Major new approaches to increasing clinical trial enrollment launched in the past 5 years have produced some early signs of success. Accrual to clinical trials has increased, public awareness and attitudes seem to be improving, and some key trials have accrued much faster than projected.
At the same time, the intensified efforts have cast a spotlight on some fundamental and contentious issues related to accrual. Marketing efforts aimed at the public, for example, are raising ethical concerns, with some researchers questioning whether patients understand the purpose of trials when they sign up. And efforts aimed at increasing physician participation have stirred and heightened a debate about what the optimal system should and could be.
Signs that recruitment efforts may be producing results come from several sources. Enrollment in National Cancer Institutesponsored, cooperative group treatment trials has grown from a little over 20,000 in 1998 to about 25,000 in 2003. For 2004, that figure will probably be around 27,000, said Jeffrey Abrams, M.D., who heads NCI's Clinical Investigations Branch. Accrual to NCI's contract (noncooperative group) trials has also grown, bring the total number of patients to about 30,000 annually.
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The increase, coming after many years when accrual hovered around 20,000 per year, has heartened trial leaders. "There's no question the cooperative group system has seen a substantial increase," said Robert Comis, M.D., chairman and president of the Coalition of National Cancer Cooperative Groups. "Something positive is happening."
Public Awareness Push
Along with these signs of success have come indications that a new approach to raising public awareness of trialspaid, national advertisingmay be having some success. For the past 4 years, the Coalition has purchased space in Newsweek for a special advertising section promoting clinical trials. Another well-financed national effort, the Lance Armstrong Foundation's Tour of Hope, promotes clinical trials with full-page newspaper ads.
Newsweek sponsored a survey of its readers that found that a high percentage97%of readers recalled seeing the special section on clinical trials. In 2003, 42% of those who recalled the section said they had been aware of clinical trials before reading it, whereas in 2004, that figure climbed to 50%.
The Newsweek survey also found that 95% of the readers who remembered the special section said that if they were diagnosed with cancer, they would investigate clinical trials as a treatment option. While this figure is encouraging, it also raises a fundamental issue confronting patient recruiters: Does the term "treatment option" imply that the main purpose of clinical trials is treatment?
Therapeutic Misconception?
Ethicists point out that the primary purpose of clinical research is not to administer treatment but to develop future treatments. Any promotional language that blurs the distinction between research and treatment could contribute to what the National Bioethics Advisory Commission has called the "therapeutic misconception"the belief that the primary purpose of a clinical trial is to benefit the individual patients rather than to gather data.
Steven Joffe, M.D., and colleagues at the Dana-Farber Cancer Institute, Boston, have examined this issue from several angles, most recently in a January article in The Lancet that attracted attention from major media outlets. The researchers concluded that there is no good evidence that patients in clinical trials have better (or worse) outcomes than patients treated outside of trials.
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Joffe said that the finding of no evidence of difference in outcomes is at odds with statements that promote clinical trials by suggesting they offer the best treatment. Many promotional materials claim that participation in trials ensures excellent care and careful monitoring. But some marketing language goes further, suggesting that clinical trials are the best option, and this is more questionable, Joffe said.
"In my view, suggesting that clinical trials `offer high-quality treatment' is an acceptable claim, though it does leave some room for misinterpretation both in terms of blurring lines between research and treatment and in terms of overpromising benefits," Joffe said. "In contrast, to say that clinical trials `offer the highest-quality treatment' is a factual claim for which I don't think we have sufficient evidence."
In the Lancet article, Joffe and his co-authors say this therapeutic misconception constitutes an "important threat to the validity of informed consent." In fact, clinical investigators are sensitized to this issue, said Malcolm Smith, M.D., who coordinates pediatric trials for NCI. The Children's Oncology Group (COG) and the American Society of Clinical Oncology sponsored a meeting on ethics at the last COG meeting, at which informed consent was a major topic, Smith said, and efforts to refine and improve the COG informed-consent process are ongoing.
Focusing on Physicians
The other major new approach to increasing accrual to trials has focused on physicians both inside and outside clinical trials system. Underlying this effort is the fact that most oncologists do not actively participate in trials. Comis said that although 70% to 80% of oncologists are members of trial organizations, only about 30% to 40% actively enroll patients.
So far, the effort to increase physician involvement has primarily taken place within the cooperative group system. The centerpiece of the effort is NCI's Cancer Trial Support Unit (CTSU), a central, Web-based system through which investigators can place patients on trials of any cooperative group, regardless of their own affiliation. Four years after its launch in 2000, the CTSU has grown substantially and for the past 6 months has accrued 350 to 400 patients per month.
"We are finally getting into the numbers we originally envisionedabout 4,000 to 5,000 patients per year," Abrams said. The CTSU now lists 50 active protocols, and another 33 are in development, adding up to a substantial proportion of all cooperative group trials.
Moreover, three major CTSU trialsin renal cell carcinoma, multiple myeloma, and breast cancercompleted their accrual in half the time expected. All had substantial accrual from investigators who would not have otherwise had access to clinical trials except through the CTSU, Abrams said.
In addition to offering easier access to trials, the CTSU's regulatory support system has helped ease the paperwork burden imposed by clinical trials, often seen as a barrier to physician involvement. The CTSU has also developed an electronic reporting system, and a demonstration project of that system is now under way in connection with a large colon cancer trial of the North Central Cancer Treatment Group. The project is about a year away from the point at which it can be evaluated, Abrams said, "but the data are coming in."
The CTSU's progress has occurred amid ongoing discussion about what the optimal clinical trials system should be. The Coalition, for example, has developed a paper citing the need to improve the system and proposing to undertake "a 6- to 9-month study to identify more efficient organizational structures, workflows, and common data platforms to facilitate acquisition and sharing across the groups, including the CTSU."
In the meantime, the NCI has formed a Clinical Trials Working Group, which is considering a redesign of the clinical trials system. The group's charge includes trials not only in cooperative groups but also at cancer centers, NCI's specialized programs of research excellence, and those conducted through individual investigator grants. "No other group of external advisers has addressed the clinical trial process across all venues," said James Doroshow, M.D., director of NCI's Division of Cancer Treatment and Diagnosis, who is leading the effort.
Among the CTWG's subcommittees is one focusing on improving clinical trial accrual management. Here, an area of discussion could be ways to provide active, hands-on help with accrual to specific trials, similar to that provided in drug company trials, Doroshow said. CTWG subcommittee recommendations are due in June 2005.
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