," said Philip Krause, a deputy director at the FDA's vaccine office. "If the endpoints are infection, that can, with some additional work, be a feasible endpoint but the science isn't there to do that right now."
Keeping vaccines cold will be a challenge
The leading experimental vaccines, from Moderna and partners Pfizer and BioNTech, must be distributed and stored at very low temperatures — minus 70 degrees Celsius in the case of Pfizer and BioNTech's shot.
The CDC, however, is not recommending hospitals and other healthcare providers buy heavy-duty freezers because of the companies' supply chain plans, said Janell Routh, medical officer at the agency's National Center for Influenza and Respiratory Diseases.
Pfizer plans to ship doses of its vaccine directly to vaccination sites in thermal containers with dry ice that can maintain the right temperature for 15 days. The containers will have GPS-linked temperature control monitors to ensure they're not stolen, or lost in shipping.
Moderna's vaccine needs to be distributed and stored at -20 degrees Celsius, only slightly lower than standard consumer freezers for food. The company will pack doses in cold shipping cases that can be loaded onto pallets containing more than 230,000 doses each, to be transported on temperature-controlled trucks.
Plans are in place to ensure people receive their second shot
Both Pfizer and BioNTech's as well as Moderna's vaccines are given as two shots several weeks apart, raising questions from the committee of how people would receive the right second dose when supplies are likely to be extremely limited initially.
An electronic records system, with backups, will be used to confirm people get the right vaccine, Routh said.
Individuals will also be given a card detailing which vaccine they received and instructions on when to return for a second dose, she said. Patients will be reminded via text when to return for the booster shot.
Mistrust of government is a major concern
A safe and effective vaccine is widely viewed as the most powerful tool to ending the coronavirus pandemic. In the U.S., however, there are worrying signs that a sizable number of people don't trust public health authorities and may not initially get a vaccine.
In May, a poll by the Pew Research Center found 72% of surveyed Americans would "definitely" or "probably" get a vaccine, should one be approved. By September, that number dropped to just 51%.
Another poll, conducted in early October by The Harris Poll and STAT News, found a similar percentage, 58%, of respondents would get a vaccine as soon as it's made available. Only 43% of Black respondents said they would, suggestive of a lack of confidence in vaccine development.
That mistrust was put in stark terms Thursday by a presentation from the Regan-Udall Foundation, a nonprofit that recently conducted a series of listening sessions with healthcare and retail workers, as well as people identifying as Black, Latino, or indigenous or Native American.
Participants' concerns were broad, spanning general distrust of the healthcare system to concerns about the speed of the process and fears of being used as a "guinea pig" for experimental vaccines.
"I don't think the FDA can be trusted to keep people safe," one person in the listening session told the foundation.
"We all know how long vaccines take, so to hear that it will be ready in a few months is concerning," said another.
The feedback, which foundation CEO Susan Winkler called "sobering," make clear the challenge awaiting health authorities once any vaccine is authorized by the FDA.