Richard Pazdur, MD: A Candid Conversation on the FDA and What Lies Ahead

John Marshall, MD: Hey, everybody out there. John Marshall for Oncology Unscripted, and I am lucky enough to, over my life, have known some famous people, some people who had really big impact on the world of cancer care and drug delivery, et cetera.

So, I am honored to get to speak again, after many years, to what used to be an old friend and now hopefully a current friend, Dr. Rick Pazdur. And the reason I say we've known each other for many years is that he used to be a card-carrying GI oncologist, and he could give 5-FU just as well as I could give 5-FU.

And then he made a decision to shift gears, come up here to Washington, DC, and has worked at the FDA for what, 20, 25, 30—

Richard Pazdur, MD: 26 years.

John Marshall, MD: 26 years, and is gracious enough to join us on Oncology Unscripted. So, Rick, first, thank you, thank you, thank you, and welcome to Oncology Unscripted. Tell us a little bit about your old 5-FU-giving days, and you decide that you wanna come up to Washington and join the FDA.

Tell me what’s going through your head at this point, and why’d you do that?

Richard Pazdur, MD: When I was at MD Anderson, I was not only doing GI drug development, but I was also doing kind of phase 1, early-phase drug development. We did a lot of work on the oral fluorinated pyrimidines, capecitabine, UFT, other drugs similar to that, oxaliplatin, CPT-11, Taxotere, kind of the conventional cytotoxic drugs that were being discovered at that time and developed at that time.

What happened is I was working with several pharmaceutical companies, and I came with them to present data at the FDA. Okay. And that was my first kind of view of the FDA. I had no idea what people did there, what the issues were. The only thing I knew was that they had a profound impact on the people at the drug company. They were trying to guess what was going on behind the scenes. If somebody smiled, it must have meant this. If somebody said this, it must have meant this.

John Marshall, MD: Were you nervous that first time you’re going in and you probably had a good suit on and—

Richard Pazdur, MD: Yes, I was nervous because they were nervous, okay? And we had to practice like 2 days ahead of time before the meeting, then regurgitate what was said, like, this person meant this, this person said this, this person wasn’t at the meeting.

So, it was very unclear what the advice sometimes that the FDA was giving was. And in addition to that, the people that were at the FDA—it was a really small program at that time. It was only about 10 medical oncologists there. I didn’t know any of them, okay? They weren’t really engaged with the oncology community for the most part.

Then I happened to be reading the New England Journal of Medicine, and in those days it was a print edition, okay? And it had want ads in it, and there was a full-page want ad for a division director at the FDA, and I said, you know, I really have to do something different in my life. I want to try to do something different. I’d been in academic medicine, and I went through all of the ranks to full professor, et cetera, and tenure, et cetera. So, I really gotta do something different. And I had a vision of what I wanted to do, and that was back in 1999. And that was to bring the agency into the oncology community, so to speak, make it more academic, and really provide clarity of thinking and advice that the agency gave people.

John Marshall, MD: I don’t think I’ve ever shared this story with you, and I think it was that job interview in ’99. They needed some other people to interview, because you were clearly the winner, right? And so they wanted somebody to interview for the job, and they called me and said, “John, would you go?” I’m local. It was a cheap date. And I went up, and I thought, what a great experience. I’d learn a lot.

And I went into this big room with a big, long round table, and there were 30 people I’d never seen before interviewing me. And I’m at the head of the table, and I knew you were already—you know, and I knew you. Anyway, so I was like—

During this, of course, I’m a mouth. I’m called Oncology Unscripted for a reason. And one of the people interrupted me during my interview and said, “Dr. Marshall, you know, I hear what you’re saying and everything, how—this is a government job. How will we know when what you’re saying is from the agency versus what you’re saying is from you as a person?”

And I realized that I could not personally separate my world to where, you know, I’m always me, whether I’m talking as a doc or whatnot. How did you manage that? I mean, what’s it like having to watch that script?

Richard Pazdur, MD: Well, okay. I am a very straightforward person. I think people will agree to that. I don’t know if it has to do with my kind of Eastern European heritage, but I like to make people understand exactly what I’m thinking. I don’t like nuances, et cetera. I like cut-and-dry things—yes, no—and let’s document them.

And I think it’s important for people when they go into government to realize they’re not speaking for themselves. They’re speaking for a collective group that has a past history associated with it. People—these aren’t just—when we have meetings with companies, they’re not just a chat session. There are minutes taken. There are millions of dollars on the line with these decisions.

So, it’s not just a free-for-all of, well, this would be nice, that would be nice, and, you know, let’s just have a kind of a bullshit session here. No, it’s very regimented and—

John Marshall, MD: Like what we’re doing now? Bullshit session. So not like—

Richard Pazdur, MD: This is a bullshit session—

John Marshall, MD: I get you. I get you totally. So, you joined the FDA, 10 other oncologists there. And I want you a little bit—I mean, over the next 20-something years, you really were one of the key drivers in transforming this, not only specifically for oncology, but process in general.

Give us a high-level brag sheet.

Richard Pazdur, MD: I think, you know, one of the things that I saw immediately, the minute I walked into the agency, I said, this place needs a cancer center, okay? Community hospitals had cancer centers at this time. Local hospitals did. Universities did. Yet the agency did not. And products were spread out between CBER, CDER, CDRH, and there was very little communication.

I really kind of emphasized that we should have a cancer program, and that ultimately led, about 5 or 6 years ago, to the formation of the Oncology Center of Excellence. That was my idea. And luckily, Joe Biden, at that time, launched the Moonshot program, and that was the contribution of the agency to that.

And I would say it probably is the longest-lasting legacy of that whole Moonshot program for the agency, at least.

John Marshall, MD: Tie back to me that success, that building that, and what’s that translate into? If I’m a company or if I’m a patient on the other end, acceleration—what’s it doing for me?

Richard Pazdur, MD: Well, several things. First of all, we’re only as good in the agency as the people that work there, okay? And one of the things that I really emphasized is career development of the people and have them integrated to view themselves not as a drug regulator, but really as a medical oncologist.

In fact, when I interview people, sometimes out of their fellowship or, you know, people that have been in practice and wanna come to the agency, I ask, will you view yourself as a medical oncologist who is a drug regulator? Or do you view yourself as a drug regulator who is a medical oncologist?

The answer that I was looking for, obviously, was that people understood that they should be a medical oncologist first and then a drug regulator, because our actions obviously have to be patient-centric.

And what people don’t realize is that there’s no perfect application, and there’s always a degree of subjectivity that comes in looking at applications. Some things are pretty cut-and-dry, but even with cut-and-dry issues, there may be some warts on the application. And really it is, where do you wanna draw that line as far as approving a drug and not approving a drug?

People always ask, well, why is there a difference between the EMA and the FDA in some decisions? And my answer is, even within the FDA, there are many times differences of opinion. And it’s kind of like—I use the analogy—it’s kind of like setting a thermometer. Some people like it at 80, some people like it at 76, some people like it at 75, and subjectivity has to be there. Here again, there’s no such thing as a perfect clinical trial.

Now, the things that we recognized quite early are this need to really develop people. And what was happening during this period of the last 20 years is that drug development has escalated in oncology.

In the old days, in the 1990s, it was primarily cytotoxic drugs. And then we got into the era of targeted therapies and into the areas of biologic therapies, CAR T cells, PD-1 drugs, PD-L1 drugs, bispecifics, et cetera. That early on forced us really to take a much more academic model and develop people into specific areas of expertise.

So, we have a breast cancer program, a lung cancer program, and physicians working in these programs, very analogous to what is at your institution or all of the other major cancer centers.

No one anymore is a jack-of-all-trades. And this was really promulgated by the fact that the field was just becoming increasingly more complicated.

We in the agency had about 40% of all the work in the agency, so we went from an area of 10 medical oncologists to over 100 medical oncologists, so a logarithmic growth.

We wanted to emphasize participation within the broad oncology community, but we also realized that we needed specialized programs. These included programs such as Project Facilitate, which facilitates single-patient INDs and getting the paperwork through; an international program, Project Orbis, which facilitates the review of applications with smaller countries such as Canada, Australia, Switzerland, Israel, Brazil. And we worked together with these countries—the staff does—to make sure that we have contemporary or near-contemporary approvals of drugs throughout the world.

And this is especially important in a fast-moving situation where you have a lot of drugs being developed. You wanna make sure that the next generation of studies uses the best control. And that can only be accomplished if people in all these other countries have very similar standards of care.

John Marshall, MD: So, your success there—I got to watch this, because many of those docs you’re talking about, we trained as fellows at Georgetown. We had a lot of cross-fertilization because we were close to each other. So, it was fascinating to watch the expertise that was developed and the growth of all of that.

I wanna talk a little bit about the financial piece of this. The FDA, the way I—my simple slide that I show when I give talks on this is the FDA over here says safety and efficacy and then approves it, but then throws it to CMS, and whatever company can ask whatever amount of money. And there’s actually, in the Bush II Medicare expansion law, I think if I’m right about this, that we can’t legally judge value until only recently when Biden started to look at the cost of drugs. That you were looking at safety and efficacy. Someone else was looking at cost. And if you can’t say, well, what’s that 2 years or 2 months gonna cost me, you can’t really judge value.

Was that a frustration, if I got that right? And would you have liked to have had some say on what things should cost?

Richard Pazdur, MD: No.

John Marshall, MD: That’s easy.

Richard Pazdur, MD: We have a hard-enough job just to sort out safety and efficacy and all of the other issues.

John Marshall, MD: You don’t wanna be the judge of how much a month is worth to humankind.

Richard Pazdur, MD: I have enough people throwing at that time when I had the job. And people should realize I retired from my position at the end of the year.

John Marshall, MD: We’ll get there. We’ll get there.

Richard Pazdur, MD: And so I’m speaking from a retrospective point of view. But really, throughout my career, we really have struggled many times with just the safety and efficacy portion. And this is throughout the kind of world. There are the regulators that look at safety and efficacy, a risk-benefit analysis, and then that usually is tossed over to health care assessors in Europe, and that can slow down the process.

And luckily, in the United States, there really isn’t that slowing down, so to speak. There’s some gap in time, though, before drugs get out on the market. But there isn’t another analysis that is done on all occasions here. So, there are some differences here between us and the rest of the world.

Likewise, many of the drugs that are in compendiums, et cetera, are paid for but are not approved by the FDA. And I’m talking about supplemental indications for the most part.

John Marshall, MD: Well, let’s get to sort of current state. And we’ve talked a lot on this program—we’ve interviewed many people who have been involved in the administration, the current administration, and the changes, the impact that that’s had on science, on grants. We interviewed Dr. Fauci, you know, 6 months ago. So, people who’ve really had to deal with and been affected by the changing perspective that is being thrust upon us.

And I know you’ve lived this roller coaster, and you hung in there. And the way I saw it from the outside was you were trying to hold on to what was good and sacred and positive, but got to a place where you couldn’t do it anymore.

I don’t know what you’re willing to share or reflect on that, but—

Richard Pazdur, MD: I’m happy to share kind of highlights of this area. This could fill an entire 5-hour discussion, and I don’t want to get into the details here.

Really, traditionally, the agency was apolitical, and there was a firewall between the Office of the Commissioner, which had political appointees, and then the review divisions of CDRH, CBER, and CDER. And those people were really separated from any political considerations, the review staff and leadership of that staff.

What you saw during this period of time really was an unprecedented breach in that firewall, so to speak, manifested most recently by the commissioner’s voucher program. There are other issues that come into play here, but really much more involvement of the people in the Office of the Commissioner that really have political ties.

So, that is somewhat different.

The whole agency and government, I think—and this is not unique to the FDA, okay, but throughout all of the government agencies—suffered a lot during this past year. And I think we have to be cognizant of this.

And that started with DOGE and their “fork in the road” memo that basically read like, if you don’t—we want you to get out of government, and if we don’t appreciate you necessarily, please leave. You could take early retirement. You could just get out. But basically there was a very negative stance on that.

And that led a lot of people either to consider early retirement or leaving. The atmosphere changed from one of collaboration and comfort to one where, to have a good scientific atmosphere, you have to have the people comfortable in their work, in the sense that they can express differing opinions without fear.

But what happened in the agency, beginning with DOGE and then with some of the RIFs that occurred in April, you really had a situation where people felt very uncomfortable. There was a palpable sense of anxiety, if not fear.

And this led to many people, especially senior people that had other options to go work in industry or other areas, to consider leaving.

John Marshall, MD: And they’re—to be blunt—they’re very valuable over there in industry because of their experience. And they would make a whole lot more money all of a sudden than you there. And so these are people who are sacrificing finance, if you will. They’re already a lot of the smartest people on the planet.

And anyway, so it gets crazy.

Richard Pazdur, MD: I knew we were in a lot of trouble when about 20% of the staff left, okay? And many of the senior people left, as I said.

I knew I was in a difficult situation when my 2 deputies all of a sudden decided they would leave in the same month or so, or contemporaneously with each other. And they did not leave because they were unhappy. It was just this sense of anxiety, not knowing what was going to happen.

You know, it goes back to the situation, John. When you’re at an airport and somebody tells you why the plane is delayed, you’re comfortable. Like, the plane is delayed because we don’t have a pilot, okay? We’re looking for a pilot, and he’s coming down.

If you just have this amorphous, free-floating anxiety, it leads to a lot of issues here. And we really didn’t have a good path of where the agency was going.

On April 1 or so, there was a big RIF. We had people that just came to work, they put in their cards, and they couldn’t get in. And to this date, I don’t think we have had an accounting of who was lost and who is still there. We obviously know now, over months, just by word of mouth, who’s there, what structures—

John Marshall, MD: Are there kids’ pictures still on their desks?

Richard Pazdur, MD: They were allowed to take things home.

John Marshall, MD: Okay, good. Good.

Richard Pazdur, MD: They were allowed to take things home. But this anxiety of not knowing where you’re going is very hard.

And again, the agency is doing a lot to try to recruit people, et cetera. But you’re dealing with a situation where the people that are coming in don’t have the experience necessarily as those senior people that have left, that have had decades of experience. And this is going to be problematic as the agency moves forward. I really feel the learning curve is considerable.

John Marshall, MD: So, give us your vision of, at the current state, shifts in drug approvals, quality of what we’re doing.

Richard Pazdur, MD: Well, what has happened here—and this is well documented by the agency or by outside people in industry—is that there’s been a lot of inconsistency in approval standards, changes of approvals.

Here again, that tended not to be the case when we had a change of administration, because you had the career people in place, so to speak, and so the ship was sailing here, and whoever was the commissioner really didn’t matter to that extent on the day-to-day decisions. In fact, most of the commissioners did not and did not want to become involved.

On my 25th anniversary, we did a podcast similar to this, and we had all of the commissioners that I’ve worked with, starting from Jane Henney during the Clinton administration, Rob Califf, Peggy Hamburg, Andy von Eschenbach—to a T, everybody said our role is to protect the career staff from any political involvement.

And as I said, this has been transgressed, and now you have basically leaders in many of the centers that have had, I would say, quite noticeable political involvement.

John Marshall, MD: Well, there were a couple of really good editorials by leaders, groups of leaders, even from both sides of the aisle, that got together to express their concerns about this in that same newspaper. I never thought I would see—this is a flashback for you—I never thought that I would see on the front page of The Washington Post the word leucovorin. But this past year, there it was.

Richard Pazdur, MD: Was it DL or L?

John Marshall, MD: Well, exactly. But it was not, of course, for 5-FU enhancement or reversal of toxicity. It was for what? Autism and—

Richard Pazdur, MD: Allegedly, yeah.

John Marshall, MD: Right. And so talk a little bit more about that firewall, if you will, because here we are with no evidence, really—

Richard Pazdur, MD: I want to make sure that people understand we do have the career staff still in place, and I really have to give encouragement and honor to the people that have been there, that are doing the work, getting things out, and having the same degree of rigor. But they are somewhat under attack at this time, I would say, by increasing expectations of moving applications faster.

And I think it’s important for people to realize it’s not how fast we go. It’s really the efficiency that people should be looking at. What are things that we could do that still maintain quality, okay, but move things faster along?

And speed and efficiency are 2 different concepts.

And here again, looking at efficiency is somewhat difficult for people if they’re not familiar with what goes on in the agency, as many of these political people are not. They have had no prior history of drug regulation or working in a regulatory environment.

But just to say, well, we’re going to approve things in 2 months, I think is somewhat misguided. And here again, one of the things I really would advocate for is that we have a floating scale, for example, on our timelines.

There are applications, for example, single-arm trials that have 30, 40, 50 patients in a rare disease versus trials that have thousands of patients. And obviously the degree and the time that one would spend in looking at those applications vary.

And hence, we really should think about how we look at applications from a complexity point of view rather than just, well, we’re just gonna do this because it plays well for John Q. Public. That’s it. This administration is cutting the review times.

John Marshall, MD: Rick, you talked about the unsettled feeling inside the agency, going to work every day not really sure whether your key card’s gonna work or not, and what your job will be at the end of that day.

I do wanna share with you that out here it feels that way, too. You don’t really know what’s gonna happen tomorrow as a drug developer, as a provider of cancer care, as an overseer of a cancer center. There are a lot of moving parts there that you don’t know what the morning will bring.

You know, we just, at our NCI meeting today, saw that they signed into law at least the extension of the budget through September, I think it is, which means that at least current NCI funding is in place for our NCI centers around the country. But you learn that on a day, and then you move on.

So, we feel you, and we feel the discomfort that your team has had. But we also, at the same time, applaud all that you have done and all that you’ve been able to maintain through this.

So, not only the growth, but the maintenance of stability that you’ve been able to do, that has allowed for cures and novel therapies to make their way to the patients out there on the front lines.

So first, thank you again for the time you spent today, and thank you for all you’ve done for us as a country and us as a world, as cancer researchers.

Richard Pazdur, MD: My pleasure. And it’s been great to chat and catch up with you after all of these years.

John Marshall, MD: We will have to do more one day. John Marshall for Oncology Unscripted. Thank you for joining us, Rick, and for all of you out there for listening in.

This transcript has been edited for clarity.