Many Trial Volunteers Got Placebo Vaccines. Do They Now Deserve the Real Ones?
Many Trial Volunteers Got Placebo Vaccines. Do They Now Deserve the Real Ones?
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.
Dr. Petersen, a retired physician, became a little fatigued after his shot, and developed redness and swelling on his arm. But Ms. 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, Ms. Munz 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.
Ms. 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 Ms. 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. Mr. Peto and his colleagues laid out their concerns in a new commentary in The New England Journal of Medicine.
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, Dr. Salk declared, “would make Hippocrates turn over in his grave.”
But Dr. 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 F.D.A. 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 F.D.A. 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, Mr. 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,” Mr. 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 F.D.A.’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 S. Fauci, the director of the National Institute of Allergy and Infectious Diseases, said that the ethical case for giving the vaccine to people like Ms. Munz was more compelling now that the vaccines had turned out to work surprisingly well.
Confused by the all technical terms used to describe how vaccines work and are investigated? Let us help:
- Adverse event: A health problem that crops up in volunteers in a clinical trial of a vaccine or a drug. An adverse event isn’t always caused by the treatment tested in the trial.
- Antibody: A protein produced by the immune system that can attach to a pathogen such as the coronavirus and stop it from infecting cells.
- Approval, licensure and emergency use authorization: Drugs, vaccines and medical devices cannot be sold in the United States without gaining approval from the Food and Drug Administration, also known as licensure. After a company submits the results of clinical trials to the F.D.A. for consideration, the agency decides whether the product is safe and effective, a process that generally takes many months. If the country is facing an emergency — like a pandemic — a company may apply instead for an emergency use authorization, which can be granted considerably faster.
- Background rate: How often a health problem, known as an adverse event, arises in the general population. To determine if a vaccine or a drug is safe, researchers compare the rate of adverse events in a trial to the background rate.
- Efficacy: A measurement of how effective a treatment was in a clinical trial. To test a coronavirus vaccine, for instance, researchers compare how many people in the vaccinated and placebo groups get Covid-19. The real-world effectiveness of a vaccine may turn out to be different from its efficacy in a trial.
- Phase 1, 2, and 3 trials: Clinical trials typically take place in three stages. Phase 1 trials usually involve a few dozen people and are designed to observe whether a vaccine or drug is safe. Phase 2 trials, involving hundreds of people, allow researchers to try out different doses and gather more measurements about the vaccine’s effects on the immune system. Phase 3 trials, involving thousands or tens of thousands of volunteers, determine the safety and efficacy of the vaccine or drug by waiting to see how many people are protected from the disease it’s designed to fight.
- Placebo: A substance that has no therapeutic effect, often used in a clinical trial. To see if a vaccine can prevent Covid-19, for example, researchers may inject the vaccine into half of their volunteers, while the other half get a placebo of salt water. They can then compare how many people in each group get infected.
- Post-market surveillance: The monitoring that takes place after a vaccine or drug has been approved and is regularly prescribed by doctors. This surveillance typically confirms that the treatment is safe. On rare occasions, it detects side effects in certain groups of people that were missed during clinical trials.
- Preclinical research: Studies that take place before the start of a clinical trial, typically involving experiments where a treatment is tested on cells or in animals.
- Viral vector vaccines: A type of vaccine that uses a harmless virus to chauffeur immune-system-stimulating ingredients into the human body. Viral vectors are used in several experimental Covid-19 vaccines, including those developed by AstraZeneca and Johnson & Johnson. Both of these companies are using a common cold virus called an adenovirus as their vector. The adenovirus carries coronavirus genes.
- Trial protocol: A series of procedures to be carried out during a clinical trial.
The two companies at the front of the U.S. vaccine race, Pfizer and Moderna, both have reported efficacy rates of about 95 percent. 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,” Dr. Fauci said. “When you have efficacy as high as this, the case becomes stronger.”
Dr. 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,” Dr. Fauci said.
The issue will likely come to a head on Dec. 10, when an F.D.A. 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. Dr. Fauci said that it was likely he, Dr. Collins and other top N.I.H. officials would talk more about the issue with Moderna, whose vaccine was developed in collaboration with researchers at Dr. Fauci’s institute.
If the F.D.A. 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, Ms. 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.”
Katie Thomas and Sharon LaFraniere contributed reporting.