In the 1990s, a number of influential studies sponsored by NIH, IOM, and AAMC and the American Medical Association (AMA) identified some major problems in clinical research and highlighted NIH’s role in addressing some of these problems. First, there was a general concern that clinical research was receiving substantially less support than basic research at NIH, yet there was little systematic data to document how much, in fact, NIH was spending on clinical research. In an analysis of NIH investigator-initiated extramural grants active in 1991, an IOM committee found that 16 percent involved human research. A few years later, a panel appointed by the NIH director known as the “Nathan Panel,” developed a broad definition of clinical research (the definition NIH now uses) and, applying this definition to all NIH competing extramural research grants in fiscal year 1996, found that 27 percent of grants and 38 percent of dollars were devoted to clinical research. The Nathan Panel believed that this fraction of the extramural budget devoted to clinical research was reasonable and should remain about the same, as efforts to increase the NIH budget as a whole were pursued. The studies sponsored by NIH, IOM, and AAMC/AMA recommended that NIH monitor and track its expenditures on clinical research. A second concern was that clinical research proposals, especially those from individual investigators, did not fare as well as basic research proposals in peer review at NIH. Grant applications for clinical trials, clinical research centers, and clinical research training are typically reviewed by the sponsoring institute; however, the peer review of individual investigator grant applications usually takes place centrally, within CSR. CSR has approximately 65 study sections that review research. A study section is a panel of experts established according to scientific disciplines or research areas for the purpose of evaluating the scientific and technical merit of grant applications. In 1994 an NIH- commissioned study reported that patient-oriented research applications were less likely to receive favorable reviews in CSR than laboratory- oriented research applications when reviewed in study sections with less than 30 percent patient-oriented research applications. However when patient-oriented research applications were grouped in study sections with greater than 50 percent patient-oriented research, they fared as well as laboratory-oriented research applications. Consequently, this report recommended that study sections reviewing patient-oriented research should have at least 50 percent of such applications and that a means should be developed and implemented to collect and track data prospectively on research applications that are predominantly patient- oriented, laboratory-oriented, mixed, or clinical epidemiology and behavioral research. Similarly, the Nathan Panel recommended that panels that review clinical research must include experienced clinical investigators and that at least 30 to 50 percent of the applications reviewed by these panels must be for clinical research. The IOM committee also recommended more oversight of study section composition, functions, and outcomes pertaining to human research. A third problem identified in these studies was the adequacy of support for the infrastructure (that is, facilities, equipment, data systems, and research personnel) for the conduct of clinical research. Since the late 1950s, NIH has funded GCRCs across the U.S to provide clinical research infrastructure—facilities, equipment, and personnel—for NIH-funded investigators as well as non-federally funded investigators conducting patient-oriented research. Interdisciplinary and collaborative research is encouraged at these centers. The Nathan Panel, the IOM committee, and others recommended increasing financial support for GCRCs and broadening their leadership role in clinical research and research training. A fourth concern was the decline in the number of physicians conducting clinical research. According to data collected by the AMA, the number of physicians reporting research as their primary career activity fell by 6 percent from 1980 to 1997 (from 15,377 to 14,434), while the number reporting patient care as their primary career activity almost doubled (376,512 to 620,472). Observers identified a variety of challenges in pursuing a career as a clinical investigator, including the indebtedness of medical students, the length of time a clinical scientist must train, the culture of academic medicine, as well as the competition from other career options. For many years NIH has supported the training of investigators through extramural and intramural predoctoral, postdoctoral training and career development awards. However, there was concern that these awards were being directed toward basic research and were not sufficiently supporting the training and development of clinical investigators. The IOM committee, the Nathan Panel, and the AAMC/AMA reports recommended that NIH provide substantial new support for clinical research training, career development, and debt relief. NIH reports that it increased its funding of clinical research and expanded its clinical research activities in response to CREA. NIH estimates that it spent about one-third of its budget, or approximately $6.4 billion, on clinical research in fiscal year 2001. Based on these estimates, the proportion of the NIH budget spent on clinical research has remained fairly constant since fiscal year 1997. NIH’s estimates of clinical research expenditures represent the best available indications of financial trends over time, but they are not precise figures because the process of counting clinical research dollars varies widely across ICs. Finally, in response to CREA, some NIH ICs have developed specific clinical research initiatives. In fiscal year 2001, NIH estimated that it spent approximately $6.4 billion on clinical research, which represented about 32 percent of total research spending (see table 1). The institutes that spent the most on clinical research in fiscal year 2001 were the National Cancer Institute (NCI); the National Heart, Lung, and Blood Institute (NHLBI); and the National Institute of Mental Health (NIMH) (see app. I). NIH’s estimated expenditures on clinical research have kept pace with the overall growth in NIH’s budget. As NIH’s reported clinical research expenditures increased by 44 percent (adjusted for inflation) from fiscal year 1997 to fiscal year 2001, the proportion of research dollars spent on clinical research remained constant, at 32 percent, each year. NIH estimates that in fiscal year 2001, it spent approximately $5.9 billion on extramural clinical research, about 35 percent of its total extramural research expenditures. NIH’s extramural clinical research dollars were spent through a variety of funding mechanisms in fiscal year 2001. About 40 percent of the awarded dollars were grants to individual investigators, followed by other funding mechanisms, center grants, cooperative agreements, research program projects, and research and development contracts (see fig. 1). Of NIH’s total extramural research expenditures for cooperative agreements and center grants, the majority of dollars were spent on clinical research in fiscal year 2001. In fiscal year 2001, NIH estimated that it spent about $529 million, or 27 percent of its intramural research expenditures, on clinical research. NIH’s intramural clinical research activities include research at the Clinical Center on NIH’s Bethesda, Maryland, campus, as well as research by individual institutes. The Clinical Center’s budget represents more than half of the intramural clinical research expenditures. The budget of the Clinical Center increased from approximately $204 million in fiscal year 1997 to an estimated $303 million in fiscal year 2002. This budget increase supported an increase in admissions, inpatient days, and outpatient visits. NIH’s reports of clinical research expenditures represent the best available indications of financial trends, but are not precise figures. The methods NIH uses to count clinical research dollars are inconsistent across ICs, potentially underestimating or overestimating its actual clinical research expenditures. Since fiscal year 1997, the Office of Budget, within the Office of the Director, has collected information from each IC on its extramural and intramural clinical research expenditures. The ICs use the NIH definition of clinical research (described earlier), but they count the dollars in very different ways. The 20 ICs that fund clinical research reported three different ways of counting clinical research dollars. First, 12 ICs count 100 percent of the grant dollars of research projects that include any clinical research. Second, one institute, NCI, codes a research project’s “percent relevance” to clinical research. Projects are coded as 100 percent, major, minor, or 0 percent clinical research. If they are classified as “major,” they are assigned a percentage relevancy of 50 percent, and 50 percent of the dollars are counted. If they are classified as “minor,” they are assigned a percentage relevancy of 5 percent, and 5 percent of the dollars are counted. Third, 7 ICs either attempt to estimate the dollars of a research project spent on clinical research or the percentage of a project that is clinical research and apply that percentage to the total grant dollars. These different methods of counting clinical research dollars can produce very different results. For example, given a hypothetical grant to an investigator of $300,000 for which an IC has estimated that $50,000 of the budget would be spent on clinical research, some ICs would report that $300,000 was spent on clinical research; NCI could conclude that this grant has only minor relevance to clinical research and therefore would count 5 percent, or $15,000, as clinical research dollars; the rest of the ICs would estimate that this project is about 17 percent clinical research and therefore count $50,000 of the grant as clinical research dollars. The Office of Budget said that the reason the ICs count clinical research dollars differently is that each developed its own methods over time, and for historical consistency, they are reluctant to change. One IC director, who heads an NIH Director’s committee concerned with clinical research spending told us that NIH is working on ways to make its process of tracking and reporting clinical research dollars more consistent and accurate. In response to CREA, some institutes have developed new clinical research initiatives. For example, since the passage of CREA, NCI has funded two new clinical cancer centers and funded 22 new Specialized Programs of Research Excellence for different types of cancer, all of which involved early phase clinical trials.