What Happened to the US Cancer Cooperative Groups? A Status Update Ten Years After the IOM Report

Abstract

The US Cancer Cooperative Groups were founded in the 1950s to establish a standing infrastructure to conduct multi-institutional cancer clinical trials. Initially funded almost entirely by the US National Cancer Institute (NCI), over the years the research conducted by the Groups has evolved to meet the demands of cancer clinical research, with a scope now encompassing trials to advance cancer treatment, cancer control, biomarker development and validation, and health services research, with corresponding broadening of their funding sources. The Cooperative Groups are also a critical mechanism for educating the next generation of cancer clinical trialists from many different disciplines. This review outlines the overall mission, structure and funding of the Cooperative Groups, beginning in 1955 when they were first established by the NCI, and describes the considerable progress against cancer achieved over the past decade.

Lay Summary

The US Cancer Cooperative Groups (Cooperative Groups) are a network of cancer clinical research physicians from both academic institutions and community cancer centers across the country who work together to bring clinical trials in cancer prevention, treatment, and care delivery to a wide range of patients. This manuscript reviews the history of the Cooperative Groups and details their current status as members of the National Cancer Institute’s National Clinical Trials Network. This review also describes the ways in which Cooperative Group research has expanded in response to new research opportunities afforded through partnerships with private industry and philanthropic organizations.

Precis

The US Cancer Cooperative Groups were founded in the 1950s to establish a standing infrastructure to conduct multi-institutional cancer clinical trials. Today, they have evolved to meet the increasing demands of cancer clinical research, with a scope encompassing trials that advance cancer treatment, cancer control, biomarker development and validation, and health services research.

Five Decades of Growth: 1955–2004

In the 1950’s, cancer researchers began to achieve treatment responses using chemotherapy, and in response the United States Congress provided funding to the National Cancer Institute (NCI) to create the Chemotherapy National Service Center. It soon became clear that multi-institutional collaboration was the best way to test the promising new anticancer agents that were emerging from the NCI’s drug development program. In response, the NCI established the Clinical Trials Cooperative Group Program, providing grants to fund clinical research networks known as Cooperative Groups. Instead of funding individual trials, the Cooperative Group Program established a standing infrastructure, allowing teams of researchers to design and launch new studies as opportunities arose, advancing the new field of clinical trials by experimenting with different scientific approaches and collaboration models. Each Cooperative Group established clinical research agreements with a number of health care institutions, developed policies and procedures for governance and study conduct, and initiated statistics and data management programs to collect and analyze data from across the member network. The Cooperative Groups also convened disease- or modality-focused scientific committees and charged them with designing clinical trials to test the most promising new approaches to treatment and cancer control. Each Cooperative Group was managed by a governance committee, made up of leaders from the member institutions, and one member was elected to serve as Group Chair and Principal Investigator of the Group’s primary grant from the NCI.

Beginning with studies for children and adults with acute leukemia, the Cooperative Groups evolved over subsequent years in response to the needs of the cancer clinical research community. Separate Cooperative Groups emerged to study pediatric and adult cancers, and some focused on specific tumor types or emphasized contributions from surgery, radiation therapy, and imaging. In 1981, the mechanism of support for the Cooperative Group Program was changed from a grant to a cooperative agreement. This altered the role of NCI in Cooperative Group activities, establishing the NCI as a research partner with the large academic medical centers leading the Cooperative Groups, and giving NCI considerable influence on Cooperative Group activities, including review and approval of trial concepts, protocol development, and trial operations (1). In 1983, NCI added the Community Clinical Oncology Program (CCOP) Network to enable cancer control research and provide a mechanism for community oncologists to participate in clinical trials. Many CCOP institutions joined Cooperative Groups as institutional members, and the Cooperative Groups received NCI funding to serve as coordinating centers known as Research Bases, signaling a change in Cooperative Group funding from a single NCI program to two, each with slightly different priorities and rules of engagement.

Over the next several decades, clinical trials became increasingly more complex. Development of most new therapeutic agents shifted to the growing pharmaceutical industry, and in 1984 the NCI released a policy statement addressing the need for collaboration between NCI and the private sector to study anticancer drugs of mutual interest (2). To make the best use of public funding, the Cooperative Groups focused on research of less interest to companies, such as trials comparing the effectiveness of different treatments already approved for clinical use, studies determining optimal duration and dose for approved drugs, or trials for patients with rare tumors. Patient advocates were added to the scientific and operations teams of the Cooperative Groups to ensure that the research optimally addressed the needs of cancer patients. An expanding basic science knowledge base also led to a demand for translational research. In response, the Cooperative Groups developed tissue biorepositories, and specimens collected from clinical trial participants were used to validate new prognostic and predictive biomarkers. In addition, large cancer screening and prevention trials were undertaken, and treatment trials were leveraged to address important secondary endpoints, such as quality of life as defined by patient-reported outcomes, financial burden or the influence of age on treatment outcomes.

Over time the Cooperative Groups were forced to adapt to significant headwinds created by steadily expanding regulatory requirements, increasing operational complexity, and rising health care costs. Initially, these challenges were alleviated by increased support that came after thousands of people gathered at the National Mall in Washington DC in September 1998 to demand an increase in NIH funding. Following this, NCI’s budget doubled from $2.5 billion in 1998 to $4.6 billion in 2003. With this additional funding, access to clinical trials expanded to patients across a wide range of communities, from large urban academic medical centers to small rural practices, and yearly enrollment of patients on Cooperative Group trials grew to a high of roughly 29,500 in 2001 (3).

After 2002, NCI budgets remained static, resulting in declining spending power that worsened over the next decade. These funding challenges came at a time of seismic change in oncology drug development. The surge in clinical trials demand over the next 25 years is best illustrated by the number of FDA oncology approvals that followed, increasing from a total of 75 in the decade from 1995–2004 to 133 from 2005–2014, and to 192 in the five years after that (4,5). In addition to that of the Cooperative Groups, a great deal of high impact cancer research was conducted by the pharmaceutical industry, and this latter approach dominated international drug trials. The objectives of the Cooperative Groups remained complementary to those of private industry. With their multi-modality perspective and a mandate to use public funding wisely, the Cooperative Groups emphasized combination therapies, and often tested secondary indications such as those supported by adjuvant therapy trials. Because of their large accrual networks and extensive experience with biospecimen collection and analysis, the Cooperative Groups were particularly suited for studies involving molecularly-defined disease subsets. For example, during this time a retrospective analysis by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and Genomic Health Inc. showed that a new molecular test predicting breast cancer recurrence could identify a high-risk subset of women who benefit most from chemotherapy (6). Following this, the Eastern Cooperative Oncology Group (ECOG) launched the Trial Assigning Individualized Options for Treatment (Rx) or TAILORx, a prospective trial that determined the optimal treatment approach for patients with a midrange molecular risk score (7).

During the years of flat NCI funding, the challenges of maintaining research productivity in the face of increasingly complex operations led the Cooperative Groups to look beyond NCI for support. This additional support came from a number of sources, including participating health care institutions, industry, philanthropic organizations, and state governments. Many Cooperative Group institutional members were large academic medical centers that were willing to subsidize the research conducted by their faculty. These institutions had always supported research faculty salaries and travel, but as flat NCI funding persisted and clinical trials volume remained steady, the member institutions also began to bear an increasing share of the cost of treating patients on Cooperative Group trials. In a 2010 analysis commissioned by NCI’s Director and presented to NCI’s Clinical Trials and Translational Research Advisory Committee (CTAC), member institution cost sharing was estimated as providing 24% of total Cooperative Group funding, not including pro-bono investigator time which was estimated as an additional 8% of overall cost (8). During this time the Cooperative Groups also developed research agreements with both private industry and philanthropic foundations. To do this, they established foundations that were not-for-profit corporations whose governance was tied to that of the Cooperative Groups. In 2010 the foundations contributed an estimated 15% toward the cost of research, with 11% provided by agreements with industry and approximately 4% from other sources (8). All told, the 2010 analysis estimated that 47% of the cost of Cooperative Group research was covered by non-NCI sources.

By 2009, although Cooperative Group accrual remained steady, it became evident that the Program was struggling to meet timelines, and at the request of NCI Director Dr. Harold Varmus, the Institute of Medicine (IOM) of the US National Academies of Science convened an expert panel to perform a comprehensive review. In April, 2010, the panel, chaired by Dr. John Mendelsohn, released its consensus report entitled “A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program” (9). The report reaffirmed the value of Cooperative Group research, stating that “a robust, standing cancer clinical trials network is essential to effectively translate discoveries into clinical benefits for patients. There are hundreds of cancer therapies in development and a continuous need for design and implementation of new clinical trials, so it would be highly inefficient to fund and develop infrastructures and research teams separately for each new trial. Thus, it is imperative to preserve and strengthen the unique capabilities of the Cooperative Group Program as a vital component in NCI’s translational continuum.” (5). However, the report also concluded: “Despite the unique mission and history of accomplishments of the Cooperative Groups, the Program is facing numerous challenges that threaten its ability to undertake large-scale, innovative clinical trials that benefit patient care… Fundamental to these challenges is a clinical trials infrastructure that has not evolved to accommodate the rapid pace of biomedical discovery. Stagnant funding, inefficient processes, extensive and complex government oversight, and a growing trend toward the conduct of industry trials overseas have contributed to inadequate physician and patient participation in clinical trials, threatening the Cooperative Group Program’s ability to efficiently translate discoveries into clinical applications.” The panel emphasized that “the current structure and processes of the entire clinical trials system need to be redesigned to improve value by reducing redundancy and improving the effectiveness and efficiency of trials. Numerous changes are needed, including an evaluation and justification of the unique contribution of each Cooperative Group and a shift in the primary focus of NCI from oversight to the facilitation of Cooperative Group trials (9).”

Response to the IOM Report: 2010–2020

The IOM recommendations came during a time of economic recession, and neither the NCI nor the member institutions had the additional funding required to adequately maintain the ten US Cooperative Groups that were active at that time. Shortly afterward, therefore, the NCI announced that all of the existing cooperative agreements would be discontinued, and that the Cooperative Group Program would be replaced by a new clinical trials system known as the NCI National Clinical Trials Network (NCTN). Similarly, the CCOP mechanism was discontinued and replaced by the NCI Community Oncology Research Program (NCORP). The new enterprise was designed to achieve efficiency and cost savings by consolidating the existing Cooperative Groups, and by centralizing many functions under the direction of the NCI. The new funding announcement called for a competition to award up to five US Network Group Operations Centers that would provide scientific leadership of former Cooperative Group Trials and become a nexus for engaging multi-disciplinary research teams to design new trials and to mentor junior researchers. Clinical site-specific awards were also announced, and prominent US academic institutions and community oncology programs competed directly for funding of their scientific leadership and study accrual, with a mandate to support research designed by all NCTN teams, instead of receiving this support through a specific Network Operations Group. NCI also increased the level of accrual-based funding provided to institutions who contributed the highest accrual to the network. Many functions formerly managed by individual Cooperative Groups were centralized under the direction of the NCI. Data management was updated by implementing a common electronic format, central IRB participation was required of academic member institutions, and an Imaging and Radiation Oncology Core (IROC) Group was created to monitor and ensure quality in trials involving these modalities. Strict study development timelines were instituted, and trials that failed to meet deadlines were not activated. Individual Cooperative Groups were required to pool their existing biorepository holdings into a common NCTN tissue bank program. To facilitate use by the scientific community, Cooperative Group biorepositories became searchable by a web-based system, with access to specimens controlled by a review panel convened by the NCI. In addition, new Integrated Translational Science Awards (ITSAs) funded teams working across the enterprise to identify and qualify predictive biomarkers. To expand access to clinical trials data to the widest possible research community, the NCI also launched an NCTN/NCORP Data Archive that includes patient-level, de-identified clinical datasets, data dictionaries, and metadata fields for all variables used in published phase III studies as of January, 2015. Finally, as with the previous cooperative agreements, the authority to approve new clinical trials rested with the NCI, largely following recommendations provided by scientific oversight committees known as NCI Disease/Imaging Scientific Steering Committees. Led by non-governmental co-chairs who do not hold leadership positions in the NCTN groups, these oversight committees also included representatives selected by each group, participants from other NCI-funded consortia such as the Experimental Therapeutics Clinical Trials Network (ETCTN) and the Specialized Programs of Research Excellence (SPOREs), biostatisticians, patient advocates, and NCI disease and biostatistics experts.

The new structures instituted by the NCI achieved almost all of the goals detailed by the IOM consensus report. Compared to the previous Cooperative Group Program, the NCTN/NCORP is more standardized and efficient, with greater collaboration across its many components. None of the pre-2014 Cooperative Groups were eliminated entirely (Table 1). Three groups, the American College of Surgeons Clinical Oncology Group, Cancer and Leukemia Group B, and the North Central Cancer Treatment Group, merged to become the Alliance for Clinical Trials in Oncology (Alliance), and ECOG joined with the American College of Radiology Imaging Network to become ECOG-ACRIN. NSABP, the Radiation Therapy Oncology Group (RTOG), and the Gynecologic Oncology Group (GOG) formed a federated group, known as NRG Oncology, maintaining the complementary structures of its components. Only one of the pre-NCTN adult-focused Groups, SWOG (later SWOG Cancer Research Network), proceeded without joining a merger. The Children’s Oncology Group was already the result of an NCI-directed merger that took place in 2000, joining four prior pediatric Cooperative Groups: the Children’s Cancer Study Group, the Pediatric Oncology Group, the National Wilms Tumor Study Group, and the Intergroup Rhabdomyosarcoma Study Group. NCTN funding was also provided to the Canadian Cancer Trials Group, continuing a direct relationship with an important international partner. Each of the reformatted US Cooperative Groups successfully competed for funding as both NCTN Network Operations Groups and to serve as NCORP Research Bases. Responding to a need for innovation in science and trial design, the new NCTN successfully launched a series of novel molecularly-guided trials (10). The Lung Cancer Master Protocol (Lung-MAP) uses a single, multi-arm trial design to explore whether this approach can efficiently identify treatments for advanced lung cancer using small subsets of patients with molecularly characterized tumors as well as a marker-agnostic arm. The NCI MATCH and Pediatric-MATCH trials ask whether molecular markers predict response to targeted therapies in patients with advanced cancer resistant to standard treatment, and ALCHEMIST is screening 8,000 surgically treated lung cancers for mutations in EGFR and rearrangement of ALK, identifying patients with early-stage disease that are eligible for one of four trials of targeted adjuvant therapy or immunotherapy. The infrastructure built around these studies is now being used to launch the next round of trials, which will address combination regimens (Combo-MATCH) and biomarker-driven immunotherapy studies (iMATCH) and leukemia trials (MyeloMATCH). Finally, understanding the importance of public-private partnership in cancer research, the NCI coordinated system-wide improvements to address industry concerns, and pharmaceutical partners also came forward, providing drugs, drug distribution, and other essential support. As a result, the number of NCTN trials collecting data intended to support regulatory approval has increased considerably. One of the recommendations of the IOM report was that the primary focus of NCI shift from that of research oversight to the facilitation of Cooperative Group trials. Whether this has occurred is a matter of perspective. For current Cooperative Group research funded by the NCI, some essential centralized clinical trials operations are directed by NCI staff, who also convene the Scientific Steering Committees, approve many studies in response to letters of intent issued by NCI, and play a major role in design and execution of large basket trials like NCI MATCH and its successors, Combo-MATCH and iMATCH.

Table 1:

US Cancer Cooperative Groups

Cooperative Group	Associated Research Foundations
Alliance for Clinical Trials in Oncology	Alliance Foundation Trials, LLC
Children’s Oncology Group	Children’s Oncology Group Foundation
ECOG-ACRIN	PrECOG, LLC
NRG Oncology	GOG Foundation, Inc. NSABP Foundation, Inc. RTOG Foundation, Inc.
SWOG	SWOG Clinical Trials Partnerships, LLC

Expanding Role of the Cooperative Group Foundations

The past ten years have been an exciting time in cancer clinical research, and the current high volume of promising new therapies means that it is not possible for NCI to fund many important studies arising from Cooperative Group scientific committees. Because of this, after the arrival of the NCTN/NCORP the Cooperative Group foundations began to take on a larger role, shifting from supplementing NCI-funded research to becoming full-service Academic Research Organizations (AROs) conducting clinical trials that do not engage the NCI-funded infrastructure (Figure 1). In contrast to Clinical Research Organizations (CROs), who provide clinical trials infrastructure as directed by a study sponsor, these AROs ensure independent scientific oversight and transparency of study operations by employing Cooperative Group-led scientific steering committees, by involving Group statisticians and data managers in study design and analysis, and by requiring inclusion of study data in publicly-accessible data repositories. Leveraging the Groups’ experienced scientific leadership and stable, extensive network of academic and community clinical researchers, the foundations provide an alternative infrastructure for trials that are either not approved by the NCI Steering Committees, or are identified from the beginning as studies better suited to a different operational structure. For example, the Cooperative Groups are currently coordinating health services delivery research funded through the Patient-Centered Outcomes Research Institute (PCORI), a government-sponsored non-profit institute created through the 2010 Patient Protection and Affordable Care act. Multi-institutional trials funded by industry partners are also conducted by the foundations. Depending upon the size and nature of the required accrual network, some trials are managed by a single Cooperative Group, and others that are either very large or involve multiple international sites are achieved by collaboration between two or more Cooperative Group foundations, often also engaging clinical trials consortia outside of the US.

Figure 1.

Cooperative Group Structures. The four US adult Cooperative Groups and one pediatric Group (COG) each provide a forum for research study design, central administration, and clinical care site (member) engagement. The four US adult Cooperative Groups conduct their research either through support from the NCI (NCTN/NCORP), or from other sources (Foundations). In contrast, COG research is conducted through collaboration with the NCI or industry partnerships with its Operations Center, with the COG Foundation managing philanthropic support only.

When the new NCTN/NCORP was first announced, there was great concern that the Cooperative Groups would not retain participation of the volunteer members of their scientific committees. This was because consolidation led to fewer leadership and mentorship opportunities for academic members, and a pull toward better-resourced investigator-initiated industry trials. In the early years of the NCTN/NCORP, significantly fewer trials were approved, also making it more difficult for institutional members to offer trial participation to their patients. Total patient accrual across the system was reduced by about a third, from approximately 30,000 to 20,000 patients per year. These negative effects of the NCTN/NCORP were offset by increased research conducted through the foundations, whose greater flexibility allowed the Cooperative Groups to considerably expand their research portfolios. In creating this alternative funding approach, it was critically important not to harm the work of the NCTN/NCORP. To ensure this, the Cooperative Group scientific committees begin as they always did by identifying and prioritizing the most important research questions and designing the best trials to address them. Now, however, instead of immediately proceeding to NCI Scientific Steering Committee review, study concepts are first evaluated by the Group’s operations team to determine whether the study is best achieved through the NCTN/NCORP mechanism, or best approached through the Cooperative Group foundations. Because the priorities of the NCTN/NCORP and the foundations are complementary rather than competitive, and the Cooperative Groups maintain a priority for the NCTN/NCORP mechanism when this is possible, concerns that foundation research would inhibit the work of the NCTN/NCORP have not been realized.

Looking to the Future

The transition of Cooperative Group research from being almost entirely dependent upon the NCI to one where NCI is a critical but not exclusive partner has been a positive one for all parties. More work remains, as all stakeholders need clinical trials to be simpler, faster, and more inclusive of diverse patient populations. Many good ideas still remain unfunded, and occasional studies do not meet their accrual goals. However, a decade after some predicted the demise of the Cooperative Groups, the collective knowledge and passion of thousands of Cooperative Group researchers remains undiminished. The NCTN/NCORP broadly engages all stakeholders to design, prioritize, and conduct research addressing questions that are meaningful to the diverse US patient population and that fill a need not met by other stakeholders, such as private industry (Table 2). For example, a recent look at 154 currently enrolling NCTN/NCORP trials showed that 90 (58%) were for patients with rare tumors, using the NCI definition of tumors with an incidence of fewer than 6 cases per 100,000 people per year (21, 22). In addition, central management of NCTN/NCORP operations has created a publicly-funded clinical trials vehicle that is efficient and able to respond to emerging scientific knowledge and evolving technologies, allowing successful execution of large precision medicine initiatives. The ability to adapt quickly also became evident when the covid-19 pandemic hit in early 2020. The NCTN/NCORP acted quickly to maximize patient safety while continuing to allow them to be treated on study protocols. Each protocol was scrutinized to determine ways in which treatment and on-study evaluations could be streamlined without sacrificing either safety or data quality, and some beneficial adaptations will likely become permanent. For example, the new approach of allowing oral study medications to be shipped to a patient’s home not only helps to reduce infection risk, it facilitates inclusion of patients from rural locations who must travel greater distances for study-related visits. In addition to serving the public through partnering with the NCI, Cooperative Groups meet the needs of industry partners by providing access to experts in cancer treatment, cancer biology, health outcomes, genomics, imaging, bioinformatics, and many other fields who work together to design, analyze and publish practice-changing research, with an option of working through either the NCI or the Cooperative Group foundations. Within the Cooperative Groups, scientific leaders remain fully engaged because they have additional options to pursue when their ideas are not taken forward by the NCI Scientific Steering Committees, and institutional members have more studies available for their patients and better support for the required infrastructure. Lastly and most important, Cooperative Group research remains an important source of clinical trials for patients across the entire continuum of cancer care.

Table 2:

Cooperative Group Milestones

Year	Event	Ref.
1955	NCI establishes the Clinical Trials Cooperative Group Program and trials begin for adults and children with acute leukemia	11
1958	Acute Leukemia Group publishes first Cooperative Group Trial: Frei, et al. A comparative study of two regimens of combination chemotherapy in acute leukemia. Blood; 1958:13:1126.	12
1958	The Surgical Adjuvant Chemotherapy Breast Project launches a trial studying addition of chemotherapy to radical mastectomy	13
1965	First trials for treatment of Wilms tumor involving surgery, radiotherapy and chemotherapy	14
1968	Radiation Therapy Oncology Group is founded and launches first trial testing addition of methotrexate to radiotherapy and surgery for head and neck cancer	15
1970	Gynecologic Oncology Group founded	16
1980	Southwest Oncology Group launches the first Cooperative Group molecular oncology trial using a human tumor cloning assay to select chemotherapy for patients with treatment-refractory ovarian cancer	17
1981	NCI funding of Cooperative Groups changed from grant to cooperative agreement (IOM p 43)	9
1983	NCI launches the Community Clinical Oncology Program to establish a cancer control effort and increase participation of community oncologists in clinical research	11
1984	NCI policy statement regarding the relationship of NCI, the pharmaceutical industry, and the Cooperative Groups conveys the need for collaboration to pursue joint development of anticancer drugs of mutual interest	11
1985	National Surgical Adjuvant Breast and Bowel Project reports results of Protocol B-06, showing that breast conserving surgery and radiotherapy was equivalent to mastectomy for breast cancer local disease control	18
2000	Children’s Oncology Group formed by a merger of the Children’s Cancer Study Group, Pediatric Oncology Group, Intergroup Rhabdomyosarcoma Study Group and the National Wilms’ Tumor Study Group	19
2002	American College of Radiology Imaging Network launches the National Lung Screening Trial, a study for high risk patients showing that evaluation using low dose helical CT scan resulted in a 15–20% reduction in risk of dying from lung cancer compared to standard chest X-Ray (NEJM 2011)	20
2009	NCI establishes Disease-Specific Scientific Steering Committees charged with prioritizing, refining and collaborating on concepts for Phase III and selected phase II therapeutic clinical trials	9
2010	Release of Institute of Medicine consensus report: “A Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program“	9
2010	NCI announced termination of existing cooperative agreements with the intention of issuing new agreements governing a consolidated program	11
2014	New funding of 4 adult groups and 1 pediatric group in the US as the NCI National Clinical Trials Network (NCTN) and launch of the NCI Community Oncology Research Program (NCORP)	11
2019	NCTN/NCORP Biospecimen Resource holdings include 119 clinical trials, 72,363 patients, and 852,946 biospecimens	23
2019	Renewal of NCTN/NCORP U10 awards	24