AZN AstraZeneca PLC

By Jenny Strasburg, Thomas M. Burton and Joseph Walker 

AstraZeneca PLC promised the world more vaccines, at a lower cost, than any of the more established vaccine makers. It is finding how hard living up to those commitments can be.

A public spat this week with U.S. officials over the precisely effectiveness of its Covid-19 shot has upset regulators and chipped away at the drugmaker's reputation in its biggest market. The fight has heightened doubts among senior U.S. medical officials about the company's data analysis, threatening to lengthen the regulatory review. That is already months behind schedule after a separate standoff with the Food and Drug Administration in the fall over disclosures about the vaccine's U.K. trials.

Wednesday evening U.S. time, AstraZeneca revised its estimate of the shot's efficacy from large-scale U.S. trials based on additional data, saying it was 76% effective in preventing symptomatic Covid-19, down from the 79% it reported from an analysis on Monday.

The FDA, which needs to sign off on the vaccine before it is used in the U.S., normally sends staffers to clinical trial sites to assess how data is compiled before any approval. The FDA now expects to dispatch more employees to more sites than normal because of the level of mistrust that has built up, according to a senior U.S. official.

In Europe, meanwhile, the British-Swedish drugmaker faces near daily attacks by politicians facing a public backlash over slow vaccination rollouts and angered by big shortfalls in AstraZeneca's production commitments. That, in turn, has drawn its chief executive into diplomatic tensions over vaccine supplies and which countries should get them.

Around the start of this year, under pressure to make up for the European production shortfalls, Chief Executive Pascal Soriot called then-U.S. Health Secretary Alex Azar with a proposal. He asked whether the U.S. would allow several million doses of the company's shot, sitting unapproved and unused in the U.S., to be sent to Europe, according to a person familiar with the matter.

Mr. Azar countered that he would be willing to send over two AstraZeneca shots for every dose of Pfizer Inc.'s vaccine that European governments would be willing to send to the U.S., this person said. The Pfizer vaccine had already won FDA authorization, at a proven effectiveness rate of 95%. Mr. Azar didn't respond to a request for comment.

It couldn't be determined whether Dr. Soriot ever shared the proposal with European officials. Europe hasn't received any finished AstraZeneca doses from the U.S., according to European Union officials.

An AstraZeneca spokeswoman said governments have asked the U.S. about potential donations of doses. "If those donation actions were to proceed, we would seek guidance from the U.S. government on replacement of doses for use in the U.S.," she said.

In many ways, AstraZeneca, which developed the vaccine in partnership with the University of Oxford, is delivering on its main promises. More than 70 countries, including the U.K. and much of the rest of Europe, have found the shot safe and effective. Although it isn't a big player in vaccines, AstraZeneca helped make an experimental shot ready for mass use in less than a year. The company has built a manufacturing and distribution network that is delivering doses to the world's poorest. Unlike most of its big competitors with vaccines or vaccine candidates, it has promised to do all this at no profit. The vaccine has been crucial to the U.K. drive that boasts one of the world's best per-capita vaccination rates.

But at crucial moments, company executives have fumbled communications with governments, regulators and the public. That has left a reputational cloud over the vaccine effort -- an effort that Dr. Soriot has said reflects the company's desire to play a leading role in battling the pandemic.

In some cases, such as with its handling of the U.S. trial data this week, AstraZeneca deviated from what outside experts said should be standard disclosure protocol for a large pharmaceutical company. In dealings with European governments, AstraZeneca has been put on the defensive by politicians, who have portrayed the company as unreliable.

"The worst part about this is that we, as a planet, are relying on their success," said Eric Topol, professor of molecular medicine at Scripps Research in La Jolla, Calif., who ran clinical trials for 15 years and has written about clinical-trial conduct. "It's extraordinary, when you have a vaccine that's the least expensive and most ordered in the world, expected to be given to billions of people, to have it self-destruct like this."

Dr. Soriot and other AstraZeneca officials have expressed frustration that politicians and critics haven't appreciated the magnitude of the task and the risks the company has taken on, according to people familiar with their thinking. They have complained privately they aren't given enough credit for their no-profit pledge and the ambitious targets they have set for global distribution, particularly to poor countries, and deserve some leeway as they get up to speed.

This week's standoff with U.S. officials delivered a fresh hit to the drugmaker's credibility. On Monday, AstraZeneca released long-awaited efficacy data from a large-scale U.S. human trial, reporting the shot was 79% effective across age groups and ethnicities. The National Institute of Allergy and Infectious Diseases, which had overseen the trials, sent out its own news release endorsing the figures.

Later that day, members of a government-appointed board working with AstraZeneca to provide an independent analysis of drug trial data wrote to the NIAID. The Data and Safety Monitoring Board raised concerns that the company might have used outdated information that made the results appear better. The NIAID issued a press release just after midnight Tuesday urging the company and the board to work together to ensure the most accurate data be made public as soon as possible.

"That's the ironic part about it," Dr. Anthony Fauci, President Biden's chief medical adviser and director of NIAID, said in an interview early this week. "I mean, this is kind of unfortunate that this happened because, at the end of the day, it's still a good vaccine."

The company first stumbled last year when it released the results of human trials in the U.K. The data was muddled by what many researchers and some government advisers described as confusing and incomplete explanations for a range of efficacy rates.

Oxford scientists and AstraZeneca executives initially said a subgroup of participants had been given a smaller initial dose, which they said appeared to boost the efficacy of the shot to 90%. They later disclosed that the group was accidentally given a lower dose than intended.

U.K. regulators, in approving the vaccine, rejected the lower-dose explanation for the higher efficacy rate, and stuck with recommending two full doses.

Apart from the dosing discrepancy, the range of efficacy AstraZeneca disclosed, between 62% and 90%, was difficult to compare with U.S. trial results of rival vaccines, one from Pfizer and Germany's BioNTech SE and another from Moderna Inc. Both were found to be more than 94% effective in U.S. trials.

Several European governments restricted the shot to people 55 years old or younger, based on sparse trial data showing how the vaccine worked in older adults. Those countries mostly relaxed that restriction after real-world data from the U.K. showed the shot to be safe and effective in older recipients.

AstraZeneca surprised European governments in January when it said it would miss by a wide margin the volume it promised to deliver in this year's first quarter. The company had suffered manufacturing problems at a plant in Europe. Later, it promised to make up for the shortfall by importing doses, but then backtracked on that, too, citing export bans.

European politicians have pilloried the company for the confusion and production setbacks, while taking swipes at the shot directly. French President Emmanuel Macron at one point called it "quasi-ineffective."

In the company's defense, executives including Dr. Soriot have repeatedly said that AstraZeneca is making more vaccines than any other drugmaker, and is doing so without profit.

Another setback came earlier this month with reports of a small number of serious blood clots, including several reported deaths, in recently vaccinated Europeans. Several big countries, including France and Germany, paused their use of the shot until Europe's main medicines regulator investigated the incidents.

Last week, that regulator, the European Medicines Agency, said it didn't find evidence of a link between the clotting problems and the vaccine, but also couldn't rule one out. It said the benefits of the vaccine outweighed the risks, and that serious clotting occurs naturally in the population. The agency recommended a new warning be provided to healthcare professionals and the public to alert them of the need to monitor carefully for potential severe blood clots.

AstraZeneca said the U.S. trials identified no increased risk of serious blood clotting. In its statement Tuesday, NIAID didn't raise questions about the trial's findings regarding blood clotting or any other safety issues, but cited incomplete information related to the vaccine's effectiveness.

The U.S. provided more than $1 billion in funding to support the development of the AstraZeneca vaccine. The U.S. trial, which started recruiting volunteers there and in Chile and Peru in August, was standardized to meet FDA guidelines.

The relationship between AstraZeneca and U.S. officials has been tense in the past. The FDA felt last year that AstraZeneca hadn't informed it quickly enough when a participant in the U.K. trials got sick, The Wall Street Journal has reported, and that the company was slow to provide follow-up information.

AstraZeneca paused U.S. and global trials, which were just getting under way. The trials resumed after a weekslong delay that pushed back AstraZeneca's ambitions for getting its shot quickly approved for use in the U.S.

As AstraZeneca responded to FDA questions during the U.S. trial pause, officials inside the agency got the impression the company was struggling to pull together the necessary information, the Journal reported, citing a senior U.S. administration official.

Dr. Soriot defended the company's disclosure of the illness and its interactions with the FDA.

Since then, skepticism has been mounting among government health officials about the accuracy of AstraZeneca statements on trial results, according to senior U.S. officials.

Some officials of the National Institutes of Health, an umbrella agency that includes the NIAID and helps fund, conduct and direct U.S. medical and basic science research, have questioned why AstraZeneca balked at providing more recent data in its U.S. trial analysis, according to people familiar with the matter.

AstraZeneca said Tuesday it provided analysis for data up to Feb. 17 and that it would "immediately engage" with the monitoring board to share its analysis of "the most up-to-date efficacy data."

Trial-safety monitors wanted AstraZeneca to look at data as of mid-February, but also data accumulated since then, people familiar with the matter said.

The monitoring board that complained about the data is the same independent group of physicians and other medical experts that has worked with other vaccine makers that accepted U.S. funding, including Moderna, Johnson & Johnson's Janssen unit and Novavax Inc. Its job is to review data from trials and provide an independent assessment of trial results. None of the previous trials produced any major scientific disputes, at least not ones that became public.

The data that the monitoring board was reviewing showed efficacy of about 70% to 79%, a number that shifted regularly based on new data, according to senior government officials. In recent days, the monitoring board debated with AstraZeneca what number to use in any public disclosure, according to one of these officials, and monitors were adamant that the number shouldn't be more than 75%, reflecting data after Feb. 17.

AstraZeneca's analysis differed, according to one person familiar with the company's internal discussions. Technically, the board's role is strictly to make recommendations, with no authority to dictate to a drugmaker what data they disclose to the public. In practice, it can be difficult for companies to reject the board's recommendations because of the stamp of approval that comes with its endorsement.

AstraZeneca executives felt pressure to disclose some results of the U.S. trials as soon as they could, even though they were preliminary, people familiar with the matter said. The company was under pressure in Europe and beyond to show whether health problems similar to blood-clotting issues among a very small number of vaccinated Europeans had shown up in U.S. trials.

In its Wednesday night news release on U.S. trial results, AstraZeneca said the top-line efficacy result across the whole trial was marginally lower than previously suggested. It said two doses were 76% effective in preventing symptomatic Covid-19, compared with 79% in Monday's preliminary report.

Among people 65 and older, the vaccine was 85% effective, compared with 80% in Monday's report. In both analyses, the vaccine was found to provide 100% protection against severe disease and hospitalization, though the numbers of such serious cases were small.

AstraZeneca has said it plans to submit findings to the FDA by mid-April, in hopes of gaining authorization to use the shot in the U.S.

--Laurence Norman in Brussels contributed to this article.

Write to Jenny Strasburg at jenny.strasburg@wsj.com, Thomas M. Burton at tom.burton@wsj.com and Joseph Walker at joseph.walker@wsj.com

(END) Dow Jones Newswires

March 25, 2021 14:25 ET (18:25 GMT)

AstraZeneca (NASDAQ:AZN)
Historical Stock Chart
From Mar 2024 to Apr 2024

AstraZeneca (NASDAQ:AZN)
Historical Stock Chart
From Apr 2023 to Apr 2024