PALO ALTO—While FDA Commissioner Robert Califf, MD, MACC, speaks with a charming and charismatic South Carolinian accent, it’s not enough to sugarcoat his choice of words. During the opening fireside chat, in an overflowing Berg Hall at the Li Ka Shing Center (LKSC) at the 2023 Stanford Drug Discovery Symposium, Califf pointed at the serious health problems facing the United States, although he believes most of them are solvable.

While Commissioner Califf doesn’t think anyone would argue with the concept that the U.S. is number one in biomedical innovation, product development, and food safety, he expressed concern that the U.S. ranks almost last among high-income countries for health outcomes.

“Why do I have to call the U.K. to find out which treatments work best for COVID-19 and why do I have to call Israel to figure out what to do with the next vaccine?” Califf pondered. “There’s something going wrong between the innovation process and what happens after that. I’m now having a historian say that the U.S. looks like Russia after World War II. That’s not a very exciting prospect. With all the intelligence that we have here, we have got to do better!”

Part of this gap between biomedical innovation and healthcare comes down to getting the information to match patients to treatments—a problem that Califf reckons hinges on the lack of “real-world” data.

“Real-world evidence does not mean non-randomized, sloppy observational studies for which you can’t really draw an adequate conclusion,” said Califf. “Real-world evidence is essentially data coming from what I would call a traditional clinical trial. That’s what the law says.”

But traditional clinical trials are typically weighed down by “huge amounts of paraphernalia” that don’t contribute that much to getting the answer, add tremendously to the expense, and ultimately limit the scope of clinical trials. The solution, Califf proposes, is to make use of all the available tools to collect real-world data, whether via an electronic health record, a sensor, or a patient report on a cell phone.

“We need evidence derived from the real world using whatever method is appropriate,” said Califf. “We need a system of evidence generation that lasts for a lifetime for people, where you don’t have to have a company spend a hundred thousand dollars per patient to get the information that’s needed. We all have electronic records that ought to be almost free.”

Diversity, disinformation, and death

Califf thinks that the narrative on patient diversity has become old, stale, and irrelevant. While the FDA put out draft guidance quite recently on diversity in clinical trials, Califf is deeply concerned about education and wealth. He quoted an article by science writer Ed Yong in The Atlantic: “Technological solutions also tend to rise into society’s penthouses, while epidemics seep into its cracks.”

On this topic, Califf said, “It’s one thing to provide excellent, high-tech care to people who show up at your doorstep with insurance, but it’s a whole different thing to do what we know actually affects health outcomes the most, which is reaching out into homes and interacting with people in communities in ways that change the way they proactively deal with health.”

To address this, the FDA is going to require that the industry produce a plan to account for this diversity. This is a move the NIH has made that the FDA can’t fully match because they aren’t holding the money. “If you look at the NIH over [the past] five years, trials by race, sex, and ethnicity mirror the country,” said Califf. “But we need to move to the next level to measure all disparities.”

Califf believes that misinformation is the leading cause of premature death in the U.S. “There’s an old saying: life is a sexually transmitted disease with 100% mortality—we are all going to die,” Califf said. “But dying early because you didn’t do something that people who are knowledgeable know would save your life—that’s really tragic.”

COVID has provided the best example: hundreds of thousands of Americans died needlessly had they received a prevaccine or been administered Paxlovid if they got infected and were at high risk. Califf said that according to a recent NIH analysis of mostly academic medical centers, only nine percent of eligible patients received Paxlovid. And yet, the real-world evidence showed that there was an 80 percent reduction in mortality in those who got the drug compared to those who did not.

Califf thinks that we’ve lost our way in terms of how we communicate with people, which plays out in the growing divide across the country between urban and rural communities. “We all know what you need to do day in and day out to live longer and avoid chronic disease, but it’s not happening in this country,” said Califf. “It’s very tied to cultural norms, which then play out in the politics of what elected officials do based on what they’re hearing from their constituents.”

While there’s a lot of hype surrounding gene editing, the Commissioner said that he is uncertain of the right way for the FDA to regulate the field. “What worries me is that a well-intentioned person thinks I’ve got a treatment that will prevent this disease, but you don’t see the benefits of that for years to come,” said Califf. “You will see the risks, and to approve it with no demonstration that the benefit-risk equation is positive is a very scary thing to do, particularly for big diseases that affect millions of people.”

To illustrate, Califf uses the analogy of cardiac valves. “If you had to wait 15 years to know how long a cardiac valve would last before you put it on the market, there would be no investment in cardiac valves,” said Califf. “We intend to have a pretty robust societal discussion about this issue because we know it’s coming.”

Setting the stage for the day

The fireside chat with the FDA Commissioner was the first session of a jam-packed day in Palo Alto, with multiple sessions on drug development, including a panel discussion on funding. The conference was bookended by another fireside chat, this time a panel of CEOs, including Alexander Hardy, MBA, CEO at Genentech, Robert Bradway, MBA, chairman and CEO at Amgen, and Michelle McMurry-Heath, MD, PhD, former president and CEO, Biotechnology Innovation Organization. Other notable speakers throughout the day were Hal Barron, MD, CEO at Altos Labs, and Mathai Mammen, MD, PhD, newly designated CEO FogPharma.

The icing on the cake was the presentation by Lifetime Achievement awardee Brian Druker, MD, director of the Oregon Health & Sciences University (OHSU) Knight Cancer Institute and professor of Medicine in the Division of Hematology/Medical Oncology at the School of Medicine at OHSU, who walked the audience through his journey in the development, approval, and utilization of Imatinib (Gleevec).

The second and final day of the conference will end with a session consisting of a local Nobel Laureate panel: Carolyn Bertozzi, PhD, Jennifer Doudna, PhD, Brian Kobilka, MD, and Roger Kornberg, PhD. The panel discussion, moderated by Marc Tessier-Lavigne, PhD, is dedicated to the late Paul Berg, PhD, Nobel Prize winner and recombinant DNA pioneer.

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