Science‘s COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation
Success in the push to find a COVID-19 vaccine at record-breaking speed could hand the world a new problem. The first vaccine to cross the finish line might be only marginally effective, yet ethicists warn it could disrupt ongoing studies of good—or even great—candidates in the wings.
In all likelihood, the U.S. Food and Drug Administration (FDA) or other regulators will issue the first approval or emergency use authorization (EUA) for one COVID-19 vaccine while clinical trials for many other candidates are still underway or in the planning. At that point, ongoing studies of any candidate—including that first one—arguably could become ethically bound to offer the vaccine with proven efficacy to everyone in a placebo group. “It’s a very vexing issue,” says Christine Grady, who heads the bioethics department at the National Institutes of Health (NIH) Clinical Center, which organized a “grand rounds” webinar on the challenges earlier this month.
“What’s really important is that the science does continue,” says Seth Berkley, who helps run the COVID-19 Vaccine Global Access Facility, an international effort to develop and manufacture a portfolio of COVID-19 vaccines. Berkley, who also heads the advocacy group Gavi, the Vaccine Alliance, predicts the world will need multiple vaccines against the pandemic coronavirus SARS-CoV-2. Not only might some work better than others, but factors such as cost or side effects mean some might offer benefits to specific groups, such as the elderly, pregnant women, or people in low-income countries.
According to the World Health Organization, 44 COVID-19 vaccine candidates were in clinical trials as of 19 October. Ten are in phase III trials, in which tens of thousands of participants randomly and blindly receive either the candidate or a placebo while their health is closely monitored. If efficacy signals surface along the way, vaccinemakers could seek EUAs before a trial’s planned end date (see graphic, below). The EUA guidance issued by FDA stipulates that a candidate only needs to achieve 50% efficacy at preventing symptomatic COVID-19 and, as an added measure of safety, have had 2 months pass after roughly half the participants have received their final dose. (Russia and China have granted early approval for various vaccines but without any evidence of efficacy.)
Participants in the NIH webinar agreed that the first EUA for a COVID-19 vaccine will change the landscape for phase III trials, including the one for the permitted vaccine. Should people in the placebo group immediately receive that vaccine, or should the blinded trial continue, to make sure that the early benefits pan out over a longer period? Continuing the trial could also reveal rare side effects or shed light on the vaccine’s efficacy in the elderly versus young adults.
CREDITS: (GRAPHIC) C. BICKEL/SCIENCE; (DATA) LARRY COREY/FRED HUTCHINSON CANCER REAEARCH CENTER
And should ongoing phase III trials of other vaccines also replace their placebo with the vaccine that just showed efficacy? Will participants in those other trials drop out en masse? Will people refuse to even join new trials, reasoning that they can get a vaccine that already works to some extent?
For such questions, Grady says, the ethical equation “boils down to a fairly simple calculus”: the individual versus the societal value. During the webinar, philosopher Joseph Millum framed the issue as “fundamental” to all clinical research. “Clinical research is ethically challenging because it exposes participants to risks for the benefit of others,” said Millum, who works with Grady at the NIH Clinical Center.
Scientists and ethicists don’t always solve the simple calculus the same way. Grady says if early results for a COVID-19 vaccine candidate lead to an EUA, participants in that trial would have a right to know whether they had received a worthless placebo or a vaccine that potentially could help them. “It’s a benefit that people in the trial should have access to,” she contends.
Millum counters that the benefit to society of continuing a blinded trial can outweigh the risk to participants who receive the placebo. If the chance that a person in the trial would be exposed to SARS-CoV-2 is relatively low, he said at the webinar, then continuing the blinded study “could then be justified” in light of the need “to gather socially valuable information.” This is especially true, he added, given that the world will likely benefit from having more than one COVID-19 vaccine, both because of the needs of different populations and so that supply can meet demand.
Stanford University epidemiologist Steven Goodman agreed, stressing that vaccine studies differ “dramatically” from treatment trials, which aim to help people who have a disease. “If someone asked me whether a therapy for a serious disease should first be given to people participating in the control arms of the clinical trial testing that therapy,” Goodman reasoned, “I would say, ‘absolutely, yes.’” But people receiving a placebo in a vaccine trial don’t need it the way sick people need a treatment, he argued. A widely used vaccine, he noted, can create “herd” immunity by reducing spread of a virus in a community. “If everyone around you has gotten a highly effective vaccine, you don’t need it,” Goodman said. “That shows that you don’t have a problem that needs treating, but the population does.”
Gaming out the impact of an EUA on other COVID-19 vaccine trials is even more complicated, Grady says. If a trial of a different candidate has yet to start, ethical considerations may demand that the candidate be compared to the newly permitted product instead of a placebo. Such studies, known as a noninferiority or superiority trial, are slower and more costly than placebo-controlled trials. If a trial is already underway—especially if it is close to fully enrolled—investigators could explain to participants the value to society of continuing the blinded study. They might choose to stick with it, she says, especially if they were given this promise: “Whenever this trial is finished, we will give you the vaccine that’s the most effective.”
If the first proven vaccine only offers a modest benefit, Grady adds, participants may be more willing to continue in a blinded study, hoping to receive what might turn out to be a better vaccine. Many people in vaccine trials also have strong altruistic motives for participating, she notes. And if the first validated COVID-19 vaccine is scarce, the incentive to leave the trial may be lower. “If it’s not available, it’s not available,” Grady says.
If an EUA or a full approval does disrupt vaccine trials, Berkley says, “bridging” studies could fill the gap. Researchers may identify immune factors that correlate with protection by the approved vaccine and then pivot efficacy trials to assessing whether other candidates trigger a similar response, avoiding a placebo comparison. (Researchers would have to inform potential participants that a proven vaccine existed, but they would not face the more serious ethical dilemma that a placebo presents.) Those correlates of protection might be enough proof of efficacy for an EUA or full approval of a COVID-19 vaccine. It’s the same practice used to approve each year’s influenza vaccine.
Bridging studies are also used after a vaccine proves itself in an efficacy trial to show that it works in different populations. “That’s what’s so beautiful about having the correlate of immunity and an understanding of the vaccine,” Berkley says.
The telltale sign of efficacy for a COVID-19 vaccine, researchers suspect, will be antibodies that “neutralize” the spike, the surface protein of SARS-CoV-2, preventing the virus from infecting cells. If trials find that a certain level of these neutralizing antibodies does correlate with protection against infection or severe disease, it can serve as a benchmark for comparing vaccines in development to proven ones. “I think that’s the way it will ultimately get done,” Berkley says.
With an early vaccine approval possible by the end of the year, Grady says she’s glad to see discussion of its possible unintended consequences. “This is something that everybody needs to be talking about.”