For years, researchers have called out a glaring gap in many clinical trials: Despite having far higher rates of many diseases, older adults are largely excluded from studies testing new therapies that might help them.
For how extensively experts have studied the issue of age disparities, though, it remains a significant problem — and one that has grown all the more pressing during the Covid-19 pandemic, given that the virus has hit older adults particularly hard. An analysis published this week found that older adults are likely to be excluded from more than half of Phase 3 Covid-19 trials on Clinicaltrials.gov — which could make it more difficult for researchers to evaluate doses, efficacy, and safety across all age groups.
“It is important we have a trial population that reflects the real-world population,” said Ethan Ludmir, a clinician-researcher at the University of Texas MD Anderson Cancer Center who has studied age disparities in clinical trials. “We don’t know if an 18-year-old and a 55-year-old will tolerate [a] treatment differently or respond to it differently.”
That analysis, along with several other recent studies, suggest there’s a need for a course-correction — not just for Covid-19 studies, but for a wide range of research.
Another paper, published this month in JAMA Internal Medicine, looked at the inclusion of older adults in cardiovascular clinical trials before and after the National Institutes of Health rolled out what’s known as the Inclusion Across the Lifespan Policy in January 2019. The policy requires anyone applying for NIH funding for studies involving human participants to include a plan for including people of all ages — or explain the scientific or ethical reason why they’re not doing so.
Researchers looked at 97 cardiovascular trials listed on Clinicaltrials.gov and found that before the policy went into effect, one-third of trials had age limits. In the year after the policy went into effect, one-third of trials still had age limits.
Age limits weren’t the only factor that could limit enrollment of older adults. Two-thirds of the trials also used exclusion criteria that weren’t specific to age, but which would disproportionately winnow out older adults, such as having preexisting conditions. Most of the studies also didn’t include endpoints focused specifically on a treatment’s effects on older adults, such as whether older adults were less likely to adhere to the treatment regimen or more likely to experience problems with their mobility.
“Older adults bear a lot of the burden of cardiovascular disease in our country and yet are not always included in the study to see whether the drugs are safe for older adults or effective for older adults or have side effects,” said Colette DeJong, chief medical resident at University of California, San Francisco. DeJong was not involved in the study, but co-authored an editorial on its findings.
Experts said the NIH plan is the type of policy that will take time to pay off, given how far in advance studies are designed and how early funding — including the NIH grants that would come with policy stipulations — for studies is allocated.
“It’s going to be a few years before we know the effects of the policy… because they only looked at the first year, so time is going to tell us more,” said Kenneth Covinsky, a clinician and researcher who specializes in geriatrics at UCSF. Covinsky co-authored the editorial on the study with DeJong.
In another study, published in October 2019 in JAMA Oncology, Ludmir and his colleagues analyzed the average age of participants in 302 trials for breast, prostate, colorectal, or lung cancer, and compared it with the average age of patients worldwide with those diseases.
“We wanted to assess over the last 20 years or so, whether our cancer clinical trials effectively represent the patients that we see every day in our clinics,” said Ludmir.
On average, study participants were far younger than the real-world population affected by a disease. The biggest age disparities were seen in industry-funded studies and trials testing a targeted therapy. Another troubling finding: Those age gaps seemed to be widening over time.
“Age disparities among cancer trial participants are pervasive, worsening, and associated with industry sponsorship,” Ludmir and his co-authors wrote.
Experts are quick to note that in some cases, the exclusion of older adults from a participant pool is justified. In some cases, there are concerns about comorbidities or patient consent. In other scenarios, there might be risk involved with delivering experimental treatment in combination with other drugs commonly used among older adults.
In the analysis of Covid-19 trials, concerns about compliance — and specifically, the ability to consent to a study — were the most common age-related exclusion. Older participants were also often at risk of exclusion because of other disease diagnoses or technology requirements.
Taken together, experts said the recent findings underscore how often trials exclude older adults, whether directly or indirectly.
And fixing the problems won’t be as simple as changing the inclusion criteria for trials. There are a number of other barriers that affect whether older adults, including enrollment outreach and transportation concerns. Going forward, experts agree clinical trial sponsors will need to think creatively — and carefully — about the best ways to recruit and enroll older adults in a trial.
“It’s imperative that we let patients across all ages have the opportunity to participate in trials and use thoughtful decision-making in who we include and exclude,” Ludmir said.
And he and other experts say that should be a conversation that happens early in planning a study.
“The fundamental question is, if this drug were to be approved, who would it be used [for]?” asked Covinsky.