Change Makers: FDA Commissioner Dr Robert Califf Discusses the Challenges of Protecting Public Health

John Whyte, MD, MPH; Robert M. Califf, MD


May 31, 2023

WebMD Chief Medical Officer John Whyte, MD, MPH, speaks with FDA Commissioner Robert Califf, MD, about the vital role of the FDA in protecting public health and how it is responding to recent issues.

This transcript has been edited for clarity.

John Whyte, MD, MPH: The US Food and Drug Administration (FDA) regulates a wide variety of products beyond just food and drugs, including biologics, tobacco, veterinary products, medical devices, and even cosmetics. Their broad jurisdiction represents about 20 cents of every dollar in our economy, so it can have a big impact on our lives. I recently sat down with the head of the FDA, Commissioner Dr Robert Califf. We discussed the threat of misinformation and what needs to be done to restore our trust in science. I asked him about drug shortages and whether the situation is getting better or worse. We also reviewed what the FDA is thinking as it relates to potential regulation of marijuana and cannabis. With all the recent news around medications for weight loss, I pointedly asked him about factors that play a role in obesity: Is it mostly biologic or lifestyle? He also shares his opinions on whether artificial intelligence (AI) will soon be used in the drug review process. It was a far-reaching interview, and I'm happy to share it with you.

Whyte: Dr Califf, thanks for joining me.

Robert M. Califf, MD: Great to be here.

Whyte: You've been quoted as saying that misinformation is a leading cause of death. You revised it a bit to say that it's a leading cause of preventable death? What do you mean by that?

Califf: What I really mean by that is that if you look at why people are dying today at an earlier age, rather than just aging as a phenomenon, it's been COVID, where we have vaccines that work and antivirals that work, and they're free. Chronic diseases are on the rise. Stroke and heart attack are on the rise now, as are drug overdose, consequences of depression, gun violence — those are the big things. They're all related to people's processing of information, what they come to believe based on the ecosystem of information that they exist in. And while you could say, "Well, if it's stroke, it's because you have a blood clot or some other phenomenon"; but you could also say, "Blood pressure wasn't controlled." We have a bunch of generic drugs that work. Why aren't people getting the right information?

Whyte: So what's the fix to it?

Califf: That's a great question. A real advantage of being an FDA commissioner is that people usually return my calls. I've talked to all the experts I can find. I think we're learning more and more about misinformation — how it works, how bad information is transmitted, how much more quickly it moves around the internet. But the formula for changing it, for fixing it… I haven't found anyone yet who believes that they have the right answer. We have a number of things that everyone agrees should be done. We need to restore faith in our key institutions where, on average, there will be more reliable, truthful information. That's a really important thing that needs to be done. We need to anticipate when misinformation might [arise] — something very important to the FDA — or previse it, so to speak. And then if misinformation is promulgated, we need to react quickly.

Whyte: When it comes to misinformation, trust, as you alluded to, plays a key role. You talked about restoring trust. We know there's been decreased interest of government over the past few years. But let's play out the scenario that the public often hears. They hear about a drug that's been approved by the FDA under an expedited pathway or breakthrough designation. And that gives the impression that the public needs this therapy now. Then it goes to CMS (Centers for Medicare & Medicaid Services), a sister agency. The same department often looks at the same data and then says, "Oh, wait, we're not going to pay for this." Yet we just said it's so important that it has to be an expedited pathway. Or they say, "We're only going to do it as part of a clinical trial," for which there were just clinical trials done, or "We're going to have a more limited population." So, what does that say to the public? Who should they trust?

Califf: Well, John, a couple of things about that. First of all, they don't often do that. In fact, it's been quite rare. They're only a couple of—

Whyte: Recently, though, it happened a few times, as you know, in some high-profile—

Califf: Just a couple of times. Often the press seizes on it. There might be 100 things where there's no issue and then there are two where there is an issue. What gets all the attention? The two where there is an issue, and so we have to—

Whyte: Because there's an issue and people are concerned about it.

Califf: Well, it's really important to point out that the FDA has a statutory obligation to look at safety and effectiveness for an intended use. Congress passed laws creating these accelerated pathways, because the public spoke and Congress said that Americans, on average, are willing to take more risk — because, you know, "it's reasonably likely" is the criteria for an accelerated approval, not—

Whyte: Often for diseases for which we don't already have good therapies. So there is a burden of disease and need, but can you see the perspective of the public when they're excited that FDA has approved something, maybe for a rare disease, maybe for a disease with unmet need, and then it's not going to be paid for? And realistically, because these are new drugs, there's a big cost and people can't afford that. So even if it's only a few cases over years, those are still important cases for people. And that decreases trust, because they can't understand how the government — and we know it's not one entity — can come to different conclusions, often with the same data.

Califf: The way I've looked at it — I mean, again, remember, we need to do a better job of explaining it, because CMS has different criteria than FDA. CMS' criteria—

Whyte: Medically necessary and reasonable.

Califf: Yeah.

Whyte: But the public doesn't understand those distinctions.

Califf: So we have to keep talking about it, and people like you need to help us do that. But for the reasons that I just gave, we have limited venues of expression. But the other part of it is, you might ask the question: Why, historically in America, have we not had a tight connection between FDA and CMS? And we could have a long discussion about why that might be the case.

Whyte: Are you fixing that?

Califf: Well, "fixing it" would be an overstatement. But the way I look at it, it's like a relay race: We run a lap; we don't want to drop the baton in the dark and have CMS try to pick it up and run because they are using a different set of criteria to make their decisions. But we need to hand off that baton much more smoothly, and work with companies as they develop their products to develop more of the information that CMS needs to make the decision that they need to make.

Whyte: What information do they need that's different from looking at whether a drug is improving outcomes for people?

Califf: Well, remember that accelerated approvals are not based on outcomes; they're based on biomarkers, for the most part. There might be an intermediate outcome.

Whyte: A surrogate.

Califf: And by a requirement in those approvals, there has to be a follow-on trial to prove it. So CMS increasingly is going to need to look at, what's the magnitude of benefit? And how does it compare to other options that people have? At the end of phase 3, there's a lot that we can do to move into the era of pragmatic clinical trials using electronic health records — for example, to look at large populations — remembering that FDA is typically looking at an accelerated approval in a small patient population, carefully selected, not at the broader population that might be treated. Alzheimer's is a case that has been the most talked about; that's a lot of people. And ever since being an intern on the Duke coronary care unit, we would develop a treatment, but it was often in postmarket that we would clarify exactly who gets the benefit. What are the subpopulations who are at risk? That's the kind of information that would really help CMS and the commercial payers who also have to pay for it. After all, we're spending $4.3 trillion a year on healthcare and we have worse outcomes than any other high-income country. So we're paying for something that's not working here.

Whyte: I want to turn to food safety. I ran into you in Boston, when you were speaking at a conference, and said I wanted to talk about what we're doing in terms of food safety. There have been issues, as you know, in terms of food recalls. Just a pointed statistic is a 700% increase in recalls in 2022 compared with 2021. We all know about the infant formula shortage. Most people don't know, despite the fact that "food" is in the moniker of the US Food and Drug Administration, that it has a role in the safety of our food supply. So I wanted to ask you: What is FDA doing to make sure that our food supply is safe? And how is that different from the Department of Agriculture?

Califf: There's sort of a division. The FDA is responsible for about 80% of the food supply in terms of safety. Tom Vilsack, who's the Secretary of Agriculture, told me a simple way to remember it is barnyard animals. The Department of Agriculture has responsibility for barnyard animals and, interestingly, catfish; we're responsible for all the other fish. But one thing, just to clarify: The Economist did a global ranking of food safety, and the United States was tied for first with Denmark and Canada. We've got a lot of improvements we can make. When I went through the nomination process this time, I got a lot of calls saying, "You've got to pay attention to food. It's been underserved." The number of people on the food side of the FDA is the same as it was 20 years ago. Remember that the medical product side has been boosted by user fees from the industry; those don't exist on the food side. And so it's been really undernourished, I guess you'd say, sort of as a pun. We do inspections, we do a lot of analyses, we work with the CDC…

Whyte: You're doing some restructuring, though, and making some changes in terms of how the processes work.

Califf: That's right. Because of the fact that there were not user fees and the food industry is enormous with all of these different parts and components, the food side of the FDA had sort of grown organically into a lot of different components. So we're going to put it all together under a single program, the human food system. We are going to bring together the inspectorates and the subject-matter experts in food into a much tighter, information-driven organization. Altogether, there are something like 600,000 entities that we're responsible for. But, having been at FDA, I'm sure you also know that the states have a lot of responsibility here too. And we work closely with the states for retail entities; the states do all of those inspections, but we set the standards and have many contracts and relationships with the states.

Whyte: I want to talk about cannabis. You've stated that CBD products need a different regulatory pathway. They're not a food, they're not a drug. I want to take a step back. If you could help educate folks, what's the difference between marijuana, cannabis, and CBD products? And what exactly is the FDA going to regulate?

Califf: It's complicated. There are over 20 derivatives of the cannabis plant that are different chemicals that do different things. Congress stepped in and by law mandated that if the concentration of the active component of marijuana that we all think about is below a certain level, then it's called hemp, and that's not regulated by FDA. And it's available in a lot of different forms. CBD is a different form, and it's being sold, but there's no legal regulation of CBD at this point. A lot of people thought we should regulate it as either a dietary supplement or a food. We spent a couple of years looking carefully at this. And there are safety issues that make it so that it really doesn't fit into either of those categories. So we think that CBD should be regulated through a new pathway. We're currently working with the executive branch and Congress to define that. It's up to Congress to write a law, as you know, for us to be able to regulate it, so I can't say what we're going to do.

Whyte: But as it stands now, it's not regulated.

Califf: That's right. And then recreational marijuana is a whole different issue, because a number of states have… And medical marijuana — there is one drug which is a derivative of marijuana that's been through the whole process of drug development. But for the most part, people are using marijuana for medical purposes, buying it at stores since it's legal in many states. That's a whole other issue. And then we have new components of marijuana now being marketed, some that have big effects and significant dangers, that are going to need to be regulated.

Whyte: Let's turn to drug shortages. We've seen them typically in antimicrobials, sometimes chemotherapeutic agents, and we've heard from a lot of viewers who have gotten caught up in terms of the shortages, in terms of what the quotas are from DEA (Drug Enforcement Administration). So, what can you do to assure patients today who are prescribed a prescription for ADHD about their ability to get that prescription fulfilled?

Califf: Let's back up a little bit, because when we talk about drug shortages, what's in the news now has more to do with generic drugs than Adderall. And if we think about the pharmaceutical industry, people tend to think of it as one industry; but really, we have an innovator industry, which develops new drugs, and they have a patent life. There's a lot of talk about the profits that are made in doing that and the risk involved in development. Then you have the generic industry, which is 90% of prescriptions today, where it's all based on the lowest price. And this has caused a big problem, where a number of generic drugs are in shortage at any given time, because there's not enough profit for a company to say they want to go into the business of making that drug. Adderall is a very special case because it's—

Whyte: A controlled substance whose quota is controlled by the DEA.

Califf: That's right.

Whyte: A different agency.

Califf: And in addition to that, we have two other factors that have come into play. There's been a tremendous increase in prescribing, some of it related to virtual prescribing. That's caused a number of problems. Some firms apparently have put prescribers on bonuses for prescribing more, and so there's been this big growth in prescriptions. So if you have DEA setting a quota and prescriptions go up, it's understandable that you'd have a shortage. But I think there's also a professional responsibility here. And if you can tell me, among people who may have some degree of attention-deficit disorder, who needs a prescription and who doesn't, I would love to hear what the answer to that is. We really need much better evidence and professional standards here.

Whyte: Some people will argue, and they've said it on Medscape as well, that the clinical community doesn't take conditions like ADHD in adults as seriously as they do for children. And in some ways that creates an inaction. So you're right. We've had some bad apples who have overprescribed, but the majority of the patients who have a legitimate prescription, a legitimate diagnosis, are getting frustrated that they don't have access to medication. And then they're suffering from executive dysfunction in a way that then they have to do all these things to try to get it, which complicates their lives. That's what we've heard from a lot of people saying, "Well, what is the FDA doing about that?" What can they do about it, recognizing they don't have all the authority to do everything?

Califf: It's very frustrating and painful for us. And right now there's a shortage of fundamental cancer drugs. We wish that we could fix all these things, but we don't make the medicines and we can't tell someone that they must make medicines. There are some things that are out of our control. But what we do is work with all the companies involved. Very often a shortage occurs because one company has a quality problem with their manufacturing.

Whyte: Often abroad, with issues.

Califf: So we work on all those things as much as we can. I also say that if only the people that needed these drugs got them, there probably wouldn't be a shortage. There's a large amount of use which is on the margins. And this is why I say we need better clinical standards. But having said all that, we're working with the DEA frequently as they try to work out what the quotas are. And we're working with the companies to optimize production. So that shortage should go away. It's better now than it was a few months ago, and it's going to continue to get better.

Whyte: Let's talk about what everyone's talking about: AI, digital tools, ChatGPT. Dr Jeff Shuren, who runs the Center for Devices and Radiological Health, recently said at an FDLI (Food and Drug Law Institute) meeting as it relates to these tools, "Be afraid; be very afraid." What should the public be afraid about in terms of these tools, and do you share that perspective?

Califf: Well, first of all, just to disclose to those who may be listening, between my two FDA stints I spent part of my time working at Alphabet, the parent company of Google.

Whyte: Yes, that's why I know you know about this. That's why I'm interested in your perspective.

Califf: I have spent a lot of time thinking about this. I would say this is like a lot of the great innovations for humankind: It can be used for tremendous good or it can be used for tremendous harm. I think Jeff's statement about being afraid is that we'd better be paying attention to the potential for harm, trying to do what we can to move the technology in the direction that it does good.

Whyte: That's a negative perspective. You could have the other perspective as well, that here we have this opportunity.

Califf: Oh, yeah.

Whyte: We have to have guardrails. But we don't have to be fearful.

Califf: I think it's always good to have in the back of your mind that harm can be done. I've lived my whole career, as you know, working with people developing new treatments. And if you're excited about the treatment, you may not see the downside. It's just in my nature to think about the potential downside, but I'm very excited about the upside. After 35 years as a clinician, the idea that maybe I wouldn't have to copy and paste all of my notes, that I could edit a large language model–derived note... I saw in my work on Googles and, verily, components that cultivate the pruning of information to correct inaccuracies in the record, that that's the kind of thing that AI can do very well. So it should make our lives easier. But it also can reach into knowledge bases that are just very hard for us to reach into in our cognitive thinking — the difference between thinking on a search to find what you need, and saying, go find what you can about problem X that might be relevant to this patient. That's going to be a big difference, and it's going to get better and better. So I'm very excited about that.

Whyte: Now, drug company sponsors often are using AI to look for potential new compounds, new indications for compounds. Do you foresee, say, in the next few years, that AI will be used as part of the drug review process?

Califf: The short answer is yes.

Whyte: What's the long answer?

Califf: AI is in more of what we do every day than people realize — that, I could see in my previous job. I mean, if you are driving from point A to point B, you're using algorithms that are anticipating what your preferences are, and also keeping track of incoming information about traffic all at the same time. In a very same way, with biology, it is being used increasingly. I had a chance to see AlphaFold as it developed, and this is really making a difference in drug discovery. But there are also clinical trials. How do you optimize the conduct of clinical trials? And in the reviews — you've been there — the amount of rote pulling forward of all material is going to be much easier.

Whyte: In the old days, it was truckloads of paper.

Califf: And so now in a review, I could really edit things in the future and not have to go back and redo.

Whyte: So you wouldn't be surprised if we see AI tools as part of drug review.

Califf: Not at all; I wouldn't be at all surprised.

Whyte: As many people know, you're a cardiologist and spent much of your professional career at Duke. We were just talking about it. That's the place for the Duke Center for Living, one of the first places that focused on behavioral interventions. They even have a section on the website called behavioral cardiology. So I have to ask you, Dr Califf: Is obesity primarily a biological disease?

Califf: I am very excited about this. And again, in full disclosure: Back in my old academic life, when the GLP-1 agonist first came along, I got involved with Professor Rury Holman at Oxford and we were co-PIs on what was really the first big cardiovascular outcome trial with a GLP-1.

Whyte: Used for diabetes, not for obesity.

Califf: But you could see the weight loss. At first, we thought, well, gee, this is just like nausea causing it. But it turns out that the integration of the circuits between the gut and the brain is an amazing thing. And so you could say that it is an interaction of biology and behavior at the same time, but much more biologically driven than we thought.

Whyte: But some people are out there saying it's mostly biologic.

Califf: I don't know how to really interpret that, because our biology hasn't changed that much from generation to generation, but we're more obese now than we were. So that's got to be some behavioral… You know, when rural people are exercising less than urban people, I don't know how you can say it's just biologic. But what we do know is that you can make it better through manipulation of these circuits. And it seems like every trial that's coming in is looking better and better. I always have to say that we need the big trial data for people with obesity without diabetes. And those trials are underway and will soon be coming.

Whyte: Will there be phase 4 postmarket surveillance? The field of obesity-related drugs is littered with some bad outcomes when you're looking 5, 10 years later — the impact on the heart, the impact on some of the organs. Will there be more requirements for postmarket studies?

Califf: There will be a lot of postmarket studies because this is such a big issue for society. And of course we can do the postmarket data a lot better than we could before now with electronic records, etc.

Whyte: Do you expect there to be more enforcement actions against those companies that perhaps are promoting weight loss therapies that aren't indicated for it or going beyond full discussion of risks and benefits? In the past, the number of warning letters or enforcement actions has decreased. Do you expect there perhaps to be a difference as we're starting to see greater attention in terms of obesity?

Califf: You bring up a really interesting area that we are all going to need to do more work on. As you know, we regulate the pharmaceutical companies; we don't regulate doctors, we don't regulate the practice of medicine. And this is actually related to the Adderall issue that we were describing. If you're a doctor and you're advertising that you're prescribing Adderall and how great it is, or a weight loss drug, that's a very ambiguous area for FDA to get into. And yet we know that there are examples of harm being done in that regard. We also have similar issues with stem cell therapy. So this is a complex and difficult area, and I can't say I'm happy with where we are right now.

Whyte: What's the remedy?

Califf: I wish I knew exactly what the remedy is. One part of the remedy has to be better behavior by the medical profession.

Whyte: You're a professor; you've graded a lot of students and residents over the years. What grade would you give the FDA since you've become commissioner?

Califf: I learned in my very first hearing not to give grades about the place that I work, so I won't give a grade. What I'd say is that we are coming out of the COVID pandemic. It was an amazingly stressful time. We had all the issues that were compounded in the FDA from just routine business, plus the pandemic. And as we've been lifting the hood, we are making a lot of changes in the FDA, all at one time. So it's a bit stressful. But show me anyone who argues that the US is not number one in innovation in medical products — drugs, devices, biologics. The Economist ranked us as number one, tied with Canada and Denmark, in food safety.

Whyte: We're at a bad place in terms of infant mortality; we're at a bad place in terms of life expectancy; we still see increases in cardiovascular deaths. So we also still have a lot of these other challenges.

Califf: When I'm wearing my FDA hat, I say, we're doing our part. Where we're failing as a country is in the implementation. We're inventing the drugs, devices, and biologics that the world is using — and maybe using more effectively and more in the right people than we are. We also have to face the fact that a lot of our issues with premature mortality are misinformation related. Maybe there's something the FDA can do about that, but we need everyone on board. The whole ecosystem needs to get more active. But I do want to resonate with what you said, that right now we have a 5-year-shorter life expectancy than the average of other high-income countries, and we're in the negative direction; this is not getting better.

Whyte: You referenced the pandemic. We all can agree that at some point in time, there's going to be another pandemic. Everyone wants to know: What would the FDA do differently for the next pandemic?

Califf: Of course, I wasn't here when COVID started. I was watching it from San Francisco, and like many people, involved in trying to help. I feel like the FDA did a great job in its role in the pandemic. The vaccines are amazing. Who would have thought vaccines could be developed? The FDA had a big role in that. The antivirals made a huge difference. Food is an area — I shouldn't say FDA; all of government — you remember in the early days of the pandemic when the grocery stores didn't have anything on the shelves? A lot of people put work into keeping the food supply going and dealing with a lot of shortages that were underway, and working with companies to make that work out. In the diagnostic arena, we ended up with a bunch of tests. It didn't start out so smooth. Between FDA, CDC (Centers for Disease Control and Prevention), and NIH (National Institutes of Health) now—

Whyte: A course correction.

Califf: Now we're ready to go. We know that mpox came more quickly. Still a few hiccups. So I feel like we've got the playbook. I'm very concerned that Congress is not allocating money to be ready for the next pandemic. It's something we should all be worried about.

Whyte: What are you most excited about in your role here this time around?

Califf: Oh, it's just amazing to see the progress in science and medicine. But I'm most excited about the chance to change public health. So your statement about public health not necessarily going in the right direction now — I like problems. If something's working well, I don't want to work with it. I want to take on problems. We've got big problems with our public health now, and the FDA is only one player. But we live in an HHS (Health and Human Services) ecosystem that includes CDC and NIH and CMS. There's a lot that we can do. And I also love working with the private sector. I mean, American ingenuity is really important. We've got to make it work better. So it's an exciting time, but there's a lot of work to do.

Whyte: Dr Califf, thank you.

Califf: It's a pleasure. Thank you.

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