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AstraZeneca, under fire for vaccine safety, releases trial plans

AstraZeneca unveiled details of its major coronavirus vaccine trials on Saturday, the third in a wave of rare information from drug companies under pressure to be more transparent about how to test products that are the world’s best hope for ending the pandemic .

Polls show that Americans are increasingly wary of accepting a coronavirus vaccine. And researchers inside and outside the government are concerned that regulators, pressured by the president to get results before election day on November 3, may release an untested or unsafe vaccine.

“The release of these protocols seems to reflect public pressure to do so,”

; said Natalie Dean, a biostatistician and expert in the design of clinical trials of vaccines at the University of Florida. “This is an unprecedented situation, and public confidence is such a big part of the success of this endeavor.”

Experts have been particularly concerned about AstraZeneca’s vaccine trial, which began in the UK in April, due to the company’s refusal to provide details of serious neurological diseases in two participants, both women, who received their experimental vaccine in the UK. These cases prompted the company to halt its trials twice, the second time earlier this month. Studies have resumed in the UK, Brazil, India and South Africa, but are still on hiatus in the US Approx. 18,000 people worldwide have so far received the AstraZeneca vaccine.

AstraZeneca’s 111-page trial, known as a protocol, states that its goal is a vaccine with 50 percent efficacy – the same threshold that the Food and Drug Administration has set in its guide to coronavirus vaccines. To determine with statistical confidence whether the company has reached this goal, there must be 150 people who are sick with confirmed coronavirus among participants who were vaccinated or received placebo shots.

However, the plan expects a safety committee to conduct an early analysis after there have been only 75 cases. If the vaccine is 50 percent effective at that time, it may be possible for the company to stop the trial early and apply for permission from the government to release the vaccine for emergency use.

By allowing only such a temporary analysis, AstraZeneca’s plan is stricter than the others released from Moderna and Pfizer, said Dr. Eric Topol, an expert in clinical trials at Scripps Research in San Diego, in an interview. Modern allows two such analyzes 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 security and efficiency that might not hold up. Stopping trials early can also increase the risk of missing rare side effects, which can be significant when the vaccine is given to millions of people.

Dr. Topol said AstraZeneca’s plan, like those of Moderna and Pfizer, had a problematic feature: Everyone counts relatively mild cases of Covid-19 when measuring efficacy, which could hamper efforts to determine whether the vaccine prevents moderate or severe disease.

Such plans are not usually shared with the public “because of the importance of maintaining confidentiality and integrity in litigation,” Michele Meixell, a spokeswoman for AstraZeneca, said in a statement.

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

The case led to a halt in AstraZeneca’s vaccine trials to enable a safety review by independent experts. A spokesman for the company told the 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, involving more complex symptoms. However, myelitis alone can also occur after 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 became ill after 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 illness had been identified as transverse myelitis. The trial was adjourned again on September 6 after she fell ill.

The condition is rare but serious, and experts said finding a single case among thousands of trial participants could be a red flag. Several confirmed cases, they said, could be enough to stop AstraZeneca’s vaccine offerings completely.

“If there are two cases, this is starting 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 appears in the vaccine group, this vaccine may possibly be done.”

A participant information sheet dated 11 September about AstraZeneca’s trial in the UK clumped the two volunteers’ cases, stating that the diseases “were probably not linked to the vaccine or that there was insufficient evidence to say with certainty that the diseases were or was not related to the vaccine “, based on safety reviews. The next day, AstraZeneca announced that the trial had resumed in the UK.

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

An FDA spokesman declined to comment. The National Institutes of Health said in a statement that it “remains to be seen” whether disease outbreaks among trial participants were accidental or bound to the vaccine, adding that “pause to allow for further evaluation is in line with standard practice.”

Dr. Mark Goldberger, an infectious expert in the Global Antibiotic Research and Development Partnership and former FDA official, said he found the rapid restart of trials abroad “a little disturbing”, especially given the lack of details about patients’ symptoms and ambiguity about their connection to the vaccine. “Perhaps this is the best thing they could do – it may not be possible to get more security at this point,” he said. “It’s a question mark of what’s going on.”

The company did not immediately inform the public about the participants’ neurological problems. It also did not immediately warn the FDA that it was stopping its trials again after the other British volunteer developed the disease, and an independent safety committee in the US called for a temporary halt, according to several people familiar with the situation. The company’s CEO told investors about the issues, but did not discuss them publicly until the information was leaked and reported by STAT.

“The communication around it has been 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 this.”

Dr. Hotez also criticized blunt statements from government officials, including British regulators, which he said did not provide a justification for resuming their trials.

“Tell us why you came to that 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 – determined that the second case was not related to the vaccine.

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

The vaccine, developed by AstraZeneca, which formed a partnership with researchers at Oxford University, uses a virus designed to carry coronavirus genes into human cells and trigger an immune response that protects humans from 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, pursue similar adenovirus-based approaches, although there are several types of adenovirus, and specific ingredients differ from vaccine to vaccine.

While other adenovirus-based products have had some success in the past, they have also been associated with serious side effects. The most famous was the case of 18-year-old Jesse Gelsinger, who died in 1999 after receiving gene therapy through an adenovirus that triggered a deadly inflammatory reaction from his immune system.

If a serious side effect was finally linked to AstraZeneca’s vaccine, researchers would have to determine if its root cause was from the adenovirus vector or perhaps the coronavirus genes it had – compounds that could give rise to concerns about other companies’ products that depend on the same components.

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