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Clinical trials on trial: Underserved patients, institutional frustrations complicate research efforts
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Clinical trials are crucial to developing new therapies and treatment strategies. It may be impossible for medical science to advance in any kind of evidenced-based way without comparing new treatments against existing treatments.
But despite the importance of clinical trials, the Intercultural Cancer Council estimates that only 3% to 5% of adults with cancer participate in trials, and those who participate tend to be overwhelmingly white, urban, aged younger than 65 years and relatively well-off. Although participation for patients aged younger than 15 years ranges from 60% to 70%, only 10% of adolescents enroll in clinical trials. The elderly represent roughly 61% of new cancer diagnoses, and those aged older than 55 years represent 78% of diagnoses, according to the ACS, but only 25% of those patients participate in trials.
Of patients who participated in trials, only 8% were black and 2.8% were Asian or Pacific Islander compared with 88.6% who were white, according to results of a 2006 study conducted by the National Patient Advocate Foundation. That same study showed that only 5.6% of participants were Hispanic or Latino compared with 94.6% who were non-Hispanic whites.
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Photo courtesy of Electra D. Paskett, PhD |
This lack of diversity is significant when evaluating new treatments, in part because blacks and Hispanics with cancer are more likely to die of their disease than whites. Elderly patients do not necessarily react the same way to a drug as younger patients, and studies have demonstrated clear racial and ethnic differences in the pharmacokinetics of certain drugs.
The experts who spoke to HemOnc Today said there is a clear and obvious need to improve the diversity of patients who participate in clinical trials, but they did not always agree on the best way for these improvements to come to fruition.
Influence of physicians
In 1998, Robert L. Comis, MD, of the Coalition of National Cancer Cooperative Groups, and colleagues surveyed 1,000 adults from the general population, including 200 blacks and 200 Hispanics; conducted telephone interviews with 538 patients with cancer; and online interviews with 5,377 patients; and collected self-completed interviews with a national sample of 425 primary care physicians and oncologists.
Among the patients who responded, 85% said they were unaware that they may have been eligible to participate in a clinical trial. Seven in 10 patients who were aware of a clinical trial chose not to enroll. Among respondents who did not participate in a trial, only 35% said their physician told them about the possibility of joining a clinical trial.
Conversely, among respondents who participated in a trial, 64% said their physician made a great effort to educate them, 62% said their physician made a great effort to help them find a trial and 32% said their physician made a great effort to persuade them to join a trial. Just 4% of respondents who did not join a trial said their physician made a great effort to persuade them to enroll.
“[The motivations of] an individual physician makes a huge difference. The starting point is whether or not the doctor cares to participate in available clinical trials. It’s a major commitment,” said Derek Raghavan, MD, PhD, president of the Levine Cancer Institute, Carolinas HealthCare System, in Charlotte, N.C.
In their study, Comis and colleagues said: “Patients who participate in clinical trials are much more likely than those who are ‘aware’ but do not participate to have first learned about the possibility of participating through a doctor. Trial participants are also far more likely to have had a doctor educate them about the pros and cons of participating and help them find a clinical trial that was suitable for them. And, most of those who do participate say that a doctor had a great deal of influence on their decision to do so.”
A 2008 study published in Contemporary Clinical Trials showed the impact Latino physicians had on their patients. Researchers surveyed 695 physicians identified as general internists, family physicians, gynecologists or oncologists who treated populations with high numbers of Latino patients.
Latino doctors (n=297) were significantly less likely than whites (n=398) to refer their patients to clinical trials administered by other physicians (42.1% vs. 53.8%), less likely to recruit patients into the trial administered by the physician (16.2% vs. 22.9%) and less likely to refer a patient who was not accepted to the trial (8.4% vs. 23.4%). Furthermore, 73.9% of white respondents either agreed or strongly agreed with the statement “that the value of what can be learned from clinical trials outweighs the limitations, risks and ethical concerns” compared with 62.2% of Latinos. Conversely, 18.0% of Latinos disagreed or strongly disagreed with that statement compared with just 9.3% of whites.
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“The doctor is the gatekeeper,” said Morton D. Coleman, MD, clinical professor of medicine at Weill Medical College of Cornell University, director of the Center for Lymphoma and Myeloma at New York Presbyterian Hospital, and a HemOnc Today Editorial Board member. “If the doctor is not interested in doing a clinical trial, then chances are that the patient is not going to go [into] a clinical trial.”
According to Coleman, there is plenty of opportunity for patients to join trials. The real failure is in researchers’ lack of outreach to community physicians. He said researchers should come to community practices because “that’s where the patients are.”
“Not that many people are treated in the university setting,” he said. “If we want to enhance our ability to get patients on trial, we have to reach out to the community physician. It will not happen unless we do that.”
Trial design as a barrier
In 2003, Electra D. Paskett, PhD, Marion N. Rowley professor of cancer research with the Ohio State University College of Medicine, and colleagues published results of a study evaluating recruitment of underserved populations into clinical trials in the journal Clinical Advances in Hematology & Oncology. In the results, Paskett and colleagues identified not just patient and physician barriers that keep patients from joining trials, but systemic barriers as well. They found that trial designs often disproportionately eliminated minority patients because of the higher prevalence of comorbid conditions in the population.
“The protocols we write disproportionately exclude participants from minority communities because of what we put in the eligibility criteria and the diseases we study,” she said.
In her study, Paskett cited an example from the Women’s Health Initiative: Researchers set BMI criteria in the initial design, however, the body weight cutoff to participate in the study — which Paskett said was not set for any scientific reason — would disproportionately disqualify African-American, Hispanic and American-Indian women.
“We realized that BMI category was set for safety, but there were no real studies done to determine what body weight was safe — it was just convention that this body weight was included in clinical trials,” she told HemOnc Today. “So we changed the eligibility criteria, and we were able to get 17% of minority women accrued to the Women’s Health Initiative. A lot of clinical trials before that had only 5% minority participation. When we write our clinical trials, why are we including eligibility criteria? Are we doing it because it’s boilerplate that we’ve used forever with no good reason, or is there a documented reason for every eligibility criterion?”
Using the results of the study and their experience developing and implementing strategies to recruit minorities, Paskett and colleagues devised the eight-point Accrual to Clinical Trials framework (see Sidebar on page 14). Recommendations include involving members of the target population in recruitment planning efforts, accurate identification of the target population and taking the message to the target population.
“Minority populations often live in their own ethnic neighborhoods and areas, and it is essential to understand the media that best reach the target population,” the researchers wrote. “In addition, local clinics and physicians’ offices may be useful for educational, as well as recruitment purposes for specific studies.”
For the past year or so, Coleman and Francis P. Arena, MD, have been principals in the Clinical Research Alliance in Lake Success, N.Y., a consortium of community oncology clinics that have joined to participate in phase 2 or phase 3 drug studies. The studies are generally funded by pharmaceutical companies.
Similar to Coleman, Arena said he takes pride in seeing patients in a community setting, rather than an academic setting, and community practitioners are an often overlooked piece of the recruitment puzzle.
“We give them the infrastructure, the support, the nurse coordinators, to do the regulatory work, do all the heavy lifting they cannot do,” Arena said. “We work together as physicians and as investigators in order to complete these trials.
“We have shown this model can indeed work. We can deliver pristine data, we can do it in a more timely fashion and we can do it via the community physician,” he said.
Which is not to suggest there is no research taking place at the community level. The National Cancer Institute’s Community Clinical Oncology Program (CCOP) has been helping community practices get involved in clinical research for nearly 30 years. A CCOP operates as a network that connects academic centers conducting cancer prevention and treatment clinical trials with community physicians who accrue patients to those trials.
In 2010, 47 CCOPs and 16 minority-based CCOPs involving 3,375 physicians and 395 hospitals received funding for participation in 300 NCI-approved active treatment trials and more than 70 active prevention and control trials.
“What you want is a partnership with the academic centers and the community physician,” Lori Minasian, MD, chief of the Community Oncology and Prevention Trials Research Group, which manages the CCOP program, said. “The community physicians are often very interested in accruing to the trial, but don’t necessarily have the time or the infrastructure to develop and write the studies. They’re contributing to study design in a partnership way.”
Minasian added that involving community cancer centers in the research process was vital not only for improving diversity and faster recruitment, but also to advance both the science and practice of medicine.
“Then you actually have the possibility of moving the science through the clinical trial into actual practice,” she said. “We see that through the Community Clinical Oncology Program and other community sites that are significant contributors to the clinical trial.”
Strategies for improvement
The barriers to participation — lack of access, physician bias, lack of awareness, simple mistrust — are well known. Yet, for all of the strategies that researchers and physicians would like to try that may improve enrollment of underserved populations, few have actually been successful. Brewster and colleagues published results of one such successful strategy in Gynecologic Oncology in 2002.
For 1 year, researchers recruited mostly low-income Latino women to participate in a single-visit cervical cancer prevention study. For the first 6 months, all women who visited one of two community-based study clinics were invited to participate. Recruitment then switched to a media-based strategy involving advertisements in English- and Spanish-language community newspapers and fliers left in local businesses and organizations for the final 6 months of the year.
All study participants completed demographic and medical questionnaires delivered by bilingual staff. Women who declined to participate in this study were asked to provide reasons for this preference.
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Brewster and colleagues found that 51% of women recruited through the media agreed to participate in the study compared with 26% of women in the clinic registry group. Furthermore, the no-show rate was significantly improved among women solicited from the media strategy. There were no significant differences in the median age, number of months since the last Pap smear, incidence of abnormal Pap smear, education or income of the participants based on the recruitment strategy.
The National Colorectal Cancer Research Alliance established OncoLink, an online database, and a telephone call center in 2001 to evaluate whether patients were more likely to register for a trial via the database or the call center. As detailed in results published in the Journal of Clinical Oncology in 2004, 2,162 participants registered in the first 16 months that the database went live, 88% of whom did so online.
However, although the results demonstrated that online registration is a feasible option, researchers said only 11% of total participants were minorities. Among those registering online, only 3.4% were black and 2.3% were Hispanic. Participants registering online were also younger, 48.8 years vs. 55 years.
Results of a small study published earlier this year in Mayo Clinic Proceedings showed that patient-initiated research through a social networking site may offer a new way to recruit patients, particularly for rare diseases.
In that study, Marysia S. Tweet, MD, and colleagues used an international disease-specific support group of 12 women to investigate their condition, spontaneous coronary artery dissection. Recruiting was completed within 1 week, and the researchers concluded that the results “demonstrates the feasibility of and is a successful model for developing a ‘virtual’ multicenter disease registry through disease-specific social media networks to better characterize an uncommon condition.”
Raghavan, for his part, was not convinced that the results from the Tweet study were strong enough to draw any definitive conclusions about the value of social networking as a recruiting tool.
‘Irrational compensation’
One issue relevant to both improving recruitment of underserved populations and enrollment in clinical trials, in general, is that of compensation to physicians who participate in trials. In most cases, either the physician absorbs the costs associated with trial participation or is reimbursed for his or her costs, but sees no financial benefit.
Raghavan said the simple decision to enroll a patient on a trial can double the amount of time it takes to design and explain a treatment plan, besides the extra paperwork a trial creates. With physicians squeezed on the margins and forced to take on more and more patients to make ends meet, Raghavan said many physicians find it difficult to get involved with trials.
“People who serve the underserved population are committed to patients,” Raghavan said. “They would love to get patients involved in trials, but they are just getting slammed by patient loads. They just don’t have time. Sometimes, they don’t even have time to keep up with the relevant trials.
“A physician can give a patient good information and move him into a treatment plan pretty comfortably in half-an-hour. If you want to move them into a treatment plan that involves a clinical trial, you add at least another half-hour to the process. And I don’t mean 30 minutes for the entire consultation. I mean that when you’re just at the point of discussing treatment, a clinical trial will double the time commitment,” he said.
According to Coleman, physicians should be compensated for trial participation. The physician’s time is valuable, he said, and compensation would likely encourage greater participation. Arena went further, calling the entire system of clinical trials in the United States a failure.
“What has happened over these past 30 to 40 years is a kind of medical Reaganomics,” he said. “By giving clinical research protocols to the tertiary care institutions and hoping that somehow, mysteriously and mystically, research would trickle down into the community is absolutely erroneous. It did not happen.”
Arena said Clinical Research Alliance represents a complementary model to the current system of clinical trials that are based primarily at tertiary centers, but he added that 45% of clinical trials are closed prematurely because of inadequate accrual and only 15% of patients are treated in the academic setting. So it is obvious that researchers are missing out on thousands of potential trial participants.
“The community is where the action is, and that’s where the emphasis should be placed,” he said. These are the men and women who can facilitate trials in an expedited way with better representation of the patient population — those who are minorities, those who are elderly and those who may not have the financial wherewithal to go to a tertiary facility.” – by Jason Harris
Disclosures: Drs. Arena and Coleman are co-owners of Clinical Research Alliance. Dr. Paskett reported receiving grant funding from Merck. Dr. Raghavan has served as a consultant/adviser to Sanofi-Aventis. Dr. Minasian reports no relevant financial disclosures.
For more information:
- Agoda L. Increasing minority participation in clinical research. Available at: www.hormone.org/Public/clinical_trials_content/loader.cfm?csModule=security/getfile&pageid=1131. Accessed Sept. 7, 2011.
- Bolen S. Cancer. 2006;106:1197-1204.
- Brewster WR. Gynecol Oncol. 2002;85:250-254.
- Comis RL. A quantitative survey of public attitudes toward cancer clinical trials. Available at: www.cancertrialshelp.org/CTHpdf/308-9.pdf. Accessed Sept. 7, 2011.
- Comis RL. J Clin Oncol. 2003;21:830-835.
- Ford JG. Cancer. 2008;112:228-242.
- Goss E. J Clin Oncol. 2009;27:2881-2885.
- Howerton MW. Cancer. 2007;109:465-476.
- Lai GY. Clinical Trials. 2006;3:133-141.
- Lara PN. J Clin Oncol. 2001;19:1728-1733.
- Paskett ED. Clin Adv Hematol Oncol. 2003;1:607-613.
- Pritchard-Jones K. Lancet Oncol. 2008;9:392-399.
- Ramirez AG. Contemp Clin Trials. 2008;29:482–492.
- Tweet MS. Mayo Clin Proc. 2011;86:836-837.
- Wei SJ. J Clin Oncol. 2004;22:4730-4736.
Is working with community physicians the best way to increase participation in clinical trials?
There’s no other way of doing it.
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There has been a recent push to move clinical trial recruitment from academic centers mainly to community centers. However, this reality has not caught on in the United States in a meaningfully large way as yet. There needs to be cooperation between the pharmaceutical companies and physician organizers that devise the clinical trials and community hematologists and oncologists, and this should include meaningful incentives, including both financial and supportive services for community physician participants. The goodwill of community physicians cannot be solely relied upon.
The Europeans are way ahead of us, in part because hematologists and oncologists there receive a salary. Clinical trials are just part of a day’s work. Physicians in the United States are on a “piece work” system. Participating in a clinical trial can mean that a community physician loses remuneration, because she or he is unable to see as many patients for which one is compensated.
There are signs that this is changing. Community hospitals are coming to see that clinical trials are very pertinent to them for both prestige and financial gain. The investigators who devise the trials are now recognizing that incentives to community-based physicians and their hospital affiliations are important. A good example of services provided is the use of nurses going out to physicians’ offices to oversee data collection, and to insure that trials are proceeding according to protocol.
Arthur A. Topilow, MD, is the Director of Hematology/Medical Oncology at the Jersey Shore University Medical Center in Neptune, N.J. Disclosure: Dr. Topilow reports no relevant financial disclosures.
Community physicians also have to be receptive to joining trials.
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The majority of patients are treated in the community by community physicians, so it’s important to take that research out into the community. The models that seems to work are when community physicians are partnered with the academic institutions so that the clinical trials that are appropriately done in the community can be conducted there with the support of the academic institution — the expertise that comes from those who work in research all the time.
There can be an issue when community physicians refer the patient to the academic institution either for a second opinion or a clinical trial. Oftentimes, when the patient completes the clinical trial at the academic institution, they’re reluctant to go back to the community physician for a number of reasons, so the community physician feels that they might lose patients if they encourage them to join clinical trials.
Academic institutions don’t always do a great job reaching out to community physicians and community physicians aren’t always aware of or don’t want to participate in clinical trials. There is room for improvement on both sides.
Debra Wujcik, PhD, RN, is the Director of Clinical Trials at Meharry Medical College for Vanderbilt-Ingram Cancer Center. Disclosure: Dr. Wujcik reports no relevant financial disclosures.