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White House allows FDA to release long-awaited COVID vaccine EUA guidance 

CBER’s Marks: guidance aimed at increasing public confidence in FDA’s integrity

CBER’s Peter Marks says the guidance is aimed at increasing public confidence in FDA’s integrity.

Oct 6, 2020 | 2:40 PM GMT

In a move that is intended to bolster public confidence in FDA’s integrity, the agency Tuesday posted guidance about emergency use authorization of COVID-19 vaccines.

FDA posted the guidance after the White House dropped a weeks-long hold it had placed on the document. The White House green light came hours after the agency had bypassed the Trump administration by releasing key provisions from the guidance in a briefing document distributed in advance of an advisory committee meeting.

Release of the guidance is aimed at increasing public confidence in the integrity of FDA’s regulatory decisions, Peter Marks, director of FDA’s Center for Biologics Evaluation and Review (CBER), said Tuesday at a virtual symposium organized by Johns Hopkins University and the University of Washington.

Suppressing the guidance served no purpose, former FDA Commissioner Scott Gottlieb said at the symposium. Gottlieb said he couldn’t remember a time when “so much political dust was created by political officials for so little effect.” He added that regardless of whether the guidance was made public, FDA was going to enforce its provisions, the agency’s advisory committee was going to support them and sponsors would adhere to them.

While there has been broad support for releasing the guidance, some public health opinion leaders Tuesday called for the agency to revise the guidance to set a higher bar for demonstrating safety.

Meanwhile, President Donald Trump said in a tweet that the guidance will slow progress by vaccine makers.

“New FDA Rules make it more difficult for them to speed up vaccines for approval before Election Day. Just another political hit job!” he tweeted, tagging FDA Commissioner Stephen Hahn.

Duration of safety data is controversial

The guidance addresses the most politically contentious aspect of COVID-19 vaccine EUA standards, stating that two months of safety data will be required before authorization. Trump and White House officials have accused FDA of attempting to sabotage his reelection prospects by creating standards that preclude vaccine authorization before the election. Trump’s statements prompted seven former FDA commissioners to call for the White House to allow FDA to act independently based on science and the best interests of the American public. 

“Data from Phase 3 studies should include a median follow-up duration of at least two months after completion of the full vaccination regimen to help provide adequate information to assess a vaccine’s benefit-risk profile.”

Safety data FDA will consider include “adverse events; cases of severe COVID-19 disease among study subjects; and cases of COVID-19 occurring during the timeframe when adaptive (rather than innate) and memory immune responses to the vaccine would be responsible for a protective effect.”

In addition, according to the summary provided to the Vaccines and Related Biological Products Advisory Committee, “safety data would include a high proportion of enrolled subjects — numbering well over 3,000 vaccine recipients — followed for serious adverse events (SAEs) and adverse events of special interest for at least one month after completion of the full vaccination regimen.” 

To assess the potential for the vaccine candidate to cause vaccine-induced enhanced respiratory disease, EUA criteria include the presence of at least five severe COVID-19 cases in the placebo arm. 

The requirement for two months of safety data is based on the need to balance speed with confidence that the vaccines will not hurt those who receive them, Marks said. Most adverse events caused by vaccines are detected within two or three months of vaccination, he said.

Marks acknowledged that “we will have a narrower amount of safety data” than is usually required for vaccines. He said the urgent need to combat a pandemic that is killing about 1,000 Americans daily, as well as advances in postmarket surveillance, support the decision to reduce the duration of safety data.

COVID-19 vaccine safety will be assessed with active surveillance systems, including collection of data from insurance claims records, as well as the traditional passive monitoring systems, Marks said.

Call for higher safety bar

The duration of safety data is likely to be debated vigorously at the advisory committee meeting on Oct. 22.

Some prominent public health researchers believe that a median of two months is not sufficient.

More than 60 scientists signed a letter sent to Marks Tuesday urging FDA to “require a high bar for safety.” It called for “a minimum of two months of safety observation for all trial participants.”

The letter states that “trial participants are already a sample of the population; to diminish the weight of some trial participants does not make sense. Under the FDA’s proposed lower bar, a vaccine could be authorized before many trial participants have been observed through the period when most adverse vaccine events occur.”

Signatories of the letter include Ezekiel Emanuel, vice provost and chair of the Department of Medical Ethics and Health Policy at the University of Pennsylvania; Peter Hotez, co-director of the Texas Children’s Hospital Center for Vaccine Development and dean of the National Tropical School of Medicine at Baylor College of Medicine; Tom Inglesby, director of the Johns Hopkins Center for Health Security; and Eric Topol, director of the Scripps Research Translational Institute. Emanuel and Sharfstein are advisers to the Joe Biden presidential campaign.

EUA based on interim data possible

The guidance and the briefing document state that an EUA could be granted based on “an interim analysis of the clinical endpoint from an ongoing Phase 3 efficacy study.” The analysis would have to show at least 50% efficacy in a placebo-controlled trial, with a lower bound of the confidence interval around the primary endpoint of more than 30%. 

FDA said it has made it clear to vaccine developers that if it grants an EUA, they must not halt their Phase III trials. “FDA has advised sponsors that FDA would not consider availability of a COVID-19 vaccine under EUA, in and of itself, as grounds for stopping blinded follow-up in an ongoing clinical trial.”

Consistent with a June 2020 guidance on BLAs for COVID-19 vaccines, an EUA would be based on “adequate manufacturing information to ensure its quality and consistency and a determination by FDA that the vaccine’s benefits outweigh its risks based on data from at least one well-designed Phase 3 clinical trial that demonstrates the vaccine’s safety and efficacy in a clear and compelling manner.”

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