Margaret Hamburg is a former Commissioner of the U.S. Food and Drug Administration (FDA), having served in this post from 2009-2015. A physician-scientist and public health expert, she recently completed a term as Chair of the Board/President of the American Association for the Advancement of Science (AAAS). HVP Editor Kristen Jill Abboud recently spoke with Hamburg about the regulatory issues concerning the eventual licensure of COVID-19 vaccines. These issues are particularly relevant given recent reports that indicate vaccine candidates being developed by Pfizer/BioNTech and Moderna are highly effective.

An edited version of the conversation appears below.

What do you think about the potential risk of politics influencing the licensure of COVID-19 vaccines?

Developing a vaccine is a very big scientific challenge that requires enormous focus and attention on conducting the right studies, ensuring that they are sufficiently rigorous to determine safety and efficacy, and making sure that they are designed and structured ethically. Those issues are generally taken for granted, but in this highly charged political environment there have been concerns raised about the chance that either there will be corners cut in the effort to accelerate vaccine development, or that political pressure will lead regulators to make decisions without adequate and complete information. In my view, it is essential that all of the stakeholders come together to support a robust vaccine research and development process, and I think that has been happening. I have enormous confidence and faith in the FDA and in the teams of scientists and experts that are reviewing these candidate vaccines. We need to have COVID-19 vaccines, preferably more than one, and we need them to be safe and effective. But we also need people to have trust and confidence in those vaccines. If they don’t trust these new vaccines, they won’t take them and then they will not serve their intended purpose to help manage, control, and ultimately end this devastating pandemic.

Pfizer/BioNTech and Moderna have both reported that their vaccine candidates are 95% effective against COVID-19. Was this surprising? Do you anticipate that COVID-19 vaccines will far exceed the U.S. FDA’s minimum efficacy level of 50%?

This was very encouraging news. We are all eager to see more data, but these announcements suggest that these vaccines will meet criteria for authorization and their administration in priority, high-risk populations may begin soon. The data also suggest that the SARS-CoV-2 Spike protein is an appropriate vaccine target, and this bodes well for many of the other vaccine candidates in development that are using different approaches, but are using the Spike protein as the antigen.

Many vaccines are not as effective as we would ideally want them to be. The FDA was thinking about COVID-19 vaccines with regard to the experience with influenza vaccines, which range from 40-70% efficacy. The FDA guidance indicated a 50% efficacy as the minimum threshold for authorization/approval, so these results are coming in dramatically higher than initially expected for this respiratory virus.

Do you suspect these trials will be sufficient to determine the efficacy of COVID-19 vaccines in specific subpopulations such as the elderly?

Determining efficacy across all relevant populations is a problem for vaccine studies, but we are noticing it more acutely now because there is a very wide range of individuals that will ultimately need to be vaccinated against COVID-19. There has been an effort from the beginning to include elderly individuals in the vaccine studies because we know they are a very important target group because of their elevated risk. Other high-risk groups have been included in the vaccine studies as well, including those with comorbidities, but there will probably need to be expanded studies in some key subpopulations as well. One critical group will be pregnant women, who have not been recruited in a targeted way in the ongoing studies. Another important group is children and youth. A couple of the studies, most notably Pfizer/BioNTech’s, have lowered the age cutoff down to include age 12 and up, but we are going to have to do additional work to understand safety and efficacy, as well as appropriate dosing and immunization schedules in younger children, who may not be at the greatest risk of life-threatening disease, but are certainly important in the dynamics of disease transmission. We will want to have COVID vaccines for all of these population groups, and this will require bridging studies to further flesh-out appropriate use of these vaccines in populations that either weren’t included or a large part of the initial studies.

It will be important to have ongoing oversight of vaccines, even as they move out of the research context and into broader use, because we always want to monitor for emerging safety concerns and deepen our understanding of efficacy. It will be particularly important that we learn more about the duration of protection and determine if certain vaccines work better in specific subpopulations. We will learn much more about that over time and with expanded use as we go from controlled studies of tens of thousands of people, to millions, or even billions of people receiving vaccines worldwide.

If the first candidate vaccines are found to be effective, will all future vaccine candidates need to be compared to those in head-to-head trials for them to receive licensure?

That is a hugely important question and one that is being debated as we speak. It is unusual to be developing and testing so many different vaccines for the same disease at one time. The good news is that there are lot of potential COVID-19 vaccines, but this does make the testing scenarios much more complicated, both scientifically and ethically. Some of the best scientific minds and most qualified vaccine researchers are discussing these issues and it will be critically important that a clear strategy is developed. For now, it is still very much under discussion.

As data from efficacy trials continues to emerge, what are some of the most pressing issues facing regulators?

One of the critical regulatory issues is whether COVID-19 vaccines will receive an Emergency Use Authorization (EUA) or a full approval. I think it’s pretty safe to say that the first candidate vaccines will most likely be authorized using an EUA and that their use will be targeted to a well-defined set of priority groups for vaccination. The EUA allows more flexibility to move a vaccine out in the context of a massive public health crisis. The process of getting a full licensure is a longer one with more specific data and administrative aspects. My guess is that companies that seek an initial EUA will move quickly to a full licensure application, but that the FDA might ask them to collect additional information before full licensure is granted.

One of the regulatory issues related to actually moving vaccines out into larger and larger populations involves the continued need for “pharmacovigilance” as touched on earlier, which is the ongoing monitoring/oversight to detect any emerging safety concerns and to learn more about levels of efficacy and duration across various subpopulations. Another key regulatory focus will concern vaccine scale up and manufacturing. There has been a great deal of attention paid to this early in the development process of COVID-19 vaccines, which is atypical. Because of the urgency of this situation, decisions were made to “manufacture at risk” before the candidate vaccines are authorized or approved. That will significantly speed the ability to get the vaccine out to people who need it, but there will still be a need for robust regulatory oversight of the scale up and manufacturing process to compare different lots of vaccine as it gets manufactured in larger and larger volumes.

From the beginning of this crisis, regulators around the world have tried very hard to work together and I think have done so in important ways, including collaborative activities to look at the science of developing COVID vaccines and accelerating both the research and development efforts and the regulatory process for reviewing these candidates globally.

What other issues do you think we will face as vaccines become available?

One of the important issues is understanding what having a vaccine will mean. Early on, vaccines will be a huge step forward, but we will still need to follow many of the non-pharmaceutical public health interventions we have come to know so well—wearing masks, social distancing, washing hands, and avoiding large groups. We have to realize that even though there has been a huge push to scale up the manufacturing of vaccines even before authorization or approval, there are still going to be limited quantities in the beginning, and so it could be a while until everyone who wants the vaccines are going to be able to get them. Many of the vaccines that may be available early on are going to require two doses so that limits the supply, and also means it will take longer until you reach your desired level of protection.

Vaccines differ, and some may reduce the seriousness of the symptoms of disease or the length of the course of disease, but they may not always prevent infection per se, so people can still get sick. And if you can get sick, most likely you can still transmit the virus, so we’re going to have to be mindful of all of that as we move into a world where vaccines are available.

We need to be careful not to convey the message that vaccines are going to be the magic bullet that will turn the COVID crisis around overnight and we can go right back to our normal lives. On the other hand, we need to work much more aggressively to help the public understand why vaccines matter and to encourage use of the vaccines once they are available. It’s been distressing to see the decreasing number of people who are expressing the conviction that they will take the vaccine. We have to ensure that the right message about the safety and efficacy of the vaccines is getting out so that people trust the vaccines. That message shouldn’t just come from the government or companies. We also need to engage a network of communities—and trusted community leaders—to do outreach to help people understand the use of these vaccines and their potential benefits in a way that is meaningful to them. The great tragedy will be if we have vaccines that work and are safe and nobody wants to take them.

Interview by Kristen Jill Abboud