The Truth As We Know It with Dr. Robert Califf

Someone last week published something that said the FDA has been decapitated and eviscerated at the same time. That's a very graphic way of saying it, but basically almost all the leadership that was there is gone. A large part of the workforce that holds the organization together is gone. All this means that if something effective and different isn't done, things are going to grind to a halt because the inerts have been taken out and the people with the institutional knowledge have been taken out.

Yes, I had had a long career at Duke, and every five years I got a new job within the institution, always trying to compare it with what was outside, and it just seemed like a great place for me. And then finally Peggy Hamburg came down and made a visit and told me she was about to retire after a six-year tenure, which is a pretty long stint for an FDA commissioner. There was thought that maybe I should be the next commissioner, but of course the problem is the president has to offer you the job. You can't just announce you're going to be in the job. But I was ready for something different. I came up during the Vietnam War, and my draft number was very high, so I did not serve, and I had never done government service. So I volunteered and went up as a civil servant, which lasted a year. And it was a great experience when the American people are your customers, and you know that, I mean, as you well know, it's a very inspiring mission that you have. Then things happened, and the president asked me to be commissioner.

But I'd say the main thing that you just can't really fathom until you're in the middle of it is the way the executive branch works. You kind of expect from everything you hear that interactions with Congress are going to be difficult, and you're dealing with typically people that are 30 years younger than you with these major decisions where the members of the House or Senate don't have time to know everything about everything. But the way the executive branch works is just as an example. The last year, as I was giving the various talks and lectures that commissioners do, I always made it a point of asking, do you know what OIRA is? And I swear, you know, these are like schools of public health and public policy. Almost no one knew what it was. Almost no one. And yet anything that you want to do, as you all know, that has to do with policy has to get through that lens, which is completely controlled by the White House.

And just for listeners, OIRA is the branch of OMB that manages the regulatory process, which would include regulations, but also some subregulatory guidance would also go through that, which is distinct from the budget side of OMB. It's one of the many reasons why I always bridle a little bit when people say the FDA didn't do this, the FDA didn't do that. Well, more than half the time, the FDA wanted to do it but couldn't do it because there were other considerations. Now, I want to be clear, this has nothing to do with approval of individual products like a drug or a device. That's historically been kept at the civil service level. Political interference is not allowed. Not that people don't try, but it's not allowed. I'm really talking about policies like one that's pertinent today, which is what do you do if food dies. It's not as simple as the FDA deciding what the answer is.

I came in in the middle of the pandemic, and so I came into an agency which was doing all of the routine work and dealing with the many issues. You remember the Delta and Omicron waves that left many, many people dead and disabled, with its own enormous tranche of work under tremendous pressure. And so I would say that agenda of focusing on medical product efficiency really took a second seat until we were well into the term, because there was only so much that people could do, and the workforce, as dedicated as it is, you can only work a certain number of hours in the day. But we did some things that were less focused on cancer per se, because the cancer center at FDA, which had come into being during my first administration, had really flourished. The cancer community was pretty happy with what it was doing. But we really had issues with rare diseases, where we had this amazing opportunity to treat diseases that were previously completely untreatable, often leading to death in childhood with no other options. So we really had to be creative, and we put together a hub for rare diseases to focus on coordination within the agency, but also coordination with patient groups, who are very important here, and working with the industry on the methods. What do you do when there are only 100 people in the world with a disease? You can't do your traditional clinical trials. So you have to develop alternative methods that involve Bayesian statistics and probabilities and things like that. So a lot of effort went into that part of it.

I get the impression, although I've not been in the seat, that in most areas in the US people don't want more regulation, they want less. And that certainly came up as a big issue during the last election and is playing out as we speak. But the regulated industries with FDA live and die based on FDA guidance. They want more guidance, not less. It's very hard to get people to understand that. This is really important. Nine out of 10 drugs which get into human clinical trials don't make it to market. And the reasons for that are: number one, you have an off-target toxicity that you couldn't predict; number two, you engage the biological target, but the benefits aren't clinical, aren't relevant — it just doesn't have the effect you expected; and number three would be you can't manufacture it in a reliable way to make it a viable product to distribute to the world where you have accountability for good manufacturing. And so what that means is, trying to rush drug approval, you'd better do that carefully, because most things don't work. And in fact, if you really just rushed it through, you'd end up causing a lot of harm, much more than the good that would be done.

Yeah. So first of all, I would emphasize it is a global leadership role, and it really just feels good when you're making the rounds as FDA commissioner that the whole world looks at the US as a source of new technologies, biomedical science, of discovery science, all the things that lead eventually to medical products that improve longevity and functionality and quality of life. But that is an infrastructure, which is a vast infrastructure that includes universities, the NIH and CDC, the many other federal agencies in HHS that deliver services that keep stability in the system, and of course a regulatory process that helps the industries not go off the rails. And it sort of gets back to why is it that people want more FDA guidance. And you know, of course it's just my opinion, but the part of the industry that says they're developing highly effective products, it's so hard to do that. If the standard drops, you'll have a bunch of bad stuff on the market, and it really undercuts the value of the things that actually work. So my position at the pinnacle of biomedical innovation as the FDA commissioner is on the shoulders of all the universities and biotech startups and other federal agencies that are involved.

I've just been amazed by how often FDA is couched as drugs, when devices are a huge part of American society and what the FDA does, and especially now with AI and algorithm-driven devices and all the imaging. It's just an amazing time for that. That is a very big part of what FDA does. But then the FDA does stand for food. It's at least 40% of the effort, although it's been very poorly funded by Congress relative to the medical product side. And you know, the primary missions there are, as written under the law, what I would call immediate safety, and by that I mean viruses and bacteria in the food, things that make you sick when you eat the food. But then you've got the much — well, I want to say more important, but equally important and vast arenas of nutrition, where FDA is responsible for food labeling, of chemical safety — the hot topic today, actually. Those areas have been so underfunded, it's been a skeleton crew at FDA working on them, but it's a big deal. Then I'd also mention the Center for Veterinary Medicine, very important and at the forefront of the H5N1 response, and responsible for animal drugs and devices, but also animal food. And you want to see worked-up Americans, have something go wrong with dog food. That was the biggest response in the history of the FDA from the public was when the dogs were getting renal failure due to contamination of dog food. And then of course tobacco was added just in Obama's first term. And this is a huge effort. We're seeing great progress there, but we still got 30 million people using combustible tobacco. And of course, vaping came into being, sort of started in my first term, really took off during Trump's first term and got out of control, and it's gradually coming under control now, with the question of what control of vaping is as a really hot societal topic. And then, you know, I want to mention cosmetics, because there had been work for 25 years to improve cosmetic regulation. You know, I love the quiz: how many cosmetics does the average woman use in America every day? The answer is 12, but the average man uses six. Wow. So, you know, you think about deodorant and shampoo and hairspray and all the things that we apply on our skin. And some of this stuff has real health risks, like formaldehyde in hair straighteners, predominantly used by people of color. It's a broad array of stuff.

It started before I came back with a really major role in Operation Warp Speed. So the development of the vaccine was a huge issue, dealing with the catastrophe we had with PPE, things that people needed that were not being made in the United States, and laboratory testing. How do you diagnose the disease? And there were some issues between FDA and CDC that I think we all agree on. And I'm not here to lay blame, but the testing rollout was too slow. Then the floodgates were opened and a bunch of bad tests got on the market, which gives us some reason to continue to work on trying to get the right balance when things happen where you don't have a test and it's a public health emergency. And then you have the whole array of biologics and antivirals that had to get evaluated first. Most of them didn't work. The ones that did needed to get an emergency use authorization. And of course, in the midst of all this, we had the crisis in public confidence. While all that was being done, the FDA still had to deal with the normal pace of all the other diseases and products that were being developed. A whole new way of doing clinical trials. What happens, like, you know, I think about the pulmonary hypertension community, people really sick, where we had tremendous new drugs being developed, but these people couldn't come to a clinic because if they got infected at all, they wouldn't make it. So they had to do all kinds of virtual clinical trials and had to be creative in how to deal with that.

Sure. Well, I'm celebrating the end of my third month of civilian life. Now, you know, the biggest thing that's happened is the massive firings that have happened in waves. You had the first wave like day one. There was an executive order about DEI, and no one really has all the information about this, but it looked like all the people that had DEI language in their job descriptions were laid off at that point. And then you had a wave of everyone who was a probationary employee. And as you know, in the federal government, that means within two years of being hired, you didn't get all your civil service protections until that two-year point. And so they could be fired without cause, and that also includes, by the way, people who got promotions within two years. So some of the best people who had done the best jobs also were laid off. And then the third wave: 3,500 people at FDA, and it was done in a brutal fashion. They were told to take their computers home. They would get a notice over the weekend as to whether they still had a job. The notice didn't come because everyone is required to report to work. People were coming to work at 5:00 a.m. They apparently sent the notices at 5:15 a.m., but most people had had their computer access shut off before then. So you had this mass of people showing up to work, many of whom couldn't get into work because their credentials were disabled. So you had one line of people going to work, and in very public view, another line of people who had been fired. I've run academic contracting organizations doing clinical research. I've been on the boards of biotech companies. I've been at big tech. I've been involved in a lot of reductions in force because you don't have money to pay people. You got to do that. But there's a humane way of doing this. That's not what happened here. It was like they turned a bunch of software engineers loose on human beings with no interface to make it a human experience. Many of these people only got 30 days' pay, no benefits afterwards. A lot of them have children in school, many of them debts, because many of these people have PhDs and had racked up some debt before they went into government service. So I spent a lot of my time over the three months trying to help people who were just left in the cold by this completely, at least in my view, unnecessary exercise.

I don't really know, but I can only go by what I've read, which is Project 2025, and the man who's the head of the Office of Management and Budget, he literally publicly said his goal was to make it so that civil servants felt sick to their stomachs at the thought of going to work in the morning. I have to say that seems to be the purpose, is to destroy the infrastructure, and that was my comment about FDA as we know it. I stand by that comment. It doesn't mean it's not possible to put something back together that could be better. And I think we've all got to try to contribute to that at some point. I'm widely promoting Humpty Dumpty as the analogy here that people should be using. I don't think that Humpty Dumpty has fallen all the way to the floor yet, but I'm relatively sure it's going to happen, and there will be more chaos. But then, I don't know about you, but everybody I know that's been in the federal government can think of a lot of things they wish were different that you just couldn't change. Maybe we can figure out how to do this better.