Does the FDA Think These Data Justify the First Full Approval of a COVID-19 Vaccine?

By Peter Doshi

The U.S. Food and Drug Administration should have demanded adequate, controlled studies with long-term follow up, and made data publicly available, before granting full approval to COVID-19 vaccines, says British Medical Journal Associate Editor Peter Doshi.

EDITOR’S NOTE: This analysis was published Monday before the U.S. Food and Drug Administration announced it had granted full approval to Pfizer’s COVID vaccine. The information in this piece provides insightful arguments for why the FDA should not have rushed to license Pfizer’s COVID vaccine.

On July 28, 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 (March 13, 2021) as the April 1 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 U.S. 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 September 20, the U.S. 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 March 13 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 U.S., 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.

[…]

Via

Does the FDA Think These Data Justify the First Full Approval of a COVID-19 Vaccine?

3 thoughts on “Does the FDA Think These Data Justify the First Full Approval of a COVID-19 Vaccine?

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