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COVID-19 Vaccines Ex-FDA Leaders Urge High Bar For Emergency Use Authorization Cover Image

An emergency use authorization for a COIVD-19 vaccine might be appropriate following strong Phase II data if product use is limited to a very narrow and high-risk population, three former US FDA leaders in vaccine and countermeasures work told the Pink Sheet.

But FDA should exercise extreme caution in issuing an emergency use authorization for a COVID-19 vaccine, these past leaders and other vaccine and medical research experts emphasized, in part because such an EUA for a vaccine would be unprecedented and the agency could be setting a standard for future EUAs. The success or failure of this emergency use could also have ramifications for the public’s trust in the entire vaccine enterprise, they said.

The 2004 Project BioShield Act allows FDA to authorize the use of an unapproved medical product during a declared emergency related to a naturally occurring emerging infectious disease. The standard for an authorization is lower than the standard for product approvals, allowing FDA to permit use of a medical product that “may be effective.”

The criteria for an EUA is subjective and so loose that earlier this week the agency granted an emergency use authorization to two antimalaria drugs to treat COIVD-19 based only on laboratory data and anecdotal clinical reports, acknowledging there is not yet evidence of clinical efficacy of the drugs for coronavirus. (Also see "FDA's Emergency Use Authorization for Malaria Drugs Could Hinder Trials of Other COVID-19 Treatments" - Pink Sheet, 30 Mar, 2020.)

That move raised concerns about political pressure on the agency, given President Trump's advocacy for the products. Worries that FDA might not be able to follow its best scientific judgement would be particularly acute for a vaccine to inoculate recipients against SARS-CoV-2, the virus that causes COVID-19 disease. A universally administered vaccine should allow normal life in the country to resume, and thus the pressure to bring it out as soon as possible could be enormous.   

FDA has never granted an EUA to a previously unapproved vaccine. The only vaccine-related EUA that the agency has granted so far went to Emergent BioSolutions Inc. anthrax vaccine in 2005-2006, authorizing expanded use of an already cleared vaccine. (Also see "Coronavirus Efforts Could Benefit From Little-Used Medical Countermeasures Incentives" - Pink Sheet, 29 Jan, 2020.)

‘You’re Never Going To Answer The Question’

Because vaccines are given to healthy people, the standard for a COVID-19 vaccine EUA must be higher than what would be acceptable for drugs to treat COVID-19, such as that used for hydroxychloroquine and chloroquine, experts said.

If FDA is “going to let large swaths of people have access to the vaccine, there should be a study that actually demonstrates vaccine efficacy,” against a placebo, said Karen Midthun, former director of FDA’s Center for Biologics Evaluation and Research. Immunogenicity data or another surrogate endpoint would not be enough for an emergency use authorization, unless it was limited to a very small population, said Midthun, who is now a principal at Greenleaf Health.

Midthun said immunogenicity data, combined with strong safety data, might be acceptable for an EUA that was limited only people at very high risk of the disease, like healthcare workers or first responders. This should ensure that full trials evaluating a clinical endpoint could be completed.

This is “uncharted territory,” Midthun said. “You need to be really careful” about who would be permitted to get the vaccine under an EUA, “because if it becomes targeted in a broad way, then you’re never going to answer the question, does this vaccine prevent disease or not.”

If pivotal studies are positive, Midthun also suggested an EUA could be used to bridge the gap between the time the trials complete and FDA’s review of the vaccine.

Jesse Goodman, who served as FDA’s Chief Scientist from 2009 through 2014 and head of CBER for about a half dozen years before that, said that if there are continuous outbreaks of coronavirus, he could see an emergency use authorization being issued after completion of Phase II, noting that if studies are taking place during an outbreak it might possible to see an efficacy signal in trials.

For safety, Goodman said, there should be data on antibody-mediated toxicity prior to an EUA. “The last thing you want is to have more susceptibility [to the disease] in vaccinated people,” he said.

“The messaging” around any EUA, “has to be extremely candid,” he added, so people clearly understand an EUA is not the same as an FDA approval, the amount of safety and efficacy data known, and what risks they may be exposing themselves to.

This communication should come from clinical scientists and public health professionals, not politicians, and needs to consider the implication an EUA could have on the public’s perception of vaccines as an entire class of medicines, he said.

“Trust in the whole enterprise and vaccines in general is something that is very precious, so I think that is going to make this doubly important,” he said.

Norman Baylor, who retired from FDA in 2011 as the Director of the Office of Vaccine Research and Review, came to a similar conclusion as Midthun and Goodman, that an EUA might be possible after positive Phase II data if it was limited to first responders and health care workers who would have a different risk-benefit calculus than the average member of the public.

Others More Cautious Than ex-FDA Leaders

Johnathan Kimmelman, director of biomedical ethics at McGill University, was even more skeptical of the EUA mechanism than the former officials. “I can't think of any reason why you would want any different evidentiary standards today as what you would have in a non-pandemic setting,” he said. “Most drugs and vaccines that go into early phase investigations turn out to be either on unsafe and/or ineffective.

He worries that any EUA will make patients unwilling to enter ongoing clinical trials of the vaccine that may randomize them to a placebo. “The last thing you want in a pandemic setting is to start deploying treatments that are pulling patients away from the clinical trials you need to run to evaluate these interventions. ... And anything that's going to slow down that process of a critical and rigorous evaluation of a new intervention is something we ought to be really, really careful about.”

Exposing the public to an unproven vaccine comes with an “added variable” that is not present with an unproven drug, Kimmelman added. If patients receive a vaccine that they assume is protective, they may change their behavior and potentially amplify their risk to the disease.

“This is a what people call the risk treadmill, you give a person a vaccination, they now undertake riskier behavior because they think they're protected. And if in fact, the vaccine turns out to be ineffective, they're actually amplifying the risk.”

Holly Fernandez Lynch, a bioethicist at University of Pennsylvania, worries that moving forward with an EUA too quickly could lead to significant safety issues when the product reaches a large population, potentially jeopardizing broader public trust in vaccines.

“Vaccine safety issues are dangerous of course because of the adverse events for vaccinated individuals, but are also socially dangerous given what precarious footing vaccines are on already.”

While Lynch feared the FDA may move too quickly on a COVID-19 vaccine EUA, given the standard set by the hydroxychloroquine and chloroquine EUA, some regulatory consultants were confident that FDA will think very differently about a vaccine EUA than a drug EUA.

Kelly George, a FDA-focused consultant at Avalere health, said she believes FDA will be “very cautious” when considering granting an EUA for a vaccine. “I don’t think they will necessarily jump too quickly.”

George said there’s already a higher bar for vaccine approval than for drugs, and she believes the bar for an EUA for a vaccine will be higher than an EUA for a drug.

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