Breaking Barriers to Participation in Cancer Clinical Trials

This issue of The Scientist chronicles many promising areas of cancer research, comprising a wide range of approaches to the treatment and prevention of our second-leading cause of death. But before any of these disparate approaches can begin to affect the rate of cancer mortality, they must pass through the bottleneck of human clinical trials. The pace of new ideas through the clinical trial process can seem maddeningly slow to patients and researchers alike. It takes far too long to get safe and effective new treatments to the general public, and it also takes far too long to back out of unsafe or ineffective blind alleys. The result can be seen in a comparison of childhood and adult cancers, notes Andrea M. Denicoff, a clinical trials nurse specialist in the National Cancer Institute's (NCI) Office of Clinical Research Promotion. "When you look at the number of children with cancer who get their treatment in clinical trials versus adults, the difference is amazing," she points out. "Historically, anywhere between 60 and 90 percent of children with cancer go on clinical trials, whereas only 2 to 3 percent of adults with cancer get their care through clinical trials. If you look then at how much progress has been made with the disease, I think there are many, many more success stories in pediatric oncology than in adult oncology because of these numbers." The rate of participation among children is high because childhood cancer is relatively rare, which means that few pediatric oncologists make their livings in private practice. Most are employed by major academic medical centers where they are likely to participate in--and refer their patients to--cancer clinical trials. The low rate of participation among adults has many causes. To list just a few of them, inclusion and exclusion criteria may be overly strict; patients--and their physicians--may not be aware of the availability of clinical trials; clinical trials may be hard to find; patients may be reluctant to be randomized or to risk receiving a placebo; and insurance providers may refuse to cover their costs. Unfortunately there are no reliable studies of the relative contributions of these factors to the problem. Education can address some of these factors. People with cancer will be more likely to consider clinical trials if they realize that all Phase I and most Phase II trials use no placebos at all, and while patients in Phase III treatment trials are usually randomized, the trial compares the experimental treatment with the best available standard treatment. No one is left untreated. Patients also appreciate knowing that they needn't depend on their physicians to recommend clinical trials. NCI, for example, has set up an excellent Web site at cancertrials.nci.nih.gov where patients--or health care professionals--can search the PDQ [Physician Data Query] database, which contains detailed information on all NCI-sponsored clinical trials and many other trials as well. NCI is addressing other barriers to entry by restructuring its system.1 As Denicoff explains, "Our system is part of the problem. It's not very open to new investigators, to small community investigators, to putting clinical trials in all the areas they need to be to get patients that option. If a physician can't participate in our cooperative groups or our network, how is he or she going to be able to say to the patient, 'Well, you can do this or that,' especially patients who don't necessarily want to leave where they're getting treatment? Part of the restructuring effort is to remove some of these barriers by expanding the number of investigators." NCI has a pilot project under way called the Expanded Participation Project that, among other things, will let oncologists participate in trials conducted by several cooperative groups and will provide centralized data management, easing the burden on physicians who may not be comfortable with the complex data-collection requirements of clinical trials.2 Problems with insurance reimbursement present another possible barrier to entry. Many health insurance and managed care programs specifically deny coverage for even routine medical care when patients seek to enroll in clinical trials. Though it may seem obvious that such exclusions would tend to decrease participation, the General Accounting Office (GAO) has issued a report that surprisingly concluded that evidence for such an effect is lacking.3 The GAO surveyed 26 private health insurers and 11 of the 48 NCI-designated clinical and comprehensive cancer centers. According to the report's authors, the survey revealed that although many of the insurers did exclude coverage for clinical trials, many allowed for exceptions on a case-by-case basis. And most of the cancer centers surveyed failed to report serious difficulties enrolling patients into NCI-sponsored clinical trials. The GAO report has come under serious criticism from within the National Institutes of Health, and in fact an NIH rebuttal is published with the report itself. The rebuttal charges that the GAO report contains "serious conceptual and methodological flaws, which significantly bias the study's results." The rebuttal notes, for example, that the survey examined a small and nonrepresentative sample of insurers and failed to survey patients at all. In addition, by examining only NIH-funded trials, the report missed those trials that failed to receive continued funding because they were unable to recruit a sufficient patient group. And the report completely ignored the thousands of trials sponsored not by NIH, but by other government agencies and by pharmaceutical companies. Legislators at both the state and federal levels are clearly not waiting for the resolution of this dispute. Several states, including Georgia, Rhode Island, and Illinois, have passed laws requiring insurance companies to pay the routine costs of standard medical care for at least some patients enrolled in approved clinical trials. At the federal level, various proposals regarding insurance coverage of clinical trials have been part of bills in Congress, but none has passed. There are clinical trial provisions in the Patient's Bill of Rights, but the bills passed by the two houses of Congress vary substantially in many areas and have not yet been reconciled. The bills passed by the Senate and the House of Representatives both require coverage of the routine costs of patients enrolled in approved cancer clinical trials, but they differ substantially in the number of Americans who would be affected. The House bill covers all 161 million Americans who have private insurance. The Senate bill covers only 48 million Americans in self-funded insurance plans. A House-Senate conference committee will attempt to hammer out a compromise sometime this spring. Neither bill covers Americans who receive their coverage through Medicare, and that is the subject of proposed legislation that has to date not passed either house. Medicare coverage is particularly critical because of solid evidence for the underrepresentation of the elderly in cancer clinical trials.4 None of the proposals for increased insurance coverage would require that health plans pay for the cost of the clinical trial itself. These costs are always paid by the trial's sponsor. Health plans are being asked to pay only for the routine costs of standard medical care. According to several recent studies, those costs are only modestly higher than the costs of cancer care for people who are not enrolled.5 Of course, not all insurance companies deny coverage to patients participating in clinical trials. To name just one example, Aetna U.S. Healthcare, which currently has 21 million members, has long covered patients in clinical trials. And in December 1999 the New Jersey Association of Health Plans announced that all of its member companies had agreed to cover approved Phase I through IV cancer clinical trials. According to Paul R. Langevin, president of the association, his members began considering a voluntary agreement when the New Jersey legislature began considering a law that would mandate coverage. "I didn't have any doubt that the New Jersey legislature could probably pass a bill that would mandate coverage," recalls Langevin, "but if this is really about accruing more patients actively into trails, getting them to the right trial for the patient, and setting up a network that would serve everyone's purposes, probably a piece of mandate legislation was not the best approach." The health plans were concerned that they would be forced to cover unapproved treatments, notes Langevin. "There were a lot of off-protocol studies being pitched to our members as clinical trials that could help them when in fact they weren't accepted clinical trials, their design was such that their benefit was dubious, and from a scientific standpoint the information being generated wasn't useful." Langevin ended up brokering an agreement that pleased both sides. As he explains, "It seemed to us that if we could make the researchers feel we weren't in the business just to say no and make the health plans feel that this was not just about getting people into more trials with more money and opening a Pandora's box, that we could probably get to an agreement. Much to my surprise, after a lot of very honest and frank discussion between the research community and the health plans, the plans agreed to cover all four phases." Although no one can say for sure that such initiatives will speed the pace of cancer research, it stands to reason that removing barriers to participation in cancer clinical trials can't hurt and may well improve matters substantially. Robert Finn is a freelance science writer and the author of a book on cancer clinical trials.6 He lives in Half Moon Bay, Calif., and can be reached at finn@nasw.org. References 1. National Cancer Institute, Clinical Trials: A Blueprint for the Future, Publication T348, 1999. Available online at cancertrials.nci. nih.gov/researchers/restructuring or by phoning (800) 4CANCER. 2. A description of the Expanded Participation Project can be found at light.emmes.com/epp. 3. United States General Accounting Office, NIH Clinical Trials: Various Factors Affect Patient Participation, GAO/HEHS-99-182, 1999. 4. L.F. Hutchins, et al., "Underrepresentation of patients 65 years of age or older in cancer-treatment trials," New England Journal of Medicine, 341[27]: 2061-7, 1999; H.J. Aaron and H. Gelband, (eds.), Extending Medicare Reimbursement in Clinical Trials, Washington, D.C., National Academy Press, 1999. 5. See, for example, J.L. Wagner et al., "Incremental costs of enrolling cancer patients in clinical trials: a population-based study," Journal of the National Cancer Institute, 91[10]:847-53, 1999; B.H. Fireman et al., "Cost of care for patients in cancer clinical trials," Journal of the National Cancer Institute, 92:136-42, Jan. 19, 2000. 6. R. Finn, Cancer Clinical Trials: Experimental Treatments and How They Can Help You, Sebastopol, Calif., O'Reilly & Associates, 1999. This book may be purchased from Amazon.com

Breaking Barriers to Participation in Cancer Clinical Trials

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