COVID-19 Vaccine Standards Questioned at FDA Advisory Meeting

Kerry Dooley Young

October 22, 2020

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

Federal advisers, researchers, and several medical groups on Thursday suggested changes to the US Food and Drug Administration's (FDA) current plans for deciding how to eventually clear vaccines for COVID-19, arguing tougher standards would help bolster confidence in these critical medicines.

The FDA's Vaccines and Related Biological Products Advisory Committee met Thursday for a wide-ranging discussion. The FDA did not ask the panel to weigh in on any particular vaccine or vote on questions, as is the usual procedure. Instead, the FDA asked for the panel's feedback on a series of questions, including considerations for continuing phase 3 trials if a product were to get an interim clearance known as an emergency use authorization (EUA).

At the conclusion of the meeting, Marion Gruber, PhD, director of the Office of Vaccines Research and Review at the FDA Center for Biologics Evaluation and Research, sought to recap the main points raised by advisers. They had questions about when patients in the placebo groups of trials would be able to take approved vaccines, citing concerns about potentially clouding the results of studies.

And concerns were raised about the FDA's decision to set a median follow-up duration of 2 months in Phase 3 trials in connection with expected EUA applications for COVID-19 vaccines.

"If it cannot be longer, then by no means should it be shorter," Gruber told the panel's Acting Chair, Arnold Monto, MD, of the University of Michigan, Ann Arbor, as they tried to summarize the main points of the meeting. "That's what I heard."

Monto agreed that there has been concerns about the 2-month benchmark.

During the deliberations, the consumer representative on the panel, Sheldon Toubman, JD, of the New Haven Legal Assistance Association, said the EUA option should not be used at all for the COVID-19 vaccines and drugmakers should have to go through the normal biologics license application (BLA).

That approach would help efforts to overcome people's concerns about these vaccines, which have been developed at a quick pace, he said. Earlier at the hearing, Susan C. Winckler, RPh, JD, chief executive of the Reagan-Udall Foundation for the FDA, told the panel about the feedback her group has heard about COVID-19 vaccine concerns. The Reagan-Udall Foundation is an independent organization created by Congress to aid with the FDA's work.

Winckler didn't offer solutions or advice to the FDA. She instead presented statements from what she termed listening sessions, including ones that reflected fears stemming from past racial discrimination in medical care. 

"In this particular case, public trust equals success. Lack of trust means no success," Toubman said. "Where that leads me to is the conclusion that EUA probably should not be used here."

The EUA approach makes sense for medicines where people's lives are at stake, he added.

"They are ill so you have to do something, so the balance changes there," Toubman said. "With vaccines, it's a different story. Almost everyone who is going to be injected is going to be healthy at the time they get the injection."

He noted earlier that some COVID-19 vaccines being developed use new technologies that have not been used in other medicines.

"There could be adverse effects we don't know about, and so, isn't 2 months a little short?" he asked.

Striking a Balance

In response, Doran Fink, MD, PhD, of the FDA's Office of Vaccines Research and Review, elaborated on the agency's approach to considering COVID-19 vaccines. It's seeking to assure safety while also gathering enough data for a fairly quick response to COVID-19, which has claimed more than 220,000 lives in the United States.

"Here we are trying to strike a balance between getting information on the most clinically significant outcomes of COVID-19 and how a vaccine might be able to prevent those outcomes versus being able to make an impact on the pandemic in as reasonable amount of time as possible based on good data," Fink said.

Drugmakers are free to choose their own primary endpoint and FDA staff felt they couldn't mandate ones focused on severe disease, he said. Cases of severe disease tend to be less common with COVID-19, so they would have less evidence to determine the frequency of this outcome.

"But we do expect to have some [data] and we will use that evidence as one piece of information to inform our benefit–risk determination," Fink said.

FDA panelist James E.K. Hildreth,  MD, PhD, who is president and chief executive officer of Meharry Medical College in Nashville, Tennessee, noted that COVID-19 has taken a higher toll on some groups than others. 

The Centers for Disease Control and Prevention (CDC), for example, recently released an analysis of US COVID-19 deaths between May and August that showed Black and Hispanic persons were disproportionately represented. Black people accounted for 18.7% of overall deaths despite representing just 12.5% of the US population, and Hispanic people accounted for 24.2%, while making up about 18.5% of the US population.

Members of these populations are already concerned about how they are being treated in this crisis, given that they have suffered more serious effects, Hildreth said.

He also noted earlier concerns raised during a public hearing session of the meeting about the approach to testing COVID-19 vaccines. Among the speakers was Peter Doshi, PhD, an associate professor at the University of Maryland School of Pharmacy, Baltimore, who argued that current trials won't answer the right questions about COVID-19 vaccines.

"We could end up with approved vaccines that reduce the risk of mild infection but do not decrease the risk of hospitalization, ICU use, or death — either at all or by a clinically relevant amount," Doshi told the panel.

In his presentation, he reiterated points about improper trial design he had previously made, including in an October 21 article published in BMJ, of which he is an associate editor. Doshi also raised these concerns in a September opinion article published in The New York Times, coauthored by Eric Topol, MD, director of the Scripps Research Translational Institute and editor-in-chief of Medscape.

FDA panelist Hildreth asked that the agency to make sure approved vaccines do address severe cases of COVID-19.

"If we put vaccines out there that don't address that issue, we're just going to perpetuate the perception that that population, or that segment of our population, does not matter much," he said.

Hildreth also noted there has been significant investment of federal money in vaccines. Since March, the Trump administration has made several announcements about federal funding for experimental vaccines, such as $1.5 billion to support the large-scale manufacturing and delivery of Moderna's investigational vaccine candidate.

"You might have more authority to mandate than you might think," Hildreth told Fink.

A Vaccine for Everyone

Panelist Michael R. Nelson, MD, PhD, questioned how the EUA would work for groups of patients not well represented in a study. FDA's Fink said there may be cases where there is less demographic information than the agency would like.

"Those types of gaps would not necessarily in and of themselves result in a restriction," Fink said. "We would have to think about whether it makes sense from a scientific basis."

For example, FDA staff won't automatically assume that a vaccine that works for younger people would work for older people, he said.

"If we have very limited data on safety or effectiveness on elderly individuals, that would cause us concern and we would have to consider whether the data really did support authorization or licensure of the vaccine for use in the elderly population," Fink said.

Earlier in the day, speakers at the hearing made a variety of requests, including asking for data showing COVID-19 vaccines can prevent serious illness and urging transparency about the agency's deliberations for each product to be considered.

FDA staff are closely tracking the crop of experimental vaccines that have made it into advanced stages of testing, including products from Pfizer, AstraZeneca, Johnson & Johnson, and Moderna.

"Time for a Reset"

Among the speakers at the public hearing was Peter Lurie, MD, who served as an FDA associate commissioner from 2014 to 2017. Now the president of the Center for Science in the Public Interest, Lurie was among those who asked the agency to make its independence clear.

President Donald Trump has for months been making predictions about COVID-19 vaccine approvals that have been overly optimistic. In one example, the president, who is seeking re-election on November 3, last month spoke about being able to begin distributing a vaccine in October.

"Until now the process of developing candidate vaccines has been inappropriately politicized with an eye on the election calendar, rather than the deliberate timeframe science requires," Lurie told the FDA advisory panel. "Now is the time for a reset. This committee has a unique opportunity to set a new tone for vaccine deliberations going forward."

Lurie asked the panel to press the FDA to commit to hold an advisory committee meeting on requests by drugmakers for EUAs. He also asked the panel to demand that informed consent forms and minutes from institutional review board (IRB) discussions of COVID-19 vaccines trials be made public.


Risks of a "Rushed Vaccine"

Other presenters added to the questions about the FDA's plan for a 2-month follow-up time after vaccination, which was seen as too short. ECRI, a nonprofit organization that seeks to improve the safety, quality, and cost-effectiveness of medicines, has argued that approving a weak COVID-19 vaccine might worsen the pandemic.

In an October 21 statement, ECRI noted the risk of a partially effective vaccine, which could be welcomed as a means of slowing transmission of the virus. But public response and attitudes over the past 9 months in the United States suggest that people would relax their precautions as soon as a vaccine is available.

"Resulting infections may offset the vaccine's impact and end up increasing the mortality and morbidity burden," ECRI said in the brief.

"The risks and consequences of a rushed vaccine could be very severe if the review is anything shy of thorough," ECRI Chief Executive Officer Marcus Schabacker, MD, PhD, said in a statement prepared for the hearing.

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