Oncology Unscripted with John Marshall, MD brings you a unique take on the latest oncology news. In this episode John tackles the cost of cancer care. Episode topics include: whether ASCO is a medical meeting or celebration, the wildest ASCO booths and buzz, the winning ASCO presentations, survival benefits in clinical trials, clinical trial accruals, and drug price negotiations. In an in-depth interview with Laura Esserman, MD, MBA, Dr. Marshall discusses smarter clinical trial research.
John Marshall, MD: Hey everybody, John Marshall for Oncology Update. Believe it or not, second episode. They let me do a second one. There's bad judgment on their part.
ASCO Buzz
[00:00:13]
We're just back from ASCO, so you know how everybody's doing. You're still trying to pile out of your emails and figure out if you're actually going to get reimbursed for that dinner or not try for it. You never know. It might work out.
Let's start and kind of reflect a bit on this meeting, that is ASCO. You know, is it really a medical meeting, or is it really a celebration? Let's think about this. You walk into that place, there's signs everywhere. You get out at O'Hare Airport, there's signs everywhere. They're welcoming you to ASCO. You get a bunch of cancer centers marketing their cancer centers that aren't in Chicago, in the Chicago airport. And then you get to the meeting itself, it's like a celebration. You go in to where the booths are now. This makes it look like we have won, that we have cured cancer! The lights are going off, everything is all shiny and sparkly, the carpets are extra cushiony when you get onto one of the drug company booths.
I asked people while we were there which booth was by far the over-the-top booth and there is a clear winner here. We're going to give it to AstraZeneca. Amazing booth. Also, the most likely to cause a seizure was this booth, the lights and everything going on; most likely to cause a seizure for sure.
But there was also a really fun booth. I'm not going to name the company where it came from, but they had the most funky lights. There were these huge tubes that were bigger than a human. And all the lights were hanging from the ceiling from these huge tubes. All I could think about as I was walking by is that, somehow, those things must be really for erectile dysfunction, right? I mean, that's kind of what it looked like—it solved that problem. I went to the booth, turned out, no, they were just decorative. Not any erectile dysfunction problem at all. But, you know, go figure. It's what it seemed like to me.
It was clearly a super spreader event. We pretty much figured out that the best COVID comes from Western Europe, the sort of romance language part of Europe. The Germanic language part not so good, their COVID is more serious, the romance language COVID is the best.
There weren't many community oncologists there because they had to make a decision to go there, lose RVUs to gain CME. And that trade off just wasn't there for them. If you remember from the first episode, when we really drilled down on the RVU and its value, it's going to be a disincentive for somebody to go to a medical meeting like this to try and learn the state of the art of cancer care. So, clearly that's not who was at this meeting.
Probably the wildest thing I heard somebody say was that when I was asking about the booth, and a typical booth, even a small, modest booth might cost half a million dollars, is that they came back and said, ‘you know what, this is a good use of our money.’ Wait a second, half a million dollars, that could fund a phase 2, small phase 2, clinical trial for goodness sake. So, you know, is that the best use of your money is to have this big booth, and then the other part is who's paying for those booths? That's our health care dollar at work, whether it's the National Cancer Institute's booth, which is our tax dollars at work, or the pharmaceutical industry and all the money that they have because of the health care industry. So, that's our money they're spending in there on these celebratory booths that we need to kind of come back and think about why is that the right way to go.
Our theme today is going to be all about costs and expense, and why is it so expensive? Why is cancer care so expensive? And we're going to really drill down on a few main areas around that, the cost of drugs and the cost of clinical research.
ASCO Wins
[00:04:17] Let's start with looking at the success, amazing success, of the clinical research that was presented at ASCO. There were three standing ovations among the five plenary abstracts that were presented, and the one that probably deserved it was a drug called osimertinib. You know, this is for EGFR-targeted non-small cell lung cancer. And the benefit was dramatic. A huge delta between the curves. And all of a sudden, everybody said, this is the way to go. I think probably yeah, there's a terrible disease. It's a therapy that works very, very well. Huge improvement in outcome for patients in the curative setting. All in, right? We're all in in that group. Worth standing up and clapping for.
But, did you know that the rumor is, a little gossip, that, uh, that the other two standing ovations also, drug therapy studies were actually started by plants from the companies who wanted everybody to stand up for their therapies as well. I hope that's not true. I really hope that's not true, but it might be. You never know. Could be true that they're trying to get more standing ovations to applaud this victory that everyone is claiming that we have in cancer.
[00:05:40] I can't resist telling you about one other study was done in colon cancer. My baby. A study that could only be done, where they have the best COVID, in France. This was a study led by a brilliant surgeon who has set so many standards for us all around the world, a guy named Rene Adam. And believe it or not, liver only metastatic colon cancer, half the patients got standard chemotherapy, The other half got a liver transplant. Do you think you could ever do that study here in the United States? No way. There is no way you could ever do that study here. What patient would allow you to randomize them to a transplant over there or continued chemotherapy over there? If you were eligible, I want that transplant, baby. I'm American, I can have whatever I want. They pulled it off over in Paris, and what they were able to show is again a dramatic difference for the transplant. Something like 70% versus 15%, a huge delta between the two groups. And even though it was a small study, it was very well done, very well, conceived and followed correctly. So, setting a new standard for in the right patient liver transplantation for metastatic colorectal cancer.
Clinical Research Reality Check
[00:06:55] This has made me reflect a bit about clinical research in general. What is the value of clinical research? Well, one of our lines has always been that if you're on a clinical trial, you live longer; that somehow patients who participate in clinical research live longer.
There was a recent paper that was in JAMA that actually did this. They took a bunch of studies, and they pulled it apart and they actually did show that there was some benefit to being on a clinical trial. So, you're okay in saying that, but then the authors went a little bit deeper and actually compared it to what if you were on standard therapy, and, if they pulled out those clinical trials where the control arm or whatnot was a standard therapy that was in place right now, there wasn't any survival advantage. So, it was only when you compared it against other kinds of approaches that people showed that survival advantage. So, it was a little bit of a mixed message of, yeah, there's a survival, but maybe not so much as we thought before. That was a little bit of water on our flame.
[00:08:03] And then a second approach that was, was presented in Cancer Medicine actually looked at how we've done not a very good job of increasing accrual to clinical trials. There are all sorts of strategies and studies and education and all of this that we've done to try and increase awareness of clinical trials; increase participation in clinical trials. And, yet we really haven't made too much out of that.
So, on the backdrop of all of that, we’ve still got a lot of work to do. I don't think we have a victory just yet.
Drug Price Negotiations
[00:08:41] Let's get back to this value question. You may not know that there's a law in the United States that says, I can't judge value. I can't put together the cost of something and the magnitude of benefit. We're the only country in the world that has this law. And so, to begin to undo that law. A year ago, the folks from the government said, we're going to put out 10 drugs. We're going to give you a list of 10 drugs that we would like to negotiate price on. And we want to start this discussion. Well, lots of people said, this is never going to go. It wasn't just cancer drugs, but some of them are cancer drugs. People said, this is never going to happen. We're not going to have that discussion. It's just going to go away. There's too much going on that’s good with the way the current system works. So, we're not going to mess with that.
The reason this has come back to mind is that it didn't go away. Just about a month ago here near me, in Maryland, the state legislature had a meeting. They put together a committee and had a meeting. And in this case, they picked eight of those ten drugs, and they began to talk about how are we going to think about this. Now, I worry a little bit because who's on this committee? Who's making this decision? Well, we do have people from the pharmaceutical industry, we have insurers on that, we have medical communities, and unions, and patient representatives, etc. So, you know, probably pretty good representation to discuss the impact of should we or shouldn't we. And you must remember that Maryland is quite, I don't know if you want to call it progressive, but it's out there with regard to government healthcare, has completely different laws around Medicare than any other state in the country. They might just take this on and think about it in more detail.
You know who I really find missing in all of this discussion is the payer. So where is Medicare on a huge pot of money over there? Where are the Blue Crosses and Blue Shields in all of this discussion? Because the way I think about it, we are each paying into those banks, whether it's Medicare or your own health insurance company. Each month coming out of your paycheck, taxes going into those banks, and you haven't gotten a raise in a while because companies are putting in more and more on our behalf. So, the bank's getting filled up, and then they guard it. The insurance companies guard the bank, but distribute it to people as they need it. And that's the model of insurance, of course. We hate our insurance companies because they're always fighting. We don't like the way they guard that bank. We want them to let everything out of there if they can. But on the flip side, we don't want our individual costs to rise. So, we kind of talk out of both sides of our mouths.
I've been thinking like a crazy idea. Go with me on this. What if you just got diagnosed with, I don't know, say metastatic colon cancer? And your insurance company calls and says, sorry, you've got metastatic colon cancer. We'll offer you today half a million dollars, five hundred thousand dollars cash, to not take treatment. Would you take the money? Who out there would take the money? I see you. Who out there would not? Turn it down and take treatment? Because in fact, we're about to spend more than half a million dollars on you. And so, I never understood why insurance companies don't offer you a buyout to get out of all of this and just pay some cash and go, but that's never going to happen. We know that.
So, we are in fact having the discussion. We probably will over time begin to whittle away at this concept of negotiating drug prices so that that component of our over-expensive health care system can at least fall into line. That yes might make for less fancy booths at ASCO. We're going to have to realize that you won't be able to get quite as good a cappuccino at that favorite drug company booth that you got when you were in Chicago this past weekend. But I think we'd be willing to make the trade for, some sort of better pricing, better access to drugs, in our country and around the world.
I want to shift gears to a really, I think, even bigger problem than the expense of new drugs. Because one of the arguments that the companies make is that clinical research has gotten really, really expensive.
And there's a law that you might know about sort of a theoretical law called Moore's law, that I think, came around building computer chips, that with every year, with every five years, it not only got cheaper to build the chips, the chips got dramatically better. They could hold more data, they were faster, etc. So, that Moore's Law of it gets cheaper and faster, is how much most things work in the development world. Well, in drug development, jokingly, they call it Eroom's Law, it's Moore's Law backwards. And essentially this says that with each passing year, it is getting more expensive and less efficient to do clinical research. And this has been going on, as an old guy, this has been going on for gosh, 10, 20 years.
We thought we'd do is deep dive into this subject, and we have invited maybe one of the brightest people on the planet with regard to clinical research. And not only smart about it, but is determined to do something about it. We will meet Dr. Laura Esserman right now.
Smarter Clinical Research: Interview with Dr. Laura Esserman
[14:40] As I just promised you, I have found maybe. the smartest person on the planet about how clinical research has to evolve in order to actually cure cancer. Because remember, that's what we're here to do. And Dr. Laura Esserman is a professor of surgery at the beautiful UCSF out in San Francisco. And for the last while she has built this incredible program around breast cancer research, and now other cancers are starting to follow suit. And she's nice enough to take a bit of a break out of her own clinic day to come and join us and talk about this.
Dr. Esserman ,Laura, thank you first for joining, but right away, what the heck happened to clinical research? What happened over the evolution of the last 10, 20 years that's got us in this bad state?
Laura Esserman, MD, MBA: In an effort to try and make it more consistent, I think we took a wrong turn. I have two words to sum it up, misplaced precision. We have two systems, one for clinical research and one for clinical medicine. They're both terrible, and, what we need to do is improve both with one better approach. People say clinical data isn't good enough for research. Really? So, it's really only good enough for patient care?
What is that? Right? You know, who would accept that? There are a certain set of facts that you would not forego if you're taking care of a patient with colon cancer. Same way for me with breast cancer. The surgeons want a little bit more detail on this, and the medical oncologists want a little more detail on this, the radiation oncologists might want something else, but all of us know what it is that we need to collect. We need to get to the business of collecting the right data once. And just having a commitment to high-fidelity, high-quality data as we go. And then you've got all the data you need for clinical research. Now we've got these CROs who are coming in and combing through the data, and they make money every time you find a discrepancy. So, our incentives are completely misaligned to make things better. And everything's gotten so bureaucratic that no one wants to do any of this stuff. This is crazy.
John Marshall, MD: I kept thinking that we become highly paid data entry specialists, right? And even then we don't do it correctly, as you say, and they in the CRO thing. I remember the day when a clinical trial might be $2500, $5000 a patient and you could abstract out from the data, and cooperative groups accepted this, the FDA accepted this, this was good enough. And then this CRO thing came in, and what is it, one-third of the total budget of most trials is this data discipline over top of us that's paid, as you say, to find us making mistakes. If we don't make any mistakes, then they don't have a job.
Laura Esserman, MD, MBA: That model, I think needs to go, I've dispensed with it. And you don't need it. And the thing is, there's already data you can extract. We've developed these tools called OneSource. You can pull the data out. I mean, why, why are we having data coordinators extract lab values from one electronic system to another?
One of the things that isn’t going to break the bank is the patient reported outcomes because the patient's only going to report them once. And we only need them once, and, again, the patient should report what they know best. You don't need the clinician or the study coordinator to report what the patient's going to know. They know if they are having aches and pains. And then, the clinicians should focus on grade three and grade four adverse events, adverse events of special interest, and immune related events. And anything that causes a dose delay, reduction, or discontinuation, and that is it. Are we collecting adverse events so we can report them to the FDA? Okay? Are we collecting information so we can get them to the clinician to manage, improve and minimize toxicity? Again, a complete lack of focus on what matters, what's important to patients.
Imagine if you had a trial where you were constantly learning and evolving and figuring out the best sequence of therapies, trying to learn and manage and optimize the management of toxicities as they arrive. Everyone would want to participate in such a trial. And that's what I-SPY is. That's what we've done.
John Marshall, MD: you brought it up, the I-SPY, and I have watched you. I was your IRB reviewer here at Georgetown for many years, so I know it well. and as you know, I'm really interested in it for us in the GI cancer space. I think it is a great model for us all to follow. Getting back that control over decision-making, simplifying, expediting; all the things you talk about. So maybe, those of us who know, know, but there are a lot of us who don't know about your solutions for this, and so maybe some highlights of that for our audience.
Laura Esserman, MD, MBA: Let me just sort of give you a quick summary. And again, I think there's plenty of complexity in the trial, but it's focused on clinical decision-making, not on, you know, the nitty gritty detail of every last event.
All disease is heterogeneous. And all of us really know that, and we'll say, oh, well, it's a heterogeneous disease, but then we go ahead and treat everybody the same. That makes no sense. And then people are like, oh, well, you can't do subset analysis. I'm like, okay, fine. So let's start. We started, actually, I started in the cooperative groups, and I left the cooperative groups because they weren't moving at a pace that I felt was appropriate. I mean, the cost of drugs and the cost of development is astronomic because we've allowed it to be so.
John Marshall, MD: And time is a factor in that
Laura Esserman, MD, MBA: Time is a factor, and If you think about it, the person sitting across the table from you does not have 10 years for you to get your act together. So, what we started with first was, let's take the fast-growing, molecularly high risk, stage two, three breast cancers, where we showed in I-SPY 1 in the cooperative groups that, you know, if you could actually start with the therapy first, and you could make that tumor go away, you've got your intact biomarker. By the time you operate, you're getting in the course of care. The important information that tells you what to do next. So, if the tumor's gone away, that is strongly associated with event free survival and distant recurrence free survival, which is what kills people, right? So that with a hazard rate of 0.2, that is an amazing early surrogate marker.
So, your goal should be to try and figure out what are the different disease subtypes? How do you start figuring out what the right drugs are for the right patient at the right time and constantly learn and evolve and improve the algorithm so that you can optimize everybody's chance at getting that good outcome. In the first 10 years of the trial, we studied 23 drugs in control and 10 of the arms graduated. And some of them are on the market today or were superseded by other drugs. We had Taxol (paclitaxel) with a novel therapy, plus or minus any one of a number of therapies, followed by ACE, adriamycin, which is a terribly toxic drug, then followed by surgery. The next person coming into the trial would get the benefit of what we learned from that. That's actually not what patients want. They want to know that they're going to be on a trial that is smart, and that will actually give them some agency and some learning.
At the beginning, we couldn't do that because we didn't have the drugs, but now we're running the trial the way I'd envisioned in the first place, which is three blocks of therapy, three shots on goal. Again, everybody starts with the systemic therapy first. I'm a surgeon. I'd love to be here, but you know what? You know, everybody would love to do much less surgery. I can do less if the tumor is gone but if the tumor isn't gone, my surgery isn't going to fix them. So, you've got to figure out the next drug. I think everyone's like, ‘oh my God, you're putting them at risk.’ You're not putting anybody at risk. I think we've learned that. Right. And that's how you found, you know, in colon cancer to some remarkable treatments for immune drugs in the right patients, but you don't bring them to the wrong patients because they have a lot of side effects. So, the idea is you give them the first set of drugs, but you make that a non-standard chemo. It can be, you know, bispecific antibodies. It can be anybody drug conjugates, you know, any number of things.
John Marshall, MD: What's so crazy about that from most of our traditional thinking is that this is curative. In this neoadjuvant, I mean, think about the old days that it would take 10 years to find an adjuvant therapy because you had to wait forever—you've developed a system where you can change the standard of care within a year or two based on neoadjuvant pathologic complete responses, right?
Laura Esserman, MD, MBA: Right. So, here's the thing, patients care about efficacy and toxicity.
John Marshall, MD: Exactly.
Laura Esserman, MD, MBA: Right? Not just efficacy, you know, and I think a lot of clinicians are like, I just don't want to be blamed for making a mistake. You know,
John Marshall, MD: Regret avoidance,
Laura Esserman, MD, MBA: You’ve got to come up with a strategy that makes people feel comfortable. So, what we did was we've been using MRI and quantitative imaging, not RESIST criteria, that it's like doing some two dimensional thing when you've got really, you know, rich data.
John Marshall, MD: You created a new endpoint of essentially pathologic complete response that ultimately gets regulatory approval, right? So, you changed the rules on, you know, the old established rules that weren't doing us any good.
Laura Esserman, MD, MBA: Right. As you know, we have to let go of some of the rules stuck in our heads because you can't improve without that. The thing is, we need to not be afraid to do some safe experiments. You know, it's true, you might make a decision that you might find that something's wrong. Okay, just set it up in a way that you've got your safeguards built in, but you're giving everybody the chance for benefit. These new drugs, you don't know if they're going to work, but six weeks, no one's going to die in six weeks. And there's a huge upside if they work in avoiding future therapy. And, if by 12 weeks it really works, you can skip the toxic chemotherapy and go to the OR. Same thing for going on to block B. So, you've got some agency in the middle, and we have good algorithms, and we keep working on making them better. If you want these companies to build these new exciting therapies, you've got to give them a place to test them and to do it much more quickly. You know, the whole Silicon Valley, the whole dot tech tech revolution is about systems-based learning and, you know, rapid learning. You know if it's not going to work, learn fast, fail fast. If it's going to work, great, build on that and move on.
John Marshall, MD: You've done it, right? Got it. And the way I think about…
Laura Esserman, MD, MBA: People are following it.
John Marshall, MD: Yeah, we're coming after you.
Laura Esserman, MD, MBA: And now we're working with the FDA on developing a regulatory strategy around it. We haven't finished we haven't gotten there quite yet, but we will.
John Marshall, MD: It really is Innovation and individualization are the two priorities, that you want to make sure that that patient in front of you, their individual tumor characteristics are recognized and optimized, the therapy for them learned from that through innovation. And you bring those two things together and then you create a new way of practicing medicine and cancer.
Laura Esserman, MD, MBA: So, the basis of this new trial is a smart, sequential, multiple, Assignment randomized trials,
John Marshall, MD: You certainly sold me as a GI oncologist of how we might partner with your team for similar things you have learned. You've already done it. You're doing it with COVID vaccines as well
Laura Esserman, MD, MBA: During the COVID trial, you know, the, one of the agencies that was sponsoring us was concerned. I said, look, we do not need to have, every time there's an adverse event, someone doesn't have to fill out an adverse event report because when people are dying of COVID, they have ARDS, they're dying. They have multi system organ failure. I mean, you could be filling these forms in all day. Here's a checklist of 10 things that happens to every patient. Do it the same on every single patient. It'll take you two minutes. That's a much smarter way of going about it. But they were concerned that we were hiding things or not collecting information. And they made us do this full audit. And you know, we spent six and a half million dollars doing this audit. And we didn't find one adverse event.
John Marshall, MD: You know, you say that that would have bought a kick ass booth at ASCO, six and a half million dollars. That would have been money well spent, is to take that money on your audit and spend it on a fancy booth.
Laura Esserman, MD, MBA: I'm trying, I'm trying to get this published, but, you know, it's going to be very threatening to the industry, but it should. But, to us, it's like we need to take back control of our profession. We need to, like, develop better systems for clinical care that actually help us with research because the goal of clinical medicine, what are we practicing for? We should be practicing to improve, but if you don't know what you're doing, you can't improve it. So that's my story and I'm sticking to it.
John Marshall, MD: I think we should just leave it right there. Dr. Laura Esserman taking a break out of her clinic from UCSF Department of Surgery there and the leader of the I-SPY program, transformative. Dr. Esserman, thank you for joining us.
Laura Esserman, MD, MBA: Oh, you're welcome. Thanks for having me.
John Marshall, MD: I hope everybody enjoyed this episode of Oncology Update. My name is Dr. John Marshall and maybe while you're out there, think a little bit about why is cancer so expensive?
Oncology Update With John Marshall: Episode 2: Why is Cancer so Expensive? With Special Guest Dr. Laura Esserman
John Marshall, MD: Hey everybody, John Marshall for Oncology Update. Believe it or not, second episode. They let me do a second one. There's bad judgment on their part.
ASCO Buzz
[00:00:13]
We're just back from ASCO, so you know how everybody's doing. You're still trying to pile out of your emails and figure out if you're actually going to get reimbursed for that dinner or not try for it. You never know. It might work out.
Let's start and kind of reflect a bit on this meeting, that is ASCO. You know, is it really a medical meeting, or is it really a celebration? Let's think about this. You walk into that place, there's signs everywhere. You get out at O'Hare Airport, there's signs everywhere. They're welcoming you to ASCO. You get a bunch of cancer centers marketing their cancer centers that aren't in Chicago, in the Chicago airport. And then you get to the meeting itself, it's like a celebration. You go in to where the booths are now. This makes it look like we have won, that we have cured cancer! The lights are going off, everything is all shiny and sparkly, the carpets are extra cushiony when you get onto one of the drug company booths.
I asked people while we were there which booth was by far the over-the-top booth and there is a clear winner here. We're going to give it to AstraZeneca. Amazing booth. Also, the most likely to cause a seizure was this booth, the lights and everything going on; most likely to cause a seizure for sure.
But there was also a really fun booth. I'm not going to name the company where it came from, but they had the most funky lights. There were these huge tubes that were bigger than a human. And all the lights were hanging from the ceiling from these huge tubes. All I could think about as I was walking by is that, somehow, those things must be really for erectile dysfunction, right? I mean, that's kind of what it looked like—it solved that problem. I went to the booth, turned out, no, they were just decorative. Not any erectile dysfunction problem at all. But, you know, go figure. It's what it seemed like to me.
It was clearly a super spreader event. We pretty much figured out that the best COVID comes from Western Europe, the sort of romance language part of Europe. The Germanic language part not so good, their COVID is more serious, the romance language COVID is the best.
There weren't many community oncologists there because they had to make a decision to go there, lose RVUs to gain CME. And that trade off just wasn't there for them. If you remember from the first episode, when we really drilled down on the RVU and its value, it's going to be a disincentive for somebody to go to a medical meeting like this to try and learn the state of the art of cancer care. So, clearly that's not who was at this meeting.
Probably the wildest thing I heard somebody say was that when I was asking about the booth, and a typical booth, even a small, modest booth might cost half a million dollars, is that they came back and said, ‘you know what, this is a good use of our money.’ Wait a second, half a million dollars, that could fund a phase 2, small phase 2, clinical trial for goodness sake. So, you know, is that the best use of your money is to have this big booth, and then the other part is who's paying for those booths? That's our health care dollar at work, whether it's the National Cancer Institute's booth, which is our tax dollars at work, or the pharmaceutical industry and all the money that they have because of the health care industry. So, that's our money they're spending in there on these celebratory booths that we need to kind of come back and think about why is that the right way to go.
Our theme today is going to be all about costs and expense, and why is it so expensive? Why is cancer care so expensive? And we're going to really drill down on a few main areas around that, the cost of drugs and the cost of clinical research.
ASCO Wins
[00:04:17] Let's start with looking at the success, amazing success, of the clinical research that was presented at ASCO. There were three standing ovations among the five plenary abstracts that were presented, and the one that probably deserved it was a drug called osimertinib. You know, this is for EGFR-targeted non-small cell lung cancer. And the benefit was dramatic. A huge delta between the curves. And all of a sudden, everybody said, this is the way to go. I think probably yeah, there's a terrible disease. It's a therapy that works very, very well. Huge improvement in outcome for patients in the curative setting. All in, right? We're all in in that group. Worth standing up and clapping for.
But, did you know that the rumor is, a little gossip, that, uh, that the other two standing ovations also, drug therapy studies were actually started by plants from the companies who wanted everybody to stand up for their therapies as well. I hope that's not true. I really hope that's not true, but it might be. You never know. Could be true that they're trying to get more standing ovations to applaud this victory that everyone is claiming that we have in cancer.
[00:05:40] I can't resist telling you about one other study was done in colon cancer. My baby. A study that could only be done, where they have the best COVID, in France. This was a study led by a brilliant surgeon who has set so many standards for us all around the world, a guy named Rene Adam. And believe it or not, liver only metastatic colon cancer, half the patients got standard chemotherapy, The other half got a liver transplant. Do you think you could ever do that study here in the United States? No way. There is no way you could ever do that study here. What patient would allow you to randomize them to a transplant over there or continued chemotherapy over there? If you were eligible, I want that transplant, baby. I'm American, I can have whatever I want. They pulled it off over in Paris, and what they were able to show is again a dramatic difference for the transplant. Something like 70% versus 15%, a huge delta between the two groups. And even though it was a small study, it was very well done, very well, conceived and followed correctly. So, setting a new standard for in the right patient liver transplantation for metastatic colorectal cancer.
Clinical Research Reality Check
[00:06:55] This has made me reflect a bit about clinical research in general. What is the value of clinical research? Well, one of our lines has always been that if you're on a clinical trial, you live longer; that somehow patients who participate in clinical research live longer.
There was a recent paper that was in JAMA that actually did this. They took a bunch of studies, and they pulled it apart and they actually did show that there was some benefit to being on a clinical trial. So, you're okay in saying that, but then the authors went a little bit deeper and actually compared it to what if you were on standard therapy, and, if they pulled out those clinical trials where the control arm or whatnot was a standard therapy that was in place right now, there wasn't any survival advantage. So, it was only when you compared it against other kinds of approaches that people showed that survival advantage. So, it was a little bit of a mixed message of, yeah, there's a survival, but maybe not so much as we thought before. That was a little bit of water on our flame.
[00:08:03] And then a second approach that was, was presented in Cancer Medicine actually looked at how we've done not a very good job of increasing accrual to clinical trials. There are all sorts of strategies and studies and education and all of this that we've done to try and increase awareness of clinical trials; increase participation in clinical trials. And, yet we really haven't made too much out of that.
So, on the backdrop of all of that, we’ve still got a lot of work to do. I don't think we have a victory just yet.
Drug Price Negotiations
[00:08:41] Let's get back to this value question. You may not know that there's a law in the United States that says, I can't judge value. I can't put together the cost of something and the magnitude of benefit. We're the only country in the world that has this law. And so, to begin to undo that law. A year ago, the folks from the government said, we're going to put out 10 drugs. We're going to give you a list of 10 drugs that we would like to negotiate price on. And we want to start this discussion. Well, lots of people said, this is never going to go. It wasn't just cancer drugs, but some of them are cancer drugs. People said, this is never going to happen. We're not going to have that discussion. It's just going to go away. There's too much going on that’s good with the way the current system works. So, we're not going to mess with that.
The reason this has come back to mind is that it didn't go away. Just about a month ago here near me, in Maryland, the state legislature had a meeting. They put together a committee and had a meeting. And in this case, they picked eight of those ten drugs, and they began to talk about how are we going to think about this. Now, I worry a little bit because who's on this committee? Who's making this decision? Well, we do have people from the pharmaceutical industry, we have insurers on that, we have medical communities, and unions, and patient representatives, etc. So, you know, probably pretty good representation to discuss the impact of should we or shouldn't we. And you must remember that Maryland is quite, I don't know if you want to call it progressive, but it's out there with regard to government healthcare, has completely different laws around Medicare than any other state in the country. They might just take this on and think about it in more detail.
You know who I really find missing in all of this discussion is the payer. So where is Medicare on a huge pot of money over there? Where are the Blue Crosses and Blue Shields in all of this discussion? Because the way I think about it, we are each paying into those banks, whether it's Medicare or your own health insurance company. Each month coming out of your paycheck, taxes going into those banks, and you haven't gotten a raise in a while because companies are putting in more and more on our behalf. So, the bank's getting filled up, and then they guard it. The insurance companies guard the bank, but distribute it to people as they need it. And that's the model of insurance, of course. We hate our insurance companies because they're always fighting. We don't like the way they guard that bank. We want them to let everything out of there if they can. But on the flip side, we don't want our individual costs to rise. So, we kind of talk out of both sides of our mouths.
I've been thinking like a crazy idea. Go with me on this. What if you just got diagnosed with, I don't know, say metastatic colon cancer? And your insurance company calls and says, sorry, you've got metastatic colon cancer. We'll offer you today half a million dollars, five hundred thousand dollars cash, to not take treatment. Would you take the money? Who out there would take the money? I see you. Who out there would not? Turn it down and take treatment? Because in fact, we're about to spend more than half a million dollars on you. And so, I never understood why insurance companies don't offer you a buyout to get out of all of this and just pay some cash and go, but that's never going to happen. We know that.
So, we are in fact having the discussion. We probably will over time begin to whittle away at this concept of negotiating drug prices so that that component of our over-expensive health care system can at least fall into line. That yes might make for less fancy booths at ASCO. We're going to have to realize that you won't be able to get quite as good a cappuccino at that favorite drug company booth that you got when you were in Chicago this past weekend. But I think we'd be willing to make the trade for, some sort of better pricing, better access to drugs, in our country and around the world.
I want to shift gears to a really, I think, even bigger problem than the expense of new drugs. Because one of the arguments that the companies make is that clinical research has gotten really, really expensive.
And there's a law that you might know about sort of a theoretical law called Moore's law, that I think, came around building computer chips, that with every year, with every five years, it not only got cheaper to build the chips, the chips got dramatically better. They could hold more data, they were faster, etc. So, that Moore's Law of it gets cheaper and faster, is how much most things work in the development world. Well, in drug development, jokingly, they call it Eroom's Law, it's Moore's Law backwards. And essentially this says that with each passing year, it is getting more expensive and less efficient to do clinical research. And this has been going on, as an old guy, this has been going on for gosh, 10, 20 years.
We thought we'd do is deep dive into this subject, and we have invited maybe one of the brightest people on the planet with regard to clinical research. And not only smart about it, but is determined to do something about it. We will meet Dr. Laura Esserman right now.
Smarter Clinical Research: Interview with Dr. Laura Esserman
[14:40] As I just promised you, I have found maybe. the smartest person on the planet about how clinical research has to evolve in order to actually cure cancer. Because remember, that's what we're here to do. And Dr. Laura Esserman is a professor of surgery at the beautiful UCSF out in San Francisco. And for the last while she has built this incredible program around breast cancer research, and now other cancers are starting to follow suit. And she's nice enough to take a bit of a break out of her own clinic day to come and join us and talk about this.
Dr. Esserman ,Laura, thank you first for joining, but right away, what the heck happened to clinical research? What happened over the evolution of the last 10, 20 years that's got us in this bad state?
Laura Esserman, MD, MBA: In an effort to try and make it more consistent, I think we took a wrong turn. I have two words to sum it up, misplaced precision. We have two systems, one for clinical research and one for clinical medicine. They're both terrible, and, what we need to do is improve both with one better approach. People say clinical data isn't good enough for research. Really? So, it's really only good enough for patient care?
What is that? Right? You know, who would accept that? There are a certain set of facts that you would not forego if you're taking care of a patient with colon cancer. Same way for me with breast cancer. The surgeons want a little bit more detail on this, and the medical oncologists want a little more detail on this, the radiation oncologists might want something else, but all of us know what it is that we need to collect. We need to get to the business of collecting the right data once. And just having a commitment to high-fidelity, high-quality data as we go. And then you've got all the data you need for clinical research. Now we've got these CROs who are coming in and combing through the data, and they make money every time you find a discrepancy. So, our incentives are completely misaligned to make things better. And everything's gotten so bureaucratic that no one wants to do any of this stuff. This is crazy.
John Marshall, MD: I kept thinking that we become highly paid data entry specialists, right? And even then we don't do it correctly, as you say, and they in the CRO thing. I remember the day when a clinical trial might be $2500, $5000 a patient and you could abstract out from the data, and cooperative groups accepted this, the FDA accepted this, this was good enough. And then this CRO thing came in, and what is it, one-third of the total budget of most trials is this data discipline over top of us that's paid, as you say, to find us making mistakes. If we don't make any mistakes, then they don't have a job.
Laura Esserman, MD, MBA: That model, I think needs to go, I've dispensed with it. And you don't need it. And the thing is, there's already data you can extract. We've developed these tools called OneSource. You can pull the data out. I mean, why, why are we having data coordinators extract lab values from one electronic system to another?
One of the things that isn’t going to break the bank is the patient reported outcomes because the patient's only going to report them once. And we only need them once, and, again, the patient should report what they know best. You don't need the clinician or the study coordinator to report what the patient's going to know. They know if they are having aches and pains. And then, the clinicians should focus on grade three and grade four adverse events, adverse events of special interest, and immune related events. And anything that causes a dose delay, reduction, or discontinuation, and that is it. Are we collecting adverse events so we can report them to the FDA? Okay? Are we collecting information so we can get them to the clinician to manage, improve and minimize toxicity? Again, a complete lack of focus on what matters, what's important to patients.
Imagine if you had a trial where you were constantly learning and evolving and figuring out the best sequence of therapies, trying to learn and manage and optimize the management of toxicities as they arrive. Everyone would want to participate in such a trial. And that's what I-SPY is. That's what we've done.
John Marshall, MD: you brought it up, the I-SPY, and I have watched you. I was your IRB reviewer here at Georgetown for many years, so I know it well. and as you know, I'm really interested in it for us in the GI cancer space. I think it is a great model for us all to follow. Getting back that control over decision-making, simplifying, expediting; all the things you talk about. So maybe, those of us who know, know, but there are a lot of us who don't know about your solutions for this, and so maybe some highlights of that for our audience.
Laura Esserman, MD, MBA: Let me just sort of give you a quick summary. And again, I think there's plenty of complexity in the trial, but it's focused on clinical decision-making, not on, you know, the nitty gritty detail of every last event.
All disease is heterogeneous. And all of us really know that, and we'll say, oh, well, it's a heterogeneous disease, but then we go ahead and treat everybody the same. That makes no sense. And then people are like, oh, well, you can't do subset analysis. I'm like, okay, fine. So let's start. We started, actually, I started in the cooperative groups, and I left the cooperative groups because they weren't moving at a pace that I felt was appropriate. I mean, the cost of drugs and the cost of development is astronomic because we've allowed it to be so.
John Marshall, MD: And time is a factor in that
Laura Esserman, MD, MBA: Time is a factor, and If you think about it, the person sitting across the table from you does not have 10 years for you to get your act together. So, what we started with first was, let's take the fast-growing, molecularly high risk, stage two, three breast cancers, where we showed in I-SPY 1 in the cooperative groups that, you know, if you could actually start with the therapy first, and you could make that tumor go away, you've got your intact biomarker. By the time you operate, you're getting in the course of care. The important information that tells you what to do next. So, if the tumor's gone away, that is strongly associated with event free survival and distant recurrence free survival, which is what kills people, right? So that with a hazard rate of 0.2, that is an amazing early surrogate marker.
So, your goal should be to try and figure out what are the different disease subtypes? How do you start figuring out what the right drugs are for the right patient at the right time and constantly learn and evolve and improve the algorithm so that you can optimize everybody's chance at getting that good outcome. In the first 10 years of the trial, we studied 23 drugs in control and 10 of the arms graduated. And some of them are on the market today or were superseded by other drugs. We had Taxol (paclitaxel) with a novel therapy, plus or minus any one of a number of therapies, followed by ACE, adriamycin, which is a terribly toxic drug, then followed by surgery. The next person coming into the trial would get the benefit of what we learned from that. That's actually not what patients want. They want to know that they're going to be on a trial that is smart, and that will actually give them some agency and some learning.
At the beginning, we couldn't do that because we didn't have the drugs, but now we're running the trial the way I'd envisioned in the first place, which is three blocks of therapy, three shots on goal. Again, everybody starts with the systemic therapy first. I'm a surgeon. I'd love to be here, but you know what? You know, everybody would love to do much less surgery. I can do less if the tumor is gone but if the tumor isn't gone, my surgery isn't going to fix them. So, you've got to figure out the next drug. I think everyone's like, ‘oh my God, you're putting them at risk.’ You're not putting anybody at risk. I think we've learned that. Right. And that's how you found, you know, in colon cancer to some remarkable treatments for immune drugs in the right patients, but you don't bring them to the wrong patients because they have a lot of side effects. So, the idea is you give them the first set of drugs, but you make that a non-standard chemo. It can be, you know, bispecific antibodies. It can be anybody drug conjugates, you know, any number of things.
John Marshall, MD: What's so crazy about that from most of our traditional thinking is that this is curative. In this neoadjuvant, I mean, think about the old days that it would take 10 years to find an adjuvant therapy because you had to wait forever—you've developed a system where you can change the standard of care within a year or two based on neoadjuvant pathologic complete responses, right?
Laura Esserman, MD, MBA: Right. So, here's the thing, patients care about efficacy and toxicity.
John Marshall, MD: Exactly.
Laura Esserman, MD, MBA: Right? Not just efficacy, you know, and I think a lot of clinicians are like, I just don't want to be blamed for making a mistake. You know,
John Marshall, MD: Regret avoidance,
Laura Esserman, MD, MBA: You’ve got to come up with a strategy that makes people feel comfortable. So, what we did was we've been using MRI and quantitative imaging, not RESIST criteria, that it's like doing some two dimensional thing when you've got really, you know, rich data.
John Marshall, MD: You created a new endpoint of essentially pathologic complete response that ultimately gets regulatory approval, right? So, you changed the rules on, you know, the old established rules that weren't doing us any good.
Laura Esserman, MD, MBA: Right. As you know, we have to let go of some of the rules stuck in our heads because you can't improve without that. The thing is, we need to not be afraid to do some safe experiments. You know, it's true, you might make a decision that you might find that something's wrong. Okay, just set it up in a way that you've got your safeguards built in, but you're giving everybody the chance for benefit. These new drugs, you don't know if they're going to work, but six weeks, no one's going to die in six weeks. And there's a huge upside if they work in avoiding future therapy. And, if by 12 weeks it really works, you can skip the toxic chemotherapy and go to the OR. Same thing for going on to block B. So, you've got some agency in the middle, and we have good algorithms, and we keep working on making them better. If you want these companies to build these new exciting therapies, you've got to give them a place to test them and to do it much more quickly. You know, the whole Silicon Valley, the whole dot tech tech revolution is about systems-based learning and, you know, rapid learning. You know if it's not going to work, learn fast, fail fast. If it's going to work, great, build on that and move on.
John Marshall, MD: You've done it, right? Got it. And the way I think about…
Laura Esserman, MD, MBA: People are following it.
John Marshall, MD: Yeah, we're coming after you.
Laura Esserman, MD, MBA: And now we're working with the FDA on developing a regulatory strategy around it. We haven't finished we haven't gotten there quite yet, but we will.
John Marshall, MD: It really is Innovation and individualization are the two priorities, that you want to make sure that that patient in front of you, their individual tumor characteristics are recognized and optimized, the therapy for them learned from that through innovation. And you bring those two things together and then you create a new way of practicing medicine and cancer.
Laura Esserman, MD, MBA: So, the basis of this new trial is a smart, sequential, multiple, Assignment randomized trials,
John Marshall, MD: You certainly sold me as a GI oncologist of how we might partner with your team for similar things you have learned. You've already done it. You're doing it with COVID vaccines as well
Laura Esserman, MD, MBA: During the COVID trial, you know, the, one of the agencies that was sponsoring us was concerned. I said, look, we do not need to have, every time there's an adverse event, someone doesn't have to fill out an adverse event report because when people are dying of COVID, they have ARDS, they're dying. They have multi system organ failure. I mean, you could be filling these forms in all day. Here's a checklist of 10 things that happens to every patient. Do it the same on every single patient. It'll take you two minutes. That's a much smarter way of going about it. But they were concerned that we were hiding things or not collecting information. And they made us do this full audit. And you know, we spent six and a half million dollars doing this audit. And we didn't find one adverse event.
John Marshall, MD: You know, you say that that would have bought a kick ass booth at ASCO, six and a half million dollars. That would have been money well spent, is to take that money on your audit and spend it on a fancy booth.
Laura Esserman, MD, MBA: I'm trying, I'm trying to get this published, but, you know, it's going to be very threatening to the industry, but it should. But, to us, it's like we need to take back control of our profession. We need to, like, develop better systems for clinical care that actually help us with research because the goal of clinical medicine, what are we practicing for? We should be practicing to improve, but if you don't know what you're doing, you can't improve it. So that's my story and I'm sticking to it.
John Marshall, MD: I think we should just leave it right there. Dr. Laura Esserman taking a break out of her clinic from UCSF Department of Surgery there and the leader of the I-SPY program, transformative. Dr. Esserman, thank you for joining us.
Laura Esserman, MD, MBA: Oh, you're welcome. Thanks for having me.
John Marshall, MD: I hope everybody enjoyed this episode of Oncology Update. My name is Dr. John Marshall and maybe while you're out there, think a little bit about why is cancer so expensive?