In what is assuredly a rushed decision, the Food and Drug Administration (FDA) announced its approval of the Pfizer-BioNTech COVID-19 vaccine on Tuesday. A year ago, as polling numbers confirmed vaccine hesitancy existed among Americans centered squarely around the safety of potential COVID-19 vaccines, the FDA explained that the “whole government” approach used by the United States’ towards COVID-19 would be applied to the development of vaccines, with the assurance of a transparent advisory committee consisting of independent experts to review data about authorizations and licensures.

To ensure the safety and effectiveness of any COVID-19 vaccine, the FDA first declared that authorized vaccines would meet appropriate standards for safety and efficacy. As outlined in June 2020, the FDA distributed information for vaccine performance before the introduction of Phase III trials. Second, the agency “committed to use an advisory committee composed of independent experts to ensure deliberations about authorization or licensure [of COVID vaccines] are transparent for the public.”

FDA Ignores Assurances

Despite these assurances—and likely due to mounting pressure on the FDA to grant the market approval license for COVID-19 vaccines, whose immunity is fading—the agency expedited the approval process for the Pfizer-BioNTech vaccine, bypassing any Advisory Committee participation. Still, when speaking of the approval of Pfizer’s vaccine, Acting FDA Commissioner Janet Woodcock, M.D., declared:

“The FDA’s approval of this vaccine is a milestone as we continue to battle the COVID-19 pandemic. While this and other vaccines have met the FDA’s rigorous, scientific standards for emergency use authorization, as the first FDA-approved COVID-19 vaccine, the public can be very confident that this vaccine meets the high standards for safety, effectiveness, and manufacturing quality the FDA requires of an approved product. While millions of people have already safely received COVID-19 vaccines, we recognize that for some, the FDA approval of a vaccine may now instill additional confidence to get vaccinated. Today’s milestone puts us one step closer to altering the course of this pandemic in the U.S.” 

BMJ Points Out Waning Immunity

Peter Doshi, the senior editor at BMJ and a member of CAALM (who is petitioning the FDA to halt full approval of COVID-19 vaccines), points out that on July 28, 2021, in a MedRxiv preprint, Pfizer-BioNTech posted updated results for its ongoing Phase III COVID-19 mRNA vaccine clinical trial. The distribution of the 20-page release of data “came almost a year to the day after the historical trial commenced, and nearly four months since the companies announced vaccine efficacy estimates “up to six months.” The abstract is important and deserves rigorous scrutiny because it represents the most detailed public report of the “pivotal trial data Pfizer submitted” in the fast-track race as the world’s first “full approval” of a COVID-19 vaccine from the FDA. Despite a year’s passing, BMJ states of the report:

“You won’t find ten-month follow-up data here. While the preprint is new, the results it contains aren’t particularly up to date. In fact, the paper is based on the same data cut-off date (13 March 2021) as the 1 April press release, and its topline efficacy result is identical: 91.3% (95% CI 89.0 to 93.2) vaccine efficacy against symptomatic COVID-19 through “up to six months of follow-up.”

Doshi warns of the assurances of Pfizer senior vice president William Gruber, an author on the recent preprint, who told the FDA’s advisory committee last December, “We’re going to be looking very intently at the durability of protection.” Persistently pushing for more details and the raw data on COVID vaccine efficacy, Doshi writes that “even the most enthusiastic commentators have acknowledged that measuring vaccine efficacy two months after dosing says little about just how long vaccine-induced immunity will last.” He explains his concerns surrounding waning immunity further:

“If vaccine efficacy wanes over time, the crucial question becomes what level of effectiveness will the vaccine provide when a person is actually exposed to the virus?

And so, the recent reports from Israel’s Ministry of Health caught my eye. In early July, they reported that efficacy against infection and symptomatic disease ‘fell to 64%.’ By late July, it had fallen to 39%, where Delta is the dominant strain. This is very low. For context, the FDA’s expectation is of ‘at least 50%’ efficacy for any approvable vaccine.

Now Israel, which almost exclusively used Pfizer vaccine, has begun administering a third ‘booster’ dose to all adults over 40. And starting 20 September 2021, the US plans to follow suit for all ‘fully vaccinated’ adults eight months past their second dose.”

Delta Variant Not Responsible for Waning Immunity

Indicating the Delta variant, which wasn’t established in the U.S. until months after the data cut-off, most likely does not play a role in waning immunity. Doshi explains that diminishing protection was already apparent in the data by the Mar. 13, 2021 data cut-off. Importantly, waning immunity can dramatically alter the risk-benefit calculus of a vaccine. Doshi asserts, “whatever its cause—intrinsic properties of the vaccine, the circulation of new variants, some combination of the two, or something else—the bottom line is that [COVID-19] vaccines need to be effective.” 

Study Criteria Omits Critical Data on Severe Disease

Another misleading efficacy timepoint reported in Pfizer’s preprint, according to Doshi, is “from four months to the data cut-off.” With only half of the trial participants (53%) making it to the four-month mark, the confidence period in the report is “wider than earlier time points.” Doshi explains:

This all happened because starting last December, Pfizer allowed all trial participants to be formally unblinded and placebo recipients to get vaccinated. By 13 March 2021 (data cut-off), 93% of trial participants (41,128 of 44,060; Fig 1) were unblinded, officially entering “open-label followup.” (Ditto for Moderna: by mid-April, 98% of placebo recipients had been vaccinated.)

Despite the reference to “six month safety and efficacy” in the preprint’s title, the paper only reports on vaccine efficacy ‘up to six months,’ but not from six months. This is not semantics, as it turns out only 7% of trial participants actually reached six months of blinded follow-up (‘8% of BNT162b2 recipients and 6% of placebo recipients had ≥6 months follow-up post-dose 2.’) So despite this preprint appearing a year after the trial began, it provides no data on vaccine efficacy past six months, which is the period Israel says vaccine efficacy has dropped to 39%.

It is hard to imagine that the <10% of trial participants who remained blinded at six months (which presumably further dwindled after 13 March 2021) could constitute a reliable or valid sample to produce further findings. And the preprint does not report any demographic comparisons to justify future analyses.

Pfizer and other clinical trials were not intended to investigate severe COVID-19 disease. In the data that supported Pfizer’s EUA, the company itself portrayed the “severe COVID-19” endpoint results as “preliminary evidence.” Additionally, hospital admission numbers were not reported, and zero COVID-19 deaths occurred. The crucial question, according to Doshi, is whether the waning efficacy observed in the primary endpoint data also applies to the vaccine’s effectiveness against severe disease. Unfortunately, Pfizer’s new preprint does not report the results in a way that enables evaluating this problem. 

Approval Without Data Transparency or an Advisory Committee Meeting

The Emergency Use Authorization (EUA) of the Pfizer-BioNTech vaccine was granted in December 2020 using limited data. Presently, Doshi emphasizes that the FDA has given a marketing license 13 months into the still ongoing, two-year pivotal trial, with no reported data past Mar. 13, 2021, uncertain efficacy after six months due to unblinding, evidence of waning protection irrespective of the Delta variant, and biased reporting of safety data. 

Facing harsh criticism from those demanding transparency, the FDA’s decision not to hold a formal advisory committee meeting to discuss Pfizer-BioNTech’s application for full approval has left many bewildered. After pledging its commitment last year to “use an advisory committee composed of independent experts to ensure deliberations about authorisation or licensure are transparent for the public,” the FDA said in a statement to The BMJ that a meeting was not necessary, declaring:

“The FDA has held numerous meetings of its Vaccines and Related Biological Products Advisory Committee (VRBPAC) related to COVID-19 vaccines, including a 22 October 2020 meeting to discuss, in general, the development, authorisation, and licensure of COVID-19 vaccines.

The FDA also has held meetings of the VRBPAC on all three COVID-19 vaccines authorised for emergency use and does not believe a meeting is needed related to this biologics license application.

The Pfizer BioNTech COVID-19 vaccine was discussed at the VRBPAC meeting on 10 December 2020. If the agency had any questions or concerns that required input from the advisory committee members we would have scheduled a meeting to discuss.”