FDA Provides the Latest COVID Updates

John Whyte, MD, MPH; Janet Woodcock, MD

Disclosures

February 24, 2021

Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

  • In an effort to decrease the risk for escape variants, the US Food and Drug Administration (FDA) recently revised the emergency use authorization for two monoclonal antibodies — bamlanivimab and etesevimab — to be used in combination to treat mild to moderate cases of nonhospitalized COVID-19.

  • The challenge in using monoclonal antibodies for outpatient cases has been treatment access. The FDA will soon allow clinicians to place a direct order, which should improve treatment availability.

  • The current vaccines are effective against the COVID-19 variants, although there is diminished protection against the South African variant. More variants are likely to emerge, however, and the FDA is conducting worst-case scenario planning to be prepared for variants resistant to vaccines and/or therapeutics.

  • Hundreds of repurposed drugs are being studied around the world for COVID-19 treatment, for both inpatient and outpatient cases. However, only 5% of trials could yield definitive data that would be actionable.

  • COVID-19 could change the way that clinical trials are conducted. We need more community-based clinical research to reach diverse populations, not when an emergency occurs but after building trust and a research infrastructure.

This transcript has been edited for clarity.

John Whyte, MD, MPH: Welcome, everyone. You're watching Coronavirus in Context. I'm Dr John Whyte, chief medical officer at WebMD.

Today I'm joined by a very special guest, Dr Janet Woodcock, the acting commissioner of the US Food and Drug Administration (FDA). Dr Woodcock, thanks for joining me again.

Janet Woodcock, MD: Really happy to be with you.

Whyte: There's been a lot of activity at FDA, especially in the past few weeks. There have been revisions of two emergency use authorizations (EUAs), one for convalescent plasma — we recently talked to Dr Peter Marks about how that has been revised — but then also one for monoclonal antibodies. That's when you and I last talked, about the use of this therapy. Can you talk about the revised EUAs?

Woodcock: A new EUA was issued for a combination of bamlanivimab, which is a monoclonal antibody from Eli Lilly that first had an EUA. This EUA is for a combination that adds a second monoclonal antibody (etesevimab). The reason to do that is to decrease what are called "escape variants," which is treatment-emergent virus that comes up during exposure to the antibody. It's much less probable if you have two different antibodies that recognize two different parts of the virus. That combination was studied in a large trial in high-risk patients.

Whyte: This was based on the supplementary data you talked about, and it sometimes speaks to additional data restricting utilization (as it did in convalescent plasma). Here, it could be broadening it, where we're talking about patients with mild to moderate disease, people who are not hospitalized and not on oxygen but are at high risk for problems with COVID.

With monoclonal antibody therapy, the challenge has been how to get the information out there. How do we let clinicians and patients know about it, given that the US government has purchased over a million doses? Approximately 250,000 have been utilized. Have we made progress in terms of how people can find out about it, how we can create infusion centers? What's the latest on that?

Woodcock: I think a lot of progress has been made. Very soon, we should open up the monoclonal antibodies to direct ordering so that they can be ordered by anyone who has the capacity to administer them. I think that will provide a lot more sites. With the publication and announcement of the results of the last Lilly trial with the combination therapy (where they had a statistically significant impact on hospitalization and death, and they also showed the markedly decreased admission to ICU), I think there will be a lot more enthusiasm for using these products because it's been definitively demonstrated what they can do.

As far as getting the word out, there's a bottleneck in infusions of people who are highly infectious. We can't use regular infusion centers unless we're willing to sanitize them in between giving them to infected patients and the usual people who come in, who may have cancer or be immunosuppressed. So we're finding different outlets. People are using creative solutions to get outpatients as early as possible (people who are at high risk), and get the antibodies into them so that they won't progress in their disease.

Whyte: Dr Woodcock, we can't discuss the vaccines without discussing the variants and whether the vaccines are effective against the variants. How do we even know that? What is FDA doing in case we need to have a booster? I understand that there will be an expedited process for that as well.

Woodcock: As far as we know, the vaccines that we have under EUA right now are effective against prevalent variants circulating around the world. Although we think there is some diminished efficacy against the South African origin strain, we think they will still be effective. However, we have to consider that with the whole world incubating the virus and it replicating in so many people, there will be many mutations that arise, and we have to be prepared.

The FDA is doing scenario planning in case the worst-case scenario occurs and the resistant variant arises. We're also planning to issue three guidances, one on vaccines and how manufacturers should both surveil and then augment their vaccine in case of a variant arising. Another is about diagnostics, because the tests could return false negatives against a variant if it were different enough, and that has different parameters for the PCR test vs the antigen tests, which use antibodies and are more susceptible. The third one is on the therapeutics that could lose efficacy against various variants. We have a pretty good handle on that and have been doing a lot of testing.

Certainly, some of the monoclonal antibodies could be less effective or lose effectiveness against certain strains, and there's already work to develop additional monoclonals. We have a very good pipeline, and we also have an understanding of which variants will affect which monoclonal antibodies. So, we should be issuing those guidances soon.

Whyte: What does "soon" mean — a couple of weeks?

Woodcock: I hope and would certainly think so. There will be drafts for public input and comment, and then we'll issue a final guidance. In the meantime, we're talking to individual manufacturers as they begin to do their own scenario planning and think about how they could modify their vaccines or additional therapeutics and so forth if variants become prevalent.

Whyte: The other big issue for vaccines relates to children and how soon they might be vaccinated. Is that something that could be possible — a vaccine authorized for children in the new school year? Or are we going to have many different types of trials based on a child's age? An elementary school student is different from an early high school student. You've often talked about that — kids aren't mini adults. How much work needs to be done before we're at a point where we can be realistically talking about the availability of vaccination in children?

Woodcock: There is work ongoing in the adolescent population, and we would expect to get some information about that fairly expeditiously. Younger age groups then would have to be studied, looking at the immunogenicity of the vaccines. The virus appears to affect younger children differently. Traditionally, those children are studied separately from vaccines. So, additional work is needed for the younger age groups.

Whyte: I do know that they're looking at enrolling kids aged 12 through 16, and then they are talking about enrolling children younger than 12. You were the therapeutics lead at Operation Warp Speed. Something that's overlooked is the number of therapeutic agents that are being studied for COVID treatment, whether it's already approved drugs (such as metformin) or new molecular entities. Can you help give our audience the sense of the number of drugs being studied for treatment of COVID? It's a vast number, isn't it?

Woodcock: Yes, it's hundreds. We did an inventory as part of our work at FDA and then have maintained that based on the registries around the world (the trial registries). The vast number of agents being studied are repurposed drugs. There are a huge number being studied in patients in the inflammatory stage because we have a large number of anti-inflammatory or immunomodulatory agents. So, there's a lot being studied there.

Then there are a huge number of oral repurposed drugs (everything from colchicine to fluvoxamine to ivermectin to metformin and so on) that are being studied in the outpatient setting. We're trying to get together a larger pragmatic trial in outpatients so we can study more quickly and definitively.

A problem with a lot of the repurposing studies that are going on is that they don't yield definitive data. In fact, we found that of all the trial arms going on around the world for therapeutic agents, only 5% would actually give us an answer that would be actionable. This is a huge problem because then we get all of this suggestive data and we don't know what to do with it.

Whyte: You've always been a big proponent of adaptive clinical trial design and master protocols. Has COVID changed the way that clinical trials are going to be done? We're talking about doing clinical trials in the home to improve the number of diverse populations. Do you expect there to be a real change in the way that clinical trials are conducted for new drugs?

Woodcock: If I have anything to do with it, there will be. I believe that we need much more community-based, clinical research. That's how you reach various populations. You can't try to do that at the moment there's an emergency. You have to build that trust and that research infrastructure.

I think we should have clinical trial networks with ongoing study of the chronic diseases that afflict Americans, and the best way to treat them as outpatients. And then if we have another emergency like this, we have that infrastructure in place, and it could be rapidly repurposed to study repurposed drugs and get definitive answers. There's a real opportunity and hope there that we can improve the clinical trial ecosystem as a result of this experience.

Whyte: A lot of the pundits are saying that the risk-benefit framework is permanently changed at FDA as a result of the pandemic. Do you think the COVID pandemic is going to have a lasting effect in terms of how the FDA evaluates risks vs benefits?

Woodcock: I don't think so. The benefits and risks haven't changed the way you look at harm and the way you look at effectiveness. The issue with this disease is, in its late stages, it's a mortal disease, and it has tremendous morbidity associated with it as well.

So under those circumstances, the FDA has long had flexibility in trying to move therapies along vs a new treatment for hypertension, depression, or something like that, where the benefit-risk has to be nailed down much more clearly. So, I don't think that what was done for EUAs (which overtly have a lower standard and the EUA can be withdrawn when the public health emergency is over) — I don't think that FDA has shifted its standards. It’s simply responding appropriately to this tremendous emergency.

Whyte: It's using the authority that it has (such as an EUA) in a public health emergency.

I wanted to ask you about diversity in the vaccine trials. They've done fairly well in terms of enrolling African Americans and Hispanics. They've done well where others have not. Do you think that will be a shift as well in terms of stating upfront a commitment to diversity in clinical trials?

Woodcock: As a part of a movement to really recognize the contributions and needs of all Americans, I believe that this will be highlighted more. In some ways, the vaccine trials were successful because of the collaboration with National Institutes of Health and the COVID vaccine network. They have made a lot of efforts to have connections and relationships with communities of color in underserved areas, and that really assisted in trust and ability to recruit people of varied backgrounds.

Whyte: Finally, a lot of past and current employees of the FDA say it's very hard to please various stakeholders; you approve a drug either too fast or too slow. What's morale like at the FDA right now?

Woodcock: We've just recently looked at some of the employee viewpoint surveys, and I'm pleased to tell you that morale is very high. These are public health individuals, and they have stepped up in a crisis. Some of them are just on their knees with work. But actually, the dedication to the mission, the understanding of how critical FDA is to the management of this pandemic and the work that we do, have kept morale up even in the face of a real crisis. It has been a very long slog. But morale, I believe, is doing pretty well because that's what they went to school for and sacrificed for — so that they could serve their country.

Whyte: Is there a silver lining in the pandemic?

Woodcock: Well, hopefully there are many things that we can learn. We're mounting formal lessons learned from the US government operation perspective from therapeutics, to try to collate all of these things we've learned (including about platform trials) and the barriers that exist to getting trials done.

To our surprise, I think we've all learned how much we can do remotely. Look at telemedicine. It's going to change medicine quite a bit because things that people were reluctant to do — or couldn't do or wouldn't do — all of a sudden became possible and pretty routine. I believe that a lot of things are going to change, and many will change in the medical field.

Whyte: Back to the issue of clinical trials. The FDA issued a significant amount of regulatory flexibility in the design of trials, and that's likely to stay. Things that we thought were so important, we now realize there are more gray areas than true black and white.

Dr Woodcock, I want to thank you for taking the time today to update us about the variants and the therapeutics, as well as for all that you've been doing for 30-plus years as a public servant at the FDA, working to keep us all safe.

Woodcock: Thanks for the opportunity.

Whyte: And I want to thank you for watching. If you have a question about FDA and COVID or COVID in general, you can email it to us at drjohn@webmd.net as well as post it on Facebook, Twitter, and Instagram. Thanks for watching.

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