En español | The race to develop a coronavirus vaccine is moving at record speed, and experts predict the finish line is near. Phase 3 clinical trials testing the safety and effectiveness of four vaccine candidates are underway in the U.S., and the federal government is putting plans into place for how the data will be reviewed and how the medicine will be distributed.
But with everything happening so quickly, Americans have questions: Will the shots be safe? How effective will a vaccine be at preventing COVID-19 or lessening the severity of the illness, which so far has killed more than 1.1 million people worldwide?
Food and Drug Administration (FDA) Commissioner Stephen Hahn recently spoke with AARP to answer these questions. His responses have been edited for length and clarity.
To date, the fastest vaccine created took four years. We're not even one year into the coronavirus pandemic, and already we have multiple vaccine candidates in late-stage clinical trials. How were we able to fast-track this vaccine? What steps were skipped over or accelerated, and is patient safety being protected in the process?
This is a public health emergency like we haven't seen in many, many years, and so the urgency around this is to find a vaccine that is safe and effective as quickly as possible — that's the goal. There are a number of things that can and have been done to accelerate that process, but I want to emphasize, up front, that no corners are being cut.
We can start with the clinical-trials aspect of the development: The genetic sequence of the new virus was first identified in January, and soon after, attempts were made to develop a vaccine. That happened very quickly; it doesn't typically happen that quickly. Then, there was a coordination of the preclinical studies so that the different types of vaccines could be studied in animals, and the whole effort quickly moved on to the clinical trials.
Now, what we did at the FDA was we used what's called a rolling review: Typically, we would look at the animal data and then say whether it's okay to proceed to a phase 1 trial. We did that, but we did that in real time with each of the manufacturers. Then, we worked with the manufacturers so they could design what's called a “seamless” clinical trial design, so that when they reached a certain parameter — say, safety in phase 1 — they were permitted to move very quickly to phase 2, which is to look for an immunologic response to the vaccine. The same thing occurred to move to phase 3. You can cut weeks, months, significant amounts of time, using the seamless clinical trial design.
The Phases of Clinical Trials
Phase 1: The first phase of the clinical trial process tests the safety of a drug or treatment in a small group of people for the first time. Researchers also determine a safe dosage range and identify side effects.
Phase 2: The next phase tests the drug or treatment in a larger population to see if it is effective. This phase also evaluates safety.
Phase 3: In this phase, a drug or treatment is given to large groups of people. The point is to confirm its effectiveness, monitor side effects, study different populations and different dosages, and collect information that will allow the experimental drug or treatment to be used safely.
Phase 4: This phase takes place after a treatment is approved for use by the FDA. It provides additional information including the treatment or drug's risks, benefits and best use.
And then, finally, we've been working with the manufacturers around the quality of their manufacturing, the consistency of it. So that if a vaccine were to be authorized or approved, we could immediately know that quality manufacturing is in place. And again, that process normally takes months.
The last thing to mention is that there's been manufacturing done at risk, meaning that companies have started manufacturing their vaccines [before the trials are complete], so that if an authorization or approval occurs, the vaccine is ready to go. And as you can see, this really shrinks the development time. But all the steps necessary to ensure safety and efficacy have taken place. And of course, that's the next thing that we need to see — the data from the phase 3 clinical trials — before any consideration of authorization or approval takes place.
What happens after you see this data? Can you talk about the approval process and what the FDA will be looking for in the phase 3 trial results?
We have made every attempt to be transparent about this, and will continue to do so, so that all Americans understand what we're doing from a regulatory point of view.
These phase 3 clinical trials are large trials with 30,000 or more participants, and they compare the active vaccine with a placebo to determine whether an infection occurs in a person participating in the trial — because what you're looking for is a vaccine to prevent infection [with the coronavirus, SARS-CoV-2]. That's the effectiveness side of things, and in our guidance for vaccine manufacturers [posted to the FDA's website in June], we were very clear about the criteria: We said the floor for effectiveness would be 50 percent. [This means that the vaccine should be effective at preventing a coronavirus infection or decreasing its severity in at least 50 percent of vaccine recipients. For comparison, the influenza vaccine is between 40 percent and 60 percent effective.]
We also said that safety would be of the utmost importance to us, and on the safety side of things, we're looking for side effects. Most recently in our guidance for emergency use authorization, we said that we need to see at least two months of follow-up for 50 percent of the participants after they get the final dose of the vaccine. Looking back at other vaccines, our scientists determined that two-month window was when the overwhelming majority of side effects would be seen.
What's the difference between standard FDA approval and an emergency use authorization when it comes to a vaccine?
When the developers of the vaccine are in their clinical trials, they determine when their data are mature, and there's an independent board, called a data safety monitoring board, that helps the manufacturers look at the data and determine whether they reached specified criteria. Then, they'll apply to the FDA for either emergency use authorization (EUA) or a biological license application (BLA), which is the typical process for vaccine approval. Normally, it takes us months to go through an application in the BLA process. We could, and can, and will expedite that, but it's a significant process.
The emergency use authorization process tends to take a shorter amount of time, and will in this case — not because we'll skip steps, but because we've been working with the companies ahead of time on the various components of their application. The major difference between the two applications is that the standard for EUA approval looks for effectiveness and that the vaccine's benefits outweigh the risks.
We haven't seen the data, so I can't prejudge when or if that assessment will take place. But what I can tell you is our scientists will look at the data — we've made it clear [in the guidelines] what kind of level of effectiveness we want to see, we've made it clear that we want a safe vaccine and what follow-up we need to see — and will make a decision based upon this data. And they will take the time necessary to ensure that the vaccine is safe and effective.
And then the last part of that, in terms of the authorization or approval process, is that we plan to have a vaccine advisory committee, which is a group of outside experts who will look at the data with us. We will ask them a series of questions and they will give us their opinion about the safety and effectiveness — and that is an open process, so the American public can see the data that we've given the committee and the questions raised.
So far, two out of four phase 3 trials in the U.S. have paused over safety concerns. What would you say to people who see this as a concerning sign?
I spent my career in cancer clinical research and performing clinical trials, and what I would say to folks who are looking at this is: The system is working. In fact, this is what the clinical trial system was designed to do — to protect the safety, both of the volunteers in these trials and also the American people. There's a very careful approach to this. If there is a safety concern, a trial may be paused. And at that point, a very detailed look at any safety concern is performed.
We may find out that a specific event that we've seen isn't at all related to a vaccine, but that pause is important because careful consideration needs to take place. So I see this as a very positive sign, in that the folks who are performing these trials are paying very close attention to this. And it's a sign that safety is uppermost in mind for all of those who are involved in the vaccine development process.
Many AARP readers are at increased risk for severe illness from COVID-19 because of age and underlying health conditions. Other populations, including Black and Hispanic Americans, have also been disproportionately impacted by the virus. Vaccine manufacturers are making an effort to recruit a diverse participant pool — some have even posted a demographic breakdown of their volunteers. But how can we be sure that a vaccine will be safe and effective in the populations that have been hit hardest by the virus?
When we issued our guidance to vaccine manufacturers in June, we made it clear that we want vaccine developers to ensure diversity — and as you mentioned, not just diversity around underrepresented minorities and ethnic groups, but also with respect to age and comorbidities or other illnesses that would affect a person's outcome if they were to get COVID-19. So this was really important, and we spent a lot of time with the developers of the vaccines to emphasize this.
Now, we don't have the complete breakdown of that right now, but our expectation at the FDA is that these trials will fully represent those in an older population, as well as those with other illnesses that impact the disease. We'll look at the data when they come out of the phase 3 trials and we'll ask the questions that you are asking me right now.
I don't want to prejudge those data, but we do know from years of understanding vaccines and immune response that the elderly may have a less vigorous response to vaccines than folks who are younger. And so that is something that we have paid very close attention to throughout the development process. And in the process of reviewing the data, we'll make it clear what populations we have data for, and we will tailor our approval or authorization based upon that.
I think the question on everyone's mind is really what happens after a vaccine is approved. Is there any information yet as to who will be among the first to receive a shot once it's made available?
It's not in the FDA's purview to be directly involved in the distribution plan and the prioritization plan for a vaccine, but the data that we review will be important because it will inform whatever approval or authorization takes place, and we will be in very close contact with the Centers for Disease Control and Prevention (CDC) and the Department of Health and Human Services (HHS), who are responsible for distribution.
[The CDC notes on its website that if the FDA authorizes or approves a COVID-19 vaccine, a federal advisory committee will quickly hold a meeting to review all available data about that vaccine and then vote on whether to recommend the vaccine and, if so, who should receive it — especially if supplies are limited early on.]
What happens after a vaccine is distributed? Will its safety continue to be tracked?
In FDA language, this is called pharmacovigilance. What it really means is that after a vaccine is authorized, we think it's very important — and we will insist upon — a very vigorous and detailed follow-up program so that we can understand who has received the vaccine, whether any additional side effects have been seen, and also what the effectiveness is. Because as the vaccine is given to a broader population, we'll have more information about all of that.
So this is a typical approach the FDA uses. We will have a stepped-up and enhanced program because of the urgency of the situation, and we'll be working with industry and other partners to have that program in place the minute a vaccine is authorized or approved and ready for distribution.
What is an EUA?
- Emergency use authorization (EUA) allows the FDA to provide more timely access to drugs and devices during a public health emergency.
- The EUA process is different from the traditional approval process. For starters, it's much faster. (Standard approval can take six to 10 months.) For an EUA, the FDA evaluates options using the evidence available and balances the risks and benefits.
- Both the EUA and standard approval pathways require data demonstrating a drug's safety and effectiveness.
- Issuance for a coronavirus vaccine EUA “would require a determination by FDA that the vaccine's benefits outweigh its risks based on data from at least one well-designed Phase 3 clinical trial that demonstrates the vaccine's safety and efficacy in a clear and compelling manner,” the agency says in its guidance to vaccine makers.
- Vaccine makers who apply for an EUA for a coronavirus vaccine are also encouraged to “work toward submission of a Biologics License Application (BLA) as soon as possible,” the FDA says. They must also plan to assess long-term safety and efficacy.
- Prior to the issuance of an EUA for a coronavirus vaccine, the FDA will meet with an advisory committee “to discuss whether the available safety and effectiveness data support authorization of an EUA for the specific request under review."