Voices: FDA Commissioner Dr. Robert Califf on Covid vaccines, tests, naloxone, Alzheimer's drugs, and more.

Last week, I interviewed FDA Commissioner Dr. Robert Califf for MedPage Today and Inside Medicine. The edited videos (slightly abridged) are available at Medpage (Part I and Part II) and the full unabridged audio and transcript are below.

In addition to potentially making a little bit of news in our interview (which I’ll get to in a moment), we also learned that Dr. Califf has been an active Inside Medicine reader for quite some time! Here’s a clip from an interview he gave at UCSF this week:

Dr. Robert Califf, speaking to the UCSF Department of Medicine this week.

“A very nice column…about various things.” Woot. On behalf of the Inside Medicine community, we’ll take it!

Fun trivia aside, let’s get to the substance. The one potential piece of news that stood out came when I asked Califf about whether as FDA Commissioner, he would ever overrule the vote of an FDA advisory committee—such as the one that advises on vaccine policy. Here’s his response:

“We're reevaluating advisory committees, we want to have more advisory committees but less voting, because people get all worked up about the voting and the voting doesn't matter. What the FDA wants to know is: what is the thinking behind the reasons someone might vote one way or another? We need knowledge that we may not have inside the FDA.” —Dr. Robert Califf, FDA Commissioner.

While Califf has spoken about the need to overhaul the advisory committee system at the FDA, I’m not aware that he has ever directly said that there should be less voting by committees. (If that’s wrong, than this was less newsworthy, but interesting to me nonetheless. He fills out details in the interview).

Other highlights include:

• Openness to reconsidering a spring booster for Covid-19 for high-risk populations. (Rumors are this may occur).

• Even though the Covid-19 public health emergency is officially ending, the emergency use authorization pathway will remain available in some instances. (Exactly when is unclear.)

• Agreement that at-home rapid tests for a variety of infections are likely to be an area where more growth will occur.

• Nuance on telehealth (He believes in it, but remains worried about misuse by bad actors).

As you listen, you might notice that I was able to ask many of your questions.

Here’s the audio and transcript (with timestamps):

Faust (00:00):

Hello, it's Jeremy Faust, editor in chief of MedPage today. Today we're joined by Dr. Robert Califf. Dr. Califf is a cardiologist and a member of the National Economy of Medicine, and this is his second stint as the Commissioner of the FDA. Dr. Califf, thanks so much for joining us today.

Califf (00:15):

Hey, good to be here.

Faust (00:17):

Let's jump right in on what's top of mind for so many readers and, and viewers, which is spring boosters for Covid 19. The immune compromised. I think increasingly this is the area of importance and in older populations as well. Will the F d A reconsider a spring booster? And what would it take to trigger that kind of reassessment? You've got the UK and Canada going forward, Israel studying this very carefully. Is it too late?

Califf (00:43):

Let me just make a couple of points first. I'm glad people are interested because I've recently had several conversations with people who have been studying the history of pandemics, and there's this actual thing called amnesia that comes into play where people just don't want to hear about it or think about it when they're in, you know, thank goodness we're in this relatively quiet ascent phase. But it's good that people are interested. It's not too late. We're looking at all the data coming in and as soon as we have the evidence that we need one way or another, we'll make a decision and let people know. We're not quite at that point yet, but you know, we're aware that people are interested. I'm 71 years old myself, and I'm seven months out from my last updated boost. So very much on our minds here at F D A. So, you know, it's not like we go months without looking at anything. It's really for people that work in the center for Biologics. It, there's a group that is looking at this every day and across the administration, of course. Dr. Sha is always very interested in what we're doing.

Faust (01:55):

How fast can these things move. We just came off this pandemic period where things were moving at a lightning pace and, you know, during the normal times, that's not the usual pace here. We, I feel like we're sort of in between here. If, if it's early April right now, how quickly can, can the FDA come and say, you know, we did see some new data. Let's go ahead and do every six month booster or even more often for the immune compromise c may, June. Like when, what kind of timeline are we talking about?

Califf (02:21):

Everybody always wants to know the timeline, and I appreciate that. And I would just say it's, you know, you know, the machine is well oiled and when it's time to make the decision, we can make it quickly. I can't really put an exact timeline on it cuz we never know what new data may come in. As everyone around the world is following the course of both the pandemic and of the impact of vaccination on outcomes. You know, so far it's, I think it's speed expectation so much more than I ever thought with this dramatic reduction in death and hospitalization for those that are up to. So it's quick once the decision is made and we're constantly looking at the information.

Faust (03:04):

Does the end of the public health emergency, the PHE, does that affect the the lever of the EUA pathway, the emergency use authorization pathway for vaccines for these particular vaccines?

Califf (03:17):

It doesn't. We're those go on separate tracks, obviously. They're related in some ways, but it, we still have the authority for EUAs in place.

Faust (03:29):

And what about for totally different areas with EUA, for example, like if, if there were to be a new treatment for long covid that that came out in the, in the, the public health emergency is over what's the apparatus? Is it the still the same apparatus or is it a new day? It's not PHE anymore, so back to the old way.

Califf (03:48):

Well, that's a, that's an an interesting question. And I, I think, you know, the answer to that is probably all depends. The authority is still there. But we, you know, we wanna be careful not to use it unless it's needed because we got a lot of other therapeutics and other diseases that are taking a toll. I'm sure you're aware of the life expectancy in the US is dropping right now, not just due to covid. So I feel like we got all the tools we need if we need to move quickly to do it. But we wanna be careful in the use of that authority.

Faust (04:27):

One more question about the EUA pathway. The, I think it's been very successful. I mean, there's no argument there. We've seen some really big wins with this pathway during the pandemic. But one thing that I think is interesting is that it, it, these are not FDA-approved drugs, right? So you can't just use them off label and academic or investigator initiated trials aren't as aren't really possible, right? If Pfizer doesn't want to give uax lobi to study, you can't study, you can't do a randomized controlled trial because you, you can't just go to your pharmacy and dispense the drug. Do you think that the e u a pathway can be refined in a way that can actually allow investigator driven studies to be done more quickly in the future?

Califf (05:05):

Well, I think, you know, the reauthorization of so-called Papa, the Pandemic Preparedness bill is up this year. And I think there'll be a number of fine-tuning efforts with various approaches to the pandemic, including this one. I do think though it is entirely possible to do trials in this situation after all, the government, for example, with the vaccinations bought a huge stockpile of vaccines. So it's, it's not that you can't do the trials, it it's just a mechanism is a bit different. You know, it's Jeremy, you brought up the investigator initiated studies. I'm all four of those. I've spent 35 years in academia, but I think we'd be a lot better off if the investigators worked together and did trials that were large enough to, and coordinated enough to actually answer the questions. We gotta, you know, there's a phrase that was Janet Woodcock had coined that an interaction I was involved with, with the NIH a few years back. The SCT: the small crappy trial. What we need are small, there's a real place for small trials when they're well done. But we need more trials that answer the critical therapeutic questions definitively. And that that is a major effort that we're thinking a lot about right now.

Faust (06:26):

STAT news reported that the that one of the reasons that the FDA's less interested in like Interferon lambda , this is the New England Journal study done overseas is because it wasn't sort of industry funded US study. Is that, is that true?

Califf (06:38):

No. we're, we, we don't care who the sponsor of a study is. What we need is good data, well designed study and someone putting in an application who can actually manufacture the product and distribute it with the kind of quality that's needed. I think sometimes the academics forget about all the rest of what has to go into getting a, a drug distributed. It's not just a clinical trial result. You gotta have a manufacturing facility, you gotta pass inspections, you have to have a distribution mechanism. It's many, many other aspects involved in a drug application than just the clinical trial. And we have nothing against data coming from foreign countries that the studies are well done. We, I personally, you know, in my career done, you know, mostly did multinational clinical trials where the US was not the major enroll in most of those trials because we're only 4% of the world's 8 billion people. You wouldn't expect the US to be the major enroll in global studies. So no, I think there are a lot of myths out there, but hopefully this will clarify some of it.

Faust (07:48):

That's very helpful. I'm also interested in sort of reciprocity in general. Look, I think we should, we, we have our own FDA and, and it probably one of the greater regulatory bodies in the world on this question. But when you look at Europe and other parts of the world where they have many, many more rapid tests for covid, and now even one of my readers talks about, you know, a four in one that they've got in Europe where you have both flus, rsv, covid all in one point of care test. Is, is should there be like a, a reciprocity pathway for something like an inexpensive point of care test? I mean, that, that seems to me like low hanging fruit. Like why have all this infrastructure devoted to a question that's actually sort of already, we're already on the 10 on, on the 10 yard line first in goal. Like, let's, let's, well,

Califf (08:30):

Yeah. I really think, Jeremy, that's a little bit of misdirected thinking. I mean, if someone has developed a test and they've done the studies to demonstrate that the operating characteristics of the test, you know, sensitivity, specificity, predictive value numbers, and, you know, hopefully even operating characteristics measure beyond that, and they've submitted it to a regulatory agency in Europe and it's been okay, it's not a hard deal for them to come to the US and just submit their data. That's all we really are saying. You don't have to redo the studies if they've been well done and they're inter representative population and meet all the quality characteristics. I'd also say that in general in Europe, it's not that there's a whole bunch of more tests that are actually being used. In fact, I think one of the characteristics of countries that may have done a bit better with testing than we did in the US is that they focused on a smaller number of overall tests, but made sure that they were used by a much larger proportion of the population. I mean, we've ended up with a lot of tests in the US and you're probably aware that early on when there was a period where it was perhaps too restrictive and then a period where the gates were open and a lot of tests turned out not to be so good and had to be rain back in if you got good day to bring it. And we're wide open to look at it.

Faust (09:59):

Yeah, I mean, I think the early on the antibody tests were really problematic, the antigen test, I think that it feels like a lot of companies applied only a few got it. But there seemed to be a, a big public demand for this moving forward, not just for Covid, but for flu or strep or RSV I, I think. Do you think that do you see that market expanding?

Califf (10:18):

I think at home testing is gonna be a huge area. And the only part of it I'm really concerned about. I mean, again, if people do good tests develop good tests, do good studies advertise what their operating characteristics are in a way that people can understand it it's gonna be really good. But I'm worried about equity here because you said inexpensive to someone who's you know, in the lower half of incomes in the us you know, buying a test in the drug store is not a minor decision. And so we really gotta think about how all this is gonna get paid for in a way that leads to equitable availability. Because I would argue the people that are gonna benefit, who should benefit it from it, the most of those who are in the working class and have to go to jobs and take kids to school, not those of us who are professors. And you know, there's a, there's a great quote from the Atlantic that Ed Yong wrote. Technological solutions drift into society's penthouses diseases seep into society's cracks. And so I'm not worried about the technology. I'm not worried about evaluating having a market. I'm worried about equity when it comes to the use of this technology.

Faust (11:42):

All right, let's transition to speaking of equity. One place where equity is an issue is telehealth. Not everyone has access, but it's something that there are programs can actually give people telehealth for the purposes of medicine and that kind of a thing. But I think that the telehealth story, another sort of success of the pandemic is that CMS and, and to some extent F d a really bolstered that, that that infrastructure by its support, by its immature of saying this is okay. And I, I know you've talked a little bit about this in terms of a balance on telehealth. You've talked about how with, for example, with drugs like Adderall, you'd like to see in-person evaluations or some kind of balance. Do you feel the same way about things like buprenorphine, you know, opioid assisted medication for opioid use disorders? I think it's been a big win Harvard study a CDC study all show that if you, if you have telehealth people are, are, are much more likely to get the treatment they need for op opioid use disorder. What does the FDA come down on that,

Califf (12:50):

That's really not an FDA issue it's not in our swim lane. We have no control over the telehealth rules, but, you know what I would say it's, it's what, it's publicly known. I helped to found a not-for-profit in Dayton, Ohio dealing with addiction issues. And we found telehealth to be pretty amazing. Our general view backed by some evidence yet to be published. So I don't wanna talk about it too much, but our general view is that it's really important to get the right mix of in-person in telehealth. And I, you know, I mean, you're very involved in patient care. I, I'd be surprised if you thought that pure telehealth was the right way to take care of someone with these kinds of intense problems that require a lot of input on the other hand intermittent in-person visits, and then the ability to literally talk to someone every day.

(13:51):

I think that's a tremendous advantage. So I think this is one of the major professional responsibilities. Now what is the right mix? That's an issue of implementation research to figure out and develop standards, because we definitely have seen in the Adderall space that you alluded to that these for-profit systems that give incentives to prescribers to prescribe more of a drug without attention to the real clinical need that is a huge problem. And it shouldn't invalidate all the great uses of telehealth, but we gotta get it right because this has really created a significant problem in our society.

Faust (14:38):

Yeah, I mean, I think that I think that telehealth, to answer your question, I would say that I would never let perfect be the enemy of the good. I'd rather see some combination of telehealth and in person. But if the only way to get somebody started on, on medication for opioid use disorder is through telehealth, I'm, I'm all for it. And I don't think that we want to, you know, sacrifice any lives because of, you know, the way we see each other or the, you know, that kind of a thing.

Califf (15:01):

Well, this is this is a burden of a regulator, right? Because I used to be in your shoes and you can't even imagine the things that people on the fringes of our society do. So I have no argument with your, again, I'll emphasize this is not an issue for the FDA to make a decision about. It's not in our jurisdiction. I would just say I can, I would in no way disagree with your view that we don't want to sacrifice someone who could benefit from this because of the bad behavior of someone else. I'm just saying in your fervor to do all the good things you can do with the technology, keep in mind, or if you don't develop professional standards for the right way to do it in a way that someone can keep track of. This is a runaway train of profitability for some bad people. And we, we just gotta keep both these things in mind.

Faust (15:55):

Perfect transition to my next question about profits and getting everyone's values aligned. FDA made really big news last week now about moving Narcan nasal naloxone over the counter. This is opioid reversal antidote, saves lives when given in time. And I thought that was a great move. I think it's got a lot of support. The one of my readers had a question about what the FDA can do to make sure that a price gouging doesn't happen. And, and the example cited was EpiPens, that when one company bought the device from a competitor, the price went up from 94 bucks to 700 bucks. And are you worried about Narcan or an naloxone following, following the same kind of pathway? And what can the FDA do to make sure that what you're trying to achieve actually occurs, which is to get this drug to those who need it?

Califf (16:52):

Well, we have we have limits as you know, when it comes to, we can't set the price of a drug. We can't tell a manufacturer to make a drug and enforce it. We can encourage them to give a reasonable price and to make enough. But there are some, this is not the same as the EpiPen situation in any way. And I'll just give you a couple reasons why. Number one, we have spent a lot of time with CMS on this issue because when something goes over the counter then CMS can't pay for it by law. But there are mechanisms that we're gonna use to try to make sure that the drug is available, that available either free or at a reasonable price, depending on the circumstance. But importantly there, this is just one form of naloxone.

(17:40):

There are many others that will still be on the market by prescription. And little known fact that I learned a lot about over the last few months is that the majority of Naloxone is now actually distributed by public health groups who buy it in bulk and then distribute it essentially for free. And as a cardiologist, the analogy is easy for me. We don't charge people for defibrillators. If you dropped over dead in your office and got a external defibrillator shock, you wouldn't be charged, you know, ahead of time for that. And I think Naloxone is a very similar thing. It can save a life, so we gotta make it available. We'll get it worked out. But I don't want anyone to think that FDA can actually set the price or enforce that a manufacturer makes a drug. We don't have that legal authority.

Faust (18:32):

Can you talk a little bit about controlled substances and the FDA, the DEA, HHS, SAMSHA -- there's a lot of alphabet soup here. Do, how does FDA-- what's the FDA's role in deciding something like or influencing something like the recent decision on the X waiver going away, which is this waiver that allowed prescribers to, to prescribe buprenorphine and, or, or things like, oh, well, we're not gonna have that anymore, so there's gonna be some training on these controlled substances. Is this completely out of the FDA's purview? Like where do you sit in terms of these kinds of issues?

Califf (19:08):

Yeah, I think you know, I'm a basketball ex basketball player and basketball fan, so this is one of many cases where I think the team analogy is really useful. FDA's position, if you will, is that we judge the safety and efficacy of drug as it's being developed and make a key decision as to whether it can be marketed for an intended use based on the data that manufacturers bring to us. Or as you pointed out, it might be a public group that could bring the data if there's a way to distribute the product. And then during the post-market phase where we have a lot of safety authority but we don't control the practice of medicine and really can't interfere with the practice of medicine, and we don't have any role in the payment system. But we're part of a team, the HHS family, if you will, that includes CMS, the biggest payer SAMHSA, which deals with these issues and clinical implementation and societal implementation, CDC, et cetera. So we're around a table with the other teammates and we work together, hopefully increasingly we'll work together on issues like education. We do know, learn a lot about it in the context of what we do. So we have opinions about provider education, and they've been taken into account as the decisions being made about what to do.

Faust (20:40):

I wanna move to a different topic. Just generally speaking about some controversial approvals and, and related to that, the FDA's accelerated approval pathway has definitely had its moments. And I think the Alzheimer's drug issue is a kind of a the sine qua non example of that. Is FDA changing its approach to the accelerated approval pathway based on that example and, and others?

Califf (21:07):

You know, it's always interesting that out of all the accelerated approvals, this one gets the attention. It's an important disease and you know, a difficult issue. But the basic answer is we're not changing our general approach. I mean, the American public has spoken through Congress and the laws to create the accelerator approval pathway. It's per, it's clearly laid out. It's based on when, when there is a disease without an adequate treatment that's a serious disease, life-threatening or very serious. And it's based on the opinion of the FDA full-time civil servants, not political appointees like me, but the people in the centers who don't have a financial conflict of interest that a a biomarker that's measured is reasonably likely to predict the clinical benefit. Now, what has changed and with our, our support is a change in the law with a omnibus bill that just passed that gives us much more authority to require, for example, that companies start their confirmatory trial before the accelerated approval and better authority that if things don't work out in the confirmatory trial, that the drug can be pulled from the market.

(22:26):

So things are being tuned up with accelerate approval, but the American public, compared to many other societies, people are willing to take greater risk for potential greater benefit. And that's manifested through laws that the elected officials have passed than, you know, I think a good way to think about the FDA, we're more like referees than anything else. We have a rule book that's the laws that are passed by Congress. We do interpret the rules, and that's a really important part of our jobs. But fundamentally we we're not the teams that are playing on the playing field. We're the referees.

Faust (23:03):

With respect to that, though, we, you have to figure out which which fouls to call. And that's part of the that's part of a job of a ref let 'em play or, or, or not, or enforce. And a lot of it you do set certain standards. So you talked about biomarkers being a reasonable proxy, that being enough especially for certain diseases. But how do you feel about FDA a approving a drug that missed its own primary goal? Like this study is done by industry who miss their own primary outcomes in these studies. Sh can, can an approval of a, of a substance like that really be justified based on secondary outcomes or, oh, we, we see a signal here. Like what's, what do you think? Where do you weigh in on, on, on that

Califf (23:46):

Oh of course, it's interesting, the do the Monday morning quarterbacking after the game is over, was the call, right? My job as commissioner is not to make the calls my, those are made by the full-time civil servants based on their best judgment. Is it a hundred percent of the time wrong? When a primary endpoint is not met in one trial to say that all the other evidence is there by invalidated, I don't, I don't think, you know, anything is a hundred percent. That's why we have people making these judgements. And you know, I disagree with some of the judgements made by FDA people during the course of my work, but the fact is this is what they do for a living. They cannot have a conflict of interest in their work, and no referee gets it right a hundred percent of the time, but in this case, on Alzheimer's, the story's not over yet.

(24:42):

Right. And in, you know, maybe we should have this conversation in a year. One other point, just to keep in mind about FDA, because the information that FDA sees that's not from a particular drug or device is com is confidential, that other companies may be in development. FDA gets to see a lot of data in the, in the field that are not publicly available. And you know, we'll see when all the whole story is done on this, but just keep in mind that the sort of drama of the public proceeding is only a part of this entire story of how drugs get evaluated and approved. And nothing wrong with criticizing that's part of our jobs is to listen to criticism and get better.

Faust (25:31):

We'll, we'll be watching that story. You mentioned something about how you've got at the FDA, these the, the professionals and the advisory committees, and then, then there's you, there's the, the commissioner of the FDA. And do you have in your role, the ability and wherewithal and desire to, to override those, those pieces of advice, maybe an advisory committee or a policy? What, what's the FDA commissioner's sort of power to, to, to, to override something or to, or to move something in one exam in one direction or another? I could think of a time, one time when CDC director, Rochelle Walensky overrode vote. Do you feel like your role needs to do that ever? Can you do that?

Califf (26:18):

First of all, let's be clear, advisory committees are advisory. They are not decision making. And in fact, as we're reevaluating advisory committees, we want have more advisory committees, but less voting because people get all worked up about the voting, the voting doesn't matter. What the FDA wants to know is what's the thinking behind the reasons someone might vote one way or another? What are they really, we, we need knowledge that we may not have inside the FDA. When it comes to the commissioner, there is a chain of command. There's literally a chain of command by law goes all the way to the president. But everyone above the center directors at the FDA are political appointees, and I'm on record for in 2016. In the case of Sarepta is adhering to what's been the standard for all FDA commissioners, which is that you would only overrule the judgment of the civil service in an extreme situation.

(27:18):

For example someone corruption was detected or someone was temporarily insane and made a bad decision at center director level. Once you open the floodgate of political appointees making decisions about drug approvals or device approvals, where would it stop? And I'd urge you to think about some of the politicians that have been elected in America. Would you want them reaching in with the connections to companies that they have and overruling the decision on full-time civil servants? I think it's much better, like refereeing in sports to live with the decisions of referees. I had a top, when I'm a Duke guy, that call at the end of the Virginia game was one of the worst calls I've ever seen. But you live with it and go on. And if consistent bad decisions are made, then you need to look at the personnel and make a change. But you open this up to politicians, let me tell you that would be a mess. So yes, I have the authority. I would use it in extreme circumstances, but it would take something really, really extreme for me to do that.

Faust (28:30):

I know you've spoken about misinformation being an important thing to worry about. From the FDA's perspective, though, the FDA's supposed to be apolitical, and I think that misinformation can be seen through a political lens. And also misinformation is hard to defy. And at some point saying, SARS-Cov-2 is airborne would've been misinformation, and someone could say, oh the vaccine causes myocarditis. But depending on how you say it, it's, it's either true or, or sort of bordering on, bordering on misinformation. How do you think the FDA can get involved in the misinformation fight without risking the public thinking that you are political?

Califf (29:08):

First of all, I think it's a little bit of a misstatement to say the FDA is totally apolitical. I'm a political appointee, so I had to go through a Senate confirmation, and I was dumb enough to go through it a second time after having been through it once. There, there's politics involved, there's no way around it. But part of my job is to protect the civil service from undue political influence, let me just say with regard to information and scientific discourse, it is in our mission statement to provide information to the public and to practitioners to enable them to use products safely and effectively. And when someone is saying something that's completely untrue, that's undermining the health of the public, we have an obligation to put the truth out. So I, I think I want to avoid calling it a fight.

(30:03):

What I wanted say is that we have a mission in putting out truthful information to the public and to practitioners, and we'll continue to do that generally. I do believe that misinformation is one of the major causes of death right now because we have so many effective treatments and we just look at vaccines and covid almost everyone who's died or ended up in the hospital with Covid sense of vaccination became available, was not up to date on vaccination. So I think it's really critical that we succeed in getting the truth out.

Faust (30:44):

All right. Well, we'll be watching on that issue and many others. Dr. Califf, thank you so much for joining us today.

Califf (30:49):

You bet. Take care.