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Oncology clinical trials are complex and require a different approach than trials in many other therapeutic areas. Patient recruitment is among the most challenging obstacles-especially in the United States, where oncology trials have notoriously low participation rates among adult patients. While more than 1.2 million Americans will be newly diagnosed with cancer this year, participation in oncology trials remains very low.
Oncology clinical trials are complex and require a different approach than trials in many other therapeutic areas. Patient recruitment is among the most challenging obstacles—especially in the United States, where oncology trials have notoriously low participation rates among adult patients. While more than 1.2 million Americans will be newly diagnosed with cancer this year, participation in oncology trials remains very low. In fact, according to the American Society of Clinical Oncology (ASCO), only 3 percent of U.S. adults with cancer participate in clinical trials.1 Lack of participation can cause an oncology trial to recruit slowly, often lengthening the trial's timeline by months or even years.
There are many reasons why the rate of participation in cancer clinical trials is much lower than expected. Both physicians who enroll their patients in clinical trials and those individuals who agree to receive their care in a clinical trial may encounter barriers to participation. All of these obstacles must be addressed if the clinical trials system is to improve. Understanding these obstacles and knowing how to improve the process can help bring effective therapeutics to the people who need them.
In the United States, patient costs associated with clinical trials are often not reimbursed by third-party payers—Medicare, Medicaid or private insurers—since the cost of caring for a patient in a clinical trial can be much higher than the cost of standard care. Currently in the United States, no consistency exists regarding federal or private reimbursement for participation in clinical trials.
Advocacy and other nonprofit organizations have stepped in, pushing for more federal regulation over inclusive reimbursement, labeling it an issue of patient rights. For more than a decade, the National Coalition for Cancer Survivorship (NCCS), other patient advocacy organizations, and the American Society of Clinical Oncology have collaborated in a legislative effort to address the failure by third-party payers to pay for routine patient care costs in trials. After many years of unsuccessful legislative effort, these organizations were able to persuade the Clinton administration to issue an executive memorandum instructing the Medicare program to allow all beneficiaries, both those with cancer and with other diseases, to participate in high-quality clinical trials. With this change and the leadership role of Medicare in health policy, reimbursement has seemingly become less of an obstacle than before.2
However, a recent decision by the Centers for Medicare and Medicaid Services (CMS)—referred to as the demonstration project—is threatening the recent clinical trial reimbursement advances. This decision by CMS has resulted in the coverage of oral drugs and biologics only for FDA-approved indications. The demonstration project, mandated by the Medicare Drug Improvement and Modernization Act of 2003 (Section 641), is intended to cover drugs taken orally that are not currently paid for by Medicare or will not be covered until the new prescription-drug benefit takes effect in January 2006. Childhood cancer advocates are concerned that with this decision comes the potential to influence Medicaid and private insurance coverage for drugs in pediatric cancer clinical trials. Ninety percent of eligible childhood cancer patients participate in clinical trials, which typically study the treatment effects of drugs approved for adult use, but which are studied in children off-label.3
Recognizing the need to strengthen legislative support, several states, including Arizona, California, and New York, have passed laws for clinical research insurance coverage. According to the American Cancer Society, some states have also worked out voluntary agreements with insurance companies to provide clinical trial coverage.4
Although awareness of cancer clinical trials may be growing overall, not everyone appears to be getting the message. Racial and ethnic minorities, women, and the elderly are less likely to enroll in cancer clinical trials than whites, men, and younger patients, according to a study from the Yale University School of Medicine in New Haven, CT. Elderly patients are strikingly underrepresented compared to their younger counterparts.
According to the National Cancer Institute (NCI), 60 percent of breast, lung, colorectal, pancreatic, ovarian cancer, and leukemia cases in the United States occur in a population of 65 and older.
However, the Yale University School of Medicine Study found that from 75,215 participants in therapeutic nonsurgical NCI Clinical Trial Cooperative Group breast, colorectal, lung, and prostate cancer clinical trials (from 2000 through 2002), only 0.5 percent of patients older than 75 and 1.3 percent of patients age 65 to 74 participated in these trials.
During a seven-year period, the FDA found that several factors contributed to this disparity, including difficulty understanding complex protocols and poor compliance. In addition, physicians, patients, and families often believe older patients are less likely to benefit from and tolerate aggressive treatments.7 Cytotoxic drugs, the commonly accepted and tested treatment for most cancers, are very toxic.
The elderly may also be restricted by the availability of caregivers, financial concerns or by travel constraints. And physicians who believe treatment will not be as successful in an elderly patient might opt for a less aggressive treatment. Yet growing evidence shows there are feasible and successful treatment options for elderly patients. A large Italian study compared chemotherapy with Navelbine to supportive care without chemotherapy in elderly lung cancer patients and determined that survival was prolonged in those who received chemotherapy.
A second trial conducted in Tennessee showed that Taxotere was able to induce tumor shrinkage in 26 percent of lung cancer patients who were elderly and had medical conditions that would have otherwise precluded treatment. This rate is approximately equal to that seen in other Taxotere trials in younger lung cancer patients.
Lastly, a large clinical trial recently compared chemotherapy with the combination of Gemzar and Navelbine to either Gemzar or Navelbine alone. Administration of two agents is the prevailing preference among lung cancer patients as a whole, but in this group of patients over age 70, Gemzar or Navelbine as single agents worked as well and had fewer side effects than the doublet.8
Nonetheless, the delivery of relative dose-intensity (RDI) is particularly problematic in the elderly since advanced age is associated with a higher incidence of neutropenic complications (a direct result of many chemotherapy regimens). In a 2004 study conducted by the University of Rochester Medical Center of 4,522 Non-Hodgkin's lymphoma patients, 60 percent of older patients received less than 85 percent of the relative dose-intensity (RDI) in any chemotherapy regimen they were given, compared with 44 percent in younger patients. A major cause of this reduction in dosage was the development of patient complications, including neutropenia.9 When you couple the issue of relative dose intensity with new drugs or regimens that are being tested, especially in Phase I/II dose escalation studies, the problem of toxicity among the elderly becomes exacerbated.
The issue surrounding the toxicity or aggressive nature of therapy of cancer trial drugs or regimens may be changing, however. Many new innovative drugs have been introduced in the last decade that are biologics—including monoclonal antibodies like Rituxan. Many of these drugs are tolerated rather well and present a promising solution to current oncology treatments. More research is needed, however, to study the long-term side effects of these drugs or the side effects that can result when they are in combination with other drugs from oncology treatment regimens.
Many patients are not willing to participate in cancer clinical trials because of negative perceptions that the treatments are "experimental" and therefore inferior to currently accepted treatments. Likewise, if a physician does not believe a trial is better than current treatments, then he or she is not likely to recommend it.
For example, the ethical basis of oncology Phase I trials has often been questioned because these trials involve potentially vulnerable patients at the end of their lives. Patients who choose to participate may experience significant risks with limited chance to benefit. Another concern is that those who participate in these trials may have unrealistic expectations about their chances to benefit from the trials, despite having participated in the informed consent process.
Researchers at the Massachusetts General Hospital Cancer Center, however, have recently challenged these concerns through data compiled of Phase I trial results, reported at ASCO's annual meetings from 1991 through 2002. The study included an analysis of 213 trials, excluding radiation therapy trials, lymphoma, and leukemia trials. In total, this database included about 6,500 enrolled patients. The researchers analyzed how often patients died from drug toxicity, cancer-related deaths or other toxic treatment effects, and whether or not a treatment caused tumors to shrink. The most significant change during the study period from 1991-2002 was the more than 90 percent drop in drug-related deaths. The risk was about 1 percent in the first four years and dropped to .06 percent in the last four years.10
The reasons for this significant change can be attributed to the fact that organizations are more actively increasing their attention to patient safety regulations, using less toxic targeted therapies, particularly monoclonal antibodies, and are using more improved supportive care products, such as the new treatments for chemotherapy-induced anemia and neutropenia.
The United States' decentralized health care system contributes to the challenge of recruiting oncology trial participants. Many of the most promising oncology trials in the United States involving novel treatments are recruited first at major cancer centers across the country. These centers have the resources—personnel, state-of-the-art equipment, "thought leaders," and NIH funding—to lead successful trials. The obstacle is that there are only 61 major cancer centers officially recognized by the NCI. Cancer patients across the country and especially in rural areas or non-major metropolitan areas may need to travel long distances in order to participate in promising studies at these centers. This can lead to absence from work, conflicts with family time, and cost of travel that often exceed what patients are willing to manage. For the elderly, the issue of distances becomes one of logistical support and quality of life.
The challenge of logistics, however, is gradually being addressed. Sponsors of clinical trials such as pharmaceutical and biotech companies, along with CROs, are partnering with site management organizations (SMOs) that specialize in oncology clinical research to access a network of sites to directly recruit patients. SMOs offer clinical trials through their network of community cancer centers that have experienced clinical investigators. These centers are spread throughout the United States in various cities and towns, not just major metropolitan centers. This network of sites offers an alternative for patients wanting state-of-the-art treatments without the hassle of traveling hundreds of miles to the nearest major comprehensive cancer center.
Another drawback to the United States' decentralized system is a lack of a comprehensive, easily accessible database of trials being conducted throughout the country. Currently, there are various databases listing clinical trials such as
. However, these databases are not inclusive of all cancer trials being performed—making it difficult for patients and doctors to do their own research on what trials are available to them.
The pharmaceutical industry is addressing this issue on a global scale through an initiative to better disclose clinical trial data and establish a worldwide register of trials relating to new prescription drugs. According to the industry's leading trade group, the Pharmaceutical Research Manufacturers Association, the global clinical trial register will be free and available to the public online so that patients and doctors can access more inclusive information about what trials are available and how to enroll.11 Links to medical journal articles and peer-reviewed research is a part of the proposed registry, adding to the depth of information that will be available from one comprehensive resource. The first clinical trial data expected to be published using the registry is scheduled for July 2005.
In the United States, the cost of performing cancer trials has become increasingly expensive and time consuming. For drug companies, many have turned to international trials, which can save money and time. Research in different countries can also give better results because it allows for testing a drug or method on a population with diversity of genomes, environments, diet, and—in cancer trials in particular—on patients that are treatment-naïve, having no exposure to previous treatments. The FDA will not release current numbers, but in 2000, 27 percent of all drug applications submitted by pharmaceutical companies to the agency relied upon at least one foreign clinical trial, a number that experts say is significantly higher today.
Progress is being made in the United States to address these unique complexities of conducting oncology trials. According to the Center for Drug Evaluation and Research's 2003 Report to the Nation, five new drugs were approved in the United States for people with chronic myelogenous leukemia (CML), prostate cancer, small cell lung cancer (SCLC), and multiple myeloma in 2003 alone.13 And the American Cancer Society states that new treatments resulting from high-quality, peer-reviewed clinical trials offer the best hope for survival and improved quality of life.14 Overcoming issues of reimbursement, the need to recruit older patients and treatment-naïve patients, negative perceptions of clinical trials and logistical complications are important factors that are contributing to the success of these trials.
1. 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition),
Journal of Clinical Oncology
(July 15, 2004).
2. E. Stovall, CEO and President of the National Coalition of Cancer Survivorship, Testimony by Before the House Committee on Government Reform, May 13, 2004.
3. "CMS Stance on Off-Label Use Concerns Cancer Advocates," Boston Globe (February 10, 2004).
4. "Clinical Trials: What You Need to Know," American Cancer Society, www.cancer.org, posted September 22, 2004.
5. V.H. Murthy et al., "Participation in Cancer Clinical Trials," Journal of the American Medical Association, 2720-2726 (June 9, 2004).
6. "FDA Study Shows Older People Are Underrepresented in Cancer Clinical Trials," National Cancer Institute, www.cancer.gov, posted May 31, 2003.
7. L. Talarico, G. Chen, R. Pazdur, "Enrollment of Elderly Patients in Clinical Trials from Cancer Drug Registration: A 7-year experience by the Food and Drug Administration (FDA)," Journal of Clinical Oncology (November 15, 2004).
8. C. Dunn and A. D'Orazio, "Clearing the Air: New Lung Cancer Therapies," CURE Magazine (Summer 2003).
9. "Risk of Treatment-Related Death Down in Phase I Trials," Hematology Today (December 2004).
10. T.G. Roberts, Jr., B.H. Goulart, L. Squitieri, S.C. Stallings, E.F. Halpern, B.A. Chabner, G.S. Gazelle, S.N. Finkelstein, J.W. Clark, "Trends in the Risks and Benefits to Patients With Cancer Participating in Phase 1 Clinical Trials," Journal of the American Medical Association, 292, 2130-2140 (November 3, 2004).
11. E. Berton, "Drug Cos to Coordinate Clinical Trial Data Publication," Wall Street Journal (January 6, 2005).
12. "Policy, Society and Ethics," ACUMEN, Vol. II, No. II.
13. 2003 Report to the Nation, Center for Drug Evaluation and Research, www.fda.gov, posted May 24, 2004.
14. "Clinical Trials Cost No More Than Standard Care," American Cancer Society, www.cancer.org, posted May 26, 2000.
Mark Grose is vice president of program management for Endpoint Research, Mississauga, Ontario, (416) 626-0299, fax (416) 626-2063, e-mail: firstname.lastname@example.org.