How Will the Government Approve the Vaccine?

Vaccine development is advancing at a record pace, with one candidate announcing the first results from a Phase 3 study in the US this week and likely more. If all goes well, the first doses of the coronavirus vaccine could become available in early 2021. But given these urgent deadlines, how do we know it’s safe?

How a vaccine can be approved

The public can access the vaccine in three ways. At an advisory group meeting a few weeks ago, the FDA discussed all three. (While the CDC oversees the outbreak response, the FDA is responsible for drug and vaccine approval.)

Full approval

First, there is the usual route a vaccine goes through: approval of a biological product license application , or BLA . Many vaccines have been approved by the FDA in the past, and instructions on the process can be found here . In addition to data from all three phases of clinical trials , the FDA also wants to inspect the facility that manufactures the vaccine.

The FDA also generally requires “phase 4” studies after vaccine approval to provide more information on safety and efficacy than was known at the time the vaccine was approved. These studies are helping to find out if there may be long-term side effects or if the protection fades over time.

The FDA has laid out the specifics of what it is looking for in COVID-19 vaccine use in this document .

Whatever vaccine we get, it will probably go through this process sooner or later. But timing is of the essence: the sooner we get a safe and effective vaccine, the more lives we can save. Therefore, regulators are looking at two other avenues that could make the vaccine available earlier.

Emergency Use Authorization (EUA)

EUA is a kind of temporary approval and it can only be granted with a fraction of the extensive bureaucratic red tape required for full approval. It can also be canceled if further research indicates that the risks or harms outweigh the benefits. For example, the FDA issued an EUA for hydroxychloroquine early in the pandemic and then canceled it when the drug was found to be ineffective for widespread use. (Hydroxychloroquine has already been approved, but the EUA has authorized the use of the drug from national stocks for COVID-19 patients.)

The FDA has issued guidelines for vaccine manufacturers with their criteria for issuing an EUA. Like the approval document mentioned above, it represents the agency’s “current opinion” of what they are looking for, but leaves them free to change their minds as new information becomes available.

It is important to note that the FDA expects vaccine manufacturers to continue to work towards full approval, even if they receive an EUA, and to continue whatever trials are in progress. This raises an ethical question, as potentially half of the subjects in the phase 3 trials received only a placebo and not the actual vaccine. Should they be told they received a placebo and allowed to receive the recently approved vaccine? Or do they have to stay on the list to continue collecting placebo-controlled safety and efficacy data? At an FDA advisory committee meeting a few weeks ago, panelists did not seem to agree on how best to address this dilemma.

Extended access

Instead of full or temporary approval, there is another way to make drugs available: expanded access , sometimes called compassionate use. This is usually used when the patient is very ill, the treatment in question is otherwise not available and there is no way to include it in a clinical trial. The potential benefits of treatment must still outweigh the potential risks.

It is unclear whether the FDA would consider the COVID-19 vaccine a suitable candidate for expanded use, as it is given to healthy people for prevention and not to people with life-threatening illnesses as a last resort.

But some ethicists argue that expanded access is appropriate because it will allow a small number of people at high risk to start receiving the vaccine, while placebo-controlled trials continue.

How the FDA will define “safe” and “effective”

Regulators are already worried that they are losing public confidence, especially now that the president has used the vaccine opportunity as political football – remember the orders to prepare vaccination sites by November 1, just before the election?

During that FDA meeting I mentioned, presenter after presenter expressed concerns that even the title “Operation Warp Speed” might lead people to think that vaccine development is in a hurry. They talked about the balance between the need for a timely vaccine and the ability to roll out something before it is fully tested.

Trust isn’t just a vanity issue – honestly, who cares if the FDA’s feelings are hurt? The important thing is that if people think the vaccine is untrustworthy, they don’t want to receive it. And what good is a vaccine that no one takes?

Fortunately, as I listened, I was reassured that a decent amount of safety and efficacy data would be available before the vaccine was deployed. According to the FDA, their EUA requirements will be similar to those for full approval. The difference will be in things like paperwork and factory checks, not safety data.

The critical numbers for approval or EUA are as follows:

  • Vaccine efficacy, measured in a placebo-controlled study, must be at least 50%.
  • To collect safety data, trial participants should, on average, be followed for at least two months after vaccination.

In comparison, many childhood vaccines, such as measles, are more than 90% effective. The effectiveness of a flu shot ranges from 30% to 60%, depending on the year. Preliminary results from Pfizer’s COVID vaccine trials appear to show that it is 90% effective, which would be surprising if true as more data comes in. (Nerd I need to insert a note here that efficiency and effectiveness are not exactly the same , but you get the idea.)

How do we know if safety issues arise after a vaccine becomes available

If the FDA only requires two months of follow-up at the time of an EUA or approval, then there is no way to know if a vaccine’s protection has waned over many months or years. It is also impossible to know if there might be “side effects” or serious side effects in the future.

Regulators are currently planning several ways to monitor vaccine recipients for safety. First, vaccine manufacturers are likely to continue to monitor their research participants and possibly recruit people for further research.

Second, there is already a system called the Vaccine Side Effects Reporting System or VAERS . Anyone can apply if they think the vaccine has harmed them. This is one way that regulators and manufacturers can give advance warning that a problem may arise, even if it is unusual and not detected during testing. (Regulators sometimes refer to VAERS as a “hypothesis generating system” because the reports it contains are not necessarily validated. In other words, they are not proof that something is happening, but they can be a start in figuring it out.)

Then there is a system called the Vaccine Data Link that CDC is launching in partnership with healthcare organizations. This data does not cover as many people as VAERS, but it can be more reliable and can also be updated very quickly with what the agency calls “fast cycle analysis.” Like VAERS, this system has been used for other vaccines, including HPV and influenza vaccines.

The CDC is also planning a system called V-SAFE , which will involve asking people who have received the vaccine to know in advance how they are feeling. The first groups of people to receive the vaccine – up to about 20 million people – will receive daily text messages asking about symptoms for the first week, followed by weekly text messages up to the six-week mark.

There are other plans you can read about here on the CDC website . Regulators plan to comb these data sources for symptoms and complications that they believe are most likely to be of concern, collect additional data on what is happening, and closely monitor whether the vaccine meets safety and efficacy criteria.

Even with all these precautions, a lot remains unknown, and it is possible that this entire process will occur with four different vaccines at the same time. Whether the vaccine is deemed safe will depend on how things end up, but it’s good to know that the FDA and other government agencies take safety concerns seriously.


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