Oldest patients are often left out of drug trials

Dr. Daniel Forman (left) and Kenneth Manning, an exercise physiologist research assistant, monitor a 91-year-old World War II veteran as he exercises on a treadmill during a clinical trial at the VA Boston Health Care System campus in Jamaica Plain. Jessica Rinaldi/Globe Staff

When Dr. Daniel Forman sits across the desk from an older patient, the Brigham and Women’s Hospital cardiologist must develop a treatment plan despite little published evidence to guide his clinical decisions.

It’s not that his patients take experimental drugs or undergo cutting-edge procedures. Cardiac medications and devices have been studied extensively, but not in patients like the older men and women Forman treats, both at the Brigham and at the VA Boston Healthcare System. That’s because medical trials — the basis by which a drug’s effectiveness, dosing, and adverse effects are determined — often fail to include older participants.

“There are almost no data to guide cardiovascular disease management for people who are over 80 and relatively poor data for people over 70,” Forman says. “You have smart and caring doctors trying to practice evidence-based medicine, but there is little evidence.”

While doctors and policymakers have long recognized that translating drugs from adults to children might not be as easy as halving the dose, and that the toxicities that are common in men might be different than in women, researchers say that the same understanding lags when it comes to older adults. But now, with aging baby boomers and the so-called oldest old — people age 85 or older — making up the fastest-growing segment of the US population, the issue is gaining attention.

“Clinicians are seeing these patients in the hospital or in the office and are, essentially, making extrapolations that may not be appropriate at all,” said Dr. Nanette Wenger, a professor of medicine at Emory University School of Medicine in Atlanta, who was an early proponent of studying cardiovascular disease in women. “People should be demanding that they have the same information when it comes to medications for grandma and grandpa that they do for their children.”

For at least 25 years, it’s been known that drugs that work one way in an otherwise healthy younger adult might not work the same way in the elderly. Many older adults are frail and might metabolize medications more slowly or suffer unforeseen drug interactions. Blood thinners, for example, might be riskier in someone with a tendency to fall. Medications to control blood pressure could be harder to dose appropriately in a patient with poor kidney function. In 1989, the FDA set guidelines encouraging drug companies to study how their drugs affect the elderly, with the goal that the population being studied prior to drug approval should resemble the population that would ultimately take the medications. But the guideline was not a mandate.

And so, two decades later, when Dr. Donna Zulman was working as an internist for many older patients at a Veterans Administration Hospital in Michigan, she was bothered by a “disconnect between the evidence that was available and the information that I needed.”

Fueled by her experience, Zulman and colleagues in 2007 reviewed more than 100 trials that had been published in major medical journals. They found that one in five trials excluded potential participants based on their age alone. In half of the remaining trials, patients were excluded from participating because of conditions that disproportionately affect older adults, such as cognitive dysfunction or limited physical activity. And only one quarter of the studies looked at outcomes that might be relevant to older adults, such as quality of life or physical function.

This matters, Zulman notes, because studies in the past have shown that when doctors take data derived from a younger group of patients and apply it to their older patients, the results might be different than expected. She points to a recent trial of glucose control in patients with diabetes, called the ACCORD trial, in which study investigators included adults over 65. Researchers found that, contrary to what had been assumed, very strict blood sugar control was associated with increased risk of death and more dangerous episodes of low blood sugar. These results led to “a real change in clinical practice,” Zulman noted.

However, Zulman and others acknowledge the difficulties inherent in broadening clinical trials to older patients. For one, there’s the problem of designing and then analyzing the results of a trial to include participants who might suffer from more health issues than just the disease that’s being studied. Dr. Cynthia Boyd, an associate professor at the Johns Hopkins Center for Aging and Health, describes an inherent tension that exists between the drive to encourage innovation and bring a new drug to market, and the need to examine how these drugs work in messy real-world populations. Just getting elderly patients into trials isn’t enough, she notes, if these participants don’t reflect reality.

“We may be getting the marathon-running elderly in the trials, but that doesn’t help us figure out how to manage people with heart failure and diabetes and emphysema,” Boyd says.

Doctors note that recruiting older patients to a study also poses new, but potentially surmountable, challenges. Studies have historically required participants to travel to a study site at regular intervals, to have their blood drawn or for follow-up interviews and examinations. That might be impossible for an 80-year-old who lives in a nursing home. Wenger, the Emory cardiologist, notes that some researchers have dealt with this by sending investigators to a patient’s home or to a church or a senior center. Mail-in questionnaires might take the place of in-person appointments, or the study might have to budget in the cost of arranging transportation.

That’s complicated and possibly costly, Zulman notes, but on the other hand, “The alternative is that we conduct large expensive trials and in the end we aren’t certain whether the results apply to our most complicated and costly patients.”

Some worry that even if trials are better designed to include older and possibly sicker participants, these patients simply might not want to take part. That was the bias Dr. Margaret Kemeny, a surgical oncologist who directs the Queens Cancer Center in New York, found when she studied the patterns of older women’s participation in breast cancer trials in the early 2000s. Kemeny and colleagues interviewed women with breast cancer and their physicians and found that those older than 65 were offered the chance to participate significantly less often than younger patients. When asked, physicians pointed to concerns about age or a medication’s toxicity as the reason not to offer trial participation. But if patients were given the opportunity, Kemeny noted, they were just as likely as younger women to agree to enroll.

“The main impediments weren’t comorbidities” or lack of interest, Kemeny says. “They just weren’t offered.”

Now, some doctors are looking to change policy. This past fall, a group of physicians — Forman, the Brigham cardiologist and geriatrician, Wenger, and Dr. Adam Skolnick, an assistant professor of medicine at NYU Langone Medical Center — sat before a group of FDA committee members to discuss why studying older patients is so important. This led to a public meeting last month, in which the FDA sought comments on how to improve age, sex, and ethnic diversity in clinical trials.

Fueled by his daily clinical experiences of looking “across my desk . . . at folks who would have been excluded from the trials,” Skolnick attended the public meeting as the only vocal advocate for the elderly. He noted that the way the FDA has dealt with studies of drugs for children could serve as a model for drug trials for older adults. For instance, one regulation rewards companies that have conducted successful clinical trials in children with a six-month patent extension. “I think that’s the only way we’re going to move forward,” Skolnick says. “Otherwise, you’re testing drugs in 50-year-old white men and using them in 90-year-old women, assuming the efficacy and side effects are the same.”

Says Skolnick: “The baby boom population represents the majority of the patients we’re going to be seeing over the next 20 to 30 years. They’re not just going to blindly take a medication in their older years unless someone can show them the evidence.”