FDA's Hahn to Topol: Decisions Will Be Made Based on Science Alone

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Eric J. Topol, MD: Hello. I'm Eric Topol, editor-in-chief of Medscape, and I have the privilege today to interview Dr Stephen Hahn, the commissioner of the FDA. So, Stephen, welcome. It's great to have you with us.

Stephen M. Hahn, MD: Well, Eric, it's great to be here. I appreciate the invitation. And I'm looking forward to our conversation. These are really important topics for the country.

Topol: No question. Just as a way of background. Dr Hahn came on as commissioner of the FDA in December. I don't think he knew exactly what he was getting into. He has an amazing background. Undergraduate at Rice and Temple for medical school. We actually shared some history at the University of California, San Francisco, where he did his medical residency. He was also trained at NIH in oncology. He went on to have an illustrious career. He was at the University of Pennsylvania where he was chair of the radiation oncology department, and from there he moved to the University of Texas MD Anderson Cancer Center, where he was the chief medical executive. So, quite a pedigree background, Steve, that got you ready for this tough mission ahead.

Hahn: Thank you.

Topol: It's remarkable how we came together. We didn't know each other until I sent you a very tough letter back on August 31 about the convalescent plasma decision. Little did I know that it would be a blessing because it would bring us together. Dr Hahn was kind enough to get in touch with me and we've actually become friends. I've developed immense trust in him and his efforts. We're going to get into that with respect to vaccines and monoclonal antibodies today.

Let me start off, Steve, with the acronym of the day: EUA. Can you tell us what that is and how it's become kind of center stage in the midst of the pandemic?

Hahn: Eric, first of all, when you sent the letter — I have to tell you, I learned this in medicine: You run toward friction and you talk to people about things. I very much appreciated your communicating with me. And I feel the same way. So thank you.

It's hard to believe that EUA, or emergency use authorization, has become part of the lexicon of the United States, maybe the world. After the 9/11 terrorist attacks, we received this authority from Congress to issue EUAs to allow for medical products to get into the hands of providers and patients before the full set of data were available that we would normally use during our regular approval process.

There are two important points of EUA. One is that, from a treatment or a therapeutic point of view, the standard is "may be effective." There has to be evidence that something may be effective. We have to have data behind that.

The other one is the assessment of the risk-benefit ratio. And that's where the safety comes in. You can imagine a situation where you have an incredibly life-threatening infectious disease — COVID-19 and Ebola would be examples of that — where the risks are high. Eric, just like doctors would make a decision in a situation where the risk for death is high, you might accept more risk on the therapeutic side from a safety point of view.

And that, of course, plays directly into the issue of therapeutics vs vaccines, because therapeutics are given to people who are sick, maybe even in life-threatening situations. Vaccines are given to people who are, in general, healthy but may be at risk for life-threatening complications. All of that has to play into our decision-making, and that's what the experts at FDA are really good at.

Topol: Well, that's really being put to the test now with the vaccines. There are multiple phase 3 programs underway. We were fortunate that we pushed the manufacturers to release their protocols because I don't think that was their initial intention, but they did. First it was Moderna and Pfizer, then AstraZeneca and Johnson & Johnson, and finally Novavax.

These protocols have a lot of homology. Most of them have approximately 150-160 endpoints of infections. These are some of the largest trials that have ever been conducted, from 30,000 enrollees up to 60,000 for Johnson & Johnson's. What's interesting here is that you have a relatively small number of events that could lead to an interim analysis — 32, for example, in Pfizer. And you're extrapolating that to tens of millions, even hundreds of millions, of people.

That makes for a strain. I mean, it's hard to know from a trial like this, when you're evaluating it for EUA, that you've nailed it, that it's truly efficacious and safe. Can you comment about this? This is a momentous time for clinical trials when, even though they're large, the number of events that will be influential in making critical decisions is small.

Hahn: Eric, this is, as you point out, the central issue. It's why we issued guidance on June 30th about our expectations. One of the reasons that these trials are the size they are is because we established a floor of 50% efficacy. Now, you and I and the rest of the country want to have a hugely efficacious vaccine and certainly a safe one. But these trials were powered and designed based upon that — detecting a 50% difference.

That being said, you're right. A data and safety monitoring board (DSMB) could look at prespecified time points and see if the boundaries of that efficacy have been reached. What we've been very clear about with the manufacturers and sponsors is that the FDA needs to see clear and compelling evidence around both safety and efficacy. In the absence of that, it's going to be very difficult for us to consider authorization of a vaccine. Of course, the proof is in what the data show, and we don't know what the data will show. But I think we've been very clear about that and we've had conversations with the sponsors, which I can't reveal here because it's confidential commercial information about what we would expect to see, because I think we need to be very, very clear about what "clear and compelling" evidence is. And we need to make sure that it is something that is durable, that it's not just seen in an initial analysis and then goes away later. We're working on that without revealing the details of the conversations. It's top of mind for us, Eric.

Topol: What's interesting is that there's kind of two compartments. There's Pfizer, which is working on its own trial, and there's Operation Warp Speed (OWS). I'm not sure that's the best name but it's "Warp Speed." Do OWS and the FDA have any interactions, and, for the medical community, what is this OWS?

Hahn: This is really, really important. OWS is run jointly by the Department of Health and Human Services (HHS) and the Department of Defense. It is a program to help expedite diagnostics, therapeutics, and, of course, vaccines, and to provide government money. This is the people's money, their tax dollars, supporting the expediting of medical product development, including vaccines, which means manufacturing at risk before there is an authorization of approval, just for one example, and creating a common platform for potentially testing therapeutics and vaccines.

We have drawn from the beginning a very bright line between FDA activities and OWS. We provide technical assistance. But neither I, nor anyone at FDA, is involved in any decision-making, because think about it, Eric: Let's say there's a commercial company that's developing a product. If FDA were involved in the commercial decisions of that company, how could we possibly be an independent regulator? So we've made it clear that we're not going to — and we haven't — participate in any decisions. We'll provide them with technical advice just like we would for any other sponsor of a medical product. Now, OWS's job is to work with various sponsors and manufacturers to facilitate the development of vaccines and other medical products. That's actually happening. But we're only in the position of providing technical assistance to them, which I think is the appropriate place for us to be.

Topol: Pfizer is running its trial on its own and has its own DSMB. There are four interim analyses, which is more than the other vaccine protocols. And for each interim analysis there are stopping rules and they could apply for an EUA at any time. This is why we got concerned; they could come in with a small number of events and they could kind of bypass the FDA and go right to HHS, which I guess has authority over EUAs, such that they could essentially bypass the review process. Is that right by legal authority?

Hahn: That's a really good question. I don't think people know this, but the secretary of HHS by statute in the Food, Drug, and Cosmetic Act delegates his authority to the commissioner of FDA. And I'll go through that in just a minute.

What I've done, and what previous commissioners have done, is delegate that authority to the center directors — in this case, the Center for Biologics Evaluation and Research (CBER), and in terms of monoclonals, it's the Center for Drug Evaluation and Research (CDER). So under my watch those decisions will be made by scientists within the centers.

Our expectation is that when an application comes to us — and again, that's the decision a sponsor makes based upon their determination that data are mature — we're going to work with them; we're going to be flexible. But we're also going to be insistent about our criteria. And we've communicated those criteria both in our guidance and also in letters to the manufacturers. Once a sponsor submits an application to us, we're going to look at those data, but we're also going to open this up to a vaccine advisory committee. That will allow us to have independent experts comment on this. So there are a lot of safeguards in place, both for our scientists and also for this external public-facing advisory committee, to assess those data. Everybody's aware of that. I think when an application comes in, we're confident that it's going to be ready to be assessed. But either way, we promise that the process will be the same for every application.

Now, to speak to some theoretical situation where someone else could make the decision, it's been made very clear to me by Secretary [Alex] Azar in HHS that they're delegating this authority to us and that they have the same expectation with respect to our scientists making decisions. I've had no indication otherwise, and nor do I expect that, Eric.

Topol: That's good to hear. That's reassuring.

One of the troubling features here was that there was concern in the past around the EUAs for hydroxychloroquine and the convalescent plasma. But you took initiative here to tighten the EUA criteria for vaccines. Back in June you established the vaccine efficacy criteria and you published it in The New England Journal of Medicine. And then more recently you said, "We're going to make this tougher and we're going to have this 2-month median safety follow-up; we're going to require some serious COVID-19 events that have to be part of this."

These were really important for tightening the EUA guideline, but they were met with very strong resistance. We saw publicly, even during the debate between Trump and Biden, Trump saying that he doesn't believe in that, it's not necessary, and that the FDA is not moving fast enough.

It's bad enough to have a pandemic, but then you have this matter. What was really interesting is that this past week, there were still articles in the papers about how Trump and the White House are going to block your tightened guidelines. And then the next day the White House signed off on it. Then, next thing we know is that Trump is tweeting about it to you. How do you deal with all of this? It seems chaotic, but you showed remarkable autonomy and independence here. You initiated this tightening of the EUA guidance. You got it to the manufacturers. You got it into the guidance document in Appendix 2. Even though it's nonbinding, all of the manufacturers of vaccines understand this. You took a really big step. And that's what made me understand how committed you are to doing this independently. But this must have been tough.

Hahn: We're in the middle of an unprecedented pandemic. We're in an election year. And it's the political season. I know it doesn't always seem this way, but our decisions have been made by our career scientists — you and I have had that discussion — and they continue to be made by the scientists.

We made the commitment back in June to establish these criteria. And what I think is interesting, Eric, is that I don't actually see these as being tougher. I see it as a natural progression to our guidance on June 30th. And we've been communicating since August about the criteria that are in the EUA guidance that we've just published with the companies. We wanted to be very, very clear and transparent with the companies, and ultimately the public, about what our criteria would be.

Because at the end of the day, Eric, that's how you're going to judge us: based on whether we stuck to our criteria and put them out there. Letting people know what both the criteria and the process are is very, very important to the agency. These were generated by our career scientists based upon their look at previous data with vaccines and the information we had available.

I'm incredibly proud of the career scientists and what they've done. My commitment to the American people, to the providers of this nation, is that we will stand by those criteria and we will use our external advisors and the vaccine advisory committee to further vet this.

This is where we stand. I said it in the most recent Senate hearing: There's going to be no other criteria that are going to influence our decision. No externalities, nothing else. It's going to be about the science and the data and the medicine.

Topol: That's really important. There are no more important clinical trials I know of in our generation than these vaccine trials; it's our exit strategy for the pandemic. The fact that you stood up and did this — and you stood up for these 17,000-plus people at FDA — to show this country that you're going to tighten things up because this is the rate-limiting step, the EUA.

Also, just to point out, the EUA is the right path for all the vaccines, because the BLA (Biologics License Application), the licensure, would be a long, long process and we don't want to wait for that. So the EUA is what we want to see for each of the vaccines.

You've stood up, in a masterful way, in what had to be a difficult situation. I can just imagine that you're putting your neck on the line here. You don't have to agree, but that's just the external perception.

Hahn: Eric, you made a really good point, if you don't mind my commenting on this. A lot of people have said, "No EUA. Only a biological license application." When you're talking about a pandemic where people are dying, you want to expedite it as much as possible. And this is the pathway that Congress provided us.

Topol: I want to just take a detour now and talk about monoclonal antibodies, because I think we now have a pretty good handle on the process for a vaccine EUA. And it's going to take a process — that is, once an EUA application comes in from one of these various companies, it will go through internal review and external review. It doesn't happen overnight. It's going to take some weeks to happen. I think we've seen already that there's an acquiescence that there won't be a pre-November 3rd vaccine approval, which was touted for some time.

But the monoclonal antibodies are a different story because here, unlike the convalescent plasma or the hydroxychloroquine, we have two randomized trials with phase 2 data that are encouraging, even with some clinical endpoint data, such as reduced hospitalization need. (These are both outpatient trials.) Plus, these two manufacturers have considerably more data in ongoing trials regarding safety.

Both companies are putting in applications for an EUA and they have what seems to be a pretty solid footing. But here again, we have this obfuscation and appearance of interference because we see reports in the media yesterday and today that, again, the White House is exerting pressure on the process where it seems like it would naturally flow in a very positive direction. So this is an optics issue. Can you address that?

Hahn: I can only speak to what's publicly released by the companies, and they both announced that they have submitted applications. We will go through our typical rigorous scientific process of evaluation. This will happen in our CDER, very ably led by Dr Patrizia Cavazzoni, who has a remarkable amount of experience and is a career scientist and clinician herself. These will be evaluated within that center. And just like with the vaccines, my promise is that the only information that will be used to make this decision — either yea or nay — will be based upon the science and data we receive. Again, the externality around this will not influence our decision-making around it.

Now, you and I, I think we both would agree as doctors, if there are data available on any therapeutic that look like it could save a life during a pandemic, and it is safe and it fulfills the criteria of "may be effective," and the risk-benefit ratio is in the right direction, then we should go forward with it. But we intend to be transparent about the rationale behind an EUA, when and if it occurs, for therapeutics. We're going to have to encourage the sponsors to be transparent about the information we provide them, because we are restricted by law from releasing confidential commercial information. But we will, to the extent allowed, be very transparent about it.

But Eric, it is no different from vaccines with respect to needing to see data to make a decision about the criteria for an EUA. The decision is different. As you point out, because if this is for someone who's sick with COVID-19, that's different from someone who's healthy and doesn't have COVID-19.

Topol: Right. And that brings up the point about an unmet need. We have dexamethasone and remdesivir for severe advanced illness, but we have nothing in the early phase or prevention.

The point here is that you have the president with videos that he's made about the cure and all these other things, and we know that there is no cure for COVID-19. And he now appears to be using this as a political lever instead of the vaccines, which didn't work before the election. He's using this as the miracle he's going to bring forth for the country. So here again we have this problem of politics clouding the discussion, using advances in science and medicine that are notable. The vaccines obviously have had a remarkable path, with speed that we've never seen. And now the monoclonals are another similar thing. We've never seen monoclonals developed this quickly.

Can you give us any reassurance that this process will be totally immune from any interference and will not be influenced by, for example, November 3rd?

Hahn: Eric, I can absolutely promise you that there is no prespecified date for this. We will look at the data when it's available to us and we will make a decision based upon this data. I think it's really important to remember that there are 17,000-plus incredible scientists, doctors, pharmacists, nurses, etc., at the FDA. These are career people who've dedicated their lives to public service and to protecting and promoting the public health of America. Throughout the pandemic, they've done that. They only make decisions based upon the science and the data.

We have internal processes in place, Eric, that allow for any employee to raise concerns about decisions that have been made. There is a process for adjudicating those and for any appeals that occur internally, because we want to be sure that folks are comfortable with the decisions that are being made. That doesn't mean everybody gets a veto. But what it does mean is that if someone feels that anything other than the science and data are being used, they can raise the issue and we have a process internally to address the concerns.

I can also tell you my personal commitment. I am not going to allow outside pressure to affect the decision-making. I told you this before when we've had private conversations. I have delegated decisions to our center directors. I, of course, am briefed on those, but I have great confidence in the people at CDER and CBER to make these decisions. And just like I said with vaccines, I and the agency won't permit any factor other than the scientific data to influence those decisions.

Topol: It's really important for the medical community, and indeed the public, to know that, because there are concerns. We have challenges out there. We have a pandemic that is not going away. And we have this unnecessary added dimension of a president and White House that seem to get into an interference mode quite frequently.

Hahn: Eric, conversations like this, you asking questions that might be uncomfortable — I don't feel like they are — these questions are really important to ask and answer. As a provider, I'd be asking these questions. You want to have confidence to recommend something to your patient. So let's keep this up, because I think the dialogue and the transparency are really important.

Topol: What's exciting here is that we've all been through a really rough year but we can look forward to the vaccines getting rolled out by perhaps the end of the year or early next year, and the monoclonal antibodies perhaps even earlier than that — these are fundamental things that will improve our lives, and there will be much better safety for treatment, for prevention, and ultimately for population immunity.

The last thing I want to get to is the rapid tests. They are the third prong, if you will. Everyone has tremendous hope that we can have home tests, pregnancy-like paper tests, which would give the answer right away. It is a separate path. It's basically testing infectiousness rather than infected, as PCR does.

Is there a willingness, do you think, at the FDA to open things up for a new path of testing infectiousness and not use the PCR standard as the reference?

Hahn: Absolutely. This is something that I think is a fascinating scientific and medical issue. The PCR tests detect pieces of RNA from the virus, and the antigen tests for antigen released by the virus in the nares. Putting this together to understand who is infectious is a really important component.

We started initially prioritizing PCR tests, because not many people were infected when the community started developing tests. We had to use contrived samples to actually do the testing and evaluation of these tests. And then we had to use real-world evidence. Now we're at a point where we can actually use patient samples to help us determine the positive predictive value, negative predictive value, sensitivity, and specificity of these tests.

We've now prioritized our resources on point-of-care tests and particularly around the antigen test, because they tend to be inexpensive and they tend to be rapid. We really believe that that's where we have to go to help with the mitigation efforts, but also at-home tests.

But as you can imagine, Eric, it's a whole different level with at-home tests because there won't be a provider that's providing information and guidance to someone who's doing this at home. We need to make sure that they're easy to use, easy to understand, and highly reliable. So there has to be good sensitivity and specificity. We have to have data that suggest, in a fairly large population, that they're going to be accurate for people to use, which is different from the beginning of the pandemic. Not that we didn't want accurate tests then, but we knew that providers and others were going to guide decision-making and that if you had a test result that didn't make sense, you'd repeat a test.

This is a totally different situation. So we are working very closely with manufacturers on at-home testing. We do not intend to provide any roadblocks, but we also want to protect the public health and make sure that these tests are as accurate as they can be, and reproducible.

Topol: Well, that's very encouraging and understandable.

Let me close with a couple thoughts and get your final thoughts. First, it's been a great experience getting to know you after a wobbly start of our relationship, because I was troubled. I was troubled, especially after the convalescent plasma, that we were heading into the vaccine story. And this was the biggest of all of your key decisions. But what you've done, not just in this conversation but in our other conversations and interactions, is shown what I believe is just remarkable independence and being forthright and getting the main trust established.

If there was ever a question about credibility, in my mind, that's not an issue. You have restored that and you have led during a very difficult time. I don't know how you do it on a daily basis, but kudos to you and everyone else at FDA. So, any closing thoughts on your side?

Hahn: Well, thank you. I really want to highlight something, and that is we have a remarkable workforce at FDA. They are America's FDA. This is science in action. We are pragmatic, but we're also very dedicated to the science. And I really appreciate the opportunity to highlight their great work. This isn't Steve Hahn's work; this is the work of career folks who have dedicated themselves to this, and they're remarkable. They are nonstop in this response. They've not been sleeping; it's been continuous since February and March.

I just want to end by saying that my hat's off to them, and to the medical community who have been taking care of sick COVID-19 patients. We're partners in this together.

Topol: We support you. We rely on you. I don't know of a juncture in medicine that's come like this. We certainly will be following everything that's being done at FDA. And we are hoping also —something that you can't control — to stop the interference from HHS and the White House and let you all do your jobs that you are meant to do, that you can do so well. We hope in some way that that extra noise will stop because we just don't need that.

Thanks so much for joining us today, Steve, Dr Hahn, Commissioner Hahn, and thanks to all of your colleagues who are working tirelessly to get the job done.

Hahn: Thank you, Eric. My best to all the folks who are watching this. And again, my thanks to everybody on the front line who is taking care of patients. Thank you.

Eric J. Topol, MD, is one of the top 10 most cited researchers in medicine and frequently writes about technology in healthcare, including in his latest book, Deep Medicine: How Artificial Intelligence Can Make Healthcare Human Again.

Stephen M. Hahn, MD, was sworn in as commissioner of the US Food and Drug Administration in December 2019. Prior to that he had been the chief medical executive at the University of Texas MD Anderson Cancer Center.

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Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.

Cite this: Eric J. Topol, Stephen M. Hahn. FDA's Hahn to Topol: Decisions Will Be Made Based on Science Alone - Medscape - Oct 09, 2020.