Coronavirus vaccine studies run by Pfizer and Moderna are expected to soon deliver results that show whether or not the experimental shots truly work. If data are positive, the companies will likely ask the Food and Drug Administration for emergency clearance.
Such an early approval, should one be granted, would be a turning point in a pandemic that looks far from over. But an emergency use authorization, or EUA, could also raise thorny questions about how the companies complete their trials, and might complicate studies of other vaccines.
"We are concerned about the risk that use of a vaccine under an EUA would interfere with long-term assessment of safety and efficacy in ongoing trials and, potentially, even jeopardize product approval for not only the first vaccine, but maybe even follow-on vaccines," said Marion Gruber, director of the FDA's Office of Vaccines Research and Review, at a meeting of independent advisors convened by the agency Thursday.
Gruber's concern isn't a trivial one. The first vaccine isn't guaranteed or even likely to be the most effective. And behind Pfizer's and Moderna's shots are several other promising candidates in late-stage testing that work differently.
With the pandemic still raging, however, an EUA will be the fastest route to quickly rolling out an effective vaccine to healthcare workers and other priority groups.
Pfizer's and Moderna's trials, as well as the late-stage tests run by others, randomly assign participants to either receive the vaccine under study or a placebo. That protocol gives these trials their power, allowing researchers to conclusively determine a vaccine's safety and effectiveness.
At issue is whether the availability of a vaccine would spur study volunteers who suspect they are receiving placebo to withdraw from trials. If enough do, the studies may never be fully completed or the data may be compromised — a situation that Derek Lowe, a longtime drug researcher, has called a "tragedy of the clinical commons."
An authorization might also obligate a developer, ethically, to "unblind" the study and offer their vaccine to everyone.
"Once a decision is made to unblind an ongoing placebo-controlled trial, that decision cannot be walked back and that controlled follow-up is lost forever," Doran Fink, Gruber's deputy at the FDA's vaccine office, told advisors at the meeting Thursday.
The FDA has said a vaccine authorization is not necessarily grounds to automatically unblind a placebo-controlled study, asking developers to continue study for "as long as feasible." Pfizer, however, plans to propose allowing volunteers in its study who are assigned to placebo to "cross over" and receive a vaccine, should its shot be authorized.
The first authorizations for a coronavirus vaccine, whether Pfizer's, Moderna's or another's, will likely come after a so-called interim analysis, when independent trial monitors reviewing preliminary study data can declare an early success or failure. Pfizer, for example, has planned for interim data looks after 32, 62, 92 and 120 COVID-19 cases have occurred in its Phase 3 trial. Moderna's study has two, at 53 and 106 cases.
Companies could then request an EUA, provided they have a median of two months of follow-up safety data to meet rules newly set out by the FDA.
But researchers will still want to collect, and the FDA will still eventually want to see, full results, including at least six months of safety follow-up, before granting a full vaccine approval, Fink said.
How an EUA would affect ongoing vaccine research was among the questions posed by FDA officials to the advisory committee, which will play a critical role in the public review of any would-be shots.
The FDA's concerns were shared by committee members, who debated how much impact an EUA would have and whether that impact could be mitigated. Fink had few reassurances to offer the panel, telling one member he had no "specific remedies to offer" for reducing the risk of participants withdrawal from study.
Others, however, pointed out that even if volunteers who received a placebo are notified, many may not be able to receive an authorized vaccine right away because they aren't from groups initially prioritized for inoculation. “If anything the average trial recipient might be at a lower priority,” said Philip Krause, a deputy director at the FDA's vaccine office.
Committee member Archana Chatterjee, vice president for medical affairs at Rosalind Franklin University, agreed. "There will be this lag in which the data continues to accumulate," she said.
Should running a placebo-controlled study become untenable following the authorization of several coronavirus vaccines, developers could eventually turn to "non-inferiority" studies, which assess whether an experimental vaccine is just as good as an approved one.
Proving non-inferiority may be equally challenging, however. "These types of non-inferiority trial designs require much larger sample sizes than placebo-controlled trials so feasibility will certainly be an issue," said the FDA's Fink.
Moderna this week completed enrollment of 30,000 volunteers into its Phase 3 trial, while Pfizer had recruited nearly 40,000 of a planned 44,000 by Monday morning.
Jonathan Gardner contributed reporting