Dr Robert Califf - Episode 9 - Regulatory Voices

Good to be here.

Well, first of all, I think it's a real privilege to be in the leadership position at a place like FDA. It has so much influence over the day-to-day lives of people, and that's what I think makes it challenging. Also, in academia there's a lot of theory. In the practice of medicine, you do make a lot of decisions, particularly in my specialty of cardiology, that have serious implications for individuals. But at the FDA, decisions that are made can affect the entire country, so there's a lot at stake, and that leads to a lot of interest and a lot of pressure. So, at least given the way the FDA has normally functioned, from my perspective, the most important part of the job is maintaining equilibrium across all the interests that are involved and clearing the way for civil servants to do their jobs without interference or undue influence by money and politics. And then at the same time, as a political appointee, you are in the world of politics and money as part of your job.

As a cardiologist, I've thought about the ideal role of FDA commissioner sort of like the AV node in the heart. You have a lot of impulses generated up in the atria, but only the AV node governs what gets through to the functioning main muscle of the heart. And I think that's sort of the way the FDA commissioner should function, but it has its stresses and people go after you every day.

I think they're both essential. Without standard operating approaches that are codified, it's very hard to know how to navigate such complex things as developing and producing medical products or growing and selling food to the world. These are really complicated endeavors. So you need a way of approaching it that people can understand and depend upon. But also because every situation is a bit different, so you have a way of doing things but the specifics are different. You need a culture which is operating well at this interface that you described in your introduction. You have people that aren't used necessarily to working together with the COVID mission inside the FDA. But I'd say over time the culture has really fostered pretty deep understanding between, let's say, scientists, clinicians, public health people, lawyers. As a cardiologist in practice, when I talked to lawyers, it was usually not a good thing. But there are a lot of lawyers at FDA who are outstanding people who understand public health and are really working to pave the way for better outcomes in the public.

Well, it's important just to keep in mind that I initially went to FDA as a civil servant. Usually a commissioner comes from outside having been appointed through a political process. But what happened with me is I went up as a deputy commissioner for medical products and tobacco and spent a year as a civil servant. So by the time I became commissioner, I was sort of ingrained into the culture, and I would say far and away it wasn't a surprise, but the intensity of it is hard to appreciate until you're there. The public health mission is an enormous driving force. You feel it every day when you work at FDA, and it's front of mind for everyone who works there. Now, of course, like any large organization, the second time around I think we peaked out at about 18,000 employees. Like any large organization, you've got to have some people who aren't with the mission or go astray or have personal problems. But as far as I know, I've worked in every sector of biomedicine and healthcare. I've been a clinician, a health system leader, an academic leader, a researcher. I've worked in tech, biotech, the device industry, in pharma, and I even, while I worked at Alphabet, helped start an insurance company. And I can't say that I've come across a more dedicated workforce than the people who work at FDA. It's just very driven by the mission.

Yeah, the last couple of days I've been thinking about this because I went to the DIA meeting, and I'm a fellow at the DIA, but most years I haven't gone to the meeting because I've had other conflicts. But at this meeting, I bet I ran into a hundred people who either are still working at FDA or worked at FDA but were DOEd or left because of what they thought was a toxic environment. And I'd say the majority would go back.

Well, you said a mouthful there in that sentence, so I'll try to pull it apart a a little bit. The FDA's function is codified into law in the Food, Drug, and Cosmetic Act, and then there are rules and guidances that sort of lay out what the rules of the game are. The FDA doesn't make the rules. The rules are made by either Congress or the executive branch when a federal rule is put into effect. But like a referee, the FDA interprets the rules and applies those rules to practice. And so the way that's done, I think, needs to be consistent. But it's also important to remember that the law is different for different commodities. So I suspect that your audience is mostly drug and device people, but food is a very large part of the FDA, and tobacco regulations are also different, as are cosmetic regulations. But the general method of evaluating risk and benefit and using evidence-driven policy, that needs to be consistent. And then within an area, I do think there's tremendous importance to being consistent in the way you do things and the way you approach problems, even within drugs and devices for different diseases. There are really big differences. For example, rare diseases with accelerated approvals, those are very different ways to approach clinical development than common diseases where there are already effective treatments, and the specifics of what the endpoints are and all that can be obviously quite different. I think what we really want to avoid is arbitrary changes in the middle of development programs. But even having said that, the science does change. So given that a development program takes a decade or more from the time you're developing the pre-clinical evidence, there will be times when, let's say, a competing product comes on the market that changes the whole field, and now the goalpost actually does need to move. But what we don't want to do is to move the goalpost for arbitrary reasons that are not justified. And I've got to say I'm scratching my head right now over, I won't go into all the details, but there's a memo a couple of weeks ago from Mike Davis, who's the acting head of CDER, about the fact that he reversed the decision by his predecessor, basically because his predecessor had overruled the staff twice but left no documentation of why she did it. And I think that's what we want to avoid. It made it easy for him to overturn it because there's no argument to be had. But if you're going to change what's being done and you're a regulator, you really need to have an administrative record that puts the argument forward for public discussion.

Well, as you might imagine, I think it's really serious. I had met almost all of those people my first term, and then I came back for the second term in the middle of the Omicron wave, and it was very reassuring to have highly competent and experienced people on board because the agency at that point was having to do all the work related to COVID and all of its normal work. It was really quite a stress. And of course, they're only a small fraction of the experienced people that have left. And many of the people below them were DOEd, as the statement goes, which my interpretation of that is you had a bunch of young people who knew nothing about what they were doing who came in and just arbitrarily fired people for no reason other than sometimes their job description included a word. It's just horrible. And so, does that affect drugs or devices that have already gotten to the end of the road and the final decision needs to be made? I would say only in the cases like the one I mentioned, where for whatever reason, political or ideological, one of the new leaders with no experience really just sort of arbitrarily changes course. But for the most part, not a big effect on that part. What people underestimate is that the vast majority of work at the FDA is dealing with the 90-plus percent of products that never make it to market. Of course, because they enter human studies in a development program where almost 100 percent of the time, the first time you do something to a human being with a new product, things you didn't expect happen. And it's that knowledge and wisdom of having seen a lot across multiple products and product types that's so valuable to help steer industry towards development decisions that lead to the best outcome. And so we'll only know the full effects of this a decade from now. And I hope that we're already beginning to see a stabilization and a reversal of some of these effects, but the FDA lost a bunch of national treasures, and the people that you mentioned are among them.

Well, I think the most important thing is that experience of having seen what happens when you make a decision, the sense of what the next step needs to be, deciphering what's going on on the other side of the fence. I wish all companies were fully transparent and above board, but they're not. And so there is a bit of a regulatory game that goes on where people may not be revealing what would really help make the best decisions, often for complex reasons that have to do with personalities within companies or companies dependent on investors and how those relationships work. And you mentioned AI. I think much like clinical medicine, I think AI will really be able to help sort of fill in things. And so the interaction between the knowledge base that will come through effective use of AI and the human judgment that's needed, that's going to be a really fascinating area to watch. But at least as of right now, AI is not there yet. It's changing quickly, it's getting there, but at least for now, it's really that human judgment part which you can't make up. You have to, like all things in life, have some errors and failures. And it is also a hierarchical system. So you mentioned those leaders at the top, the Richard Pazdurs of the world, much like, I don't know, this may not resonate with people who haven't been a doctor, but when you're an intern, you hope there's a senior resident and an attending physician who's watching over you and giving you the leeway to make decisions, but knowing when to step in when the right decisions are not being made. And that's a big part of the way the FDA functions.

It's critical, and we talk about reviewers, but it's really the whole review team, which includes pharmacokinetic modelers and people who know about manufacturing, and all those components that have to be put together. And we shouldn't forget the inspectors, the investigators at FDA. I mean, it's a big deal to walk into a sophisticated manufacturing plant and try to figure out what the heck is going on. And so the learning over time and the supervision of new people is so important there.

Well, it already has been the case. The FDA hasn't been able to do everything society expects of it. One of the challenges of being commissioner is that you're looking out over the entire agency. You have a certain number of lawyers, you have a certain number of investigators who can do inspections, and you have an overwhelming number of issues that need to be dealt with. The part of the FDA that's been most effectively staffed has been the medical product side because of the user fees, and that more runs like a business. I mean, time tracking goes on. The time and effort taken to accomplish a job in pre-market discussions and evaluation is handled through metrics. So that's been a lot better. But now that's jeopardized also because the workforce is down. And while AI can help, it can't make up for the human effort that's needed. One of the things that was most, I guess this was a surprise, you asked about surprises. I helped with two sets of user fees, and both times the more mature parts of the industries, remember there are multiple user fees, but the drug and device user fees and the generic user fees, the biggest issue the industry wanted was more meetings. It wasn't faster timelines. Of course, everybody wants faster timelines if you can get them, but experienced people recognize that the time from an application to decision by FDA is a tiny fraction of the time it takes to go through the full development program, and they want a lot of meetings and there's a limited number of people. Those meetings, maybe we'll have meetings of industry AI agents with FDA AI agents, but we're not there now. And I actually don't think that's going to cut the mustard either.

Well, what I'll tell you is by the time I became commissioner, I was so old, probably not very mutable in terms of my general attitude and views about leadership. And people have different styles, but mine is to support the people around me, always assuming that the people around me are smarter than I am, particularly about the topic that they're discussing. But as a leader, and I've led different organizations, as a leader you have a view of all the components that the experts in an area may not see how what they're doing affects or is affected by these other areas. But I guess a couple of things just stand out as having an impact on how you think about the whole thing. Jobs like this in public service are accompanied by physical threats against you and your family. That brings it home that you're having an impact on people, and sometimes in ways that they don't appreciate. And then you have to put up with politicians. I had a fun day yesterday up at a place in rural America which is trying to develop new approaches to congenital heart disease. Our daughter has congenital heart disease. She's 48 years old now and had a great outcome from a huge operation when she was an infant, and I was an intern. So that's part of what I'm working on in older age. But we were talking about the impact of politicians on all this. And I think the point is you may think you're a great leader when you're at the FDA, but to most of the politicians, you're just a representative object of an institution. And so you'll get attacked by people who will say, 'Oh, it's nothing personal when you're assigned,' but they're attacking you on national television or putting out press releases about you. It was personal. And you have to have your inner compass be strong to not take the bait and do stupid things when you're in that situation. So those are the kind of things that are a factor.

I'm very concerned about where all this is headed. And I see health and healthcare as one of the biggest topic areas in what you might call the information or the misinformation ecosystem. And I think within that, the FDA is in a central role. And what I'd say is, in general, we're going through this amazing change in the way we interact with information and the world. It starts with the internet and then goes to social media, and now it's evolving into the AI-driven internet and social media. And we don't know what to do with it because we've gone from, not that long ago, living in a small personal ecosystem with people that we know, and maybe looking at a national news program that everybody looked at the same thing, reading newspapers and magazines. Now we have a 24/7 assault on our senses by the internet. And for someone like me, it's amazing because I love to soak up information and I can do that. But also, if you look at all the information on the internet, there's only a small part of it which is actual fact. The majority of it is either somebody's opinion or frank misinformation. And health is one of the most important areas there because most of what affects how long we live and how functional we are is not what doctors do, it's what we do in everyday life. It's whether we eat well and exercise and don't use addictive substances. And then the things that doctors do, the most important parts are actually now pretty much in the generic world, controlling blood pressure and cholesterol, mental health interactions. And soon even obesity and diabetes are going to be genericized and available at a very low cost. But we're assaulted by people selling other things that aren't effective or may even be harmful on the internet. So it's a really serious situation, and I think it's a significant part of why the US has experienced a stagnation in life expectancy, because we are, as Americans, we're the main targets of people purveying misinformation, often trying to sell us things on the internet.