Does the FDA think these data justify the first full approval of a covid-19 vaccine?
The FDA should demand adequate, controlled studies with long term follow up, and make data publicly available, before granting full approval to covid-19 vaccines, says Peter Doshi
On 28 July 2021, Pfizer and BioNTech
posted updated results for their ongoing phase 3 covid-19 vaccine trial. The preprint 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.”
But you won’t find 10 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.”
The 20 page preprint matters because it represents the most detailed public account of
the pivotal trial data Pfizer submitted in pursuit of the world’s first “full approval” of a coronavirus vaccine from the Food and Drug Administration. It deserves careful scrutiny.
The elephant named “waning immunity”
Since late last year, we’ve heard that Pfizer and Moderna’s vaccines are “95% effective” with even greater efficacy against severe disease (
“100% effective,” Moderna said).
Whatever one thinks about the “95% effective” claims (my thoughts are
here), 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. “We’re going to be looking very intently at the durability of protection,”
Pfizer senior vice president William Gruber, an author on the
recent preprint, told the FDA’s advisory committee last December.
The concern, of course, was decreased efficacy over time. “Waning immunity” is a
known problem for influenza vaccines, with some studies showing near zero effectiveness after just three months, meaning a vaccine taken early may ultimately provide no protection by the time “flu season” arrives some months later. 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? Unlike covid vaccines,
influenza vaccine performance has always been judged over a full season, not a couple months.
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 may not be responsible
Enter Pfizer’s preprint. As an RCT reporting “up to six months of follow-up,” it is notable that evidence of waning immunity was already visible in the data by the 13 March 2021 data cut-off.
“From its peak post-dose 2,” the
study authors write, “observed VE [vaccine efficacy] declined.” From 96% to 90% (from two months to <4 months), then to 84% (95% CI 75 to 90) “from four months to the data cut-off,” which, by my calculation (see footnote at the end of the piece), was about one month later.
But although this additional information was available to Pfizer in April, it was not published until the end of July.
And 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.
Waning efficacy has the potential to be far more than a minor inconvenience; it can dramatically change the risk-benefit calculus. And 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 vaccines need to be effective.
Until new clinical trials demonstrate that boosters increase efficacy above 50%, without increasing serious adverse events, it is unclear whether the 2-dose series would even meet the FDA’s approval standard at six or nine months.
The “six month” preprint based on the 7% of trial participants who remained blinded at six months
The final efficacy timepoint reported in Pfizer’s preprint is “from four months to the data cut-off.” The confidence interval here is wider than earlier time points because only half of trial participants (53%) made it to the four month mark, and mean follow-up is around 4.4 months (see footnote).
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.)