What we know and don’t know about the pauses in COVID-19 trials
Johnson & Johnson announced Monday that it has halted its massive COVID-19 vaccine trial after a participant became ill.
Less than 24 hours later, Eli Lilly paused a study of a COVID-19 antibody treatment for the same reason.
What does this all mean?
We reached out to two San Diego scientists, Dr. Davey Smith of the University of California, San Diego and Dennis Burton of Scripps Research, for the answer. Both researchers are deeply involved in the search for new COVID-19 treatments and intimately familiar with clinical trials.
As with most things related to the coronavirus, there are more questions than answers, but here’s a breakdown of what we know and what we don’t about the paused trials.
What we know
1. This is how clinical trials work
Both Burton and Smith were clear on one point – study pauses happen all the time.
Clinical trials start. And stop. And start again.
“If people weren’t looking at safety, then these trials wouldn’t get paused,” Smith said. “The brakes are being tapped, which makes me feel better about the trials.”
All major clinical trials are monitored by a panel of researchers who are not affiliated with the company sponsoring the trial or any government regulatory agency.
The researchers on these data safety monitoring boards are the only people who know which study participants got the experimental treatment and who got the placebo. Based on that information, they can recommend continuing a study interrupted, stopping because of clear evidence a treatment works (or doesn’t), or pausing to investigate a safety issue.
Monitoring boards for both Eli Lilly and Johnson & Johnson’s trials have opted for a pause. So did the board tasked with monitoring a COVID-19 vaccine trial sponsored by British pharma giant Astrazeneca back in September. That trial has since resumed in most countries, though not in the U.S.
These pauses are happening despite immense pressure to quickly roll out treatments and vaccines for a disease that has claimed the lives of more than 215,000 Americans. And that level of caution reassures Burton, an immunologist who studies vaccine design.
“They’re playing by the rules, which is what you would hope,” Burton said.
2. No San Diegans took part in the Eli Lilly trial, though some received Johnson & Johnson’s vaccine before the pause
Eli Lilly has 51 study sites for its ACTIV-3 study, which tests whether a combo of the antiviral remdesivir and an antibody against the coronavirus treats COVID-19 better than remdesivir alone.
San Diego is not one of those sites. But the county is home to two sites of Johnson & Johnson’s vaccine trial. One of them, run by UCSD, was set to launch Tuesday in National City. No participants have received the vaccine at that site, according to director Dr. Susan Little.
The county’s other trial site, located in the city of San Diego, is run by M3 Wake Research, an organization that provides clinical research facilities and services. Some participants have been vaccinated there, according to site director Dr. Laurie Han-conrad, who would not disclose the exact number.
Roughly half of participants would have received the placebo, a saltwater injection. And given Johnson & Johnson’s statement that it paused the trial to investigate a single illness, it’s highly unlikely the event occurred in San Diego.
What we don’t know
1. What symptoms prompted the trial pauses?
Announcements from both companies offered scant specifics, which has left researchers and the public guessing at what happened.
It’s possible, says Smith, that participants’ symptoms were simply stronger than what researchers expected. For instance, many people who get a flu shot get a mild fever or a sore arm for a day or two. That’s normal.
But a dangerously high fever would be cause for concern. So would any unexpected symptoms, such as a heart attack or stroke.
The data safety monitoring board will have access to that information, and they’ll know the answer to the following question.
2. Did the participant(s) who got sick receive the placebo or the experimental treatment?
By design, trial participants don’t know whether they’ve gotten the placebo or the real thing. Neither does the person delivering the injection. Researchers do this to avoid changing participant behavior and how scientists collect and analyze the results.
If the monitoring board finds that the participants who fell ill in both trials trial got the placebo, then these pauses may not last long.
But if they did get the experimental treatment, that leads to yet another question.
3. Did the treatments cause the symptoms?
Johnson & Johnson’s study aims to enroll 60,000 participants; Eli Lilly is shooting for 10,000.
In trials that large, says Smith, you can have people who get an experimental treatment and later get sick for a completely unrelated reason.
“If you took 60,000 random people and follow them for a year, you would expect (some) to have heart attacks and strokes, without ever doing anything with them – just watching them,” Smith said.
To separate coincidence from cause, the monitoring board will have to take a careful look at a participant’s medical history to understand if they were predisposed to having certain symptoms even before joining the study.
But what if researchers find the illnesses were likely caused by the experimental treatments?
That’s where it gets complicated, as the monitoring boards would have to provide some guidance to the sponsor company and Food and Drug Administration on whether to continue the studies based on the benefits and risks.
But those discussions are likely still a long ways off, cautions Burton.
“There’s too little information to say very much and too little information to be too worried at this stage.”