An Overview of NCI’s National Clinical Trials NetworkOn March 1, 2014, after several years of extensive consultation and coordination with many stakeholders, NCI transformed its longstanding Cooperative Group program into the new National Clinical Trials Network (NCTN). Guided by recommendations in a 2010 Institute of Medicine (IOM) report, the design and implementation of the NCTN incorporates feedback from Cooperative Group investigators, NCI Comprehensive Cancer Center directors, several NCI working groups, leading cancer researchers, industry representatives, and patient advocates.
The Need for a More Responsive, Efficient, and Collaborative System
The recommendations and feedback from the IOM and others emphasized the need for a more efficient and streamlined system that could respond more rapidly to scientific opportunities. The IOM report supported earlier NCI initiatives to centralize certain functions common to all trials, such as the regulatory and patient registration tasks performed by the Institute’s Cancer Trials Support Unit and the single ethics review for multicenter trials performed by NCI’s Central Institutional Review Board (CIRB).
The implementation of deadlines for writing and activating clinical trials recommended by the Operational Efficiency Working Group (OEWG)—a working group established by the NCI to provide guidance on streamlining the process of developing trials—was also uniformly applauded as a very positive step. Similarly, the introduction of a single electronic data management tool for all Group trials was felt to be essential in fostering greater collaboration among the different groups. The IOM report recommended additional changes, as well. The Cooperative Group Operations and Statistical Centers (referred to in the report as “front and back office operations”) were felt to be overly redundant in their activities, so consolidation into fewer centers was strongly suggested. Hence, NCI undertook a reorganization of the Cooperative Groups.
The program that emerged from this restructuring, the NCTN, has a different focus than its predecessor. Competition between the individual groups has been replaced by teamwork among investigators, efficiency is viewed as critical to success at all organizational levels, and collaboration among the groups is now specifically rewarded at the time of grant review. Although these changes are viewed as vital for the health of the public system, they also come at an opportune moment, with exciting changes in oncologic science that are offering new avenues for rapid advances, particularly the development of new systemic treatments.
Changing Science Requires Changes to the Clinical Trials Structure
Recent advances in deciphering the cancer genome have enabled the development of targeted therapies that have fundamentally changed our approach to cancer treatment. Drugs like imatinib (Gleevec®), erlotinib (Tarceva®), crizotinib (Xalkori®), and vemurafenib (Zelboraf®), to name but a few, inhibit molecular pathways that are critical to tumor growth and survival. The discovery of “genetic drivers” has led to a new molecular classification of tumors, distinct from the traditional histologic classification.
To effectively treat cancer with targeted therapies, the molecular signature of an individual’s tumor must first be diagnosed with sophisticated genetic techniques; only then can an appropriate therapy be selected. Future cancer clinical trials will, therefore, require the screening of large numbers of patients with the same or even different histologic tumor types to identify those patients whose tumors contain the distinct molecular targets of the therapies being tested.
Conducting this new generation of clinical trials requires sophisticated new technologies and work processes, including tissue collection (fresh biopsy samples are often necessary), advanced DNA and RNA sequencing methods with rapid turnaround times, and complex analytic algorithms to distinguish normal genetic variants from tumor-specific changes. These, in turn, entail new expenses for surgery, interventional radiology, molecular pathology, and bioinformatics that have not typically been a part of clinical trials.
Although the screening tests may need to be performed on very large numbers of patients to find those whose tumors exhibit the appropriate molecular profile, the numbers of patients required for interventional studies are likely to be smaller than what was required in previous trials. That is because the patient selection is based on having the target for the new therapy, leading to larger differences in clinical benefit (such as how long patients live overall or live without tumor progression) between the intervention and control groups.
NCI’s NCTN has been developed with these new scientific challenges in mind and is organized to take maximal advantage of the opportunities afforded by the improved understanding of tumor biology as well as the improved efficiencies created by the centralization and streamlining of many critical functions, such as tumor banks, ethics approvals, and imaging support.
The following overview provides important information about the structure of the new NCTN, a summary of the changes taking place as a result of the launch of NCTN, and a synopsis of how these changes build on the success of the Cooperative Group program and how they will further facilitate important cancer clinical trials.
The NCTN Structure
The sweeping nature of the changes to the NCI clinical trials program requires NCI to award multiple new grants in order to establish the new infrastructure.
NCI’s prior clinical trials system, the Cooperative Group Program, produced many important improvements over more than 50 years. Extensive reviews by expert committees concluded, however, that to more effectively and efficiently complete trials and take advantage of the rapid changes in technology and vastly improved understanding of the underlying biology of cancer, the system had to be restructured.
The nine former adult Cooperative Groups have consolidated into four adult groups in the NCTN. In addition, as was the case under the previous clinical trials system, another large group is focused solely on childhood cancers. The structure also includes a Canadian Collaborating Clinical Trials Network award.
The U.S. groups are each funded through two separate awards—one to support Network Operations and another to support the Statistics and Data Management Centers. The Operations Centers are responsible for developing new protocols and managing the regulatory, financial, membership and scientific committees of each group. The Statistical Centers are responsible for data management and analysis, manuscript preparation, and safety monitoring, in addition to assisting in trial design and development. The Network Operations and Statistical Centers for each NCTN group are geographically separate but work closely together. They are often located at an academic institution that has offered to “house” the group; however, in several cases, a Center is located at a freestanding site that is funded via a nonprofit foundation.
The only exception to the above is the Canadian Collaborating Clinical Trials Network, which received a single award for its Operations and Statistical Center.
Lead Academic Participating Sites
Thirty U.S. academic institutions are being selected to receive a Lead Academic Participating Site (LAPS) grant, which is a source of funding that was created especially for the NCTN. Eligible sites are academic research institutions with fellowship training programs, and most of the awardees are NCI-designated Cancer Centers. To receive these awards, sites had to demonstrate their ability to enroll high numbers of patients onto NCTN trials, as well as scientific leadership in the design and conduct of clinical trials.
Higher levels of patient enrollment require a sustained level of data management work over several years, and the LAPS grants support the research staff required to manage this effort. The funds provided in the LAPS grants to cover this increased workload effectively raise the per-patient reimbursement level at the selected sites. Raising the reimbursement for these high-accruing sites was one of the strongest recommendations from the IOM, NCI advisory boards, and other stakeholders.
In the previous Cooperative Group system, a U10 award (cooperative agreement grant) was provided to sites that enrolled large numbers of patients, but these sites could only affiliate with a single group. The new LAPS awards are different in that any site with such an award can affiliate with multiple adult NCTN groups and participate in any trial proposed by an NCTN adult group. The LAPS awards also provide some funding for scientific and administrative leadership at the site itself, as the principal investigators at the site will need to prioritize the clinical trials in which they will participate, as well as educate and train staff at the sites in clinical research and develop strategies to promote patient enrollment.
Community Hospitals and Medical Centers
Many other investigators at community hospitals and medical centers will be able to participate in NCTN trials, even if they are at sites that did not receive a LAPS award. These sites, as well as a number of international sites, will either receive research reimbursement directly from one of the network groups with which they are affiliated or they will receive awards from the newly developed National Community Oncology Research Program (NCORP). NCORP is a new program that has resulted from the consolidation of the Community Clinical Oncology Program (CCOP), the Minority-Based Community Oncology Program (MBCCOP), and NCI Community Cancer Centers Program (NCCCP).
Imaging and Radiation Oncology Core Group
To help monitor and ensure quality in trials that involve new imaging modalities and/or radiation therapy, NCTN has established a consolidated Imaging and Radiation Oncology Core (IROC) Group that will assist all of the NCTN groups that use these modalities in their trials. Previously, these tasks were carried out by five separate organizations—the Radiological Physics Center, Quality Assurance Review Center, Advanced Technology Consortium for Clinical Trials Quality Assurance, Radiation Therapy Oncology Group, and the American College of Radiology Imaging Network. The consolidation of these activities under the leadership of a centralized core team is anticipated to improve efficiency and optimize the use of this resource by the entire network.
Integrated Translational Science Awards
The final component of the NCTN, the Integrated Translational Science Awards (ITSAs), did not exist in the former Cooperative Group program. The seven academic institutions that received ITSAs include teams of translational scientists who will use innovative genetic, proteomic, and imaging technologies to help identify and qualify potential predictive biomarkers of response to therapy that the network groups can incorporate into future clinical trials.
These awards will be used to leverage work already ongoing in these investigators’ laboratories, often supported in part by other NCI grants, with the expectation that these researchers will help the network groups bring new laboratory discoveries into clinical trials. These labs all employ cutting-edge technologies that will enable better characterization of tumors and help to identify changes in tumor biology in response to treatment that may help explain how treatment resistance can develop.
For a list of current NCTN awards, see the NIH RePORTER Search Results.
Scientific Oversight Committees
The NCTN groups propose concepts for new clinical trials to the NCI Disease/Imaging Steering Committees. These committees are organized by NCI to evaluate and prioritize new clinical trials. Each committee is led by non-governmental co-chairs who are not permitted to hold leadership positions in the NCTN groups, although they can be group members. The remainder of the committee membership consists of NCTN group members selected by each group, other disease experts not involved in leadership positions in the groups, representatives of NCI-funded SPORE and Consortia, biostatisticians, patient advocates, and NCI disease experts. These committees evaluate concepts and recommend to NCI those most likely to have the highest scientific and clinical impact.
The oversight of the entire NCTN—its organizational structure, funding, and long-term strategic direction—is under the purview of the Clinical Trials and Translational Research Advisory Committee. This federal advisory committee is composed of clinical trials experts, industry representatives, and patient advocates from across the nation and provides recommendations to the NCI Director.
The NCTN Budget
The overall NCTN budget for these awards is $151 million. This amount is the same as the total budget provided to the Cooperative Groups for awards in each of fiscal years 2012 and 2013, despite the substantial reductions in the NCI budget that resulted from sequestration starting in 2013. What has changed, however, is the distribution of funds to the various components of the NCTN, as compared with the components of the former Cooperative Group program.
The distribution of funds to the Network Group Operations Center grants changed from 62 percent in fiscal years 2012 and 2013 to 47 percent in fiscal year 2014 due to the consolidation of the infrastructures of the Operations and Statistical centers; funding of new components in the NCTN, including the LAPS and ITSAs; and expansion of the IROC for the entire network.
The new system provides for an annual enrollment of about 17,000 patients on interventional trials, a 15 percent reduction compared with about 21,000 enrolled patients in recent years. This reduction is anticipated to occur gradually, over 2 to 3 years. To this end, NCI has reserved funds to distribute to the NCTN groups later in the current fiscal year (FY2014) to accommodate an enrollment of about 21,000 patients.
NCI believes that reducing the budget of the Network Group Operations Centers will not impede the NCTN’s ability to perform important trials. For example, as discussed above, future clinical trials will, in many cases, require fewer numbers of patients due to the selection of patients most likely to benefit from the intervention being tested.
Although screening patients for tumors with specific molecular characteristics may require large numbers of patients, the screening components of studies are less costly than the actual interventional study. Hence, clinical trials in the future are likely to involve screening components, which will be reimbursed at a lower rate, with smaller interventional components that will be reimbursed at higher rates. More precision in patient selection will permit study designs that can aim for larger therapeutic effects and thereby further decrease the size of trials.
These changes will, however, require the NCTN groups to function differently compared with how they functioned in the previous system. For example, NCTN groups should be able to reduce the costs of conducting trials by sharing resources. If a particular group has many active trials, it may have to decrease the number of new trials it is planning. Groups with fewer active trials can take up those new trials instead. This collaborative approach should allow members of one NCTN group to support trials led by other groups and should afford NCTN members an ability to conduct a full portfolio of trials in the most common cancers.
Because the NCTN has only four U.S. adult groups, with fewer Operations and Statistical Centers that require financial support, some savings are anticipated. This consolidation was planned for over the past several years, and NCI provided $24 million in funding supplements to the newly consolidated groups to help them absorb the costs of their ongoing trials as well as to fund the integration of their separate infrastructures.
NCI also provided more than $40 million in other funding supplements to transition all the groups to a common data management system (Medidata Rave®), develop an integrated IT system for the tumor banks, and implement specific precision medicine clinical trials.
For the past several years, NCI has provided significant additional annual support for the Cooperative Groups and will continue to provide these funds for the NCTN, in addition to the grant funding described above. Clinical trials are complex undertakings that require a host of support organizations and funding streams. The new system includes a number of other features that are not included in the NCTN awards but that are essential to carrying out the NCTN mission.
The additional support includes:
- Central Institutional Review Boards, an important component of NCI’s clinical trials system that has added speed, efficiency, and uniformity to ethics review
- The Cancer Trials Support Unit (CTSU), an NCI-funded contract that provides clinical investigators and their staff with one-stop online access to NCTN trials and allows investigators to register new patients
- A dedicated tumor bank for each Network group funded through a separate NCI award mechanism
- The Biomarker, Imaging, and Quality of Life Studies Funding Program (BIQSFP), a separate funding stream for NCTN trials that supports correlative science studies on group trials. NCTN groups compete for funds that are specifically reserved annually for this purpose. The availability of dedicated funds greatly facilitates coordination as clinical trials must meet stringent deadlines.
- In addition, approximately one-quarter of patient accrual on NCTN treatment trials is paid for by the CCOP/MB-CCOP program. The community hospitals and medical centers participating in the CCOP/MB-CCOP program are reimbursed for accruing patients to NCTN treatment trials by their CCOP/MB-CCOP awards, not via the NCTN Group Operations award. The NCCCP program does not pay for patient accrual but rather sites are reimbursed for accruing patients to NCTN trials from their academic centers, academic affiliates, or existing CCOPs/MB-CCOPs. The CCOP and NCCCP community-based networks are soon to be funded as NCORP, as described above in the section on Community Hospitals and Medical Centers.
Finally, in addition to these substantial annual expenditures, NCI also subsidizes the NCTN by paying for many other essential clinical trial functions, thereby further reducing costs borne by the Network groups:
- NCI will pay for the licenses and hosting fees of the electronic, common data management system, called Medidata Rave®, used by all of the NCTN groups.
- NCI will oversee a national audit system for NCTN trials.
- NCI will manage Investigational New Drug applications to the Food and Drug Administration along with the distribution of these drugs for many NCTN trials.
It is estimated that support for these activities costs NCI approximately $15 million annually.
An Exciting Future
With its state-of-the-art clinical trials infrastructure, the NCTN is poised to implement and complete trials far more rapidly than in the past. For physicians and their patients, a menu of important trials will be widely available throughout the country, in large cities and small communities alike. NCTN offers access to the best approaches available for many common and, increasingly, even rare cancers.
NCI’s new approach has appeal for industry partners. The NCTN and a large number of biotech and pharmaceutical companies are already collaborating on a series of precision medicine trials for some types of lung cancer and other tumor types. These trials will harness next-generation DNA and RNA sequencing methods to inform treatment choices and are greatly facilitated by the NCTN’s organizational structure, which is ideal for screening large numbers of patients to find those whose tumors exhibit the molecular features that give them the best chance of responding to new, targeted treatments.
Change of this magnitude always presents challenges. NCI is working with the NCTN groups and the advocacy community to make this transition as smooth as possible. The reward will be a clinical trials system that will allow us to test promising treatments more rapidly and efficiently, ushering in an era when patients have access to treatments that are most effective for their particular cancer.
NCTN's Precision Medicine Trials
As more cancers are molecularly defined and classified into smaller subsets, NCTN will support precision medicine trials that test targeted treatments for such cancers. NCTN’s precision medicine trials include:
SWOG S1400: Phase II/III Biomarker-Driven Master Protocol for Second Line Therapy of Squamous Cell Lung Cancer (Lung-MAP) - This study aims to find out what effects targeted therapy has on squamous cell lung cancer. It is a large scale, phase II/III screening/clinical registration protocol that will genomically screen patients with advanced stage lung squamous cell cancer moving to second-line therapy, and will use the screening results to direct each patient to the most appropriate one of five (or more) sub-studies. Patients on each sub-study will be randomized to either standard of care (docetaxel or erlotinib) or biomarker-driven targeted therapy with an investigational agent.
Lung-MAP: Master Protocol for Squamous Cell Lung Cancer
ALCHEMIST: Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials - The ALCHEMIST trials are three integrated precision medicine trials that are designed to identify people with early-stage lung cancer who have tumors that harbor EGFR and ALK gene alterations and evaluate whether drug treatments targeted against those molecular changes can lead to improved survival compared with current standard of care therapy alone (i.e., chemotherapy with or without radiotherapy after complete surgical resection, as prescribed by a participant’s treating physician).
The ALCHEMIST Lung Cancer Trials