Monica Bertagnolli is “someone who goes up against the odds and has confidence that we can do it,” FDA Commissioner Robert Califf said of the newly confirmed NIH director at a recent annual meeting of the Friends of Cancer Research (The Cancer Letter, Nov. 10, 2023). “It may take a cancer surgeon actually to overcome this.
“I think the FDA wants to put all of its weight into helping to make this happen because it’s really, really needed.”
To the average healthcare provider, a clinical trial can be seen as an inconvenience: an expensive add-on that detracts from a clinician’s time with patients and exposes institutions to liability, Califf said.
That’s a major hurdle, because clinicians and administrators should instead be focused on “answering the questions that are relevant to practice and to their institutional decisions,” Califf said in a conversation with Bertagnolli and Friends President and CEO Jeff Allen at the Nov. 14 meeting in Washington, D.C.
“As long as that goes on, we’re not going to get there. And all those things are in play right now. We’re going to have to come up with policies that overcome them.”
This quandary is compounded by at least four real-world challenges:
- Consistently low rates of clinical trial participation: About 5% of all U.S. cancer patients enroll in studies. Oncology notwithstanding, only about 9% of all Americans report that they’ve been invited to participate in a clinical trial, and 41% say they don’t know anything about trials.
- A dearth of national thought leadership in the postmarket setting: Outside of phase I-III trials, there is a need for more comparative effectiveness, dose optimization, and cost effectiveness research.
- Reimbursement impediments: Clinicians often encounter obstacles to enrolling patients to clinical trials because of payer requirements.
- Unnecessarily complex trial protocols: Ballooning data collection requirements, long consent forms, and endpoints that aren’t fit-for-purpose.
Over the past year, FDA and NCI—in what has been described as an unprecedented collaboration in oncology across government, academia, and advocacy and industry groups—showcased a new streamlined study design in a trial called Pragmatica-Lung, which focuses on overall survival and collection of essential data (The Cancer Letter, Dec. 2, 2022; Pragmatica-Lung).
“There’s not a better example than Pragmatica,” Califf said at the Friends annual meeting. “It’s fairly well known that Dr. [Richard] Pazdur [director of the FDA’s Oncology Center of Excellence] and I, every month, or every other month, we have a dinner where we mostly argue about which is better—cardiology or oncology.
“Monica joined us for some sessions and I think both sides have really worked hard, and I think it’s going well from what I hear.”
Earlier this year, during her stint as NCI director, Bertagnolli created a Clinical Trials Innovation Unit, a “research acceleration lab” that will focus on radically new study designs and operational procedures (The Cancer Letter, Feb. 10, 2023).
“That team is working together and they’re doing really hard work,” Bertagnolli said at the Friends annual meeting. “I can tell you I’m not at liberty to say what’s coming out soon, but I can tell you I think that the ideas that that team is working on are truly transformative.”
As NIH director, Bertagnolli is determined to make the following changes:
- Transition the design of clinical trials as well as the culture of clinical care toward a “learning laboratory” that serves as a multi-platform environment for evidence generation,
- Federate cancer research data and increase access to more complete data sets (The Cancer Letter, Dec. 4, 2020).
- Increase enrollment in government-funded trials.
“If you just look at the number of patients who go on trials and you look at the number of patients who go on government-funded trials, it’s been completely flat over the last decade,” Bertagnolli said Nov. 14. “If you go and look at the number of people who go on pharma sponsored trials, it’s just had this tremendous increase, and the ratio is getting worse and worse and worse.
“I mean, pharma is producing amazing results for us, and I wouldn’t want to deemphasize that in any way, but we’ve got to get the trials out and funded and available that are answering all those questions that are not of central interest to pharma. That, to me, is one of the places where we’re the most critically behind.”
Bertagnolli said her vision for NIH will focus on revamping the U.S. health system’s relationship with data repositories—an all-inclusive approach to clinical data collection and access is key to building the next generation of more complete databases.
“I am a clinician. It’s not so long [ago] I sat in clinic and you realize every time you’re there that the data you’re operating on, the knowledge that you’re using, so little of it is really, truly, absolutely solid,” Bertagnolli said. “You’re operating with incomplete data constantly. And we do pretty well because our clinicians are dedicated and dedicated to their patients.
“But we could do so much better with better evidence. And I want to get the kind of evidence that helps those doctors and patients to make their decisions together. It’s a big task.
“And it does not underplay in any way—in fact, it magnifies the importance of fundamental science. It magnifies the importance of technology and it magnifies the importance of our health system. And I think at NIH, we do research, we don’t do care delivery, but it’s still got to be a big concern for us. And who else is going to help understand how you make those outcomes better?”
Said Califf: “We’re together on that. I always said, if I’m sick, I want to have a great doctor, but I’d rather have a great doctor armed with high-quality evidence.
“I could have sworn Monica said she was going to make research fun again.”
“It is fun!” Bertagnolli said. “It’s fabulous.”
Excerpts of Allen’s conversation with Califf and Bertagnolli at the Friends annual meeting Nov. 14 follow:
Robert Califf: What is the right proportion of people to be in clinical trials? And I think at least the way I see it, if we change it to evidence generation from clinical trials the way we standardly think of them, I would hope we can approach 100%.
Because we know, with technology where it is today, there’s no reason we can’t have quality assessment, observational analysis of what’s working and what’s not going 100% of the time humming in the background—because the technology’s there to do it, and most industries work that way.
And then, when there’s a question that needs to be answered through randomization and a clinical trial, you insert that into a system and we don’t need 100% of people to do that. We need the right number to get the answers. We’ve also got to consider that the U.S. is 4% of the world’s population.
There are 8 billion people in the world, we’re 340 million or so, and so, we need a global evidence generation system. But I would point out those industry-funded trials that Monica’s talking about. I see Dr. Pazdur sitting up there, he may opine on this later, but from what I’m hearing, even in oncology now, we’re seeing a migration of industry funded trial enrollment out of the U.S. into other countries.
That happened in my field of cardiology 20, 25 years ago. It would be wrong to enroll 100% of people in the U.S. with 4% of the world’s population, but we need to come to grips with the fact that although pharma is doing a great job of getting their trials done, U.S. may not be the preferred place to enroll when you really talk to the people.
One other point I want to make, which I think is really important and germane:
I think if you look at phase I through III clinical trials, the system in general works pretty darn well—90% of drugs don’t make it to market because the trial system weeds them out where there’s toxicity. You wouldn’t want to wait until millions of people are treated to figure that out.
So, the system’s doing that part of it really well, where we really don’t have a system that works is post-market where NIH has such a huge role potentially, and we’ll see what the director chooses to do.
All these questions that are left on the table after FDA approval: How does it compare to other treatments? How do you combine treatments? How long should you treat?
My mom had multiple myeloma, and she was rescued by an accelerated approval, but no one could answer the question, “Do you just keep giving it forever?” Or, “When do you stop?”
And it’s understandable that industry’s for profit, there’s not an incentive to answer a lot of these questions. This is a matter where we all as an ecosystem need to work together. And it’s also a place where we can simplify quite a bit, because we’ve already answered in phases I through III those critical questions about any possible side effect or toxicity.
Because we collect all that data, we don’t need to keep collecting it when the 10,000th patient has been entered into a clinical trial. And we can then reduce the costs, make it simpler, make it easier for patients and clinicians to participate. I hope we’ll really take that seriously.
Jeff Allen: From your vantage point, you described earlier on some of the silos that have been built across the healthcare system that makes evidence generation and clinical research a challenge, but it very much sounds like you two are on the same page here moving forward.
So, do you have any thoughts that you could share with us about ways that FDA and NIH could collaborate even stronger than they do already?
Monica Bertagnolli: I can give you an example of a beginning of building the infrastructure that I think we’re going to need. Remember, we need data that really speaks to the doctor and the patient. They’re in the room together.
Well, there’s project ongoing at NCI. It’s called CC-DIRECT (Childhood Cancer–Data Integration for Research, Education, Care, and Clinical Trials). And one of the things that NCI has really done successfully recently is build a community around the use of pediatric cancer data.
So, the Childhood Cancer Data Initiative is not only about bringing data together, it’s about bringing the community of people who are using the data together. There’s a new project, CC-DIRECT, that’s come out of that that is trying to dramatically expand that community in a dynamic way that can facilitate knowledge.
What does it do? It’s got three major components.
Component one is permissioning. We don’t say consent. It’s a permissioning based on the parent saying, “I give you permission to have access to my child’s medical record for as long as you want it.”
As you know, this means that, now, in December when the law finally goes into effect, that any health system is going to be required to submit that record based on permissioning we get from the parent.
Number two, when that record comes in, there’s a core team working on turning that record into a standardized health record that serves the needs of a pediatric cancer patient—all the data that we need to be able to evaluate and treat that child.
And then the third part of it, which is really important, to give back to the patients that we’re working with, is a navigation service to make sure that this child is getting to the people they need in order to treat them.
It has a graduation program when the child turns 18, because losing kids at adulthood, often our survivors fall off the end. And so, the idea is to create a system that allows us access to all kids who agree to participate with pediatric cancers.
And then there’s an additional consent that every child’s family can agree to, which says, if there’s any research relevant to our child, can we recontact you? And so, they get plugged into the Childhood Molecular Cancer Data Initiative. Any child with a rare tumor is automatically plugged into a network that allows them to be approached and identified when a new treatment comes on board.
So, this team has been working. They’ve made tremendous progress on the permissioning, on the standard health record format and on the navigation, and we’ll see this roll out over the next two years for kids.
Why did we pick kids? We picked kids, because [there are] 13,000 new diagnoses a year. It’s something we can get our arms around and it’s nationwide. It’s not only major academic medical centers, kids with cancer come from everywhere. So, we’re really reaching the most distributed possible population to build these new tools.
And I’ll just say, finally, we’re going to have this data learning network now. We hope to see this successfully work out of a lot of kinks, and then we want to see it go to scale, pilot and scale, go to the next population where we start pulling in the data required to create a learning health system.
Allen: Rob, on the postmarket side of things, that sort of void of information or the delinking that you described not mixing that up with the phase I through III trials—when you think about research in the healthcare practice, what role do you think CMS has to play?
Califf: Let me explain that to payers in general, but CMS obviously is a special payer. I think that there are little things that, policy-wise, CMS can think about. I actually don’t want to get into details right now because we want to, now that Monica’s on board, we want to preserve the ability to have some internal discussions.
But I would just say I wouldn’t expect payers to run the research activities. But if they ask the question, what can we do every day to make it more likely that we get the answers to the questions, we need to know what to pay for and what to get rid of. I mean, remember we’re spending $4.3 trillion, and I’m not asking for tiers right now, but male life expectancy in the U.S. hit 73 last year. There’s just a paper yesterday showing that it’s going in that direction.
Women live to be 79, the gap is widening, but combined, we’re in last place in high-income countries now in health outcomes and headed the wrong direction and we’re spending $4.3 trillion.
So, imagine if we actually knew what worked and what didn’t and we knew comparatively where to spend our money, what an impact we could have on health and longevity. Now, this is not all just about drugs and devices or medical care, but I think there’s a lot to be said for having the evidence we need to know what to focus on given the situation that we’re currently in.
But so far, I’ve found that anytime we have a question that needs to be answered that’s really relevant to practice if we don’t make it hard, clinicians are very excited about participating and a very high proportion of people will volunteer if they’re asked.
Bertagnolli: And I can also add that relevant to CMS, but relevant to all of HHS, we cannot do the research we need to do without deeply engaging, understanding and motivating the health systems.
We absolutely have to deeply understand the health systems in their great variability throughout this country if we’re going to deliver what the patients need.
So, for me, thousands and thousands of great research questions, but every single one of those questions we have to view through, okay, who are we trying to engage? And that means which health system are we trying to get into, make it possible to do that research?
I’ll just say finally that one of the things in my new role I’m very interested in is we have a lot of really, really challenged communities that we need to get into, we need to get into for oncology.
A place that is just so dear to my heart: Pine Ridge Indian Reservation, where a man’s life expectancy is 49 and a woman’s is 53—the worst in the nation. You don’t walk into Pine Ridge and say, “Hey, we’re the NCI, we’re here. We want to do clinical trials,” and say we’re only here for cancer.
You have to walk into those communities and be there for every single health issue that that community needs you to support. This is frankly one of the reasons why I am thrilled to be working with Rob and I’m thrilled to be at NCI, because if we’re going to succeed for cancer in these places, we have to bring everything.
And then finally, we had an IC director’s meeting, my first one, which was really exciting, because I looked around the room and I said, “Is there anybody in this room who isn’t worried about obesity? Anybody?”
And the answer is really no. Believe it or not, the Institute on Drug Abuse, NIDA, has now got really interesting data, which we’ve been talking about, showing that heavily processed foods are addictive. So, those kinds of issues that are really truly relevant to cancer, that we need to tackle across all of the agency.
Allen:Before we wrap up, let me ask you guys both one more question. Maybe I’ll start with you Rob, since you’ve had a little bit more time to think about this. I can only imagine that your roles are, oftentimes, perhaps unpredictable and encountering issues that you may not have even thought you’d encounter that day. But as you think about the tenure leading your respective agencies, what’s one thing that you want to be sure that you don’t take your eye off of?
Califf: People around me know this. I bugged the heck out of people about our decline in life expectancy and all the things that go with it. And so, you say, okay, keep your eye on it.
It’s not really the FDA’s primary responsibility, but I think we ought to be asking the question every day, what are we contributing to turning this around? And for example, things that come to mind: We have entire areas like, when was the last time you saw a modern product for tobacco cessation?
We’re going to lose almost 500,000 Americans this year to tobacco-related illness. We need more treatments for addiction. Mental health is not going great in terms of new product development.
So, that’s really the thing for me is we’re a public health agency and there are a gazillion things we need to do every day. I actually feel pretty good about our center directors, who are doing a great job of doing those things.
But in aggregate, this is the thing that I think we got to just not forget, because it’s easy to say, “It’s really not our problem. We do our job well, don’t worry about the rest of it.”
Bertagnolli: So, I led with mine. I mean it really is. I am a clinician. It’s not so long [ago] I sat in clinic and you realize every time you’re there that the data you’re operating on, the knowledge that you’re using, so little of it is really, truly, absolutely solid.
You’re operating with incomplete data constantly. And we do pretty well because our clinicians are dedicated and dedicated to their patients. But we could do so much better with better evidence. And I want to get the kind of evidence that helps those doctors and patients to make their decisions together.
That’s what we’re lightning focused on. And it does not underplay in any way—in fact, it magnifies the importance of fundamental science.
It magnifies the importance of technology and it magnifies the importance of our health system. And I think at NIH, we do research, we don’t do care delivery, but it’s still got to be a big concern for us.
And who else is going to help understand how you make those outcomes better?