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Vaccine development proceeds at record speed, with a candidate announcing the first results of a phase 3 trial in the US this week and probably more to come. If all goes well, the first doses of a coronavirus vaccine could be available in early 2021. But with this hasty timeline, how do we know it’s safe?
How a vaccine might be approved
There are three ways the public can access 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.)
Full approval
First, there is the usual route a vaccine would go through: approval of a Biological Product License Application, or BLA. The FDA has approved many vaccines at the time and Guidelines for the process can be found here.. In addition to the data of the three phases of clinical trials, the FDA also wants to inspect the facility that makes the vaccine.
The FDA also generally requires “phase 4” studies after the vaccine is approved, to obtain more information on safety and efficacy than was known at the time of approval. These studies help determine if there may be long-term side effects or if the protection wears off over time.
The FDA has established the details about what it is looking for in a COVID-19 vaccine application at this document.
Whatever vaccine we receive, it will probably go through this process sooner or later. But time is of the essence: the sooner we get a safe and effective vaccine, the more lives we can save. So regulators are considering two other avenues that could make the vaccine available sooner.
Emergency use authorization (USA)
A USA is a kind of temporary approval and can be granted with only a fraction of the extensive red tape required for a full approval. It can also be rescinded if further investigation shows that the risks or damages outweigh the benefits. For example, the FDA issued an EUA for hydroxychloroquine earlier in the pandemic, and then revoked it when the drug turned out to be ineffective in widespread use. (Hydroxychloroquine has already been approved, but the US allowed the drug to be distributed from national stocks for COVID-19 patients.)
FDA released guidelines for vaccine manufacturers with their criteria for granting an EUA. Like the aforementioned approval document, this represents the agency’s “current thinking” on what they are looking for, but leaves them room to change their minds as new information is entered.
Importantly, the FDA expects vaccine manufacturers to continue working toward full approval, even if they obtain an EUA, and to continue with ongoing trials. That raises an ethical issue, as potentially half of the subjects in phase 3 trials have only received a placebo, not the actual vaccine. Should they tell them they got the placebo and allow them to get the newly licensed vaccine? Or should they remain enrolled to continue collecting placebo-controlled safety and efficacy data? At an FDA advisory committee meeting a few weeks ago, panelists did not appear to reach a consensus on how best to handle this dilemma.
Extended access
Instead of full or temporary approval, there is another way to make drugs available: extended access, sometimes called compassionate use. It is usually used when a patient is very ill, the treatment in question is not otherwise available, and there is no way to enroll them in a clinical trial. The potential benefits of treatment have yet to outweigh the potential risks.
It is unclear whether the FDA would consider a COVID-19 vaccine as an appropriate candidate for expanded use, as it is given to healthy people for prevention and not to people with fatal diseases as a last resort.
But some ethicists are arguing that expanded access is appropriate because it would allow a small number of high-risk people to begin 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 political football, remember the orders prepare vaccine sites for November 1, just before the election?
During that FDA meeting I mentioned that speaker after speaker expressed fears that even the name “Operation Warp Speed” might make people think that vaccine development is accelerating. They spoke of balancing the need for a timely vaccine with the optics of implementing something before it is fully tested.
Trust is not just an issue from a vanity perspective; honestly, who cares if the FDA’s feelings are hurt? The important thing is that if people think that a vaccine is not reliable, they will not want to receive it. Y What good is a vaccine that nobody takes?
Fortunately, as I listened, I was reassured to learn that there will be a decent amount of safety and efficacy data available before the vaccine is released. According to the FDA, your requirements for an EUA will be similar to those for a full approval. The difference will be in things like paperwork and factory inspections, not safety data.
The critical numbers, for approval or USA, are these:
- The efficacy of the vaccine, measured in a placebo-controlled trial, must be at least 50%.
- Trial participants must have been followed for at least two months after vaccination, on average, to collect safety data.
By comparison, many childhood vaccines, such as those against measles, are more than 90% effective. The flu vaccine is 30% to 60% effective depending on the year. Preliminary results from Pfizer’s COVID vaccine trial appear to show that it is 90% effective, which would be surprising if it held true as more data is entered. (The nerd in me should insert a note here saying that efficacy and effectiveness are not exactly the sameBut you get the idea.)
How we will find out if there are safety problems that occur after a vaccine is available
If the FDA only requires a two-month follow-up at the time of an EUA or approval, then there is no way to know if the protection of vaccines diminishes over the course of many months or years. There is also no way to know if “adverse events” or serious side effects could occur later.
Regulators are currently planning multiple ways to monitor vaccine recipients for safety concerns. First, it is likely that vaccine manufacturers will continue to follow study participants and possibly enroll people in additional studies.
Second, there is already a system called the Vaccine Adverse Event Reporting System, or VAERS. No one they can file a report if they think a vaccine has harmed them. This is one way that regulators and manufacturers can get early notice that a problem could be emerging. even if it is rare and did not appear in the trials. (Regulators sometimes refer to VAERS as a “hypothesis-generating system” since the reports it contains are not necessarily verified. In other words, they are not proof that something is happening, but they can be a start to finding out. )
Next, there is a system called Vaccine data link, which CDC manages in partnership with healthcare organizations. This data doesn’t cover as many people as VAERS, but it can be more reliable and can also be updated very quickly in what the agency calls “fast-cycle analysis.” Like VAERS, this system has been used for other vaccines, including 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 proactively ask how they feel. The first groups of people to get the vaccine, up to about 20 million people, will receive a daily text message asking about symptoms for the first week, and then weekly text messages until the six-week mark.
There are more plans, that you can read about here on the CDC website. Regulators plan to review these data sources to detect symptoms and complications they think may be of concern, collect more data on what is happening, and closely monitor whether the vaccine still meets criteria for safety and efficacy.
Even with all these precautions, there are many unknowns, and IIt is very possible that this whole process is carried out with four different vaccines at the same time. Whether the vaccine is deemed safe will depend on how everything is developed, but it’s good to know that the FDA and other government agencies are taking safety considerations seriously.
