The letter, from 11 leading statisticians, infectious-disease physicians and ethics experts appointed by the National Institutes of Health to review the trial data for all the major coronavirus vaccines supported by the federal government, says the company’s decision puts the vaccine in the most favorable light — a grave scientific misstep that could erode trust in the vaccine.
The letter is a rare window into the typically confidential interactions between a company and the Data and Safety Monitoring Board that polices the integrity of the data.
“The DSMB is concerned that AstraZeneca chose to use data that was already outdated and potentially misleading in their press release,” the letter states. “The point that is clear to the board is that the [vaccine efficacy number] . . . 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.”
The letter goes on to explain that while the company announced its vaccine was 79 percent effective on Monday, the panel had been meeting with the company through February and March and had seen data showing the vaccine may be 69 to 74 percent effective, and had “strongly recommended” that information should be included in the news release.
Federal officials were taken aback by the letter from the board. One said the AstraZeneca results were 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.
Anthony S. 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 “numbers don’t lie” and that the vaccine looked good.
“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.”
On Monday, Oxford and AstraZeneca appeared to have redeemed months of scientific missteps and poor communication when it announced via news releases and interviews that its 32,000-person clinical trials in the United States, Chile and Peru showed its vaccine was 79 percent effective in protecting volunteers from symptomatic covid-19, the illness caused by the coronavirus — and that it was 100 percent effective against severe illness.
The 79 percent 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 percent effective. The vaccine has been approved for use in ongoing inoculation campaigns in Britain and Europe. Millions of people have gotten their first dose.
Adrian Hill, one f the scientists at Oxford who developed the vaccine, said in an e-mail that this was “extraordinary behavior” by a data and safety monitoring board.
“Talk about efforts to maintain confidence in vaccines,” Hill wrote. “What is going on?!”
But U.S. officials said the data and safety monitoring board and the company had been going back and forth for weeks over how AstraZeneca was handling the data. They said the board advised the company to use a later data analysis with more cases but that the company did not follow the recommendation. The board was dismayed to see the company’s news release on Monday highlighting the 79 percent overall efficacy, the officials said.
The letter from the data and safety monitoring board was sent to the NIH and officials of the Biomedical Advanced Research and Development Authority Monday evening, officials said. Some pushed hard for it to be released as soon as possible so that it wouldn’t leak. Also, said one of the officials, the White House “did not want the 79 percent story to go unchecked.”
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 the effectiveness was lower than the efficacy for the one-dose Johnson & Johnson shot. 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 vaccines becoming more plentiful.
In its statement, the National Institute of Allergy and Infectious Diseases urged AstraZeneca to work with the independent monitors “to review the efficacy data and ensure the most accurate, up-to-date efficacy data be made public as quickly as possible.”
In a brief statement, AstraZeneca said its efficacy results published Monday “were based on a pre-specified interim analysis with a data cut-off of 17 February. We have reviewed the preliminary assessment of the primary analysis and the results were consistent with the interim analysis. We are now completing the validation of the statistical analysis.”
The pharmaceutical company said it would “immediately engage” with the independent data and safety monitoring board to discuss the most up-to-date efficacy data. AstraZeneca promised a more detailed analysis within 48 hours.
AstraZeneca said Monday it would apply for emergency use authorization by the Food and Drug Administration in coming weeks. The U.S. government has preordered 300 million doses of AstraZeneca vaccine, but with three others vaccines already approved 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 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 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 a handful of the vaccinated.
And now comes push-back from independent monitors over AstraZeneca’s interpretation — and claims — of effectiveness in the U.S. clinical trials.
The concerns raised by the Data and Safety Monitoring Board did not mention any concerns it had that AstraZeneca had downplayed possible 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.
While most European countries that paused the use of AstraZeneca’s vaccine last week have restarted their programs with additional warnings to patients about risk factors, Scandinavian nations have held back.
The Norwegian medical regulator said Sunday that two more people among about 120,000 people in the country that had recently received the AstraZeneca vaccine had died, taking the total to four. They were among six people hospitalized for unusual forms of blood clots after receiving the vaccine.
The medical regulator said it could not rule out that the cases were related to the vaccine. It said the unusual pattern of side effects, which includes blood clots, bleeding and a low platelet count, had not been reported with other coronavirus vaccines in the country.