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AstraZeneca’s absurd and unprecedented dispute with regulators, explained

The company said its Covid-19 vaccine developed with Oxford had 76 percent efficacy in the US after a rare public rebuke from the NIH.

Ampoules of the coronavirus vaccine of the Swedish-British manufacturer AstraZeneca stand on a table.
The Covid-19 vaccine developed by the University of Oxford and AstraZeneca was found to have 76 percent efficacy against disease in the US. The company was criticized by the NIH for how it presented its results this week.
Nicolas Armer/DPA/Picture Alliance via Getty Images
Umair Irfan is a correspondent at Vox writing about climate change, Covid-19, and energy policy. Irfan is also a regular contributor to the radio program Science Friday. Prior to Vox, he was a reporter for ClimateWire at E&E News.

AstraZeneca announced on Thursday that the Covid-19 vaccine it developed with the University of Oxford had 76 percent efficacy against Covid-19 cases that produce symptoms, based on an analysis of its US phase 3 clinical trial.

The data release comes after a remarkable public rebuke from the National Institutes of Health for how AstraZeneca presented some of its older results showing higher efficacy earlier this week.

On Monday, AstraZeneca announced in a press release that its two-dose adenovirus vector-based vaccine demonstrated 79 percent efficacy at preventing symptomatic Covid-19 and 100 percent efficacy in preventing hospitalization and death.

But shortly after the announcement, the team of 11 independent scientists that had been supervising the trial, known as the Data and Safety Monitoring Board, sent a letter to AstraZeneca, the National Institute of Allergy and Infectious Diseases, and the Biomedical Advanced Research and Development Authority criticizing the pharmaceutical giant’s choice of data to share with the public.

“The DSMB is concerned that AstraZeneca chose to use data that was already outdated and potentially misleading in their press release,” according to the letter, obtained by the Washington Post and the New York Times. The information “they chose to release was the most favorable for the study as opposed to the most recent and most complete. Decisions like this are what erode public trust in the scientific process.”

After the leak, the NIH publicly admonished the company on Tuesday, urging it to make sure its most accurate and up-to-date vaccine trial data was published “as soon as possible.”

AstraZeneca then responded with its own press release Wednesday noting that the results it presented were based on an interim analysis and were consistent with its more recent findings.

Finally, on Thursday, it released its findings from its completed primary analysis: The vaccine has 76 percent efficacy against symptomatic Covid-19 across the board, 85 percent efficacy against symptomatic Covid-19 in people 65 and older, and 100 percent efficacy against severe disease and hospitalization.

It’s a seemingly small reduction in overall efficacy compared to the interim results (76 percent versus 79 percent), but the fact that an open spat between a vaccine developer and regulators arose at all could have negative effects on public acceptance of a vaccine, according to experts.

“Whether or not people think differences between one release and the next are important, the events themselves are serious: a role of the DSMB is oversight and to ensure ethical conduct,” Hilda Bastian, a health researcher who used to work at the NIH, told Vox in an email. “Drug companies have to be scrupulous about this, and a breach in that relationship on this scale is serious in itself — and the implications for trust are wider.”

Unfortunately, this week’s events are just one of many recent embarrassments for AstraZeneca around its Covid-19 vaccine. Earlier this month, almost two dozen countries in Europe halted its use due to concerns about it causing rare, dangerous blood clots. (The pharmaceuticals regulator for the European Union later ruled that the vaccine was “safe and effective.”)

But that pause in distribution followed one in South Africa after researchers found that it was ineffective against the B.1.351 variant of the virus that causes Covid-19 that is predominant in that country.

The company also faced scrutiny for mistakes and other problems with its earlier clinical trials, including a dosing error in one of its trial arms and inconsistent placebo controls. This led to wide variance in the efficacy of the vaccine depending on the arm of the trial, in different countries and different timepoints, ranging from 62 percent to 90 percent.

Despite all of this drama, the AstraZeneca/Oxford vaccine remains crucial to the global effort to contain the Covid-19 pandemic. It’s one of the most widely used vaccines so far, one of the cheapest, and one of the easiest to store. It’s now being distributed in 89 countries, more than any other Covid-19 vaccine.

Yet the recent communication missteps by AstraZeneca are undermining trust in its product at a critical time. For experts, the fear is these communication failures may ultimately lead to more hesitancy around this vaccine — and preventable deaths and hospitalizations in the long run.

Why regulators singled out AstraZeneca for how it presented its vaccine results

There are now multiple highly effective vaccines against Covid-19 being distributed around the world, and they remain the best hope for a return to normal.

Getting to this point was a hard-fought process. Health officials, faced with thousands of deaths per day, desperately needed vaccines. But the vaccines, some of them using brand new technologies, needed testing on large scales, a difficult, time-consuming, and expensive process.

In particular, health officials were looking for the results of phase 3 clinical trials, where the vaccine is tested in tens of thousands of people in the real world against the actual SARS-CoV-2 virus, the pathogen that causes Covid-19.

AstraZeneca completed arms of its phase 3 trials of its Covid-19 vaccines in other countries last year, but due to concerns about how those trials were run, the company did not apply for an emergency use authorization (EUA) from the Food and Drug Administration, the same provision that has allowed other Covid-19 vaccines to begin use in the US. The company instead conducted a separate US-based trial.

There are some critical safeguards in place in any US vaccine trial. The trials are double-blind, where neither the participant nor the company sponsoring the trial knows who received the placebo and who received the actual vaccine. And the company has to declare its methodology and its checkpoints ahead of time. The DSMB serves as an intermediary between trial participants and the company, letting the sponsor know how the trial is going at predetermined intervals.

Once a given number of symptomatic Covid-19 cases (a.k.a. “events”) are detected in the trial pool, the company is allowed to peek behind the curtain to see how the events are divided between the vaccine group and the placebo group. That allows them to calculate how well the vaccine prevents disease, severe disease, hospitalizations, and deaths.

The problem with the recent AstraZeneca announcement was that the company highlighted its vaccine’s performance based on interim results with a cutoff date of February 17. The DSMB, however, believed that there were more complete results that should have been included. The more recent events may have altered the overall efficacy results. Since the company hasn’t released its completed primary analysis yet, the public doesn’t know how it will affect the reported efficacy results. But the fact that the DSMB felt obliged to intervene hints that the more complete results were less favorable to the vaccine.

“I work directly with [AstraZeneca] on this trial, so I can’t say anything too controversial here,” said David Benkeser, an assistant professor of biostatistics at Emory University, in an email. “I will say that it was entirely appropriate for the DSMB to express concern about the way the results were being disseminated.”

It’s hard to say why AstraZeneca chose to present interim results rather than its full analysis to begin with. It may have been a result of miscommunication between the company and regulators, or it may have been a deliberate effort to shape the public narrative about their vaccine. Either way, AstraZeneca’s press release earlier this week and the rebuke from the NIH may erode confidence in the company and its vaccine.

“This is a little bit of a self-inflicted injury in the communications process about this,” said Jesse Goodman, a former chief scientist at the FDA.

AstraZeneca’s ordeal this week highlights the perils of science by press release

The Covid-19 pandemic has repeatedly highlighted the importance of communicating information to the public and the costs of getting it wrong. This is particularly crucial with vaccines, which require lots of people to choose to get them in order to effectively control the spread of the virus. As more people get vaccinated and more doses become available, the picture in the US will shift from one of scarcity to one of abundance. At that point, the most important task will be convincing holdouts to get their shots.

Companies like Pfizer and BioNTech, Moderna, and Johnson & Johnson all initially announced the efficacies of their Covid-19 vaccines in press releases rather than in peer-reviewed papers or filings with regulators. The companies said that they wanted to communicate vital information about their vaccines to the public as soon as they had it. But the press releases allowed companies to pick what they wanted to emphasize, elide some caveats, and make it harder for others to scrutinize their findings. While the companies did eventually publish their results in peer-reviewed journals, they came weeks after the press releases.

Yet the authorization of a vaccine hinges on the results the companies present to regulators like the Food and Drug Administration. “At the end of the day, the FDA looks at the data, not the press releases,” Goodman said. “Looking at that data and doing their own analysis is what’s going to determine whether this vaccine gets an EUA, whether the benefits outweigh the risk.”

In the case of the AstraZeneca/Oxford vaccine, the company decided not to file for an EUA from the FDA based on its earlier trials and instead conducted a US-based trial with more than 32,000 participants. The initial efficacy results last year were based on trials with 2,741 participants in the United Kingdom and 8,895 in Brazil.

The US trial was funded in part by the US government under Operation Warp Speed, which spent $1.2 billion backing research into the vaccine.

But the vaccine has now been in use since December, and almost 20 million people between just the UK and the European Union have received a dose (other parts of the world that are distributing the vaccine don’t all report their numbers publicly). So why is the US still waiting for the results of its trial of the vaccine? After all, the US has already paid for it, has ordered 300 million doses of it, and is sitting on a stockpile of millions of doses.

“It’s a critical trial, because we haven’t had a well-designed large trial for this vaccine yet, and you need the clarity of that kind of data,” said Bastian. “The disparities and other differences that feed into what you see in a rollout, make the randomized data critical. And the studies that will come of people who weren’t included in the phase 3 trials will be critical too. We need both.”

In the meantime, AstraZeneca will also have to take steps to rebuild confidence in the company and its vaccine. “I think we need to understand what went wrong in this communication and I think that they are going to need to be completely forthright in communicating all their data,” Goodman said. “They need to overcome that with just complete transparency.”

If the company is not transparent about the decision-making that led to the back-and-forth with regulators this week, that could undermine public perception of the vaccine, which has proven useful against Covid-19. In a pandemic that has killed more than 545,000 people in the US and 2.7 million worldwide, leaving effective vaccine doses unused would be tragic.

AstraZeneca plans to file for an EUA for its Covid-19 vaccine from the FDA based on its recent phase 3 trial results. After it files its application, a team of outside advisers to the FDA will review the company’s data and meet in about a month to vote on whether to recommend the vaccine for an EUA.

If the vote is favorable, the FDA can accept the recommendation and allow the vaccine’s distribution. That can happen in as little as two days after a vote by advisers. So the AstraZeneca/Oxford shots could get into arms in the US as soon as next month.

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