NIH Support for Basic and Clinical Research: Title and subTitle BreakBiomedical Researcher Angst in 2006

The noose around the budget of the National Institutes of Health (NIH) is once again tightening as its appropriations remain almost level for the third year, after the virtual doubling of its budget between 1998 and 2003. Many biomedical researchers feel profoundly threatened, and some are laying part of the blame at the feet of the director of NIH because he has developed several new trans-NIH research programs—within the NIH Roadmap for Medical Research¹ —including ones aimed at strengthening clinical research. However, this finger-pointing is very misdirected.

When, right after the Second World War, Vannevar Bush persuaded President Harry Truman to endorse a major investment of federal funds in science, a field Bush described as “the endless frontier,”² the die was cast to expand the purview of what was then the National Institute of Health. The former sleepy campus, nestled on a corner of the Wilson estate in Bethesda, Md, grew exponentially and today has become a center for medical research and the underpinning of much of US academic medicine through its extramural grants programs. But some may not remember or may choose to forget that Bush strongly recommended that federal grants to universities should only support basic sciences and that the funding agency not have its own research program.

Congress agreed that federal support of scientific inquiry was warranted, but the senators and representatives were besieged by patients with serious chronic diseases. The patients insisted that some of the newly invested federal funds should be devoted to their diseases. Congress, at the urging of research supporters like Mary Lasker and NIH Directors Rolla Dyer and James Shannon, rejected the Bush formula and insisted that better management and prevention of human diseases should be a strong focus of new intramural and extramural NIH programs for basic science and clinical research. The march of disease-linked NIH institutes began and led to the unique and extraordinary growth of the NIH since 1950.

Ever since that fateful decision, a tug-of-war has existed between those who favor free-flowing inquiry into basic biological principles (basic science) and those who insist on practical discovery of new preventive and therapeutic tools (clinical research). No one argues, of course, that one or the other discipline should subsume 100% of the budget. The quarrel is over proportions, and the argument can become unseemly when a crisis occurs in the NIH budgeting process.

In these crises, such as the current one, the adherents of one position or the other can become strident even though both types of research are mutually dependent. A very large amount of basic research carried out by scientists free of specific applied goals is absolutely required, because most basic inquiries do not lead to practical development but rather provide data that are parts of a larger framework. Until the larger system is understood, rational clinical research cannot be undertaken.

Conversely, clinical research, when wisely undertaken, can and does reveal mechanisms of disease that provide vital platforms for further basic research, as well as fulfilling its central goal of improving health. The application of the “smart” drug imatinib in chronic myelogenous leukemia and gastrointestinal stromal tumor, and the imaging systems that revealed the rapid destruction of huge tumor masses by imatinib, are perfect examples. Now, basic and translational science and intense collaboration with pharmaceutical companies are needed to solve the problem of resistance to this drug, as well as to push ahead with innumerable other opportunities to accomplish major steps in preventing or treating other diseases.

In 1995, Harold Varmus, then director of the NIH, became concerned that the NIH was not providing sufficient support for clinical research. He formed a panel of experienced academic leaders who accomplished 3 important goals.³ First, the panel defined clinical research broadly and estimated that about one third of the NIH extramural budget was devoted to clinical research. That amount seemed reasonable to the panel, considering that much basic research would be expected to be required in such a scientific program because most basic research provides only a small piece of information that, by itself, cannot be used in the clinic without further information. But the panel cautioned the NIH not to let the ratio decrease further.³

The second contribution of the panel was to define the angst of clinical investigators as carefully as possible. Lawrence Shulman, an experienced NIH administrator, toured the country and personally interviewed young and established clinical investigators.⁴ As a result of his efforts and their own experiences, the panel did not operate in the dark.

The third contribution of the panel was to suggest and implement solutions. As a result of the panel's advice, the NIH instituted new classes of grants for individuals devoted to clinical research, as the panel defined it, and for training in the field. The panel also supported educational debt relief for nascent clinical investigators and supported changes in study section organization that might better support clinical research applications. However, recent data suggest continued losses in the proportional funding of grant applications in the clinical area.⁵

In 2002, when Elias Zerhouni became the NIH director, he immediately turned his attention to the support of clinical research, as well as several other trans-NIH issues.^{1 ,6} He did so not only because he is interested in clinical research but also because his trustees, the Congress of the United States, have been incredibly generous to the NIH, and they demand results. Quite reasonably, the results Congress demands are related to the satisfaction of their constituents. “What steps,” they ask for example, “are you taking to improve the health of the folks in my state? What exactly are you doing to make arthritis more bearable, infections more treatable or preventable, cancer more tractable, and heart disease less frequent?” Congress never asks about the health of a mouse or discoveries involving yeast, even though many in Congress recognize the importance of individual research project grants, which comprise the vast majority of both basic and clinical research grants. In addition, Congress never permits any budget carryover or other flexibilities that could help ameliorate some of the challenge of budget restriction, but regularly demands progress in the treatment and prevention of disease.

Zerhouni, a distinguished imaging scientist and academic administrator with skills in systems analysis, found the efforts of the panel important but insufficient. He concluded that clinical research is faltering in the United States because it lacks an infrastructure within the academic health centers.^{7 - 8} There is no question that Zerhouni is correct. Sustenance of clinical research by the NIH is far more complete in the National Cancer Institute–designated cancer centers, where core laboratories and infrastructure for clinical trials are partially provided, unlike in many other clinical areas. Most clinical researchers outside of these National Cancer Institute centers must scrounge for resources for training, data management, regulatory oversight, and related functions. Yet NIH-funded clinical studies remain the gold standard for the world and continue to achieve landmark importance, as illustrated by the recent published reports from the NIH Women's Health Initiative.

To address that gap, Zerhouni and the directors of the individual NIH institutes have proposed, vetted, and implemented the beginning of a program to “re-engineer” clinical research that may require extensive reorganizations in highly complex academic health centers.^{1 ,6} A recent component of this plan, which incorporates the timeworn General Clinical Research Centers and much new infrastructure, has been controversial and opposed by some clinical investigators but welcomed by others. The discourse might have been seen as a big fight over small issues, except that the growth of the NIH budget has been truncated in the last 3 years.⁹ Individual investigators, both in basic and clinical research, will have a much more difficult time achieving funding. Both young and experienced investigators most likely will have grant applications turned down that would have been readily funded only several years ago.

In response to the funding crisis, some leaders of academic medicine have become quite concerned. They are worried about the implementation of these new trans-NIH programs,^{1 ,6} which include highly competitive individual grant programs supporting new technologies and new research teams to enhance both basic and clinical research as well as new “clinical and translational” research centers. This concern is arising even though the funds for these new programs are currently slightly more than 1% of the NIH budget and are slated to be less than 2% of the almost $29-billion NIH budget for the foreseeable future. These leaders are concerned that the new programs have not been subjected to pilot treatment and may well cause disruptions in established research programs. Despite their concerns, however, it is important to recognize the need for the NIH paradigm to continue to evolve. The creation of the National Institute of General Medical Sciences 45 years ago to boost basic research was also controversial at the time but proved very successful.

Several recent commentaries on the issues affecting US biomedical research have spanned the gamut from being lucid and balanced to being condescending or overtly hostile.^{10 - 13} This is of particular concern in an era when those in high government posts in medicine and science must work in an ever-increasingly complex financial and political environment. Any NIH leader would have a difficult time adjusting programs to the abrupt cessation of the extraordinary increase in NIH funding that occurred between 1998 and 2003. Some believe that the NIH should not plan new programs but should concentrate on stabilizing funded individual investigators—while also somehow ensuring that the ratio of clinical to basic science research grants from the NIH does not decline further and that funds for new research opportunities and new investigators are supplied. However, these new programs actually may help to prevent what many fear is a serious continuing decline in patient- and population-oriented research.⁵

The NIH administration is aware of the opinions of many academic leaders, established clinical researchers, and productive basic scientists and is charged to study, listen, reach conclusions, and then implement. Academic medicine organizations should not try to blame Zerhouni (and the other senior NIH officials) for the current difficult situation¹⁴ or try to force changes in his plans, as his leadership is scientifically and medically knowledgeable, as well as intellectually honest and forthright. A strong consensus of almost all interested and knowledgeable groups has backed the NIH over the last 60 years¹⁵ ; a robust dialogue on NIH policies must continue but without divisiveness and rancor.