NCI, cooperative groups gear up for changes in clinical trials system
New policies initiated in response to Institute of Medicine report
When the Institute of Medicine (IOM) issued its report on the National Cancer Institute (NCI) Clinical Trials Cooperative Group Program in April 2010, it recommended 12 major changes aimed at more rapidly translating scientific discoveries into successful patient treatments.
Issued at the request of then-NCI director John Nieder-huber, MD, the report called the current clinical trials system inefficient, cumbersome, under funded, and overly complex and recommended that the program be restructured and its funding increased.
“In the 1970s, when the War on Cancer was first begun, we didn't really know what caused cancer,” says John Mendelsohn, MD, chair of the IOM committee and president of The University of Texas MD Anderson Cancer Center in Houston. “Now we do, and we've made incredible progress with drugs that target the genetic abnormalities that cause cancer. But we want the clinical trials system to become more effective and efficient in applying what's been learned so we can find out which drugs work best in which situations.”
Authors of the report identified 4 overarching goals to improve efforts:
Improve the speed and efficiency of the design, launch, and conduct of clinical trials.
Make optimal use of scientific innovations.
Improve the selection, prioritization, support, and completion of clinical trials.
Foster expanded participation of both patients and physicians.
In response to the IOM's recommendations, the NCI has begun to initiate some of these changes, most notably the consolidation of the 9 groups that currently conduct clinical trials in adult cancer patients into 4 entities that will design and perform improved trials of cancer therapies.
Founded more than 50 years ago, the current program involves greater than 3100 institutions and 14,000 investigators and enrolls more than 25,000 patients in clinical trials each year. Four pediatric groups were consolidated into 1 group a number of years ago, and that group will not with the others.
“Modern clinical trials typically use sophisticated genetic profiling of tumors, and for these types of studies, it is necessary to screen large numbers of patients to find subsets that have tumors that demonstrate changes in specific genetic pathways,” notes James Doroshow, MD, director of the NCI's Division of CancerTreatment and Diagnosis, in the NCI Cancer Bulletin.1
These types of trials also require systems for collecting and distributing specimens, sequencing DNA, performing molecular stratification, and correlating genomic data. “Needless to say, these circumstances increase the complexity of the trials, and multi disease, multimodality groups with adequate resources are best suited to manage such complex trials. In addition, a few large cooperative groups will be better able to train investigators and adopt new clinical discoveries,” Dr. Doroshow adds.
During this process of consolidation, all current, active cooperative group trials will still be completed. The goal of consolidation, according to the NCI, is to improve the efficiencies of operations centers, data management centers, and tumor banks and to reduce redundancies. The groups have also provided opportunities to comment on the proposed changes and explore the reorganizations in consultation with the NCI. At the same time, the unique needs of subspecialties, such as radiotherapy, surgery, and imaging, are also under consideration.
Improving Efficiency, Focus
In addition to improving efficiency, the consolidations will improve focus. notes Dr. Mendelsohn. adding. “instead of 9 different groups deciding what to study in lung or breast cancer, we'll have 4 different groups making proposals and 1 disease site-specific scientific committee setting priorities.”
He adds that when NCI research first was launched after World War II, activities primarily focused on laboratory research. Since then, clinical research has become huge, and the system has not yet met the need for an enormous investment in infrastructure as well as support of clinical researchers' time and effort. “Now the clinic has become the lab in many ways,” Dr. Mendelsohn says. “We still very much need basic and translational research. But the exchange of information that is going back and forth is amazing in terms of its rapidity and the progress being made.”
In March, the Cancer and Leukemia Group B (CALGB), the North Central Treatment Group (NC-CTG), and the American College of Surgeons Oncology Group (ACOSOG) announced plans to merge (see sidebar).
At press time, the Radiation Therapy Oncology Group and the National Surgical Adjuvant Breast and Bowel Project reportedly were involved in merger talks. Meanwhile, the Eastern Cooperative Oncology Group and the Southwest Oncology Group (SWOG) say they do not have plans to merge; however, an NCI spokesman notes that the entire realignment may be a multiyear process.
We want the clinical trials system to become more effective and efficient in applying what's been learned so we can find out which drugs work best in which situations.—John Mendeisohn, MD
In addition, on January 1, 2011, the NCI imposed new deadlines, formulated by its operational efficiency working group. These deadlines reduce by half the time to initiate new clinical studies and will terminate studies not performed within 2 years of concept approval.
In further efforts to increase efficiency, the NCI is:
Decreasing the average time for final sign-off and approval on protocols for national trials by its centralized institutional review board from 150 days (in 2007) to 42 days.
Prioritizing a revamped review process with a new emphasis on disease-specific and modality-specific oversight, such as imaging or cancer control.
Modernizing information technology so that a single system can collect standardized clinical trial data, such as patient information and outcomes.
Funding, of course, is one of the biggest challenges in improving the cooperative group program, experts agree. With Congress struggling to address the federal deficit, the NCI's funding, along with any increase for the cooperative groups program, remains uncertain.
“Everyone realizes that they're doing this as a labor of love and that physicians have not received adequate reimbursement and support,” says American Society of Clinical Oncology (ASCO) President George Sledge Jr, MD. “If we don't increase the budget to these cooperative groups, we will have a decrease in the number of patients going onto trials, which will slow the pace of cancer research and lengthen the time we'll have to develop cures for many of these diseases.”
Dr. Mendelsohn concurs, noting that if funding is not increased for the cooperative clinical trials program, the authors of the IOM report recommended that fewer clinical trials be performed in the future, focusing on high-priority, fully funded studies that deal with innovative concepts such as personalized medicine. They also encouraged more funding for and collaboration on cooperative group trials by pharmaceutical and biotechnology companies. “Trials can get done faster in Europe,” he says. “If we can reduce the timeline for trials here, I'm confident the pharmaceutical companies would be willing to be more active in our cooperative group trials.”
Other goals spelled out in the report include funding for centralized biorepositories, centralization of scientific steering committees to drive prioritization and efficiency, support of clinical researchers through salary and protected research time, and payor coverage of nonexperimental costs associated with clinical trials. Such coverage is already required by law in some states, is covered by Medicare, and is scheduled to go into effect as part of the Patient Protection and Affordable Care Act, but no one is sure what will happen with the last requirement.
The IOM report noted that although the estimated cost of trials is approximately $6000 per case, the NCI only funds approximately $2000 of that amount. An ASCO survey found that approximately one-third of 509 US and Canadian NCI-supported cooperative group sites plan to limit their participation in federally funded clinical trials because of this reimbursement problem.2
Despite the many areas that the NCI and other stake- holders are attempting to improve, “unless there is a solution to the economic problem, the rest of it doesn't matter,” notes Laurence H. Baker, DO, chair of SWOG. Recognizing problems with the system, SWOG began implementing its own internal changes 3 years ago, he notes. “We were much more critical of our behavior than the IOM, and we've done many of the things that they suggested in the report;' he says, noting that SWOG has been multidisciplinary for long time and has an active cadre of survivors as well as liaisons with patients, nurses, and pharmacists.
In addition, the group has reduced its timeline for opening and closing its studies, identified the highest priority protocols in their portfolio, and made people accountable for moving them forward. Furthermore, SWOG requires study sites to accrue a minimum of 6 patients per year. “Two years ago, we reduced our ranks by 200 sites, but our accrual rate went up;' he says. “You save money because you staff and pay attention to the sites that participate.”
SWOG also has made an effort to accept and support good ideas from other cooperative groups, Dr. Baker says. “Fifty percent of the patients we accrued were not part of SWOG studies but rather those of other cooperative groups.”
Some have criticized SWOG—aud in some cases justly in the past—for not providing access to their biorepository, Dr Baker adds. As a result, the group has formed a task force of leading physician scientists to provide oversight and ideas, and 2 of these advisors already have applied for and received access to the biorepository to conduct their research.
The NGI and clinical trials oooperative groups have begun to make changes in response to the April 2010 IOM report.
Three cooperative groups recently announced a merger; others currently are in merger talks.
The consolidations are expected to improve efficiency and focus and bring new, promising treatments to patients faster.
The NGI imposed new deadlines that reduce by half the time to initiate clinical trials and decrease the average time for final sign-off and approval of protocols from 150 to 42 days.
At the same time, SWOG is seeking investigators whose studies have or will improve the practice of medicine. “Most pharmaceutical trials are overpowered studies with small gains,” Dr. Baker says. “That's not what we want to be engaged in. We're interested in significantly changing things.” Dr. Sledge cites an example of the type of study a cooperative group pursues versus that pursued by pharmaceutical companies: the recent finding that epidermal growth factor receptor inhibitors are not effective in colon cancer patients with KRAS mutations. “The company that makes these inhibitors may not want to know the answer, even though its clearly in the public benefit; he says.
Understanding the importance of such federally funded cooperative group clinical trials, leaders such as Drs. Mendelsohn and Sledge are confident that progress can be made. “Pretty much everything that's wrong with the current system is a self-inflicted wound,” Dr. Sledge says. “Part of it is finances, but a lot of it is us thinking smarter about how we do business.”