Introduction

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 trials 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 trials 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, whether conducted by the National Cancer Institute (NCI), cancer treatment institutions, or the biopharmaceutical industry.

National Cancer Institute–Sponsored Clinical Trials Activities

The NCI supports the development of more than 100 agents for cancer treatment and prevention (many in collaboration with pharmaceutical and biotechnology companies) and has an extensive clinical trials 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 therapeutics development (primarily phases I and II trials), including many sites with grants and contracts to complete these early trials. The NCI also supports a large program of Clinical Trials Cooperative Groups that conduct later-phase trials, predominantly pilot studies and phase III trials. Clinical Trials Cooperative Groups funded by the NCI provide a standing mechanism for performing large-scale multicenter treatment, cancer control, diagnostic, and prevention trials. Phase III trials are conducted nationally, and a member of any NCI-supported Cooperative Group is able to participate in trials conducted by any of the Groups, because they all share a common menu of trials on the Cancer Trials Support Unit Web site (www.ctsu.org). Over the years, this system has supported an experienced cadre of clinical researchers, biostatisticians, and research support staff who can respond to new clinical discoveries by organizing definitive phase III clinical trials. Because of their size and complexity, these trials require extensive infrastructure support to manage the necessary regulatory and data-reporting tasks. Although these Cooperative Group trials have 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 caused the NCI to review and restructure aspects of its clinical trials program beginning in 1998. The major goals of these restructuring efforts were to increase access to NCI trials for patients and their physicians; eliminate barriers to participation in clinical trials; improve the coordination and cooperation among the functionally diverse elements of the NCI clinical trials program, including relationships with industry and the U.S. Food and Drug Administration (FDA); improve the prioritization process for developing clinical trials leading to increased scientific quality; enhance the standardization of tools for clinical trial design and data capture; increase operational efficiency so that trials could be executed in a more timely manner; and most recently, restructure the Cooperative Groups into a tightly integrated network by reducing the number of Groups and changing the review criteria for funding to emphasize collaboration and cooperation.

Through surveys among physicians and the public, it was found that the obstacles to accrual in adult oncology were multifactorial (Table 20-1).^3–3 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 Cooperative Group and Cancer Center leaders, patient advocates, representatives from the FDA and the pharmaceutical industry, and government staff. The detailed reports of these reviews are available online: the 2005 review (http://integratedtrials.nci.gov/ict/ctwg_report_June2005.pdf from 2005), the 2008 review (http://ccct.cancer.gov/files/OEWG-Report.pdf), and most recently, the 2010 Institute of Medicine (IOM) Report (http://books.nap.edu/openbook.php?record_id=12879). Several important projects were launched based on the recommendations, all of which were aimed at modernizing NCI’s clinical trials regulatory and data collection systems, opening trial access to more patients and investigators, and simplifying the role of local Institutional Review Boards (IRBs) in multiinstitutional clinical trials. New opportunities were created for community physicians to participate in a broad array of clinical trials, and new tools were created to enable this participation. Two major initiatives, the Cancer Trials Support Unit (CTSU) and the Central Institutional Review Board (CIRB), were uniformly supported by all stakeholders and have now become integral parts of NCI’s clinical trials system; they are described next.

Cancer Trials Support Unit

The NCI CTSU is designed to facilitate one-stop online access to a broad menu of phase III trials, large phase II trials, and selected international collaborative trials by a national network of NCI investigators. Network investigators can access the CTSU menu of treatment trials from a public Web site (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. 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 group affiliation and academic/practice affiliation(s), Office for Human Research Protection assurance numbers for their sites, 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 group 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 group 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 IRB (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.⁴ To provide an idea of the scope of the duplicative effort that occurs, consider that NCI has more than 8000 registered investigators at more than 1500 sites. On average, there are 160 ongoing phase III trials and 30 new trials entering the NCI system annually, resulting in approximately 16,000 IRB reviews (3000 initial reviews) conducted each year.⁴ 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 a new, centralized approach to human subjects protection for its large phase III trials program.

Customarily, CIRB models were instituted when LIRBs were lacking. In these cases, for-profit central IRBs contract their services to institutions without IRBs and maintain close contact with the sites by sending staff for frequent visits, thereby fulfilling the Office for Human Research Protection requirement that the IRB of record have knowledge of the local context. By contrast, LIRBs exist throughout the NCI system, and this fact led NCI to initially use a model in which responsibility is shared between the CIRB and LIRB. The CIRB provides the initial full-board review and then transmits its decision and detailed minutes of the meeting to the LIRB participants via a confidential Web site. The local sites have the option to perform a facilitated review, whereby a LIRB chair (or a designated subcommittee) can review the CIRB documents rapidly, determine whether local issues exist that should be addressed, and then expeditiously approve the protocol, without the need for a full-board review at the local level. If facilitated review is accepted by the local site, then the CIRB becomes the IRB of record for that protocol.

The NCI CIRB Initiative provides a centralized approach to human subject protection through this “facilitated review” process. The initiative currently consists of two central IRBs, one for adult trials and one for pediatric trials. The NCI’s CIRBs are composed of distinguished panels of oncology physicians, nurses, and patient representatives and include a pharmacist, an ethicist, and a lawyer. The adult CIRB reviews all phase III adult clinical trials groups’ studies and select phase II studies, and the pediatric CIRB reviews all phase II, phase III, and pilot studies by the pediatric clinical trials group, the Children’s Oncology Group. Unlike most LIRBs, the CIRB is focused exclusively on cancer trials and has sufficient time and expertise to review each protocol in detail. This model for human subjects protection in multicenter trials is now used by more than 1000 sites, a third of all major NCI-designated Cancer Centers, and many other university medical centers.

The benefits to research participants include study review by persons who represent a broad range of oncology expertise. The benefits to LIRBs include the ability to carry out local review without convening the entire Board. Continuing reviews, amendments, and nonlocal adverse events are handled by the CIRB as well. The benefits to investigators include time and effort saved because they can download an already completed IRB application for each study, as well as eliminating the need to submit amendments, continuing reviews, and nonlocal adverse events to their IRB. An economic analysis demonstrated that local sites have a substantial cost savings as members of the CIRB.⁵ In addition, subjects are enrolled in trials more quickly because the full LIRB does not need to meet. In 2011, the NCI launched a pilot program to change the model for the NCI CIRBs to that of a full IRB (i.e., single IRB of record) for participating institutions. Thus in the future the NCI CIRB will function in a fashion similar to commercial IRBs.

NCI National Clinical Trials Network

The 2010 IOM report (http://iom.edu/Reports/2010/A-National-Cancer-Clinical-Trials-System-for-the-21st-Century-Reinvigorating-the-NCI-Cooperative.aspx) noted that, despite its impressive record of accomplishment, the current NCI-supported trials system had become less efficient, had difficulty prioritizing studies, and was underfunded for the number of trials it conducts. The IOM report recommended that the existing adult Cooperative Groups be consolidated into a smaller number of Groups, each with greater capabilities and appropriate incentives to promote a more integrated system overall. Consolidation should promote efficiency by encouraging a structural makeover of clinical trial group operations centers, statistics, and data management centers.⁶ It should also facilitate prioritization in clinical research by focusing trials more strictly than previously on questions unlikely to be addressed by the private sector. As a result of the IOM review, as well as input received by the NCI from stakeholders across the oncology community, the NCI developed a comprehensive plan to transform the previous NCI-sponsored Clinical Trials Cooperative Group Program that funded multiple separate organizations conducting cancer treatment trials into a new, consolidated, and integrated program referred to as the NCI National Clinical Trials Network (NCTN).

In the NCTN Program, Network Groups are expected to collaborate with each other and with NCI to achieve the overall goal of the Program. Member institutions/sites of Network Groups will be able to enroll patients in all adult phase III trials, as well as select early phase trials and trials in adolescents and young adults, irrespective of the specific Network Group that is leading the trial. Network Groups will also provide trial operations, data management, and statistical support for approved, multi-center phase II and phase III trials originating outside the Network Group. The NCTN Program, including each of its six key components, is illustrated in Figure 20-1. Although the reconfiguration of the former Cooperative Group program previously described will not officially be in place until 2014, several of the Cooperative Groups have already publicly announced their consolidation plans (http://www.cancer.gov/ncicancerbulletin/032211/page9) and are working together to develop new clinical trials.

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 trials participation by practicing oncologists, advocates, and translational scientists, a number of other important mechanisms provide additional options for support and participation.

Biopharmaceutical Industry–Sponsored Cancer Clinical Trials

During the first three decades of the development of the field of medical oncology, there was relatively little participation by the pharmaceutical industry. In part, this lack of participation was a reflection of the complexity of therapeutics development during a period when an insufficiently detailed understanding of cancer biology made rational drug development difficult. This relative lack of industry involvement, coupled with the significant public health problem presented by cancer, was responsible for the development of the large NCI-sponsored clinical trials apparatus described in detail in this chapter. During the past 25 years, however, a remarkable increase in biopharmaceutical investment in cancer drug discovery research has occurred, along with a parallel increase in both the extent and sophistication of industry sponsorship of clinical trials for the development of new cancer therapeutics. Hundreds of new agents are currently in different stages of clinical evaluation by industry, either alone or in cooperation with the NCI or similar organizations in other parts of the world.

Expectations of Clinical Research Sites

Staffing is foremost among the critical components for an effective research practice listed in Box 20-1. The number and precise composition of the necessary staff depend on the number of patients who are enrolled in clinical trials and the nature of the practice. In some settings in which the number of patients in studies is small, one good research nurse can perform many of the required functions. At more active sites, research nurses, clinical research associates, and research pharmacists perform separate functions. For budgeting purposes, for example, it is often estimated that one full-time clinical research associate can handle 25 new patients and up to 50 patients in follow-up in a year. Some of the structures that support clinical trials participation, such as the CCOP program, provide substantial up-front funding to support salaries for the necessary staff in return for a commitment to substantial accrual. Many others, including the CTSU and the Cooperative Groups, provide funding only on a “per-case” basis, and thus start-up costs must be borne by the site.

Conclusion

Although involvement by oncologists in clinical trials introduces additional complexities to their daily practice, it also provides substantial benefits to all participants and ultimately contributes to the goals of improving cancer treatment and prevention. A growing number of clinical practices have been able to integrate clinical research into their activities successfully. Online tool kits can be helpful to sites as they prepare for participation in a clinical trial. For example, the CTSU provides IRB submission packets, protocol calendars, and summaries. As frequently occurs in industry-sponsored trials, it is envisioned that the availability of a central IRB nationally for NCI-sponsored trials along with a common electronic data reporting system will eliminate critical barriers and will make it easier for community physicians to participate. The biopharmaceutical industry continually seeks interested, conscientious physicians to participate in its trials. The shortage of such physicians creates a potentially serious limitation on the rate of development of new treatments for cancer. Surveys suggest that the attitude of the treating physician is perhaps the most critical factor in patient enrollment in clinical trials. An increasing number of resources and tools are now available to enhance access, with the potential to benefit both current and future patients with cancer.