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
17. No. Image

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More from @EricTopol

7 Dec
Great credit to this team for quickly getting us Omicron lab neutralization data. The bright side is that there is incomplete immune escape from vaccination👍
For people who had Prior Covid plus vaccination, the preserved Omicron neutralization level (FRNT) likely reflects solid protection. Not seen with 2 doses of Pfizer vaccine, but would expect that a 3rd shot, with its marked effect on raising nAbs, would simulate that
Here are some relevant data for the small sample. The 6 vaccinated individuals range from 10-39 days post-vaxx.

Take home point is how powerful hybrid immunity (vaccine + prior Covid) vs all variants that we've seen now, including Omicron
Read 4 tweets
7 Dec
Does Omicron lead to less severe illness than prior variants ? We don't yet but let's review what is the basis for the hope /1
In South Africa, among those hospitalized, less requirement for ICU for those admitted compared with Delta /2
And the same, much less ICU need among those testing positive /3
Read 9 tweets
29 Nov
This is actually a BIG deal and fully warranted, evidence based. Great to see!
Thanks @CDCgov @CDCDirector Image
Revised: Image
People are asking why not 3rd shots for age <18, i.e. teens?
There is no application yet from a vaccine manufacturer to FDA for age <18, so it can't be recommended yet. That will change soon......
Read 4 tweets
28 Nov
The US markedly lags many countries with boosters, in part because of poor messaging, and lack of priority to get *all* adults with fully restored vaccine effectiveness.
Would help vs Omicron, too. Boosters induce a striking increase in level & breadth of neutralizing antibodies.
Today's @washingtonpost editorial
"The [waning] phenomenon should compel all adults to get a booster shot."
Our editorial on boosters, @mtosterholm @PostOpinions
"Each day in the United States, the number of people with waning immunity greatly exceeds those who are getting newly vaccinated"
Read 4 tweets
26 Nov
The @WHO has named B.1.1.529 Omicron, a Variant of Concern [O, not Nu)
Here's their full statement, summary of data
This is only the 5th Variant of Concern since the pandemic began: Alpha, Beta, Gamma, Delta, and now Omicron.
That it was not named as a Variant of Interest is interesting and raises concern ;-)
There have been thousands of uninteresting #SARSCoV2 variants
Read 5 tweets
24 Nov
Our oped on the big mistake @CDCgov on boosters: All adults, not just age 50 plus, need them. Here's why
@washingtonpost @mtosterholm
washingtonpost.com/opinions/2021/… @PostOpinions
Now is not the time to withhold a vital and validated means of boosting our efforts to contain the virus
Each day in the United States, the number of people with waning immunity greatly exceeds those who are getting newly vaccinated. Accordingly, rather than building our wall of population immunity, the United States is suffering attrition.
Read 4 tweets

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