Older adults make up a hefty proportion of cancer patients but a much smaller slice of clinical trial participants—a long-standing and vexing problem the U.S. Food and Drug Administration (FDA) wants drug companies to tackle. The agency yesterday released recommendations urging companies to boost representation of people over 65 years old, and especially over 75. The recommendations span studies of experimental cancer treatments, including in the earliest phases, where the skewing to younger people appears more pronounced. Although the agency’s guidance isn’t binding, oncologists hailed it as an important step toward badly needed change in cancer clinical trials.
“The data upon which we approve drugs and issue guidelines are based mostly on younger people and applied mostly to older people,” says William Dale, director of the Center for Cancer and Aging at the City of Hope Comprehensive Cancer Center. At least one-half of cancer patients are over 65 years old, he noted, but only about one-quarter of those in trials fall into that age group. Most cancer trials technically allow even 90-year-olds to sign up, but in practice they rarely qualify. That’s because of a laundry list of enrollment criteria that often eliminates many older adults, in part because companies aiming for approval may worry older people are more likely to suffer serious side effects from an experimental treatment. These criteria can include normal kidney function—it naturally declines with age—or no prior bouts with a different form of cancer. “That 25% who are included [in trials] are the rock stars of older adults,” Dale says. “They’re the healthiest people because they’re the ones who meet the criteria for enrollment.”
Excluding older adults can lead to unpleasant surprises after a cancer drug is approved and prescribed to a very different group of patients—those who have an assortment of health problems, take multiple medications, are frail, or simply have different biology because of their age. For example, older individuals can struggle with blood pressure regulation, in part because of declining kidney function, and certain cancer drugs can cause their blood pressure to spike, Dale says.
A clinical trial that included no one over age 60 may conclude that combining a chemotherapy with immunotherapy, which rouses the immune system against tumor cells, enhances survival rates for a particular form of cancer. “But if you’ve got an 80-year-old in front of you, they may not have the physiologic reserve” to endure both treatments and benefit in the same way, says Ethan Ludmir, a radiation oncologist at MD Anderson Cancer Center. Furthermore, he notes, the disease itself may be different in an elderly person—some cancers in older people are less aggressive than in younger ones—meriting a lower dose or a different therapy.
The new FDA guidance, which was released in draft form in 2020 before being revised to yesterday’s final version, urges companies to enroll older adults in even early cancer studies, in which safety is initially assessed. Those early phase studies could help refine drug doses in older patients to guide the much larger later trials. FDA is also pressing companies to get creative. Probe interactions with other medications early in a drug’s development, the agency suggests, because older people often take multiple medications. Older adults could make up a distinct arm of a trial for a separate safety analysis. And, FDA says, companies should make every effort to include people with a history of cancer or with lowered liver, kidney, or other organ function. FDA’s push follows a similar, broader effort at the National Institutes of Health, which in early 2019 began to require those running clinical trials it funds across medicine to detail plans for including older individuals.
Work by Ludmir and his colleagues suggests that although the exclusion problem stretches across trial funders, studies paid for by industry are more likely to cut out older people than government-backed trials. That result, he says, indicates that it makes sense for FDA to direct its guidance to companies. Ludmir and his colleagues reported in 2019 in JAMA Oncology that among 302 cancer clinical trials, studies testing cancer therapies targeting specific molecules skewed younger than those studying broad strike chemotherapies, and were more likely to be funded by industry. Last month, he and others reported in Cancers that studies that excluded people who had another cancer diagnosis within the previous 5 years also disproportionately affected older people. “If they had an early stage breast cancer, is it medically reasonable to exclude someone from a pancreatic cancer trial if they get pancreatic cancer 3 years later?” Ludmir asks. Sometimes, he suggests, the exclusion makes scientific sense. But other times, it may not.
“Ultimately, the FDA guidance statements illuminate the need but are ‘guidance,’” says Ashley Rosko, medical director of oncogeriatrics at the Ohio State University James Comprehensive Cancer Center. People across the clinical trials universe—industry, individual researchers, and research networks—need to “take action to address this,” she says. FDA could also require companies to submit data on older adults, as a senior FDA oncologist, Harpreet Singh, wrote recently in a paper she co-authored.
Rosko and Dale note, too, that there are barriers beyond the science of trial design—older adults may have trouble getting to trial sites, and mild cognitive impairment may make it hard for them to participate and require companies to put in more effort to include them. Despite the hurdles, Rosko says, “We owe this to our patients to close the evidence gap.”