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Clinical trials stymied as patients balk at 'experiments'

Without enough participants enrolled in studies, time, money and important research may be lost


by: TRIBUNE PHOTO: JAIME VALDEZ - Josie Henderson decided not to join a clinical trial for breast cancer because she didnt feel comfortable giving her care over to researchers.Josie Henderson wanted to say yes. She’d been told she had a highly aggressive form of breast cancer that was already at an advanced stage. She’d been told that she could volunteer for a clinical trial that would offer her the best care for her cancer, and possibly more in the form of the trial’s experimental chemotherapy agent.

She knew that signing up for the trial meant she could contribute scientific knowledge that would help other breast cancer patients in the future.”I thought I would choose science,” says Henderson, who is executive director of a Portland public health nonprofit.

Henderson agreed to participate in the preliminary screening, including a biopsy, as well as bone and liver scans, which would determine if her cancer met the clinical criteria for the trial. That experience put an end to Henderson’s participation.

“I didn’t feel cared for,” she says. “I felt experimented on.”

Prior to learning about the trial, Henderson had one visit with a chemotherapy oncologist who works with the Knight Cancer Institute at Oregon Health & Science University. She says he treated her with compassion and empathy. The clinical trial investigators, on the other hand, were “competent and professional,” but oddly disconnected from the fact that she was a woman told she might be facing a death sentence. And agreeing to fully participate in the trial would have meant the clinical investigator for the trial would become her oncologist.

Even knowing the trial’s experimental therapy might help save her life, Henderson opted out. Eventually, conventional chemotherapy did eliminate her tumor and her prognosis has brightened considerably. But her brief participation in a clinical trial left Henderson wishing the physicians and scientists who conduct experiments involving people rethink their approaches.

“I believe in science,” Henderson says. “I work in public health. I wanted to participate in this study. It was the right thing to do for science, for loved ones and other women who might someday get this disease, and for my own health. But I needed to be cared for as much as I needed to be cured.”

Increasingly, medical researchers are finding it difficult to recruit sufficient people to conduct clinical trials. A study from Oregon Health & Science University two years ago revealed that OHSU wastes about $1 million each year setting up fully funded clinical trials that researchers eventually cancel because they cannot attract sufficient participants. More than 200 trials are canceled each year at OHSU after no one, or one person, enrolls.

Reasons for reluctance unclear

The difficulty facing OHSU is shared by most of the nation’s academic medical centers, which is where the bulk of clinical trials are conducted. But there is little consensus about the reasons behind people’s unwillingness to volunteer for trials, and how to reverse their attitudes.

“The community needs to understand that medical research isn’t all about being guinea pigs,” says Dr. Eric Orwoll, an endocrinologist who oversees clinical research at OHSU and co-authored the study. “It’s really about the partnership that’s necessary to everybody’s good.”

That partnership, Orwoll say, isn’t just between the public and researchers. Just as critical is that community physicians recommend to their patients that they participate in trials, and take the time to find trials that are appropriate for individual patients.

“Our health system is dysfunctional in a variety of ways, and this is one of them,” Orwoll says. “Our community health system discourages referrals from other hospitals to those with trials.”

Orwoll says researchers who have to terminate a trial because of insufficient enrollment are going to find it hard to get funding for future trials. He bemoans the wasted time and money when trials get called off, and the loss of important science.

Low recruitment is especially vexing in cancer research, says Dr. Tomasz Beer, an oncologist and cancer researcher at OHSU. Beer says that only about three to five out of every 100 adult cancer patients participate in trials. He says most cancer patients should join a trial at some point in their treatment. He notes that breast surgery trials led to the advances in surgery, such as lumpectomies, that have benefited thousands of women.

Unlike some participants in research trials, cancer patients will always get the recognized industry standard of care, Beer says, with the possibility of something better in the form of the new therapy being tested. Yet Beer says only about 10 to 20 percent of OHSU cancer patients enroll in trials.

Beer is convinced the public is saddled with a lack of information and a number of biases and unfounded fears regarding trials. Mary Durham, director of The Center for Health Research at Kaiser Permanente in Portland, thinks changing societal attitudes also are a big part of the problem. “It’s alarming because we’ve never needed more participation in science, but I think part of it is there’s a growing skepticism of science,” Durham says.

But Dr. Harlan Krumholz, professor of Investigative Medicine and Public Health at Yale School of Medicine, doesn’t think a lack of information is the primary problem. Krumholz places most of the blame with doctors and hospitals who have never considered how participation in a clinical trial feels to patients. Telling people that their participation will help move science forward isn’t enough, Krumholz says.

And telling them, in double-blind trials, that there is only a 50 percent chance that they will get the experimental therapy, rather than a placebo, definitely isn’t enough, say a number of experts. The public, Krumholz says, is learning that, for instance, half of completed clinical trials never even result in published studies. They’ve read stories about biased researchers and drug companies failing to disclose negative data that trials reveal about their products.

Sometimes, the public is just confused. In December, a number of medical centers decided to discontinue their participation in a trial after a report went public about potential life-threatening danger from a heart device they were investigating. But media stories revealed that a number of other centers continue to enroll patients in those same HeartMate II trials.

Feeling like a guinea pig

Here’s another criticism of the status quo: Krumholz says patients who have participated in trials have discovered that researchers rarely get back to tell them what was learned from their trial.

“We’ve failed to create a system that inspires people to be part of research and provides them with trust that their participation will be meaningful,” Krumholz says. “They feel used.”

Krumholz says he saw that first-hand when a cousin with advanced lung cancer called him after having had a physician recommend he participate in a clinical trial. His cousin, Krumholz says, had not responded to several rounds of chemotherapy and was desperate. But Krumholz investigated and found that the trial his cousin had been offered was an early Phase One trial for a cancer with a different molecular signature. There was no possibility his cousin would be helped by the experimental drug, according to Krumholz.

“It was a dosing trial to learn what doses might make him sick,” Krumholz recalls. “I couldn’t believe it was offered to him.”

Krumholz says that offering patients trials of therapies that won’t help them not only violates the patient’s trust, but it can engender a trust gap with community physicians.

“If I were an oncologist and that trial were offered to my patient that was offered to my cousin, I would never send another patient there,” he says.

Krumholz, director of Yale’s Center for Outcomes Research and Evaluation and a board member of the Patient-Centered Outcomes Research Institute, is trying to encourage a different attitude toward clinical trials. Trials in which the institute is involved solicit input from prospective participants during the trial’s design. And participants are promised they will hear about the trial results once the study is completed.

As an example of how patients might contribute to designing a study, Krumholz points to cancer trials. Researchers, he says, are mostly interested in whether a new therapy shrinks a tumor and prolongs the life of trial participants. But patients might want the researchers to monitor how much pain they are feeling throughout their trial participation.

Krumholz would set ethical standards for researchers recruiting participants in Phase One trials like the one his cousin was asked to join.

“How about start by being honest,” he says. “Like, ‘This is not going to help you, but it will help others?’ How about steering the trial to the people with the molecular signature for whom the drug is eventually intended to help, so that there may be some prospect of benefit, however small?”

Inclusion is key

Most community physicians don’t mind referring people to clinical trials, even though that can mean they lose patients, says Ken Getz, founder of the Center for Information & Study on Clinical Research Participation in Boston. But in surveys, many community doctors say they are too busy to research which trials might be applicable for each patient.

As a solution, Getz recommends researchers treat community physicians much as Krumholz says they should treat patients — by including them in every step of the trial. If OHSU researchers called community doctors and their nurses to thank them every time they referred a patient for a trial, and then followed up every few weeks and offered the doctors visits to see how the trial was being done, those doctors might be willing to take more time to help out, Getz says.

“I’m afraid that is part of the nut we have to crack,” Getz says. “We have to get our investigators to realize you don’t conduct research in a vacuum.”

Another part of the problem, according to Getz, is the demands made upon clinical trial participants. On average, participation requires 11 visits with 167 procedures, a 60 percent increase in procedures from 10 years ago. That’s greatly because in an era of targeted, individualized medicine, researchers are narrowing the biomarker criteria they are looking at in trials, which means more tests.

A solution, Getz says, is a new, more flexible process to trials in which researchers recognize from the start they may have to change their approach as the study progresses. That might allow researchers to use fewer patients and to finish studies quicker if initial results are positive.

Otherwise, Getz says, the trend of recent years, in which more trials are moved overseas where volunteers are easier to find, may continue. In Latin America, India and China, he says, recruitment for trials generally takes half as long, mainly because in some areas the only way a patient is going to get first-rate treatment for their disease or condition is by participating in a trial.


Researcher thinks outside box to recruit minorities

When Kaiser Permanente researcher Nangel Lindberg wanted to study how to help immigrant women from Mexico lose weight she knew she would have to configure her study a little bit differently.

With researchers across the country desperate for clinical trial participants, recruitment of minorities has proven even more of a challenge. And with researchers increasingly testing targeted therapies that work on a smaller population of people with a specific genetic makeup, it has become more important than ever that minorities be included in trials.

Most weight-loss experiments, Lindberg says, require volunteers to come in multiple times to complete questionnaires before they are accepted, and then require participants to keep food journals listing everything they consume.

The women Lindberg wanted to study didn't have the time or the language capabilities to meet those criteria. Most, she says, weren’t even accustomed to using measuring cups and spoons.

So Lindberg streamlined the registration process so applicants only had to come in once, and made learning how to keep a food diary — and use measuring utensils — part of the study. Rather than advertise in newspapers in her search for participants, Lindberg went on Spanish-language TV and radio call-in shows and handed out fliers in Hispanic grocery stores.

Lindberg says that most researchers focus on finding candidates for trials who will be easy to work with and dependable, and that often means middle-class people with health insurance and free time. But those criteria don't fit most minorities, she says.

Lindberg was able to find the 50 immigrant women she needed for her yearlong, Portland-area study, she says, because she didn't think conventionally.

“If I had asked them to keep a food diary before they registered I would not have had a single participant in my study,” she says.


For one patient, two decades of trials

Casey Donahue has participated in clinical trials most of his life. Donahue, 30, developed a form of epilepsy that on some days could bring on more than a dozen seizures. The seizures began when Donahue turned 10. Medication helped some, but didn't completely stop the seizures. By the time he was 12, Donahue and his parents were told that newer experimental drugs had been developed, but they were only available through clinical trials.

For the next few years Donahue went on and off a number of new drugs. Some seemed to help, others clearly didn't. One, his parents say, caused him to lose 60 to 70 pounds in a week and left him sleeping all day. When Donahue was 18 years old a device called a Vagus Nerve Stimulator was implanted beneath his arm with wires sending pulses to his brain. That trial lasted a year, says his father, Tim, with monthly adjustments. In Tim Donahue's view, it increased his son's seizures.

Still Donahue's parents pushed ahead, hoping something would work to completely eliminate the seizures. More trials with experimental drugs were tried. Five years ago Donahue's neurologist at OHSU recommended a new device called a NeuroPace System be implanted in Donahue's skull. It might be able to detect and stop seizures before they started, by sending electrical impulses to his brain.

For the first two-plus years of the NeuroPace trial his family had no idea if Donahue's implant was turned on or not. They had been told that half the trial's original 250 participants would act as the control, and their devices would not be operational. Tim Donahue says his son's seizures have abated a bit more with the device, but not completely. Eventually they learned it had been on all along, and that fine-tuning the settings might bring more relief.

Twenty years of trials have left Tim Donahue philosophical about having his son participate in experiments. He says he's learned to stop listening to the long explanations about side effects that come with each new trial because he's not willing to give up on a complete cure for his son's condition. And he says OHSU researchers have kept Casey's primary-care physician informed of his status with each new experiment.

“There's always a fear factor that you have to overcome,” Tim Donahue says.

He says every time physicians talk up a new solution he gets excited. And he never considers turning down the latest trial for his son.

“I think you have to have some faith in your doctor because common people like us, we have no idea what these drugs are about.”


Medical centers pull out the stops to recruit patients

A handful of academic medical centers have started patient recruitment offices in an attempt to bring a universitywide approach to the problem of finding participants for clinical trials, says Nariman Nasser, a patient recruitment expert who headed the program at the University of California, San Francisco.

Funding for trials is won by individual researchers, Nasser says, and they often haven't considered the feasibility of getting enough participants when they write their grant applications. In addition, Nasser says, researchers often let trials go on too long after it has become apparent that a sufficient number of participants can't be found and that subjects already on board are receiving experimental treatments from which little knowledge will be gained. Nasser says there needs to be a formal mechanism for determining when to suspend a trial.

Individual researchers aren't experts in marketing or advocacy so they often don't know how to find the participants they need in the university's large bank of patients. Recruitment needs to be professionalized, Nasser says.

“If recruitment is a pervasive enough challenge, which everybody agrees it is, there has to be some sort of top-down approach. And to date, it has always been a bottom-up approach, where researchers are involved in solving the problem,” Nasser says.

Ironically, Nasser's position at UCSF disappeared when the university decided to close its patient recruitment office as part of a round of budget cuts.