By Arthur Allen, KHN
As I prepared to get my shot in mid-December as part of a COVID-19 vaccine trial run by Janssen Pharmaceuticals, I considered the escape routes. Bailing out of the trial was a very real consideration since two other vaccines, made by Moderna and Pfizer-BioNTech, had been deemed safe and effective for emergency approval.
Leaving the trial would be a perfectly sane decision for me or anyone who had volunteered for an ongoing COVID experiment. Why risk getting COVID if I was given a placebo, a shot with no vaccine in it? The way tests are designed, I might not be told whether I received the vaccine until the clinical trial is over, months from now.
Dropping the placebo arm could also be ethically sound from the company’s point of view. Researchers frequently halt trials when they have a product that works—or manifestly doesn’t. And the two approved vaccines are 95 percent effective.
That very real choice for thousands of people offering to join or remain in the ongoing vaccine tests creates a conundrum for science and for society. If trials can’t go forward, it could very well have an impact on the world’s supply of COVID vaccines and eventually on vaccine prices, especially if booster shots are needed in years to come. In markets where there are only two competing drugs, prices can shoot sky-high. If there are four or five on the market, competition usually kicks in to control costs.
In short, the welcome arrival of two COVID vaccines deemed safe has uncovered a series of ethical and logistical challenges. And it has governments, companies and scientists scrambling for solutions.
“The world’s vaccine experts are saying the longer we can carry out a placebo-controlled trial the better,” Matthew Hepburn, who runs the vaccine development arm of Operation Warp Speed, the multibillion-dollar federal program to fight COVID-19, told me. “But as a volunteer in the Janssen trial, you can always drop out.”
As for the best way to resolve broader problems, “it’s a debate in real time,” he said.
Generally, there are two aspects to the debate. First, what should be done with placebo recipients of the Moderna and Pfizer trials now that it’s clear both shots prevent the disease and appear safe? Second, how can the scores of companies in the United States and overseas that are still testing COVID vaccines adapt when there are apparently reliable products already on the market?
The FDA’s advisory committee debated the first question during two meetings in December. They heard Stanford University statistician Steven Goodman argue in favor of a “double-blind crossover” modification of the Pfizer and Moderna trials. Everyone who got placebo shots in the trials would now get two doses of the real vaccine, and vice versa. That way everyone would be protected but still “blind” as to when they were properly vaccinated.
Such a rejigger of the current trial would provide more data on the vaccine’s safety and durability of protection, although the longer-term comparison of vaccine versus placebo would be lost. It’s a marvelous idea in principle, the panelists agreed, but pretty hard to carry out. Neither Moderna nor Pfizer has agreed to it.
Pfizer wants to “unblind” placebo recipients of its vaccine—to reveal they got the saline solution and give them the real thing—once their risk group gets its turn in line for the vaccine. It has already started vaccinating health care workers who got the placebo.
Moderna, which has thousands of soon-to-expire leftover doses from its trial, said it intends to unblind its trial and vaccinate all the placebo recipients. In doing so, it would be recognizing the altruistic service the test subjects made to science and society by joining the trial.
Another proposal would split the placebo recipients in the trial into two groups. In one group, everyone would get a single dose of the vaccine. In the other, each would get two doses. This would be a way of testing evidence that emerged during the Pfizer and Moderna trials that a single dose might provide sufficient protection. If that were true, vaccination of the country could happen nearly twice as fast, because there would be twice as many doses of vaccine to go around.
No one knows to what extent the Food and Drug Administration could force the hands of the two companies, which still expect to get full licensure for their vaccines in 2021. Moderna is considered more amenable to the suggestion since, unlike Pfizer, it got nearly $1 billion in federal funding to develop its vaccine.
Other vaccine developers—including Operation Warp Speed participants Janssen (owned by Johnson & Johnson), AstraZeneca, Novavax, Sanofi and Merck & Co.—are closely watching to see which path is taken.
They are in a race against time—a race that may not end well for those running late in getting their vaccine out. And halting those efforts could hurt billions of people elsewhere in the world whose lives and livelihoods will depend on the arrival of plentiful, cheap vaccines.
One problem is finding willing test subjects. As increasing numbers of Americans are vaccinated, and the virus recedes from our shores, “the fewer the number of people eligible to participate in trials,” said Susan Ellenberg, professor of biostatistics at the University of Pennsylvania.
For now, AstraZeneca and Janssen appear well situated. Both have closed enrollment in their U.S. trials and are likely to file within a few months for emergency use authorizations, like those that have allowed Moderna and Pfizer to start vaccinating the public.
Novavax officials hope to start their late-stage trial in the U.S. soon and predict they can get full enrollment in a trial before the majority of the U.S. population is vaccinated.
Sanofi and Merck, whose timetables are more drawn out, are more likely to conduct most of their trials overseas.
In theory, drug companies could overcome these hurdles by testing multiple vaccines against one another and against approved vaccines. Dr. Steven Joffe, a University of Pennsylvania bioethicist, proposed in a recent JAMA article that Operation Warp Speed pay for such a trial.
Scientists and policymakers batted around the idea of a single U.S. trial, with multiple vaccine candidates competing against one another and a single placebo arm, during initial discussions in the spring about the creation of Operation Warp Speed.
The idea went nowhere in the United States. It was taken up by World Health Organization officials and major biomedical research groups, which have tried to create such a vaccine trial in the rest of the world —with little success thus far.
So, for now, future vaccine trials are somewhat up in the air.
“There’s this tension created by getting the first vaccines out there so quickly,” said David Wendler, a senior researcher in bioethics at the National Institutes of Health’s Clinical Center. “For public health it’s good, but it has the potential to undermine our ability to keep going on the research side and really knock out the virus.”
Companies, governments and outside funders need to quickly develop consensus on appropriate trial designs and regulatory processes for additional COVID vaccines, added Mark Feinberg, president and CEO of the International AIDS Vaccine Initiative.
As for me, I decided I would stay in the Janssen trial. However, the day before I was scheduled to get my injection—real or fake—the research organization running the inoculations called to say I failed to make the cut: J&J had stopped its trial enrollment.
So, I’ll buy some new masks and get in line for my vaccine with everyone else.
Arthur Allen is an editor at KHN and the author of “Vaccine: The Controversial Story of Medicine’s Greatest Lifesaver” (WW Norton, 2007).