[Ip-health] WSJ: AstraZeneca and Oxford’s Bumpy Partnership Hangs Over Covid Vaccine’s Future

Thiru Balasubramaniam thiru at keionline.org
Wed Dec 30 23:01:19 PST 2020


https://www.wsj.com/articles/astrazeneca-and-oxfords-bumpy-partnership-hangs-over-covid-vaccines-future-11609336498
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AstraZeneca and Oxford’s Bumpy Partnership Hangs Over Covid Vaccine’s Future

The latest Covid-19 shot wins approval in the U.K. but continues to face
challenges sown by confusing trial results

By Jenny Strasburg
Dec. 30, 2020 8:55 am ET


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 Prof. John Bell wanted university scientists closely involved when
information was presented about Oxford’s and AstraZeneca’s vaccine.

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 as the
vehicle carrying genetic code specific to the coronavirus 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.

<SNIP>

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 at wsj.com



-- 
Thiru Balasubramaniam
Geneva Representative
Knowledge Ecology International
41 22 791 6727
thiru at keionline.org


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