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AstraZeneca and Oxford’s Bumpy Partnership Hangs Over Covid Vaccine’s Future

AstraZeneca and Oxford’s Bumpy Partnership Hangs Over Covid Vaccine’s Future

By Jenny Strasburg Close Jenny Strasburg Dec. 30, 2020 8:55 am ET LONDON—The U.K.’s authorization of a Covid-19 vaccine developed by the Univ

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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.

Photo: Mary Turner for The Wall Street Journal

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.”

The historic university city of Oxford

Photo: Mary Turner for The Wall Street Journal

AstraZeneca offices in Cambridge

Photo: Alastair Grant/Associated Press

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.

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Dose Destinations

The Covid-19 vaccine developed by the University of Oxford and AstraZeneca is being counted on to help expand inoculations in the developing world.

Countries with advance commitments for the vaccine

(2.7 billion doses worldwide)

Countries with advance commitments for the vaccine

(2.7 billion doses worldwide)

Countries with advance commitments for the vaccine

(2.7 billion doses worldwide)

Countries with advance commitments for the vaccine

(2.7 billion doses worldwide)

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.

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Another Shot

The Oxford-AstraZeneca Covid-19 vaccine is the second to be approved for use in the U.K. and the third to be authorized in the West.

Vaccines in phase 3 clinical trials

Covid-19 genome sequenced

World Health Organization declares Covid-19 a global pandemic

University of Oxford/AstraZeneca

Authorized for use in the U.K.

Phase 3 trial

Pfizer/BioNTech

Authorized in the U.K.

Authorized in the U.S.

Authorized in the U.S.

Moderna/NIAID

Sinopharm (developing two vaccines with the government agencies Wuhan Institute of Biological Products and Beijing Institute of Biological Products)

Rollout targeted by end of the year

Rollout targeted by end of the year

CanSino Biologics/Chinese Academy of Military Medical Sciences

Cleared for military use for a year

Expected to be available in the U.S. early 2021

Johnson & Johnson

Russia started roll out in December

Gamaleya Research Institute

U.S. phase 3 trial is expected to start soon

Bharat Biotech

Anhui Zhifei Longcom Biopharmaceuticals/Chinese Academy of Sciences

Medicago/GlaxoSmithKline

Covid-19 genome sequenced

World Health Organization declares Covid-19 a global pandemic

University of Oxford/AstraZeneca

Authorized for use in the U.K.

Phase 3 trial

Pfizer/BioNTech

Authorized in the U.K.

Authorized in the U.S.

Moderna/NIAID

Sinopharm (developing two vaccines with the government agencies Wuhan Institute of Biological Products and Beijing Institute of Biological Products)

Rollout targeted by end of the year

Rollout targeted by end of the year

CanSino Biologics/Chinese Academy of Military Medical Sciences

Cleared for military use for a year

Expected to be available in the U.S. early 2021

Johnson & Johnson

Gamaleya Research Institute

Russia started roll out in December

U.S. phase 3 trial is expected to start soon

Bharat Biotech

Anhui Zhifei Longcom Biopharmaceuticals/Chinese Academy of Sciences

Medicago/GlaxoSmithKline

Covid-19 genome sequenced

World Health Organization declares Covid-19 a global pandemic

University of Oxford/AstraZeneca

Authorized for use in the U.K.

Phase 3 trial

Pfizer/BioNTech

Authorized in U.K.

Authorized in U.S.

Authorized in the U.S.

Moderna/NIAID

Sinopharm (developing two vaccines with the government agencies Wuhan Institute of Biological Products and Beijing Institute of Biological Products)

Rollout targeted by end of the year

Rollout targeted by end of the year

CanSino Biologics/Chinese Academy of Military Medical Sciences

Cleared for military use for a year

Expected to be available in the U.S. early 2021

Johnson & Johnson

Gamaleya Research Institute

Russia started roll out in December

U.S. phase 3 trial is expected to start soon

Bharat Biotech

Anhui Zhifei Longcom Biopharmaceuticals/Chinese Academy of Sciences

Medicago/GlaxoSmithKline

Covid-19 genome sequenced

World Health Organization declares Covid-19 a global pandemic

University of Oxford/AstraZeneca

Phase 3 trial

Authorized for use in the U.K.

Pfizer/BioNTech

Authorized

in the U.K.

Authorized

in the U.S.

Moderna/NIAID

Authorized in the U.S.

Sinopharm (developing two vaccines with the government agencies Wuhan Institute of Biological Products and Beijing Institute of Biological Products)

Rollout targeted by end of the year

Rollout targeted by end of the year

CanSino Biologics/Chinese Academy of Military Medical Sciences

Cleared for military use for a year

Johnson & Johnson

Expected to be available in

the U.S. early 2021

Gamaleya Research Institute

Russia started roll out

in December

U.S. phase 3 trial is expected to start soon

Bharat Biotech

Anhui Zhifei Longcom Biopharmaceuticals/ Chinese Academy of Sciences

Medicago/GlaxoSmithKline

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.

Pascal Soriot, CEO of AstraZeneca

Photo: Zach Gibson/Bloomberg News

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.

A volunteer received an injection at a South African hospital as part of a clinical trial of the vaccine developed at the University of Oxford in conjunction with AstraZeneca.

Photo: Siphiwe Sibeko/Associated Press

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.

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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.

A Stay Home campaign cautions Londoners about a new Covid-19 virus strain.

Photo: Dinendra Haria/Zuma Press

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.

Write to Jenny Strasburg at [email protected]

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This post first appeared on wsj.com

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