The U.S. Food and Drug Administration (FDA) last week issued guidance to provide sponsors, or vaccine makers, with information on requesting an Emergency Use Authorization (EUA) for COVID-19 vaccines.
The October guidance, which complements June guidance issued by the agency, specifically provides recommendations regarding the data and information a sponsor would need to support the FDA issuing an EUA for an investigational vaccine to prevent COVID-19.
FDA Commissioner Dr. Stephen Hahn during an Oct. 8 event on COVID-19 vaccines sponsored by the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota, explained that an EUA from the FDA allows unapproved medical products to be used in an emergency to diagnose, treat or prevent life-threatening disease or conditions.
Thus far, the FDA has used several of them during the pandemic to more swiftly get diagnostic tests for COVID-19 to market compared to the agency’s typical approval process, which is done via a biological license application (BLA).
Hahn said a BLA actually could take months to get to the point where you develop a platform with a vaccine, go through the studies and the preclinical trials, and then stop and analyze the data. A manufacturer then would also take months to analyze the research data, he said.
“A typical BLA is tens of thousands of pages and it would likely take months for the FDA to review it,” said Hahn, noting the application contains “very comprehensive information” about quality manufacturing, safety and efficacy.
Comparatively, the EUA standard is different by statute and is a risk benefit assessment that gives the FDA a lot of flexibility, Hahn said.
“The EUA was put in place following the 9/11 terrorist attacks to ensure that potentially life-saving medical products could be available to people before they were fully studied to the same level we would use for approval,” said Hahn.
“With that being said, we know that our vaccine is going to be given to millions, perhaps hundreds of millions of people so the standard for risk benefit assessment would change because we’re not talking about someone who is sick with COVID-19 in the intensive care unit; we’re talking about a preventative measure as a vaccine,” he said. “So we very carefully have to look at both safety and efficacy.”
Specifically, Hahn explained that during a public health emergency like the current pandemic, statutory authority permits an EUA so the FDA can use a standard of assessing risks and benefits that determine a medical product is appropriate.
Regarding the speed of the COVID-19 vaccine development now under way, he said it has really been made possible by advances in molecular biology that have allowed developers and manufacturers to understand the genetic sequence of the coronavirus and then use it either with established platforms or newer technologies to produce the vaccine candidate.
Such candidates, Hahn added, then were taken through rapid non-clinical studies and then in early studies, in phase 1 and phase 2, to assess safety and induction and immune response. This summer, the candidates went into large, well-designed, minimized-controlled trials.
At the same time, Hahn said companies are making vaccines and scaling up manufacturing at risk “so if — and I stress if — the vaccine is shown to be safe and effective, then the vaccine will be ready relatively quickly after the authorization approval.”
“In this particular instance, what is being done is that these phase 3 trials are events-driven, so when the data safety monitoring board advises the manufacturers that an event has been reached — in this case the efficacy of the vaccine — they will analyze those data and then they will apply to the FDA” for either the standard BLA or an EUA, said Hahn.
The new EUA guidance clarifies that the FDA needs to see clear and compelling evidence on efficacy and safety from at least one well-designed, well-performed phase 3 clinical trial, Hahn added, saying that the trials are large, comprising about 30,000 people or more from a variety of categories.
“This is based in part on our June COVID-19 vaccine guidance where we asked for certain efficacy endpoints,” he said. “We do acknowledge that for an emergency use authorization, that although the efficacy endpoints are very similar to what we would require for a biological license application, the follow up to safety may be shorter.”
To make up for this, Hahn said the FDA will be working with companies to have a very robust collection of safety data on an ongoing basis after the vaccines are deployed. “So, the duration of safety for authorizing a vaccine may be shorter than a BLA, but there will be safety surveillance of millions of individuals,” he said.
Dr. Margaret Hamburg, a former FDA commissioner who recently completed a term as the foreign secretary at the National Academy of Medicine, underscored another reason why there has been an ability at the FDA to move much more swiftly.
“It’s also about partnership; it’s about the elements of the vaccine, research and development, and the review ecosystem all working together,” said Hamburg during the CIDRAP virtual vaccine event.
While the FDA is the regulatory body that will say yay or nay to a final product, Hamburg said it’s also a science-based public health agency with a regulatory mission. The agency’s ability to sit down early with those that are doing the R&D — the academic scientists, the industry scientists, and the government research sponsors — to map out critical questions and concerns and about how to think about hastening the development process without abandoning quality science and rigor, “has been important and it really speaks to the central role on both science and regulatory review and oversight that the FDA can and should play,” she said.
Event moderator Michael Osterholm, regents professor at the University of Minnesota and CIDRAP director, agreed, calling the FDA’s role “unparalleled in the world.” The infusion of the agency’s expertise into this process is critical, Osterholm added.
And while the timelines for vaccine development have been compressed, Hahn emphasized that there are no changes to FDA standards.
“We’ve been very clear in our guidance … what would be our criteria for an EUA and what will be our criteria generally for safety and efficacy,” Hahn said.
That’s particularly crucial for the public to know and understand because even if a vaccine is deemed safe and effective, “if the public doesn’t have trust in that vaccine and won’t use it, then it won’t achieve our public health goals,” said Hamburg, an internationally recognized leader in public health and medicine.
Hamburg also pointed out that finding the right balance in this situation is enormously important and “this kind of weighing and balancing of risks and benefits is what the FDA practices every day,” even though some decisions are much harder than others.
For instance, FDA approval of a vaccine now would come during a particularly challenging context in which making such hard decisions requires more data than what is available, she said. “In addition,” said Hamburg, “it’s in a fish bowl of media and public scrutiny, but also with a lot of external political pressures and competing priorities, needs and interests. This is a very, very challenging situation.”
Hahn reiterated that the FDA would consider an EUA if a vaccine sponsor first requested one, but he would not speculate on when any vaccine sponsor would be ready to submit a product to the FDA for either an EUA or BLA.
Currently, according to reports, there are five COVID-19 vaccines in the final stages of American clinical trials that are being developed by AstraZeneca, Moderna, Novavax, Pfizer, and Johnson & Johnson.
“Every application will be taken on a case-by-case basis,” Hahn said. “Our intention is when or if we make a decision about a vaccine … we will be transparent about the information.”
“The more engagement, the more transparency, the better off we all are and the more accountability there will be,” added Hamburg.