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Bourla, FDA leaders say two-month follow-up key to timing for COVID-19 vaccine authorization

Oct 17, 2020 | 1:18 AM GMT

An open letter from Pfizer’s Albert Bourla and a commentary from FDA’s heads of vaccine research and review respectively spell out how FDA’s guidance is shaping the timeline for what could be the first COVID-19 vaccine authorized in the U.S., and justify the reasoning behind that criteria.

Both communications, published six days before an Oct. 22 FDA advisory committee on COVID-19 vaccines, highlight FDA’s requirement that sponsors provide at least two months of follow-up data after the final vaccine dose for half of the trial’s participants.

That requirement was at the heart of the weeks-long hold the Trump administration’s placed on FDA’s guidance on Emergency Use Authorization (EUA) of  COVID-19 vaccines. The president tweeted that the rules “make it more difficult for them to speed up vaccines for approval before Election Day.”

The hold came to an end on Oct. 6 when FDA bypassed the White House by releasing key provisions from the guidance in a briefing document distributed ahead of the advisory committee meeting; the Trump administration then gave the document the green light.

Some public health opinion leaders have called for the agency to set a higher bar for safety by calling for “a minimum of two months of safety observation for all trial participants,” instead of half of the cohort.

In Bourla’s letter, the Pfizer Inc. (NYSE:PFE) chairman and CEO said the company would seek EUA for BNT162b2, its mRNA vaccine candidate that is partnered with BioNTech SE (NASDAQ:BNTX), only after three milestones had been reached: the vaccine met its predetermined efficacy criteria, the sponsors accumulated two months of safety data for half of trial participants, and manufacturing data demonstrated “the quality and consistency of the vaccine that will be produced.”

Bourla said an answer on the efficacy data, which Pfizer is blinded to and is being reviewed by a committee of independent scientists, could be available as early as end of October, though changes in infectious rates could shift the timing earlier or later.

The company estimates it won’t meet the two-month safety data requirement until the third week of November; it anticipates the manufacturing data will be ready before the safety data.

In a meeting at the end of September, Moderna Inc. (NASDAQ:MRNA) CEO Stéphane Bancel said the company would have enough safety data to seek EUA for its vaccine candidate mRNA-1273 on Nov. 25. The company did not respond to a request for an update on its timeline.

All in the timing

New England of Medicine perspective article from FDA’s Office of Vaccine Research and Review Director Marion Gruber and Deputy Director Philip Krause walked through the agency’s thinking on the median two-month follow-up requirement. 

The authors said the requirement is necessary because it “will allow identification of potential adverse events that were not apparent in the immediate postvaccination period and will also provide greater confidence in their absence, if none are observed.”

They said the two-month time period was appropriate because “adverse events considered plausibly linked to vaccination generally start within 6 weeks after vaccine receipt,” and added that because of the dynamics of adaptive immune responses, “a median of 2 months is the shortest follow-up period required to achieve some confidence that any protection against Covid-19 is likely to be more than very short-lived. “

In response to arguments that the requirement is insufficient, Gruber and Krause said it is justified by “extensive historical experience with adverse events after vaccination, the need for a vaccine to address the current pandemic, and the magnitude of vaccine effectiveness that will be required to support a favorable benefit–risk profile for use of a Covid-19 vaccine under an EUA.”

The authors also addressed FDA’s guidance that sponsors “continue to collect placebo-controlled data in any ongoing trials for as long as feasible” to inform ongoing assessments of a vaccine’s benefits and risks, and evaluation of subsequent generations of vaccines.

“Issuance of an EUA should not, in and of itself, require unblinding of a Covid-19 vaccine trial and immediate vaccination of placebo recipients, since doing so may jeopardize approval of these products,” they wrote.

In his letter, Bourla wrote that “Pfizer will continue running the trial through its final analysis point even if it is declared effective at an earlier stage.”

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