The Oxford-AstraZeneca effort held great promise to help arrest the pandemic. But a series of miscues caused it to fall behind in the U.S.
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 F.D.A.’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 F.D.A. officials heard the news, according to people with knowledge of the discussions.
The F.D.A.’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. F.D.A. 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.
The result is that a vaccine that was expected to account for a substantial portion — by one metric, as much as 60 percent — of the total vaccine supply in the United States faces an uncertain future. Two other highly effective vaccines are nearing federal authorization. But with more than 2,000 Americans dying daily, a delay of even a few weeks in deploying another effective vaccine could have deadly repercussions.
Federal officials and public health experts viewed AstraZeneca’s vaccine, which is less expensive and easier to store for long periods than some rival vaccines, as a leading candidate to help bring a swift end to the pandemic.
AstraZeneca officials repeatedly said they hoped to roll out their vaccine in the United States as early as October. Today, though, AstraZeneca hasn’t even finished enrolling people in its U.S. clinical trial. A key reason: The trial was grounded for nearly seven weeks because the company was slow to provide the F.D.A. with evidence that the vaccine was not associated with neurological symptoms that had appeared in two clinical-trial participants, according to the people with knowledge of the discussions.
On Tuesday, Oxford researchers published detailed data from their clinical trials in the scientific journal The Lancet. The study built on findings that the developers had announced last month showing that their vaccine worked, but that its effectiveness varied widely depending on the strength of doses.
Regulators in Britain, India and several other countries, armed with data from clinical trials outside the United States, are expected to authorize the vaccine’s use in the coming weeks. But in the United States, where regulators have been frustrated with AstraZeneca and want to examine data from a greater number of participants, that approval appears further off.
Developing vaccines is hard, and it is common for the work to fall behind schedule. Moderna and Pfizer, whose coronavirus vaccines appear to be 95 percent effective and are awaiting federal authorization, also faced delays. And even with the problems, AstraZeneca and Oxford’s vaccine is likely to be among the fastest ever developed.
Yet 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.”
He added, “If they just were upfront on safety, on efficacy, on dosing, on everything, from the get-go, they’d be in such a better position. But what they’ve done now is diminish credibility, and I don’t know how they’re going to regain that.”
In an interview on Tuesday, Prof. Andrew Pollard, the lead investigator of the Oxford vaccine trial, said the Oxford team had been “as transparent as we can all along.” He noted the team’s publication of peer-reviewed articles and trial blueprints.
“We continue to share all data with the F.D.A. and other regulators around the world in a timely manner,” said an AstraZeneca spokeswoman, Michele Meixell.
An F.D.A. spokeswoman declined to comment.
Years in the Making
Scientists at Oxford had been laying the groundwork for a vaccine for years.
The vaccine uses an approach that scientists have been testing for decades. It involves genetically modifying a harmless virus, known as an adenovirus, that causes the common cold in chimpanzees so that it can train the immune system to respond to a threatening virus — in this case, the one that causes Covid-19.
In 2018, Oxford researchers had run a safety study using a vaccine deploying that approach to protect against the coronavirus that causes Middle East respiratory syndrome, or MERS. Last December, as the virus now known to cause Covid-19 was spreading undetected in China, a second trial to test that MERS vaccine got underway in Saudi Arabia.
So when Covid-19 emerged, Oxford researchers had at the ready a vaccine platform that had been shown to be safe in use against a similar coronavirus.
When Chinese researchers released the genetic sequence of the virus that causes Covid-19 on Jan. 9, an Oxford vaccine researcher, Dr. Sarah Gilbert, was able to start work the very next day.
Dr. Gilbert’s team raced to insert genetic material from Covid-19 into its adenovirus platform. By March, the vaccine was being tested in monkeys in Montana.
A next step for Oxford was to find a pharmaceutical company to shepherd the vaccine through development — and, eventually, to mass-produce and distribute it.
At the time, the Trump administration was fighting for first-in-line access for certain vaccines. British health officials, who provided early funding to the Oxford team, believed that any homegrown vaccine should be quickly and easily accessible to Britons. “They made it pretty clear to me and others that they wanted to know about the deal and they were anxious about vaccine nationalism,” Dr. John Bell, an Oxford professor and a member of the British government’s vaccine task force, said in an interview in September.
AstraZeneca was not Oxford’s first choice. Dr. Gilbert’s team had been in discussions with “a previous company or two,” Adrian Hill, one of the Oxford scientists, said last month. One was the American pharmaceutical giant Merck, The Wall Street Journal reported.
But those talks fell apart, and AstraZeneca, a British company, emerged as a safe alternative. The company agreed to distribute the vaccine worldwide at cost — only a few dollars per dose — until at least July 2021 and in poorer countries forever.
The downside was that AstraZeneca, which is known for drugs to treat cancer, asthma and other chronic conditions, had scant experience with vaccines.
Hundreds of Millions of Doses
From the start, Oxford scientists expressed great confidence. In April, Dr. Gilbert told a British newspaper that she was 80 percent sure the vaccine would work, even though it had not been tested in humans. By then, Moderna had already started testing its vaccine candidate on people.
The Oxford team’s claims encountered skepticism from some scientists who expressed doubts about the approach and the ambitious timeline. “Some were a little cynical of the hubristic claims that were being made,” said Stuart Neil, a virologist at King’s College London.
The British and American governments nonetheless poured money into the vaccine.
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 M. Azar II, the health secretary, played up the deal as “a major milestone” in the program’s work. AstraZeneca’s stock hit a record high.
Those 300 million doses represent 60 percent of what the United States has ordered from the three manufacturers that have announced late-stage results so far. If other vaccines reach fruition or if the U.S. government exercises options to buy more doses, the reliance on the AstraZeneca candidate would decline substantially.
More countries soon placed orders. Even if other vaccines become available, the AstraZeneca offering is on track to account for 43 percent of all doses available in low- and middle-income countries, according to Airfinity, an analytics firm that tracks deals between vaccine manufacturers and governments.
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.
A Strange Discrepancy
In Britain, Oxford researchers wrapped up their first safety trial in May. No serious problems surfaced. Their next step was a larger so-called Phase 2/3 study, involving thousands of British participants, to assess how well the vaccine worked.
Oxford hired an outside manufacturer to produce large quantities of the vaccine for the trial. But when researchers received a sample of the vaccine and measured its strength, they noticed something strange. Using a different measurement technique than the manufacturer, Oxford found the concentration of viral particles in the vaccine to be double the level that the manufacturer had found.
Oxford researchers didn’t know which measurement to trust. They decided to use a lower-strength dose. That way, even if their measurement was wrong, the dosage was sure to be safe, albeit smaller than originally intended.
Participants would get two injections, which were supposed to be about a month apart. Oxford began administering the vaccine. Within a few days, participants reported fewer side effects like sore arms or slight fevers than participants had during the first trial. The Oxford researchers later identified an ingredient in the outside manufacturer’s vaccine batch that had skewed their measurement upward. That confirmed they were using a half-strength dose.
When the confusion over the dosing emerged months later, it would complicate efforts by scientists and public health officials to understand how well the vaccine worked.
In the meantime, public health authorities were increasingly embracing the inexpensive, easy-to-produce vaccine. In June, Soumya Swaminathan, the World Health Organization’s chief scientist, called it “probably the leading candidate.” In July, the head of the British government’s vaccine task force, Kate Bingham, told lawmakers that it was “the most advanced vaccine anywhere in the world.”
Trump administration officials, too, were enthusiastic. The White House chief of staff, Mark Meadows, told congressional leaders on July 30 that the Oxford-AstraZeneca vaccine could win emergency authorization from the F.D.A. as early as September, two people briefed on the discussion previously told The New York Times. (A spokesman for Mr. Meadows disputed that he had discussed AstraZeneca’s prospects.)
Such optimism was premature.
Federal health officials had said in June that in order to authorize a vaccine, the F.D.A. 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 F.D.A. threshold. (The agency has never closed the door on relying entirely on data from overseas trials to authorize a vaccine.)
AstraZeneca planned for its U.S. trial to include 30,000 people. But that trial was weeks away from even starting.
Neurological Symptoms
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.
Neither AstraZeneca nor Oxford announced the pause. Ms. Meixell, the AstraZeneca spokeswoman, said the company informed the F.D.A. about the illness on July 15 “in order to be as transparent as possible.” But at least some top F.D.A. officials didn’t learn about it, according to the people with knowledge of the discussions between AstraZeneca and the F.D.A. (The participant was later found to have multiple sclerosis, deemed unrelated to the vaccine.)
Later in the summer, another participant in the same trial fell ill with similar symptoms. It wasn’t necessarily a catastrophe: Transverse myelitis can be caused by a variety of factors. And a small percentage of people in any big vaccine trial are likely to develop conditions unrelated to the vaccine. Still, it was concerning, because there was a chance that it was linked to the vaccine.
On Sept. 6, AstraZeneca paused its global trials to investigate. The news became public two days later. F.D.A. officials were blindsided.
A day later, Pascal Soriot, AstraZeneca’s chief executive, compounded the problem. Instead of publicly releasing more information about the participant’s illness, he provided new details to investors in a private conference call organized by the investment bank J.P. Morgan.
In Britain, Brazil, India and South Africa, regulators allowed testing to resume in less than a week. In Japan, the pause was just under a month.
But in the United States, the delay dragged on. During the prolonged pause, new participants couldn’t be enrolled in the study — and that the small number of volunteers who had gotten their first inoculation in the early days of the trial couldn’t get their booster shot about a month later.
AstraZeneca was in part to blame for the delay, said the people with knowledge of the F.D.A. talks. The company was slow to provide the F.D.A. with all the data that regulators wanted to review before allowing the trial to start up again.
Far Behind
In late October, after 47 days, the F.D.A. 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 F.D.A.’s 30,000-person threshold.
In November, Pfizer and Moderna each reported that analyses had found their vaccines to be about 95 percent 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 percent 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 percent 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.
‘I’m Very Confident’
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,” Dr. Slaoui said last week.
Another wrinkle emerged on Tuesday. The Lancet article said some participants who got the initial half-strength dose didn’t receive their second shot until at least three months later. They were supposed to get the booster about a month after the first dose. For clinical trials that are usually carefully scripted, that represented another unusual deviation from the original plan.
Developers at Oxford and AstraZeneca have been frustrated by the torrent of questions overshadowing what they regard as their vaccine’s impressive efficacy.
“I’m very confident we have a vaccine that is effective,” a senior AstraZeneca executive, Menelas Pangalos, said in an interview.
But for Dr. Jesse L. Goodman, the F.D.A.’s chief scientist from 2009 to 2014, AstraZeneca’s missteps reinforce the importance of clear, transparent communication. “People need to know what is known and what is not known so they can trust in the process,” he said.
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 on Tuesday that, based on feedback from the F.D.A., 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.
Katie Thomas and Nicholas Kulish contributed reporting.
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