The latest blow to AstraZeneca’s tortured effort to bring a Covid-19 vaccine to the world arrived by way of a terse statement released on Tuesday at 22 minutes past midnight in Washington.
In an unprecedented late-night intervention, the National Institutes of Health warned that an independent board of experts overseeing a large US study of the vaccine had “expressed concern that AstraZeneca may have included outdated information” when it announced results from the trial in a press release on Monday.
The dispute between AstraZeneca and the independent scientists — who sit on the trial’s data and safety monitoring board, or DSMB — centres on whether the company was wrong to publish data collected before a February cut-off point instead of including more recent figures as well.
In a letter sent to AstraZeneca on Monday, which was copied to the NIH and another US government agency funding the trial, the DSMB said it thought a broader analysis including up-to-date results would show a lower efficacy rate of between 69 per cent and 74 per cent, according to a person who has seen it.
Anthony Fauci, a senior official at the NIH, told the Financial Times the body was “not accusing anybody of anything”, adding: “[We are] just saying very, very frankly and simply, that we urge the company to work with the DSMB to review the data, and to ensure that it’s the most accurate, up-to-date data that was made public.”
AstraZeneca responded to the NIH statement by promising to publish the final data set from the trial within 48 hours.
The vaccine is already approved for use in the EU, the UK and other countries, and the primary purpose of the trial in question is to also secure a greenlight from regulators in the US.
But the US trial has acquired a significance that goes far beyond paving the way for an authorisation from the Food and Drug Administration, an endorsement that Pascal Soriot, AstraZeneca’s chief executive, has long sought.
Instead, the study offered a shot at redemption for a company that had been accused of bungling previous trials, which left unanswered questions over whether the jab was as effective in older people.
It was also hoped that the US study would boost global confidence in the vaccine by alleviating concerns over whether it causes rare but potentially deadly blood clots, which prompted several European countries to suspend its rollout.
According to a person briefed on the matter, AstraZeneca was “under pressure” to release the findings on Monday to prove that the vaccine had strong efficacy in people aged 65 years and more. The drugmaker also worried that it might be “accused of sitting on the data and not being transparent”, they added.
However, far from quelling concerns over the AstraZeneca jab, the findings from US trial have caused even more confusion.
Art Caplan, a professor of medical ethics at New York University who has served on about 20 DSMBs, said the scientists’ decision to challenge AstraZeneca’s claims of efficacy was “very close to going nuclear”.
The DSMB members must have been “gravely concerned that the claims in the press release were not merited” by the data they had seen, added Caplan. “The next move by AstraZeneca is going to determine the fate of the vaccine. If they mess it up, the vaccine may be beyond redemption in some countries.”
This was not the first time that the DSMB had questioned how AstraZeneca handled its trial data, according to a person briefed on the relationship, who said the scientists had become “impatient” with the company. But now the simmering tensions have spilled into public view.
AstraZeneca, the UK-based pharmaceuticals group that has developed the vaccine invented at the University of Oxford, has huge ambitions for its rollout: it wants to produce more jabs that any other company and to sell them at a non-profit price.
But AstraZeneca has struggled in the spotlight compared with other vaccine makers, including a clutch of much smaller and younger companies such as Moderna, the US biotechnology group.
AstraZeneca’s efforts have been tarnished by difficulties understanding how it sliced and diced data from its first phase 3 trial in November, an episode that has echoes of the latest drama, replete with confusing press releases that frustrated scientists. The company has also been embroiled in a dispute over production shortages in the EU.
When AstraZeneca released its US trial results early in the European morning on Monday, it appeared as though the data would finally put to rest many of the lingering doubts over the vaccine.
In addition to an overall efficacy rate of 79 per cent, the press release said the vaccine was 100 per cent effective at stopping severe disease and hospitalisation — an improvement on its earlier phase 3 trial. Nor was there any evidence of problematic blood clots.
Armed with the trial’s findings, executives took to US television studios to tout the benefits of the jab, with Ruud Dobber, AstraZeneca’s US president, telling the business news channel CNBC that the company was “thrilled”.
But behind the scenes, things were about to go wrong. Within hours of the press release, a frustrated DSMB contacted AstraZeneca, Fauci at the NIH and the US Biomedical Advanced Research and Development Agency, or Barda, which has provided funding for vaccine development, according to people familiar with the developments.
AstraZeneca scrambled to address the DSMB’s concerns, with a person briefed on the matter suggesting that Soriot had taken a lead in resolving the dispute. “He would obviously rather this hadn’t happened but he is completely focused on sorting it out,” the person said.
A person briefed on the disagreement suggested that the DSMB had only seen “raw data”, where Covid-19 cases had not been confirmed by a positive test result. Once “adjudicated” it might be found that a positive case was in fact the flu, or someone simply losing their sense of smell, the person added.
Now AstraZeneca is speeding through the final analysis. “It is a painful way to spend 48 hours,” the person said.
Another person with knowledge of the situation said that, before Monday’s announcement of the interim data, AstraZeneca had already been in the process of assessing the newer data that arrived after the February 17 cut-off point. The company does not anticipate that the newer figures will result in a meaningful change to its conclusions on efficacy, they added.
The person pointed out that the company had always said that it would conduct a so-called interim analysis and had twice described the findings as “interim” in its press release.
“This isn’t just something they have cooked up . . . It was very clear more data was coming,” they said. The efficacy figure announced on Monday was likely to be “pretty close to where it will end up in the final analysis”. they added. “If the numbers do move around they probably won’t move around massively.”
However, that does not explain how the company ended up angering the scientists on the DSMB. Dan Barouch, a professor at Harvard and a clinical trial investigator in the Johnson & Johnson vaccine trial, said it was unusual and “not optimal” that the board had not seen what was going to be released.
“Typically, the DSMB does an analysis and provides that to the company and in this case the government . . . The statement that comes out is one that everybody agrees to in advance,” Barouch added.
One observer said the company may have been trying to “keep it simple” after the November debacle, when the company and Oxford reported three separate efficacy numbers.
In the US, the White House was concerned enough to ask for a briefing from the NIH. The impact will also be felt in Europe, where health officials were hoping for a readout with clean, easy-to-understand figures to help increase public trust in the vaccine. One global health official asked: “How does AstraZeneca manage to screw up every time?”
London-listed shares in AstraZeneca closed 1.76 per cent lower on Tuesday as investors, who do not stand to profit from the vaccine during the pandemic, fretted that the company’s broader reputation could be hurt by its handling of the situation.
Dan Mahony, co-head of healthcare for Polar Capital and an AstraZeneca investor, said the company was developing the vaccine for the “right reasons”, but described the latest developments as “frustrating”.
He added: “It is becoming a bit of a PR headache and it seems to be sucking up a lot of management time . . . As an investor you think ‘was it really worth it’? You don’t want to be constantly fighting fires, particularly over something that isn’t making you much money.”
Additional reporting by Kiran Stacey in Washington