After serving as commissioner of the US Food and Drug Administration (FDA) under President Obama, Robert M. Califf, MD, recently returned to the role, overseeing a critical federal agency that regulates food, drugs, therapeutics, and medical devices in the US. In a wide-ranging discussion with JAMA Deputy Editor Gregory Curfman, MD, Califf discusses COVID-19 vaccine modifications, the FDA’s approach to evaluating evidence, and efforts to combat health misinformation. Recorded April 26, 2022.
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Dr. Curfman: Hi, my name is Dr. Gregory Curfman, and I'm a Deputy Editor of JAMA. I have the privilege today of speaking with Dr. Robert Califf, who is now for the second time commissioner of the US Food and Drug Administration.
Prior to assuming this important role in our nation's government, Dr. Califf was head of medical strategy and senior advisor at Alphabet Inc.
He is an internationally recognized authority in cardiovascular medicine and has served as Professor of Medicine and Vice Chancellor for Clinical and Translational Medicine at Duke University. Thank you very much for joining us, Dr. Califf.
Dr. Califf: It's great to be with you.
Dr. Curfman: Now, Dr. Califf, as I mentioned, you are now serving your second term as Commissioner of the FDA. You first served in the Obama administration from February 2016 to January 2017. And now five years later in the Biden administration. And I'd like to begin by asking you, why did you decide that you wanted to serve in this critically important role for a second time?
Dr. Califf: You can imagine a number of phone calls and messages from friends asking that very question, why on earth would you want to come back? And I really had not planned on coming back, but when the call came, I had a lot of unfinished business from the first time around.
I think there's nothing more important than national service at this critical time in our nation's history. And although I am 70 years old, I thought I'd be on the front porch in a rocking chair at this point in my life.
I'm thinking about my kids and grandkids and things that need to be done that I'm highly motivated through national service to work on. So I'm glad to be back with the FDA team again.
Dr. Curfman: As you look back on your first experience, do you plan to do things differently this time or approach the job in any different ways?
Dr. Califf: Well, I think this time around, I'm a little more knowledgeable about how things work in Washington and how to get things done. I'm much more cognizant of the role that interpersonal relationships, for example, with Congress play.
And I'm embolden in I think enhancing the mission that I really had in 2016, which is developing the infrastructure at FDA. But I think I can do it with a lot more intensity now, sort of have a good feeling for what's in play and what might work.
I mean, after all, the FDA is an amazing decision-making machine full of talented people that makes hundreds of decisions every day, about 20% to 25% of our economy, but it needs an upgrade in technology and data systems in order to function at it’s peak.
Dr. Curfman: That's most interesting. And we're going to be talking about some of the specific priorities that you're going to be pursuing. But I wonder just to get us started, if you could list just briefly a few of your top immediate priorities for the agency.
Dr. Califf: As I've thought about priorities, I have divided them into what I agree you should term immediate. That is they need to be acted on right away. And some longer term issues that I think are going to be critical as we look at the life that my grandkids are going to look forward to.
So right at the top, no surprise to anyone, is a pandemic. We still have a lot of work to do there. We're dealing with vaccines. A lot of hot vaccine topics this week. But we also have therapeutics, where we've made tremendous advances, but not optimally utilized in the country.
And we can't forget testing, which has been a bit of a conundrum, I think, for a lot of people to figure out how to use testing. But we've come a long way. Then we got the opioid or overdose crisis. Over 100,000 Americans died in the last 12 months from overdose.
And we're seeing a huge increase now in chemistry factories, essentially, that are making very high-dose fentanyl and methamphetamine and sending them by the mail to unsuspecting people who think they may be getting a more benign drug when they're ordering it through the mail.
So I think we're in for more trouble ahead and a lot of work to do in this regard. And then tobacco. And there'll be a lot of interesting developments in the tobacco front over the next few months.
We've made a lot of progress since the FDA was given the authority to regulate tobacco just at the beginning of the Obama administration. We now have an infrastructure, we have some federal rules and we're moving along. We can talk at your wishes about the longer term. Those are the top three immediate priorities.
Dr. Curfman: Of course, I'd like to move on now to COVID-19, a very, very high priority. And you mentioned vaccines. And on April 6th, there was a meeting of the Vaccines and Related Biological Products Advisory Committee to discuss the pandemic going forward and particularly potential changes in strain composition and how to best modify vaccines to prepare for possible further surges.
And I listened very carefully to that advisory committee meeting and was fascinated by the discussion. And I wonder if you might comment on what the FDA took away from that committee meeting and how the agency sees vaccine strategy evolving.
Dr. Califf: Well, Dr. Curfman, I think you had the full experience. And as a recovering academic, I regret that I couldn't listen to the whole meeting because I know it was a fast of knowledge and reviewed really the whole picture.
And I'd make a couple of points about what we took away from it. First, vaccines work, and we need to do a better job of getting that message to the public. And I'm glad to talk more about that.
Secondly, the first booster is critically important given the new variants that we're seeing in circulation. And far too few Americans have availed themselves of the first booster, which would be after the primary series of an mRNA vaccine, the Pfizer or the Moderna vaccine would be that next shot, or after the first dose of the J&J vaccine would be the next shot.
And there was consensus in the committee, this is important, the data showed its life saving and prevents serious illness. Very important. Then looking to the future, we don't have control over what variants might show up, but there's good reason to believe we'll continue to see circulation of the virus for the foreseeable future. And we're going to face an important time point in the fall, anticipating that if we don't do anything, we'll see another major surge during the winter when people go indoors with the cold weather, but we can intervene. And in this regard, the focus on the characteristics of the vaccine that we would prefer was a big topic at the meeting.
The important takeaway is that the advisors reached a consensus that they would like to see all of the offered vaccines have the same composition. And right now the research is in full swing to try to determine what the best composition might be. That's not clear. It'll be determined by the outcome of studies that are ongoing right now.
Dr. Curfman: And staying on the COVID topic, there have been a significant number of emergency use authorizations that have been issued in recent months, and decisions will need to be made on how to transition these emergency use authorizations. And I wonder if you might be able to explain to our listeners how the FDA will approach the process of sorting through and making decisions about the emergency use authorizations?
Dr. Califf: Well, I appreciate the interest in the topic. It's very important and very complicated and hard to describe in a short few sentences, but a couple of key points I would make. This is a very important transition from the emergency use authorization to full authorization. We have done a couple of those with vaccines already, but given the fact that Congress has not yet figured out how to allocate the money to make vaccines and therapeutics widely available in the future, we've been thinking a lot about contingency to deal with this. That is, it needs to become part of the routine use, paid through insurance and other mechanisms rather than an emergency act.
Now, we still don't know what Congress is going to do. Our view on this is pretty clear that we need the funding, but in the absence of the funding, this will be even more critical. We do have the advantage now with all of these EUA therapeutics and tests, that we have real-world evidence. We know what's happened since they've been deployed. And so the transition from the data sense is a matter of making sure we got the right data with the right questions answered, which there's a lot of data out there, so the quality of that evidence is going to be really important.
And then there's doting the i's and crossing the t's on things like manufacturing, where we have a lot of experience. So this is going to be easier than a de novo, brand new application. But for a full authorization, we still need to make sure that all of those elements that are in our standard approval for a vaccine or a drug are in place.
I want to really thank the FDA staff. I was enjoying life in San Francisco while they were working night and day for two years on the pandemic. We all know it's not over, and this is going to be a significant workload. And I think it will be interesting. We will obviously need to prioritize for what's most important. And that will, I believe, be a vibrant discussion.
Dr. Curfman: You brought up the issue of evidence, and I'd like to drill down on that a little bit more. As the FDA makes decisions about the safety and efficacy of novel therapies, the agency relies heavily on medical and scientific evidence to support the decisions. I wonder if you could please discuss how the quality of research evidence affects the FDA's decisions about product approvals.
Dr. Califf: That's such an important point, Dr. Curfman. I'm glad to have a chance to talk about it. I do have a few quips about this one that I think should help people at least understand how I think about it, is a frequently used phrase about the FDA, in God we trust, all others must bring data. And so opinions are cheap and easy. But when really looking at the data and turning that into evidence that is applying a method to draw an inference about causation of an intervention, it's a really serious and difficult business that we struggle with every day, because all the evidence is not perfect.
That brings out the second quote that I'm increasingly using, which is that the intensity of the heat emitted by politics and what I call the twitterati, people who like to comment on FDA decisions. The intensity of that heat is inversely proportional to the quality of the evidence. That is when we have really good evidence, we can weigh the benefits and risks.
And there may be an argument of about interpretation of the analysis that's done. That's a very different argument than where we have to make a decision, but we don't have the kind of evidence we'd like to have, but there's no choice, but to make a decision because of a timeline or a public health emergency, or other factors that come into play.
Another quip that I really like is a longtime academic is when you write an academic paper you almost always conclude by more research is needed. In our case, we're frequently at a point where we just have to make a decision, whether more research is done or not. And it affects a lot of people. So a lot of my energy over these next few years is going to be spent trying to improve the evidence generation system in the United States, because I think it's very deficient right now.
Dr. Curfman: Well, this has been a big interest of mine as well. And, of course, biomedical journals such as JAMA and many other medical journals also place a high priority on the quality of the evidence included in the articles selected for publication. Now, you've published over 1300 articles in biomedical journals. And I wonder if you might compare and contrast how the FDA on the one hand, and biomedical journals on the other, evaluate and utilize clinical and scientific evidence.
Dr. Califf: Well, I'd point to several key differences. One I've already mentioned, which is that in many cases, the biomedical journal might choose to publish something which is not the highest quality evidence, but raises an important point. Here I mean in a perfectly legitimate way, as long as it has the correct editorial interpretation and statement. It might even choose to publish a counterpoint to something that's not entirely clear. That's not really an option that FDA has.
The second is that biomedical journals come in all shapes and sizes. This is not new, but one of the major problems, as you know. And the pandemic was the widespread publication of erroneous articles that were not based on sound quality in which led many people to jump to treatments that were proven later to be ineffective. And for every JAMA, there are a dozen, this increasing number of even almost fake journals that I'll still get emails from these journals wanting me to publish things in fields I've never worked in. So you have a very heterogeneous... and I like to think that it's best the FDA has standards that regardless of what field you're in the standards are written in the law. The FDA is like, and as a journal editor I suspect that you relate to the same concept, the FDA is like a referee in a sports' event. There's a rule book, you play by the rules and there's nothing you like better than a team that wins by playing by the rules and having a superior performance. Well, we all feel the same way. When a therapy really works and the evidence is clear, that's a home run for the public and we can all rejoice. So there are these key differences that are important.
And then the last one, which I do want to speak about, because I think it's so important that people understand this, the FDA is the only regulatory agency that gets a copy of the raw data set and does its own analysis of the data. And that's something as you know most journals don't do, although there's the increasing movement to make the data set available for others to look at. One of the early lessons for me, serving on FDA advisory committees, was how often the analysis, when you had all the data, drew you to a somewhat different conclusion than what might even be published in good medical journals, because all the medical journal could see is the result of the choices that you made about the totality of the data that you had. So, this independent analysis is a critical function at FDA that medical journals don't do, and it not only serves the American public, but it's a global benefit.
Dr. Curfman: Well, those are very, very perceptive points, and thank you very much for them. And just to sort of cap things off on the question of evidence, I wonder, how do you view the current state of the evidence generation, and the evidence generation system? And where would you like to see progress moving forward?
Dr. Califf: Well, I feel a little sad about this one because, like you, I spent my whole career trying to make the system better and I feel that the theory has gotten better and better, the practice is still falling far short. And a simple way to sum it up is to compare what happened in the US during the pandemic with what happened in the UK during the pandemic. In the US, to our credit, we had thousands of clinical trials that were started, most of them local by local investigators with interesting topics of interest to them supported by their institutions, and many thousands of patients volunteered to be in those clinical studies. In the UK, basically the message was, "We have to work together to answer the most important questions, it's part of your mission as an employee of the National Health Service to participate as a doctor or a nurse." And patients were encouraged to enroll in studies that were greatly simplified to make sure that the important questions were answered with an adequate sample size and number of events.
And the result was that the vast majority of US studies either never finished or didn't answer an important question. The UK reeled off important result after an important result. Now I'm not arguing we should do away with the investigator initiated small study, we need those to be done, it's a real contribution of the United State's system to have those studies. But what we don't need is a study which pretends to answer a major question, it doesn't really have a hope because the sample size is too small or the design is not appropriate, and we have way too many of those. So somehow we have to figure out when there are important questions to public health that we reward the investigators for participating and trim down all the unnecessary bureaucracy to make sure we get the answer as quickly and as definitively as possible.
Dr. Curfman: Speaking of the importance of evidence, you've mentioned that there's a collective need to address public health misinformation that became particularly evident and harmful during the pandemic. How harmful is misinformation and what are you and the FDA doing to address it?
Dr. Califf: Well, what I'd like to get across, is first of all, it's not new to the pandemic. We were experiencing a rapid growth in the misinformation industry well prior to the pandemic, it only was exacerbated by the opportunity of the pandemic for the combination of poorly intentioned people and well intentioned people who just didn't know better to flood the environment with misinformation. And before the pandemic, we were already seeing a reduction in life expectancy in the US that was unique.
We now have hit a milestone of a five year shorter life expectancy than other high-income countries, only partly due to the pandemic, but mostly due to good old-fashioned chronic disease, heart disease, lung disease, kidney disease, depression with suicide and mental health issues, particularly overdose, but also the secondary impacts of many mental health issues. And this is all fueled, it's not the original cause, obviously we're all at risk of these diseases, but people are being misled to not do the things that we know are effective that could make such a huge difference. Now what is FDA doing? Stay tuned, because I can honestly say there are many, many people who are aware and want to do something about this. I haven't talked to anyone who has the solution yet. So we are going to come up with a plan. People should be aware of the Surgeon General, Dr. Murthy, has made this a priority of his, and we will have a plan to deal with misinformation. I do know the basics because you mentioned my lineage at Alphabet or Google. The basics are, you got to be out there 24 by 7 with the truthful information. For me, that means we can't just make a decision about a product and put out one statement.
I think for you, in a journal, publishing one article when it's followed by 24 by 7 misinformation on the internet is not enough. We have to elevate reliable, truthful information. And whether it's disinformation or purposeful intent to hurt people, we have to go after that aggressively. Most information, or a large part of it, is in the middle where there are legitimate arguments to be made, but we have to make sure that doesn't spill over into the places where we know there's a human benefit to a particular intervention or practice.
Dr. Curfman: Earlier you referred to another very important aspect of FDA's work, and that is the regulation of tobacco products. And I'd like to ask you a few things about that. To begin, e-cigarettes, and I wonder if you could comment on the status of regulatory actions for e-cigarettes and if you believe there is a legitimate role for them in smoking cessation.
Dr. Califf: Well, during my initial term, we made a maneuver called deeming, which in lay terms just means stating that the FDA has authority to regulate e-cigarettes or vaping, or ENDS as it's called, electronic nicotine delivery systems. That went through and here I come back and the products of that work are just rolling out in a major way now. So we do regulate vaping. We have significant regulations that will be announced probably between the time of this interview and the time that it airs that I think will be very significant. Unfortunately though, we still have over two million teenagers and children who are vaping today, and essentially it's fair to assume that most of them are now addicted to nicotine. So we still have significant work to do, but I think the things that will be rolled out over the next several months will have a major impact on this.
Also, of some interest to people, I actually want to mention two things here. One, we didn't expect that when we said we're going to regulate vaping that there would be 6.7 million vaping products on the market. That's an approximation of the actual number. So imagine that you had to figure out what to do with 6.7 million products. So it's been a heroic effort by the Tobacco Center at FDA and 99% of the products have now been regulated. Most of them are in the sways of being taken off the market. There are a few, which gets to the second part of your question, which have received authorization for marketing based on evidence submitted, just like an application for any other product, that the benefits to an adult trying to get off of tobacco or not use tobacco outweigh the risks of youth taking up that product.
And so this has required actual empirical studies, just like other areas of the FDA, and I want to applaud the Tobacco Center for doing this. I want to put in just a combination word here about misinformation. We need the medical profession, universities, and health systems to wake up about misinformation in general and become much more actively involved. This is not something the FDA can do alone. And I think tobacco is an important area. I'll just say, when I came to FDA, remember, before my time as Commissioner, I spent a year as a civil servant, which was a wonderful experience, but I'd, as a cardiologist, thought, "Well, we figured out what to do with tobacco."
I'd seen a lot of people die from end use of tobacco, but year, 2022, 500,000 Americans will die from tobacco related illness. And so I don't think we're paying the attention to a lot of these bread and butter problems. We're so enamored of the fancy technology and all things that health systems do to make money, or that are exciting at medical meetings. We've got to get back to the basics here like, what do we do about tobacco and what do we do about nutrition?
Dr. Curfman: Well, there's another very important and current aspect to the tobacco issue, and that is menthol in tobacco products. And I understand that you may be coming down with a decision fairly soon about the possible regulation of menthol products. Are you in a position to be able to tell us anything about that today?
Dr. Califf: Well, it's a matter of record that I worked hard on menthol regulation in 2016, and it stopped in the Office of Management and Budget, which there are many factors involved in that. It just never made it out to come to fruition. So I would just say that there will be news soon about the menthol regulation. We know it's important because advertising of the tobacco industry is focused on particularly disadvantaged populations who are generally underserved in their health status by our health systems, and they've been targeted for menthol in tobacco. And so it is something that we need to do something out, and you'll hear more about this very shortly.
Dr. Curfman: Well, Dr. Califf, I want to thank you very much for your insightful comments.
Dr. Califf: Thank you, Dr. Curfman.
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