As one of the National Institutes of Health’s 27 Institutes and Centers, NCI’s broad mandate is exercised via its two key programs: the Extramural Research Program and the Intramural Research Program. The former links the NCI to a myriad of off-site investigators at academic institutions, research centers, and other sites throughout the country and overseas, whereas the latter encompasses the work of “almost 5,000 principal investigators, from basic scientists to clinical researchers [that] conduct earliest phase cancer clinical investigations of new agents and drugs.” The NCI’s Extramural Research Program includes five divisions:
The NCI’s Intramural Research Program includes:
Hence, given its large budget ($5.1 billion requested by the President for FY 2014) and reach, the NCI has the financial resources to, and does in fact, fund most of the nation’s non-private cancer research at any given time. This financial muscle, backed by an excellent and far-reaching organizational infrastructure, gives the NCI the power to plan, prioritize, direct, coordinate, evaluate, administer, and serve as the focal point for most of the nation’s basic and applied cancer research. It is ironic that the country that stands the tallest among nations for the free flow of ideas leads its War on Cancer through a central bureaucracy whose mandate is to control the type and direction of nearly all publicly funded cancer research. Thus, given its extraordinary influence on the direction of basic and applied cancer research, the NCI must be credited for the nation’s advances in molecular biology and genetics of cancer, but should also be held accountable for four decades of near-stagnation in cancer management and control.

In 1961, the NIH established three new grant programs aimed at fostering cancer research in the United States. They included the Cancer Research Facilities Grant (CRFG), the Program Project Grants (PPG), and the Cancer Clinical Research Center Grant (CCRCG). These funding mechanisms were intended to support broad-based institutional and individual basic and applied cancer research. But it was the National Cancer Act of 1971 that broadened the center’s mandate and scope to include research, patient care, training and education, and cancer control within the same institution. The intended multidisciplinary approach to Cancer Centers was patterned after well-established models, such as Roswell Park Cancer Institute in Buffalo, NY, M.D. Anderson Cancer Center in Houston, Texas, and Memorial Sloan-Kettering Cancer Center in New York City. Evolution of the model led to three types of cancer centers in the 1980s: Basic, Clinical, and Comprehensive, but the classification of NCI-designated Cancer Centers was simplified in 2004 to include Cancer Centers and Comprehensive Cancer Centers, based on the center’s depth and breadth of research activities in laboratory, clinical, and population-based research. Together, they are the centerpieces of the nation’s efforts to reduce morbidity and mortality from cancer. In 2012, the NCI Cancer Center Program supported a total of 67 Cancer Centers, including 41 Comprehensive Cancer Centers in 34 states, plus the District of Columbia, at a cost of $278.3 million in 2011, or 5.5 % of NCI’s total budget [534]. With 10 Cancer Centers, California had the most, followed by New York State with 6 and Pennsylvania with 5. It is noteworthy that, in contrast, NCI’s Intramural Research Program cost $833.6 million in 2011, or 16.5 % of its total budget [535]. However, NCI is currently in the process of implementing a comprehensive approach to transform its clinical trials system into a highly integrated, national clinical trials network [536].

At the urging of Sydney Farber, Mary Lasker, and other cancer advocates, Congress launched the Chemotherapy National Service Center in 1955 with an annual budget of $5 million. This initiative evolved into today’s Cancer Therapy Evaluation Program (CTEP) within NCI’s Division of Cancer Treatment and Diagnosis (DCTD). With its nine branches and offices, over 900 active trials enrolling 30,000 patients annually, nearly 400 grants and cooperative agreements, and about 100 investigational new drugs (INDs), including targeted agents, CTEP coordinates the world’s largest publicly-funded oncology clinical trials network. Its international research sites are spread throughout the United States, Canada, and Europe to conduct cancer treatment trials through the Clinical Trials Cooperative Group Program (CTCGP). They include [537]:
Together these organizations engage nearly 15,000 investigators at over 3,100 institutions to accrue approximately 25,000 patients annually to either group-designed or NCI-sponsored clinical trials. Other NCI-sponsored clinical trials programs include the Community Clinical Oncology Program (CCOP), the CCR, the Office for Cancer Centers, and the Cancer Imaging Program, among others. Launched in 1983 to engage community physicians in NCI clinical trials, CCOP engages approximately 3,000 community-based physicians at nearly 400 hospitals in 37 states and Puerto Rico to participate in NCI-sponsored cancer-control studies. In 1990, the program was extended to include a minority-based CCOP (MB-CCOP) to facilitate access to clinical trials at institutions that serve large minority and underserved communities [538]. However, while most clinical cancer trials in the US have been sponsored and funded by public funds, the pharmaceutical industry has more recently taken an increasingly prominent role in sponsoring and funding clinical trials, enticed by the implied riches from mining data from the Human Genome Project and its preeminent role in drug marketing, accounting for most new anti-cancer drugs being developed today.

The value of clinical trials extends beyond cancer. Indeed, reliance on clinical trials to assess the therapeutic value and toxicity of new drugs for any disease or condition is so widespread that applications for any drug approval by the FDA requires submission of scientific data gathered via clinical trials. Consequently, incorporation of clinical trials in experimental therapeutics as a prelude to official sanction and widespread drug use can be viewed as one of the major advances in modern medicine, especially as it pertains to the promotion and safeguard of public health. This approach of using the scientific method to assess the potential benefit of new drugs via human trials that we now take for granted was first proposed in 1834 by French physician Pierre Charles Alexandre Louis (1787–1872). In a treatise entitled Essays in Clinical Instruction, Louis advocated the numerical method for assessing the benefit of therapies when he wrote, “It is necessary to account for different circumstances of age, sex, temperament, physical condition, natural history of the disease, and errors in giving therapy” [539]. Anticipating resistance to his scientific approach to medicine, he wrote, “The only reproach which can be made to the numerical method is that it offers real difficulties in its execution…it requires much more labor and time than the most distinguished members of our profession can dedicate to it.” His demonstration that resorting to bleeding for treating pneumonia was an illusion sanctioned by theory, tradition, and personal perception rather than by scientific proof [540] was hailed as “one of the most important medical works of the present century, marking the start of a new era in science” by the editor of the American Journal of Medical Sciences, where his article was published [541]. It was, he added with remarkable foresight, “the first formal exposition of the results of the only true method of investigation in regard to the therapeutic value of remedial agents.” At first, Louis’ approach to medical practice encountered fierce resistance, for physicians were unwilling to have their therapeutic decisions held in limbo until sanctioned by the numerical method, nor were they prepared to discard treatments sanctioned by tradition and by their own personal preference. Skeptics were unwilling to hold “their decisions in abeyance till their decisions received numerical approbation… [and were not prepared to discard therapies] validated by both traditional and their own experience on account of somebody else’s numbers” [542]. Some of the raging arguments surrounding Louis’s work launching “evidence-based medicine” were recently published [543]. Eventually, when practitioners recognized that Louis’ numerical method enhanced rather than hindered their clinical skills and brought objectivity to their therapeutic choices, his method gained acceptance, eventually becoming the norm for assessing and validating the usefulness of new and old therapies. Louis attracted many notable foreign disciples, including Austin Bradford Hill, whose studies on streptomycin for pulmonary tuberculosis reinforced the notion of clinical trials [544], and William Osler, who applied Louis’ and other principles of medical practice to medical education at Johns Hopkins University in 1893. Today, Louis is considered the direct or indirect mentor of most American and English scientists in public health, epidemiology, medicine, and biostatistics. As of this writing (June 2013), NIH lists 147,963 clinical trials in 50 states and 185 countries [545].

In order to understand how cancer research is translated into patient care, and how it impacts the War on Cancer, it is necessary to have an understanding of the nature of clinical cancer trials, especially how they are designed, conducted, and interpreted [546]. Clinical trials are the final stages in the long process of evaluating the positive and negative biological effects of an agent potentially useful in the prevention, diagnosis, or treatment of any disease, though the focus here is cancer. There are three types of clinical trials according to their purpose: Preventive, Diagnostic, and Therapeutic. While they differ somewhat in design, this section will focus on the treatment trial model, and more specifically, drug trials.

The review process of potential anti-cancer drugs follows successive steps that include:

This process ensures that new drug sponsors, whether research institutions or drug manufacturers, take responsibility for developing a drug, and gives the FDA oversight of an orderly and sequential process ranging from preclinical animal testing to evaluating the safety (phase I) and activity of a drug administered alone (phase II) or in combination with other drugs (phase III). For the clinical phases of a study to proceed, an IND must be reviewed and approved by FDA and by the institutional review board (IRB) that oversees clinical research at the sponsor’s institution, as well as an informed consent form to ensure that risks of the study are minimized and fully disclosed to participants, respectively. Although participants must sign an informed consent form before entering a study acknowledging understanding the potential risks and benefits to themselves and other details of the study, they can withdraw their participation at any time without prejudice.