Eric Topol Profile picture
19 Sep, 18 tweets, 8 min read
We have the protocols. Now we know how there will very likely be an Emergency Use Approval (EUA) for a vaccine prior to November 3. The company and political motivations are fully aligned.
1. The criteria for an EUA is that it "may be effective"
fda.gov/regulatory-inf… Image
2. Nearly every day we hear from @pfizer's CEO @AlbertBourla that they will know if their vaccine is working by the end of October.
Only the Data and Safety Monitoring Board is reviewing the data at specific intervals, the interim analyses
So how will they (Pfizer) know that?
3. The 1st interim analysis for that trial is at 32 events, infections, which can and likely will be mild. The stopping rules as reviewed by @biosbenk @EmoryRollins are "aggressive" and "unusual" for the number of interim analyses (4) and Bayesian approach
github.com/benkeser/pfize… Image
4. As presented in a poll, ≥ 26 infections in the placebo group at the 1st interim of 32 events would fulfill the stopping rule and support a claim of efficacy.
But the EUA only requires *"May be effective"* so even <26 placebo events could qualify
5. The DSMB reports to the sponsor. The trial data should not be unblinded unless it has been stopped (for futility, safety, or efficacy stopping rule) or completed. But it is easy to discern which group (vaccine or placebo) by the early adverse effects without unblinding.
6. Note the similarity in some symptoms for #COVID19 (which are the endpoint) and the early adverse effects of the vaccine (dose of 100 ug was used in Phase 3)
nejm.org/doi/full/10.10… Image
7. So with or without fulfilling pre-specified efficacy criteria at the 1st interim look, which will occur within weeks, Pfizer can apply for an EUA with the low threshold of "may be effective"
(If Pfizer hits the stopping rule and doesn't stop the trial, that's another story)
8. The EUA criteria are so minimal that even the Phase 1/2 serology data (NEJM paper above) could fulfill "may be effective" and that would equate to the Russian vaccine approval and roll out.
9. There has only been one FDA EUA for a vaccine in history, which was for anthrax, and that didn't go well theatlantic.com/health/archive… by @sarahzhang Image
10. What if the FDA says NO, the data from 32 infections isn't enough? Clearly at that juncture there would be very limited data for the vaccine's safety.
The HHS can override that an issue the vaccine approval.
And we've already seen @HHSGov do that with FDA LDTs weeks ago.
11. The same issues apply for the @moderna_tx first interim analysis at 53 events, but a conventional O'Brien-Fleming stopping rule is being used and the 1° endpoint definition of infections is tighter
12. This is obviously a rush job—a race between companies with big political stakes. Once an EUA is issued for a vaccine, the whole landscape shifts. Safety issues could crop up later and engender mistrust. Ability to conduct placebo-controlled trials could be impaired.
13. These are the most important clinical trials of our lifetime. There's no need for this rush. We need to do them right; get the Phase 3 trials completed as planned at 150-160 events. That will only require waiting weeks, it'll give us more confidence about efficacy and safety
14. Just as pressure was applied to @pfizer @BioNTech_Group and @moderna_tx to release their protocols, we need to apply intense pressure to the companies, the FDA, and HHS to preempt any EUA until Phase 3 trials are *fully* completed.
15. Translation, TLDR:
We need a shot in the light, not in the dark.
A matter of weeks to nail the efficacy issue down is well worth the wait.
Zero tolerance for company or governmental shortcuts and related back door BS. Image
16. If there was any doubt about @HHSGov @SecAzar's plan to make sure there is an EUA for a vaccine before Nov 3 (see 10. above), then you can read this by @BySheilaKaplan
nytimes.com/2020/09/19/hea…
17. No. Image

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More from @EricTopol

22 Nov
The good news is that many of the worst-hit states for the US pandemic have started their descent.
Nebraska, New Mexico still on a sharp ascent Image
South Dakota peaked with the highest death rate per capita for any place in the global pandemic Image
Nice that the @CDCgov is discouraging travel at Thanksgiving. Where were they when 450,000 people were assembling for the #SturgisRally?
Read 4 tweets
20 Nov
Today the @WHO rejects Remdesivir for #COVID19.
The same drug the @US_FDA gave a full approval.
Because the @WHO reviewed all the data and made the right call.
bmj.com/content/bmj/37…
@bmj_latest
Read 4 tweets
18 Nov
It was "incalculable" on May 24th.
The loss of 250, 000 Americans as of Nov 18th is indescribable. Unfathomable. And mostly preventable.
"They Were Not Simply Names on a List"
"They Were Us"
Each American lost an average of 10 years of life and left behind an average of 9 family members grieving. Still grieving their loss, 6 months later.
Now multiply that 2.5 times.
Our family, friends, patients, coworkers, neighbors, our fellow Americans. Lost souls.
Today we had the highest number of deaths since early May @COVID19Tracking
Read 4 tweets
18 Nov
The @Pfizer/@BioNTech_Group vaccine trial is complete for efficacy. Of 43,661 participants, 170 events, 162 in placebo group, 8 in the vaccine. That's 95% efficacy; *phenomenal*; replicated @moderna_tx, ~ as good as it gets👇
statnews.com/2020/11/18/pfi… @damiangarde @matthewherper
The only silver lining of rampant covid spread in the US is that the vaccine trials are getting completed much faster
Good timing for this FAQ today @washingtonpost washingtonpost.com/health/2020/11… by @Carolynyjohnson @asteckelberg @PostGraphics
Short answer: They work really well
We'll see all the data, w/ safety, very soon at external advisory mtg
Infographic: where we go from here, important stuff
Read 4 tweets
18 Nov
This is great news tonight--the first--and hopefully a @US_FDA precedent for may more rapid (<30 mins) home covid tests
@LuciraHealth
FDA EUA letter fda.gov/media/143810/d…
My post from July on this. It has taken waaaaay too long but we're getting there. RT-LAMP today, antigen tests to come.
Without prescription, cheap, every household, ASAP
Read 4 tweets
18 Nov
Yes, America, there is a state with a 62.9% test positivity, the 3rd highest new cases per capita in the world, and a rapidly rising death rate
This section of the country (started w/ the Dakotas), is spreading in every direction. Minnesota now going vertical. Grossly inadequate testing w/ positivity now:
South Dakota 57.5%
Iowa 51.7%
Idaho 42.0%
Kansas 40.9%
Montana 24.6%
covidexitstrategy.org
Brilliant.
Read 5 tweets

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