Trials of treating the elderly: Determining drug safety and effectiveness
■ Older participants are not usually recruited for clinical trials, leaving the path to proven treatments littered with uncertainty.
It's no surprise that a huge group of baby boomers is advancing toward old age. But what may surprise physicians as they begin to see more and more elderly patients is how shaky the research base is for treatments in this age group.
Elderly people are not generally included in clinical trials that test the safety and efficacy of medications and treatments, even though they are the prime recipients of these regimens. Physicians can find themselves wrestling with the dilemma of doing the right thing for patients without solid evidence of what works.
"The bottom line is that we have very little information on older people," said Lodovico Balducci, MD, professor of medicine and oncology and program leader of the Senior Adult Oncology Program at the H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida. "The reason is partly because clinical trials are not offered to older people."
The need for information spans the diseases from cancer to diabetes and heart disease. "Cancer is the ideal model to study because it is a chronic disease, and cancer increases with age," said Dr. Balducci. "But you could apply that to any other disease."
Consider these other areas of inquiry: What is the optimal blood sugar level for people in their 80s and 90s? Is it the same as it is for those in their 40s and 50s? How about blood pressure or cholesterol?
"These are all questions that have not been properly asked," said Dr. Balducci. "And, unfortunately, people are not always interested in asking them."
However, in a rare bright spot, a group of international researchers did set out to determine whether lowering blood pressure in people 80 and older was beneficial. The 3,845-patient Hypertension in the Very Elderly Trial, coordinated by researchers at the Imperial College in London, was halted in August because early findings showed lowering blood pressure significantly reduced both stroke and mortality in the over-80 group. Trial data are still being collected from various sites, and publications should be forthcoming.
This type of information is precisely what is needed, said physicians who care for the elderly.
Robert Butler, MD, the president and CEO of the International Longevity Center-USA, a nonprofit policy and education group in New York City, and founding director of the National Institute on Aging, has been campaigning for such efforts since 1977.
"Back when I was the NIA director, I went to the Food and Drug Administration to voice my concern that older people aren't routinely required to be included in clinical trials. And after some talk, voluntary guidelines were created. But that has not been sufficient," he said.
"In any given year about 17% of people 65 and older have an adverse drug reaction," said Dr. Butler. "And since older people use over 40% of the drugs, clearly they are the ones who are the most adversely affected when there are untoward drug reactions."
Admittedly this group of patients is hard to include in trials. They often have a number of co-existing conditions, and the question of safety arises. But excluding this population in order to protect them could also mean "protecting them from the fruits of research," said Dr. Butler.
Plenty of additional reasons are cited for not including older people in trials, but those reasons can sometimes be made to disappear, according to advocates for the trials.
The erroneous belief they don't want to participate is among the most frequent explanations. But that's not true, according to many. "There have been enough studies to show that," said Dr. Butler.
Older people may not be as Internet-savvy as their younger counterparts and not be able to find such trials for themselves, said Lillian Siu, MD, associate professor at the University of Toronto and a medical oncologist at Princess Margaret Hospital, also in Toronto.
And even if elderly patients are referred to a trial, they have to vault the barrier of "preconceived ideas," said Dr. Siu. "I think there is definitely ageism from physicians." Researchers may avoid enrolling older people because the individual might not tolerate the treatment and also because they don't want to "ruin the stats," she said. Including patients with more diseases and conditions could influence the results.
"But if we are going to do big trials that will change practice, we should make an effort to ensure that a reasonable proportion of patients on the trials are older, because they will be reflective of the population we are going to eventually treat -- the consumer of the resources," said Dr. Siu.
Despite this need, there are barriers that are difficult to overcome. "Death rates are higher, relocations to nursing homes occur and there are higher instances of cognitive impairment [that] one needs to take into account," said Kenneth Schmader, MD, associate professor of medicine at Duke University Medical Center's Geriatric Research Education and Clinical Center in Durham, N.C.
In a typical trial with a 35-year-old, researchers aren't thinking about having proxies to help subjects answer questionnaires, he added.
Peter Boling, MD, professor of internal medicine at Virginia Commonwealth University, believes that while there have been increases in recent years in the number of older people participating in clinical trials, most are conducted with fairly healthy elderly people.
Those who use care the most and would benefit from trial data -- in other words, those less healthy -- are underrepresented. "I'm not sure how we will meet that goal because they will be typically disqualified on the basis of disease burden or they may not choose to be involved because they don't feel well," said Dr. Boling.
"It's kind of a 'Catch-22' situation."
But it's not impossible, as indicated by the blood pressure trial findings, said Rebecca Silliman, MD, PhD, professor of medicine and public health at Boston University's Schools of Medicine and Public Health and a spokeswoman for the American Geriatrics Society. "I will say they are incredibly difficult to do and they cost a lot of money."
Often it's not the latest therapy that is being tested, but one that has been around for awhile, just not tested in older people. "So that's another challenge; since it isn't going to benefit a drug company, who will pay?" she asked.
Another hurdle is the difficulty of assessing older people's health status, said Dr. Balducci. "We are just learning what aging is all about."
Who is old?
One thing aging is not about is the number of years a person has spent on the planet. Many researchers avoid citing an age for who is elderly. Dr. Balducci might peg it at "beyond 70," but that's only a "general landmark," he noted. "Age is only a number."
Dr. Boling wouldn't even venture a rough estimate. He said some of his 50-year-old patients are just as sick as the 75-year-old who has diabetes, high cholesterol, high blood pressure and some coronary artery disease. "It's not the years, it's the mileage," he said. Doctors generally agree physiological age trumps chronological age every time.
A lot of research has gone into determining life expectancy, which might be a better way to decide which older patient can participate in a trial or even benefit from aggressive treatment. "If you don't select patients with adequate life expectancy, you are not going to see improvement from chemotherapy," said Dr. Balducci.
It's easy to identify the frail, debilitated patient with poor organ function, said Dr. Siu. "They are not good candidates for clinical trials or for extensive treatment for that matter," she said. And then there's the 70-year-old who looks 40 or 50. "That's another easy decision, because they are so fit, you won't even think twice about putting them in a trial."
The hardest call is for those in the middle. This group, which accounts for the majority of older patients, is the most difficult to evaluate.
To that end, researchers have developed screening tests to determine levels of frailty and mortality. For example, researchers at the San Francisco Veterans Affairs Medical Center created an index to predict the likelihood of death within four years for people 50 and older. The index was published in the Feb. 15, 2006, Journal of the American Medical Association.
The technique uses a 12-question form that can be completed by a patient, said the researchers. It employs age, race, comorbidities and ability to perform such daily tasks as bathing and dressing, to calculate mortality.
Linda P. Fried, MD, MPH, director of Johns Hopkins University's Division of Geriatric Medicine and Gerontology in Baltimore, found patients' frailty could be assessed using various demographic characteristics.
While such measures can prove useful to the busy physician, what is needed is a national registry where older people are all classified the same way according to comorbidity, said Dr. Balducci. That way, outcomes studies could be conducted to determine which treatment is valuable. "We are far from there," he noted.
In a 2003 issue brief, the longevity center called for legislation requiring the FDA to issue standards mandating the inclusion of a certain proportion of older people in trials.
Sergei Romashkan, MD, PhD, chief of the clinical trials branch at the NIA's geriatrics and clinical gerontology program, would like to see a law like the Best Pharmaceuticals for Children Act, but this time for elderly people. That 2002 law encourages the manufacturers or sponsors of drugs that are still under patent to conduct trials with children. If they do that to the agency's satisfaction, the FDA extends their patent protection for six additional months.
Without adequate information from trials, Dr. Silliman believes errors are being made in both directions. Too much is done for the frail elderly and too little for the robust folks who may be 80 but have a life expectancy of 10 or more years.