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COVID-19 vaccine safety, dueling efficacy standards, and representation of groups from racial and ethnic minorities to children drew focus Thursday at arguably the most watched FDA advisory committee meeting ever.

The FDA's Vaccines and Related Biological Products Advisory Committee (VRBPAC) featured a brief appearance by Peter Marks, MD, PhD, director of the agency's Center for Biologics Evaluation and Research, who called this, "an exceptionally well-attended advisory committee meeting." In addition to the FDA's website, the meeting was broadcast on YouTube, with over 15,000 views when it concluded in the early evening.

FDA's director of the Office of Vaccines Research and Review, Marion Gruber, PhD, set the tone in her opening remarks:

"I want to take a moment to reassure the American public ... today's discussions will provide transparency about the data we will request and evaluate," she said. "Vaccine development can be expedited, but ... it cannot and must not be rushed."

But safety was foremost on the minds of committee members, who expressed concern that median 2 months of safety data required by the FDA seemed "arbitrary." Some worried that if products receive emergency use authorization (EUA), blinding in their phase III trials would be immediately broken and placebo controls stopped, instead of allowing them to continue for vital additional data collection.

FDA staff said the 2-months mark was chosen because most vaccine adverse events occur within the first 6 weeks.

A presentation by the Reagan-Udall Foundation for the Food and Drug Administration -- a nonprofit established by Congress to advance the agency's overall mission -- shared results from "listening sessions" on vaccine hesitancy. These indicated that the public harbors concerns about the speed of the process, as well as distrust of government and the healthcare system.

Some committee members seemed to share their skepticism.

Members of the public are "probably not going to have an appetite for anything short of the rigorous process we're used to seeing," said Hayley Altman-Gans, MD, of Stanford University Medical Center. "This is not going to be enough for this particular vaccine."

Archana Chatterjee, MD, of Rosalind Franklin University in North Chicago, said that she thought safety needed to be the top priority, even before effectiveness.

"Whatever products are put on the market under whatever mechanism" should be safe, she said. "Then you get to effectiveness."

However, efficacy standards received plenty of attention, too. A presentation by Hilary Marston, MD, of the National Institutes of Health, argued for a primary efficacy endpoint of at least 60%.

FDA guidance, however, stated a goal of 50%.

"We are really trying to strike a balance between getting information on the most significant clinical outcomes and ... being able to make an impact on the pandemic in a reasonable amount of time based on good data," said Doran Fink, MD, PhD, of FDA's Office of Vaccines Research and Review.

Fink fielded a number of questions from committee members about the FDA's vaccine standards, including why vaccine manufacturers were allowed to use relatively broad definitions of COVID-19 in their primary endpoint. Some panelists thought it should be severe disease as opposed to any evidence of COVID-19 -- the latter could allow a vaccine that protects against mild disease without impact on hospitalizations or other major adverse outcomes.

"We felt we could not mandate a specific primary endpoint," he said.

The agency also drew heat at the idea that minority populations might be underrepresented in the vaccine trials, but Fink said that "less than desirable" representation would not be a reason to restrict the vaccine in those groups, as the FDA has never mandated a particular demographic composition to support licensure of a vaccine, let alone an EUA.

"Since severe disease and death occur among minorities" this is "just going to perpetuate the perception that population doesn't matter much," said James Hildreth Sr., PhD, MD, of Meharry Medical College. "If I'm not mistaken, the taxpayers of the United States of America are paying the tab for this, so you may have more authority than you think."

Calls for minority representation were echoed in the feedback from the Reagan-Udall Foundation, which cited fear based on past experiences as a reason for vaccine hesitancy. One quote -- "The more they study me, the more they know how to get rid of me" -- drew an audible whistle of disbelief during the meeting.

A variety of advocates and clinicians took the calls of many committee members a step further during the open public forum. Speaking on behalf of the HIV Medicine Association (HIVMA), Andrew Pavia, MD, of the University of Utah, said the group "would prefer" vaccine approval through a biologics license application versus an EUA.

HIVMA also supported the 60% efficacy standard, as well as sharing trial data with the CDC's Advisory Committee on Immunization Practices (ACIP), "the source most practitioners turn to for advice." ACIP previously promised a meeting on COVID-19 vaccines after the FDA has issued an EUA.

Another demographic group that drew attention was children, with committee members split on the idea of "immuno-bridging," or using data from adult vaccine trials to extrapolate efficacy in a pediatric population.

"Because of issues of immune response ... and MIS-C [multisystem inflammatory syndrome in children], it may be inappropriate to use standard bridging guidelines," said acting VRBPAC Chairman Arnold Monto, MD, of the University of Michigan.

The FDA promised additional VRBPAC meetings for each vaccine product for which EUA or approval is sought. The agency is not required to follow advisory committee recommendations but it often does.

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