Conversely, it shouldn’t come as a shock if some of these vaccine candidates do turn out to be ineffective. The development process from Phase 1 to 2 to 3 has gone very smoothly so far. But, 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. With 46 vaccine candidates already in clinical trials around the world, scientists are optimistic that at least some will be effective.
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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. Normally, a pause doesn’t become public if the trial is resumed, but COVID-19 vaccines are under special scrutiny. “Hearing there is a pause means the system is working,” Karron says, because it means safety concerns are being investigated.
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. Experts agree that this is reasonable, given the pandemic, but regulators will continue monitoring the vaccine’s safety after emergency authorization and approval.