The company published only a few details on the two cases of serious illness in its study.
AstraZeneca on Saturday revealed details of its major coronavirus vaccine trials, the third in a wave of rare disclosures from drug companies under pressure to be more transparent about how they are testing products that represent the world’s best hope of ending the pandemic.
Surveys show that Americans are increasingly concerned about accepting a coronavirus vaccine. Scientists inside and outside the government fear that regulators, pressured by the president before election day on November 3rd, could bring out an unproven or unsafe vaccine.
“The publication of these protocols seems to reflect some public pressure,”
Experts were particularly concerned about AstraZeneca’s vaccine trials, which began in the UK in April, as the company refused to provide details of serious neurological conditions in two participants, both women, who had received the experimental vaccine in the UK. These cases caused the company to suspend its lawsuits twice, the second time earlier this month. Studies have restarted in the UK, Brazil, India and South Africa, but are not yet completed in the US. Around 18,000 people worldwide have received the AstraZeneca vaccine to date.
AstraZeneca’s 111-page study, known as the Protocol, states that the target is a vaccine with 50% effectiveness – the same threshold that the Food and Drug Administration set in its guidelines for coronavirus vaccines. To be able to determine with statistical certainty whether the company achieved this goal, 150 people must be infected with confirmed coronavirus among the participants who were vaccinated or received placebo shots.
However, the plan provides that a security agency will conduct an early analysis after only 75 cases. If the vaccine is 50% effective by this point, the company may have the opportunity to stop the study early and seek government approval to release the vaccine in case of emergency.
Since only such interim analysis is allowed, AstraZeneca’s plan is stricter than the others published by Moderna and Pfizer, said Dr. Eric Topol, clinical trial expert at Scripps Research in San Diego, in an interview. Moderna allows two such analyzes and Pfizer four.
He said the problem with looking at the data too often after a relatively small number of cases is that it increases the likelihood of finding a sheet of safety and efficacy that may not endure. Stopping studies prematurely can also increase the risk of missing rare side effects, which can be significant after the vaccine is given to millions of people.
According to Topol, like Moderna and Pfizer’s plan, AstraZeneca’s plan had one problematic trait: all of them count relatively mild cases of COVID-19 when measuring effectiveness, which could hamper efforts to determine whether the vaccine prevents moderate or severe illness.
Such plans are typically not shared with the public “because it is important to maintain the confidentiality and integrity of processes,” Michele Meixell, a spokesman for AstraZeneca, said in a statement.
The company published only a few details on the two cases of serious illness in its study. The first participant received a dose of the vaccine before developing an inflammation of the spinal cord called transverse myelitis. This emerged from a July participant information sheet for the AstraZeneca vaccine. The condition can cause weakness in arms and legs, paralysis, pain, and bowel and bladder problems.
The case triggered 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 afterwards.
Transverse myelitis can sometimes be the first sign of multiple sclerosis, which brings with it more complex symptoms. Myelitis alone can also occur when the body encounters an infectious agent such as a virus.
The company said it had not confirmed a diagnosis in the second case, a participant who fell ill after receiving the second dose of the vaccine. A person familiar with the situation, who spoke to the Times on condition of anonymity, said the participant’s disease had been identified as transverse myelitis. The trial was interrupted again on September 6th after she fell ill.
The condition is rare but serious, and experts said finding even one case among thousands of study participants could be a red flag. Multiple confirmed cases could be enough to completely halt AstraZeneca’s vaccination offering.
“When there are two cases, it looks like a dangerous pattern,” said Mark Slifka, a vaccine expert at Oregon Health and Science University. “If there is a third case of neurological disease in the vaccine group, this vaccine can be done.”
A September 11 participant information sheet of the UK trial against AstraZeneca summarized the two volunteers’ cases, stating that the diseases “are unlikely to be linked to the vaccine or that there is insufficient evidence to be safe to be that the diseases are related or not the vaccine ”based on safety reviews. The next day, AstraZeneca announced that the UK trial had resumed.
But the FDA has not yet allowed the company to start again in the US.
An FDA spokesman declined to comment. The National Institutes of Health said in a statement that it “remains to be seen” whether the onset of the disease in study participants was accidental or related to the vaccine, adding that “a pause to allow further evaluation is compatible with standard practice “.
Dr. Mark Goldberger, an infectious disease expert with the Global Antibiotic Research and Development Partnership and a former FDA official, said the rapid restart of studies abroad was “a little worrying,” especially given the lack of detail on the patients. Symptoms and the uncertainty about its connection to the vaccine. “Maybe this is the best you can do. It may not be possible to get more security at this time, ”he said. “It’s a question mark what’s going on.”
The company did not immediately inform the public about the neurological problems of both participants. Nor did she immediately alert the FDA that she was pausing her trials again after the second UK volunteer developed a disease and an independent safety agency called for a temporary halt, according to several people familiar with the situation. The company’s executive briefed investors on the issues but did not discuss them publicly until the information was leaked and reported by STAT.
“The communication was terrible and unacceptable,” said Dr. Peter Jay Hotez, a virologist at Baylor College of Medicine in Houston. “That’s not how the American people should hear about it.”
Hotez also criticized blunt statements by government officials, including UK regulators, who he believed failed to provide a reason for retrying their trials.
“Tell us why you made this decision,” he said.
Dr. Paul Offit, a professor at the University of Pennsylvania and a member of the FDA’s Advisory Committee on Vaccines, said it was unclear how the company – or the UK government – found the second case unrelated to the vaccine.
He and other experts found that transverse myelitis is rare, only diagnosing about 1 in 236,000 Americans each year. Only about 8,000 volunteers were involved in the UK process, a spokesman for Oxford researchers said last month.
Developed by AstraZeneca, which has partnered with scientists at Oxford University, the vaccine uses a virus that is designed to deliver coronavirus genes into human cells and trigger an immune response that protects people from the coronavirus. This so-called vector is a modified form of an adenovirus that causes colds in chimpanzees but is considered safe for humans. Several other companies, including Johnson & Johnson and CanSino, are taking similar adenovirus-based approaches, although there are several types of adenoviruses and certain ingredients vary from vaccine to vaccine.
While other adenovirus-based products have had some success in the past, they have also been linked to serious adverse events. Most famous was the case of 18-year-old Jesse Gelsinger, who died in 1999 after receiving gene therapy from an adenovirus that triggered a fatal inflammatory response in his immune system.
If a serious side effect were definitely linked to AstraZeneca’s vaccine, scientists would need to determine whether the cause is the adenovirus vector or possibly the coronavirus genes it contains – compounds that could raise concerns about other companies’ products based on the same components.
Denise Grady, Katherine J. Wu, and Sharon LaFranierec. 2020 The New York Times Company