Dr. Joseph Ross: Omicron; The Drug Approval Process

Harlan Krumholz: Welcome to Health & Veritas. I’m Harlan Krumholz.

Howard Forman: And I’m Howie Forman. We are physicians and professors at Yale University. We’re trying to get closer to the truth about health and healthcare.

Harlan Krumholz: Today we’ve got a great episode with Joe Ross, one of our colleagues at Yale, a true expert in regulatory science, someone who knows the FDA inside and out. We’ll talk with him a little bit about the performance of the FDA in the time of COVID, but Howie, look, the news is just all over the place on this new variant of concern, Omicron. And I was saying this sounds like out of the Marvel Comics. I get it that this is out of the Greek alphabet. They wanted to skip nu because they thought it sounded like a new variant, so they skipped over to omicron. But I think when the public hears the word Omicron, that’s just scary in its own right. So what are you thinking about this? There’s been a lot circulating; you’ve been on a lot of calls. What are you hearing, and what do you think it portends for what’s going to happen next?

Howard Forman: We have a huge advantage this time compared with about a year ago. If you think back to when Delta variant was first identified, it was in December. It became a variant of interest in April. It became a variant of concern in May. We basically were overspread by it by the time we were taking it as seriously as we should have. We weren’t doing a lot of genotype surveillance at that time. We’re in a very different place right now. Our South African colleagues and many around the world have collaborated across nations to not only identify this as early as possible but ask the right questions. And so we have a head start on this, and we have a lot of other advantages going for us now. Our testing apparatus is much stronger. We have a very good vaccine program already in place, and we have therapeutics that are coming online over the next several weeks in all likelihood, one of which will come under review by the FDA this week.

So we’re in a very different place. On the other hand, this is very concerning. There are a little bit less than 30 separate mutations in the spike protein alone. There are probably a couple dozen more mutations compared with the last variants that we’ve looked at. This is a very different variant from Delta. It comes from a different lineage. And so people are concerned. Is it possible that this will evade our vaccines completely? Possibly, but probably still have some protection from vaccines. Is it possible that people’s native immunity that they’ve acquired through prior COVID infection will no longer protect them? It is definitely possible. So these are all questions that we need to pursue. We need to learn more about transmissibility. I’m not going to be a fearmonger, but I am going to stay very acutely aware of what’s going on. What are your thoughts?

Harlan Krumholz: I think it shows that we’re really very much, early into this, and we’re likely to be into this for a long time with the virus. New variants are going to show up. And I think the difference here was that there was a rapid response time before there was clear public information to indicate that this was going to be a highly consequential variant. Jeremy Faust, who we’ve mentioned before on this podcast, who has a really great blog called Inside Medicine that went on to ask this question, whether the WHO upgraded Omicron prematurely.

As you said, there are these various levels for the variants. There’s a variant under monitoring, which is when you can see that the genetic changes may affect the virus, may affect its behavior. There’s a variant of interest. There are genetic changes which are predicted or known to affect the viral characteristics, and it’s been identified to cause significant community transmission. Well, we didn’t actually really get that. The information out of South Africa is a little fuzzy. We’re not quite sure how many people were infected or what happened as a result. We’re hearing results from Britain, but whether this is actually causing problems is not yet known. You go from “variant under monitoring” to “variant of interest” to “variant of concern.” And at that point you want to have documented increased transmissibility, documented increase in virulence, and documented decrease in effectiveness of public health or social measures or vaccines.

And really, what I think happened was, the world said, “We’ve been burned before. We saw this thing going on in Wuhan. We sort of thought that maybe it could be contained, and everyone got burned by that.” And now you’ve got a situation where a new variant comes out of South Africa, now in Europe, with 30 mutations in the spike protein. And yeah, it suggests that it could be a problem, but it’s lacking these other criteria that we usually associate with escalating to calling something a variant of concern. A lot of the public may not have paid attention to the nomenclature here. Variants, variants of what. The variants of concern is supposed to be reserved for documented problems. And then you’ve got actually one more, which is a “variant of high consequence,” which is when there’s clear evidence that prevention measures or medical countermeasures aren’t working and that this thing is really spreading.

So the question everyone should have right now is whether this is truly of consequence or whether it’s just another variant that’s unlikely to actually cause considerable harm. There’s reason to be concerned about it. I know that sounds like “variant of concern,” but I don’t think it rises to the level that we’ve commonly associated with variant of concern. So we’ll have to keep posted. Look, the markets tanked on the news. I think there was a lot of widespread concern. We’re in a moment of uncertainty, anxiety; nobody wants to see the economy shut down again.

So I would tell everyone to hold tight, don’t panic. Probably we should stay with the fundamentals. We need to anyway. New variant or not, we’re not really having this current pandemic under control in any of the countries yet. And we need to get people vaccinated, we need to get them boosted, and we need to continue to practice good public health measures and stay tuned. Meanwhile, we do need good genetic surveillance of these variants so we can track and learn quickly whether or not they are consequential, because just because it has genetic changes doesn’t mean it’s going to translate into something consequential yet.

Howard Forman: Yeah. Look, a year ago, we were basically tracking the genome in less than 1 percent of positive tests. Now in the state of Connecticut, we’re about at one third, thanks to Nathan Grubaugh at the Yale School of Public Health and so many others that work with him. We have a testing apparatus in place. There are so many advantages that we have right now that allow us to watch this carefully. But as you point out, what can we do? We can continue to get vaccinated. We can continue to boost people who aren’t vaccinated. We can be judicious in our use of masking and avoiding events that we know are high-risk. And we can continue to watch this very carefully and encourage the scientists throughout the world, without necessarily taking draconian measures prematurely. So I may feel a little differently than you do about whether we should call it a variance of concern right now, but I do think our actions have to be tempered. And I appreciate you saying that.

Harlan Krumholz: Yeah. And just going back to basics, nobody’s behavior probably should be different today than it was last week. And on a national policy, we should be pushing hard to get people vaccinated. Everyone who wants to be vaccinated should be able to get vaccinated, everyone who wants to get boosted should be able to get boosted, and we should continue to practice good public health measures, recognizing that we’re not yet through this. And meanwhile, we should try to foster a sense of defiance as a society. Be strong, be resilient, support other people, be sensitive to the kind of stresses others are on. And let’s continue to try to move forward, be together, work together, and try to make some progress together.

Howard Forman: You know, meanwhile, all eyes are on South Africa right now. And I look at the data coming out of there right now, and people get confused by it. A week ago they were not counting antigen tests. Now they are counting antigen tests, and it scares people to see the number of cases go up by 600 percent in a short amount of time. But the data doesn’t even tell you whether that’s real or not. So we’re all sort of stepping back. We just got to watch this, be careful. I talked to one of my former students in South Africa early this afternoon about this. I think they’re reacting much more measured and carefully than we are right now. And I think we’ve learned a lot from their measured response to be driving the rest of the world.

Harlan Krumholz: My final thing is, I’m not sure about the travel shutdown. Look, I think that we could institute screening. We can actually even put in some quarantining, but when we start saying, “We’re going to shut down world travel,” I just think it sends all sorts of negative messages even before we know what’s going on. Again, I’m not suggesting we don’t do anything. There are measures that we can take that can contain this and can do screening and so forth, but we just have to stay tuned. Look, there’s a lot of concern, a lot of anxiety, and we just got to do our best to try to make progress together.

Howard Forman: I agree with you 100 percent, Harlan. Let me turn it back to you to introduce our friend and colleague.

Harlan Krumholz: Glad to do it. Joe Ross, who’s joining us today, is a professor of medicine and also of public health. He has more integrity than almost anyone I know and has contributed importantly to helping us see ways that we can improve the research ecosystem, our clinical care networks, and the way in which we interact with patients and the public. And I’m just so happy to have him here. Welcome today, Joe.

Joseph Ross: Harlan, Howie, thank you for having me on. It’s an honor.

Howard Forman: Thanks for coming here.

Harlan Krumholz: I hope, Howie, we can get into asking him a lot about the FDA and the FDA in the era of COVID and what’s going to happen next. But I wanted to get to some of the papers that you’ve written, and I wanted to talk to you about what they meant to you and what do you think that they meant to the field. So I’m going to take one for example that I just want you to try to explain to the listeners, what did it mean? So here, it’s got this fancy title, “Postmarket Safety Events Among Novel Therapeutics Approved by the U.S. Food and Drug Administration between 2001 and 2010.” It was published in JAMA, one of our best journals, in 2017. Most people won’t be able to make heads or tails of that title or why this was important. What was this about?

Joseph Ross: Well, thanks, Harlan. And thanks for giving me a chance to talk about it. I always try to do work that I think is at the precipice of the questions a policymaker is sort of flummoxed by. What are they trying to decide, what kind of information or research results can help them take better actions that can then lead to a healthcare system or lead to a regulator or other policies that are going to improve care for patients.

In that case, that was a paper led by an extraordinary Yale medical student named Nick Downing, who I worked with over many years, where we looked exclusively at what happens after a drug is approved with respect to new safety information, and how does the FDA act, what actions does it take. We all know that when a new drug is approved for use, there’s a lot of uncertainty at that initial time. And we don’t always know the full picture of its safety. And often, actually, we don’t know a picture of its benefits.

Harlan Krumholz: But wait a minute, I thought the FDA, when they approve things, tells us that they’re safe and effective.

Joseph Ross: Well, they do, but there’s “safe and effective,” Harlan, and then there’s “safe and effective.”

Harlan Krumholz: Wait a minute. You’re telling us that the FDA approves something, and they don’t know if it’s safe and effective?

Joseph Ross: When the FDA proves a new product for use, we almost never have a full and complete understanding of its safety. We understand whether it’s toxic. So if someone was to use a product in that immediate instant, is something bad going to happen to them? Maybe an anaphylactic reaction or something else that’s bad. But other types of safety problems, they take thousands of people in order to understand the full spectrum of safety of a product, but “safe and effective” is not a guarantee, and we continue to learn more about a product once it reaches the market.

So in this case, that paper in JAMA, what we were looking at is how often does the FDA take a new safety action after the product reaches the market? How often does new information accrue that leads the FDA to say, “You know what, we’re going to change the label of the drug to let people know that there’s this new safety problem,” or “We’re going to send a letter out,” like what they call a “Dear Doctor” letter. So in that paper, what we found was that about a third of drugs, there’s a new safety action that’s taken after approval.

Harlan Krumholz: So does this mean I shouldn’t be first in line to take the drug once it’s approved by the FDA?

Joseph Ross: Now you’re causing controversy, Harlan. That question of being first in line as the prescriber, as the taker, is really complicated. It depends on the individual context with which a person is trying to decide whether to use that medication. Maybe they have a severe life-threatening illness, and there’s no other therapy out there.

Harlan Krumholz: I know Howie’s chomping at the bit to get into the FDA and COVID, but let me just ask you one other quick one, because I think it’s related to this. You published another paper that I thought was really important. All your papers are important, but this is another one I thought related. “Assessment of Clinical Trials Supporting U.S. Food and Drug Administration Approval of Novel Therapeutic [Agents, 1995–2017].” So you looked at the quality of the evidence that was being used to make the approval decisions. What did you find there? Why was that important?

Joseph Ross: Well, that paper, I think, asked one of the most fundamental questions that we have to decide on as a society, in terms of how much evidence should be needed in order to demonstrate safety and effectiveness when bringing a product to market. How many patients should be enrolled into a trial? How big should that trial be? How long should it go on for? What we often hear from industry is that the bar is really high and really difficult to get over. What we often hear from patient groups is, “We want earlier access to treatment.” And when we started that paper, there had been no level set. We didn’t know what were the standards that were being applied.

So we reviewed, over eight years, every new product that came to market for the first time. What were the pivotal trials that supported that approval? And I think quite surprisingly, we found that common understanding is that every new drug is supported by two pivotal trials that clearly demonstrate safety and effectiveness. What we found is that a third of new drug approvals are approved on the basis of a single pivotal trial, and that when you look at the overall size of the trial, it’s not in the thousands, it’s often in the hundreds.

Howard Forman: Just for the audience, your word “pivotal,” can you just be clear what you mean by that?

Joseph Ross: By “pivotal,” what we were looking at is the key trials on which FDA rests its decision.

Howard Forman: The modern FDA is about 60 years old right now. It’s going to have its 60th anniversary effectively this coming October. And the FDA, as you’ve pointed out, is really charged with safety and effectiveness and obviously a whole bunch of other regulatory things but related to drugs. And what we’ve seen during this pandemic is both the unintended consequences of previous policy, as well as how difficult it is to come up with a one-size-fits-all policy that will work for every possible situation. One of the things that I was interested in most when you published it was your unapproved drugs initiative, which is drugs that got approved before the FDA’s modern era and never got reapproved after that. And the unintended consequence for me was that a pill had been pennies a pill was now costing dollars per pill. And I’m just curious what you think about sort of the unintended consequences of good policy. And maybe if you could explain what that initiative was, why it makes so much sense and what those unintended consequences were.

Joseph Ross: Yeah, the FDA’s unapproved drug initiatives is one of those great examples of the best-laid plans. Even when you introduced that, those drugs actually were not technically approved. Before the 1930s, there were no rules. I’m bringing a product to market, essentially. And there weren’t a lot of drugs either, so it was less of an issue. In the 1930s, we started doing regulations based on safety. And that was because the drugs that were available were things like cocaine and heroin, and they were being put into products and people were being hurt and harmed because they didn’t even understand what was in them. The modern FDA of the late 1960s, that’s when we start requiring products to demonstrate both safety and efficacy prior to coming to the market.

But there were a lot of compounds that were being used and were available for use like colchicine for gout, or levothyroxine for thyroid disease, and lots of other products, even insulin, that had been used and were available before the 1960s. And what the FDA decided much later on, I think in the 2000s or so, was that they were going to incentivize companies who were selling those products to go back essentially and confirm their benefit. This is like a best-laid plan, where they’re going to say, “We all know these work. Show us how they work. Let’s give you an approval that will help with regulation. Everyone will be happier for it.” But the way they set up the program is they gave companies essentially an opportunity to own the compound once they got it through the approval process.

And so while there were many companies maybe selling a product like colchicine beforehand and so it was available for pennies, even if the FDA had trouble regulating it, once it went through this process, the companies that now owned the approval were able to raise prices. And this is one of the biggest challenges FDA has. They don’t pay attention to price.

They pay attention to safety and effectiveness, and they’re responsible not just for drugs but also for medical devices and a host of other compounds. But obviously most people associate the drugs and food, of course. And when they make these decisions on what’s best from the regulatory standpoint, it often can have unintended consequences on the prices that we pay as patients, or when we’re prescribing the drugs as physicians.

Howard Forman: And another thing that is striking about the FDA, it’s probably the one example where the industry directly funds the regulatory process, and now is seen for many years as being brilliant because it came along during the big budget battles of the late 1980s and early 1990s, and was a way to fund the FDA without either raising taxes, which one party was not apt to do, or taking money away from other services, which the other party was less apt to do, so to speak.

So we were left with a situation where you either had a poorly funded FDA, which was approving things very slowly, or you had to come up with some other novel way, and they came up with this. Originally, it seemed brilliant, basically what we call PDUFA, for the Prescription Drug User Fee Act. But I’m curious about your take, particularly in the context of Aduhelm, which is the Alzheimer’s drug, about how do we make policy that doesn’t seem to involve too much of the hands of industry on the approval process. And I’m just wondering what your thoughts are on that.

Joseph Ross: So the user fee agreements that the FDA uses to fund a host of activities within the agency raise a lot of concerns around what, the term would be “regulatory capture.” And it’s a pervasive problem across a lot of government, even within the legislative system and in Congress, where the organizations and groups or agencies that are supposed to be regulating an industry are being paid by them to do the work. And it raises all sorts of challenges of conflicts and influence. From the FDA side, it also creates perverse incentives, so the user fee agreements are explicitly structured to fund certain activities with the agency.

So they are designed to support the pre-market activities, which means that they’re designed to fund and support medical officers to review applications, to ensure rapid reviews, bringing products to market. But those funds can’t be used for other things. So while they can be used to make sure that we get products to market more quickly, they can’t be used to ensure that the products remain safe and effective postmarket. They can’t fund postmarket activities. So they tie the industry’s hands in many ways by being so directed. It almost raises questions of whether it was shortsighted at the beginning to not raise taxes.

The FDA, it’s a billion-dollar agency. Now the number is escaping me. And that’s regulating essentially 25 percent of what’s being sold, used in the GDP. It is a huge bargain for the American people. The FDA has such broad oversight in such a small comparative or relative budget that perhaps we should revisit how funding is allocated and not be so reliant on industry to pay these user fees.

Howard Forman: Do you want to just say two quick words about Aduhelm before? I’m just curious if you want to just a few quick words about that.

Joseph Ross: I don’t know if you could hold me to two quick words on Aduhelm. This unfortunately I felt like was the sort of conflicts of a number of unfortunate events that coming together, where so this was this product that was being developed to treat patients with Alzheimer’s disease, an absolute horrendous disease that nobody would want to see a family friend or loved one suffer with. The idea was that this product was going to slow the decline, the cognitive decline of patients with the disease. And it was studied in two pivotal trials and both trials were actually stopped early by the data safety and monitoring committee because of futility. And by “futility,” that’s a term that was used to describe that when they looked at the two groups blinded to which one had gotten the drug and which one had not, they confirmed that there would never be a sufficient separation that one product would be considered better than the other.

So the trials were stopped. Those data were submitted to the FDA, as they have to be. And then there were discussions that people are not really aware of what happened, but essentially there were discussions between the FDA and the company. And there was a decision made about looking at specific subgroups. And that’s also done frequently, where when a trial is stopped, you look at subgroups, you try to figure out “Well, was there benefit somewhere else? Was something else happening that we should be paying attention to?” And that’s usually used to inform the next set of trials, but instead, those post hoc analyses were proposed to support the approval of the product.

All of this information I’m trying to summarize quickly was brought to an advisory committee, a group of independent experts to advise the FDA. They unanimously or near-unanimously recommended against approval, not only because they weren’t convinced by that subgroup analysis in that one trial and they thought that there was little evidence for effectiveness, but because there were clear concerns about the safety of the product. But despite that, the FDA approved it, and the company in turn set the price at nearly $60,000 per patient, just an astronomical sum.

So essentially what the company is asking patients and doctors to do is to use a drug with very limited, if any evidence of benefit—I would say none—clear evidence of harm, and to pay gross sums out of pocket in order to do that. And it was really a tipping point in the way people were thinking about this sort of earlier access to therapies and what it means, because the FDA relied on a surrogate, an unproven surrogate marker to support the approval.

It’s brought attention back to the oncology approval space, where there’s a lot of reliance on surrogate markers and to others, and a lot of discussion and debate around what should that evidentiary standard be? And getting back to that JAMA paper that Harlan asked me about, what should the standard be? How much evidence do we need before we say a drug should be safe and effective? Because once it’s approved, we almost never get good evidence afterwards proving its benefit.

Harlan Krumholz: Yeah, that’s a really good point. Look, I want to make sure that since we have you here, I wanted to just ask a question or two you about the FDA’s performance during the time of COVID. You’re an expert on regulatory science, you’re an expert on the FDA. The FDA has been challenged in ways that it never has been before to confront this pandemic. How do you grade their performance, and what do you think they’ve done best and what do you think they need to do better?

Joseph Ross: Well, I think it’s important to think about the FDA within the divisions that it operates within. So just sort of grossly, there’s the drug side; there’s the biologic side, which is responsible for vaccines; and there’s the device side, which is responsible for both medical devices as well as diagnostic tests. And all three have been asked to take on a just huge and enormous load in the context of this pandemic. Early on, it was about which therapies might prove effective, and the FDA, as I’m sure you guys have discussed on prior episodes, issued emergency use authorizations for products that were already available for use, essentially allowing them to be manufactured at a higher scale, knowing that they would be used in ways that they hadn’t been used before. Things like hydroxychloroquine. And that was based on really limited evidence.

It’s hard to fault the FDA for erring on the side of providing therapies and authorizing these products for use in an emergency fashion, because there was so much uncertainty and so much cause for concern in the early days of the pandemic. What I would have appreciated is that they reverse their decision when evidence was later shown that the drug was ineffective and unsafe, in the case of hydroxychloroquine. The emergency use authorization pathway was also used for remdesivir and others. And what I hope is that those drugs are going to still be held to the high standard or the higher standard of a normal new drug approval, that it’s going to come through the same process, it’s going to reach the same standards of a pivotal trial, and it won’t be based on limited evidence.

On the medical device side, I am less expert in the diagnostic testing space, but I think that what anyone can say, having watched what’s happened at the FDA, is that there’s just a substantial amount of confusion. At first, they seemed like they were making a glide path to bring almost any product to market that would be able to both diagnose the disease. That turned into a mess. I think is fair to say that the head of the center that regulates the devices wrote a paper in the New England Journal [of Medicine], almost like a mea culpa, like, “This didn’t work, let’s stop. We’re going to go back to enforcing higher standards.”

And then on the biologic side, the side in responsible vaccines, I don’t think you can make any criticism. I think they learned from the other center’s mistakes and tried to both impose higher standards while still going through the emergency authorization pathway. They’ve tried to be as transparent and clear as possible around what information and what data is being used to support the approval.

And on top of that, they’ve made excellent use, I think, of their advisory committees and making sure that other independent experts had access to and reviewed the data. And whenever they hold an advisory committee, it ensures that all the information is made public. So anyone can look at it. So I think that group learned from the others and has been really been the North Star on how to manage in a pandemic.

Howard Forman: So we have what I would call a very sophisticated audience, but they’re not necessarily physicians or scientists. What do you want them to know about the FDA right now, when we’re in the midst of a pandemic and where the actual load on the FDA is about as high as it has ever been. Do you have confidence in their ability to make the decisions that need to be made about the upcoming therapeutics, new vaccines? We haven’t even had full approval for most of the vaccines. Where do you come out on that?

Joseph Ross: I have a huge amount of confidence in the FDA and a huge amount of admiration and respect for the agency. One of the things that I think people often mistake my work for is criticism of the agency, because I think it’s one of the most important, crucial government agencies. It’s bound by science; it’s fostering public health. It’s really trying to act in the public’s best interest. But all of my work is really designed and dedicated toward trying to make the agency work better.

To me, the biggest threat right now is not COVID, it’s the load that COVID has put the agency under. So many people, there’s been massive brain drain, there’s inadequate funding to support the infrastructure that the FDA needs. It’s the overreliance on user fees, like we talked about earlier. And there’s the constant push among members of Congress and the broader patient populace that we just need products. It needs to be easier to bring things to market.

I think it’s misguided and very shortsighted. The regulatory standards that we have in the United States are highest, still, bar none around the world. We don’t do a good job on coverage, but we do an excellent job on regulation. And by that, I mean the FDA is the model for the world on what evidence should be needed to bring a product to market. I think the bar should be higher, but I understand that most of our society thinks the bar should be lower, but that doesn’t mean that I think that we should be dropping it. And so that pressure on the agency is going to have massive ramifications for all of us.

Harlan Krumholz: Well, I just want to say, I’ve been observing your work for the longest time, and I can say that you and then the work we’ve collaborated on, and we’ve always wanted to convey the deepest respect for the FDA, but improvement requires critical thinking and sometimes critical evaluation. And I think you’ve walked that so well. And it’s emblematic of it that you’re actually running a center funded by the FDA to try to advance regulatory science. And I think that that’s real success.

I want to thank you so much for joining us today. It’s been a great pleasure to be able to have you share your thoughts, for us to be with you, and we just want to say thanks.

Howard Forman: Thanks, Joe. And thanks, we want you to come back sometime, but we’re grateful that you made time today.

Joseph Ross: Oh, I’m delighted to be asked. I’m happy to join anytime. And of course, utmost respect for both of you, and thank you for having me.

Harlan Krumholz: Thanks, Joe. You’ve been listening to Health & Veritas with Harlan Krumholz and Howie Forman.

Howard Forman: So how did we do? To give us your feedback or to keep the conversation going, you can find us on Twitter.

Harlan Krumholz: I’m @hmkyale, hmkyale.

Howard Forman: And I’m @thehowie. That’s @thehowie.

Harlan Krumholz: Health & Veritas is produced with the Yale School of Management. Thanks to our researcher, Sherrie Wang, and to our producers, Blake Eskin of Noun & Verb Rodeo and Miranda Schaefer. Talk to you soon, Howie.

Howard Forman: Thanks, Harlan. Talk to you soon.