Executive Summary
US FDA plans to leverage large safety surveillance databases to make up for the fact that a vaccine authorized for emergency use likely would have only one-quarter to one-half as much safety data follow-up as a typical vaccine licensed under a BLA, says CBER director Peter Marks.
A COVID-19 vaccine that comes to the US market under an emergency use authorization is likely to have one-quarter to one-half as much safety data in length of follow-up relative to a typical vaccine approved under a biologics license application.
However, what the US Food and Drug Administration may lack in patient-years of safety follow-up preauthorization it intends to make up for through enhanced pharmacovigilance, including leveraging large surveillance systems that are capable of identifying vaccine safety signals, Center for Biologics Evaluation and Research director Peter Marks said.
Speaking during the Friends of Cancer Research’s 24th annual cancer leadership reception on 29 September, Marks also defended the potential use of the EUA mechanism to get a safe and effective COVID-19 vaccine to market, and he discussed what he now sees as his primary job – that of trust-builder – in the run-up to the availability of a COVID-19 vaccine in the US.
Four vaccines for which the government’s Operation Warp Speed has made financial commitments for their development, manufacture and/or purchase are now in Phase III in the US, with the furthest along in the process being the mRNA vaccines from Pfizer Inc. and Moderna, Inc. (Also see “Pfizer Appears Slightly Ahead Of Moderna In COVID-19 Vaccine Race” – Pink Sheet, 17 Sep, 2020.)
Novavax, Inc., which also has OWS backing, recently started its first Phase III trial in the UK.
President Trump repeatedly has predicted that a vaccine could be publicly available by the 3 November elections. However, the ongoing nature of the Phase III trials appears to make that timing highly unlikely, even under the EUA process.
At the FOCR event, Anthony Fauci, director of the National Institutes of Allergy and Infectious Diseases, said that while it is possible there could be an answer in October on whether there is a safe and efficacious vaccine, such data are more likely to come in November or December.
Enhanced Safety Monitoring After Authorization
Although the EUA route has a lower evidentiary bar than the “substantial evidence” required under a BLA, CBER has said it expects the data package supporting an EUA request will be closer to the BLA threshold, an “EUA plus” approach. (Also see “US FDA Expects COVID-19 Vaccines To Meet ‘EUA Plus’ Standards, Marks Says” – Pink Sheet, 10 Sep, 2020.)
The FDA also is asking sponsors for a median of two months of follow-up on study subjects, a time window that is based on adverse event patterns seen with other vaccines. (Also see “US FDA’s Two-Month Safety Window For COVID Vaccines Based On Adverse Events In Other Products” – Pink Sheet, 28 Sep, 2020.)
Nevertheless, Trump’s push for a vaccine by election day, the appearance of political interference in emergency authorizations for hydroxychloroquine and convalescent plasma, and the lower evidentiary bar for an EUA relative to a BLA has public health experts, academics, lawmakers and other stakeholders raising alarms that a vaccine could be rushed to market without enough information on safety.
“The person-years of follow-up won’t be quite as large to start, but we have these excellent surveillance systems and that’s something that’s really come along in the past 5-10 years.” – FDA’s Peter Marks
The Department of Health and Human Services’ own National Vaccine Advisory Committee has urged the FDA to exercise “great caution” if it uses the EUA path. (Also see “COVID-19 Vaccines: HHS Advisory Committee Urges ‘Great Caution’ On Use Of EUA” – Pink Sheet, 28 Sep, 2020.)
While acknowledging that the data at the time of authorization would be more limited than would be the case with a BLA approval, Marks nevertheless tried to dispel concerns that the agency would give short shrift to safety in the EUA process.
“Typically our vaccines have had somewhere between 8,000 and 160,000 person-years of follow-up when a BLA is issued,” Marks said. “Now here if we do an emergency use authorization, it will probably be a quarter or possibly it could be even a half of that.”
Following an authorization, the FDA intends to gather as much real-world safety information as possible using large databases such as the Sentinel system, he said.
“So the person-years of follow-up won’t be quite as large to start, but we have these excellent surveillance systems and that’s something that’s really come along in the past 5-10 years,” Marks said. “That’s not something that we had back in 1976 with swine flu, and we certainly didn’t have it back in the ‘50s. These are really systems that can help us. We know they can detect signals from previous experience, and so we’ll use those to the fullest extent.”
The Centers for Disease Control and Prevention and other government agencies also plan to leverage existing surveillance and data platforms for real-world effectiveness studies of COVID-19 vaccines following authorization. (Also see “Real-World Evidence: CDC Prioritizing Populations, Outcomes For COVID-19 Vaccine Effectiveness Studies” – Pink Sheet, 29 Sep, 2020.)
“I’m not trying to falsely reassure anyone because we have to always be cautious when we’re approving products because that’s what we’re paid to be,” Marks said. “We’re paid to be cautious and to really care about health of the American people for vaccines and make sure they’re safe and effective and do what they’re supposed to do.”
However, the desire for as much certainty on safety as possible must be balanced with the need to get a vaccine to the public that, based on all the evidence to date, is safe, effective and potentially could help bring the pandemic under control, Marks said.
Underestimating Demands Of BLA Process
Marks said that those who suggest a vaccine should only come to market under a BLA, rather than an EUA, “simply don’t understand the nature of a biologics license application for a vaccine. They underestimate what goes into these.”
BLAs can be hundreds of thousands of pages long, and they take a long time for sponsors to put together and for the FDA to review, Marks said.
He noted that more than 1,000 people had been dying each day in the US from COVID-19. “The idea of waiting months for somebody to put together a license application and us to review it when potentially we could have the application of a safe and effective vaccine, that would be, I think, not a good public health maneuver.”
Attempting To Build Transparency Through Guidance
The FDA had intended to explain this reasoning through a draft guidance that would transparently lay out evidentiary expectations for an EUA, including the request for two months of safety follow-up.
However, the guidance has turned into a political football, with Trump characterizing it as an attempt by the FDA to slow down the process for getting a vaccine to market. (Also see “Hahn Says COVID Vaccine Review Could Take Months As Trump Floats Rejecting New EUA Guidance” – Pink Sheet, 23 Sep, 2020.) The document remains unpublished.
“The companies know what we’re expecting. This guidance was an attempt to help the public see what we were requiring of COVID-19 vaccines” under an EUA, FDA’s Peter Marks said.
Marks suggested the guidance was more about transparency of the EUA process for the public’s benefit than it was about actually giving advice to vaccine sponsors, who have for months been getting agency input on clinical trial design and other aspects of their development programs.
Health and Human Services secretary Alex Azar made similar comments during a 2 October congressional hearing.
“The companies know what we’re expecting,” Marks said. “This guidance was an attempt to help the public see what we were requiring of COVID-19 vaccines” under an EUA, which he described as the “moral equivalent” of getting as close as possible to a licensed vaccine but “not quite licensed.”
“The guidance was trying to explain that, explain what we expected, and to reassure the public that we were going to have a transparent advisory committee meeting for each and every emergency use authorization that comes through.”
Regaining Public Trust
As director of the FDA’s biologics center, Marks sees himself as playing an important role in ensuring the public trusts any vaccine that passes muster with the agency’s scientists.
“The most important thing that I think I can do and I can help do in the coming months is to help generate trust, regain trust, in vaccines,” Marks said. “Vaccines have saved public health previously. They will save it again. We just are going to have to believe in them, and so anything we can do to help engender trust in the process is critical.”
In a 29 September opinion piece in the Washington Post, seven former FDA commissioners spanning Democratic and Republican administrations wrote that if the White House “takes the unprecedented step of trying to tip the scales on how safety and benefits will be judged, the impact on public trust will render an effective vaccine much less so.”
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