Implementing a National Cancer Clinical Trials System for the 21st Century 

IOM meets again to follow up on 2011 goals.

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We have significantly cut the time from study development to trial activation. Between 2006 and 2008, the median time to activation for phase III trials was 830 days. Now, as a result of new targets, our median time to activation is 395 days.

—James M. Doroshow, MD

In March 2011, the National Cancer Policy Forum of the Institute of Medicine (IOM), in conjunction with ASCO, held a workshop to discuss a collaborative approach to making the National Cancer Institute (NCI)-funded clinical trials system more viable and productive.

That workshop included discussions about the roles of NCI and the cooperative groups; how payers are and could be involved; interactions among industry, the Food and Drug Administration (FDA), and the publicly funded clinical trials system; and the roles of investigators and patient advocates. At the end of the 2-day workshop, the IOM established four goals.

1. Improve speed and efficiency of the design, launch, and conduct of clinical trials.

2. Incorporate innovative science and trial design into cancer clinical trials.

3. Improve prioritization, selection, support, and completion of cancer clinical trials.

4. Incentivize the participation of patients and physicians in clinical trials.

Efforts to Meet the Goals

Two years later, in February 2013, IOM and ASCO held a follow-up workshop on the same topic. It fell to James M. Doroshow, MD, NCI Deputy Director for Clinical and Translational Research, to address the goals.

Goal 1—He described the new NCI National Clinical Trials Network (NCTN), which consists of up to four adult groups and one pediatric group, designed to meet the first goal regarding speed and efficiency. Its peer review process focuses on research strategy, collaboration, and operational efficiency. To that end, trials are designed with integral molecular screening and translational science. NCTN contains radiotherapy and imaging services, strategic planning and prioritization, adult and pediatric central institutional review boards, a data management system, and centralized round-the-clock patient registration.

“In addition, we have significantly cut the time from study development to trial activation,” he said. “Between 2006 and 2008, the median time to activation for phase III trials was 830 days. Now, as a result of new targets, our median time to activation is 395 days.”

He added that, to increase speed and efficiency, NCI has agreed with FDA to rapidly review approved phase III trials at the concept stage, has coordinated processes for development and review of trials under FDA Special Protocol Assessment, and works with FDA to coordinate early review of biomarkers.

Goal 2—Regarding the goal of innovative science and trial design, Dr. Doroshow said that NCI is revising some grants to include collection of tissue samples from patients in cooperative group trials and other NCI-supported investigations, and is developing procedures for requesting biospecimens banked from NCI trials. Shared information technology (IT) infrastructure will enhance specimen inventories.

“We also have initiated the Biomarker, Imaging, and Quality of Life Studies Funding Program to ensure that critical correlative studies are incorporated into phase III and large phase II trials.

NCI is working with the Investigational Drug Steering Committee to design phase II trials, create new designs and endpoints, and focus on safety, efficiency, and selected patient populations.

Goal 3—“The Clinical Trials and Translational Research Advisory Committee will evaluate NCI’s clinical trials programs, strategic vision, and the overall effectiveness of studies conducted by NCTN. In addition, we revamped the prioritization process for phase III and large phase II trials,” said Dr. Doroshow.

NCI also is modernizing its IT infrastructure with a clinical management system, enhancing trial participant diversity, working with patient advocates in concept development and accrual planning, and increasing reimbursement for patients, as well as funding for critical biomarker, imaging, and quality-of-life studies.

Goal 4—To motivate participation in trials, Dr. Doroshow said that NCI continues to work with the National Institutes of Health and other federal agencies to define and shape national policy on participation and reimbursement, as well as educate patients and payers about the benefits of trials. It is working with the FDA to incorporate genomic tests and companion diagnostics into trials.

Bringing Clinical Trials to the Community

Worta McCaskill-Stevens, MD, Chief, NCI Community Oncology and Prevention Trials Research Group, noted how sophisticated and complex cancer management is. “We need molecular-based delivery systems to apply all the new advances, and the laboratories best suited to evaluate them are in the community. To complicate things, oncology care is changing in other ways as well—for instance, in the number of practices merging with one another and the increased hospital acquisition of private practices.”

In part because much of the cancer endeavor takes place in the community, the National Community Oncology Research Program (NCORP) was established to develop a single community-based program that integrates the Community Clinical Oncology Program, the Minority-Based Community Clinical Oncology Program, and the Community Cancer Centers Program. “NCORP builds on the strength of all, and expands research opportunities,” said Dr. McCaskill-Stevens.

Clinical trials will continue to be a significant NCORP function, along with additional research priorities and opportunities in health services and behavioral, dissemination, and outcomes research. Dr. McCaskill-Stevens outlined the salient components:

  • Linkage of community-based organizations with a variety of research capacities to NCTN
  • Support of various types of oncology practices, as well as public-private partnerships
  • Integration of cancer care disparities, care delivery research (investigation of how social factors, financing, organizational structures, health technology, and individual behavior affect outcomes), minority accrual, and clinical trials
  • Cancer control, prevention, treatment, and post-treatment surveillance trials, especially in minority and underserved populations
  • Special emphasis on over- and underdiagnosis, post-treatment surveillance, precancerous lesions, and mechanisms of treatment and cancer-related symptoms

Restructuring the Cooperative Groups

One of the major criticisms arising from the 2011 workshop was the unwieldy nature of the Clinical Trials Cooperative Group Program. It comprised 10 groups, involving more than 3,100 institutions, and 14,000 investigators who enrolled more than 25,000 patients in trials each year.

The Cooperative Group Program has been instrumental in establishing standards for patient care and clinical research. Nevertheless, it faced challenges that threatened its productivity: stagnant and declining funding, inefficient processes, extensive and complex government oversight, and lack of resources to pursue cutting-edge research.

The workshop participants focused on three areas in which the program was particularly problematic: logistics and potential consequences of consolidation, opportunities for encouraging collaboration among groups and other institutions, and mechanisms for shifting the role of NCI from oversight to support. It strongly urged consolidation.

Robert L. Comis, MD, Group Co-Chair, ECOG-ACRIN Cancer Research Group, told this year’s workshop, “If we wanted to end up with a successful reconfiguration with strong scientific programs, the groups needed to emerge from the process with an enhanced ability to perform innovative, science-driven clinical trials.” He added that flexibility was key to maximizing the potential of the restructured system. “The federal guidelines for grant review have allowed us to make our own decisions about the formation of our structures, and as I look across the system, I do see the groups preserving and enhancing areas of scientific and functional expertise.” The groups now include:

  • Alliance for Clinical Trials in Oncology, consisting of Cancer and Leukemia Group B (CALGB), North Central Cancer Treatment Group (NCCTG), and American College of Surgeons Oncology Group (ACOSOG)
  • Children’s Oncology Group (COG)
  • ECOG-ACRIN Cancer Research Group, from the merger of the Eastern Cooperative Oncology Group (ECOG) and the American College of Radiology Imaging Network (ACRIN)
  • NRG Oncology, consisting of the National Surgical Adjuvant Breast and Bowel Project (NSABP), Radiation Therapy Oncology Group (RTOG), and Gynecologic Oncology Group (GOG)
  • Southwest Oncology Group (SWOG)

These five have 426 patients in phase I trials, 4,440 in phase II, 14,486 in phase III, and 110 in pilot studies, for a total of 19,462 patients in cooperative group trials.

Notable Successes

Dr. Comis described recent examples of ways in which consolidation and modernization have been successful:

  • Excellent cross-group and cancer center interactions toward the development of proposals for Integrated Translational Science Centers, which will maximize interactions throughout the NCTN. This will provide opportunities to strengthen the interdependence among the groups and the many cancer center and SPORE investigators. As a result, these investigators can contribute their scientific insights to group studies and leverage the data generated from group trials and the associated, well-annotated specimens to generate further discoveries.
  • In non–small cell lung cancer, the Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) will be coordinated by the Alliance and ECOG-ACRIN, targeting patients with early-stage disease who harbor EGFR mutations. ALK and EGFR mutations will be assayed in Clinical Laboratory Improvement Amendments (CLIA)-approved labs prior to patient randomization, with approximately 8,000 patients screened for both mutations so that approximately 800 patients can be randomly assigned to the study arms. Deep-sequencing studies on formalin-fixed paraffin-embedded fixed tumor tissue will be sequenced by the NCI Center for Cancer Genomics—its first major interaction with the NCTN and one of the largest initiatives ever to be performed in lung cancer. Screened patients as well as randomly assigned patients will be followed for their clinical outcome.

Consolidation has been beneficial, said Dr. Comis. It continues to be a work in progress and has led to better understanding of our strengths, weaknesses, and opportunities. “There are still challenges, though. Accrual is decreasing, and infrastructure support is not what we’d like it to be. Money is always a problem, especially now, at a time of financial constriction for everyone involved,” he said. ■

Disclosure: Drs. Doroshow, McCaskill-Stevens, and Comis reported no potential conflicts of interest.