The Food and Drug Administration has asked AstraZeneca for a large amount of extra data related to its Covid-19 vaccine, further delaying the company's application for an emergency use authorization, or EUA, in the United States, according to a letter from the company obtained by NBC News.
AstraZeneca sent the letter, dated April 21, to U.S. clinical trial investigators. It reads, in part, "This is a complex submission that includes data from studies conducted outside the U.S., as well as emerging data from the global rollout of the vaccine and significant additional data requests have been received from the FDA."
AstraZeneca had anticipated filing for an EUA in either late March or early April.
Still, the company maintains that it intends to file within "the coming weeks." In a statement to NBC News, an AstraZeneca spokesperson noted "the substantial size of the file," adding that "in addition to the U.S. trial data, the filing will also include analyses and pharmacovigilance from all studies to-date, in addition to real-world evidence data."
While it is not unusual for federal regulators to request additional information from companies seeking emergency use authorization, the FDA most likely also wants to see all of AstraZeneca's data on a rare type of blood clot called cerebral sinus venous thrombosis linked to the vaccine's use overseas. Those clots have also been linked to the Johnson & Johnson vaccine in use in the U.S., which led to an 11-day pause of the vaccine's rollout. Both vaccines use the same technology, called an adenovirus, to teach the immune system to fight the virus that causes Covid-19.
"When there are unusual side effects that are occurring, there may be even greater detail that a review committee is going to ask for, so that they can render a good judgment," said Dr. Buddy Creech, director of the Vanderbilt Vaccine Research Program at Vanderbilt University Medical Center in Nashville.
"The FDA is under a lot of pressure to get things right," Creech added.
Because AstraZeneca's vaccine has been in use for several months across Europe and Asia, there is a significant amount of data the company must collect.
The vaccine is one of several authorized by the World Health Organization for use within COVAX, a global initiative working to provide Covid-19 vaccines. The WHO conducted its own safety review and concluded the vaccine's benefits outweighed any risks.
But following the reports of the blood clots — which led several countries to pause use of AstraZeneca's vaccine, and in some cases, halt its use altogether — the FDA's decision carries significant weight.
"What the U.S. thinks about a product matters," John Grabenstein, a former executive director of medical affairs for vaccines at Merck and a former Defense Department immunologist.
Dr. William Hartman, principal investigator for the AstraZeneca vaccine trial site at the University of Wisconsin, Madison, said the delays are frustrating to clinical trial teams in the U.S. who "put in a tremendous effort" to study the vaccine.
But he supports FDA's extra efforts. "They are looking under every stone, making sure that this is the safest product that can be put out there," Hartman said.
Last May, the U.S. gave AstraZeneca more than $1 billion to develop and study its Covid-19 vaccine as part of the Trump administration's vaccine initiative, Operation Warp Speed. Because of that agreement, AstraZeneca is contractually bound to apply for an EUA in the U.S. But even if authorized, the vaccine may never end up being used here.
"We can foresee that we will not be using the AstraZeneca doses that we expect to come online," Andy Slavitt, a Covid-19 adviser to the Biden administration, said during a briefing this week, adding that the U.S. plans to ship the AstraZeneca product it pre-purchased to other countries in need.
"We have sufficient supply of vaccines," Slavitt said, referring to the doses from Pfizer-BioNTech, Moderna and Johnson & Johnson.
Setbacks and missteps
Last summer, as the race to develop a Covid-19 vaccine picked up speed, Oxford University researchers, who developed the vaccine in partnership with AstraZeneca, were the first to report that the shots prompted a significant immune response by producing both antibodies to the virus and T cells, which search for infected cells and attack them.
But AstraZeneca soon experienced several setbacks and missteps that contributed to questions surrounding its data.
In November, the company acknowledged that some of the vials used in clinical trials did not have the correct concentration of vaccine, meaning some volunteers in the U.K. received a half dose, while others received the full dose. The mistake led to confusion as to the correct way to interpret findings of efficacy. AstraZeneca blamed the error on a manufacturing problem.
Then in March, the National Institute of Allergy and Infectious Diseases issued an unusual late-night statement saying that AstraZeneca "may have included outdated information" in encouraging results about its U.S. trials the company had released just hours earlier. The company was forced to review and republish its data after the Data and Safety Monitoring Board — a panel of independent experts that reviews safety and efficacy data for vaccines in the U.S. — said it had a "concern" about AstraZeneca's data.
The differing results were not that far apart — 79 percent effective vs. 76 percent effective, but the differences led to confusion, Grabenstein said. "What you want coming out of phase 3 trials is nice, clean data," he said. "You want to show people how you did the math."
Full data from the U.S. trials, such as the one Hartman ran in Wisconsin, have not yet been made public.
"That implies that there is an inadequate amount of safety data," said a source with in-depth knowledge of Covid-19 vaccines and the AstraZeneca vaccine in particular. Asked for comment, an AstraZeneca spokesperson referred to the company's previous statement that it plans to file for an EUA in the coming weeks.
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Hartman said he has not been able to see the entire data set from the U.S. trials, but added that he saw no major safety concerns among the nearly 400 people in his study of the AstraZeneca vaccine.
Still, it's clear that AstraZeneca has significant issues to address.
If the FDA were to deny AstraZeneca an EUA, it could have a dampening effect on the rest of the world. Even if the U.S. doesn't need the AstraZeneca vaccine, other countries do.
"If the FDA deems it safe and effective, and a good vaccine to be used in the American population," Hartman said, "it definitely would help its perception throughout the world."