11/2/21, 2:13 PM Does the FDA think these data justify the first full approval of a covid-19 vaccine?

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Does the FDA think these data justify the first full approval of a covid-19
vaccine?
August 23, 2021

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.

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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.)

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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.

Severe disease

With the US awash in news about rising cases of the Delta variant, including among the “fully vaccinated,” the
vaccine’s efficacy profile is in question. But some medical commentators are delivering an upbeat message.
Former FDA commissioner Scott Gottlieb, who is on Pfizer’s board, said: “Remember, the original premise
behind these vaccines were [sic] that they would substantially reduce the risk of death and severe disease
and hospitalization. And that was the data that came out of the initial clinical trials.”

Yet, the trials were not designed to study severe disease. In the data that supported Pfizer’s EUA, the
company itself characterized the “severe covid-19” endpoint results as “preliminary evidence.” Hospital
admission numbers were not reported, and zero covid-19 deaths occurred.

In the preprint, high efficacy against “severe covid-19” is reported based on all follow-up time (one event in
the vaccinated group vs 30 in placebo), but the number of hospital admissions is not reported so we don’t
know which, if any, of these patients were ill enough to require hospital treatment. (In Moderna’s trial, data
last year showed that 21 of 30 “severe covid-19” cases were not admitted to hospital; Table S14).

And on preventing death from covid-19, there are too few data to draw conclusions—a total of three covid-
19 related deaths (one on vaccine, two on placebo). There were 29 total deaths during blinded follow-up (15
in the vaccine arm; 14 in placebo).

The crucial question, however, is whether the waning efficacy seen in the primary endpoint data also applies
to the vaccine’s efficacy against severe disease. Unfortunately, Pfizer’s new preprint does not report the
results in a way that allows for evaluating this question.

Approval imminent without data transparency, or even an advisory committee meeting?

Last December, with limited data, the FDA granted Pfizer’s vaccine an EUA, enabling access to all Americans
who wanted one. It sent a clear message that the FDA could both address the enormous demand for vaccines
without compromising on the science. A “full approval” could remain a high bar.

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But here we are, with FDA reportedly on the verge of granting a marketing license 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. (The preprint reports “decreased appetite, lethargy, asthenia, malaise, night sweats, and
hyperhidrosis were new adverse events attributable to BNT162b2 not previously identified in earlier reports,”
but provides no data tables showing the frequency of these, or other, adverse events.)

It’s not helping matters that FDA now says it won’t convene its advisory committee to discuss the data ahead
of approving Pfizer’s vaccine. (Last August, to address vaccine hesitancy, the agency had “committed to use
an advisory committee composed of independent experts to ensure deliberations about authorization or
licensure are transparent for the public.”)

Prior to the preprint, my view, along with a group of around 30 clinicians, scientists, and patient advocates,
was that there were simply too many open questions about all covid-19 vaccines to support approving any
this year. The preprint has, unfortunately, addressed very few of those open questions, and has raised some
new ones.

I reiterate our call: “slow down and get the science right—there is no legitimate reason to hurry to grant a
license to a coronavirus vaccine.”

FDA should be demanding that the companies complete the two year follow-up, as originally planned (even
without a placebo group, much can still be learned about safety). They should 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.

Peter Doshi, senior editor, The BMJ.

Competing interests: I helped organize the Coalition Advocating for Adequately Licensed Medicines (CAALM),
which has formally petitioned the FDA to refrain from fully approving any covid-19 vaccine this year (docket
FDA-2021-P-0786). A full list of competing interests is available here. The views and opinions expressed here
are mine and do not necessarily reflect official policy or the position of the University of Maryland.

Provenance: commissioned; externally peer-reviewed.

Footnote: Calculations in this article are as follows. “About 1 month” past month 4 is based on the final row of
Fig 2 in the preprint: 1030/12670*12 = 0.98 months (vaccine group) and 895/11802*12 = 0.91 months
(placebo group). “53%” is based on Fig 2: (12670+11802)/(23040+23037). “4.4 months” is based on the
average of 8412/22505*12 = 4.5 (vaccine) and 8124/22434*12 = 4.3 (placebo) in Fig 2.

 Editors at large


 The global health security agenda rewards rich Academics and social media hostility: should we

nations for their selfish behaviour  give up or do more?  

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King Slechtvalk • 2 months ago

Appreciate the full clarity. Unfortunately it doesnt look like the FDA will even consider you points
and approved it anyways.
13 △ ▽ • Reply • Share ›

dephyant • 2 months ago

Fantastic article, thank you.
9△ ▽ • Reply • Share ›

Eugene William Prewitt • 2 months ago

I appreciate this sensible approach to a frenzied issue. May calm cool deliberations prevail and do
their part to quiet both irrational optimism and manic pessimism.
8△ ▽ • Reply • Share ›

Otto Rapp • 2 months ago

This makes a lot of sense, but since when has good sense been a driving factor in any decisions
made since this pandemic started?
6△ ▽ • Reply • Share ›

Whimsy • 2 months ago

The decisions being passed through the FDA of late have been wrought with issues, and I
anticipate these will contribute to the erosion of trust in regulatory authorities. The
recommendations outlined in the petition put forth in respect to the necessary considerations for
full approval for these new nucleic delivery platforms and their specific use as vaccines were not
only reasonable, but a minimum expectation. As an immunologist, I am quite surprised that there
has been no biodistribution studies made available. These could help both explain and predict
serious adverse events and their long-term consequences. For example, in the context of the
instances of myocarditis observed after the mRNA vaccines - is this a function of the expressed
spike protein fragment binding to ACE2 on cardiomyocytes, and this being recognized as a
complex by circulating antibodies? Would these antibodies then be expanded with each
subsequent shot - thereby making vascular injury worse with each booster - or real infection? It is
critically important to know these dynamics to avoid unnecessary harm. I hope regulatory
authorities of other jurisdictions take heed and take their due time for approval that responsibly
considers long-term safety and efficacy of these new platforms. - Dr. Shirin Kalyan
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4△ ▽ • Reply • Share ›

DeeAnne Raymont > Whimsy • a month ago

Permission to quote and name you (for New Zealand) I am a medical writer and board-cert
physician
2△ ▽ • Reply • Share ›

Whimsy > DeeAnne Raymont • 22 days ago

Of course.
1△ ▽ • Reply • Share ›

Liv • 2 months ago

Thank you for your questioning mind. So few will do this. Thank you from my children's health and
future.
4△ ▽ • Reply • Share ›

Erika • 2 months ago

It is disappointing to see this article being repeatedly used by anti-vaxxers to discourage others
from getting the vaccine. While waning immunity is absolutely a concern, I do not think this
concern justifies non-vaccination. The study referenced here is not the only published study on
the various COVID vaccines. Responsible and ethical science journalism requires us to ensure
that our work is not misused to spread dangerous misinformation.
4△ ▽ 37 • Reply • Share ›

Marki > Erika • 2 months ago

With respect, responsible and ethical science journalism has every right to ask for
evidence where it is lacking. To think a billion dollar company can't provide evidence of
effectivity, transmissibility, all cause mortality, is beyond belief. This isn't supposed to be a
religion. Shouldn't the emergent science shout their benefit, publish it. Demand it.
29 △ ▽ 1 • Reply • Share ›

Watchman > Erika • 2 months ago • edited

Whether it is used by 'anti-vaxxers' to discourage people from getting 'the vaccine' (there
are more than a dozen COVID-19-vaccines, also non-mRNA) is a fallacious argument. Is it
only disappointing when used by 'anti-vaxxers', or would it be just as disappointing when
used by pro-vaxxers who are only being careful and hesitant with new vaccine
technologies and because of not knowing ANYTHING about long term effects? Which is
simply common sense. If the latter is the case, mentioning 'anti-vaxxers' is beside the
point. Just look at the content matter and let that information alone help people decide
whether to take one of the vaccines. As you know, this whole matter is very complex.
23 △ ▽ 1 • Reply • Share ›

Mark S > Watchman • 2 months ago

Totally agree with the neutral stance. Its not about one or the other its totally about
adhering to medical science protocols. When did skipping a step ever work out
ll
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11/2/21, 2:13 PM Does the FDA think these data justify the first full approval of a covid-19 vaccine? - The BMJ
well.
6△ ▽ • Reply • Share ›

DavidML > Erika • 2 months ago • edited

If one combines the COVID vaccine efficacy information in this article with COVID vaccine
safety information available elsewhere, and then compares it with the safety and efficacy
information on non-vaccine alternative therapies to COVID, that's not "misinformation", it's
"information", and it's not "irresponsible and unethical", it's the bare minimum of
responsibility and ethical action. People like you believe and argue the vaccine is the only
option without bothering to look into the many, many peer reviewed studies that prove
otherwise.
13 △ ▽ • Reply • Share ›

James Miller > Erika • 2 months ago • edited

Hey Erika, I completely understand if you're afraid someone is spreading misinformation.
That's a legitimate concern. The author himself doesn't appear to be anti-vaccine, so
holding a piece responsible for the choices others make doesn't seem fair, especially if
he's citing neutral data and improper FDA protocols; which coincidentally are the same
battles current FDA scientists are facing. Also, your comment states waning efficacy is the
sole reason against vaccination, but the author, again, didn't claim that. What's more, he
cited many other reasons in addition to waning efficacy, and had them documented and
fairly represented. It sounds like you genuinely care about truth and not being caught up in
the emotions so many find themselves in. If that is indeed the case as it likely is,
remember that dangerous misinformation, such as closing independent committees and
truncating trials, is the very element these well respected and peer reviewed virologists
and immunologists (many of whom are pro-vaccine) are themselves pointing out. It alters
nuanced data and procedures; which were in first implemented by the best we have in
medicine for crucial reasons. Best of luck to you.
8△ ▽ • Reply • Share ›

Earl Kralik > Erika • a month ago • edited

You undermine your point by using a childish label like "anti-vaxxer" as though that's some
kind of argument. Raising important questions about safety data for rushed and under-
tested mRNA vaccines does not make one an "anti-vaxxer."
4△ ▽ • Reply • Share ›

Josh Scandlen • 2 months ago

BTW, I still am VERY comforted when reading this from the FDA.

" Additionally, FDA determined it is reasonable to conclude, based on the totality of the

scientific evidence available, that the known and potential benefits of Pfizer-BioNTech

COVID‑19 Vaccine outweigh the known and potential risks of the vaccine, for the prevention of

COVID-19 in individuals 16 years of age and older."

https://www.fda.gov/media/1...
△ ▽ 7 • Reply • Share ›

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