In the time before the Covid-19 pandemic, a company pausing a clinical trial drew about as much media attention as its appointing a new director of human resources. Today, such pauses are huge news.
In September, AstraZeneca put its Covid-19 vaccine study on hold because of a possible adverse reaction in a participant in the U.K. On Monday, STAT reported that Johnson & Johnson paused its vaccine trial because of an “unexplained illness” in a participant. On Tuesday, the NIH paused its trial, ACTIV-3, evaluating a monoclonal antibody developed by Eli Lilly that’s similarly designed to the one manufactured by Regeneron that President Trump received.
These pauses show that the system is working, especially in vaccine studies where participants are generally healthy and the goal is to prevent infections. In addition to being effective, a vaccine must be extremely safe. There is a higher bar for trials testing therapies aimed at prevention of infections that will be given to millions of otherwise healthy people.
And there are certain types of events or sentinel events that require a deeper dive before continuing to ensure the safety of current and future participants. This is especially true for therapies that are targeted at the immune system, such as a vaccine, that can trigger unintended immune responses or in some cases allergic reactions that are important to recognize.
The AstraZeneca trial is a good example of this. A patient in the trial developed a rare disorder, transverse myelitis, that affects the neurological system. Other rare conditions have emerged in vaccine clinical trials, such as Guillain-Barré syndrome, in which the body’s immune system attacks the nerves. It’s essential to fully understand the cause of such rare diseases or other effects, such as liver damage.
The AstraZeneca pause, called in coordination with regulators, indicates the collective attention to the rapid development of vaccines to prevent Covid-19 infections. Overall, it shows that the companies and regulators are taking a conservative approach to developing Covid-19 vaccines and therapies with an appropriate abundance of caution.
Another issue in play is the pace of development. The normal life cycle for a vaccine trial is several years, with experience or exposure accumulating over a much longer time to understand early and late effects. In the era of Covid-19, all of this development is extremely compressed into several months. That means thousands of people are being enrolled each week, and there’s a flood of data coming into the analysts. If they see a potentially worrisome signal, they’ll want to take a deeper dive while making sure there aren’t any other signals coming up elsewhere.
In a typical scenario, the natural timeline or lag of enrollment allows personnel overseeing safety to see the landscape more easily. In the current scenario, when everyone is moving at an incredibly fast pace, it’s quite appropriate to slow or pause a trial if a question emerges.
Teasing out what is causal and what isn’t is difficult to do. Diseases emerge in people all the time in or outside of clinical trials. It’s possible that the vaccine trial participant who had new-onset transverse myelitis would have developed it even if she or he hadn’t been in the trial. It’s also possible it was triggered by the vaccine. That’s why it is important to do large, randomized, well-controlled trials to understand if an event is more likely with a vaccine. Nevertheless, there will still be extremely rare events seen only during post-approval safety studies that must be compared to the background incidence of those events.
Holds and pauses certainly aren’t restricted to Covid-19 trials in the clinical trials sphere. They happen regularly, depending on the type of event, the phase of development or stage of the trial and the type of setting. For example, if a company is investigating a new treatment and identifies a severe allergic reaction or liver failure, it will pause the trial. The pause allows other data to be examined to understand if there any safety issues exist and, if so, does the trial need to be modified.
I believe that these three pauses show that the system is working. These programs have accelerated in ways we have not seen before.
Pharmaceutical companies and the government are fulfilling the duties about what is happening in the development of Covid-19 vaccines and therapies. This due diligence is important. It tells the American public that everyone is committed not just to developing new treatments, but to developing ones that are safe and effective. It also reassures current future participants about taking part in studies of these new treatments that everyone is treating safety as a primary concern, especially those who serve as the independent monitors overseeing the safety of trial participants.
The clinical trial system was designed to put on the brakes when needed and give the green light when appropriate. That’s what we are seeing with the pauses in Covid-19 trials.
Adrian Hernandez is a cardiologist and director of the Duke Clinical Research Institute.