During this week’s Friends of Cancer Research (FOCR) meeting on the use of real-world data to support oncology drug development, FDA Commissioner Robert Califf shared his take on the barriers preventing the collection and utilization of high-quality real-world data (RWD) and pondered what lessons the U.S. healthcare system could stand to learn from others.

The meeting

• This week, Friends of Cancer Research (FOCR) hosted a meeting where panelists discussed the current and potential future opportunities for using real-world data to support the approval of new anticancer therapeutics. The roster included presenters from FDA, the pharmaceutical industry, academia, patient groups, and the health data sector. Of particular interest, FDA Commissioner Robert Califf offered his opinion on the topic during an afternoon keynote session moderated by Kate Rawson of Prevision Policy.

The FDA Commissioner’s view on what’s currently impeding the use of RWD

• Califf, who earlier this year called for a revamp of how data are collected in the post-market setting, was asked to comment on what he believes to be contributors to data quality issues. He started by comparing the factors at play when it comes to collecting data in the pre- and post-market settings. While many things can still be done to increase efficiency and reduce the costs associated with bringing a new product to market in the U.S., he explained that overall, the pre-market system works well, as intended, to weed out the products in the early clinical phases that are ineffective or unsafe so that by the time a product is approved, it’s been rigorously studies, tested, and reviewed. However, crossing the finish line of product approval—both traditional and accelerated—marks the beginning of disarray, in Califf’s view. The cause? “The system is in shambles, and if you asked me what has created that… I would say it’s reflective of the American healthcare system,” he ventured.
• In contrast to the U.S. healthcare system, he pointed to the state of healthcare and life expectancy in Singapore. During the early 2000s, Califf held several leadership positions at Duke University, which is how he helped to establish the first graduate entry medical school in Singapore, the Duke‐National University Singapore School of Medicine. With the comparison perhaps top-of-mind since he’s headed to Singapore this Friday, Califf stated that despite the many imperfections Singapore has, the country has been remarkably successful in improving its citizens’ life expectancies. In addition to outpacing the United States by about 10 years in average life expectancy, he noted the striking discrepancy in average healthy life expectancies between the two countries. “They really are at a decade, now of advantage over us,” he opined, “And I think the main culprit in the U.S. can’t be that we’re not spending enough money—we spend more than anyone. And it’s not a lack of technology. Everywhere I go, people agree that the U.S. leads the world in innovation and creating new technologies—that’s what we do.”
• Why does Singapore so far outpace the U.S. when it comes to ensuring its citizens live long, healthy lives? It’s what happens after a product gets approved, explained Califf. While it’s fair to conclude that some differences are a result of social determinants of health, he said it’s become more and more clear that trying to disentangle what happens after a product is approved from the actual approval process is futile, considering that other countries that are integrating the two effectively are succeeding in increasing the overall health and longevity of their societies — while the U.S. continues to fall short.
• Rather than attempting to shield the product approval process completely from discussions about cost, patient access, and implications of long-term use, Califf said we should be putting systems in place that integrate research and practice. “To see the language of the Singaporean national strategy, he said, highlights stark differences. There, he said, the attitude is, “‘We’re already living to 85, but we want people to be healthy for at least 80 of those 85 years,’ and ‘We’re going to do it by working together, creating community systems at work where we have a collaborative approach.’” Califf added his concern “that the U.S. is headed in the opposite direction,” with rugged individualism winning out over collaboration, “unless we’re absolutely at the end of the road on other options – and I think we’re paying a price for that.”
• In an ideal healthcare system, the output from each component of the system—research, product approval, access, cost, and overall clinical care—might serve as the input for the next, creating a harmonious cycle designed to achieve the single, overarching goal of healthcare: to improve patient health. In this vision, information garnered from clinical care would be recycled for use in research, and each iteration of the cycle would marginally improve both patient care and the efficiency of the system. Yet, the picture of the American healthcare system today, as evoked by Califf, might be more accurately described as a broken wheel, where patients represent the input, yet financial gain is the universally desired output of each component. As a result, patient health is no longer either the driver or the outcome of the cycle, but rather a byproduct of a bloated and relentless healthcare system, in Califf’s view. As an example of what this looks like in practice, Califf – a cardiologist — said he’s heard increasingly about many individual cardiology practices being bought up by private equity. While these mergers aren’t necessarily a bad thing, he said, they signal that practices are increasingly looking to optimize their own well-being. For patients, these mergers could result in changes in insurance acceptance, potentially leaving some patients to search for a new provider. He emphasized, “Patients with heart disease—particularly older people—have multiple, other problems and we have a system which is almost designed purposely not to integrate. If you don’t believe me, just talk to any friend or neighbor that’s trying to get an appointment with a doctor of any kind right now, much less navigate between U.S. health systems.”
• The organization of information is central to an efficient and properly aligned healthcare system. He quipped, “I’m quoted as asking ‘Why do I have to call Israel to figure out what the next vaccine does?’ and ‘Why do I have to call the U.K. to figure out which treatments work for COVID?’ Well, the answer is because they have organized approaches to the information. In Israel, the three health systems have real-time electronic health record data.” Despite some of the issues the U.K.’s National Health Service (NHS) has, he said the one thing the NHS has gotten right is the integration of clinical research into clinical practice and the use of real-world data. In contrast, he stated that the barriers impeding the progress of clinical research and the use of RWE here in the U.S. are —in many ways—just a reflection of the overall U.S. healthcare system and its fragmentation.
• It’s tempting to write off RWE initiatives, “because you can’t really fix [clinical research] until the health system gets fixed,” said Califf. “But we’re going to be waiting a long time for that and I would argue that the health system in the U.S. is headed in the wrong direction,” he added. “At some point we’re going to wake up and realize that integration of care is what matters—not each individual part of the system optimizing its own finances.”
• “I think we have a real opportunity to overcome some of this, but every part of the research ecosystem is going to have to give a little bit for that to happen,” continued Califf, calling on the FDA, the National Institutes of Health (NIH), and the Centers for Medicare and Medicaid (CMS) all to do their parts. However, he clarified, it’s not just government stakeholders that are responsible for the current state of things: “There’s a lot of aggregation going on for the financial benefit of elements of the system. Where is it integrated for the benefit of the patient? It wouldn’t take that much give from every element of the system.”

What about the current opportunities?

• What is the FDA doing to further the use of RWE and overall, to shift the role it plays in the current system? When it comes to drug development, review, and approval, “I think it works pretty well,” he said, though he admitted that there are different opinions within the agency regarding the use and requirements for RWE in marketing applications. One area of particular FDA focus is improving how RWE factors into inspections conducted by FDA’s Office of Regulatory Affairs (ORA). Though often overlooked by people outside drug development, ORA’s work is important, as are the implications of the Office’s “major renovation,” said Califf. In contrast to the majority (about 90% per Califf) of clinical trial site and manufacturing facility inspections the inspectorate currently conducts, ORA staff isn’t very familiar with the conduct of non-traditional trials or how to handle RWE. This has made industry cautious to use such approaches for fear of being issued a Form 483 following an inspection, which has many implications, including potential delay of product approval. To combat this issue, Califf said part of the reorganization will focus on preparing inspectors to handle these types of inspections. He also mentioned that the FDA is anxiously awaiting the Reagan-Udall Report on RWE and intends to take some direction from its findings.
• While there is work still to be done on the use of RWE in the pre-approval space, Califf asserted that the biggest barriers exist in the post-market space, where the FDA is just one of many stakeholders involved. For example, “With more and more accelerated approvals, do we really know exactly who should get the treatment?” he asked. In contrast to rare diseases or cancers where there are often highly segmented populations, some new products that have received accelerated approval are aimed at treating much more prevalent indications affecting much larger, more diverse patient populations, including Alzheimer’s disease and obesity. “And we know the drugs are safe and effective for the indications that we’re studying,” he explained, “but there is a heck of a lot to be learned… I mean, should 65% of the U.S. population be treated with obesity drugs? I don’t know! We need to find out where the risks and benefits are actually distributed.” Furthermore, for indications like obesity or depression where numerous products are on the market, comparative effectiveness studies are needed to explain why certain products work better for certain patients. However, these types of studies go beyond “FDA’s swim lane,” which is why other agencies and stakeholders have to be part of the discussion and the solution. Califf cited the example of the CMS announcement earlier this year that RWE will be used in Inflation Reduction Act-mandated negotiations on Medicare drug prices. Here, Califf said that CMS consulted FDA to understand how the Agency views and defines high quality real-world data.
• Califf thinks better coordination between FDA and CMS is within reach. “It’s hard to argue we have a system now that’s very good at getting the right treatments to the right people,” said Califf. While FDA and CMS may have slightly different evidentiary requirements when it comes to supporting product approval versus insurance coverage, the way data are collected in the post-market setting and the analytical methods used to evaluate the data can be streamlined, he explained. For instance, the two agencies could work in parallel with sponsors to determine what is the most appropriate way to collect the data (e.g., from electronic health records, digital monitoring technologies, or a special research clinic). Additionally, the analytical methods used to assess the safety and efficacy of a product should be the same, even if the patient population or subpopulations (e.g., Medicare enrollees versus all patients) are slightly different.
• Developing and adopting data standards for the exchange of information (i.e., real world data) remains important, said Califf. He encouraged groups to continue working on developing standards so real-world data can more easily be used for clinical trials and post-market surveillance. However, while there is a need for standards, he also noted that “human problems” can sometimes be more of a hangup than technological problems. For instance, “I heard that it’s hard to get images,” he said. “Now, this is not a technological problem, right? Because we’re all sending images back and forth all over the world.” Rather, he said this is an issue of people hanging onto information because it gives them power and autonomy, and the type of thinking that needs to change for progress to be made. Overall, he said he is encouraged by the efforts so far and hopes that the different sectors of industry and the different government agencies will continue to collaborate to further address this issue going forward.

https://fda.agencyiq.com/article/0000018a-920a-dee9-adca-d33ec5290000