Well, dear readers, my take on "the winning formula" for Oxford/AstraZeneca did not age well. According to the Indian manufacturing partner, it isn't the "low"-dose-1st subgroup. It's another subgroup, perhaps a subgroup of a subgroup... livemint.com/science/health… HT @wogboy11 ..1/6
..The sweet spot he says is "a 2-to-3 months’ gap between dose 1 & dose 2". First let's recap their original data. They said intervals didn't make a difference. For the "standard"-"standard" group >8 wks apart vaccine efficacy was 65·6% (24·5 to 84·4). Ditto 6 weeks cutoff ..2/6
...The protocol doesn't limit the possible exploratory subgroup analyses ⬇️: so many ways they could have found a subgroup that hit this mark. Eg half the already-small "low"-dose-1st group had >12 wks apart: sliced off those perhaps? But I don't think that's the main point ..3/6
...If the proposed regimen is 2-3 mths apart, then we need to know the vaccine efficacy rate not just 2 weeks after the 2nd dose: but the vaccine efficacy since the 1st dose, because that's a long time to leave people half-ish-immunized & there's still no certainty on dose ...4/6
...Consider Tozinameran (BNT/Pfizer), the only vaccine that's given us that calculation so far. Although 95% for that primary endpoint after 2nd dose immunity kicked in, it was 82% (76-87%) if you also counted the people who got sick in the 3 weeks between dose 1 & dose 2 ...5/6
...and the range of uncertainty as subgroups get smaller & risk of multiple testing is going to matter a lot. We can't afford to throw a baby out with the bathwater. But there's an inherent risk of error in exploratory subgroup analysis too. 6/6 statistically-funny.blogspot.com/2014/03/if-at-…

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More from @hildabast

28 Dec
MHRA verdict reportedly coming any day for the Oxford/AstraZeneca vaccine. I've been asked if I think their process is comparable to FDA's. Good question, post-Brexit. So I looked at 3 regulator reports for Tozinameran (BNT/Pfizer): FDA, MHRA, EMA (Europe) ...1/6
...2 agencies have unequivocal advantages:

1) Only the EMA did manufacturing inspections, which is a very big deal;

2) FDA had greater transparency: they're the only 1 releasing manufacturer briefing, released reports pre-committee, live-streamed committee discussion ...2/6
... FDA assessment report: 92 pages, almost all clinical data/issues, extensive data analysis - released days before their decision;

MHRA: 51 pages, not as much analysis - released 2 weeks after decision;

EMA: 140 pages, extensive data analysis, wide coverage ...3/6
Read 7 tweets
27 Dec
The AstraZeneca boss says they have new data for "the winning formula" that shows as good a result as Tozinameran (BNT/Pfizer) & Moderna. Based on what we know so far, is that likely? Well, yes...and no... 1/6 thetimes.co.uk/article/covid-…
...Protocol for their pooled analysis of trials had 2 analyses, dependent on reaching set events (people sick with Covid-19 more than 2 weeks after 2nd dose) in the standard-standard dose group: 53 events for the 1st analysis, 105 for the "final"... 2/6
..We've seen 1st analysis: 98 events in that group. So they only needed a few more events to get to final of 105. Vaccine efficacy in that group was 62·1% (95% CI 41·0–75·7): with upper bound 75.7%, small data increase unlikely to get them over 90% ...3/6 thelancet.com/journals/lance…
Read 7 tweets
15 Dec
Moderna data has arrived at the FDA.... I'll be tweeting about the 54-page document by the FDA fda.gov/media/144434/d… The brief from Moderna is much smaller than BNT/Pfizer's - only 84 pages (+ a 7-page presentation) fda.gov/media/144452/d… 1/n fda.gov/advisory-commi…
..Efficacy data is for 27,817 people randomized to either vaccine or placebo; & there's safety data for 30,350 people. I'll get started with the adverse events data, because that has been a question mark for this vaccine...2/n
...The FDA raises lymphadenopathy & Bell's palsy again. More people with lymphadenopathy with Moderna's vaccine than BNT/Pfizer's: 173 in vaccine group, 95 in placebo. Bell's palsy similar. Frequency of serious adverse events (SAEs) low: 1.0% in vaccine & placebo arms...3/n
Read 17 tweets
10 Dec
#tbt This is the dedication, with Eleanor Roosevelt, for the Polio Hall of Fame, honoring 17 scientists critical to polio research & the vaccine. The only woman scientist is in the center. She's Isabel Morgan (1911-1996) ... 1/5 asm.org/Articles/2019/…
...Morgan cracked 2 major barriers that made the Salk vaccine possible: identified 3 serotypes for polio that needed to be protected against. Then in preclinical studies, she showed inactivated vaccine could work if you added adjuvant & a booster shot ...2/5
...These are her parents, both geneticists. She's Lilian Vaughan Morgan, a pioneer in using Drosophila as a model, revealing some of its chromosomes

He's Thomas Hunt Morgan, 1933 Nobel prize winner for chromosome discoveries en.wikipedia.org/wiki/Thomas_Hu… ...3/5
Read 5 tweets
8 Dec
So now the meta-analysis of phase 2/3 data from 4 of the trials of the Oxford/AstraZeneca vaccine is out @TheLancet. Because of course it is. 🤦‍♀️ marlin-prod.literatumonline.com/pb-assets/Lanc… Background: wired.com/story/the-astr… 1/n
...Mystery #1 - why Indian phase 3 trial isn't included - isn't solved. They report only that they have trials in UK, Brazil, SA & Kenya (Kenyan data not included). Trials in the US, Japan & Russia also not mentioned... 2/n
...Ah...in the statistical analysis plan, they describe the 4 studies as Oxford-sponsored. The trials that aren't mentioned presumably aren't. Given there was a serious adverse event in the Indian trial in October, this raises issues... 3/n marlin-prod.literatumonline.com/pb-assets/Lanc…
Read 17 tweets
8 Dec
The FDA will start releasing phase 3 trial data on Covid vaccine any moment now & a media deluge will start! Tips on what to watch out for | My latest @WIRED wired.com/story/new-vacc…
Not any moment now...it's out! Data at last: it's 92 pages from Pfizer/BNT fda.gov/media/144246/d… & 53 pages from the FDA fda.gov/media/144246/d…
Oops - cut & paste fail ⬆️: the 53 pages from the FDA fda.gov/media/144245/d…
Read 19 tweets

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