With COVID-19 cases once again surging across the globe and several countries considering targeted lockdowns, vaccines remain the best hope of restoring a sense of normalcy amidst the pandemic.

For vaccines to work though, people must have enough confidence in the efficacy and safety that they’re willing to get vaccinated when the vaccines become available. That’s why the emergency use authorization (EUA) guidance the FDA released Oct. 6 for COVID-19 vaccines is so important, especially since the first vaccines may be available within a few months.

On its face, the guidance is aimed at advising vaccine sponsors through the U.S.’ emergency use authorization (EUA) process. That advice basically reiterates what the FDA has been telling sponsors all along: they should submit data from at least one well-designed phase III trial to show the benefits of an investigational vaccine outweigh its risks, as well as adequate manufacturing information to ensure the quality and consistency of the doses.

So at its core, the guidance appears to be more of an effort to ensure the public that vaccine EUAs will be granted based on robust scientific data and a rigorous review process that includes advice from an independent advisory committee of vaccine and medical experts.

The Biotechnology Innovation Organization (BIO) applauded the guidance, noting that it was an important step “in earning the American people’s trust in any future vaccines.”

Just a few days before the FDA issued the guidance, BIO President and CEO Michelle McMurry-Heath had written to Health and Human Services (HHS) Secretary Alex Azar urging the public release of any new FDA guidance concerning EUAs for COVID-19 vaccines.

“We cannot allow a lack of transparency to undermine confidence in the vaccine development process,” she told Azar. “The public must have full faith in the scientific process and the rigor of FDA’s regulatory oversight if we are to end the pandemic.”

Not everyone was excited about the new guidance. President Donald Trump, who had threatened to scrap the guidance, tweeted Tuesday night: “New FDA Rules make it more difficult for them to speed up vaccines for approval before Election Day. Just another political hit job!”

According to Rep. Frank Pallone (D-N.J.), a day before the guidance was released, Trump attempted to block it, citing objections from the manufacturers developing the potential vaccines. Pallone said his staff spoke to representatives from those companies and each of them indicated they supported the public release of the guidance.

Matter of time

Any “delays” resulting from the guidance would be due to the FDA’s call for a median follow-up duration in clinical trials of at least two months to ensure safety and the agency’s pledge to convene an independent advisory committee to weigh the data for each vaccine EUA request.

Given the current status of the vaccine trials, a two-month follow-up could push an EUA to late November or December, RBC Capital Markets analyst Randall Stanicky said.

Pfizer Inc.’s vaccine candidate is leading the pack, with a phase III trial that’s expected to enroll 44,000 participants. That enrollment target would imply the two months of follow-up would be needed for about 22,000 individuals, Stanicky said. He noted that the trial had enrolled more than 11,000 participants as of Aug. 20 and had reached an enrollment of 25,000 Sept. 9.

“If we assume a final dose 21 days later, two months of follow-up would be reached in late Nov./early Dec., which pegs a potential EUA in that timeframe,” Stanicky said. “However, if FDA were to accept safety follow-up data from fewer patients … this could push an EUA to around or after the Nov. election” – provided the vaccine shows at least 50% efficacy relative to placebo.

Stanicky pointed out that the guidance referenced a safety data requirement for "well over 3,000" vaccine recipients being typical for other infectious disease vaccines. Despite that reference, “bottom line, we think an EUA before the Nov. election is unlikely,” Stanicky said, “but we could still receive interim phase 3 data from [Pfizer] by late Oct. with readouts from the remaining vaccines soon after.”

The timeline is important, as that’s what’s undermining public trust. Trump’s oft-stated desire to have a vaccine available before the Nov. 3 election has triggered political talking points from his opponents and whipped up fears that the FDA would be forced to prematurely authorize a vaccine.

Meanwhile, Trump’s advisers have been acknowledging that a more likely date for a vaccine EUA is in late November or December, stressing that such a feat is still impressive, as a 10-month turnaround for a novel vaccine is unprecedented.

In his comments at an Oct. 6 COVID-19 vaccine symposium sponsored by Johns Hopkins University and the University of Washington, Moncef Slaoui, chief adviser for the government’s Operation Warp Speed initiative, said he “feels comfortable” that one or two of the vaccines in development will have demonstrated efficacy and will be available in enough doses to begin vaccinations in November or December.

Slaoui expected the first vaccines would be those using messenger RNA (mRNA) technology. Pfizer and Moderna Inc. both have mRNA vaccines in phase III trials and should have tens of millions of doses stockpiled by late this year, he said. Other vaccines in the works probably won’t be ready for an EUA until early next year, he added.

Building trust

In another trust-building effort Oct. 6, the FDA released its briefing document for the Oct. 22 meeting in which the Vaccines and Related Biological Products Advisory Committee will discuss general issues related to COVID-19 vaccines. While the FDA generally sends its briefing documents to panel members well in advance of an adcom meeting, it typically doesn’t make them publicly available until two days before the meeting.

According to the briefing document, the agency will ask the panel of experts to advise on the type of studies – in addition to those already recommended in the June COVID-19 vaccine guidance – that should be conducted pre- or post-licensure to evaluate the safety and efficacy of the candidates.

The committee also will be asked to evaluate the immunogenicity and the duration of effectiveness of the vaccines in general, discuss the need for postmarketing safety studies following licensure and consider what’s necessary for active safety follow-up to permit an ongoing assessment of the benefits and risks of a COVID-19 vaccine following the issuance of an EUA.

The Oct. 22 meeting will provide a foundation for when the FDA convenes the panel to evaluate individual vaccine candidates for which an EUA has been requested.

Along with releasing the adcom briefing document and the EUA guidance, the FDA launched a webpage Oct. 6 dedicated to COVID-19 vaccines. The page emphasizes the agency’s commitment to the scientific process and prominently features a quote from FDA Commissioner Stephen Hahn: “We are committed to expediting the development of COVID-19 vaccines, but not at the expense of sound science and decision making. We will not jeopardize the public’s trust in our science-based, independent review of these or any vaccines. There’s too much at stake.”

The webpage, obviously intended to increase public trust in the vaccines, has links to vaccine updates, statements and publications from FDA leaders, upcoming events, and basics about vaccines and the approval process, as well as information for vaccine developers, including FDA contacts, guidances and advice on submitting an EUA request or biologic license application.

Other developments

In related news, HHS’ Biomedical Advanced Research and Development Authority (BARDA) announced that it is partnering with Vaxxas Inc., of Brisbane, Australia, in a $22 million, three-year project to develop an easy-to-use, high-density micro-array patch to administer vaccines.

The needle-free technology would offer significant advantages in public health emergencies, as it has the potential to reduce the amount of vaccine required and to offer a room-temperature-stable alternative to the cold chain needed for some traditional vaccines.

If the patch pans out, it could help in future pandemics, but it likely will not have a role in the COVID-19 fight as the phase I trial, which will use influenza vaccines, isn’t expected to begin until 2022, according to HHS.

On another note, Rick Bright, a pandemic and vaccine expert, resigned Oct. 6 from his position at the NIH and filed a new charge at the U.S. Office of Special Counsel alleging that he was constructively discharged based on the failure of the NIH to assign him meaningful work.

Bright took over the leadership of BARDA in 2016 but was removed from the position in April when he said he was demoted to a “limited” position at the NIH in retaliation for his raising “concerns about the Trump administration’s chaotic and reckless response to the COVID-19 pandemic,” according to the new complaint. Bright filed a whistleblower complaint in May.

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