5 things to know about the FDA’s COVID-19 vaccine authorization

After the US Food and Drug Administration’s emergency use authorization for the COVID-19 vaccine from Pfizer and BioNTech, Holly Fernandez Lynch sheds light on the EUA process.

The agency is holding another meeting December 17th to determine whether they will issue one for the vaccine candidate from Moderna.

EUAs will allow some members of the American public—not just those enrolled in clinical trials—to begin receiving the vaccines. But an EUA is not the same as traditional FDA approval. What exactly is an EUA, and what does this mean for future vaccine distribution and study?

Here, Fernandez Lynch, a bioethicist in the Perelman School of Medicine at the University of Pennsylvania whose work has focused on clinical research, illuminates why the FDA is using this alternative route for authorizing use of vaccines, unpack the power and limitations of the EUA pathway, and lay out the emerging ethical concerns related to vaccine research that this action raises:

1. An EUA depends on several considerations

Congress granted the FDA authority to issue EUAs in 2004 in response to concerns around bioterrorism and anthrax, says Fernandez Lynch. As the name suggests, an EUA may be issued only following the federal declaration of an emergency stemming from a chemical, biological, radiological, or nuclear (CBRN) agent. In the present context, the agent is biological: the SARS-CoV-2 virus. The Department of Health and Human Services declared a public health emergency on February 4, followed by more specific declarations allowing FDA to issue EUAs for COVID-19 diagnostics and drugs.

The fact that EUAs are limited to certain emergencies “is really important and one of the things I’m interested in studying further,” Fernandez Lynch says, “because obviously the FDA is approving products for patients facing personal emergencies all the time—a horrible cancer or untreatable neurological disease. But this authority is intended for public health emergencies that stem from those particular CBRN sources.”

Products used to diagnose, prevent, or treat serious or life-threatening conditions caused by CBRN agents can fall under the purview of an EUA. Indeed, several EUAs have already been issued this year for COVID-19 treatments, such as remdesivir, convalescent plasma, and monoclonal antibodies. And there must be “no adequate, approved, and available alternatives” according to the regulation.

“There’s a lot of work being done by those terms, ‘adequate’ and ‘available,'” Fernandez Lynch says, as there is currently no cure for COVID-19 and several therapies have been in short supply. This means that several EUAs can be issued.

While full approval from the FDA requires a demonstration of safety and substantial evidence of effectiveness, an EUA only requires a determination that the product may be effective and that its known and potential benefits outweigh the known and potential risks.

“That gives the FDA a ton of flexibility,” says Fernandez Lynch. “It also means they are making a political decision, not just a scientific decision, because they are weighing those benefits and risks on behalf of our society.”

2. Strong results made decisions easier

The calculus of that risk-benefit analysis would have been more difficult if candidate vaccines were closer to the cut-off that the FDA set for COVID-19 vaccine EUAs of 50% effectiveness. But because clinical trial data from Pfizer-BioNTech and Moderna suggest their vaccines offer greater than 90% protection against COVID-19, the rationale for authorizing their use is much stronger.

That doesn’t mean there are no questions about risks, especially considering that vaccines will be given to potentially billions of healthy people. Trials have included tens of thousands of participants, many more than usual, but rare side effects may still appear once vaccines move into the much larger general population.

There are a number of open questions about the vaccines, says Fernandez Lynch, including how long protection lasts, whether the inoculation prevents recipients from spreading the virus or only from getting sick themselves, and exactly how protective the vaccine might be for different age groups. Although the Pfizer-BioNTech and Moderna vaccines were tested in older adults, “one glaring omission is we don’t have data about younger kids,” she says, “and we don’t have data about pregnant women.” The EUA for the Pfizer-BioNTech vaccine does not apply to children under 16.

3. The EUA process was fast but thorough

Over the summer, Fernandez Lynch and many others grew alarmed by political interference in the FDA’s EUA process. Some worried that the president would push for vaccine authorization with a focus on Election Day rather than waiting for sufficient data. But after it became clear that the FDA was committed to a rigorous but expedient process, “those concerns have largely been mitigated,” Fernandez Lynch says.

“The data are being vetted very carefully, and the evidence for the vaccines that have requested EUA so far looks more promising than we could have imagined.”

When Pfizer-BioNTech and Moderna announced in November that data from their clinical trials appeared promising, that data had already been reviewed by data safety monitoring boards or DSMBs, tasked with independently analyzing the data as it was collected. But for the FDA to issue an EUA, the agency’s own scientists must review all of the data on their own and then pass publicly available briefing materials to yet another body, the Vaccine and Related Biological Products Advisory Committee, which met last week. The advisory committee is composed of several outside experts who make recommendations to the FDA. The FDA is not required to follow those recommendations, but it usually does.

“There was just a mind-boggling number of documents FDA scientists had to review,” Fernandez Lynch says. In addition to looking at the clinical trial data, the FDA also considers plans for manufacturing the vaccines to ensure safety and consistency across batches so every person getting a vaccine receives the same dose and same product.

4. An emergency could be lifted without an approved vaccine

Vaccine clinical trials will continue even after the EUA to monitor long-term safety. Yet when the time comes that enough people are vaccinated and COVID-19 case numbers significantly decline, the emergency declaration will be lifted.

“That’s the trick of the EUA. It’s supposed to be temporary,” Fernandez Lynch says. “If a company hasn’t gotten its traditional marketing approval by the time the emergency ends, then their product reverts to being an unapproved drug. I’m not worried about that for these first few vaccines, though.”

To get that full approval would require more long-term follow up of the vaccine safety and efficacy, which some predict could happen in the middle of 2021.

5. Authorization throws a wrench in placebo-controlled trials

Given the number of open questions that will persist even after the EUA, it is important for vaccine research to continue. The most rigorous way to answer those questions is double-blind, placebo-controlled, randomized trials, meaning that a portion of participants do not get the actual vaccine and neither the researchers nor the participants know who is in which group. But is it ethical to continue using placebo controls when there’s one or more effective vaccines? And is there an obligation to tell people in ongoing trials whether they received a placebo?

“It becomes much harder to run placebo-controlled trials when participants can access the product on their own,” says Fernandez Lynch. “The FDA and companies will need to work together on this.”

For now, she notes that vaccine availability is constrained by limitations in ramping up manufacturing and distribution, which means that many of the healthy individuals enrolled in trials may not be able to access a vaccine quickly and thus wouldn’t have an incentive to leave a trial. Pfizer has proposed to start vaccinating placebo participants as they become eligible for access to vaccines, based on prioritization criteria that would apply outside the trial. Fernandez Lynch says this a reasonable compromise that allows for continued data collection, gives participants less reason to withdraw, and avoids lower-risk participants being vaccinated before higher-risk nonparticipants.

Another vaccine manufacturer, Sanofi, with a product earlier in development, has indicated that it plans to test its vaccine against one that is already authorized for use rather than a placebo, a more challenging design but one likely necessary to achieve adequate enrollment.

The question of what companies and the government owe to participants in the trials versus the desire to continue to collect robust data doesn’t have a clear ethical answer, Fernandez Lynch says. “A lot of ethics is about trade-offs, and that is what we’re seeing in this circumstance.”

Source: University of Pennsylvania

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