The 32-year-old ICU nurse had just moved back to Coeur d’Alene, Idaho, the town where she had gone to nursing school and met her husband. After discovering the lump, she spent three anxious months waiting for the health insurance from her new job to kick in. By the time she saw a doctor and was diagnosed with breast cancer, the tumor occupied three lymph nodes.
She had a mastectomy and immediately began aggressive treatment, but given her youth and the swiftness of the cancer’s spread, her oncologist asked if she might be interested in trying a new drug still in the testing stage for all but extremely advanced cancer. Doing so would give her access to a medication that wasn’t yet available for her type of cancer. Called Perjeta (pertuzumab), the drug targets cells that overproduce a protein called HER2. It’s also breathtakingly expensive, costing about $6,000 a month.
She agreed, but not without pause. “It can be daunting when you’re signing those forms,” she says. “ ‘Yes, I will take this medication that hasn’t been approved.’ It can be a little scary.” She also knew there was a 50-50 chance she wouldn’t get the new medicine at all. “I felt like I was benefiting science and advancement, no matter what,” she says.
Caro received care through the clinical trial for a year, and today appears to be cancer free. She believes her participation in the trial meant she did everything possible to keep her cancer from coming back. She has the added satisfaction of knowing that the evidence produced by such studies led to the approval of the drug for earlier stage breast cancer in 2013.
Although not every study ends with success, scientific trials provide the way to medical progress and often offer state-of-the-art care not otherwise available. Yet among eligible adults, the estimate is that only 3 percent of people with cancer participate, and there’s little reason to think other branches of medicine are doing any better. One study noted that more than 80 percent of cancer trials fail to reach their recruitment goals, which adds time and expense to research. Only pediatric cancer, where two-thirds of affected children receive treatment through a clinical trial, can claim success.
Why don’t more adults participate? The answers are as varied as every individual. Often patients simply don’t know about studies because doctors rarely mention them. But if the problem were simply awareness, it would be much easier to solve. Sometimes patients have misconceptions about what studies entail and what they don’t. The requirements for enrollment can be so onerous it can be tough to find patients who meet an exhaustive checklist of criteria. Participation can become a logistical and financial burden that becomes too difficult to navigate. Sometimes enrolling in a clinical trial requires a leap of faith that many patients just can’t make in a culture that seems increasingly distrustful of official institutions.
Researchers are trying to address these challenges and encourage people to participate, especially given that precision medicine has the potential to transform clinical trials and make them more difficult as the pool of eligible patients becomes smaller. A typical protocol today may have a list of 60 criteria that each participant has to meet, says Kenneth Getz, the director of Sponsored Research Programs at the Tufts Center for the Study of Drug Development. “That’s double from what we were seeing 10 years ago,” he says. “Clinical trials are targeting very specific subpopulations, and investigational treatments are more precise. But at the same time we’ve really raised the bar in terms of what patients need to qualify to participate and the demands on volunteers once they’re enrolled in a clinical trial.”
In the early 1900s, pretty much anyone with a chemistry lab could produce a potion and sell it as medicine. Things started to change significantly after 1937, when a drug company marketed a cure for strep throat called Elixir Sulfanilamide, a preparation of the drug sulfanilamide. This was the pre-
antibiotic era, but sulfanilamide had already proven to be an effective treatment for some bacterial infections. Most drugmakers sold sulfanilamide as tablets or capsules, but the S.E. Massengill Company in Tennessee decided to develop a liquid, which they bottled as Elixir Sulfanilamide. At that time, the law did not require medicine to be tested.
The solvent used to make the drug turned out to be diethylene glycol, a highly toxic chemical cousin to antifreeze. After about 100 deaths, the resulting scandal led Congress to pass the Food, Drug, and Cosmetic Act in 1938 as a first step to protect patients from questionable products. After better safety came improved science. In the 1940s, researchers published the first documented randomized controlled trial, comparing a treatment for tuberculosis against a placebo. The modern era of clinical trials had begun.
FDA regulations today dictate that medicines can’t be sold until they pass hurdles of safety and effectiveness. Although scientific study has evolved and become more sophisticated over the decades, patient protection remains at the core. Trials are conducted in three phases, each of which answers a different question. A phase 1 trial is conducted on a small number of often healthy people to test whether the drug is safe. Phase 2 typically tests varying doses of the drug and asks whether the treatment is effective.
Phase 3 is usually the largest test of whether a drug works and can involve thousands of people. It usually consists of a randomized trial that compares the experimental drug to either a placebo or standard therapy. When Caro enrolled in her study, she received all the treatment she otherwise would have gotten. The only unknown was whether she would receive the extra drug as well.
Most trial participants in the 20th century were men. Yet researchers today appreciate the value of trying drugs in a variety of patients because of biological differences in drug metabolism, and it is now recognized that medicines should be tested in the population of people most affected by the disease. Gender disparities in participation have improved, but significant gaps remain for participation among minority populations and senior citizens. “A disease like prostate cancer is more common in older patients, and yet the participation in trials is much lower in the elderly,” says Tomasz Beer, an oncologist with Oregon Health and Science University.
Without randomized studies, it’s hard to know if a medicine is really doing what it’s supposed to, even in cases when other evidence points in that direction. Consider one now-famous scientific bombshell: During the 1970s, doctors were routinely recommending that women during and after menopause take hormone replacement therapy to protect their hearts and bones as their levels of estrogen fell. Almost all studies had indicated a benefit. To the shock of doctors worldwide, a randomized trial of 16,000 women revealed in 2002 that hormone replacement therapy in fact did more overall harm than good, raising the risk of cancer, stroke, and other problems. Without the study, millions of women would have continued to take hormone replacement therapy, unknowingly risking their lives.
Laura Kolaczkowski knew about the value of clinical trials when she was diagnosed with multiple sclerosis (MS) in 2008. Now 60, and a longtime resident of Dayton, Ohio, she told her doctor that she was eager to participate in any trial that would help find answers for her disease, a neurological condition that slowly robs the body of muscle control.
Many studies wouldn’t accept her because she was considered too old, but she eventually found a trial at Ohio State University in Columbus. The study was testing whether an extended-release version of the drug baclofen could help relieve the pain and spasticity that people with multiple sclerosis often cope with. According to the study stipulations, she needed frequent follow-up visits, which meant losing practically an entire day of work to make the three-hour round trip. She tried to coordinate the visits with her usual check-ups at the university MS clinic, but was told that wasn’t possible because the physician involved in the baclofen study only saw research patients on Wednesdays. Her MS clinic visits were on Mondays.
She was annoyed. “I’m driving 90 minutes each way. What part of this are you not hearing? You want me to take off work to see a doctor for 10 minutes?” she told the research nurse. Plus, there was the cost of gas, which the small stipend she received for participating — promised, but not paid until after a year — didn’t come close to covering. “Somebody’s got to work with me on this,” she told them. “I am the only person hurting financially.”
Nonetheless, she stuck with the trial for two years —“I know the importance of follow-up,” she says—before finally dropping out. She still believes in the importance of clinical trials, but advises fellow patients to be fully aware of what they are signing up for.
Although clinical trials can seem simple in theory, the reality is that participation is complicated, and factors such as routines, beliefs, and even schedules of both patient and doctor need to be considered. A review published this year in the journal Support Care Cancer found a complex mixture of reasons that accounted for a lack of participation in clinical trials. (These include concerns about side effects and fears of being a “guinea pig.”) The most important gatekeeper, however, is the person’s own doctor. “If the physician doesn’t recommend it, typically the patient won’t ask for it,” says Moon Chen, a professor at the University of California, Davis, who studies disparities in clinical trial participation.
Despite the belief that clinical trials often provide access to therapies not otherwise available — as was the case with Heather Caro — many doctors aren’t very committed to getting patients enrolled. Sometimes they just don’t have time. Doctors in rural and community settings don’t have the built-in infrastructure for studies enjoyed by doctors at large academic centers.
Too often doctors don’t bring up clinical trials because it’s not a priority, says Michael Lauer, the director of the Division of Cardiovascular Sciences at the National Heart, Lung, and Blood Institute. “What percentage of physicians participate in research in any way, shape, or form? Turns out that the number is less than 10 percent,” he says. “The way most medicine is practiced, you learn how to do it in a certain way and that’s what you do. It’s not necessarily a very scientifically oriented profession.”
The reason pediatric oncology has such a high rate of clinical trial participation, Lauer says, is because pediatric oncologists have long believed in the benefit to their patients. And it shows: Thanks in part to advancements in knowledge, the vast majority of children with cancer now survive their illness; some forms of leukemia now have a five-year survival rate greater than 85 percent.
Lauer says he became dedicated to clinical trials after an experience as an impressionable young physician just out of medical and cardiology training, when he was working at the Lahey Clinic in Burlington, Massachusetts. The hospital’s emergency room physicians and cardiologists were keen on participating in a study of patients who arrive in the throes of a heart attack, testing which type of clot-busting therapy worked best. “We had a few people who absolutely loved this study,” he says. “The rest of us really caught the bug. We wanted to know the answer to this question.”
The results were published in the New England Journal of Medicine in 1993, and one type of therapy emerged as the best option. Because his hospital had participated in the study and its doctors were watching for the results, they immediately switched their protocol. “We were not big-shot academic clinicians,” Lauer says, “and we were able to implement this overnight.”
Even an enthusiastic doctor sometimes can’t overcome inherent biases or communication difficulties. “To some patients, the concept of getting an unproven treatment is hard to accept and requires a level of faith in the scientific establishment that is often lacking,” says Beer. He points out the number of people who question the validity of childhood vaccines or climate change. “There are issues in this country with trust in general for scientific institutions,” he says.
Sandy Jauregui-Baza had just gotten back from her honeymoon in the spring of 2013 when she starting having trouble breathing. At first, she thought the asthma she had had as a child might be coming back. At the time, she was going to nursing school in Los Angeles and working full time. As newlyweds, she and her husband had traveled to Nepal for a visit to a base camp at Mount Everest. She had lost 20 pounds over the course of a few months. “I figured I had lost those 20 pounds because life had gotten so crazy,” she says.
Her doctor thought she had somehow developed tuberculosis, but the tests for the infection were coming up negative. A biopsy eventually revealed lung cancer so advanced it had spread to her bones. She was 29 years old and had never smoked. “I thought, ‘This doesn’t even make sense,’ ” she says. She came under the care of an oncologist at the University of Southern California, who enrolled her in a clinical trial of the drug Xalkori (crizotinib), which targets lung cancer in patients who have abnormalities in a gene called ALK. In addition, she received a second drug designed to extend Xalkori’s effectiveness as the cancer gradually becomes resistant.
She was given a prediction that she might live for only a matter of months, but she has survived almost two years. Her experience in her clinical trial prompted her to enroll in another study, done through the Bonnie J. Addario Lung Cancer Foundation, that is evaluating the genomics of lung cancer in young nonsmokers like her. She hopes the knowledge might one day lead to new approaches for therapy. “To me it’s a win-win,” she says. “You get to be a part of something potentially great.”
As studies like hers reveal more genes gone awry that cause disease, the hope is to develop better tools for treatment. Some laboratories will try to match patients with clinical trials better tailored to their tumors, but often precision also comes with a price for research recruitment, shrinking the pool of eligible volunteers. “Studies have become much more complicated,” says Stanton Gerson, the director of the Cancer Center at Case Western Reserve University in Cleveland, Ohio.
The goal would be to have the genome of every patient’s cancer recorded in a database that notes which particular molecular defect the tumor has, says Beer. “So you could say, ‘We now have an agent for a particular defect. I’m going to push a button and out will pop the 20 patients who have that kind of defect,’ ” he says. And those patients, in turn, will have access to a study that is much more tailored to their illness. “That’s what has to happen,” Beer believes, “I think it’s going to happen.”