In October, Judith Munz and her husband, Scott Petersen, volunteered for a coronavirus vaccine trial. At a clinic near their home in Phoenix, each got a jab in the arm.
Petersen, a retired physician, became a little fatigued after his shot, and developed redness and swelling on his arm. But Munz, a social worker, didn’t notice any change. “As much as I wanted it, I couldn’t find a darned thing,” she said. “It was a nothing burger.”
She knew there was a 50-50 chance that she would get the vaccine, developed by Johnson & Johnson. Judging from her lack of symptoms, she guessed she had received the placebo.
At the time, MsMunz thought that anyone who had received the placebo would get the real vaccine as soon as the trial showed it was safe and effective. She looked forward to the peace of mind it would bring. But last month, she was asked to sign a modified consent form indicating that people who got the placebo might have to wait up to two years to get the vaccine, if they got one at all.
Munz found the form vague, confusing and, most of all, unfair. “You put yourself out there with that risk,” she said. “I am owed that vaccine.”
As state and federal governments prepare to distribute the first coronavirus vaccines to health care workers and nursing home residents later this month, the tens of thousands of people who received placebo shots in trials have become the subject of a thorny debate among experts.
Some scientists agree with Munz that, if she indeed received a placebo, she should be moved toward the front of the line in exchange for her service for the greater good. “I think probably we owe them, as a consequence of their participation in the trial, some special priority in terms of access to the vaccine,” Dr. Francis S. Collins, the director of the National Institutes of Health, said at a meeting in July.
But on Wednesday, 18 leading vaccine experts — including a top regulator at the Food and Drug Administration — argued that vaccinating placebo groups early would be disastrous for the integrity of the trials. If all of the volunteers who received placebo shots were to suddenly get vaccinated, scientists would no longer be able to compare the health of those who were vaccinated with those who were not.
“If you’re going to prioritize people to get vaccinated, the last people you should vaccinate are those who were in a placebo group in a trial,” said Richard Peto, a medical statistician at the University of Oxford. Peto and his colleagues laid out their concerns in a new commentary in The New England Journal of Medicine.
“It’s possible that the vaccine immunity can fade over in some months. That would lead to a rise in vaccinated people getting sick as compared with the placebo group”
Placebos have been essential to clinical trials for decades. It’s vital that neither the volunteers nor the staff running the trial know who is randomly assigned to get the vaccine or the placebo. This “blinding,” as it’s called, eliminates the chance that people will behave differently depending on which treatment they get, potentially skewing the trial’s results.
Yet the prospect of giving people something useless in the face of a life-threatening disease has always been fraught. Even Jonas Salk balked at the idea of giving people placebos when researchers designed a trial to test his new polio vaccine in 1953.
“I would feel that every child who is injected with a placebo and becomes paralyzed will do so at my hands,” he complained. The study, Salk declared, “would make Hippocrates turn over in his grave.”
But Salk lost that fight, and the placebo-controlled trial went forward. It clearly demonstrated that the polio vaccine was safe and effective. Only when the trial was over did the children who received the placebo get the vaccine — along with millions of other children.
Given the stakes of the COVID-19 pandemic, the FDA has agreed to consider a faster, but limited approval, known as an emergency use authorization, based on early results from clinical trials. The agency said in new vaccine guidelines published in October that such an authorization would not necessarily be grounds for unblinding a trial.
But the debate is far from over. In an October statement, Pfizer said that it “would have an ethical responsibility to inform all study participants about the availability of an emergency authorized vaccine.” The company said it would propose to the FDA that volunteers who got the placebo could get the real vaccine. Amy Rose, a spokeswoman for Pfizer, said this week that its position hadn’t changed.
In their new paper in The New England Journal of Medicine, Peto and his colleagues argue that once a placebo group disappears from a clinical trial, the chance to collect rigorous data about a coronavirus vaccine will vanish.
Preliminary results don’t reveal how long a vaccine’s protection will last, for example. It’s possible that the immunity provided by a vaccine can fade over the course of months. That decline would lead to an increase in the rate of vaccinated people getting sick as compared with the placebo group. Scientists would most likely see that trend if they can keep a vaccine trial intact.
“It is clear that there is early protection, and I suspect there will be protection for quite a long time afterward,” Peto said. “But I think that we will be much better as a planet if we get clear evidence of this.”
If the companies were to encourage unblinding their trials, that could also harm their chances of receiving the FDA’s full stamp of approval — a license. And allowing a trial to continue may also be good for their bottom line, because knowing when immunity from a vaccine begins to wane will dictate how frequently people will need their product.
Dr. Anthony Fauci, the director of the National Institute of Allergy and Infectious Diseases, said that the ethical case for giving the vaccine to people like Munz was more compelling now that the vaccines had turned out to work surprisingly well.
The two companies at the front of the U.S. vaccine race, Pfizer and Moderna, both have reported efficacy rates of about 95%. It is unlikely that waiting for more volunteers to develop COVID-19 will change that number much.
“You put yourself at risk to prove that something works, so that everybody could use it,” Fauci said. “When you have efficacy as high as this, the case becomes stronger.”
Fauci sketched out one possible way to balance the obligation owed to people who took the placebo against the need for more data from the trials. Vaccine makers could give everyone who got the placebo the vaccine — while also giving everyone who got the vaccine the placebo. None of the trial participants would know which order they got the doses. The trial could therefore continue to be blinded.
In that scenario, researchers would be able to compare the two groups to see if the vaccine’s protection faded over time. The newly vaccinated placebo group would still enjoy a strong immune response, while the people originally vaccinated starting in July 2020 might have a weaker one. If both groups remained at low risk of infection, that would show that the vaccine was long-lasting.
“In my mind, that’s one really good option of fulfilling the ethical constraints at the same time as you get new knowledge,” Fauci said.
The issue will likely come to a head Dec. 10, when an FDA advisory board meets to discuss Pfizer’s application for emergency authorization of its COVID-19 vaccine. Moderna, which is just a week behind Pfizer, has yet to settle on a policy for its placebo group. Fauci said that it was likely he, Collins and other top NIH officials would talk more about the issue with Moderna, whose vaccine was developed in collaboration with researchers at Fauci’s institute.
If the FDA authorizes the Pfizer and Moderna vaccines, the limited initial supply will likely mean that the shots are slowly rolled out. As new groups of people become eligible, it’s possible that the two vaccine trials may gradually lose some people in their placebo groups as people drop out to get the authorized vaccines.
The rollout could have a bigger impact on the two other late-stage clinical trials underway in the United States, run by Johnson & Johnson and AstraZeneca. Johnson & Johnson expects to get the first results from its trial in January or February — but that will depend on its placebo group remaining unvaccinated.
After learning that it may take two years before Johnson & Johnson will provide her with the real vaccine, Munz, who is 68, is considering trying to get Pfizer or Moderna’s version as soon as she’s eligible thanks to her age.
“I’ll drop out, which I can do, and I’ll get the vaccine,” she said.
Holly Janes, a biostatistician at the Fred Hutchinson Cancer Research Center in Seattle, and her colleagues are preparing for this kind of erosion. She and her colleagues are now working on statistical methods to squeeze the most insight out of the trials no matter what their fate.
“It won’t be ideal from a purely scientific vantage point, because we lose the direct comparison between vaccine and placebo,” she said. “But we’re trying to strike a balance between doing what some would argue is right for the participants, and maximizing the public health value that comes out of these trials.”