Has COVID-19 Changed the FDA's Regulatory Process?

John Whyte, MD; Patrizia Cavazzoni, MD


June 16, 2021

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JOHN WHYTE: Welcome, everyone. I'm Dr. John Whyte, chief medical officer at WebMD. We've talked a lot about the role of the CDC lately in addressing the COVID pandemic, but we also need to focus on the role that the FDA has played, particularly as it relates to therapeutics in terms of drugs treating COVID, as well as vaccines.

So to help provide some insights, I have asked Dr. Patrizia Cavazzoni. She's the director of the Center for Drug Evaluation and Research at the U.S. Food and Drug Administration. Dr. Cavazzoni, thanks for joining me.

PATRIZIA CAVAZZONI: It's a pleasure to be here, John.

JOHN WHYTE: Now, let's start off with and tell our viewers, how has COVID changed the FDA regulatory process?

PATRIZIA CAVAZZONI: Well, it's been a journey over the past 18 months and we have had to adapt very quickly. When it comes to the development of COVID therapeutics, we had to, really very quickly, set up a new program, which we called CTAP, and this program was really a way for sponsors and researchers to come to us with questions very early in the development process, in the pre-IND process and be able to get answers very quickly in near real time.

And then once the data came to us, be that as part of a pre-IND or a preauthorization, pre-E way, and so on, we had to put a process in place that really streamlined the review and we provided feedback to sponsors much faster than we have done in the past, recognizing that we were working under very strong public health imperatives.

And also that these COVID therapeutic programs were really very, very streamlined, and therefore, developers needed to have answers sometimes very early on in the pre-IND phase, but they really needed to sit down with us and talk about the whole spectrum of the development program all the way through, ultimately, an emergency use authorization. And even in some instances, that would be -- obviously understanding that that might be followed also by an NDA or a BLA submission at some point.

JOHN WHYTE: At the end of the day, the FDA essentially has to evaluate risk vs. benefit, and some people are suggesting that how you evaluate the benefit versus risk has changed because of COVID. Is there a change in that risk assessment framework?

PATRIZIA CAVAZZONI: It hasn't. The framework has not changed and how we think about benefit/risk has not changed. Obviously, emergency use authorization has a different sort of standard when it comes to deciding whether to make a therapeutic available compared to the standard that we use for approval via the various pathways that we have.

Having said so, that benefit risk calculus remains the same, that we need to ensure that the benefit outweighs the risk in these situations. And obviously, the therapeutic area and the disease that the drug is targeted towards plays a big role in our calculus of benefit/risk.

And so if we look at the span of the pandemic so far, very early on, we had nothing. Nothing was available. It was all about trying to repurpose drugs, trying to find something that maybe there was a hint that it might work based on nonclinical data sometimes, and vitro data, and so on.

We're in a very different place now where we have therapeutics that have really been developed to target the virus, such as, for instance, the ever-growing COVID spike protein monoclonal antibodies. And so now we're in the space where our benefit/risk calculus also has to consider the fact that we have some effective therapeutics out there, and that obviously serves as context for how we look at the data.

JOHN WHYTE: Now, the FDA demonstrated a lot of flexibility during the pandemic, especially as it related to some of the clinical trial requirements. Some were just not deemed practical during the time of virtual visits and when patients really needed to stay at home. Do you expect flexibility to continue over the next few years? Is that a way that COVID has changed the regulatory process? There is more of an openness of looking at ways to be more flexible, whether it's adapted clinical trial design, whether it's decentralized clinical trials. What's your expectation about flexibility?

PATRIZIA CAVAZZONI: Yeah, John. I'm very glad that you're asking this question because it actually points to internal discussions that we have been having for a few months both as a center and also as the agency. And really, fundamentally, we're asking ourselves, the pandemic has really pushed us to do things differently.

Sometimes out of expediency because we needed to find a way to continue to do clinical trials not only for COVID, but for all the other therapeutic areas because those have not -- those diseases have not gone away. We needed to find ways to continue to evaluate our manufacturing facilities, and clinical investigation sites, and so on.

And so we issued a series of guidances that really was meant at providing advice for drug developers and sponsors on how they might be able to continue to do this important development work. And within that, obviously, we had to sort of think on our feet.

Now, my perspective is that we really need to take stock of that experience and really look at all of these additional tools that we have either created or deployed to a greater extent, and ask ourselves, what is important that we retain out of this experience.

And I can tell you that when it comes to decentralized trials, this is an area where we are very interested and committed to continue to advance these discussions and provide more guidance going forward. In fact, we do have guidance in the works because we see these approaches, be that decentralized approaches, which really go hand in hand also with digital health technologies, as being part of our permanent toolbelt when it comes to doing clinical trials.

And obviously, we don't expect, and I'm using this as an example, we don't expect that decentralized clinical trials will be the default best approach for every single trial, for every single therapeutic areas. Having said so, what we have learned through the painful experience through the pandemic is that these tools can really increase flexibility and they can also make it easier for patients to access clinical trials.

And that's also very important because we have areas such as oncology, where we know that there's only 5% of patients who are able to access clinical trials. And in oncology, clinical trials mean also the last resort for treatment in some instances.

And so making a clinical trial more accessible using decentralized tools, using digital health technologies, also in some areas is, really, is our tools to address some health equity and treatment access inequities as well. So ...

JOHN WHYTE: I'm going to come back to health equity, Dr. Cavazzoni. And before I ask you those tough questions, I'm going to give you a chance to brag. And it's my understanding that, in 2020, despite all the work that was doing around the clock on the pandemic, it was the second highest number of new drug approvals in the last 20 years. Is that right? How did you accomplish that?

PATRIZIA CAVAZZONI: Well I'm not going to brag on behalf of myself. I'm going to do a little bit of bragging on behalf of my team because that's really how we accomplished it. We accomplished it because we have incredibly dedicated and motivated people at CDER and across the agency who really rose to the challenge.

And we had to dedicate a really remarkable amount of resources to the pandemic response and, at the same time, we realized and our staff realized that we have responsibilities to the public in many areas and we're not in a position where we can say, you know what? We've got to focus on one of the biggest public health crises in history and drop everything else.

That's not what -- that's not how we can do things, and we have to continue to watch all the areas. And so this is really a testament to our staff and the people at CDER, and so I have been taking every opportunity to acknowledge this and thank them, and I'm going to take this opportunity as well.

JOHN WHYTE: Sure. A lot of people have done an enormous amount of work around the clock, on the weekends, and we want to celebrate them and thank them for their work. I want to go back to this issue of equity, this issue of diversity in clinical trials. And you mentioned oncology trials.

Often if people fail standard therapy, if they don't enroll in a clinical trial, they don't have many opportunities. Yet we know, in general, people of color are vastly underrepresented in trials, particularly cancer trials, often 3% to 4%, even when the particular disease disproportionately impacts people of color. I'd like to hear from you in terms of what the FDA is doing, what CDER is doing to ensure diversity. Because I'm just going to be honest. Some people are saying the FDA just doesn't have the will to ensure diversity. So what do you say to that?

PATRIZIA CAVAZZONI: Well, John, I think that this is a huge focus for society, for developers, and for all of us. It's something that we need to solve together. There is no one group, no one agency that can provide all the answers around this. Having said so, it has to be a huge focus for us at FDA as well because we are in a position where we can provide guidance and provide motivation and impetus.

So I can tell you that this is something that I really see central to the priorities that we have not only at the agency, but also for CDER. And while there are systemic reasons for this disparity, which, as you know, really lie in issues about access to health care, because usually clinical trials track with the presence of a hospital, the clinic, investigators, physicians, and so on.

And so we have areas throughout the country where there are some major disparities to access to health care system within which, obviously, the -- largely, the clinical trial apparatus resides. So putting those aside, obviously, what we can do on our end is really work with sponsors to guide them and set some sort of best practices, if not expectations, as to the importance of diversity in clinical trials.

And obviously, diversity is very much dependent on the characteristics of the trial, the population, the disease, and so on. But what we really want to see is that our clinical trials reflect the makeup, and the racial, ethnic groups, age groups, and so on of the population that we know will be receiving the drug.

JOHN WHYTE: Do you feel that clinical trials now currently adequately address minority populations?

PATRIZIA CAVAZZONI: I think that we have a way to go and we've certainly made some inroads, as you know, when it comes to some gender representation. In many therapeutic areas, we have a way to go when it comes to representation of minority populations.

I can tell you that the COVID experience has actually been very informative to us because very early in the pandemic, we realized that these development programs really needed to -- it was imperative that the development programs for therapeutics represent ethnic minorities because we knew, among other things, that those have, very early on, we realized that the impact on the pandemic was really much more pronounced in ethnic minority groups.

And so we really made it very clear in our guidance that we issued on development of COVID therapeutics that we really wanted to have that representation. And, in fact, we saw, if you look at the monoclonal antibody trials, you see that we actually achieved it. The sponsors achieved it.

JOHN WHYTE: The sponsors made that public commitment up front too. They said they were going to do that. So in some ways, they could hold people accountable and they made much more of an effort. You did comment that we made progress in terms of gender. But to be fair, Dr. Cavazzoni, some people will argue it's white women, it's Caucasian women, it's not brown and Black women, and we still have a lot of progress to make there as well. Do you agree with that?

PATRIZIA CAVAZZONI: I agree. I mean, if you look at breast cancer trials, obviously, there's no questions of gender there largely. However, we still see this disparity when it comes to ethnic and racial subgroups even more so. And so I think we need to continue to all work together towards that.

We have issued guidance, as you know, towards the end of last year on diversity in clinical trials. And in that guidance, we established sort of best practices for sponsors to come to us early in development to talk about diversity in clinical trials and how their recruitment plans would obviously be aimed at that goal.

We are still doing some work on this, including determining whether we want to achieve even additional guidance that would be really pointed more towards the racial diversity. Well, obviously, the guidance that we currently have, it's broader. Speaks about gender, age, and so on.

But John, I agree with you. This is an area where we all have to really join up and try to get to some tangible results soon, and we need to have sponsors who work with us. I know that sponsors are, based on the feedback that I've heard, they're worried that we may get to a rigid situation where we may require all subgroups to be represented to the extent where you can ascribe a P value to each of the subgroup analysis.

And that's not what we're talking about. I think that we're talking about taking a pragmatic approach. And also, we're talking about looking at real world evidence as a way to also help us sort of inform at the-- what we know about the effect of the drug in subgroups and subpopulations to the extent where real world evidence can be reflective of or has limitations in reflecting access to care, of course.

JOHN WHYTE: That's a whole--

PATRIZIA CAVAZZONI: That's another different story.

JOHN WHYTE: I want to ask you, you're replacing Dr. Janet Woodcock who has run CDER for much of the past three decades. What's going to be Dr. Patricia Cavazzoni's priorities?

PATRIZIA CAVAZZONI: Well, first, I am really blessed to have inherited a center that is really so stellar and so highly performing, and this is -- where the center is at now is really reflective of the incredible work envisioned that Janet Woodcock has had for decades.

So when I think about where we're going, I don't think about what am I going to do different, but rather, I ask myself, how are we going to continue to build on this incredibly strong foundation. And I think that there are -- if I have to summarize it in one word, I really would say that word is innovation.

I'm talking about innovation in spaces such as technology and using technology to support the work we do every day to make it more efficient, to make it more effective. I'm thinking about innovation when it comes to the regulatory framework that we use in certain areas.

And by that, I don't mean a revolution here. I'm talking about looking at the tools that we currently have available to facilitate development and innovation, to accelerate the delivery of drugs in areas of huge unmet need, such as, for instance, neurodegenerative diseases. And I can think about, for instance, ALS, which is a very current discussion right now, and use that, deploy the maximum flexibility within the framework that we have.

Obviously, depending on the data that we have in front of us because, obviously, the ability for us to be flexible is also intrinsically tied to the type of data that we are presented. I also have -- I think that we can be innovative in how we think about our human capital and our talent, and how we go about recruiting that talent and retaining that talent.

One of the learnings during a pandemic is that, for instance, remote work has almost paradoxically helped us to recruit more talent. You would expect that, during the pandemic, it might be more difficult to hire people. Well, in fact, what we have seen is that, probably because of the greater flexibility that people have and are -- we have seen an uptick in hiring and we have also seen an expansion of the talent pool that we're able to tap.

So these are just some examples of what I mean by innovation. I'm thinking about pragmatic innovation that is thoughtful and really looks at areas where we can make further gains, recognize that there are some areas that are already on that path and that don't need to be disrupted.

JOHN WHYTE: Well, Dr. Cavazzoni, I want to thank you again for taking the time to speak with us today. I want to thank you and all your FDA colleagues for the work that you've done over the past 18 months to keep us all safe from COVID. And I want to wish you luck in your new role and I look forward to checking in with you as time goes by.

PATRIZIA CAVAZZONI: Well, thank you, John, and I also look forward to checking in. You know where to find me.

JOHN WHYTE: And if you have questions about COVID, drop us a line. You can email us at DrJohn@WebMD.net.

This interview originally appeared on WebMD on June 16, 2021

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