Jean Reimers, a 75-year-old retired supermarket cashier, enjoys her life in Grand Island, Neb., a small city near the Platte River that boasts attractions such as the Stuhr Museum of the Prairie Pioneer and a sandhill crane nature reserve. Nearly two years ago Reimers found out from her local doctor that she had cancer. The worse news was that it was late-stage metastatic lung cancer, hard to treat and with a dismally low survival rate. The standard approach in such cases is palliative care to keep dying patients comfortable. “It looked like I probably wouldn’t be around another year,” she says.
Today not only is Reimers still around, but she says she feels great. She has lots of energy and no pain. This past fall CT scans showed all her tumors have shrunk or disappeared entirely. And she was anticipating the birth of her 11th grandchild. “I’ve got a lot of things I still want to do,” she says.
Her high-quality time, Reimers says, comes thanks to experimental drugs she received as part of a clinical trial. The treatment, a combination of two immunotherapies called ipilimumab and nivolumab, is not yet approved for lung cancer by the U.S. Food and Drug Administration. The trial Reimers took part in was one of the tests to see if the regimen works.
This would not be an unusual story if Reimers was a patient at a big-name, big-city academic medical center. The very top cancer hospitals, such as the University of Texas MD Anderson Cancer Center in Houston and New York City’s Memorial Sloan Kettering Cancer Center, enroll about 25 percent of their patients in trials. But Reimers, like Grand Island’s other 51,000 residents, lives closest to CHI Health St. Francis, a typical small community hospital that is part of a regional network but has no formal ties to any major medical institution. “I didn’t think people in small towns had the same chances for trials that people in big cities do,” Reimers says. Her only option, she thought, was to drive nearly three hours every two weeks to a bigger hospital in Omaha. She would likely have had to stay overnight instead of going straight home to rest, and she probably would not have done it. But the head oncologist at St. Francis’s cancer treatment center found out that Reimers met the criteria for the double-drug trial, filled out the forms, followed up and got her in.
The drugs available in clinical trials often represent the latest in research, and many turn out to be significantly more effective than standard treatments. Half of all drugs that make it into the last of three phases of drug trials, when most patients enter those trials, end up being approved by the FDA because of these improved results. The drug Herceptin, for instance, was only available in trials before it became a mainline treatment for breast cancer in 1998 and since then has been prescribed to 420,000 women. More recently, some 90,000 breast cancer patients have been treated with Ibrance, but before 2015 the drug was given only in trials. Another medication, Keytruda, was approved after clinical trials in 2014; now some 70,000 patients with a number of different types of cancer have used it.
But whereas about one third of cancer patients in the U.S. meet the criteria for a trial with a new drug, only about 4 percent end up in such tests, according to National Cancer Institute estimates, and some experts say the real number is even lower. The main reason for the massive shortfall: in the nonacademic community hospitals where most cancer patients are treated, doctors do not feel they have the time, the incentives or the support to learn about available trials, to qualify and enroll patients, or to provide the extra follow-up care such trials often call for. A National Academies of Sciences, Engineering, and Medicine study concluded that “community practitioners lack the needed infrastructure and support to actively participate in clinical trials.” A study in the clinical cancer journal CA called trial enrollment “embarrassingly low” and blamed it, in part, on “a lack of knowledge about available studies by community oncologists, a lack of time or interest, or a lack of resources to support the cost of performing clinical trials.” Because nationally about 85 percent of cancer patients end up at community hospitals, most of the low participation in cancer trials is attributable to the failure of those hospitals to enroll their patients.
Low trial enrollment, which effectively cuts patients off from lifesaving medicine, is a giant national health problem. For example, fewer than 1 percent of patients who have Alzheimer’s disease enter a trial. But for cancer, the missed opportunities are especially painful, experts say, because drug development in this area has been particularly strong. “Many of our drug trials involve the most promising agents we’ve seen,” says Tufia Haddad, an oncology researcher at the Mayo Clinic. Thanks to new ways of identifying and targeting mutations in tumors and to immunotherapies that help muster the body’s natural defenses against cancers, there are more than 600 experimental cancer drugs that have shown good results in animals and in early small studies in humans. And contrary to common belief, patients in the vast majority of cancer drug trials do not risk getting a placebo—these trials test the best standard treatment against a new medication.
The enrollment problem also handicaps research. Lack of patients forces many trials to stop before getting results, ending the progress of many promising treatments. Most trials are at least delayed by patient enrollment shortages. About one out of six of all trials never manage to recruit a single patient. “The biggest problem in developing new drugs is a lack of patients to treat with them,” says John T. Cole, an oncologist at the Ochsner Health System based in New Orleans, who oversees a network of oncology practices. “We can’t meet that challenge unless we solve the problem of low enrollment in community hospitals.”
Politicians and regulators have done little to help community hospitals and doctors surmount the obstacles, according to R. Alta Charo, a law professor at the University of Wisconsin–Madison, who studies medical research policy. Instead they have passed “right to try” legislation, which prohibits the FDA from denying terminal patients access to experimental drugs that are not available to them in clinical trials. In fact, the FDA almost never denies such access, so the law is unlikely to help more than a handful of patients and does nothing to improve access to clinical trials. “Helping overwhelmed and underresourced doctors at community hospitals would be a much better approach,” Charo says.
Finding effective ways to help, however, is not easy. There are partial solutions, such as artificial-intelligence programs that crunch through reams of data to match patients to trials. Other attempted remedies are low tech and involve a range of outreach, education and marketing tools that can change the antitrial culture of community hospitals. To succeed, however, these approaches need to help doctors cope with the time constraints, lack of expertise and financial obstacles that keep them from getting patients into trials. St. Francis, which shares those small hospital disadvantages, manages to place some 35 percent of its cancer patients in trials. That achievement is due almost entirely to the determination and dedication of Mehmet Copur, the head oncologist at the time of Reimers’s treatment. But counting on every other community hospital to display the same fervor is a risky gamble.
One doctor’s mission
When Reimers became ill, Copur was willing to put in the extra work required to find out about appropriate trials and get her into one—work built into the infrastructure of academic centers but not community hospitals—just as he has been doing for his other patients. To refuse to go that extra mile is to fail to provide seriously ill patients with their best possible prospects, insists Copur, who recently moved to the Morrison Cancer Center in the nearby community of Hastings, where he is building a similar clinical trial program. “The standard of care today is what was in trials 10 years ago,” he says. “To put patients in a trial is to give them a chance to get a drug that will be the standard of care 10 years from now.”
In 1995 Copur was a young medical scientist from Turkey doing basic research at the National Institutes of Health outside of Washington, D.C., when a change in government policy—an alteration in temporary work permit numbers—suddenly left him in imminent danger of losing his visa. His only hope for staying in the U.S. was a program that grants permanent visas to doctors who spend three years treating patients in an underserved community. He saw a listing for a job at Grand Island’s St. Francis. Copur grabbed the position.
“But when I got here I said to myself, ‘My God, my career is over,’” he recalls. Copur had intended to continue some clinical research in the job, but he found that St. Francis had no medical library and no Internet access at the time. Clinical trials were almost nonexistent, and when Copur proposed that he at least try to participate in some, neither his fellow oncologists nor the hospital administration seemed open to the idea. “It was a fight from the beginning,” he says. “Even in big-city hospitals people don’t always see how important clinical trials are, let alone a small-town hospital.”
The problem was that to earn his salary Copur had to see a stream of patients, five days a week. But clinical trials require extra work, with each patient taking up on average about three times as much time as a nontrial patient, thanks to extra record keeping and close patient-monitoring requirements. In academic centers, doctors are given that extra time and can draw on a trial-focused support staff. Copur had to do it all on his own, including establishing rigorous data collection, performing extra diagnostic tests, conducting extra patient visits, producing reports, training staff, and more. He also brought in funding from the NCI and joined a research consortium of hospitals that made more trials available.
Many of his patients hesitated to join a trial, saying they did not want to be guinea pigs who might end up with a highly toxic drug or a placebo — widely held misconceptions that are particularly common among rural patients, says James Atkins, an oncologist at the Southeastern Medical Oncology Center in North Carolina. Copur patiently explained to them that cancer trials today are designed with patient benefit in mind and that the worst case was usually getting the drug they would have received anyway. Most of his patients consented. Then other oncologists at St. Francis started to notice that Copur’s trial patients sometimes did surprisingly well. Of course, they were doing well, Copur explained: some of them were receiving much better drugs. Soon his colleagues began looking for trials for their own patients.
“Copur has done a great job in a completely rural environment,” says Praveen Vikas, an oncologist at the University of Iowa Health Care. “He’s that rare kind of community physician who can provide the kind of care that often beats physicians in academic settings in terms of value and patient satisfaction, while staying on top of research.”
As of 2018, Copur’s team at St. Francis had enrolled patients in 74 different trials. But to do so, Copur worked nonstop from dawn, taking off one hour at 7 P.M. to have dinner at home with his ailing father before returning to spend another three hours at the clinic. “These trials are my whole life,” he says. “Sometimes I dream about making that big fundamental research contribution, but then my patients remind me that what I am doing here is a bigger contribution.”
One of those patients is a young man (he asked not to be identified) who learned two years ago that his kidney cancer was spreading. Approved chemotherapies did not offer much hope, so he started searching out clinical trials, assuming he would have to go far from his home near Grand Island to get in one. He traveled to Washington, D.C., to meet with a specialist—who told him to get right back to Nebraska and see Copur. “To be honest, I was a little skeptical when I met Dr. Copur, and he told me he’d get me in the right trial,” he recalls. “But my phone started pinging with e-mails about trials by the time I was pulling out of the parking lot.” Today the patient is thriving and credits the immunotherapy drugs he received through the trial that Copur enrolled him in.
Copur’s experience at St. Francis proves that community hospitals can succeed as clinical trial centers. And if he can deliver on his quest to duplicate that success at the even smaller Morrison Cancer Center, which is part of the Mary Lanning Healthcare community hospital in Hastings, the evidence will be all the more impressive. Community hospitals do not need to hit 35 percent enrollment, as St. Francis has, to make a big dent in the trial gap. If only one fourth of community hospitals boosted their trial enrollment to an average of 10 percent, it would result in an increase of 50 percent in the number of cancer patients enrolled in trials. In a survey of a wide range of cancer patients, 81 percent reported their doctors did not discuss the possibility of trials with them. In a separate survey of women with cancer, more than half reported that their oncologists either did not mention trials or even actively discouraged patients from participating in one.
The St. Francis work also highlights the obstacles that community hospitals face. But a 10 percent gain in enrollment does not require daunting personal sacrifice, say clinicians who have helped other community hospitals make the jump. Atkins, who directs a large clinical trial consortium across the southeastern U.S., is working with 25 hospitals in five states to help them boost clinical trial enrollment. Many physicians have gotten onboard, Atkins says. It means going beyond the typical physician’s 50-or-so-hour week but only by five hours or less. “It’s extra work for doctors, but if a doctor doesn’t want to do it for patients, that seems a little lazy to me,” he says.
Clinical trials can also be redesigned to reduce the burden on community hospital physicians, shifting more of the workload to the research centers that originate the trials. A study led by the University of Pittsburgh Medical Center, along with six other academic medical centers and the National Institutes of Health, looked at 38 steps that clinical trial leaders can take to get more doctors at other hospitals involved in their trials, steps mostly aimed at raising doctors’ interest while reducing the workload involved in opening the trial and in enrolling patients. The steps included sending researchers out to hospitals to speak to staff about the trial’s relevance, the benefits to patients and the patients’ qualifications; providing follow-up teleconference meetings; writing articles for the hospital newsletter and for local and physician publications; establishing 24/7 access for researchers to get questions answered; putting up a Web site dedicated to the trial; and making available patient-recruitment aids such as multilingual brochures and consent forms. The study, published in 2014 in Clinical Pediatrics, found there was a 38 percent jump in recruitment after the steps were taken.
Sonika Bhatnagar, lead author and an associate professor of pediatrics at the University of Pittsburgh School of Medicine, notes that some factors stood out during the study. “The biggest physician barrier was time constraints,” she says. “Minimizing their workload was critical, and we found making everything as simple as possible made a big difference.” Among the aids Bhatnagar and her colleagues provided physicians were prepackaged talking points to use with patients, so the doctors did not have to study a trial’s methodology in detail to explain it accurately. The researchers also offered to reach out directly to a patient’s family to address their concerns. And physicians worry that putting a patient in a trial will compromise his or her autonomy in making care decisions, Bhatnagar adds, because trials often tightly circumscribe some treatment options. She has found that the best way to counter that concern is for researchers to go to hospitals to meet as many physicians as possible in person to build trust in the trial’s protocol and to create enthusiasm about what the trial might do both for individual patients and for the countless patients everywhere who might ultimately be helped by the trial’s findings. “Most physicians would take a lot of pride in contributing to research that could ultimately change treatment guidelines for the field,” Bhatnagar says.
Another study gave doctors materials designed to streamline the process of patient screening—that is, determining which patients qualify—and to make it easier to follow trial protocols during treatment. The study also involved adding one-on-one meetings between local physicians and trial researchers and on-site discussions about the disease being treated. In that study, enrollment at the targeted facilities more than doubled.
Some trial outreach efforts are being facilitated by the fact that academic medical centers are looking to expand in their states, and sometimes beyond, via acquiring or partnering with community hospitals. Existing big health networks are also pushing outreach. Kaiser Permanente—a nonprofit health care company—has nudged and supported all its 27 northern California hospitals, many of them community hospitals, into enrolling cancer patients into trials. “Instead of having to drive 50 miles or more to an academic medical center, our patients can be treated in a clinical trial in the same place they delivered their babies and got their flu shots,” says Lou Fehrenbacher, a Kaiser Permanente oncologist who oversees the region’s cancer trials program. Likewise Yale University’s main hospital, based in New Haven, has been bringing in affiliated community oncology clinics around Connecticut into clinical studies. Unfortunately, most of the nation’s 4,000 community hospitals are not closely allied with an academic center, so this approach may be limited.
The high-tech fix
It may be, though, that technology can help close that particular gap. The Mayo Clinic has been testing a pilot of an ambitious approach, based on IBM’s Watson cognitive-computing platform. That system has been looking at all the details in the records of every breast cancer patient at the medical center and matching them against the 16 different clinical trials for breast cancer available there. The Mayo claims that after 11 months the system was able to increase combined enrollment in those trials by 80 percent—though so far only at the clinic itself and not yet at community hospitals. According to the Mayo’s Haddad, who is helping to run the pilot, the big jump is owed in part to the fact that the project included increased staffing and focus around patient-trial matching. But she adds that Watson’s ability to zip through not only tightly specified data fields in the health records but also clinical notes and other unstructured data has made a big difference in the system’s hit rate. “Most electronic health record systems aren’t sophisticated enough to be able to answer questions such as which treatments the patient has already had,” she says. “More than 90 percent of the data in records is in unstructured form, and cognitive systems can go after it.”
A study run by the NCI and Case Western Reserve University, using another experimental cognitive-computing-based system called Trial Prospector, scoured the records of 60 new gastrointestinal cancer patients across several clinics and matched 57 percent of them to at least one of 15 different trials. A group of oncologists brought into the study gave the system a big thumbs-up, deeming all the matches to be accurate. Another system tested at Cincinnati Children’s Hospital Medical Center was found to reduce the time needed to match patients to trials by 85 percent.
Exciting results, but they come with serious qualifications. For one thing, such systems generally require that a hospital have a sophisticated electronic health record system in place to feed them data. Most community hospitals currently have systems that are too rudimentary to allow programming in trial-matching capabilities. But given medicine’s growing reliance on mining electronic health records for advancing patient care, those systems will inevitably be upgraded to the point where automating trial matching will become feasible—especially as more community hospitals become affiliated with larger hospitals and even academic medical centers.
Copur, for his part, maintains that what will ultimately bring clinical trial options to that great majority of cancer patients will be a slowly growing wave of peer pressure as more clinicians in community settings start to see the light. Copur himself keeps publishing—63 papers and articles to date, such as a study in the Journal of Clinical Oncology evaluating treatments for metastatic pancreatic cancer—and giving talks about what a community hospital can accomplish. “I tell doctors that if they’re not looking for ways to put their patients in clinical trials, they should be referring them to a doctor who will,” he says.
What seems poised to effect change, if slowly, is a combination of all those approaches: Trial researchers who get out into communities and market their work to local doctors, trial designs that reduce physician workload, and tools that automate patient-trial matching and related tasks. It will also take strong advocates like Copur and the NCI willing to sound a constant, loud drumbeat that links trials to the duty that all physicians—not just those in academia—have to the profession and to their patients. It will only be then, if those efforts on multiple fronts put more people in trials, that patients win the real right to try.