John Donvan:

Hi, everybody. And welcome to Open to Debate. I’m John Donvan. And you have no doubt heard about the FDA, the Food and Drug Administration, which has a long history way back to the days of Teddy Roosevelt, the agency that guarantees the safety of products we put in our bodies. They’ve probably saved and awful lot of lives over the decades just by insisting on caution. But now, remember, in the pandemic, there was an emergency unfolding and there were vaccines being rushed into existence, and even though the FDA did speed up the usual approval process, it was still criticized for moving too slowly in some aspects of all that. That is a frequent pressure point for the FDA that in wanting to keep us safe, it is accused of getting in the way of innovation and blocking people from getting drugs in time. There is a real push and pull here in achieving a balance between safety and urgency, and that’s what this debate is all about.

We’re in front of a live audience in Aspen, Colorado at Aspen Ideas: Health debating this question, Is the FDA too Cautious? So let’s meet our debaters, arguing that the answer to question is yes, that the FDA is too cautious, CEO and co-founder of Aitia, an innovative health AI company that is aimed at discovering the next generation of breakthrough drugs, please welcome to the stage, Colin Hill. Welcome, Colin.

Colin Hill:

Thank you.

John Donvan:

Have a sit. And arguing that the answer to that question is no, that the FDA is not too cautious, physician and president of the Center for Science in the Public Interest and a former associate commissioner of the Food and Drug Administration himself, Peter Laurie. Welcome, Peter.

Peter Lurie:

Thank you.

John Donvan:

Thanks so much. All right. This is lovely. We’re debating an issue of regulation and we have on our stage the regulated and the regulators, (laughs), so we’ll see how, we’ll see how that meets up. We’re going to start our first round with opening statements by each debater, they get up to 5 minutes. It’s their chance to really make their case to you, to lay out the outlines of their argument. And Colin, you’re going to go first with that. Again, you’re answering yes to the question, you’re saying the FDA is too cautious. The floor is yours.

Colin Hill:

Thank you. So we can argue that the FDA is more innovative than other agencies in Europe and Canada and Asia. We can also argue that we have now, in Rob Califf, the most innovative FDA leader, I think, we’ve had in our generation, and that’s all true. But I don’t think that’s the right question or the right point it comparison.

The real question what could and should the FDA be doing to encourage the approval of many more drugs than we currently have today versus last year with 22 drugs approved, that was the lowest number of drugs approved since 2016, versus, in the backdrop of all of the advances in science and technology, the rise of big data, the rise of generative AI and digital twins, the ability to make our mRNA vaccines and drugs rapidly when we need to.

Shouldn’t we be doing something differently? Could we see three times or five times the number of drugs approved in a given year that we see today? And I believe the answer is yes. We do have accelerated approval mechanisms within the FDA that have led to a number of drugs being brought to market faster than under traditional guidelines, 3.2 years faster.

For example, 40 cancer drugs have been brought to market that otherwise would not have been brought to market or would have been brought to markets more slowly. Out of all the drugs that have been brought through accelerated approvals, only 12% have not received full approval.

So one question is, shouldn’t we just do accelerated approvals for everything. Can we and should we be using real world evidence to create more evidence for efficacy and safety than we do now at a much lower total cost of care. So just to put it into perspective for those who aren’t in the industry, right now it takes $2.6 billion to bring a new drug to market, takes 10 years. And the number of drugs that make it to market, and make it to patients after getting to the phase one testing and clinical trials is less than 10%. That’s unbelievable.

There’s no other industry on the planet where after spending millions of dollars in preclinical testing to nominate the best drug candidates to bring into human clinical trial testing, we only have a 10% success rate, 90% failure rate. Imagine if the aerospace industry operated like this, or the semiconductor industry operated like this. Um, I believe that this is not sustainable anymore, especially in light of other advances happening in the industry even connected to the drug price controls.

The Inflation Reduction Act is changing, fundamentally, the way the industries operating. There are now lawsuits going on today, and we’ll see where that ends up landing. But can we keep going like this? Can we soon eventually get to $5 billion to develop a drug and the time scales going longer and longer? Or can we bring in innovation right to the beginning of the process, throughout the process that allows us to now change the way clinical evidence is created, to use real world studies in much more diverse populations that that reflect our real world versus relying on some outdated standards that I think, at the end of the day, don’t serve the best public interest?

And so, I’m calling for a more radical, structural change to the FDA, a smart one like not letting up on safety regulations. But I think the time has long come for a different way of evaluating efficacy of drugs and medical devices across much bigger populations and using the tools of big data, digital twins, advanced AI. On the one hand, in the rest of the industry, they’re calling for a, um, a pause on the AI research because it’s becoming so powerful, in our industry, we haven’t even scratched the surface. So let’s go through that transformation for the benefit of all of us. Thank you.

John Donvan:

Thank you, Colin Hill. And now, Peter Lurie, the floor is yours to answer no, the FDA is not too cautious.

Peter Lurie:

Okay, well, good morning, everybody. And Colin, pleasure to meet you. John, uh, thank you for inviting me.

Um, so, you know, what this debate really is about is getting the exact right balance between ensuring that patients get the drugs that they really need as quickly as possible and making sure that they aren’t unduly harmed by drugs that aren’t safe or ones that turn out to be inefficacious, and that end up costing us billions of dollars. And I think that, you know, that is the es, essence of this debate. And I think that the FDA, at this point, has more or less, gotten it right, and you’ll hear some criticisms from me.

But when caution, let’s at least unpack for the question. Are we talking about caution as in too fast or not fast enough? Um, or are we talking about caution as in this, eh, as it relates to the product approval standard? And I would submit that FDA is not too cautious with ei, with respect to either of these. Let me take them in turn.

So first of all, with respect to speed, it used to be so that it took about two or so years, but you’ll say, 30 years ago, 2 or so years to bring a product to the market. FDA was subject to all kinds of criticism. Huge changes have been made. The average times are much lower now, certainly well under a year. Uh, in fact, they’re required for, to meet the particular deadlines of the six months for what are called priority review drugs or 10 months for standard review drugs. And I can tell you, they meet those standards. And I’ll also tell you that the industry, which is largely responsible for imposing those standards upon FDA is not even asking for them to be quicker anymore because they know that all of the blood has already been taken from that stone.

The, um, in fact, I do think it’s reasonable to compare us to e, European Union. Your, your view, I understand, Colin, is very much about the future, and I appreciate that. Um, but in the world in which we currently live, looking at what’s going on in other countries seems to be reasonable. And when you do, you find out that the US approves drugs, on average, 60 days faster than in the, in the in the European Union, and you find out that the FDA has four separate expedited approval processes including the accelerated one to which Colin just referred, um, all of which are ways to get drugs to patient more quickly if they have serious or life-threatening illnesses.

So again, lots of progress has been made. Um, I don’t think that there’s a viable criticism any more that says that FDA is too slow or, and certainly not that it’s slower than anybody else.

Now, with respect to the approval standard, um, in any given period of time, FDA approves more drugs than comparable places like Europe or Canada, for example. Um, and the problem though is that there are not, as much as we would like it to be otherwise, very often, huge additions to the therapeutic arsenal. More, more often, they’re something we call me‐too drugs, drugs that that are some chemical tweak on an existing drug. That’s why we have, last I counted, two dozen nonsteroidal anti-inflammatory drugs. We don’t need a 25th, it’s not gonna make a difference to to people in this world, in all likelihood, unless they can show that it’s somehow very different.

So, researchers have gone and looked at the drugs that FDA approved. And the Europeans and the Canadians have these systems where they actually measure whether the drug has added therapeutic benefit. And when they did that under the most, you know, permissive standard, no more, uh, the, eh, eh, 60% of the, of the drugs had no added therapeutic benefit compared to their predecessors. They were not really bringing anything substantially new to the market.

Now, we’ve talked already about our accelerated approval, and another one of these expedited processes is called Breakthrough. These are processes that have fewer data requirements. Again, part of the FDA’s efforts to reform itself over the last several decades. So accelerated approval, instead of having to prove, say for a cancer drug, that you have improved survival, you can show, um, to get accelerated approval initially that you have made, had a difference on some kind of a maker. Like you can show that the tumor has shrunk, for example, or that, eh, that there doesn’t appear to be progression of the illness.

Um, on that basis, you can get, your d, your drug approved under accelerated approval as long as you do follow-up studies. Okay, sounds good. And as Colin says, about 90% of the time, they do confirm the, the approval, the, the apparent efficacy with the surrogate marker. But there are three problems. The fir… And I think 90% is a good number, by the way. I think that’s just about where it should be. Um, but there’s problems.

When they confirm the surrogate marker evidence, most of the time, they confirm it with another surrogate marker, even, sometimes, the same surrogate marker. Um, and so that’s not really, I don’t think, what we had in mind when accelerated approval came to market in the first place.

John Donvan:

We’re going to take a break right now. We are debating the question, is the FDA too caution? And when we come back, we will continue the debate. I’m John Donvan. This is Open to Debate. We’ll be right back.

Welcome back to Open to Debate. I’m John Donvan. We are debating the question, is the FDA too cautious? We’ve heard opening statements from Peter Lurie and Collin Hill. And now, we’re going to get right into the discussion.

I want to thank our debaters for their opening statements. And just to summarize a little bit of what I heard and, I think, where we will be going, we heard Colin argue that he feels that the FDA is working to an outdated standard. He’s calling for a radical structural change. He makes the point that if some approvals ha, can be accelerated and have been accelerated, why can’t they all be accelerated?

Peter responds that he feels that the FDA is getting the right balance. He was laying out various ways in which that is the case. I think we’ll hear more of that as the conversation unfolds. But he, he stresses that wo, it is also the mission of the FDA to make sure that people who are at the consuming end of these products are not unduly harmed. He also points out that he feels that the FDA, compared to other approval agencies around the world, is actually, uh, doing, uh, a very good job of approving drugs that people are asking for and that company is developing.

I want to go to Colin on the phrase that Peter brought up of unduly harmed. The medical profession has, as, as its core principle, do no harm. The FDA was founded to keep people from getting hurt by stuff that was out there. You’re saying that you feel the agency’s practices are too cautious. What is, philosophically, the correct level of caution? What’s the degree of caution that you feel makes sense?

Colin Hill:

So I believe the FDA is getting the level of caution right when it comes to safety. I’ll repeat, when it comes to safety, I think the FDA, uh, has the level of caution that it is about right. When it comes to efficacy, I do not believe that’s the case. What we’re really talking about is the creation of new drugs, going after new targets, new pathways for diseases with great unmet need. That’s the real debate here. And the question on the efficacy side is, can and should the FDA be doing something differently to allow more of these drugs to come to market to also lower the barrier of entry? I mean, what we’re not talking about here yet is, on an intimate level, what goes into the decision making of a biotech company or pharmaceutical company to advance and go after new high risk areas of science? So the amount of circuitry of human disease that is known on a genetic level is really low, it’s around 5%. So it’s really low. That means for missing 95% of the circuitries hidden after all of the advances in technology after the sequencing in the human genome, so on and so forth-

John Donvan:

Okay, I think we’re getting where you’re going with this-

Peter Lurie:

Yeah.

John Donvan:

Let’s let Peter respond. Oh, thank you. Thanks.

Peter Lurie:

Listen, I love the work that the Colin is doing, I sincerely do. The man’s in the innovator. The man is a disruptor. The problem is most of the industry isn’t Colin. That’s the problem. The, the industry is more [inaudible

] than Colin. And most of what they’re producing is not doing that much for patients. If you look back, and fortunately, I can look back at decades of experience at this point, you know, what, you don’t see as much of this extraordinary, you know, development, innovation, what you see instead, sometimes, are drugs that did very little, drugs that killed people, drugs that caused a, allergic reactions that should have been detected, and on and on like that.

The, the sad truth is that, all the way through medical history, we have had people who’ve made the promises that you have, the promises that, well, this, the antibiotic era is going to change everything. Right. The, you know, the, the, the, the new ability to divine chemical structure and match it with function, that’s gonna change everything. It’s always on the horizon. A lot of the time, it never happens, but what does happen is that, along the way, if we don’t have an FDA that is protecting people on both the safety and the effectiveness side, we end up with a lot of bodies. That’s what the agency is preventing.

Colin Hill:

Um, look, I, I am a big supporter of the FDA and its currently leader. But I think the agency needs to be pushed to do more innovative things like e, e, e, you know, it’s hard to, I think, reconcile the worlds of technology that are moving at lightning pace, lightning pace, where there’s, for the first time in my lifetime, there’s a call to slow down the technology, let’s put a positive on innovation and AI, and then on the other hand, we’re saying, we don’t think science is going to win?

John Donvan:

But I, I think I here Peter saying that the culture of the FDA is that they are the bulwark against the risk that’s in there.

Peter Lurie:

Right.

John Donvan:

And if they’re not taking the line that they take, I don’t want to call it a hard line, but the position, the stance that they take or kind of being the stern school mom about this stuff, especially when they’re under political pressure, that bad stuff can happen.

Colin Hill:

100%.

Peter Lurie:

Well, that’s right. And e, e, you know, the, all the pressures on the agency are about getting drugs out of faster. That’s where all the pressure is. You’ve got the Colins of the world up there telling, telling Congress how much they need to be faster. They’ve got, you’ve got the industry-funded patient groups who are out there telling you that you need the drugs. So all the pressures on the agency to approve. And I can tell you, personally, when we were there, when when I was there, we looked at an approval as a success.

My question to you is this, if there’s all this innovation and FDA is such an obstacle, name one drug that you think FDA is currently keeping from the market that would make a difference.

Colin Hill:

Um, so the use of MDNA in patients with PTSD.

Peter Lurie:

Studies are ongoing. They’re not completed, they will be. They’ve got their expedited pro, programs that they need to deal with it if, if that’s what they deserve. And they will, they will be duly approved if they can show their effectiveness.

Colin Hill:

And I would say, in that case, it’s about 18 months to two years later than the data shows clear efficacy, no adverse events.

Peter Lurie:

Yeah, you see, this is the thing, you know, the idea that people believe in how effective these drugs are. Not only is it true that many of them are not innovative, many of them do less for us than we wish they did. The, the degree of efficacy is very often smaller than people would like to believe. And that’s why, in accelerated approval, we had these problems in recent years. The drugs that have been controversial are ones that, even at, in the best of circumstances, Exondys, for example, or Aduhelm, even if you were generous, they did the tiniest little bit of good for people. So you know, in that case, you have to look at the side effects, right, because you can’t separate safety from effectiveness. What the standard requires-

Colin Hill:

I don’t think it’s… I don’t think-

Peter Lurie:

… a balance between safety and effectiveness.

John Donvan:

I think Colin is arguing that point, are you not?

Colin Hill:

Uh, correct.

John Donvan:

For that balance?

Colin Hill:

Uh, I, I’m absolutely arguing for that balance, but I’m arguing for that balance to be in a different place and for, let’s say, more radical approaches, which are going to look so radical after we do them, to start to be considered. Because I, I think you brought up a good example of even a recent Alzheimer’s drug-

Peter Lurie:

Mm-hmm.

Colin Hill:

… that had relatively weak efficacy-

Peter Lurie:

That’s generous.

Colin Hill:

… which, which, which has to do with the fact that we, we’re missing most of the biology, right? And-

John Donvan:

Just, just for folks out there listening who… Efficacy is a four letter Latin na, word, that it works.

Colin Hill:

That’s right.

John Donvan:

That the term-

Colin Hill:

Effectiveness is fine.

John Donvan:

… that works. Effectiveness, okay.

Colin Hill:

You’re right. And, and-

John Donvan:

So it’s just a term of art that may, may not be familiar to everyone in this context.

Colin Hill:

That, that’s right. And, and you can’t talk about efficacy or the fact that it works without talking about the personalized medicine because there’s certain drugs that will work for Peter that are just not gonna work for me for reasons that we are starting to figure out a lot faster because we now have genomics, we now have, eh, the ability to measure our biology in exquisite detail much faster, much cheaper than ever before.

Has the FDA really changed and evolved to accommodate these advances in data and science and technology? And, and that’s really what I’m arguing about, not that they’re not doing a good job within their, their current sphere. I’m Canadian, so I grew up, of, often looking at the US as the place where things were bigger, better. And I’ve spoken with my feet that I’m here. And when it comes to the regulation and the drugs, the FDA is better than Canada, better than the EU, 100%, that, this, take that off the table.

The question is, what could the FDA become as the world leader in regulatory science?

John Donvan:

Do you want to respond? I have a question for you but I want to address this point.

Peter Lurie:

Yeah, no, no, I, I, I think that’s a fair question. I, I, I do. And I do think that, you know, to the extent that people like yourself bringing new technologies and new abilities to, to evaluate drugs that can be, you know, validated, then I, I think the agency will be open to them, but they have to be validated. It’s not enough to say, you know… I feel like I’m in a, in a Beach Boys song here. … “Wouldn’t it be nice?” You know? That’s, that’s not where we are, right? That’s not where the agency lives. It has to make these life and death decisions on the drugs that come before it. And if it gets new tools, I’m sure they’ll be happy to use them, but for the meantime, what we have are randomized controlled trials that, over and over again, have proved that they can separate between the effective, the ineffective, the safe and the unsafe. And we have to stick with those until someone can show that there’s a validated, better way to do it.

John Donvan:

Colin, what, what incentives do you think are in play within the FDA to operate the way that they operate? If they get it wrong, if they approve a drug that hurts a lot of people, nobody’s going to be on their side.

Colin Hill:

Yeah, and I want to be just 1000% clear, when it comes to the safety side of things, I think the FDA has to be cautious, and I think there’s the ability to use lots of new data and technologies to do that. So the safety side has to be the way it is, I think it can be better and will get better.

But on the efficacy side, the FDA is not going to get beaten up if they approve drugs that end up showing less effectiveness than was hoped or was shown in part of a very relatively small clinical trial. And I actually think the FDA needs to embrace real world studies to test drugs in much broader populations, in much deeper ways, and prove the value, especially in a world-

John Donvan:

And, and, and for those of us who, again, would not know the details, in what way are they not doing that?

Colin Hill:

In what ways are they not using real world data to-

John Donvan:

Yeah. Mm-hmm.

Colin Hill:

Well, let’s say, for example, phase three trials could be a fair bit smaller than they are, lowering the cost, allowing a lot more investment and innovation to happen. But with the corresponding requirement for real world studies that are actually measuring both the efficacy, safety, cost-effectiveness across a wide variety of patient types and patient genotypes, this is absolutely possible.

We’ve just lived through COVID, right? I mean, we were all swv, stuck in our houses concerned about getting sick and dying, and especially knowing that how long it normally takes to get a drug or vaccine approved. Magically, things got approved a lot faster, as they were years ago during the AIDS crisis, when people were demanding change, demanding speed, speed happened. And I think we have to take that same kind of crisis mindset and say, “Well, what if we did things differently? What if we, what would that look like while we still protect the American population?

Peter Lurie:

All right. Let’s-

John Donvan:

So you propose an alternative, let’s see.

Peter Lurie:

Well, I think, you know, COVID is a fantastic example of, of the FDA, of why these standards matter at FDA. So, you know, first of all, those vaccines came to market incredibly quickly, mind you, with US government money, to a very large extent, they came to market quickly as quickly here anywhere in the world. The things that came to the, to the market sooner here mostly turned out to be mistakes. You know, discussions about Ivermectin, discussions about hi, uh, eh, convalescent plasma, you know, discussions about Hydroxychloroquine, right? And there, the FDA got incredible pressure to approve, right, to bring products to market. They did through this other mechanism called EUA, which we don’t need to get into, but spe, special for pandemics.

John Donvan:

Emergency use authorization.

Peter Lurie:

Emersery, eme, emergency emergency use authorization. And then, they had to backtrack half the time because as it turned out, they had gone too fast and there were bodies on the floor, they were people who got killed by Hydroxychloroquine, they were people who overdosed on Ivermectin because they bought it from a veterinarian, for God’s sake, right? And so, you know, I, I… And the the same thing, by the way, happened in medical devices. They lowered the standard for medical devices, they let a bunch of diagnostic tests onto the market without reviewing them. And of the first 125 that they let on the market, the great majority of them turned out to have problems.

So, that’s what happens. That’s, that’s the history of it. That’s what happened. That’s why we we have the efficacy standard from 1962. And when, in 1962, they reviewed all of the preceding drugs to clear out all the stuff that had accumulated when there was no efficacy standard, they got rid of two-thirds of them because people were sure that they worked, because they’d seen it work in the real world, because they had a patient who they knew it worked for, but they were wrong.

John Donvan:

Your response, Colin.

Colin Hill:

So, so I’m a physicist by training, right, and was moved in early into the genomics and biomedical and AI world. So I believe in science, I believe in the, the, the data proving out the efficacy and safety of new products, full stop. So if there’s crap, it shouldn’t make it market and we should, eh, you know, be even more rigorous in bringing as much data and technology as we can to evaluate it. So that’s, that’s not the question about whether we should just willy-nilly let lots of things come to market, no, let’s have the, the, the scientific standard.

But I think it’s time to evolve and modernize the scientific standard much more than in the past. So under Doctor Califf, we saw something we’ve never seen before, which is the ability to now bring drugs into human clinical trial testing that have not gone through animal tests. For the first time in decades we don’t have to kill and use animals which are not, were never a great proxy for a lot of human diseases anyway. And so, this is amazing. The use of organoids, which are spherical sets of cells, the use of labs on chips, organs on chips, the use of computer models and digital twins of patients. That’s the kind of radical innovation that the current administration is you using, but let’s take it further.

Peter Lurie:

So, if I’m not mistaken, I think you just conceded my point. Um-

Colin Hill:

(laughs).

Peter Lurie:

… the, uh, the, the standard is re, is substantial evidence of safety and effectiveness. And you seem to agree that that’s the right standard. What, what you’re asserting, and I’m not saying that this isn’t so, is that in the future there may be a different way of meeting that standard. That’s what I think you’re saying. But you’re not actually arguing that the standard is off. The standard, I think, is okay with you. I don’t think you want these lousy drugs coming to market anymore than I do. I don’t think you want unsafe drugs coming to market.

But if the solution to your fear that, you know, these new innovative drugs is, should come to market faster, the solution that people will come up with will be a lower standard. That is what it will be. It will be letting these Exondys’s on the market, it will be letting Aduhelm on the market. It… You may have a drug in mind that will be neither of those things, but what FDA has to do is to protect against the great majority of drugs that will not be, you know, as innovative as you believe yours will be. That’s what they have to do. That’s most of what their work is. And that’s why the standard is what it is.

Colin Hill:

So you’re correct, I believe in the standard. I am not advocating for less efficacious drugs to make it market. I am arguing though that there are pathways that exist today that are not being fully utilized as much as they could be. And I’m also arguing that there are, there’s massive changes in data and technology that are not, that have not yet come the way that drugs are approved. And the result is, the cost and time to bring new drugs to market just keep going up and up and up.

John Donvan:

So, Colin, what, what do you think accounts for the fact that… I, I think you’re saying that the FDA is not keeping up with the possibilities, is not evolving, is using outdated methods. What, what would account for… First of all, I, I don’t think Peter agrees with that assessment in the first place, he’s made that clear, but you’re making that case, what do you think accounts for that? Are they, are they just playing safe? Is, is it, is it just bureaucratic inertia? What, what, what would you say is going on there?

Colin Hill:

Look, I mean, at the end of the day, it’s a conservative government agency and bureaucracy, so of course, they’re playing it safe, like, and, and, and I think, they’re generally going to be playing it too safe, it’s what government agencies like that, like that do, until there’s a crisis, until there is, uh, something that pushes them faster. I think the diffusion of technology and data to really change the agency is generally too slow. And we have to take a step back and say what can and should this be? And what are the tools we have at our disposal today? And I’m not saying I know the answer, but I’m saying this is, a, something we should treat with urgency and not just kind of rest on our laurels, saying, “Yes, we’re better than Canada. We’re better than Germany. So all is well.” I think when you have patience dying of diseases where they’re just aren’t good options, you say, “Huh? Really? Do we not have better drugs for my mom’s stage three or stage four breast cancer?”

John Donvan:

We’re going to have to wrap this up here and take a short break before we get into our Q&A portion for this program. We’re debating the question, is the FDA too cautious? I’m John Donvan. This is Open to Debate. We’ll be right back.

Welcome back to Open to Debate. I’m John Donvan here with Peter Lurie and Collin Hill. And we’re defending the question, is the FDA too cautious?

Peter Lurie:

I think that you perhaps misunderstand the, the way the FDA does experience pressure because there’s… Something, John, you raised earlier. Most of the time when a drug kills people, take Vioxx, for example, right, the way that people die is, is in a statistical sense, right? You have a 1.5 times greater likelihood of a heart attack, let us say, with Vioxx than if you didn’t take it. That means that if I am taking Vioxx and I get a heart attack, it’s actually more likely than not that Vioxx didn’t do it, I just got the heart attack I was gonna get anyway. And if you take it to court on that basis, you are not gonna win your, your malpractice or product liability case.

So many of the safety concerns, unless they’re really are obvious and really unique are not even going to be, do not create pressure on the agency in that way. The pressure is on the effect of this. And that is why a, almost every single reform in the drug area in the last three decades has been in the direction of pushing FDA to be faster, to pushing FDA to lower the standards. That’s the way everything has been going. And I can tell you that, as I mentioned earlier, the agency sees getting drugs out there as a success because on Congress, in Congress, the pressure is not on the safety side anymore, it’s on the business friendly efficacy side-

John Donvan:

I have to take-

Peter Lurie:

… and that’s what the agency is responding to.

John Donvan:

I have to break in to go to questions now.

0033:06

Speaker 4:

The question is, and the Alzheimer drug is a great example of where they got into deep trouble, where they gave accelerated approval to a drug were the evidence wasn’t there and their own advisory committee voted against it. So what can the FDA do? Could it work for the FDA to having new pathway, coverage with evidence development instead of approve or not approve-

John Donvan:

Okay.

Speaker 4:

… the in between?

John Donvan:

Great. Thank you. You, you haven’t spoken in a while, Colin, so I’m gonna let you go first.

Colin Hill:

Yes. The simple answer is yes. Like what stops that pathway from being created? And that kind of goes to the heart of, of, of my issue with how the FDA works. Now, let’s let the efficacy be sorted out in patients, that’s the only way it’s actually going to happen, otherwise, we’re going to have trials that are just way, way too big to figure it out, especially as we’re getting to more precision medicine, biomarker-driven things.

Peter Lurie:

It’s about the balance of safety and effectiveness, so it would require statutory change, but the accelerated approval is supposed to be that pathway within the limits of what FDA can do, right, it’s supposed to let you on the market with the promise that something will come. The problem is, the, the studies take a long time to get done, and more over, when the drugs do come to market and they turn out to be non-confirmatory, not, you know, totally non-confirmatory, not just not another surrogate market like I earlier said, then it becomes impossible, practically, to get the drug off the market like Avastin, or Makena. These are drugs that were stone-cold negative in their confirmatory trials. And Even so, it’s impossible to get the drug off the market because the, the drug companies pull together the patient groups, the Congress people getting involved, they say that, “People are dying. You gotta do something. Keep the drug on the market. Keep hope alive.” That’s not a scientific standard.

John Donvan:

Another question.

Speaker 5:

So I have to say, first, I’m a drug developer and I worked at FDA, so I’ve seen it both ways, and it’s very important and I agree with both of you, and I’ll show you, I’ll ask the question of where the issue is. The issue in the FDA is not to approve or not approve fast or not, it’s changing the processes. And the question is why not change your processes sooner rather than later? For example, stopping using cyno monkeys for certain drugs. Could have been done 5 or 10 years ago not now.

John Donvan:

Okay. Yes, take that on, Peter.

Peter Lurie:

The general point is the agency should be open to innovation, and I agree with that. And you know, I do think that real world evidence has its role, especially in, in the safety side, much less so in the effectiveness, as I think you said. You’re gonna have to, ultimately, put it into patients and see how they do. You’re gonna have to follow them and see what happens. But I agree, you know, to the extent that the new technologies come, the agency should be open, and I, you probably right that culturally there, there is a resistance. Um, one of the difficulties is bringing in new people who are young and have fresh ideas. And what tends to happen, because of the hiring structure, within the agency is you end up with people who, you know, look like me and they stuck around for a while.

John Donvan:

So are you, are you now conceding the point?

Peter Lurie:

No, I’m not conceding the point, I, I’m conceding the point that, that agencies can be conservative in terms of their openness to new technology, yes, I would concede that point.

John Donvan:

Okay. Another question.

Erin Williams:

Good morning. Hi, I’m Erin Williams with MITRE. Um, I love the debate format. And I’m wondering actually whether there might be more consilience in your answer if we broaden the aperture and look at, the, the relationship between the innovation pipeline and the needs of public health at a large scale. What do you think about looking at the broader innovation pipeline versus just pressure on the agency.

Colin Hill:

Yeah. Eh, eh, I think that’s a fantastic question. And the answer is absolutely. And we see this in other countries like in the UK we have NICE, in Germany, they also tie, um, approvals to cost-effectiveness. It’s happening sort of slowly in this country, right? CMS now, for the first time, is going to be negotiating drug prices. And I can tell you, within the biotech and pharma community, this is a really, really big deal, especially when you combine that with the IRA.

And so, what people have been sort of scared about for a long time is coming. And I think, I actually think the industry, the biopharma industry should embrace it. And I do think we should start to tear down the most silos because it’s silly that, the, the arm that it’s paying for it is not talking to and connected to the entity regulating it or the entity funding a lot of the biomedical research. Like we can better. Is… And I think your question gets at what I’d like to see that, you know, the FDA can optimize and be the best in its little silo, and I feel like that’s what Peter is arguing, and that’s great, but we don’t want to just be the tallest daisy in the bunch, we want to make a whole new field of the daisies that, um, really changes the world and changes-

John Donvan:

Is that, is that a Canadian saying? (laughs).

Peter Lurie:

Uh, no.

John Donvan:

I love it.

Peter Lurie:

It’s actually, it’s actually from Charlottesville, Virginia, of a, a, uh, a board member from, uh, from there, [inaudible

].

John Donvan:

It’s great. Peter, you want this one as well.

Peter Lurie:

Yeah, well, I, I, you know, I agree. Yeah, having worked FDA and other pa, and dealt with other people at HHS, yes, things are very siloed. And there are things that fall down the cracks, you know, like, for example, the, you know, the the economic causes of drug shortages. That is the thing that affects every HHS agency, and yet, none of them. And so, we struggled with it for that reason, I think. So, I, I, I agree.

The sta, the regulatory, sorry, the statutory standards are different, as you know, it’s reasonable, you know, assurance of safe, uh, substantial evidence of safety and effectiveness. Uh, you know, the standard for CMS is inn effect lower than that, it has to be, you know, necessary. And that’s how you can get a space between something that FDA approves and something that CMS will not pay for, or will only pay for if the, if the evidence is generated. I think the, the more aggressive role of CMS we’ve seen in the last couple of years is a good.

John Donvan:

Another question.

Speaker 7:

So Peter, you know, I totally agree with you that, uh, if a drug in accelerated approval fails and it’s confirmatory phase three trial it should be pulled. If we stipulate that, why should the accelerated approval process be restricted to HIV and oncology and terminal diseases? Why shouldn’t we use it for the biggest public health problems we have, like cardiovascular and metabolic diseases, where we have validated biomarkers and we’ve made it impossible, but, for all, but the most well-capitalized companies to develop drugs in those areas? And I’d love for Colin to to respond as well.

John Donvan:

That was such a well-phrased question. Thank you.

Peter Lurie:

All right, ni, ni, nicely done. No, it is for medical need. That is what it’s for. And if there’s a, a, a reasonable biomarker, then in, indeed in principle, you know, it’s available people. The last thing that drugs are not getting, you know, at, at FDA is special treatment. I mean, I’ve said there are these four mark, these four different pathways, most drugs get at least one. I mean, we’re in like Wobegon world here people, where everything is special. Okay? I, it’s hard to find the drug that doesn’t get special treatment from FDA, either they get the fast track, they get an expedited approval, they get QIDP if they’re an antibiotic, they get orphan drug if they’re rare disease, they get special treatment and, and patent exclusivity if they’re pediatric drug.

John Donvan:

And does that concern you?

Peter Lurie:

No, not, not, well, I debate each of them individually. I’m, I, I think that each of them have their own niceties, but I don’t think, regardless, that it’s fair. You know, the agency is, this is, these are for medical needs. That is what accelerated approval is for. And the FDA uses a pretty laxed definition of that, which is why so many drugs fall under it.

Colin Hill:

So I, I think [inaudible

] point is emphasizing a lot of the perspectives I’m bringing here. And, and once again, we’re not talking about the me‐too drugs. I do think what keep the biotech and pharma, eh, eh, industry from investing in a lot of new breakthrough drugs is the regulatory hurdles. It’s too expensive, takes too long and therefore, they just don’t put the money in. And so, we don’t get to live in the world of, of, to see the counterfactual of what if the FDA lowered the bar on, on some of the, the efficacy requirements or used accelerated approvals for cardiovascular diseases? What would we see as a result? Still holding the efficacy bar high, but moving some of that into the real world, especially where you’re dealing with very heterogeneous diseases were it’s just not feasible to run a clinical trial that’s really getting after all of the subtypes.

John Donvan:

Any other questions? Please.

Elisa:

Um, my name is Elisa. I know you mentioned AI earlier, um, with it being so new for implement, uh, implementation, like how can you see that going forward? What’s the next step for AI to take place.

Colin Hill:

So… And, and I would say we’re on the, we’re technically on the 3rd wave of, of, of AI for people who have been in the industry for a long time. It’s still relatively new in the biomedical world, and partly because we’ve had such a dearth of data and data at a multi-omic genomic, uh, uh, level. And, and so, I think what, where we’re seeing AI start to really play a role in the industry is first in the discovery of new drugs, right, discovery, new, completely novel targets from the huge amounts of patient molecular data and then, also using it to design better drug molecules against those targets. And so, that’s coming and that’s, um, that’s starting to yield some really important fruit.

At our company, we use it to create digital twins which are replicas of humans from the genes up that we used to discover drugs and also to simulate drug treatment. And so, I, I think we’re going to start to see AI play a bigger role in clinical trial design, right? Because to the extent we can predict how a patient’s going to respond to a drug ahead of the time with these models as they get fed by more and more data, you could say, “Well, can we start to replace some of the patients in the trial with synthetic patients?” Right. They’re already doing this for s, for control arms, but I think we can now do it more broadly. And so, that’s, I think, coming in the next couple of years here.

John Donvan:

All right. Thank you everybody for your questions. So we move on to our closing round, and our closing round is when each of the debaters gets two minutes to make their closing arguments to you. And Peter, since Colin went first for our opening statements, you again have the floor for two minutes.

Peter Lurie:

All right, so I’ll jump onto it. Um, so I, crossed my mind back to, eh, October of 2016. Um, and I that was the time not long after the US had picked up more gold in total medals in the Olympic Games that had just taken place in Rio de Janeiro. I know you’re gonna say that he’s now gonna reveal that he was actually the shot put gold medalist there. No, that’s not the case. Um, uh, but I was selected to go represent the agency in testimony before the Congress, um, that had to do with expanded access and other things related to approval of of drugs.

And so, the day before I went down to testify, I went down with those someone from our office to meet with one of the congressmen. And I, we went in and I wanted to talk about the data and all of this, but he didn’t seem to want to. He, he kept going, “Was that Mitchell with one L or two L’s?” Getting incredibly frustrated by all of this. I want to talk data. I want to talk about form 3926, I wanna talk technicalities. Right.

Finally, I get him on track. And he turns around to me and he says, he says, “You know, I hear that there’s a lot of drugs in Europe that they have that we don’t have.” And I said, “You know, Senator, it’s funny you mentioned that. Turns out that of all drugs that come to the market anywhere in the world, in the 195 countries that they are, two-thirds of them come on the market in the United States before any other country.” And he said to me, “Wow, that’s better than the US Olympic team.” And I said to myself, here’s this man who’s busy with the two L’s and the one L, but what a feeling he has for a way to communicate with people. Right.

So I went back that night and I did what all, you know, fancy medical researchers do, which is I went to Wikipedia. And I looked it up and it turned out that the US indeed had won 15% of the gold medals at the Olympic games, whereas the US was getting two-thirds of them in, when, at the FDA. And as I testified the following day before the Congress, the FDA was actually outperforming the US Olympic team.

John Donvan:

(laughing). Bingo on the nose too. Colin, your closing statement.

Colin Hill:

I feel like we’re on the precipice of a major revolution in biomedicines if only the agency can kind of get on board with more than they have already with embracing some of these new approaches. And I think from some of the questions that were put forth about breaking down silos or using existing pathways more broadly, I think, we, we will get to this new place sooner than otherwise. I guarantee you, we’re going to get there. And the question is, is it going to take three years, is going to take five years, is going to take 12 years?

And when we look back at the time before we broke down some of these barriers, we’re going to say, “Oh my God, I wish we would have done that sooner. I wish we would have allowed for using digital twins of animals for testing before human clinical trials. I wish we would’ve done that five, 10 years sooner. I wish we would have, have have used accelerated pathways bigger, better or used, uh, real world evidence to drive drug approvals faster.

And, and so, I think, I’m very hopeful. Technology is changing so many aspects of our world, and it seems like that’s changing every week, every month. But yet, we sit here in the world of the biomedical research and it feels like it’s the 1960s, right, where we’re arguing for little bits and pieces of innovation. And I think we have to reconcile these two worlds in a scientifically-driven, data-driven way. But it’s possible, and I think we just need more courage. And I think we have a leader in the FDA who will embrace more of these innovations, especially even across the agencies as was brought up earlier. So thank you for, uh, your time today. This was a lot of fun.

John Donvan:

Thank you very much. So, everybody, I, I have one more assignment for you before we wrap this program, but before I get to it I wanna, I wanna let you know that we are, uh, a nonprofit organization and we do these debates to make the point that people who disagree with each other and disagree with, with each other in respectful and civil ways and and shed light at the same time, and the way that both of you did that so exemplifies it, so I really want to thank you so much for-

Colin Hill:

Thank you.

John Donvan:

… for what you did here. And on that point, as we believe in the power of ideas and the power of good faith argument and the power of opening minds, we just want to get, check in with you. And this is the part that I was waiting for. We’re just curious to, about how you experienced this. Uh, we just want to know from a round of applause if… What I’m asking is if you changed your mind during the course of this debate, if you came in as yes, became a no, or no became a yes, could you clap for us so that we can hear that. And did anybody more… A somewhat easier question, easier part, did you come away with this thinking about it in a different way than when you came in? So from our point of view, that is success. It means that you were listening, you’re open, you were, as we like to say, open to debate. So thank you for all of that.

And I wanna, again, want to thank Aspen Ideas: Health for bringing us here, and Colin and Peter, for, again, the way that you did that. Thank you so much everybody.

Thank you everybody for tuning into this episode of Open to Debate. You know, as a nonprofit, our work, combating extreme polarization through civil and respectful debate is generously funded by listeners like you, by the Rosenkrantz Foundation and by supporters of Open to Debate. Open to Debate is also made possible by a generous grant from the Laura and Gary Lauder Venture Philanthropy Fund. Robert Rosenkrantz is our Chairman, Clay Connor is CEO. Leo Mather is our Chief Content officer. Malet Sandeval is our our producer. Gabriella Mayor is our editorial and research manager. Gabriel Yanatchelli is our social media and digital platforms’ coordinator. Andrew Lipson is head of production. Max Fulton is our product coordinator. Damien is our engineer. Raven Baker our events and operations manager. And I’m your host, John Donvan. We’ll see you next time.