Safety concerns have led to temporary halt of three COVID trials
This week, two high-profile, late-stage clinical trials — Johnson & Johnson’s test of a coronavirus vaccine and Eli Lilly’s study of a COVID-19 drug — were put on pause because of possible safety concerns. Just a month earlier, AstraZeneca’s vaccine trial was paused after two volunteers became seriously ill.
Clinical trials experts said these delays were comforting, in a way: They show that the researchers were following proper safety procedures. But for now, details about the nature of the volunteers’ illnesses are scant. And although pauses of vaccine trials are not unusual, some experts said that pausing treatment trials — like that of Eli Lilly’s antibody drug — is rarer and perhaps more worrisome.
That trial was testing the treatment on hospitalized patients — a group that was already sick and in which declines in health would not be surprising. So for a trial like that one to be paused, the safety concernsmust have been significant, they said.
“I’ve done 50-plus monitoring committees, and it’s quite a rare thing to do,” said Tim Friede, a biostatistician at University Medical Center Göttingen in Germany, referring to his role as a safety monitor for drug trials.
For now, the companies behind the trials aren’t saying much. In a statement in September, AstraZeneca said it paused its trial to investigate “a single event of an unexplained illness.” But two vaccinated volunteers reportedly developed the same condition, an inflammation of the spinal cord called transverse myelitis.
Johnson & Johnson said that it was pausing its vaccine trial because of an “unexplained illness.” Eli Lilly’s trial of the antibody treatment was paused because of a — so far undisclosed — health difference between the group that received the drug and the group that received a placebo.
When people volunteer for a late-stage trial, known as phase three, they randomly get a treatment or a placebo, and neither they nor their doctor knows which one they received. In the weeks that follow, they’re carefully monitored.
Mild symptoms, like a minor rash or a headache, aren’t enough to pause a trial. But when investigators notice a serious problem — known as an “adverse event” — they have to report it to the sponsoring companies. And the sponsors then have to report to both the Food and Drug Administration and their independent advisers, known as data and safety monitoring boards.
If the board or the company judges the adverse event to be particularly concerning, they may put the trial on pause.
Once a trial is paused, a safety board may ask for a volunteer who experienced an adverse event to be “unblinded” — in other words, to find out if the volunteer got the placebo or the treatment. If the volunteer received a placebo, then the treatment can’t be the cause of the event, and the trial can continue.
If it turns out that the volunteer got the treatment, the board does a flurry of detective work. The members look over the medical records. They may ask for more information or even order new tests. The board uses this evidence to come to a conclusion about whether the treatment most likely had anything to do with the event.
If a safety board rules that an adverse event most likely was not a result of the vaccine or treatment, itmay allowthe trial to start up again. If, on the other hand, there’s some urgent problem — a contaminated batch of drugs, for example — the trial may have to stop.
“It is not at all uncommon for this to happen,” said Dr. Anna Durbin, a professor of international health at the Johns Hopkins Bloomberg School of Public Health. “In the vast majority of cases, the trial continues.”
No matter what the outcome of the pauses, many experts found the caution heartening. “It shows me that people are taking safety very seriously,” Durbin said. “This is an example of how things are supposed to work.”