Written by Rebecca Robbins, Sharon LaFraniere, Noah Weiland, David D. Kirkpatrick, and Benjamin Mueller
On the afternoon of Sept. 8, AstraZeneca officials had a conference call with the Food and Drug Administration. The discussion covered important ground: What would AstraZeneca need to do to win the FDA’s blessing for the coronavirus vaccine it was developing with the University of Oxford?
But the AstraZeneca representatives neglected to mention a crucial development: Two days earlier, the company had quietly halted trials of its vaccine around the world, including a late-stage study in the United States. It acted after a participant in Britain fell ill.
A few hours after the conference call, the story broke about the halted trials. That was how key FDA officials heard the news, according to people with knowledge of the discussions.
The FDA’s commissioner, Dr. Stephen Hahn, was stunned by AstraZeneca’s failure to disclose the halt to regulators, one of the people said. The U.S. government had pledged more than $1 billion to AstraZeneca to finance the development and manufacturing of its vaccine and to supply the United States with 300 million doses if it proved effective. FDA regulators expected to be kept in the loop.
The episode might have been chalked up to a simple miscue. But it was part of a pattern of communication blunders by AstraZeneca that have damaged the company’s relationship with regulators, raised doubts about whether its vaccine will stand up to intense public and scientific scrutiny and, in at least one instance, slowed the vaccine’s development.
Independent scientists and industry analysts have criticized AstraZeneca and Oxford for not being sufficiently transparent about their early results, the design of their studies and safety issues. Most critically, it is not clear how well the vaccine works.
“The world bet on this vaccine,” said Dr. Eric Topol, a clinical trial expert at Scripps Research in San Diego. “What a disappointment.”
From the start, Oxford expressed great confidence. In April, Oxford’s Dr. Sara Gilbert told a British newspaper that she was 80% sure the vaccine would work, even though it had not been tested in humans. Britain ordered 100 million doses, with the goal that 30 million would be delivered by September.
In the United States, Operation Warp Speed, the federal initiative to fast-track vaccine development, in May made what was then its biggest investment. The government awarded AstraZeneca up to $1.2 billion for development and manufacturing of the vaccine in exchange for 300 million doses. Alex Azar, the health secretary, played up the deal as “a major milestone” in the program’s work. AstraZeneca’s stock hit a record high.
AstraZeneca, however, would not begin testing its vaccine in the United States until August, three months after the Warp Speed deal. That was long after Oxford had started running trials elsewhere in the world — a delay that would prove fateful for the United States.
Federal health officials had said in June that in order to authorize a vaccine, the FDA would likely need to see late-stage data from at least 30,000 trial participants. By then, Oxford’s trials in Britain and Brazil were underway, and even if their results were pooled they would fall short of that FDA threshold.
AstraZeneca planned for its U.S. trial to include 30,000 people. But that trial was weeks away from even starting. Then came a safety scare.
A British participant in the Phase 2/3 trial developed neurological symptoms consistent with transverse myelitis, an inflammatory syndrome that affects the spinal cord and is often caused by viral infections, according to a notice given to participants dated July 12. That trial was briefly paused. The participant was later found to have multiple sclerosis, deemed unrelated to the vaccine. But later in the summer, another participant in the same trial fell ill with similar symptoms.
On Sept. 6, AstraZeneca paused its global trials to investigate. The news became public two days later. FDA officials were blindsided.
In late October, after 47 days, the FDA cleared the U.S. trial to restart.
It was now even further behind the late-stage trials that Pfizer and Moderna had begun in the United States about a month before AstraZeneca’s trial started. One consequence was that, at least initially, AstraZeneca would not be able to combine the data from the U.S. and overseas trials in order to hit the FDA’s 30,000-person threshold.
In November, Pfizer and Moderna each reported that analyses had found their vaccines to be about 95% effective. The spectacular results set a high bar against which to measure rival vaccines.
Still, the vaccines from Pfizer and Moderna had drawbacks compared with the Oxford-AstraZeneca approach. They were more expensive — and the companies had not pledged to forgo profits on them. Plus, they couldn’t be stored outside ultracold freezers for more than a few weeks.
As a result, the global public health community was hotly anticipating Oxford and AstraZeneca’s results. They came on Nov. 23.
The good news was that the vaccine seemed to work. It appeared safe. And no one who had been vaccinated had developed severe COVID-19 or been hospitalized.
Things got messier from there.
AstraZeneca and Oxford researchers said their vaccine was up to 90% effective, but only among those who received the initial half-strength dose. Among the larger group of participants who got two full-strength doses, the vaccine was only 62% effective.
That seemed counterintuitive. And the Oxford researchers couldn’t explain with certainty why the vaccine worked so much better when participants got a half-strength initial dose. In The Lancet on Tuesday, the scientists said they still weren’t sure.
The situation only got worse. The day after the results were announced, Dr. Moncef Slaoui, the head of Operation Warp Speed, told reporters that the promising half-strength dose had not been tested in people over the age of 55. That was concerning because some vaccines don’t work as well in older adults, who are also more vulnerable to COVID-19. It also raised the question of why the vaccine developers hadn’t themselves disclosed that important caveat.
The unclear results further sapped the confidence of American regulators. Absent a clear explanation of why the half-strength initial dose worked so much better, the results most likely “will not be sufficient for an approval,” Slaoui said last week.
AstraZeneca is now considering a new global trial that will enroll several thousand participants to gather more data on the regimen involving an initial half-strength dose. Regardless, the vaccine is likely to become available soon in Britain and some other countries.
Not in the United States. As of last week, AstraZeneca’s U.S. trial was halfway to its goal of enrolling 30,000 people.
AstraZeneca executives said Tuesday that, based on feedback from the FDA, they didn’t expect to receive federal authorization for their vaccine until after the company gets results from its U.S. trial. That could happen in January.
In the meantime, U.S. public health authorities are preparing to begin vaccinating a tiny percentage of the population using the Pfizer and Moderna vaccines, which will soon be available in limited quantities.
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