WASHINGTON, DC—For more than 50 years, the Clinical Trials Cooperative Group Program of the National Cancer Institute has been a key factor in the nation's progress against cancer— but now it needs a major reorganization and a large infusion of funds to keep it robust. That is the conclusion of the new report from a committee of the Institute of Medicine.
The purpose of the new report, “A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program,” released on April 15, is to continue to improve the system, which has previously been extensively reviewed. The report notes that the program has become stagnant, inefficient, cumbersome, underfunded and overly complex and redundant managerially at a time when its role has never been more urgent.
The Cooperative Group Program consists of some 3,100 institutions and 14,000 investigators who enroll approximately 25,000 cancer patients each year. The program, the report emphasizes, is critically important given the explosion of knowledge in genetics, molecular biology, and cancer biomarkers. Previous IOM reports have stressed the promise of biomarkers and personalized medicine in oncology.
If the NCI Cooperative Group program is not reinvigorated, the result could be more industry-funded clinical trials (focused more on commercial return) and fewer federally funded clinical trials, noted both the report and an American Society of Clinical Oncology study released on the same day.
“I want to emphasize that the NCI asked for this study,” said IOM Committee Chair John Mendelsohn, MD, President of the University of Texas M. D. Anderson Cancer Center, who spoke about the report at a special session of the American Association for Cancer Research Annual Meeting.
Asked by OT if he had had a reaction from NCI Director John E. Niederhuber, MD, Dr. Mendelsohn said he had not yet received a formal response, but that “I know he's going to take it seriously.” He said he would be meeting with Dr. Niederhuber, and that he expected he was reviewing the report carefully.
Dr. Mendelsohn added, “I want to emphasize that many of the ideas in this report came from the NCI. The NCI was not an adversary.” Rather, he said, the NCI is one of the essential stakeholders who all want the same thing: faster and more effective drugs for cancer patients.
Builds on Recommendations of Two Other Groups
Dr. Niederhuber has spoken often of the need to streamline and improve the efficiency of the NCI Cooperative Group Program, noting that he is working to implement recommendations made by two other organizations, the Clinical Trials Working Group and the Operational Efficiency Working Group. The NCI was a cosponsor of the new IOM report, which builds on recommendations made by these two groups.
Asked how he thinks investigators in NCI Cooperative Groups will react to the report, Dr. Mendelsohn said, “I think a few years ago there would have been much more pushback than today. People realize the system could get broken, even if it isn't now.”
Funding Lower Now in Effect than in 1999
Today, funding for the Cooperative Group Program is actually lower in inflation-adjusted dollars than it was in 1999 (less than 3% of NCI's total budget), and the program needs a major infusion of dollars, the IOM report states.
In his preface to the report, Dr. Mendelsohn noted that only about 60% of NCI-sponsored Phase III trials are completed, which he called “a terrible waste of human and financial resources.”
He cited examples of the essential contributions to cancer care that clinical trials have made in the past, including showing that breast-conserving surgery plus radiation is as effective at eradicating early-stage breast cancer as radical mastectomy is; that some less intensive regimens for pediatric cancers could control cancer while reducing the risks of long-term adverse effects from highly toxic therapies; and that tamoxifen could reduce breast cancer incidence by about 50% over five years for women at high risk for the disease.
Dr. Mendelsohn said that the long, complex, regulation-laden, redundant process of designing, reviewing, and starting Cooperative Group clinical trials and an inadequate system for prioritizing clinical trials result in a slow accrual of patients, which bogs down the entire system. He said the committee concluded that the total number of trials undertaken by the Cooperative Groups should be reduced if adequate funding is not forthcoming.
“This was the hardest recommendation to write,” he noted, because it could tread on investigators who are committed to a trial but might be unable to get it funded if the number of Cooperative Group trials is reduced.
Consolidate Functions, Centralize Credentialing, Increase Reimbursement
The report recommends that the system be streamlined by consolidating redundant administrative and support functions, which currently are dealt with individually by each of the 10 cooperative research groups in the cooperative group program.
Also recommended is that NCI establish a centralized credentialing system for investigators and sites that wish to participate in a national trials system to enhance consistency and eliminate the need for burdensome re-credentialing with different cooperative groups. Such a centralized system would provide a tool to eliminate research sites with low recruitment levels or a lack of capacity to manage clinical trial data, the report noted.
In addition, NCI should increase the amount it reimburses clinicians for the costs of management of each of their patients in trials, and pay for their clinical trials administrative trial design and management time.
“The per-case reimbursement of $2,000 has not increased in 10 years—it's basically very expensive to run a trial on $2,000,” said IOM committee member David M. Dilts, PhD, MBA, Director of Clinical Research at the Knight Cancer Institute of Oregon Health and Science University (OHSU), who also spoke at the AACR meeting.
Dr. Mendelsohn said the clinical trial per-case reimbursement rate should go up to at least $4,000 to $6,000, and even more if extensive genetic and biomarker testing is needed. Dr. Dilts said he will be doing a study at OHSU on the true costs of conducting a clinical trial.
Today, noted Dr. Mendelsohn, as much as half of the cost of clinical trials is borne by the clinical investigators and care providers who carry out the trials. Because of this financial reality, “almost universally, investigators are compelled to seek supplemental support from outside sources, such as pharmaceutical companies,” he wrote. “The problem is further compounded by the increased costs of trials because of the opportunity to measure biomarkers in a patient's cancer and use them to predict and monitor appropriate therapy,” he added.
Unfortunately, he noted, academic institutions place a “relatively low value” on Cooperative Group trials in evaluating faculty accomplishments, a stance that discourages physician participation—and which the IOM report said should be changed.
The committee also called on public and private health insurers to cover all the non-experimental costs of patient care for those who participate in clinical trials.
Copies of the new IOM report are available at www.iom.edu/Reports
The Institute of Medicine grouped its recommendations into four key areas:
1. Improve the speed and efficiency of the design, launch and conduct of cancer clinical trials through consolidation, harmonization of government oversight, and collaboration among stakeholders.“In a democracy you're never going to be efficient; we're trying to become more efficient,” commented Committee Chair John Mendelsohn, MD. He said the Department of Health and Human Services should lead a trans-agency effort to streamline and harmonize government oversight and regulation of cancer clinical trials.Dr. Mendelsohn also noted that broader use of electronic tools in clinical trials could contribute to efficiency and accrual, including cueing clinicians about clinical trials for which particular cancer patients might be eligible.
2. Incorporate innovative science and trial design into cancer clinical trials through the development and use of novel trial designs and biorepositories. Dr. Mendelsohn cited the BATTLE (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination) trial from M. D. Anderson—which was presented at the AACR meeting—as an example of innovative trial design.This trial is the first lung cancer clinical trial to guide targeted therapies to patients based on molecular signatures in tumor biopsies. The IOM also called for the development of unified standards for new technologies; Dr. Mendelsohn noted that the US moon landing was based on extremely precise spaceship design.
3. Improve the means of prioritization, selection, support, and completion of cancer trials by reevaluating the role of NCI in the clinical trials system, increasing the accrual volume, diversity, and speed of clinical trials and increasing funding for the Cooperative Group program.“Let's let peer review pick out the best people doing the best trials,” and the trials can then compete head to head on scientific merit, he said, noting that pediatric cancer groups prioritize their clinical trials.
4. Enhance the incentives for participation of physicians and patients in clinical trials by adequately supporting clinical investigators and by covering the cost of patient care in clinical trials (including the cost of off-label drug use if published evidence justifies such use). The AMA should establish new CPT codes for offering, enrolling, managing, and following a patient in a clinical trial, Dr. Mendelsohn said. “We should strive to make participation in clinical trials a key component of clinical practice.”
The American Society of Clinical Oncology praised the Institute of Medicine Clinical Trials report calling for overhauling of the NCI Cooperative Group Program and giving it a major infusion of funding. ASCO, one of the cosponsors of the report, also released its own survey showing how underfunding harms the program.
ASCO is calling for a doubling of the NCI Cooperative Groups (including the Community Clinical Oncology Program) budget within five years to shore up the program, from about $250 million today to $500 million by 2015. So important is the NCI Cooperative Group trials program that “the majority of what we know about treating cancer has come from this program,” ASCO Immediate Past President Richard L. Schilsky, MD, Chief of the Hematology-Oncology Section and Deputy Director of the Comprehensive Cancer Center at the University of Chicago Medical Center, said in a statement.
Today, noted Dr. Schilsky, who served on the IOM committee who wrote the new report, the program “is being starved of funding,” and “it is clearly not in the public interest that it receives such a small fraction of NCI's overall budget.
“Congress had the vision to build this unique network, which includes institutions and community-based practices, allowing access to clinical trials in virtually every community in the US. At a time of unparalleled opportunity, this collaborative system is a critical link between scientific discovery and improved treatments for cancer patients. Increased federal funding for cooperative clinical research would increase the number of cancer clinical trials, increase patient enrollment, speed translation of genetic discoveries into treatments for patients, and cover the real costs of participation.”
The new ASCO survey, published online as an Early Release article ahead of print in the May issue of ASCO's Journal of Oncology Practice (jop.ascopubs.org), shows that fully one-third of NCI Cooperative Group sites intend to limit participation in federally funded clinical trials due to inadequate per-case reimbursement.
The IOM report calls for more than doubling per-case reimbursement, which is now about $2,000. ASCO notes that one of its own studies in 2003 and a C-Change study done in 2005 determined that the actual per-case cost of conducting NCI trials was $5,000 to $6,000. ASCO has calculated that if NCI reimbursed at a per-case rate of $6,000, this would require an additional $120 million—yet the total increased funding for the Cooperative Group program called for would still account for just 3.6% of NCI's budget.
Additional troubling news, according to the ASCO survey, is that nearly 40% of respondents at sites which are planning to limit NCI Cooperative Group trials said they plan to increase their industry trial participation, despite expressing a preference for conducting Cooperative Group trials.
During a special session at the AACR Annual Meeting last month, IOM Committee Chair John Mendelsohn, MD, expressed concerns that more industry-funded trials will mean that whole areas of cancer research could be overlooked, such as rare cancers that affect small populations and thus have limited commercial potential for pharmaceutical companies.
“Clinical trials are the essential link between laboratory discoveries and new treatments for patients,” said ASCO President Douglas W. Blayney, MD, coauthor (with Allison R. Baer, RN; Chelsey A. Kelly; Suanna S. Bruinooge; and Carolyn D. Runowicz, MD), of the ASCO study containing the survey. “Adequate NCI support for the Cooperative Group Program is critical to advancing progress against cancer and improving the lives of millions of cancer patients.”
ASCO surveyed 509 US and Canadian NCI-supported Cooperative Groups to pinpoint the factors influencing participation in Cooperative Group trials.
In an April 15 letter to NCI Director John E. Niederhuber, MD, Dr. Blayney cited the results and said, “The IOM report comprehensively articulates the vital role that Cooperative Group research plays in advancing cancer prevention and treatment…. In real dollars, total funding for Cooperative Clinical Research is less today than a decade ago…. Administrative changes alone cannot sustain this vital clinical research system. Without adequate funding, continued success of Cooperative Group trials is in jeopardy.
“While overall NCI funding has increased, funding for Cooperative Group trials has been virtually flat since 2002…. The increase we are requesting will likely require both internal reallocations, as well as increased funding from Congress.”
No Word from Coalition of Cancer Cooperative Groups
BY ERIC T. ROSENTHAL
When the Institute of Medicine issued its report recommending ways to reinvigorate the NCI Cooperative Group Program, it seemed curious that there was no public comment from the Coalition of Cancer Cooperative Groups (CCCG), which calls itself “The Voice for Cancer Clinical Trials” and was founded in 1997 “to address its members' shared goal of improving the cancer clinical trials system,” according to the organization's website (www.cancertrialshelp.org).
Those members are the heads of the 10 NCI-sponsored cooperative groups, representatives from leading patient advocacy organizations, and cancer researchers.
At a cancer center reception at last month's AACR Annual Meeting, two days after the release of the report, I followed up with Richard L. Schilsky, MD, an IOM committee member, Vice Chair of CCCG and from 1995 until last month Chair of Cancer and Leukemia Group B, who was quoted in an ASCO news release about the report in his capacity as Immediate Past President.
Why did the Coalition not come forward with some sort of statement? Dr. Schilsky said he didn't know and hadn't discussed it with CCCG President and Chair Robert L. Comis, MD, Group Chair of the Eastern Cooperative Oncology Group (ECOG).
Dr. Comis was at the same reception and I later asked him the same question. He said that perhaps the Coalition would issue a statement in the future, but that in the meantime he considered that it made sense for Dr. Schilsky to comment since he had served on the IOM panel.
CCCG's Cooperative Group Members
CCCG's cooperative group members are
* American College of Radiology Imaging Network (ACRIN)
* American College of Surgeons Oncology Group (ACOSOG)
* Cancer and Leukemia Group B (CALGB)
* Eastern Cooperative Oncology Group (ECOG)
* Gynecologic Oncology Group (GOG)
* North Central Cancer Treatment Group (NCCTG)
* Children's Oncology Group (COG)
* National Surgical Adjuvant Breast and Bowel Project (NSABP)
* Radiation Therapy Oncology Group (RTOG)
* Southwest Oncology Group (SWOG)