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Agency IQ — FDA and NIH leadership weigh in on the current state of clinical research

Agency IQ — FDA and NIH leadership weigh in on the current state of clinical research

What’s New?

  • This week, Friends of Cancer Research (FOCR) hosted its 2023 annual meetingThe agenda featured three substantive sessions on topics FDA has been focused on for the past year: dose selection in early clinical studies, evaluating the use of oncology products in real-life versus in a controlled research setting, and how real-world data can be leveraged for regulatory decision-making.
  • The panel discussion was highly anticipated given MONICA BERTAGNOLLI’s very recent transition to the role of NIH Director, an appointment that was confirmed by the U.S. Senate just last Tuesday. While she’s only held the title of NIH Director for a few days, Bertagnolli is likely familiar to many given her previous role as Director of the National Cancer Institute (NCI) at NIH. Prior to her arrival at NCI in 2022, Bertagnolli was a leading cancer surgeon and researcher, most recently at the Brigham and Women’s Hospital in Boston, where she also taught as a professor at Harvard Medical School.

Big picture challenges in conducting clinical trials today

  • The first session of the meeting was organized as a fireside chat with Bertagnolli and FDA Commissioner ROBERT CALIFF. The discussion was moderated by FOCR President and CEO JEFF ALLEN.
  • To get the conversation going, Allen asked both leaders to voice their thoughts on the biggest obstacles to improving clinical trials today as well as their thoughts on addressing the issues. In Bertagnolli’s opinion, the biggest challenge—regardless of disease, treatment, or patient characteristics—comes down to how data are being collected from patients during clinical trials, and how that information is being used to inform the decisions made by patients and their providers. While she admitted that putting these ideas into motion is a “tall order,” she expressed optimism that despite these challenges, radical change is possible. Building off her response, Califf responded that clinical trials are inherently complicated, but that if a group can work together to build consensus despite differing opinions, change is possible. While the “theory of how to bring evidence into practice” and vice versa has advanced significantly during his career, Califf said he feels as though clinical practice is headed in the opposite direction.
  • Despite increased recognition of the importance of patient-focused drug development, Califf said it seems harder than ever for patients to actually participate in clinical trials. “Clinical trials are seen as an extra task that detracts from a clinician’s time with the patient and gives the administrator a pain in the neck and causes institutions to be completely concerned about liability, as opposed to answering the questions that are relevant to practice and to their institutional decisions,” he remarked. “And,” added Califf, “insurance companies make it hard for people to participate as a matter of policy… So as long as that goes on, we’re not going to get there.”
  • Still, where industry has succeeded in increasing clinical trial enrollment, government-funded research continues to lag behind, said Bertagnolli. Though a small percentage of cancer patients participate in clinical trials today, she said the participation rates for industry-sponsored versus government-funded trials are vastly different. And, while the success of the pharmaceutical industry in enrolling more patients in clinical trials shouldn’t be downplayed, explained Bertagnolli, government-funded studies play an important role and strive to answer different questions from those that industry-sponsored trials focus on. For that reason, she sees low participation rates in government-funded trials as “one of the places where we’re the most critically behind.” Again, Califf built upon Bertagnolli’s response by noting that this is one area where technological advancements should result in meaningful change. In his opinion, there is no reason for clinical trial participation rates to be low today if researchers are taking full advantage of the tools that are available to collect information from patients continuously, in a way that’s not burdensome.
  • Per Califf, the issue is not pre-approval clinical trials, but what happens after FDA approval. While the FDA approval requires robust evidence of product safety and efficacy, certain questions cannot feasibly be answered in the pre-approval setting, he explained. In the end, the agency must consider the risks and benefits of product approval and weigh the practicality and importance of any outstanding questions. For this reason, there are many questions still “on the table” following product approval, which should be addressed in the post-approval setting. For example, additional post-marketing studies might assess how the newly approved product compares to other treatments, how long the product should be taken for, whether there are slight differences in product performance for certain patients, etc. Califf said this is a place where the entire ecosystem needs to come together to improve, and an area where NIH could potentially play a big role in addressing—though he noted that it’s up to Bertagnolli how NIH will proceed.

The road ahead

  • Califf wants to see post-market studies streamlined. Said Califf, “I think when people like me in the past have railed on about the clinical trial system, how it needs to be simplified, there’s been confusion, thinking we were talking about those earlier phases. And we need to make that really clear: I think that system works well and I don’t think we want to mess with it too much.” He added a caveat, that there are also certain flexibilities when it comes to bringing a new product to market which the Agency supports, such as in the areas of rare disease drug development, oncology, and even in the development of gene therapies.
  • In fact, the two executive branch agencies are already collaborating on oncology. According to Bertagnolli, the FDA’s Oncology Center of Excellence is already working on a few innovative projects in collaboration with NCI’s clinical trial network. She added, “I’m not at liberty to say what’s coming out soon, but I can tell you, I think that the ideas the team is working on are truly transformative.”
  • Another project NCI has in the works is the Childhood Cancer–Data Integration for Research, Education, Care, and Clinical Trials (CC-DIRECT), a public-private partnership which aims to make it easier for families to navigate the landscape of approved and investigational pediatric oncologic treatment options. There are three major components of the program, which are in line with both agencies’ goals to better utilize the data that are already being collected from patients to streamline healthcare delivery. The first of these is ,’“permissioning,” explained Bertagnolli, “We don’t say consent—it’s ‘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 in December, when the law finally goes into effect, any health system is going to be required to submit that record based on the permissioning we get from the parent.” The second component of CC-DIRECT is to take the health records of the child and standardize them, which ties into the third component of the program: offering a treatment navigation service, ensuring the clinical team and the family are able to readily identify and access any applicable, treatment options.
  • What about the role of public payers? While FDA and NIH are already working to collaborate on research and policy, one party missing from the table is CMS. “I think that there are a lot of things that policy wise that CMS can think about,” said Califf, “I actually don’t want to get into details right now because we want to preserve the ability—now that Monica is on board—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 on what to pay for and what to get rid of?’ […] imagine what an impact we could have on health and longevity.”
  • There’s also an important role for private insurers to play in improving the research ecosystem, he furthered, “When I talk to clinicians, they say the number one impediment to getting the [post-market] studies done is the requirements of the insurance companies… Now there’s a phrase I love which is ‘Blame is toxic, accountability is necessary’ and I’m not blaming the health insurance companies, but we all ought to be asking: What can we do to contribute to turning these things around?”

Focusing on achieving equity in research

  • Another point made by Califf is that clinical trial enrollment shouldn’t be limited to patients located within the United States. As U.S. residents comprise just a sliver of the world’s population, he said that a “global evidence generation system” is necessary. Similar to what occurred in his field (cardiology) about 25 years ago, sponsors are conducting oncology trials more and more frequently in other countries today, said Califf. In his eyes, this is the right move since it “would be wrong to enroll 100% of people in the U.S. for 4% of the world’s population.” Furthermore, he said that the “U.S. may not be the preferred place to enroll when you really talk to the people.”
  • “We cannot do the research we need to do without deeply engaging, understanding, and motivating the health systems,” stressed Bertagnolli. Even within the United States, there is great variability in healthcare delivery, a critical issue she wants to focus on addressing in her new role as NIH Director. Furthermore, while she wants to ensure patients from underserved communities are receiving cancer treatment, this also means treating the whole patient, not just the cancer. “You don’t show up at a place that is just so dear to my heart — Pine Ridge Indian Reservation, where the man’s life expectancy is 49 and a woman’s is 53—the worst in the nation—and say, ‘Hey, we’re the NCI and we’re here to do clinical trials, but only for cancer.’” Bertagnolli made the point that cancer clinical research can’t happen in a vacuum: “You have to walk into those communities and be there for every single health issue that that community needs you to support.”
  • These issues of addressing health inequities and increasing clinical trial participation all come back to evidence generation. In concluding, both Bertagnolli and Califf underscored the need to collect evidence in a way that’s less burdensome for patients and clinicians. Furthermore, the information that is collected needs to be readily accessible in a way that’s useful to clinicians and patients in informing their treatment choices. “Our clinicians are 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,” said Bertagnolli. Califf agreed, “If I’m sick I want to have a great doctor, but I’d rather have a great doctor armed with high quality evidence.”