In a memo sent to company and government officials obtained by The Washington Post, experts who have been overseeing the vaccine trial expressed concern and disappointment that the drugmaker had presented "outdated and potentially misleading" data on its coronavirus vaccine, making the shots appear more effective than shown by fuller data.
On Monday, AstraZeneca and academic scientists trumpeted a vaccine that was 79% effective in its large U.S. clinical trial. That news release triggered concern among independent monitors who had seen more recent data, because when an additional month was taken into account, the effectiveness ranged from 69% to 75%.
The letter came from 11 leading statisticians, infectious-disease physicians and ethics experts appointed by the National Institutes of Health to review trial data for all the major coronavirus vaccines supported by the federal government. It says the company's decision to use early data that puts the vaccine in the most favorable light is a scientific misstep that could erode trust in the shot.
The letter, sent late Monday, opens a rare window into the typically confidential interactions between a company and the Data and Safety Monitoring Board that polices patient safety and the scientific validity of clinical trials. These monitors are not distant observers or whistleblowers; they are independent experts granted inside access to the AstraZeneca results for months, seeing the full data before even the company has access.
"The DSMB is concerned that AstraZeneca chose to use data that was already outdated and potentially misleading in their news release," the letter states. The data "they chose to release was the most favorable for the study as opposed to the most recent and most complete. Decisions like this are what erode public trust in the scientific process."
In other circumstances, this turmoil might be seen as a technical issue, because the additional data does not appear to overturn the fundamental finding that the vaccine works. AstraZeneca released a statement Tuesday promising that the full analysis of its data would be available within 48 hours and indicated the results would be consistent with the analysis released Monday.
"We will immediately engage with the independent data safety monitoring board to share our primary analysis with the most up to date efficacy data," the statement said.
But it appears to be the latest self-inflicted wound from the team behind the vaccine, which has stumbled with messy science and bungled communication for months.
Federal officials were taken aback by the board's allegations. One said the way that AstraZeneca handled the results was the equivalent of "telling your mother you got an A in a course, when you got an A in the first quiz but a C in the overall course." Another said the disclosure by the board would inevitably hurt the company's credibility with U.S. regulators.
The officials spoke on the condition of anonymity because they were not authorized to talk publicly about the issue.
On Sunday, company officials shared with U.S. government officials the results they would present to the world Monday. A person familiar with the matter said they also shared a preliminary analysis that suggested the result would hold up when more data were considered.
But Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said in an interview that he was "shocked" by the letter and the serious concerns it brought to light. On Monday, before receiving news of the letter, Fauci had said that "numbers don't lie" and that the vaccine appeared to be effective.
"The irony of this is that it's very likely a very good vaccine, and this sort of thing does nothing but cloud the picture. I don't think it reflects on the vaccine," Fauci said. "I think it reflects on how the data has rolled out."
Outside experts, who were stunned by the turn of events, said the vaccine might still get FDA clearance, only to be shunned by a public spooked by the string of controversies involving AstraZeneca and Oxford.
"The whole thing has been a giant debacle, and it is entirely on AstraZeneca," said Angela Rasmussen, a virologist with Georgetown University's Center for Global Health Science and Security. "Are people going to want to take the vaccine? People may think, 'There's too much going on with this vaccine, and I want something that is more reliable.' "
She said she would take the AstraZeneca vaccine today if it were available. But she worries that the data dispute will fuel vaccine hesitancy, with people becoming more suspicious of all coronavirus vaccines. "People might decide not to take any coronavirus vaccine at all," she said.
The episode may be a sign of how fraught the relationship between the company and the U.S. government has become. Early Tuesday, the National Institutes of Health took the unheard-of step of disclosing that the data board, a typically obscure part of the clinical trials process, had raised concerns that the news release Monday was "an incomplete view of the data."
Companies, scientists and participants are typically "blinded" to the data, unable to see who received a vaccine and who received a placebo. The data board can see past that firewall and make recommendations to the company about when to "unblind" and analyze the data.
David DeMets, a University of Wisconsin at Madison biostatistics expert, said that while he has no specific information on what occurred in this case, his experience serving on data safety and monitoring committees for nearly half a century was that it would be "very uncommon" for those experts to challenge a company or scientists on the content of a news release.
"Investigators and sponsors rarely present results that are in contradiction to the DSMB's interpretation of the results," DeMets said.
For weeks, the data board and the company had been going back and forth over how AstraZeneca was handling the data. When the experts initially saw the data supporting the 79% efficacy with data gathered through Feb. 17, they deemed that the vaccine efficacy number was "unstable" because of a large number of possible and probable cases that still needed to be adjudicated and might have changed the level of efficacy "enough to erode confidence in the results of the study."
At a later meeting, with figures through March 16 that showed a vaccine efficacy of 75%, the data board advised that the data be released to the company, but "strongly recommended" the drugmaker go through 33 remaining cases that were possible or probable cases of illness because the effectiveness could slide down to 69%.
Adrian Hill, one of the scientists at Oxford who developed the vaccine, said in an email the episode illustrated "extraordinary behavior" by a data and safety monitoring board.
"Talk about efforts to maintain confidence in vaccines," Hill wrote. "What is going on?!"
On Monday, Oxford and AstraZeneca appeared to have redeemed months of scientific missteps and poor communication when the company announced through news releases and interviews that its 32,000-person clinical trials in the United States, Chile and Peru showed that the vaccine was 79% effective in protecting volunteers from symptomatic covid-19, the illness caused by the coronavirus - and that it was 100% effective against severe illness.
The 79% efficacy figure in the AstraZeneca trials was higher than earlier clinical trials run by Oxford in Brazil, Britain and South Africa for the same vaccine, which found the shots 62% effective. The vaccine has been approved for use in ongoing inoculation campaigns in Britain and Europe. Millions of people have gotten their first dose.
Even before the trial results were released Monday, some federal officials were concerned about the efficacy of the two-dose AstraZeneca shot because a previous trial showed that the effectiveness was lower than the efficacy for the one-dose Johnson & Johnson vaccine. That sparked debate about how the AstraZeneca vaccine would fit into the U.S. vaccine strategy, especially with supplies of the Johnson & Johnson, Pfizer-BioNTech and Moderna products becoming more plentiful.
AstraZeneca said Monday that it would apply for emergency use authorization by the Food and Drug Administration in coming weeks. The U.S. government has ordered 300 million doses of AstraZeneca vaccine, but with three others vaccines already authorized, it is not clear what role the AstraZeneca shot will play in the United States.
Some researchers described the reaction by the U.S. scientists - and the public airing over the meaning of the AstraZeneca data - as highly unusual.
Stephen Evans, a professor of pharmacoepidemiology at the London School of Hygiene & Tropical Medicine, told reporters Tuesday that it is not unknown for a data monitoring board to disagree with investigators over the interpretation of trial results.
"It is usually done in private, so this is unprecedented in my opinion," Evans said.
Others speculated that it may be a technical issue that can be resolved quickly.
AstraZeneca's coronavirus vaccine was designed to be a cheap, easy-to-administer dose that would protect not just citizens of wealthy nations but also those in the most vulnerable countries.
But collaboration between Oxford researchers and one of the world's biggest drug companies has been plagued with missteps as other vaccine rollouts gain speed.
First, there was confusing basic science, then missed delivery targets. Last week, a confidence-sapping pause in Europe followed reports of rare blood clots among several of the vaccinated.
And now comes resistance from independent monitors over AstraZeneca's interpretation - and claims - of effectiveness in the U.S. clinical trials.
The Data and Safety Monitoring Board's memo did not suggest that AstraZeneca had minimized potential side effects.
The European Medicines Agency, which regulates drugs in the European Union, declared the vaccine safe and effective and said it was not linked to a rise in the overall risk of blood clots. But the European agency did not rule out a possible link to rare cases of clotting in the brain, known as cerebral venous sinus thrombosis.
Jason Schwartz, assistant professor of health policy and management at the Yale University school of public health, said the vaccine is sure to receive heightened scrutiny from the FDA and its outside advisers and, even if it clears regulatory hurdles, could face public skepticism.
"One of the key moments yesterday was that it seemed to stop the bleeding on a string of missteps around this vaccine as it is being rolled out in Europe," he said. "Now, that is being thrown into doubt and the hill to build public confidence has gotten that much steeper."
And if the FDA does not authorize the vaccine, he said, "that could be interpreted by the rest of the world as a lack of confidence, so we have to be sensitive to the global implications of how the U.S. reviews the data."
Published : March 24, 2021
By : The Washington Post · Carolyn Y. Johnson, Laurie McGinley, William Booth