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The Evolution of the National Cancer Institute’s National Clinical Trials Network

November 23, 2021

November 2021

Just over 10 years ago, the National Cancer Institute (NCI) shook up the hematology/oncology clinical trial landscape by reorganizing its various cooperative research groups to form a new entity called the National Clinical Trials Network (NCTN).

The NCTN brings together academic centers, clinicians, and community hospitals and medical centers to coordinate and support cancer clinical trials at more than 2,200 sites in the U.S., Canada, and select locations around the globe.1

The reorganization effort sought to streamline the research infrastructure and foster greater efficiency and coordination. Part of that effort meant downsizing the more than 50-year-old NCI Clinical Trials Cooperative Group Program from nine groups conducting trials in adult patients to just four adult groups, plus one pediatric research group, and the Canadian Cancer Trials Group.2 The reorganization merged existing groups to create four new entities: the Alliance for Clinical Trials in Oncology, the ECOG-ACRIN Cancer Research Group, NRG Oncology, and the SWOG Cancer Research Network. The Children’s Oncology Group, a key part of the NCTN, had been consolidated previously.

Now, a decade later, leaders in the NCTN say they have accomplished many of their goals and have the practice-changing cancer research to show for it, such as the TAILORx trial that showed that some women with breast cancer could safely skip chemotherapy. However, other stakeholders and researchers say it is time for another critical look at the NCTN’s structure to ensure it continues to achieve its goals of facilitating innovative research and reining in bureaucracy.

IOM Report Lays a Foundation for NCTN

While the NCI Clinical Trials Cooperative Group Program had notched many significant successes in its more than 50-year history, by 2010 the average time needed to design and launch a trial was two years. Many trials were launched but never completed. The program was also suffering from dwindling federal funding. As a result, the NCI director asked the Institute of Medicine (IOM) to evaluate the program and recommend improvements.3 That report, titled “A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program,” launched a complete restructuring, according to Richard F. Little, MD, head of Hematologic, HIV, and Stem Cell Therapeutics at the NCI’s Cancer Therapy Evaluation Program.

“The IOM report recommended the prior adult NCI Cooperative Groups be consolidated into a network structure with a smaller number of groups,” Dr. Little told ASH Clinical News. “The goal was to better leverage the centralized infrastructure to take advantage of scientific opportunities with rapidly evolving science.”

In the April 2010 report, IOM praised the decades of work done by the Clinical Trials Cooperative Group Program in advancing knowledge of cancer prevention and reducing use of toxic therapies, with the qualification that the structure meant it could not keep pace with new advances related to the genetic and molecular drivers of cancer.

“One major problem is the complex system of designing, reviewing, and initiating Cooperative Group clinical trials, which has become a lengthy and redundant process typically requiring years to complete,” the committee wrote in the report. “In attempting to optimize the effectiveness and safety of trials, proposals often are redrafted and recycled by multiple stakeholders from academic institutions, federal agencies, institutional review boards, and industry. This results in frustration and a perception that stakeholders are working at cross-purposes.”

The 300-page report included 12 recommendations for “reinvigorating” the NCI’s research program, such as consolidating many of the functions of the Cooperative Group scientific committees and statistical offices, as well as the administrative structures focused on data collection and management. The committee also called for streamlining and harmonizing government oversight and reevaluating the role of the NCI in the clinical trials system. Additional recommendations were aimed at increasing the speed of clinical trials, funding for the research programs, and collaboration among all participants in the research infrastructure.

Cancer Clinical Trials: Then and Now

Just a few months after the IOM committee issued its report, the NCI announced the consolidation of its research groups and the centralization of many of its administrative functions.

The move’s purpose was twofold, according to a 2020 review from the leaders of the individual NCTN research groups. By consolidating the groups, the NCI could achieve the efficiencies and reforms recommended in the IOM report. It could also save money at a time when the U.S. was enduring a period of economic recession.4

Under the reorganization:

  • The American College of Surgeons Clinical Oncology Group, the Cancer and Leukemia Group B (CALGB), and the North Central Cancer Treatment Group merged into a single new group that became the Alliance for Clinical Trials in Oncology.
  • The Eastern Cooperative Oncology Group (ECOG) merged with the American College of Radiology Imaging Network (ACRIN) to form the ECOG-ACRIN Cancer Research Group.
  • The National Surgical Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group, and the Gynecologic Oncology Group were folded into the NRG Oncology group.
  • The Southwest Oncology Group (SWOG) was the only cooperative group that stayed intact, but it was eventually renamed the SWOG Cancer Research Network.
  • The Children’s Oncology Group was the result of the merger of four cooperative pediatric research groups in 2000.


The NCTN’s structure also includes the Canadian Cancer Trials Group, which works with the U.S. groups on late-phase, multi-site clinical trials.

“The network structure enables studies to be conducted across all ages and diseases. The structure particularly enables precision medicine and umbrella-type trials, a key point in the 2010 IOM report,” Dr. Little said.

The NCTN has a spoke-and-wheel structure with several NCTN centralized functions at the center, surrounded by the five U.S. research groups, each of which maintains its own operations, statistics and data management, tissue banks, and member sites. The 32 lead academic sites that are part of the NCTN participate across the four adult research groups in the U.S. (See the FIGURE for an illustration of this structure.)

As part of the reorganization, the NCI centralized several administrative functions that the IOM report identified as redundant when housed in the individual research groups. The NCTN’s centralized functions include a single Institutional Review Board, Cancer Trials Support Unit, Imaging and Radiation Oncology Core Group, and a common data management system.

Each of the research groups maintains its own tissue bank but follows NCTN’s standard protocol for tissue collection. Each group must maintain electronic records for the tissue samples that provide

information on the treatment the patient received, his or her response, and outcome. If patients consent, their tissue samples may be used in other NCTN studies beyond the trial in which they originally enrolled.1

Data management was also upgraded during the reorganization, with all groups adopting a common electronic format. The NCI implemented study development timelines, and studies that did not meet deadlines were not activated.4

The various groups coordinate and share resources in other ways, too, according to Dr. Little. For example, in research groups’ investigational new drug studies that are sponsored by the NCI’s Cancer Therapy Evaluation Program, the NCI Division of Cancer Treatment and Diagnosis handles drug distribution and regulatory issues. In addition, national disease-specific steering committees ensure the clinical trials are prioritized in a coordinated way among the groups. The Cancer Trials Support Unit facilitates centralized 24/7 enrollment of patients and enables sites to participate in any active NCTN study regardless of group affiliation.

The research groups also coordinate the co-development of individual trials and setting research priorities in specific diseases, according to Peter J. O’Dwyer, MD, and Mitchell D. Schnall, MD, PhD, co-chairs of the ECOG-ACRIN Cancer Research Group.

Taking acute myeloid leukemia research as an example, “the three groups with leukemia committees have agreed to focus on evaluating the therapies in distinct molecular subsets of the disease,” Drs. O’Dwyer and Schnall explained. “Shared access to biospecimens and imaging technologies helps advance our understanding of response and resistance and ultimately drives toward a precision medicine approach to every patient.”

Outside of the NCTN structure, each of the five U.S. research groups has an associated research foundation that assists with running clinical trials that the groups consider “promising” but are not part of an NCI-funded research program. These trials cover a diverse range of topics, from industry-funded trials of new therapeutics to research into health services delivery funded through the Patient-Centered Outcomes Research Institute. Regardless of the study sponsor, the foundations provide independent oversight through their scientific steering committees.4

Measuring Success and Looking to the Future

Over the years, the NCTN has amassed a long list of success stories. That success has been measured through the evaluation of its clinical portfolio’s impact on practice, reductions in time from study proposal to activation and completion, and increases in patient accrual to studies across the entire network, according to Dr. Little. Progress has also been demonstrated through greater resource allocation for biomarker, imaging, and quality of life studies.

At the 2021 European Society for Medical Oncology (ESMO) Congress in September, SWOG leaders shared findings from an analysis looking at how NCTN’s publicly-funded cancer research has affected the landscape of cancer care.5 They reviewed all randomized phase III trials from the four U.S. adult NCTN groups reported from 1980 to 2019 and identified studies that had statistically significant findings for at least one clinical, time-dependent outcome. Of the 163 trials selected, 128 showed a positive overall survival finding favoring the experimental arm. Researchers estimated that, overall, these trials generated gains of 14 million life-years for patients with cancer. Research into how these trials influenced cost and clinical care guidelines is still ongoing, they added.

In addition, since the reorganization of the cooperative groups, the NCTN research groups have launched several studies that seek to establish new standards of care, set the stage for approval of new therapies by the U.S. Food and Drug Administration, evaluate new treatment approaches, and validate biomarkers. For instance, the NCI-MATCH and NCI-COG Pediatric MATCH trials are large-scale precision medicine studies in which cancer patients are assigned to treatment based on genomic sequencing and other molecular testing of their tumors. These trials are among the first to match patients with cancer to specific treatments based on their genetic tumor changes rather than their cancer type – demonstrating the potential benefits of using genomic sequencing to guide treatment. These two trials have also set the stage for the next round of precision medicine trials, such as Combo-MATCH to address combination regimens, iMATCH to evaluate immunotherapy regimens, and MyeloMATCH for leukemia trials.4,6,7

Drs. O’Dwyer and Schnall also noted that the NCTN’s success could be measured by the number of trials it has launched that would not have been mounted by industry. “Being free of industry’s strict focus on the market and shareholder value allows us to concentrate on patient benefit,” they said. “The most common examples are studies in indications not on a company’s development path. However, the groups are also well known for piloting combination regimens not previously considered and accelerating the development of therapies into the adjuvant space.”

Despite the progress under the current structure, there is support for reevaluating the NCTN in light of new challenges in cancer research, according to Monica M. Bertagnolli, MD, of Brigham and Women’s Hospital. Dr. Bertagnolli currently chairs the Alliance for Clinical Trials in Oncology.

“Unfortunately, clinical trials are more complex than ever, and this means that the operational infrastructure, including study review and approval processes, are as challenging or maybe even more challenging now than they were at the time of the IOM report,” she said. “I think that it would be an excellent idea to take another in-depth look at the structure and functions of the NCTN.”

Drs. O’Dwyer and Schnall echoed her concerns about the ongoing challenges in conducting cancer research today, including rising costs, the reluctance of companies to provide their new agents for trials off their registration path, and a burdensome regulatory environment. They noted that the NCTN group chairs have initiated a dialogue with the NCI about measuring progress over the last 10 years and assessing areas for improvement.

Richard Schilsky, MD, who chaired the Cancer and Leukemia Group B before the reorganization and served on the IOM committee that authored the 2010 report, said the NTCN could have a greater impact on cancer advances if it eliminated some of the bureaucracy embedded in the system.

For instance, one of the 12 IOM recommendations that has not been implemented called on NCI staff to convene, but not participate in, the scientific review of trials conducted by the group steering committees. Today, NCI staff continue to be involved in those discussions, resulting in a less independent scientific review process, he said. Another IOM recommendation proposed that the FDA lead the scientific review of study protocols that involve an investigational new drug.8 In practice, both the NCI and FDA are involved in the protocol review, which can create an iterative and circuitous process, Dr. Schilsky noted. Those two changes could go a long way to “improving the quality of peer review and reducing the bureaucracy,” he said.

Dr. Schilsky also called on NCTN to reexamine its goals going forward. For example, today’s hematology/oncology practitioners have multiple therapeutic options available to them, but have no clear guidance on how to select the best treatment for an individual patient. That type of comparative-effectiveness research would deliver value to patients, he said.

“There is no other country on earth that has a publicly-funded clinical trial system like the United States has for cancer,” Dr. Schilsky said. “Even within the U.S., most of the non-cancer medical specialties envy what we have available. So, we better be sure we’re making the best use of it. I think the time has come to take another look at how those resources are being best spent.” —By Mary Ellen Schneider


  1. National Cancer Institute. NCTN: NCI’s National Clinical Trials Network. Accessed October 13, 2021.
  2. National Cancer Institute. NCI announces plans to reinvigorate clinical trials. December 23, 2010. Accessed October 13, 2021.
  3. Institute of Medicine (US) Committee on Cancer Clinical Trials and the NCI Cooperative Group Program. A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program. Washington, DC: The National Academies Press.
  4. Bertagnolli MM, Blanke CD, Curran WJ, et al. What happened to the US cancer cooperative groups? A status update ten years after the Institute of Medicine report. Cancer. 2020;126(23):5022-5029.
  5. Unger JM, LeBlanc M, Bertagnolli M, et al. Clinical and scientific impact of National Cancer Institute: Sponsored clinical trial network group treatment trials. Ann Oncol. 2021;32(suppl_5):S1102-S1110.
  6. National Cancer Institute. NCI-MATCH Trial (Molecular Analysis for Therapy Choice). Accessed October 13, 2021.
  7. National Cancer Institute. NCI-COG Pediatric MATCH. Accessed October 13, 2021.
  8. Schilsky RL. The National Clinical Trials Network and the cooperative groups: The road not taken. Cancer. 2020;126(23):5008-501

FIGURE. NCI National Clinical Trials Network Structure.


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