Structures Supporting Cancer Clinical Trials

Summary of Key Points

Cancer clinical trials provide the evidence on which sound oncology practice is based.
Providing greater efficiency in implementing clinical trials and achieving enrollment rapidly have been major goals of the National Cancer Institute (NCI), cancer centers, the biopharmaceutical industry, and patient advocacy groups.
Oncology specialists in private practice have many opportunities to participate in clinical trials sponsored by the NCI, private foundations, and/or the biopharmaceutical industry.
Physicians and patients have online access to all US-sponsored clinical trials at ClinicalTrials.gov and have access to additional information about cancer trials at cancer.gov .
Successful execution of clinical trials includes the following clinical components:
- The attitude and commitment of the physician leader (medical, surgical, radiation oncologist)
- Sufficient preparation and infrastructure
- Trained staff, including at least some of the following: clinical research nurse, clinical research associate, pharmacist, pathologist, radiologist
- Affiliation with an institution or network that provides scientific and administrative support, such as the following: NCI-supported network group, cancer center network, biopharmaceutical industry network, research institution
- Access to an authorized institutional review board
- Access to adequate laboratory facilities to process protocol-required specimens
- Adherence to good clinical practices
- Accurate and timely data reporting
- Proper maintenance of primary source documentation
- Adequate preparation for trial monitoring and on-site audits
- Adequate financial support
Many organizations now provide access to clinical trials and/or provide the necessary training and certification; relevant Web sites are included in this chapter.

Modern oncology practice is founded on results from thousands of clinical trials conducted during the past four decades. Thousands more clinical trials are ongoing at any given time and provide the evidence base for the rapidly changing therapeutic practices of this specialty. Motivations for the decision by an oncologist to participate actively in this extensive system of medical and scientific inquiry range from the ability to offer patients state-of-the-art treatments, which are available through well-designed clinical trials, to the personal satisfaction and educational benefits that can be achieved from participation in this process. The commitment of time and resources necessary to participate effectively in clinical research, and sometimes unfamiliarity with clinical research requirements and procedures, prevent many oncologists from taking part. It has been estimated that only 3% to 5% of adults with cancer in the United States are treated while taking part in clinical trials, with even lower rates of participation in many other countries. In stark contrast, approximately two-thirds of children with cancer are enrolled in clinical trials. Although this discrepancy exists for multiple reasons, a major factor relates to the relative rarity of cancer in children (approximately 10,500 cases per year in children younger than 15 years), resulting in substantial centralization of pediatric care at major academic research centers, a culture in which participation in trials is supported and fostered. Care for adults with cancer in the United States is more decentralized, with many adult oncologists working in private practices that are not tied to academic institutions. For these practitioners, inadequate understanding of the clinical trial process plus pressures on time and reimbursement have made participation very challenging. Fortunately, because of intense publicity and educational programs by both patient advocacy groups and clinical trial organizations and widespread access to clinical trial information on the Internet, a growing number of patients now expect that clinical trials will be included in the discussion of options for the treatment of their cancers. The purpose of this chapter is to describe some of the requirements, resources, and structures that are available to enable practicing oncologists to participate in clinical trials and to discuss the responsibilities that come with such participation. Numerous opportunities now exist for practicing physicians and their patients to participate in cancer clinical trials, including treatment, prevention, and cancer control trials, supported by the National Cancer Institute (NCI), cancer treatment institutions, or the biopharmaceutical industry.

National Cancer Institute–Sponsored Clinical Trial Activities

The NCI supports the development of more than 100 agents for cancer treatment and prevention (often in collaboration with pharmaceutical and biotechnology companies) and has an extensive clinical trial system that encompasses treatment, prevention, and cancer control studies. More than 800 trials are active at any given time, and several hundred new trials open each year. In the treatment area, the NCI has programs for early therapeutic development (primarily phase I and II trials), including many sites with grants to complete these early trials.

For several decades the NCI also supported a large program of clinical trial cooperative groups to provide a standing mechanism for performing late-phase, definitive, clinical treatment trials. Although these cooperative group trials provided a significant proportion of the evidence on which oncology practice is based, public advocacy for more rapid progress, increasing fiscal pressures on medical practice, and the accelerated pace of drug discovery, especially in the new era of precision medicine, caused the NCI to review and restructure aspects of its late-phase clinical trial program. Surveys of patients and physicians found that the obstacles to accrual in oncology trials were multifactorial ( Table 19.1 ). With these barriers in mind, the NCI undertook a series of comprehensive analyses of how it conducts and funds clinical trials by involving a wide range of stakeholders that included leaders of the Cooperative Group and Cancer Center Programs, patient advocates, representatives from the US Food and Drug Administration (FDA) and the pharmaceutical industry, and government staff, including the analysis described in the 2010 Institute of Medicine (IOM) report.

Table 19.1

Barriers to Clinical Trial Participation

Physician Related	Patient Related
Inadequate funding for data management personnel	The patient's doctor never discussed or offered the option of participating in a trial
Burdensome regulatory requirements	Unaware of trials as an option Concerns about insurance coverage
Institutional review board	Fear of receiving placebo
Informed consent	Many patients have comorbidities
Conflict of interest
Overly strict eligibility criteria Inadequate reimbursement
Lack of time
Resistance by third-party payers

Based on these reviews and analyses, the NCI transformed its long-standing Cooperative Group Clinical Trials program in 2014 into a more highly integrated network. By rebranding the infrastructure as the National Clinical Trials Network (NCTN), reducing the number of groups, and changing the review criteria for funding to emphasize collaboration and coordination, the NCI has refocused its research effort. Competition among the remaining groups has been reduced and replaced with more efficient and rapid development of a menu of Network trials in which all group members are encouraged to participate in order to facilitate speedy enrollment.

The development of targeted therapies directed against specific molecular alterations identified in various cancers and the emergence of successful immunotherapeutic approaches have fundamentally changed the approach to cancer treatment and have introduced new challenges to conducting clinical trials. Identification of patient populations that can potentially benefit from these new therapies often requires clinical trials that screen large numbers of patients for specific molecular alterations. With its state-of-the-art clinical trial infrastructure, the NCTN is well positioned to implement and complete trials far more rapidly than in the past. The NCTN has streamlined administrative and regulatory processes related to the conduct of its clinical trials, including patient enrollment, data management, ethics review, and tumor banking processes, and has provided a common menu of trials for all academic and community member sites in the NCTN program.

Critical to the achievement of a tightly integrated trials network are the Cancer Trials Support Unit (CTSU) and the Central Institutional Review Board (CIRB). The CTSU provides an online menu of all trials conducted by the various NCTN groups. The CIRB provides a single, expert ethics review of all NCTN trials, avoiding repetitive costly reviews at individual sites. Although originally conceived to support only the late-phase trials, the CTSU and CIRB have been expanded to now foster efficiency and networking for all of NCI's network early- and late-phase trials, as described subsequently.

Cancer Trials Support Unit

The NCI CTSU is designed to facilitate one-stop online access to a broad menu of clinical trials and selected international collaborative trials by a national network of investigators who are members of NCI-supported clinical trial programs. Network investigators can access the CTSU menu of treatment trials from a public website ( www.ctsu.org ). The scientific leadership for each study remains within the organization that developed the trial, but patient enrollment can come from any network physician across the country, and all patient enrollment is handled through CTSU's central registration system, the Oncology Patient Enrollment Network (OPEN). By providing more physicians and their patients with the opportunity to choose from a broader menu of trials, the CTSU promotes faster accrual to individual trials, allows increased access and additional treatment options to more patients nationwide, and renders trials involving uncommon cancers more feasible. Although the clinical trials menu and centralized patient enrollment are the most visible aspects of the CTSU, another major function of the CTSU is its centralized regulatory database. For all physicians in the network, the CTSU maintains important demographic information about their sites or practices, including clinical trial program affiliation and academic and practice affiliation(s), Office for Human Research Protections assurance numbers for their sites, institutional review board (IRB) approvals for specific protocols, and conflict of interest forms for investigators. This process enables physicians, nurses, and clinical research associates to register once annually instead of having to register for each clinical trial program or trial in which they participate. Centralizing regulatory data has reduced the workload for investigators in the field, consolidated duplicative work, and allowed clinical trial program staff to partially offload this activity to the CTSU and focus instead on protocol development and analysis.

Central Institutional Review Board

In NCI-sponsored multicenter trials, the identical protocol is carried out at many sites, often including as many as 100 different practices; each site requires its own local institutional review board (LIRB) to conduct an initial full-board review and subsequent annual reviews, adverse event reviews, and amendment reviews. These multiple IRB reviews create a largely redundant, time-consuming workload at these sites, compounding the ever-mounting pressures on the nation's IRB system, which have been well documented. To provide an idea of the scope of the duplicative effort, consider that NCI currently has more than 19,000 registered investigators participating in all its clinical trial programs at more than 2700 sites. Under the former NCI-sponsored Cooperative Group Program, for example, there were about 160 ongoing phase III trials and 30 new trials entering the NCI program annually, resulting in approximately 16,000 IRB reviews (3000 initial reviews) conducted each year. In addition, investigators often mention that the amount of time, paperwork, and funding required for them to obtain IRB approval is a serious barrier to opening trials. These factors provided the impetus for the NCI to develop the CIRB and centralize the approach to human subject protection for its clinical trial programs.

In late 2012, the NCI CIRB initiative began to transition from its historic “facilitated review” model to an independent model in which the NCI CIRB is the sole IRB of Record responsible for both study review and local context considerations for enrolled institutions. The primary reason for this model change was to further streamline the IRB review process, increasing efficiency of implementation and conduct of multisite clinical trials and promoting consistency of ethics reviews. On December 13, 2012, the Association for the Accreditation of Human Research Protection Programs (AAHRPP) awarded accreditation to the NCI CIRB under its independent model, the first National Institutes of Health (NIH) entity to earn this distinction. With its adoption of the independent model, the NCI CIRB program was a forerunner of the new policy of the NIH requiring US centers participating in NIH-funded nonexempt, multicenter studies to use a single IRB for initial and ongoing ethics review, a policy that will be implemented starting in 2018.

The NCI CIRB program provides a centralized approach to human subject protection. The program currently consists of four boards: one primarily for late-phase clinical trials, including all adult oncology phase III treatment trials; an early-phase clinical trial board; a pediatric clinical trial board; and a board covering cancer control and prevention. The NCI CIRBs are composed of distinguished panels of oncology physicians, nurses, and patient representatives and include a pharmacist, an ethicist, and a lawyer. Unlike most local IRBs, the NCI CIRBs are focused exclusively on cancer trials and have sufficient time and expertise to review each protocol in detail. This model for human subject protection in multicenter trials is now used by more than 1700 sites, including NCI-designated Cancer Centers, other university medical centers, and community hospitals.

National Cancer Institute National Clinical Trials Network

The NCTN Program was conceived and developed so that it could operate as a true network with incentives for collaboration in the development and conduct of innovative clinical trials. These trials prioritize precision medicine approaches, rare cancers, rare subsets of more common cancers, multimodality therapies, special populations, and research questions unlikely to be addressed in the private sector. In the NCTN Program, network groups are expected to collaborate with one another and with NCI to achieve the overall goal of the Program. Member institutions or sites of any network group are able to enroll patients in all adult phase III and phase II/III trials, as well as most early-phase trials and trials in adolescents and young adults, irrespective of the specific network group that is leading the trial. The NCTN Program, including each of its six key components, is illustrated in Fig. 19.1 .

Figure 19.1, National Cancer Institute (NCI) National Clinical Trials Network (NCTN) structure. The key components of the NCTN are completely integrated into the other initiatives and components of the NCI clinical trial system, including the NCI Cancer Trials Support Unit, NCI Central Institutional Review Boards, other NCI-funded programs such as the NCI Community Oncology Research Program (NCORP) and the Minority/Underserved NCORP as well as NCI advisory and review committees (not illustrated in the figure), which help oversee the entire program. The six major components are (1) Network Group Operations Centers—four adult groups (Alliance, ECOG-ACRIN, NRG Oncology, and SWOG) and one pediatric group (Children's Oncology Group [COG])—which provide scientific leadership for developing and implementing multidisciplinary, multiinstitutional trials in a range of diseases and special populations with specific scientific strategy and goals; (2) Network Group Statistics and Data Management Centers, associated with specific Network Group Operations Centers, which provide the statistical expertise required to ensure effective scientific design and conduct of clinical trials, in addition to data management, data analysis, which provide support for leadership and expertise to facilitate incorporation of translational science into network group clinical trials; (4) Network Lead Academic Participating Sites, which provide scientific leadership in development and conduct of clinical trials in association with one or more adult network groups, as well as substantial accrual to clinical trials conducted across the entire NCTN; (5) Network Radiotherapy and Imaging Core Services Center, which provides scientific and technical expertise for incorporation of appropriate, integrated quality assurance and image data management for applicable clinical trials conducted by the NCTN that require specialized quality assurance or imaging data management and/or assessment; and the (6) Canadian Collaborating Clinical Trial Network (Canadian Cancer Trials Group), which will be capable of being a full partner with the US Network in conducting large-scale, multisite clinical trials. In addition, all NCTN Groups use a Common Data Management System to conduct NCTN trials.

One of the key aims of the NCTN when it was launched in 2014 was to provide for the conduct of precision medicine clinical trials by harnessing the scientific leadership of the NCTN investigators, leveraging the Network to screen large numbers of patients to identify those whose tumors exhibit molecular features that may be responsive to new, targeted treatments and/or immunotherapy, and fostering clinical research partnerships with biotechnology and pharmaceutical companies to collaborate on a series of unique precision medicine trials in oncology. NCI's Molecular Analysis for Therapy Choice (NCI-MATCH) is the archetype of a precision medicine trial. It is led by ECOG-ACRIN (one of the NCTN groups) and has active participation by member sites belonging to any group within the NCTN. NCI-MATCH opened to patient enrollment in 2015 and includes adult patients with any type of solid tumor or lymphoma whose disease is no longer responding to standard therapy. By the end of 2017, over 6000 patients had their tumors screened for molecular alterations and approximately 1000 were “matched” to one of a series of small phase II trials that target a specific mutation in their tumor. Although NCI-MATCH is led by ECOG-ACRIN, investigators from all the NCTN groups lead the individual phase II trials, illustrating the collaborative aspect of the NCTN.

Other National Cancer Institute–Sponsored Structures Supporting Clinical Trials

Although the CTSU, the CIRB, and the restructured NCTN represent mechanisms to reduce barriers and facilitate broader clinical trial participation by practicing oncologists, advocates, and translational scientists, a number of other important mechanisms provide additional options for support and participation.

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