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British Medical Journal: 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.

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by Anonymousreply 61October 31, 2021 3:27 AM

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.)

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.

by Anonymousreply 1August 27, 2021 8:49 PM

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.

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.

by Anonymousreply 2August 27, 2021 8:49 PM

I suppose the delusional here will assert that the British Medical Journal is a pro-Trump source.

by Anonymousreply 3August 27, 2021 8:54 PM

Oooh we've got forum flooding going on. Some of you might want to rethink whom you've been accusing of being trolls here.

by Anonymousreply 4August 27, 2021 8:55 PM

Do you think the American media is going to start reporting facts any time soon?

by Anonymousreply 5August 27, 2021 9:08 PM

....

by Anonymousreply 6August 27, 2021 9:10 PM

.....

by Anonymousreply 7August 27, 2021 9:21 PM

I guess no one here cares about Covid. Weird.

by Anonymousreply 8August 27, 2021 9:30 PM

[quote] 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.

This is concerning.

by Anonymousreply 9August 27, 2021 10:00 PM

This goes against the narrative. BANNED!

by Anonymousreply 10August 27, 2021 10:09 PM

Having had just one Pfizer, is it safer to pass on the second? I kind of need to know within 12 hours...

by Anonymousreply 11August 28, 2021 12:43 AM

Oh, please! Nothing could be worse than the epidemic of morbid obesity in the US right now. Just get vaxxed and be done with it.

by Anonymousreply 12August 28, 2021 12:46 AM

r11, in June, there was some interesting data out of Israel that was showing people with single injections were faring far better than both the double injected and the noninjected.

by Anonymousreply 13August 28, 2021 5:23 AM

I hope people will actually read this.

by Anonymousreply 14August 28, 2021 6:58 AM

So far, I've read 4 threads with references to this Israeli data that isn't even published through peer review yet. I think we need to reserve judgement until we see confirmation of similar results by other scientists reviewing the data. As far as I can tell, the antibodies waning situation is a red herring. That was observed among the people who were previously infected with COVID as well. But there are many components to immunity. Antibodies are only one. There are killer cells, memory B cells and many others. We don't yet have a clear picture of how the vaccinated immune system reacts to COVID and what lingers after the antibodies begin to wane. What appears to be clear is that the hospitals in the deep South are filling up with the unvaccinated. How do we know that? Because the hospitals are asking the patients as they are admitted. So, that in itself is telling.

by Anonymousreply 15August 28, 2021 8:31 AM

r15, do you think Pfizer will allow Israel's data to get peer reviewed? Do you know how many peer reviewed articles are retracted every year? Do you know that a lot of "common wisdom" about science, health, etc. comes from peer reviewed articles that have been quietly withdrawn?

by Anonymousreply 16August 28, 2021 8:33 AM

Peter Doshi, the author of this opinion piece, has been expressing anti-Pfizer and anti-Moderna opinions since day one.

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by Anonymousreply 17August 28, 2021 8:38 AM

r17, as well he and we all should. Since when did people start trusting Big Pharma to have their best interests in mind?

by Anonymousreply 18August 28, 2021 8:39 AM

r16, Pfizer has no say in whether or not an article is peer-reviewed. It might not let its own scientists participate in the review process, but they shouldn't anyway- conflict of interest. You have a strange notion of how science works.

by Anonymousreply 19August 28, 2021 8:41 AM

Did you know that Joe Biden took $13,620,673 from Big Pharma last year? And that's just in campaign contributions.

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by Anonymousreply 20August 28, 2021 8:42 AM

I wouldn't trust one BIg Pharma player, but we have 4 big and a number of small and/or national pharma manufacturers involved and competing, so that makes the situation a little "cleaner".

by Anonymousreply 21August 28, 2021 8:42 AM

You're just determined to get a little anti=vax action going here, aren't you, OP? So you keep quoting outlier, lunatic sources. You must be desperate now to be using a UK one.

You seem like a loon, op,

by Anonymousreply 22August 28, 2021 8:43 AM

F&F the OP

by Anonymousreply 23August 28, 2021 8:44 AM

r21, you can take a look for yourself and see how many members of our government Big Pharma has been brazenly bribing.

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by Anonymousreply 24August 28, 2021 8:44 AM

And DeSantis and Rand Paul both have financial interests in competing therapies (different branches of Big Pharma). What does pharma expect/hope from campaign contributions? They hope to be able to get extended copyrights on drugs so that they don't run into competition from generics on their cash cows.

by Anonymousreply 25August 28, 2021 8:45 AM

r23 is afraid of the British Medical Journal, Facts and Science. Not a good look, Pharmacrat.

by Anonymousreply 26August 28, 2021 8:45 AM

R18, Peter Doshi is "suspicious" of "Big Pharma" to the point of sounding anti-vaxx.

R23, an opinion piece is not "the British Medical Journal".

by Anonymousreply 27August 28, 2021 8:46 AM

It's not in the vested interest of any vaccine manufacturer to put out a product that is doomed to failure. It's different than marketing an antibiotic that will be 75th in line of possible treatments.

by Anonymousreply 28August 28, 2021 8:47 AM

r25, well, what they have done is suppress information about and availability of existing, tested, safe treatments for CV19. Many of which are out of patent and, thus, non-lucrative.

by Anonymousreply 29August 28, 2021 8:47 AM

17 months into Covid and the medical community knows for 100% certainty exactly three things about the behavior of the novel virus Covid-19:

You can contract and spread Covid, whether or not you are vaccinated.

Vaccines MAY prevent serious/fatal illness after contracting Covid.

Masks MAY prevent contraction and spread of Covid.

The rest is speculation.

by Anonymousreply 30August 28, 2021 8:48 AM

Here's another piece from the BMJ that says something else.

FDA approval for Pfizer covid-19 vaccine is essential and welcomed, but will it help vaccine hesitancy? August 25, 2021 We must have realistic expectations of how much influence FDA approval will have on vaccine hesitant populations, says Peter Hotez

The announcement of the Food and Drug Administration’s (US FDA) full regulatory approval of the Pfizer-BioNTech covid-19 vaccine is an important development for the US vaccination programme.

The US FDA is often considered the world’s most stringent national regulatory authority, with an extraordinary track record of approving safe and effective products for medical use. Among these products, the bar is especially high for vaccines because of the simple reality that they are mostly administered to well people in order to prevent them from becoming sick. That the US FDA has now signed off on the Pfizer-BioNTech covid-19 vaccine is in itself a milestone in efforts to halt the spread of covid-19.

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by Anonymousreply 31August 28, 2021 8:48 AM

r22, "lunatic sources" like The British Medical Journal and lefty OpenSecrets? Really? Your disconnect from reality may have something to do with those metal particulates that resulted in Japan halting their Moderna roll out.

by Anonymousreply 32August 28, 2021 8:48 AM

r27, he's the Editor In Chief

by Anonymousreply 33August 28, 2021 8:49 AM

r28, it does behoove them if they have world governments in pocket mandating their ineffective shots every five months and who have bought billions in stock.

by Anonymousreply 34August 28, 2021 8:51 AM

It's still his own opinion, r33, and Doshi is like this about all pharmaceuticals.

by Anonymousreply 35August 28, 2021 9:39 AM

R34, the BioNTech Pfizer vaccine is not ineffective and it only wanes a little after 5 months. In people with very low immunity (the elderly, people with comorbidities, the immunosuppressed) it may wane against the Delta variant to the point that a booster is needed after some months, but it's otherwise exceptionally effective.

by Anonymousreply 36August 28, 2021 9:42 AM

r36, it wanes almost immediately. 46% at 4 months. 16% efficacy at 5-6 months. People who have gotten 2 or more shots are experiencing more severe illness because of ADE, as a result of the shots.

by Anonymousreply 37August 28, 2021 9:44 AM

R37, two of my partner's great-aunts who are in their 70s and were vaccinated in February with Pfizer as they are cleaners in their local hospital somewhere in the EU and therefore considered frontline workers did antibody tests a couple ​of weeks ago and their antibody counts were through the roof.

This is in a small town in central/eastern Europe, where they are loyal to their long-term employees, so, yes, they are still working there as cleaners at their age.

by Anonymousreply 38August 28, 2021 11:33 AM

Why is the FDA allowing Pfizer and Moderna to continue these “trials” with no control group?

by Anonymousreply 39August 28, 2021 7:24 PM

So, the UK, Japan and Vietnam are admitting the shots are a failure. Israel is also admitting that, but instead of finding a solution that works, is suggesting people take more of the vaxx that doesn’t work and which their own data shows causes ADE. France, Australia, Romania, etc are devolving into civil war with protests against the vax mandates. Canada is heading in the same direction. Several Nordic countries are lifting all or most of their covid procedures. Gibralter, which in 99% vaxxed, has become a death camp in fatal infections. What next?

by Anonymousreply 40August 29, 2021 12:02 AM

r40 What unmitigated bullshit. Try again. Maybe this time, present some evidence.

by Anonymousreply 41August 29, 2021 6:59 AM

No r40, no one except morons talking bullshit, such as yourself, has claimed the vaccines are a "failure".

by Anonymousreply 42August 29, 2021 10:17 AM

Are you paid by the post, r40? Because you have been posting up a storm on Datalounge.

by Anonymousreply 43August 29, 2021 10:20 AM

You Pfizerbots really need to try changing up your rhetoric.

by Anonymousreply 44August 29, 2021 4:31 PM

Are his concerns being covered in American media?

by Anonymousreply 45August 30, 2021 2:21 AM

Sure wish this was getting published in USA Today.

by Anonymousreply 46August 30, 2021 9:32 AM

Shouting down any legitimate criticism doesn’t help, guys. You can still be pro-vax and take a balanced view.

by Anonymousreply 47August 30, 2021 9:38 AM

r47, they're not trying to help.

by Anonymousreply 48August 30, 2021 9:39 AM

If I believed for one second that the trolls here were trying to promote a scientific evaluation of the vaccines available and what is needed to improve their safety and efficacy, I'd gladly jump on their bandwagon. But r47 makes it seem that the anti-vaxxers are reasonable and willing to debate legitimate opposing views, while it is the pro-vaxxers who are unreasonable. Having spent time in a Congressional town hall recently with a room full of anti-vaxxers, I can speak with total authority that there was no "reason" involved. The kind of nonsense being spouted was over-the-top crazy. "Vaccines are designed to kill us" "they are altering our DNA" "every research animal used died after being administered the vaccine" "they're putting chips in the vaccine to control our minds" and on and on.

There will ultimately be more information as regards most common side effects from the vaccines, and which are proving to be most effective at preventing COVID infection by new variants, etc. That is the point of science. It had been hoped that COVID would not act like the many kinds of influenza strains out there, and mutate so rapidly that new flu vaccines need to be formulated every year. Unfortunately, it appears that COVID does mutate rather readily, so I suspect that for the next several decades, we'll be lining up for a flu shot AND a COVID shot in the pharmacies every fall. Big deal. What we DON'T want to happen is to have the medical systems of every country on the planet collapse because of COVID surges that overwhelm their capacities, because there are many health issues that require functioning medical systems. Their stability should be the priority.

by Anonymousreply 49August 30, 2021 8:07 PM

So, why is this "EUA" being allowed to continue without any control groups?

by Anonymousreply 50September 1, 2021 7:19 AM

Hmmm?

by Anonymousreply 51September 1, 2021 8:22 AM

Again, why no control group for this 3rd stage trial being conducted on the masses?

by Anonymousreply 52September 1, 2021 12:55 PM

No control group...

by Anonymousreply 53September 1, 2021 1:30 PM

I wonder if those resigning senior FDA regulators read this.

by Anonymousreply 54September 1, 2021 1:37 PM

So the Brits not only created a failed vaccine, they literally killed people with it. And, yet, some maudlin little medical journal over there is shading what is irrefutably the world's most scientifically successful, measured, and deliberative drug review and assessment body on Earth? The FDA is so careful that millions of Americans have died waiting for drugs they were not yet ready to approve because of their protocols and demand for result redundancies.

Is it me or does anyone else ever notice how obsessed with American politics, policy, and society the British are while turning a blind eye to the meltdown and chaos of their own society? What is it that makes them this way? And is it the same reason that you can't go to any little dark corner of the globe without bumping into some bumbling Brit making a nuisance of themselves?

by Anonymousreply 55September 1, 2021 1:41 PM

r55 = rabid Pfizerbot Pharmacrat

by Anonymousreply 56September 1, 2021 1:45 PM

So you're participating in a rushed 3rd stage clinical trial with no control group -- and with a mode of delivery that the scientist who invented it says should only be used in the elderly and otherwise immunocompromised as a Hail Mary.

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by Anonymousreply 57September 1, 2021 4:24 PM

New UK Data

Deaths within 28 days of the positive test:

1 dose: 104 (of 89,957, -> .11%)

2 doses: 679 (of 73,400, -> .92%)

unvaccinated: 390 (of 183,333, -> .21%)

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by Anonymousreply 58September 2, 2021 11:42 PM

What r58 left out is that BY FAR the largest number of deaths was in the over 50 category, vaccinated or unvaccinated - BUT, 85% of Brits over 50 have been vaccinated and 95% over 50 have been vaccinated in affluent areas, so their death rate among the vaccinated appears drastic. But to go back to morbidity results pre-vaccine, the death rate among the over 80 was something like 25%, among over 70, 15%, and over 65 10%. So, compared to those numbers, 2% is an improvement. So, as usual COVID takes the biggest toll on older people, unvaccinated or vaccinated and the largest percentage of unvaccinated are among the young - as low as 20-25% - a group in which COVID infection rarely results in death. This supports the hypothesis that older people don't have as robust a response to the vaccine as younger, and that vaccine boosters might be beneficial to that group.

by Anonymousreply 59September 3, 2021 12:23 AM

OK, I did further research to check my numbers.. Last year, the death rate for 80 and older was 9%, for 75 and older was 4.5%, for 70-75 was 2.5, and for 65-70 1.5% In r58's link, and his analysis, the death rate for the vaccinated (mostly elderly by extrapolation from national vaccination rates), was .92, so less than 1%., meaning that they are dying at a much lower rate after infection than they were last year.

by Anonymousreply 60September 3, 2021 12:34 AM

It's beginning to look a lot like ADE, everywhere the vaccinated go....

by Anonymousreply 61October 31, 2021 3:27 AM
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