• The Star Staff

AstraZeneca, under fire for vaccine safety, releases trial blueprints


By Denise Grady, Katherine J. Wu and Sharon LaFraniere


AstraZeneca revealed details of its large coronavirus vaccine trials Saturday, the third in a wave of rare disclosures by drug companies under pressure to be more transparent about how they are testing products that are the world’s best hope for ending the pandemic.


Polls are finding Americans increasingly wary of accepting a coronavirus vaccine. And scientists inside and outside the government are worried that regulators, pressured by the president for results before Election Day on Nov. 3, might release an unproven or unsafe vaccine.


“The release of these protocols seems to reflect some public pressure to do so,” said Natalie Dean, a biostatistician and expert in clinical trial design for vaccines at the University of Florida. “This is an unprecedented situation, and public confidence is such a huge part of the success of this endeavor.”


Experts have been particularly concerned about AstraZeneca’s vaccine trials, which began in April in Britain, because of the company’s refusal to provide details about serious neurological illnesses in two participants, both women, who received its experimental vaccine in Britain. Those cases spurred the company to halt its trials twice, the second time earlier this month. The studies have resumed in Britain, Brazil, India and South Africa but are still on pause in the U.S. About 18,000 people worldwide have received AstraZeneca’s vaccine so far.


AstraZeneca’s 111-page trial blueprint, known as a protocol, states that its goal is a vaccine with 50% effectiveness — the same threshold that the Food and Drug Administration has set in its guidance for coronavirus vaccines. To determine with statistical confidence whether the company has met that target, there will have to be 150 people ill with confirmed coronavirus among participants who were vaccinated or received placebo shots.


However, the plan anticipates that a safety board will perform an early analysis after there have been just 75 cases. If the vaccine is 50% effective at that point, it might be possible for the company to stop the trial early and apply for authorization from the government to release the vaccine for emergency use.


In allowing only one such interim analysis, AstraZeneca’s plan is more rigorous than the others that have been released, from Moderna and Pfizer, Dr. Eric Topol, a clinical trials expert at Scripps Research in San Diego, said in an interview. Moderna allows two such analyses, and Pfizer four.


He said the problem with looking at the data too many times, after a relatively small number of cases, is that it increases the odds of finding an appearance of safety and efficacy that might not hold up. Stopping trials early can also increase the risk of missing rare side effects that could be significant once the vaccine is given to millions of people.


Topol said AstraZeneca’s plan, like those of Moderna and Pfizer, had a problematic feature: All count relatively mild cases of COVID-19 when measuring efficacy, which may hamper efforts to determine whether the vaccine prevents moderate or severe illness.


Such plans are not usually shared with the public “due to the importance of maintaining confidentiality and integrity of trials,” Michele Meixell, a spokesperson for AstraZeneca, said in a statement.


The company has released few details about the two cases of serious illness in its trial. The first participant received one dose of the vaccine before developing inflammation of the spinal cord, known as transverse myelitis, according to a participant information sheet for AstraZeneca’s vaccine from July. The condition can cause weakness in the arms and legs, paralysis, pain and bowel and bladder problems.


The case prompted a pause in AstraZeneca’s vaccine trials to allow for a safety review by independent experts. A company spokesperson told The New York Times last week that the volunteer was later determined to have a previously undiagnosed case of multiple sclerosis, unrelated to the vaccine, and that the trial resumed shortly thereafter.


Transverse myelitis can sometimes be the first sign of multiple sclerosis, which involves more complex symptoms. But the myelitis alone can also occur after the body encounters an infectious agent like a virus.


The company said it had not confirmed a diagnosis in the second case, a participant who got sick after the second dose of the vaccine. A person familiar with the situation who spoke with the Times on the condition of anonymity said the participant’s illness had been pinpointed as transverse myelitis. The trial was paused again Sept. 6 after she fell ill.


The condition is rare but serious, and experts said that finding even one case among thousands of trial participants could be a red flag. Multiple confirmed cases, they said, could be enough to halt AstraZeneca’s vaccine bid entirely.


“If there are two cases, then this starts to look like a dangerous pattern,” said Mark Slifka, a vaccine expert at Oregon Health and Science University. “If a third case of neurological disease pops up in the vaccine group, then this vaccine may be done.”


A participant information sheet dated Sept. 11 on AstraZeneca’s trial in Britain lumped the two volunteers’ cases together, stating the illnesses were “unlikely to be associated with the vaccine or there was insufficient evidence to say for certain that the illnesses were or were not related to the vaccine,” based on safety reviews. The next day, AstraZeneca announced that it had resumed the trial in Britain.


But the FDA has so far not allowed the company to start up again in the United States.


A spokesperson for the FDA declined to comment. The National Institutes of Health said in a statement that it “remains to be seen” whether the onset of illness in trial participants was coincidental or tied to the vaccine, adding that “pausing to allow for further evaluation is consistent with standard practice.”


Dr. Paul Offit, a professor at the University of Pennsylvania and a member of the FDA’s advisory committee on vaccines, said that it’s unclear how the company — or the U.K. government — determined that the second case was not related to the vaccine.


He and other experts noted that transverse myelitis is rare, diagnosed in only about 1 in 236,000 Americans a year. The trial in Britain involved only about 8,000 volunteers, a spokesperson for the Oxford researchers said last month.

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