Vaccine development is proceeding at record speed, with one candidate announcing early results from a U.S. phase 3 trial this week and likely more to come. If all goes well, the first doses of a coronavirus vaccine might become available in early 2021. But with this rushed timeline, how do we know it’s safe?
How a vaccine might be approved
There are three ways the public might get access to a vaccine. At an advisory panel meeting a few weeks ago, the FDA discussed all three. (While the CDC oversees the response to disease outbreaks, the FDA is responsible for approving drugs and vaccines.)
First, there is the usual pathway a vaccine would go through: approval of a biologics license application, or BLA. The FDA has approved plenty of vaccines in its time, and guidelines for the process can be found here. Besides data from all three phases of clinical trials, the FDA also wants to inspect the facility that manufactures the vaccine.
The FDA also typically requires “phase 4” studies after the vaccine is approved, to obtain more information about safety and efficacy than what was known at the time of approval. These studies help to figure out whether there might be long-term side effects, or whether protection fades over time.
The FDA has laid out the specifics on what it’s looking for in a COVID-19 vaccine application in this document.
Whichever vaccine we get, it will probably go through this process sooner or later. But time is critical: the sooner we get a safe and effective vaccine, the more lives we can save. So regulators are considering two other pathways that could make the vaccine available sooner.
Emergency use authorization (EUA)
An EUA is sort of like a temporary approval, and can be given with just a fraction of the extensive red tape required for a full approval. It can also be rescinded if further research shows that the risks or harms outweigh benefits. For example, the FDA issued an EUA for hydroxychloroquine earlier in the pandemic, and then revoked it when the drug turned out not to be effective in widespread use. (Hydroxychloroquine was already approved, but the EUA allowed the drug to be deployed from the national stockpile for COVID-19 patients.)
The FDA released guidelines for vaccine manufacturers with their criteria for granting an EUA. Like the document mentioned above about approval, this represents the agency’s “current thinking” about what they’re looking for, but leaves room for them to change their mind as new information comes in.
Importantly, the FDA expects vaccine manufacturers to keep working toward full approval even if they get an EUA, and to continue any trials that are in progress. That raises an ethical issue, since potentially half the subjects in phase 3 trials have only gotten a placebo, not the actual vaccine. Should they be told they got the placebo, and allowed to get the newly-authorized vaccine? Or should they remain enrolled, so as to keep collecting placebo-controlled safety and efficacy data? In an FDA advisory committee meeting a few weeks ago, the panelists didn’t seem to come to a consensus on the best way to handle this dilemma.
Instead of a full or temporary approval, there’s another pathway to make drugs available: expanded access, sometimes called compassionate use. This is typically used when a patient is very sick, the treatment in question is not otherwise available, and there is no way to enroll them in a clinical trial. The potential benefits of the treatment still have to outweigh the potential risks.
It’s not clear if the FDA would consider a COVID-19 vaccine an appropriate candidate for expanded use, since it’s given to healthy people for prevention and not people with life threatening illnesses as a last resort.
But some ethicists are arguing that expanded access is appropriate because it would allow a small number of people who are at high risk to start receiving the vaccine, while placebo-controlled trials continue.
How the FDA will define ‘safe’ and ‘effective’
Regulators are already concerned that they are losing the public’s trust, especially now that the president has used the possibility of a vaccine as a political football—remember the orders to get vaccine sites ready by November 1, just before the election?
During that FDA meeting I mentioned, speaker after speaker expressed fears that even the name “Operation Warp Speed” might make people think that vaccine development is being rushed. They talked about balancing the need for a timely vaccine with the optics of rolling something out before it’s fully tested.
Trust isn’t just an issue from a vanity perspective—honestly, who cares if the FDA’s feelings are hurt? What’s important is that if people think a vaccine isn’t trustworthy, they won’t want to get it. And what good is a vaccine that nobody takes?
Fortunately, as I listened, I was reassured that there will be a decent amount of safety and efficacy data available before the vaccine is rolled out. According to the FDA, their requirements for an EUA will be similar to those for full approval. The difference will be in things like paperwork and factory inspections, not safety data.
The critical numbers, for either approval or an EUA, are these:
- The vaccine’s effectiveness, as measured in a placebo-controlled trial, must be at least 50%.
- Participants in the trial must have been followed for at least two months after vaccination, on average, to gather safety data.
For comparison, many childhood vaccines, like those for measles, have an efficacy of more than 90%. The flu shot ranges from 30% to 60% effective depending on the year. Preliminary results from Pfizer’s COVID vaccine trial appear to show that it’s 90% effective, which would be amazing if it holds true as more data comes in. (The nerd in me needs to insert a note here saying that efficacy and effectiveness are not exactly the same, but you get the idea.)
How we’ll find out if there are safety issues that occur after a vaccine becomes available
If the FDA only requires two months’ follow-up at the time of an EUA or approval, then there is no way to know whether the vaccines’ protection wanes over the course of many months or years. There is also no way to know if “adverse events,” or serious side effects, might occur further down the road.
Regulators are currently planning multiple ways of monitoring vaccine recipients for safety issues. First, the vaccine manufacturers will probably still be following up their study participants, and possibly enrolling people in further studies.
Second, there is already a system called the Vaccine Adverse Event Reporting System, or VAERS. Anyone can file a report if they think they were harmed by a vaccine. This is one way regulators and manufacturers can get an early heads-up that an issue might be popping up, even if it is uncommon and didn’t show up in trials. (Regulators sometimes refer to VAERS as a “hypothesis generating system” since the reports in it aren’t necessarily verified. In other words, they’re not proof that something is going on, but they can be a start in figuring that out.)
Next, there is a system called the Vaccine Data Link, which the CDC runs as a partnership with healthcare organizations. This data doesn’t cover as many people as VAERS, but it can be more reliable and it can also be updated very quickly in what the agency calls “rapid cycle analysis.” Like VAERS, this system has been used for other vaccines, including the HPV and flu vaccines.
The CDC is also planning a system called V-SAFE, which will involve reaching out to people who received the vaccine to ask, proactively, about how they are feeling. The first groups of people to receive the vaccine—up to about 20 million people—will get a daily text asking about symptoms during the first week, and then weekly texts until the six-week mark.
There are more plans, which you can read about here on the CDC website. Regulators are planning to comb through these data sources for the symptoms and complications they think are most likely to be of concern, collect further data about what is going on, and keep a close eye on whether the vaccine still meets safety and efficacy criteria.
Even with all of these precautions, there are a lot of unknowns, and it’s entirely possible this whole process will be going on with four different vaccines at the same time, too. Whether the vaccine is seen as safe will depend on how everything plays out, but it’s good to know that the FDA and other government agencies are taking the safety considerations seriously.