Moderna, for example, will conduct two interim analyses at about 53 and 106 infections. AstraZeneca is doing one at about 75 cases. Pfizer is doing four at 32, 62, 92, and 120 cases. “Pfizer’s, from what I can see, is the most aggressive,”
This is why Pfizer was the only company to once suggest that its vaccine might be authorized before the election—though it has since said it will wait until at least mid-November to finish collecting safety data.
Each trial plans for a certain number of COVID-19 infections, and to hit that number, companies can either wait a long time for fewer volunteers to get naturally infected or they can recruit lots and lots of volunteers, which is what they’ve done. “We want to be able to detect an efficacy signal as quickly as possible,” Karron says.
If most of the infections are in the placebo group—say 26 out of 32—that would suggest the vaccine is at least 76 percent effective. That’d be pretty good. But scientists have cautioned that a COVID-19 vaccine might be less effective than we’d like, based on how vaccines against respiratory viruses tend to work. The FDA has set a bar of at least 50 percent efficacy for a COVID-19 vaccine. It’ll take longer and more cases for trials to reach a conclusion if vaccine efficacy is on the lower side. So if the first interim results are a little disappointing, that “doesn’t mean this is a failed vaccine,” Lowe says. “We’re just going to keep on rolling.” We’ll have a better idea of efficacy once we’ve seen how the vaccine performs in more people.
In general, more than 90 percent of drugs and treatments fail, and close to 50 percent of them fail in Phase 3. Lowe says he expects COVID-19 vaccine candidates to do much better because scientists are building on research into MERS and SARS, two related coronaviruses.But the whole point of conducting clinical trials is to find out if a vaccine works, so we shouldn’t expect them all to succeed.
The other big question, of course, is one of safety. The smaller Phase 1 and Phase 2 vaccine trials have so far found adverse events including fatigue, chills, headache, and pain at the injection site. But the big Phase 3 trials are meant to find rarer adverse events that might turn up in only, say, one in 10,000 people. That’s one advantage of these unusually large Phase 3 studies. Then again, volunteers might get sick for unrelated reasons, too, and any connection to the vaccine can be tricky to determine. With all the Phase 3 trials going on, “you’re talking about hundreds of thousands of people, some of whom are elderly, over a prolonged period of time,” Barouch says. “So there will be heart attacks. There will be strokes. There will be cancers. There will be neurological events.”
A serious adverse event—like a neurological disorder—triggers a study pause and a review by an independent data-and-safety-monitoring board. This board is made up of scientists who do not work for the vaccine company and are not investigators for the trial itself. First, they would “unblind,” to figure out whether the person got a vaccine or a placebo. And if the participant got the vaccine, the board might seek additional medical records and data to look for any possible link between the vaccine and the adverse event. The AstraZeneca and Johnson & Johnson vaccine trials are currently halted in the U.S. due to adverse events, though AstraZeneca’s has since resumed in other parts of the world. These pauses are relatively common with vaccines, which have a very high safety bar because they, unlike drugs, are given to healthy people.
Recruiting large numbers of volunteers speeds up the trials significantly, but investigators will still have to wait to understand a vaccine’s long-term safety. While normal vaccine trials might run for years before going to the FDA, the agency says it will require at least two months’ worth of follow-up data before authorizing a COVID-19 vaccine for emergency use. (Emergency use authorization, or EUA, is a lower bar than formal approval.) Peter Marks, the director of the FDA division responsible for vaccines, has said that this time frame was chosen because most adverse events show up by the two-month mark.
When COVID-19 vaccines are eventually given to millions of Americans, some number of extremely rare—literally one-in-a-million—events will occur. The flu vaccine, for example, is linked to one or two additional cases of a rare neurological disorder called Guillain-Barré syndrome for every 1 million doses administered. But public-health officials weigh that risk against the 12,000 to 61,000 people who die of seasonal flu every year in the U.S.
With the FDA’s two months of required safety data, mid-November is the earliest companies might seek emergency approval for a COVID-19 vaccine, assuming the required number of infections is met. The interim data in a small number of people may or may not offer clear results, but the bigger picture is worth keeping in mind: Many, many candidates are in the pipeline. The first vaccine will make news, but it might not be the most effective, the easiest to deploy, or ultimately even the most widely used. [Ino-4800 might be the dark horse]
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