Assessing the Risks, Benefits of Clinical Trials

Ellen Berty of Arlington, Va., surprises or even shocks many people when she says, "I used to have diabetes."

Berty, now 55, was diagnosed at the age of 13 with type 1 diabetes—sometimes called juvenile diabetes. She estimates she took 22,000 shots of insulin over the years.

But Berty hasn't had an insulin injection since June 24, 2001—just 10 days after she received an islet cell transplant in a clinical trial at the National Institutes of Health (NIH).

"Those islet cells now live in my liver and produce insulin," she told the AARP Bulletin.

To Berty, the transplant has been nothing short of a life-saving miracle. She'd been experiencing drops in her blood sugar levels so severe that on several occasions, while driving, she just managed to pull her car off the road and stop before losing consciousness.

Berty's ticket to a new life was the trial that led to an experimental transplant under the direction of David Harlan, M.D., chief of the transplantation and autoimmunity branch of the National Institute of Diabetes & Digestive & Kidney Diseases.

NO ADVANCES WITHOUT TRIALS

Like Berty, an estimated 1 million Americans each year are willing to put the potential rewards from enrolling in a clinical trial ahead of the possible risks. CenterWatch, a Boston-based company that tracks the clinical trials industry (and a subsidiary of Medical Economics Co., publisher of the "Physicians' Desk Reference"), expected some 80,000 clinical trials designed to assess the safety and effectiveness of new drugs, devices and medical procedures to be conducted in 2002 alone.

A website developed by NIH's National Library of Medicine lists more than 7,600 clinical trials sponsored by NIH, other federal agencies, pharmaceutical companies and universities. (Berty, in fact, started her search at that site.)

With pharmaceutical companies developing an ever-increasing number of new drugs, the reason for the proliferation of clinical trials is plain enough. "Quite simply," says Andrew Kelahan, former vice president of the Coalition of National Cancer Cooperative Groups, "if we don't do the clinical trials, we can't develop new treatments."

TRIALS AND ERRORS

Not everyone, however, is as lucky as Ellen Berty. Although the vast majority of clinical trials are well-run, a number of high-profile tragedies, in which research subjects have died during trials at well-known institutions, have underscored the risks of volunteering for experimental therapies.

In September 1999, 18-year-old Jesse Gelsinger, who had a rare liver disorder, died after undergoing experimental gene therapy at the University of Pennsylvania. Jesse's father, Paul Gelsinger, sued, alleging that the lead researcher concealed his financial interest in the company developing the treatment.

In July 2000 the federal government shut down all clinical trials at the University of Oklahoma Health Sciences Center when 26 cancer patients died after receiving an experimental vaccine for melanoma, a serious form of skin cancer.

And in April of this year, the Department of Veterans Affairs ordered a nationwide review of clinical trials at 115 veterans hospitals after investigators uncovered cases of falsified data and other serious violations of federal rules—some of which may have contributed to the deaths of patients enrolled in the trials.

"A lot of research is slipshod, dangerous or unnecessary," says Peter Lurie, M.D., deputy director of Public Citizen's Health Research Group, a Washington-based watchdog organization.

Some of the experimental drugs or treatments that are being evaluated in clinical trials can have unpleasant or even life-threatening side effects. CenterWatch estimates that one of every 30 patients in clinical trials will experience a serious side effect and that one in 10,000 will die as a result of the experiment.

"Those who participate in research are taking the risks for the rest of us," says Greg Koski, M.D., a former director of the Office for Human Research Protections at the U.S. Department of Health and Human Services.

"We have to put the interests of the subjects above and beyond our other considerations," he says, "and that's not always easy to do."

Fortunately, the vast majority of patients in clinical trials receive top-flight care and are likely to be closely monitored and tested as part of the research. Even participants who are on a placebo—an inactive compound (typically a sugar pill) that looks like the medication being tested—often show significant improvement because they are, sometimes for the first time, getting regular attention from highly skilled medical professionals.

AGE, ACCESS, OPPORTUNITY

After years of being excluded from virtually all clinical trials, older Americans are, in increasing numbers, finally finding their way into such trials. And little wonder: More than 700 of the 1,000 or so drugs now being evaluated in clinical trials are aimed at treating diseases or conditions associated with aging, according to the Pharmaceutical Research and Manufacturers of America, the drug industry's Washington-based trade group.

Although medical researchers have long pointed to age-related differences in how drugs are absorbed, metabolized and excreted, it wasn't until 1989 that the Food and Drug Administration (FDA) published guidelines for including older patients in clinical trials. Today, according to the FDA, roughly 15 to 20 percent of the participants in drug trials are over age 65.

Dennis DeRosia, former chairman of the Association of Clinical Research Professionals, a nonprofit organization that accredits clinical trials, says that in many cases it makes sense to recruit older patients for drug trials.

"The only way we ever are going to know if medication is good or bad for a particular age group," DeRosia told the Bulletin, "is by testing it on that age group."

In a recent study researchers at Duke University found that older people tend to be more willing than younger people to participate in clinical trials. Eric Peterson, M.D., associate professor of medicine at Duke, says that older people generally have fewer time constraints and a greater desire to help the next generation by advancing medical research.

Nonetheless, older Americans may still be underrepresented in clinical trials. In a study published in 2001 in the Journal of the American Medical Association, Peterson and his colleagues found that only 9 percent of heart disease trials included patients 75 years or older—even though 37 percent of all heart attack victims in the United States are in that age group. They also found that more than half the trials did not enroll a single patient over 75; nearly a third of them specifically excluded older persons.

"It's not the fault of the elderly that they're underrepresented," Peterson told the Bulletin. He says that researchers often seek subjects who don't take other medications or have other conditions that might lead to "adverse events"—medical problems arising during clinical trials that must be reported to the FDA.

Robert N. Butler, M.D., founding director of NIH's National Institute on Aging and president of the New York-based International Longevity Center-USA, says that even today older people are "woefully underrepresented or even excluded from clinical trials."

The resulting lack of knowledge, Butler says, leads to "adverse reactions, inappropriate dosages and treatments and the misperception that older people cannot tolerate or benefit from new drugs and procedures."

IS ANYONE WATCHING?

The rights and interests of patients in clinical trials are supposed to be protected by Institutional Review Boards (IRBs), committees of physicians and scientists assembled by NIH or by the university, pharmaceutical company or other sponsor conducting the research. IRBs are charged with making sure that clinical trials are conducted safely and ethically. They are expected to halt trials if protocols are not followed or when significant adverse reactions occur.

But, says Public Citizen's Lurie, "There's a kind of arrogance that has suffused the ethical review system." In some cases overzealous researchers or unscrupulous physicians have played down risks or exaggerated the benefits of the trial. "There can be a problem," he says, "comparing a new drug with a placebo rather than with a proven, effective drug."

Adil E. Shamoo, professor at the University of Maryland School of Medicine and founder of Citizens for Responsible Care and Research, a Baltimore-based watchdog group, says the rush to bring new drugs to market has led to shoddy monitoring by IRBs.

"The failure is systemic," Shamoo told the Bulletin. "Federal oversight is not strong enough."

Judy Salerno, M.D., deputy director of the National Institute on Aging, says that ethical treatment in clinical trials is of particular concern for patients with Alzheimer's and other neurodegenerative diseases, who may not understand what is being asked of them.

"With cognitively impaired persons we really have to do everything we can do to make sure the research is ethical," Salerno says, "and that it protects the rights and welfare of each individual subject."

RESEARCH AND RESULTS

Despite the potential downsides of clinical trials, they generally get high marks from participants. A 2000 survey by CenterWatch, for example, found that most participants in clinical trials felt they had received excellent care and would participate in a trial again.

And for some, like Ellen Berty, participating in a clinical trial represents an opportunity to be a small but nonetheless significant part of medical history in the making—in this case, a potential cure for type 1 diabetes.

In 2002 researchers reported that 80 percent of patients who had received sufficient islet cells through transplantation no longer needed insulin injections a year later—and, most important, were metabolically stable.

That's no small miracle for Berty—and for medical research.

Beth Baker is a freelance writer in Washington, D.C. Senior Editor Patricia Barry contributed to this article.