By Jenny Strasburg
LONDON -- The U.K.'s authorization of a Covid-19 vaccine
developed by the University of Oxford and AstraZeneca PLC marks a
home-turf victory for the two British institutions, but comes after
stumbles that have sown public doubt about the shot and strained
the partnership itself.
After clearing regulators at home on Wednesday, the partners
face the challenge of convincing medicine watchdogs in the U.S. and
elsewhere that their missteps are behind them and that their
vaccine, while not as effective as shots from two rivals already
rolling out, can play a meaningful role in curbing the
pandemic.
The partners have promised to distribute their vaccine in huge
quantities and sell it cheaply throughout the pandemic. In the
U.S., AstraZeneca expects to have data from a large American
clinical trial to show to the Food and Drug Administration by
February, said a person familiar with the trial.
The partners hope for authorization across Europe by February,
and a green light in Australia could also come soon, this person
said. AstraZeneca's manufacturing partner in India has asked for
regulatory authorization there. All depend on regulatory
sign-off.
Complicating those plans are doubts seeded by the partners' own
handling of their ambitious project. In late November, they
unveiled late-stage trial results that showed a wide range of
efficacy levels, varying by dose and age group. The presentation,
which described an unusual and unexpected half-dose given to some
subjects that wasn't fully explained, sowed confusion and
skepticism about the vaccine.
U.K. regulators on Wednesday praised the vaccine's promise to
help end the pandemic but rejected use of the half-dose regimen
Oxford and AstraZeneca had highlighted as more effective, saying
the data didn't support the finding. One government health adviser
behind the authorization said the complexity of the vaccine trials
made drawing conclusions about efficacy and dosage more difficult
than he and peers typically find.
Heading into the regulatory gauntlet, Oxford officials have
demanded more control over communications about the vaccine, said
people familiar with interactions between the partners. The demands
came after some people at the university felt that AstraZeneca had
mishandled communications about the trials.
Frictions in the academic-corporate partnership were inevitable,
some people close to it said, given the economic and political
stakes, reputational risks of failure and sheer complexity of the
job. Missteps on both sides have made the high-wire act more
difficult at times. Some skeptics have questioned AstraZeneca's
prospects for restoring enough credibility to win far-reaching
public support in the U.S., or even to win FDA approval soon.
In early December, with plans in place for publication of an
academically rigorous review of the trial data, Oxford officials
homed in on making sure the release of this review would happen on
Oxford's terms.
John Bell, a senior Oxford academic who had negotiated the
vaccine deal between Oxford and the drug company, told AstraZeneca
Chief Executive Pascal Soriot that Oxford wanted its lead
scientists front and center when the company presented the U.K.
trial findings, according to people familiar with a phone call
between the two.
The day before publication of the academic review in The Lancet,
Prof. Bell told colleagues the muddled November release of trial
data had hurt the vaccine's credibility, according to people
familiar with the conversations.
Oxford's demands included having more say in dealings with the
FDA. According to a senior U.S. official, some at the FDA felt that
AstraZeneca hadn't informed it quickly enough when a participant in
the U.K. trials got sick, and that the company later was slow to
provide follow-up information.
In an interview, Prof. Bell said he wanted the university's
chief U.K. clinical-trial investigator for the vaccine to be at
AstraZeneca's next meeting with the U.S. regulators. "The FDA likes
to talk with vaccinologists," Prof. Bell said. "We should always be
on the podium together so that we always come across and operate as
a single unit."
AstraZeneca always planned to involve Oxford scientists fully in
the release of the academically rigorous review of trial data, and
company executives supported Oxford's attendance at the FDA
meeting, a person familiar with executives' thinking said.
"Oxford University and AstraZeneca share the common objective of
bringing billions of doses of our vaccine to the world at no profit
to help put the pandemic behind us," said a spokesman for
AstraZeneca. "Our strong relationship and complementary
capabilities have enabled us to move at great speed over the last
few months."
Prof. Bell said his relationship with AstraZeneca executives is
positive and called the collaboration a success. "We recognize
working with academic partners is not always easy for large
companies," he said through an Oxford spokesman. Prof. Bell called
working with AstraZeneca's CEO a delight and said he hoped "we have
both demonstrated the right levels of mutual respect."
From the beginning, publicly supported Oxford scientists viewed
the profit-driven ethos of the pharmaceutical world warily, causing
intense debates among academics. For weeks in the spring, academics
sparred over which company to join with before bringing AstraZeneca
on board in late April.
AstraZeneca had little vaccine experience but supported Oxford's
key goals. It agreed to make and distribute billions of doses of
the vaccine -- more than any Western drugmaker rival -- without
making a profit on it during the pandemic, or ever in the
developing world. The U.K. government liked having a homegrown
vaccine player. AstraZeneca is based in Cambridge.
Though trials showed a lower efficacy rate than vaccines
developed by Pfizer Inc. and Germany's BioNTech SE, and another by
Moderna Inc., the shot from Oxford and AstraZeneca has advantages.
It needs just normal refrigeration for months of storage and
distribution. That combined with a low price and large output make
it particularly suited to poorer countries and hard-to-reach
populations.
Meanwhile, it could also be a boon to wealthier countries
concerned about a shortage of vaccines. AstraZeneca has promised to
make three billion doses available in 2021, enough to vaccinate 1.5
billion people.
Some early difficulties came down to different methodologies in
the university and corporate worlds.
Last January, as scientists were just starting to understand the
coronavirus, researchers at Oxford worked around the clock to
fine-tune a vaccine, which introduces a weakened cold virus from a
chimpanzee to trigger human immunity. The university then used its
own small drug-production facility to pump out enough to test.
In April, Oxford started human trials in the U.K., which it
later expanded into Brazil and South Africa. Oxford's trials were
different in design from those typical at large pharmaceutical
companies, and it had different methods for recording trial
data.
In the spring, an Oxford biotech spinout co-founded by two
university scientists behind the vaccine was ramping up to start
clinical trials in the U.S., too. But then AstraZeneca came in as a
partner and took over responsibility for planning the U.S. trials.
The U.S. government agreed to preorder at least 300 million doses,
in a deal now valued at $1.6 billion, providing crucial
clinical-trial support.
AstraZeneca faced complications satisfying various U.S.
government officials about trial parameters. It didn't start
recruiting a targeted 30,000 U.S. volunteers until August. Some
rival drugmakers sprang into action more quickly and gained an
edge.
In the first week of September, after a clinical-trial volunteer
in the U.K. suffered a suspected neurological illness -- the second
to occur -- AstraZeneca and Oxford suspended the trials globally.
The pause lasted less than a week in the U.K., but in the U.S.
trials overseen by the FDA, the disruption dragged on for
weeks.
FDA officials learned about the illness and pause in trials two
days later when reporters called, according to a person familiar
with the matter. Agency officials got a full briefing from
AstraZeneca only in tandem with the news media, the people
said.
AstraZeneca CEO Dr. Soriot talked about the trial pause and
theories about the illness on a nonpublic call with clients of a
major investment bank. The discussion leaked.
During a public media conference the same week, Dr. Soriot
defended his and the company's disclosures. "When you conduct a
clinical trial, you basically inform the regulators, the
authorities," he said. "You don't go and publish, make big
announcements in the press. I mean, this is a scientific
process."
"It's ideal that folks don't hear about that from an investor
call," said Saad Omer, an infectious-disease specialist and
director of the Yale Institute for Global Health. "This is an
environment in which the sausage is being made in front of
everyone."
As AstraZeneca responded to questions during the U.S. trial
pause, officials inside the FDA got the impression the company was
struggling to get its arms around the process of rapidly pulling
together necessary information, according to a senior U.S.
administration official.
A complication was the time-consuming matter of reformatting
detailed Oxford-led trial data from the U.K. so it satisfied the
FDA, according to people involved in or briefed on the process. The
U.S. agency requested large volumes of additional data from
AstraZeneca, a process Dr. Soriot said in a November interview was
"nerve-racking in terms of the time that it took."
"They asked [for] a lot of data that were not necessarily
related to the case itself" but about clinical-trial design, safety
parameters and related information involving vaccines, he said.
There were wide differences in how Oxford and AstraZeneca operate
trials. The FDA declined to comment.
The U.S. clinical trial resumed in the last week of October
after nearly a seven-week interruption. AstraZeneca executives and
Oxford researchers remained upbeat about a limited rollout around
year-end.
On Nov. 23, they released preliminary results from late-stage
trials in the U.K. and Brazil. By then, public perceptions of
vaccine success had shifted, thanks to 90%-plus efficacy rates
reported by Pfizer and BioNTech as well as by Moderna.
Oxford and AstraZeneca said trial data showed their vaccine was
between 62% and 90% effective. The higher number came in a subset
of subjects who had received a smaller initial dose in the two-shot
regimen.
Scientists and executives said they couldn't satisfactorily
explain why the initial half-dose was more effective, but called
the finding good news and said they were studying it further. The
partners didn't say that researchers administered a lower initial
dose to some subjects as a result of discrepancies in measuring
vaccine concentration, making the lower dose a surprise.
Another thing they didn't initially disclose was that those who
got the smaller dose and showed 90% effectiveness were all 55 or
younger. A U.S. government official pointed that out a day later,
spurring a scramble by Oxford and AstraZeneca to counter confusion
and criticism about their limited disclosure.
In the next few days, dueling versions swirled over the
half-dose discovery. AstraZeneca said that it resulted from an
error made early on, which is when Oxford was running trials, but
that it didn't detract from results. The vaccine "is going to dent
the pandemic, whether it's 60%, 70%, or 90% efficacy," said Mene
Pangalos, AstraZeneca's head of biopharmaceuticals research and
development, in an interview at the time. "I think we're losing a
little bit the importance of that story."
But Adrian Hill, a lead Oxford scientist behind the vaccine,
told investors in the Oxford spinout he co-founded -- Vaccitech
Ltd., which stands to earn vaccine royalties -- that there was no
dosing mistake. "Let me just clarify that we did know what we were
doing and what dose we were giving," he told the investors on a
video call, which was reviewed by The Wall Street Journal.
Prof. Hill said early manufacturing failures had dented vaccine
supplies and made trying a half-dose regimen attractive, leading
researchers to discover it caused less-severe side effects. "So it
was deliberate, it wasn't an accident," he said. He declined to
comment for this article.
Oxford eventually provided more details. A spokesman said "there
were no problems with manufacturing the vaccine," but different
materials used and methods for measuring vaccine concentration
caused uncertainty in finished dosage levels.
To be conservative, the spokesman said, researchers downsized
the dose using what they considered the best estimates. That led to
an "unplanned lower dosing regimen," according to the Oxford
spokesman. He said the lower dose was fully understood only after
some trial volunteers showed fewer and less-severe side effects.
Regulators cleared the use of the initial half-dose for the
subgroup of the trial.
But it didn't clear the U.K. hurdle Wednesday. Regulators signed
off on the full-dose plan but rejected the half-dose regimen. One
government health adviser said the 90% efficacy could be more
related to a longer interval between doses than to the size of the
dose itself. He said a conclusion isn't possible without more
data.
Another adviser said Wednesday that interpreting the
Oxford-AstraZeneca vaccine data was complicated by the design of
the trials -- conducted across multiple countries with differing
age groups, dose intervals and dose sizes. Even the findings
published in The Lancet three weeks ago can't entirely be squared
with the latest analysis, the adviser said. The advisers said they
found the vaccine to be safe and effective regardless.
Oxford and AstraZeneca have said they will continue to study why
halving the first dose showed better results. FDA officials,
meanwhile, have remained skeptical about the half-dose explanation,
according to the U.S. administration official, and are holding out
for definitive U.S. trial data.
--Thomas M. Burton and Joseph Walker contributed to this
article.
Write to Jenny Strasburg at jenny.strasburg@wsj.com
(END) Dow Jones Newswires
December 30, 2020 09:09 ET (14:09 GMT)
Copyright (c) 2020 Dow Jones & Company, Inc.
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