"Unforced error": Fauci "stunned" by AstraZeneca's use of outdated data in its vaccine submission

A follow-up to Jazz’s post earlier. The fate of the AstraZeneca vaccine in the United States matters much less to Americans than to people abroad since we’ll have plenty of supply from Pfizer, Moderna, and Johnson & Johnson to take care of our own by the time the FDA approves AZ next month. (If it approves AZ next month.) Because it’s easy to store, AstraZeneca’s shot might end up being used in some rural parts of the country where its more finicky competition can’t be preserved as easily. Mainly, though, the FDA’s verdict on AstraZeneca will be useful as a vote of confidence to potential recipients overseas that the vaccine is safe and effective. Because AZ is dirt cheap and, as I say, unfussy in storage, it should be the go-to vaccine for third-world countries.

Which makes this morning’s news of experts doubting its trial data a possible disaster in the making for the global vaccination effort. This is now the *third* black eye AstraZeneca has received in the past six months. There’s the unfounded panic over blood clotting connected to the vaccine that seized Europe over the past few weeks, enabled by European governments’ decision to suspend distribution while the matter was investigated. But there was also the strange dosing error in AstraZeneca’s initial trial data released last fall in which some subjects were accidentally given half the dose they were supposed to receive — and yet seemed to have more protection than those who got a full dose. The company pooled its trial data from multiple countries in that initial study as well, a strategy Stat calls “unusual.” Put all of that together with the new concerns about outdated data being submitted to U.S. regulators and we have a toxic brew of suspicion around the vaccine, some of it totally unjustified, some less so.

A simple question, then: Is AZ playing games with its data? The press release it issued yesterday announcing that its vaccine was 79 percent effective in U.S. trials turns out to be based on data only through February 17. Both AZ and the independent expert board (the DSMB) that’s analyzing that data had more recent numbers — and it sounds from this Fauci interview with Stat like that more recent data suggests the vaccine isn’t quite as solid as the data through mid-February would lead you to believe.

In an interview Tuesday morning with STAT, Anthony Fauci, the head of the NIAID, said the DSMB raised concerns because it felt the results in a AstraZeneca press release Monday looked more favorable than more recent data from the vaccine study had shown.

“I was sort of stunned,” Fauci said. “The data safety and monitoring board were concerned that the data that went into the press release by AZ was not the most accurate and up-to-date data. That is what the DSMB communicated to AZ in a rather harsh note. Having seen that letter we could not just let it go unanswered.”

Asked why NIAID released its unusual statement, Fauci said, “We just felt we could not remain silent. Because if we did remain silent, we could be understandably accused of covering something up. And we definitely didn’t want to be in that position.”

It’s unclear at the moment what the more recent data says. Is the vaccine less effective than the mid-February data implies or is it less safe, or both? AstraZeneca issued a statement this morning saying, “We have reviewed the preliminary assessment of the primary analysis and the results were consistent with the interim analysis,” which makes it sound as though there’s no real difference between the mid-February numbers and the more recent ones. And as you’ll see below, even Fauci allows that he thinks the final analysis will show that AZ is a “very good vaccine.” But something spooked the DSMB enough to put the brakes on here. What was it?

Some experts are surprised today that Fauci’s agency, the NIAID, made its concerns about the data public instead of contacting AstraZeneca for clarification behind the scenes. Why give a “very good” vaccine another black eye if you don’t need to? This sort of thing “is usually done in private, so this is unprecedented in my opinion,” said one British medical academic to the Independent. But as Fauci says, if the NIAID had tried to gain clarification from AZ without telling the public and that fact had leaked, there’d have been an international uproar over governments supposedly concealing doubts about AstraZeneca from the public in the name of encouraging vaccine uptake. In an odd way, he and his deputies found themselves in the same position as James Comey after the FBI found a new cache of Hillary Clinton emails in October 2016. If they had kept that quiet while they reviewed the emails and it leaked, Republicans would have freaked out about the feds trying to protect Hillary by covering up for her. Comey decided that transparency was the lesser of two evils under those circumstances despite knowing that announcing the discovery of the emails would damage Clinton’s election chances. Same here with the NIAID and AZ. People will be less likely to trust AstraZeneca now — but, in theory at least, they’ll be more likely to trust Fauci’s agency and the review process for new vaccines.

And in the NIAID’s defense, this Times account makes it sound like there was more to this dispute with AZ than just outdated data:

In recent days, the independent monitoring board’s analysis was delayed several times because the board had to ask for revised reports from those handling trial data on behalf of the company, according to a person familiar with the matter who was not authorized to discuss it publicly.

Companies sponsoring drug or vaccine trials typically wait for the monitoring board to review analyses and conclude that the study has yielded an answer before they announce trial results

The monitoring board’s slow progress fueled concerns among federal officials that AstraZeneca may have been sitting on the data or that the monitoring board had concerns about the way the data it was reviewing had been presented.

Why weren’t AZ’s trial reports ready for primetime from the start? Why did they rush out a press release announcing their results before the DSMB had signed off? “I’ve never seen anything like this. It’s so, so troubling,” said one expert in clinical trials to the Times about the tension between the NIAID and AstraZeneca.

Hopefully the most recent data will confirm that the vaccine is safe and effective — again, Fauci seems to believe that it will — and final FDA approval next month will undo most of the PR damage done by this episode and the earlier trial clusterfark. Here’s Fauci trying to explain to GMA what happened.