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May 25, 2010 - In 2009, about 1.5 million people were diagnosed with cancer, according to the American Cancer Society’s Cancer Facts & Figures 2009. However, research continues to show that fewer than 10% of adults diagnosed with cancer participate in clinical trials.
Barriers to clinical trial participation — by patients and physicians — have been identified as a major issue, but other problems may exist within the framework of the clinical trials process in the United States, according to the experts interviewed by HemOnc Today.
“The clinical trial process is the best mechanism to provide legitimate evidence that medical progress has been made,” said Laurence H. Baker, DO, professor of medicine at the University of Michigan and chair of the Southwest Oncology Group.
Laurence H. Baker, DO, chair, Southwest Oncology Group, said the public may be frustrated with the lack of progress from clinical trials.
However, Baker also said asking whether or not the clinical trials process is working is an extraordinarily complicated question, and “there are many problems with clinical trials in this country as they relate to cancer.”
“I believe that the American public is terribly frustrated with our lack of progress,” he told HemOnc Today.
Organizations such as the NCI and ASCO continue to advocate and develop new programs and partnerships to try to increase enrollment in clinical trials, particularly by underrepresented populations. These organizations said if adult enrollment in clinical trials was higher, greater knowledge about possible beneficial treatments could be discovered at an increasingly rapid pace.
In fact, the Institute of Medicine (IOM) published a report in April calling for a “reinvigoration” of the NCI Cooperative Group Program. In the report, the IOM supported the NCI Clinical Trials Cooperative Group Program for its key role in developing new cancer therapies but said in recent years, “many stakeholders — including clinical investigators, patient advocates, Cooperative Group leadership, industry participants as well as the NCI — have expressed concerns that the program is falling short of its potential to conduct the timely, large-scale, innovative trials needed to improve patient care.”
Among the IOM’s goals for reinvigoration were an improvement in the participation of patients and physicians and an increase in the support of clinical trials (see related article.)
The bar for a successful clinical trials process has been set in the childhood cancer arena, in which the process is decidedly different and historically more successful. According to the ACS, each year about 10,000 children are diagnosed with cancer and about 4,000 enroll in a clinical trial. Cure rates for childhood cancers are about 80%.
“In pediatrics, we have a long standing history of being able to recruit children to clinical trials,” said Gregory H. Reaman, MD, of Children’s National Medical Center, Washington, D.C., and chair of the Children’s Oncology Group. “It has enabled us to build sequentially, from one trial to another, and improve outcomes for many childhood cancers, most notably acute lymphoblastic leukemia, Wilms’ tumor, acute myeloid leukemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma and neuroblastoma.”
Reaman said getting patients to participate in clinical trials is part of the culture of pediatric oncology. “It is how we do what we do. As a group, we have understood the importance of collaboration and cooperation,” he said.
In the adult arena, research has shown that a key to enrolling patients into clinical trials is physician participation.
“The physician plays the most important role of anybody,” said Robert L. Comis, MD, president and chairman of the Coalition of Cancer Cooperative Groups and group chair of the ECOG. “The physician is also a patient’s most trusted source of information.”
Comis and colleagues at the Coalition of Cancer Cooperative Groups, a non-profit service organization working to improve physician and patient access to cancer clinical trials, published the results of a study examining the physician’s role in patient enrollment in the Journal of Oncology Practice in 2009. In it, an Internet-based survey was performed to assess public and cancer survivor attitudes toward cancer clinical trials; specifically, the survey examined the role of the physician.
“We asked cancer survivors, and roughly 10% to 15% of them said that they were aware that clinical trials might be an option for them at the time of their diagnosis,” Comis told HemOnc Today. “If you asked them who they learned about clinical trials from, 75% said their physician. The other 25% learned from all different sources — from advocacy groups to nurses — but no group was more than 10%.
“If you asked people who actually participated in a trial, the doctors informing them about the studies, educating them about studies and helping them find studies were all directly correlated with whether or not they participated,” Comis said.
Another Internet-based survey, conducted by Maurie Markman, MD, of The University of Texas M.D. Anderson Cancer Center, and Meredith Grimm, RN, of Medscape CME, found that more than 75% of health care providers said they thought that patients derived benefit from trials, but only 20% to 40% had an awareness of educational resources, physician responsibilities or insurance coverage benefits for patients.
The results of the survey, published on Medscape’s website in October, identified several physician barriers to enrollment, including loss of patients through referral to outside clinics, lack of resources and the increased time commitment by the physician.
“There are many barriers to physician participation that need to be addressed,” Baker said. “One of the principal barriers may be financial. It takes a lot more time for physicians to explain and enroll patients into clinical trials, and there is a lot of pressure on physicians to generate income, whether they are in a solo or group practice, or they work for a university or cancer center.”
Baker said institutions frequently have to supplement the cost of enrolling patients in clinical trials, particularly in cooperative-group trials, because the amount of reimbursement per patient is insufficient.
At The Society for Gynecologic Oncologists’ 2010 Annual Meeting on Women’s Cancer, an abstract was presented that detailed the current costs of conducting a phase-3 Gynecologic Oncology Group (GOG) study compared with the amount of reimbursement provided by the GOG. They found that participants are only reimbursed about 30% of their actual costs.
The researchers established a budget for GOG-218, a randomized trial evaluating carboplatin/paclitaxel with or without bevacizumab (Avastin, Genentech) for the treatment of ovarian cancer.
The cost per patient during the treatment phase of the trial was $5,140. The maintenance phase cost was an extra $3,855 per patient, for a total average cost per patient of $8,995. For the per capita points system, the GOG reimbursed only $2,870 per patient, a significant financial loss.
“The clinical trial process has been suffering for a long time because of insufficient funding,” Reaman said. “I think things are only getting worse because of the economic stressors that institutions and physicians are now facing.”
In fact, a survey conducted by ASCO and published in the Journal of Oncology Practice found that one-third of NCI Cooperative Group Sites plan to limit participation in federally funded clinical trials. Of the sites planning to limit participation, 75% said it was because of inadequate per-case reimbursement (see related article).
Besides financial stressors, physicians also face increased work time, increased paperwork and increased scrutiny, and have to be willing to have records directly audited, Comis said.
“If you go to a physician and say, ‘I want you to do this clinical trial, and you are going to make less money to do this trial than if you didn’t do it, and you are going to have to work harder and spend more time with patients than if you didn’t do this trial …’ a lot of physicians, who are already overwhelmed and busy, are going to say sarcastically, ‘Where do I sign up?’” said Charles H. Weaver, MD, executive editor of CancerConnect.com, a developer of oncology websites, and Women & Cancer magazine. “People don’t like to talk about this situation, but this is the harsh reality.”
“There are many physicians in this country who fervently want to provide new information and new knowledge that will lead to change for the better in prevention and treatment of cancer, and they often use the clinical trial process as a method of achieving those goals,” Baker said.
Getting physicians to participate is only the first step, patient barriers to participation also exist. According to the results of another online survey study, published in Community Oncology in May 2009, among patients’ most commonly self-reported barriers to clinical trial participation were a lack of awareness of appropriate trials, belief that the current treatment is more effective, a fear of possible adverse effects and a fear of getting placebo.
“Patient barriers start at diagnosis. Their physician may not communicate to them that a clinical trial may be appropriate,” Weaver said. “Even if a patient is already aware of clinical trials, their physician may not offer a trial that is relevant to that patient, and patients may not consider that more appropriate treatment may be available somewhere else.”
“Even patients who are aware of trials don’t always participate,” Comis said. “One of the major concerns patients have is that the new treatments on trials may not be as effective as the standard treatments.”
Trials have to have value to a patient, besides the “perceived notion of helping their fellow man,” Weaver said.
“Patients are interested in getting better care for themselves. If a trial doesn’t offer the prospect, convincingly, that participation will give them better care than they can get outside of a trial, it is hard to explain to a patient why else they may want to participate,” he said.
However, some trials offer experimental treatments that may be better than the standard of care. “That is an intrinsic part of the trials process,” Comis said. Patients may participate in trials to get treatment opportunities that are not available any other way.
Regardless, explaining the issues related to the treatment and toxicity related to any given clinical trial comes down to patient education, according to Comis. “The physician needs to make sure the patient is fully informed,” he said.
One of the most difficult elements of educating patients is explaining trials involving the use of placebos.
According to Baker, there is still a great mistrust of the trials process among the American public due, in large part, to the fear of placebos.
“I agree with the public and understand that fear,” Baker said in an interview. “The way to fix that fear is to do away with placebo studies in which a placebo is the only treatment for cancer. I do not think that it would be ethical to argue that a clinical trial that includes a placebo as the sole treatment of cancer would be in keeping with my understanding of my obligation to a patient.”
Eliminating placebo-controlled trials may be easier in theory than practice. Currently, the gold standard trial design for FDA regulatory approval is a phase-3, randomized, placebo-controlled study.
“You have a national cancer infrastructure that is vested in pursuing this strategy of drug development,” Weaver said. “The experimental arm of the phase-3 trial has to be significantly more appealing or provide access to a drug that a patient could not otherwise access in order to have a patient want to go through with the trial.
“If I tell you that the standard of care is ‘X’ and the experimental arm is ‘X’ plus ‘Y,’ and all of the phase-2 data says there might be a modest benefit at best, or the treatments might be equivalent, a patient would likely ask, ‘Why would I want to participate in this trial if it is not going to benefit me?” he said.
Larger, sequential, appropriately conducted phase-2 studies, which do not involve placebo arms, could yield the same information as these phase-3 studies and answer these research questions faster, according to Weaver. “But frankly, there are a lot of people invested in the phase-3 model,” he said.
Soon, another research model may become more standard. In the American Recovery and Reinvestment Act, passed in February 2009, $1.1 billion was allocated for comparative-effectiveness research. Unlike placebo-controlled trials, comparative-effectiveness research is designed to compare the efficacy of two active therapeutic approaches, which is a far more appealing strategy to patients, according to Baker.
“In addition, the recently passed health care reform legislation established a non-profit organization called the Patient-Centered Outcomes Research Institute that will identify research priorities and conduct research that compares the clinical effectiveness of medical treatments,” said Nancy Davenport-Ennis, founder and CEO of the National Patient Advocate Foundation and the Patient Advocate Foundation.
However, not all of the response to comparative-effectiveness research has been positive. Concerns exist that insurers will be able to use the results of these trials to deny patients coverage of certain treatments.
“I am concerned that the health care bill is designed to deny access to cutting-edge therapy,” Weaver said. ‘“Comparative effectiveness,’ what does that mean? Most of the stuff in this bill has to do with cost efficacy, and improving access to care, not improving clinical outcomes.
“If your goal is to improve coverage, than cost-effectiveness is important because the cheaper you can deliver therapy, the more people you can give therapy to without breaking the system. However, as a patient advocate, I am more interested in improving patient outcomes than societal cost-effectiveness,” Weaver said.
Davenport-Ennis said she is also concerned about the line between cost-effectiveness and clinical effectiveness.
“Comparative-effectiveness research is a necessary step in the nation’s move to control cost and spending while assuring that what a patient is paying for is resulting in quality health care delivery, which right now does not necessarily happen,” she said. “It’s a step in the right direction. As we take these steps, we all have to be committed to the greater good, to making certain that if you become ill, you will have access to the therapy that your doctor defines as the most appropriate for you, and that your access will not be limited because a comparative-effectiveness research study drew a cost line between one therapy and another, and your insurance company used that information to decide what was the best therapy for you.
“The non-profit patient community is interested to see that we look at comparative-effectiveness research as a mechanism to help a patient and doctor make a better decision about which clinical intervention would offer them the greatest hope of stopping the disease or controlling the disease,” Davenport-Ennis said. “When we look at that, we look at comparative-effectiveness research as needing to be built on the shoulders of clinical evidence.”
Reaman said in many ways, physicians have been doing comparative-effectiveness research for decades, and it is too soon to predict the overall effect of this legislation. However, addressing the lack of enrollment is crucial to the success of clinical trials, regardless of whether they are placebo-controlled research or comparative-effectiveness research.
The health care reform bill has a provision that ensures payment for routine care cost for patients enrolled in clinical trials, Davenport-Ennis said. “Right now, for many patients, their insurance will not pay for those routine costs associated with their participation in clinical trials.”
This legislation is a step in the right direction, she said.
In the end, improving the clinical trials process will require a complex, multifaceted approach.
“You have to make it easier for physicians to perform trials and to want to perform trials,” Weaver said. “On the other side of the equation, you have to find ways to educate patients on the appropriate role of trials in their disease management and get them to be more active in that process.
“There is obviously not a simple solution to the problem because no one has solved it yet,” he said.
– by Leah Lawrence
Christine BorkEmail Christine(800) 458-6223