Late-stage trials for Covid-19 vaccines are signing up tens of thousands of volunteers, but only a tiny fraction will help decide whether the shots work safely enough to be given widely.
Just 150 or so of the 30,000 or more subjects enrolled in each trial need to be infected and show symptoms to provide the data to assess the vaccines, according to a Wall Street Journal review of researchers’ plans for U.S. studies from the four most advanced candidates.
Covid-19 vaccines need to be tested in a population where the virus is prevalent enough to reflect real-world infection rates, to ensure that they are safe and effective. Each trial requires a minimum number of study subjects to get sick with Covid-19.
Even fewer subjects—32 in the case of a study sponsored by
— would need to be infected and develop symptoms in each trial before researchers take an early look at how a shot is doing and see if it could be cleared provisionally, the review found.
The trial plans, called protocols, were for vaccines in late-stage, or Phase 3, testing from
in addition to Pfizer.
The low numbers of subjects who must become sick are normal, several scientists not involved in the studies say. Previous trials for non-coronavirus vaccines have relied on a similarly small number to assess whether a shot works, the scientists say.
The tiny percentages required by the late-stage Covid-19 vaccine trials, the scientists add, could be enough for researchers and regulators to make a determination on widespread use.
Researchers testing the coronavirus vaccines are enrolling so many people to increase the chances that some of them will get exposed to the new coronavirus and that about 150 to 160 of them will develop Covid-19 and show symptoms.
“It just takes a while to get enough events, so you need to have a lot of people in the trial,” said Angela Rasmussen, a virologist at Columbia University.
Yet even with the small numbers, independent scientists say, companies developing the vaccines may have a hard time meeting ambitious timelines for getting results. Moderna and Pfizer executives have said they could see initial data in late October or November.
Some outside scientists say companies might want to avoid relying on early data and wait for roughly 150 coronavirus cases to crop up before asking regulators to weigh authorizing a vaccine’s use. More time could help find side effects and help address vaccine hesitancy, they say.
“You want to feel really confident in the results,” said Natalie Dean, an assistant professor of biostatistics at the University of Florida. “You don’t want things to be in any gray area that leaves any doubt. A big part of the success of all this is people need to be willing to take a vaccine.”
The four drugmakers with Phase 3 vaccine trials under way took the unusual step of disclosing the study protocols to ease concerns about whether the trials will prove their shots are safe.
Clinical trials for vaccines usually last years, partly because they depend on a certain number of subjects becoming infected as they live normally. Statisticians figure out how many of these events a trial needs to have in order to draw conclusions about whether a shot works safely.
If a trial requires 100 events, for example, researchers will wait for 100 subjects to become sick and then compare how many of those got the experimental vaccine to how many got a placebo. If, say, 20 took the vaccine, then it would be deemed 75% effective.
The U.S. Food and Drug Administration has said any coronavirus vaccines must be at least 50% better than a placebo at preventing Covid-19 or reducing the risk.
Sick subjects must show Covid-19 symptoms, partly to reduce how much testing the volunteers would have to undergo.
By signing up tens of thousands more subjects than will be needed, drugmakers developing the vaccines hope to cut down the time it would typically take to get enough exposures to the virus. That could speed up the timetable for regulators to weigh a shot’s use.
Pfizer, which is partnering with
SE on a vaccine, recently expanded its Phase 3 trial to 44,000 people, while Johnson & Johnson said it is seeking 60,000 people.
For each trial, an independent group of experts who compose a data-safety monitoring board would take a look at results after a predetermined but interim number of events. If results are positive, the vaccine makers could ask regulators for approval or emergency authorization.
The interim analyses require a higher bar of efficacy than the final look. For example, researchers testing Moderna’s vaccine will look at trial data at various intervals, starting at 53 cases—which would need 74% efficacy—to a final analysis of 151 cases and 50% efficacy.
Researchers set the event goals with the help of statisticians and looked at factors such as infection rates, sample sizes and what is known about the vaccine, according to the trial plans and companies. Independent scientists said the numbers are in line with previous vaccine trials.
In one of the pivotal studies testing
& Co.’s cervical-cancer vaccine Gardasil, researchers enrolled more than 5,400 women for the three-year study and took a first look at the results after 75 cases, which took place about 18 months after the subjects received their third dose of the shot.
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The interim analysis targets will be tough to reach by late next month or November, some researchers say.
Some of the shots require two doses, several weeks apart, and vaccines typically take two weeks to have the desired effect on the immune system, the researchers say. Also, the virus has been contained in some parts of the U.S., meaning participants might not face as high a risk of exposure as when they enrolled.
“If the number of cases of Covid-19 in the U.S. goes down substantially in September and October, which it could before it goes up again, then there may not be enough positive samples to demonstrate efficacy,” said Stanley Perlman, a University of Iowa coronavirus researcher.
Some researchers not involved in the studies expressed concern about whether the interim cases for the trials would be enough to justify distributing a vaccine to millions of people, especially if the shot involves new technologies like those Pfizer and Moderna are working on.
“You’ll know very little about safety. You’ll know nothing about mid- or long-term efficacy or safety,” said Gregory Poland, director of the Mayo Clinic’s vaccine-research group. Waiting, he added, would also give time to monitor for a side effect so rare it can take awhile to surface.
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