Regulation
FDA will require data similar to BLA standard for COVID-19 emergency authorization
FDA officials vow rigorous standards for COVID-19 vaccines
FDA will set a high bar for issuing an emergency use authorization for COVID-19 vaccines and will present any EUA request to an advisory committee before deciding on the application, senior agency officials said Thursday.
“If we are going to do an emergency use authorization, it’s going to really be like an emergency use authorization ‘plus,’” Peter Marks, director of FDA’s Center for Biologics Evaluation and Research (CBER), said at a webinar convened by the Duke-Margolis Center for Health Policy. On the continuum between an EUA and a BLA, “it’s going to be closer to the BLA,” he said.
The legal threshold for FDA to grant an EUA is that a product may be effective and its benefits outweigh known and potential risks, while a BLA can only be approved if FDA determines there is substantial evidence of safety and effectiveness from adequate and well-controlled trials.
“If we issue an EUA, we would potentially expose millions of uninfected individuals, healthy people, to this vaccine, so we need data to support the benefit of the vaccine and these data need to be very close to those that we need to meet the [BLA] effectiveness standard,” Marion Gruber, director of CBER’s Office of Vaccines Research & Review, said at the webinar.
FDA could issue an EUA based on an interim analysis of Phase III data, but only if it meets the agency’s requirements for safety and efficacy, Marks and Gruber, said.
They indicated that an EUA would only be granted if a trial demonstrates efficacy, which FDA has defined as a 50% improvement over placebo in preventing COVID-19 infection, and if there is a median of two months of follow-up safety data. The efficacy determination will be based on the events that occur in a trial. The Phase III trials that are ongoing or expected to be launched soon in the U.S. plan to enroll about 30,000 participants. DSMBs will conduct interim analyses when about 70 events have occurred and final analyses at about 150-160 events, Marks said.
A COVID-19 vaccine EUA would not include all of the manufacturing data, and would have a shorter duration of safety data, than is required for a BLA, Gruber and Marks said.
The two-month median safety data is sufficient for an EUA because most vaccine-related adverse events occur within 90 days of administration, Marks said.
Marks also suggested that FDA will soon issue guidance about EUAs for COVID-19 vaccines. While he is legally precluded from discussing forthcoming guidance releases, he said that anyone interested in guidance on COVID-19 vaccine EUAs “might want to check back frequently on our website.”
According to FDA Commissioner Stephen Hahn, the guidance will expand on previous guidance on development of COVID-19 vaccines. It will “provide sponsors of requests for EUAs with recommendations regarding the data & information necessary to support issuance of an EUA,” he said via Twitter.
Gruber emphasized that if FDA issued an EUA, based on interim or final data, it will require sponsors to continue to collect safety and efficacy data for six months to a year. This will be intended both to better characterize safety and to assess the durability of protection, she said.
Need for diverse populations
Because COVID-19 has struck minority populations especially hard, FDA and the medical community are stressing the importance of enrolling Black Americans and other populations in clinical trials.
If the studies are successful, and 90% of those enrolled are white, and they have a low enrollment of African Americans and Latinos, you’re simply not going to have trust in the community,” Emory University School of Medicine’s Carlos del Rio said webinar. He is professor of medicine in at the school’s Division of Infectious Diseases.
Michelle McMurry-Heath, president and CEO of BIO, emphasized the importance of enrolling populations in COVID-19 vaccine trials who reflect the diversity of the U.S. population.
“We don't really understand what we're seeing in the differences in mortality related to populations,” she said. “Why are African Americans dying three times [the rate of] their white counterparts?”
It is essential to have high participation rates for minority populations to have confidence that a vaccine works for the entire population, and to build the confidence needed to persuade Americans to take an FDA authorized or approved vaccine, McMurry-Heath said.
BIO is connecting vaccine sponsors with organizations such as the Urban League that can help increase minority participating in trials.
McMurry-Heath also emphasized the need for education about trials and vaccines, and suggested that statements from some prominent African Americans have made it more difficult to recruit diverse populations. She noted Ras Baraka, the mayor of Newark, N.J., has urged Blacks to decline to participate in COVID-19 vaccine trials.
Public confidence essential
Marks and former FDA leaders speaking at the Duke-Margolis meeting stressed the importance of public confidence in FDA’s decisions about COVID-19 vaccines.
“This is one of the most important decisions that FDA will be undertaking in our lifetimes,” former FDA Commissioner Margaret Hamburg said.
Former FDA Commissioner Robert Califf said a statement issued Thursday by several senior career staff at FDA vowing to abide by scientific and legal standards for COVID-19 regulatory decisions is “extraordinarily meaningful.”
In the statement, eight of FDA’s top career officials said they “will work with agency leadership to maintain FDA’s steadfast commitment to ensuring our decisions will continue to be guided by the best science.”
They stated that they “want the American people to know that the FDA’s 17,000-plus career staff will continue to work to the best of our ability on their behalf, and with their health and well-being as our beacon.”
Califf said, “It’s a great thing that we have people that are not conflicted and can make these decisions for the public health.” He is head of clinical policy and strategy at Verily Life Sciences.
To bolster confidence, Marks said FDA and sponsors will make data about COVID-19 vaccines available to the public as part of the advisory committee process before any decisions about EUAs or BLAs.
One of the conundrums FDA is grappling with is the need for multiple vaccines and the effects that granting an EUA or full approval for one vaccine could have on other vaccine development programs.
Gruber said that while FDA hopes volunteers will continue to participate in controlled trials after a vaccine clears the EUA or BLA hurdle, it realizes that people may become unwilling to accept the possibility of receiving a placebo.
She declined to elaborate on approaches the agency could take to ensure that vaccine trials produce actionable data after the approval or authorization of alternatives. FDA is “reaching out to experts to help us with that,” she said. “We are tackling this problem because it’s an important one for which we have to have a solution.”
