The elderly's exemption from clinical trials is harming their healthcare

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Dr Ken Covinsky, a geriatrician and researcher, was in his office at the San Francisco VA Medical Centre last month, browsing through a medical journal on his computer. When he came across a study of sodium excretion, he waded into the abstract.

The research team, mostly based at the Centres for Disease Control and Prevention (CDC), had used 24-hour urine collections to estimate how much salt Americans take in each day. Salt matters to geriatricians. It’s associated with conditions many older people contend with, particularly high blood pressure, but also swelling and heart failure. Though doctors frequently urge older patients to reduce salt in their diets, it’s not clear how much reduction is necessary to improve health, or even how much salt most people actually consume.

“There’s a lot of controversy, but that’s why we need the data,” Covinsky says. So he read on, until he reached the paragraph explaining that the study used “randomly selected, non-pregnant participants aged 20 to 69 years”.

He did a double take. Once again, the population probably most affected – older adults – had been left out of an important study.

“How is this possible? Unacceptable!” Covinsky protested on Twitter. “I can think of no good rationale for this exclusion. This has got to stop.”

Geriatricians have complained for years that figuring out treatments for their patients becomes significantly more difficult when older people are excluded from clinical trials and other research. For an 83-year-old, what are the risks and benefits of a surgical procedure, drug or medical device tested primarily on those in their fifties? When a drug trial excludes those who have several diseases and take other drugs, how do the results pertain to older adults – most of whom have several diseases and take other drugs?

Too often, doctors resort to extrapolation – or, to put it less politely, guessing. So the sodium survey published in the journal JAMA, which an accompanying editorial praised as “a major advance”, stung. “If the CDC excludes old people, how do we tell drug companies not to?” Covinsky asks.

Asked to explain, the CDC said the study excluded older people because they were less likely to agree to participate in 24-hour urine collection.

Critics of age exclusion had reason to celebrate in December, when the National Institutes of Health (NIH) issued new policy guidelines for the research it funds. Starting in January, grant applicants will have to explain how they intend to include people of all ages, providing acceptable justifications for any group they leave out. The agency will monitor investigators to make sure they comply.

“It’s the right starting point,” says Dr Florence Bourgeois, a pediatrician at Harvard Medical School. (Children also end up taking drugs tested only in adults.) Yet she and other researchers point out that many studies are privately funded and thus will not be affected, and that merely eliminating age limits doesn’t mean older adults will actually be enrolled in studies. “It really requires a cultural shift in our thinking,” she adds.

How often are old people left out of important medical research? In 2011, it looked like progress when Dr Donna Zulman and her colleagues at the University of Michigan reviewed 109 clinical trials published in leading journals and found that just 20 per cent set upper age limits for participation.

An earlier review of trials published from 1994 to 2006 had found that 39 percent shut out people over age 65.

But, as the University of Michigan team also pointed out, even without age limits, studies may bar participants who have multiple disorders or disabilities, or those with limited life expectancy or cognitive impairment. Some researchers won’t enroll nursing home residents. Those restrictions effectively push older people out of clinical trials and other studies.

Maddeningly, exclusion rates remain high even for studies of diseases particularly common at older ages. Bourgeois and her colleagues looked at clinical trials for heart disease medications, for instance – primarily blood thinners, cholesterol and blood pressure drugs.

More than half the trials had upper age limits, usually 75 or 80, and only about 12 per cent of participants were aged 75 or older. Yet nearly 40 per cent of people hospitalised with heart attacks are over age 75.

Older people aren’t adequately represented in clinical trials for cancer, diabetes or osteoporosis. Covinsky recently came across a trial evaluating treatments for people with arthritic knees, “a disease primarily of people in their seventies and eighties,” he notes.

But the average age of the study participants was 58. “Why is this still happening?” he asks.

One reason is that eliminating so-called confounding variables in studies produces cleaner results. It’s easier to demonstrate the safety and effectiveness of a drug if those enrolled in the trial aren’t taking any other drugs.

It’s simpler to pinpoint the impact of surgery for a heart problem if the patients don’t also have diabetes or kidney disease. And older people metabolise drugs differently from younger ones, and may bounce back from procedures more slowly. The problem, Bourgeois pointed out, is that when researchers leave older people out, “you end up with a very homogeneous group that is not representative of your real-world patients.”

For patients in their seventies, eighties and beyond, will a studied drug interact with their other medications? Should the dose be higher or lower than for younger people?

Will it increase risks of particular concern to older people, like incontinence or falls? Will a surgical procedure fix a problem, but then send patients to nursing homes?

Without evidence, these questions become hard to answer.

“Getting this right is going to take a lot of work and changes in how studies are structured,” Covinsky says. It will also take more money and proactive research designs.

Enrolling older participants in trials may involve providing transportation or making home visits, for example, for those who can’t easily travel to study sites.

However welcome the new NIH policy, the more powerful player in this arena might be the Food and Drug Administration. It could require applicants seeking approval for new drugs and devices to include older adults in clinical trials.

“We think there needs to be a statutory change” to give the FDA that authority, says Susan Peschin, president of the Alliance for Ageing Research. That would require congressional authorisation, something pharmaceutical firms and device manufacturers (several of which financially support the alliance) would likely oppose.

In exchange, the FDA might provide incentives, like tax breaks or longer patent protections, to offset the higher costs of more inclusive trials, as it does for children’s drugs.

“You need a carrot and a stick,” Peschin says.

For now, though, we know that in 2014 American adults’ estimated sodium intake averaged 3,608 milligrams per day. “The findings provide a benchmark for future studies,” the authors wrote.

We also know that the benchmark won’t represent Americans over age 70. Covinsky, a fan of the CDC but not of this practice, finds that outcome unhelpful. “Since when does the US population stop at age 69?” he asks.

© New York Times