The NCI supports an average of over 1,300 clinical trials a year in the areas of prevention, screening, diagnostics, treatment, quality of life, supportive care, and genetics. Conducting clinical trials across multiple institutions in numerous locations requires a great deal of coordination to insure quality and consistency throughout all aspects of the trial, triggering the need for standing infrastructure with consistent policies. The NCI has supported the Clinical Trials Cooperative Group Program for over 50 years to fulfill this function.
NCI CLINICAL TRIALS COOPERATIVE GROUP PROGRAM
Depending on the type of trial and phase of testing, treatment trials may enroll anywhere from less than 30 patients in a single center to several thousand patients scattered across the country, or the globe. The Cooperative Group Program, begun in 1955, originally focused solely on chemotherapy trials. Since then the program has expanded, and is designed to promote and support clinical trials of new treatments, as well as trials that focus on therapies with other benefits such as quality of life. The program is co-administered by the Cancer Therapy Evaluation Program (CTEP) in NCI’s Division of Cancer Treatment and Diagnosis (DCTD), which manages evaluation of new cancer treatments or new uses for standard therapies in humans, and NCI’s Division of Cancer Prevention, which oversees cancer control and cancer prevention trials. In addition, DCTD’s Cancer Imaging Program oversees ACRIN (American College of Radiology Imaging Network), which performs trials with novel radiologic imaging technologies. (For information about preclinical drug development at NCI, please see Benchmarks Volume 2, Issue 3.)
Currently, NCI sponsors ten cooperative groups that are based in the United States, and provides limited funding to two international groups for trials they conduct in multi-institutional settings involving U.S.-based groups (see list below). Some cooperative groups are organized around a specific disease (i.e., gynecologic oncology), some focus on a particular technology (i.e., radiation therapy or imaging), some are centered on a particular expertise (i.e., pediatrics), and others have multiple focus areas. What the groups all have in common is that they work to develop and conduct large-scale trials in multi-institutional settings.
Cooperative groups include researchers, cancer centers and community physicians throughout the United States. Some groups also include international partners. As of 2007, the NCI Clinical Trials Cooperative Group Program involved over 3,100 institutions and placed more than 25,000 new patients into cancer treatment trials annually. The goals of the Cooperative Group Program are to:
- improve cancer outcomes through research aimed at improving survival, quality of life, and prevention
- promote complementary studies that take advantage of tumor, tissue and blood samples accumulated through the course of research to improve understanding of the biology of different cancers, and
- improve clinical trials methodology through the development and experimentation of new study designs and approaches.
In 2007, funding for the Cooperative Groups Program was approximately $147.9 million. Unlike many other National Institutes of Health cooperative clinical trial efforts, the funding for the NCI Clinical Trials Cooperative Group Program is not linked to any specific clinical trial. The groups are funded through Clinical Research Cooperative Agreements (U10s), and are supported to continually generate new trials within their particular areas of expertise. Funding for the Cooperative Group Program does not overlap or replace funding for more traditional, narrowly-focused research project grants (i.e. R01, R21, etc.).
COLLABORATION AMONG COOPERATIVE GROUPS
When a clinical trial is designed to test a therapy for a rare subtype of cancer or a very specific subset of patients, it can become necessary to recruit patients from an even larger set of locations than are available in any one group or even within the entire NCI Clinical Trials Cooperative Group Program. In these instances, national and international networks can serve to coordinate and ensure consistency across several cooperative groups involved in a single trial or among multiple trials designed to look at a single issue. One such network, The Breast Cancer Intergroup of North America (TBCI), includes six NCI-sponsored cooperative groups, and was formed to advance breast cancer therapies through collaborations between the six member groups and other strategic partners in the United States and abroad. Another network, the Gynecologic Cancer Intergroup (GCIG), serves a similar function in order to advance research into gynecologic cancers.
Several important advances have resulted from these collaborations. In January 2006, based on the results of eight clinical trials conducted by members of GCIG and other NCI sponsored cooperative groups, NCI was able to issue an important clinical announcement about recommended treatment for women with advanced ovarian cancer. These studies showed that delivering anticancer drugs after surgery directly into the abdomen via a catheter (called intraperitoneal chemotherapy) in addition to delivering therapy through an arm vein improved survival by about one year compared to delivering the same therapy through an arm vein alone.
Later that year, all of the NCI-sponsored cooperative groups that perform breast cancer research collaborated on the development of the Trial Assigning IndividuaLized Options for Treatment (Rx) or TAILORx, which is a large, randomized clinical trial being coordinated by the Eastern Cooperative Oncology Group (ECOG). This study will determine whether adjuvant (in addition to conventional therapy) hormonal therapy alone is as effective as adjuvant hormonal therapy in combination with chemotherapy for certain women with early-stage breast cancer who have an intermediate risk of cancer recurrence based on a validated diagnostic test, Oncotype DXTM. For more information on TAILORx, see Benchmarks Volume 6, Issue 3.
More recently, members of the TBCI joined with a European network of international cooperative groups, the Breast International Group (BIG), to launch one of the largest international breast cancer treatment trials to date, the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) study.
BIG is an international non-profit network of various breast cancer research groups from around the world. It was established in 1996 and coordinates complex breast cancer trials among its 41 member groups — established clinical research and cooperative groups based in Europe, Australia, New Zealand, Asia, South Africa and Canada, with affiliated research centers, hospitals and labs around the world. Better known as a communications network, their goal is to enable its members to collaborate, discuss research priorities, and combine resources to achieve rapid, efficient, high-quality study results. This allows for less duplication of effort among the various cooperative groups.
In December 2005, a global meeting on breast cancer research was held between members of BIG and TBCI to discuss across-the-board best practices for specimen and data collection. Through subsequent meetings and conferences, four working groups were assembled with representation from both BIG and TBCI. This close working relationship facilitated agreement to collaborate on the ALTTO study, a randomized, international phase III trial of adjuvant lapatinib (Tykerb) and trastuzumab (Herceptin). ALTTO will compare the efficacy and safety of lapatinib vs. trastuzumab and whether these drugs are more beneficial when taken separately or together. The BIG and TBCI networks have jointly developed this study in which all care and data collection are standardized, no matter where patients are treated. ALTTO involves 8,000 patients from 50 different countries. Potentially, four thousand of these participants will be from North America. The North Central Cancer Treatment Group (NCCTG), an NCI sponsored cooperative group that is part of TBCI, will be the lead group for the North American sites. The additional participants are being recruited from study sites all over Europe and will be managed by BIG.
By involving thousands of women across several continents, it is hoped that enrollment will occur more rapidly so that answers for patients can be provided more quickly. The ALTTO trial will hopefully serve as a model for international collaboration. For more information about targeted drugs for breast cancer being tested in the ALTTO trial, please see the lead story in this issue of Benchmarks.
RECENT INITIATIVES TO FACILITATE NCI COOPERATVE GROUP INTERACTIONS
Several new initiatives have been introduced into the Cooperative Group program to enable NCI-sponsored Cooperative Groups to work more closely and collaboratively in trial development and enrollment of patients onto clinical trials. Three of the most developed initiatives are described below:
The Cancer Trials Support Unit (CTSU) was established to increase access to NCI-sponsored clinical trials by creation of a single, web-based menu of trials for all groups. This easy access facilitates cross-group accrual and permits non-group members to enroll patients on NCI-sponsored trials. The CTSU has also fostered more uniform data entry and collection, and has reduced the regulatory and administrative burdens across the Cooperative Groups Program by developing a single regulatory support system for all group trials. Since 2001, over 27,000 patients have been enrolled through the CTSU in intergroup trials. In 2007, the CTSU began work on development of centralized web-based patient enrollment and registration for the entire cooperative group system which will be fully implemented by the end of 2008.
The Central Institutional Review Board (CIRB), sponsored by NCI in consultation with the Department of Health and Human Services’ Office for Human Research Protections was designed to help reduce the administrative burden on local IRBs and investigators while continuing a high level of protection for human research participants. A local IRB’s use of the CIRB facilitated review mechanism enables an investigator to enroll patients into Cooperative Group clinical trials significantly faster than when employing traditional methods of IRB review. The CIRB was initially formed in 2001 to review all cooperative group phase III adult clinical treatment trials. A pediatric CIRB was constituted in 2004 to review all phase II, phase III, and pilot trials conducted by the Children’s Oncology Group. Currently, over 300 institutions, including approximately 33 NCI-designated Cancer Centers and 38 Community Clinical Oncology Programs, participate in the CIRB.
The Clinical Trials Working Group (CTWG) inaugurated NCI disease-specific steering committees to address the design and prioritization of phase III trials by leveraging existing intergroup, cooperative group, Specialized Programs of Research Excellence (SPORE) and NCI-Designated Cancer Centers. All phase III concepts and selected phase II studies funded by NCI, regardless of funding mechanism, will be prioritized through this process. The first disease-specific steering committee in gastrointestinal malignancies was initiated in 2006. The major goal of the committees is to evaluate and prioritize clinical trials based on their scientific merit and increase the efficiency of clinical trial collaboration, reduce trial redundancy, and increase information exchange at an early stage of trial development. The committees are designed to provide robust analysis of proposed concepts and facilitate the sharing of ideas among a broad range of clinical investigators, basic and translational scientists, NCI staff, community oncologists, and patient advocates. In addition to gastrointestinal cancer, disease-specific steering committees are currently active in gynecologic cancer, head and neck cancer, and genitourinary cancer. It is planned that all disease areas will have steering committees by 2010.
NCI CLINICAL TRIALS FACTSHEET
NCI CLINICAL TRIALS COOPERATIVE GROUPS FACTSHEET
CLINICAL TRIALS WORKBOOK: BASIC
CLINICAL TRIALS WORKBOOK: IN DEPTH
THE BREAST CANCER INTERGROUP OF NORTH AMERICA (TBCI)
THE GYNECOLOGIC CANCER INTERGROUP
NCI COOPERATIVE GROUPS:
American College of Radiology Imaging Network (ACRIN)
American College of Surgeons Oncology Group (ACOSOG)
Cancer and Acute Leukemia Group B (CALGB)
Children’s Oncology Group (COG)
Eastern Cooperative Oncology Group (ECOG)
Gynecologic Oncology Group (GOG)
National Surgical Adjuvant Breast and Bowel Project (NSABP)
North Central Cancer Treatment Group (NCCTG)
Radiation Therapy Oncology Group (RTOG)
Southwest Oncology Group (SWOG)
INTERNATIONAL GROUPS WITH NCI SPONSORSHIP UNDER THE COOPERATIVE GROUP PROGRAM:
National Cancer Institute of Canada Clinical Trials Group (NCIC)
European Organization for Research and Treatment of Cancer (EORTC)