On Aug. 23, Pfizer announced on its website that the Pfizer-BioNTech COMIRNATY vaccine had received full U.S. Food and Drug Administration (FDA) approval for individuals aged 16 and older. While the decision was praised by several media outlets, few provided critical analysis of the data or touched on perspectives on whether approval was warranted in the first place.
A recent BMJ medical journal opinion piece commented on the FDA approval, highlighting major considerations that should have been taken into account before approval was granted.
Full approval of any vaccine should always take the most recent data available in order to provide the most accurate and safe information to the public.
On Jul. 28 in medRxiv, Pfizer and BioNTech released updated safety and efficacy results for their Phase 3 placebo-controlled, observer-blinded, multinational Coronavirus Disease 2019 (COVID-19) study involving 44,165 participants aged 16 and older. Vaccine efficacy (VE) was calculated to be 91.3% through up to six months.
Interestingly, the companies had released a press release nearly 4 months earlier with an identical data cut-off date of Mar. 13, 2021. The major conclusion of the study was the same, which was that vaccine efficacy was 91.3% against symptomatic COVID-19 through “up to six months of follow-up.”
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Pfizer stated in its press release, “For FDA approval, Pfizer and BioNTech submitted a comprehensive data package that included longer-term follow-up data from the Phase 3 trial, where the vaccine’s high efficacy and favorable safety profile were observed up to six months after the second dose.”
However, “longer-term follow-up data” is misleading, as the same 6-month follow-up data was provided to the FDA instead of 10-month follow-up data.
“We’re going to be looking very intently at the durability of protection,” Pfizer senior vice president William Gruber said at the FDA’s advisory committee in Dec. 2020. He was one of the authors of the company’s July 28 medRxiv preprint study.
One major concern for vaccines is decreased efficacy over time, a well-known phenomenon of rapidly mutating respiratory viruses such as the influenza virus. An Aug. 2018 publication in Clinical Infectious Diseases compiled the results of several scientific studies, many of which showed a drastic drop in the efficacy of flu vaccines to near 20% or even 0% after 3 or 4 months post-vaccination.
Thus, individuals who get the flu shot early may have close to zero protection by the time the flu season ultimately arrives months later. Similarly, for the COVID-19 vaccines, the duration of protection is an important consideration.
The FDA states that efficacy of a vaccine in a placebo-controlled efficacy trial should “be at least 50%.” However, Israel’s Health Ministry stated that by Jul. 5, the Pfizer-BioNTech vaccine “effectiveness in preventing both infection and symptomatic disease fell to 64% since June 6.”
Furthermore, based on an analysis of individuals between June 20 and July 17 in Israel, the vaccine’s efficacy had dropped to just 39% by the end of July, according to a CNBC report. Consistent with waning immunity, Israel has now started to give a third shot to adults over 40, and the Biden administration plans for “every adult to get a booster shot eight months after you got your second shot” starting the week of Sept. 20.
Variants not the sole culprit
As senior editor of The BMJ Dr. Peter Doshi writes, “evidence of waning immunity was already visible in the data by the 13 March 2021 data cut-off.”
The Pfizer study states, “From its peak post-dose 2, observed VE [vaccine efficacy] declined. From 7 days to <2 months post-dose 2, VE was 96.2% (95% CI [93.3-98.1]); from 2 months to <4 months, VE was 90.1% (95% CI [86.6-92.9]); and from 4 months to the data cut-off, VE was 83.7% (95% CI [74.7-89.9]).”
Doshi estimates that the data cut-off point was approximately one month after the four month mark. In other words, by Pfizer’s own calculations, its vaccine efficacy had already declined from 96.2% to 83.7% by “up to six months of follow-up,” or by around 5 months post-vaccination per Doshi’s calculation.
Notably, this additional information was already available to Pfizer in April, but was “not published until the end of July.”
Although the Delta variant is often blamed for the waning efficacy of vaccines, Doshi states, “it’s hard to imagine how the Delta variant could play a real role here, for 77% of trial participants were from the United States, where Delta was not established until months after data cut-off.”
The “intrinsic properties of the vaccine,” new variants, and other factors could all have contributed to waning efficacy. Thus, without new clinical trials showing efficacy of boosters without increasing the already alarming rate of serious adverse events, “it is unclear whether the 2-dose series would even meet the FDA’s approval standard at six or nine months.”
Only 7% of participants blinded at six months
The gold standard for effectiveness research, a randomized controlled trial (RCT), is “often blinded so that participants and doctors, nurses or researchers do not know what treatment each participant is receiving, further minimizing bias.” However, Pfizer’s study has a major flaw because “only half of trial participants (53%) made it to the four month mark, and mean follow-up is around 4.4 months.”
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.’”
Pfizer used the terminology of “up to six months” in its study title instead of “from six months” because “only 7% of trial participants actually reached six months of blinded follow-up.” Specifically, the study states, “8% of BNT162b2 recipients and 6% of placebo recipients had ≥6 months follow-up post-dose 2.”
With only 7% of trial participants still blinded at the six month mark, they will likely not “constitute a reliable or valid sample to produce further findings,” Doshi states.
Lack of data transparency
The FDA granted approval to Pfizer’s COVID-19 vaccine “13 months into the still ongoing, two year pivotal trial, with no reported data past 13 March 2021, unclear efficacy after six months due to unblinding, evidence of waning protection irrespective of the Delta variant, and limited reporting of safety data,” writes Doshi.
According to a BMJ article, the FDA had stated in Aug. 2020 that it was “committed to use an advisory committee composed of independent experts to ensure deliberations about authorisation or licensure are transparent for the public.” However, in a recent statement to the BMJ, the FDA said that “it did not believe a meeting was necessary ahead of the expected granting of full approval.”
A public statement by a group of over 30 clinicians, scientists, and patient advocates highlighted several open questions that needed to be addressed prior to the approval of any and all COVID-19 vaccines. Unfortunately, Pfizer’s preprint study addressed few of the questions and raised other new questions.
Doshi writes that the FDA should urge companies to “complete the two year follow-up, as originally planned… demand adequate, controlled studies using patient outcomes in the now substantial population of people who have recovered from covid. And regulators should bolster public trust by helping ensure that everyone can access the underlying data.”