Management Issues

Mr. Chairman and Members of the Committee: I am pleased to testify at today's hearing focused on science management issues at the National Institutes of Health (NIH). As the Director of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), I will share with you--by way of example--some of the approaches the NIH takes in managing its research portfolio--both within and across its organizational components. Key aspects of portfolio management--priority-setting and resource allocation--involve many factors and objectives. We seek to capitalize on research opportunities; fill gaps and remove barriers; address public health needs; nurture the research environment; and respond to the concerns of stakeholders--including patients and their families, research investigators, and policy makers, both in the Congress and the Administration, who represent the public. In exercising good stewardship, we want to promote research productivity and make the most efficient and effective research investments with the funds with which the Congress entrusts us. In FY 2004, this was $1,671,803,000 for the NIDDK.

In portfolio management, we are extremely fortunate to have the benefit of the NIH two-tiered peer review system for both extramural and intramural research. We also benefit enormously from continuous external input--both scientific and lay. Moreover, the scientific community's process of publishing and confirming the results of research in rigorously peer-reviewed journals provides a self-correction that helps us evaluate which research avenues produce ground-breaking results whose reproducibility makes them worthy of pursuit.

The core of NIH's investment is investigator-initiated research. The research community discovers new knowledge that provides an opportunity to improve the diagnosis, treatment, and prevention of disease. NIH managers take many proactive steps to build on this new knowledge to promote and catalyze science in response to public health needs, and to ensure that research advances and opportunities are exploited as fully, rapidly, and efficiently as possible. We issue research solicitations to incentivize investigators, and sponsor scientific meetings to spur synergistic collaborations. We establish consortia to pool talent, data and research resources to accomplish what would not be possible by individual investigators. We foster development of new therapies through clinical trials, and their translation into medical practice--by working with extramural researchers, industry, the FDA and patient advocates. Because innovative scientific research, by definition, addresses the unknown, we cannot predict where, how, or when the next major advances will occur, so all parts of the research pipeline must be primed. Therefore, the NIH funds studies across the continuum of basic, translational and clinical research, and uses multiple mechanisms--such as research grants, research centers, research training and career development awards, R&D contracts, and intramural research. For any given disease area, appropriate research mechanisms dovetail with the state-of-the-science at the time. It may be necessary, for example, to perform more basic research on a particular disease before clinical trials can be meaningfully conducted.

We must be attentive to the full range of diseases and conditions within the vast NIH research mission. Public health emergencies and diseases placing immense burdens on society are critically important. So too are devastating but rare diseases, which are unlikely to receive research attention without NIH funding. Each year, we carefully consider how we will deploy the budget that is available for new or expanded initiatives. Within the resources you provide to us, we apply our best judgment to fund the most compelling and promising science. We engage our many stakeholders and our National Advisory Council in strategic planning at multiple levels. Some of our planning focuses on cross-cutting themes such as genetics/genomics research and translational research, and leads to initiatives relevant to virtually all the diseases within the NIDDK mission. Other specific initiatives derive from NIDDK planning efforts focused on diseases of a particular organ such as the kidney, bladder or liver, or on diseases that affect multiple organs, such as diabetes.

CROHN'S DISEASE AND POLYCYSTIC KIDNEY DISEASE (PKD)

I'd like to turn now to describe two specific examples of NIDDK disease-focused research that illustrate how we apply our scientific judgment to portfolio management. The NIDDK mission--encompassing diabetes, metabolic, gastrointestinal, liver, kidney and urologic diseases--includes some of the most serious, chronic disorders affecting the American public. Two of these, Crohn's disease and polycystic kidney disease, demonstrate how a convergence of scientific opportunity, public health needs, and input from stakeholders guides our priority setting among competing areas.

Crohn's disease is an incurable, chronic, debilitating form of inflammatory bowel disease that affects an estimated 500,000 Americans. Many patients are diagnosed in their teens and twenties and must cope for the rest of their lives with problems that include intestinal inflammation, abdominal pain, fever, diarrhea, and rectal bleeding. In children, symptoms can progress to malnutrition and growth retardation. These problems dramatically reduce quality-of-life and require lifelong, expensive medical care. For decades, there were no truly effective medications, so that surgical removal of the affected parts of the intestine was often necessary.

Investigator-initiated basic research on the immune system, however, began to illuminate the fundamental mechanisms responsible for intestinal inflammation in Crohn's disease. Mice, in which certain key genes of the immune system had been knocked out, unexpectedly developed inflammatory bowel disease mimicking Crohn's disease. Importantly, bowel disease did not develop in mice raised under "germ-free" conditions in which the bacteria normally residing in the bowel are absent. Thus, the immune gene knockout alone is insufficient to cause disease, but combines with the normal gut bacteria in provoking a self-destructive immune response. These discoveries set the stage for an ambitious long-range plan for inflammatory bowel disease research with the goals of providing more effective treatment and ultimately, prevention. The NIDDK has pursued the plan's aims to: (1) emphasize basic research on interactions between intestinal cells and bacteria; (2) augment the pool of researchers and foster interdisciplinary research; (3) establish and enhance appropriate biological resources and data collections; and (4) develop therapeutic applications and preventive approaches as basic research progresses. This plan was formulated with external input from patient groups, such as the Crohn's and Colitis Foundation of America, and investigator groups, such as the American Gastroenterological Association. The plan was updated at a meeting of the NIDDK-led Digestive Diseases Interagency Coordinating Committee in April 2003. In implementing the plan, the NIDDK has deployed the full range of available mechanisms including a robust portfolio of investigator-initiated grants and pilot-and-feasibility studies, training grants, large program project grants, and Digestive Diseases Centers focused on inflammatory bowel disease.

Significant improvements in therapy have resulted, most notably the development of infliximab, a drug that targets an inflammation-causing protein whose role was illuminated by the mouse gene knockout experiments. The FDA's approval of infliximab was an important step forward in treating Crohn's disease. A report in the New England Journal of Medicine earlier this year shows that it is particularly effective in healing the fistulas, ulcerating lesions that tunnel through the intestines of patients. To facilitate testing of additional new treatments under development, the NIDDK convened a meeting in January of 2003, which included representatives from the FDA, industry, and the investigative community to seek improvements in the design of clinical trials.

An enormous new scientific opportunity emerged in 2001, when investigators announced the unprecedented discovery of a gene that confers susceptibility to this disease. This discovery represents an important payoff of the Human Genome Project. It is also a credit to the strong foundation laid by previous NIDDK research efforts--including an emphasis on targeted, interdisciplinary collaborations among researchers from different fields. Finding this gene illuminated the role of the innate immune system--the first line of defense against "foreign invaders"--in the start of Crohn's disease. This insight was then translated into a clinical trial demonstrating the potential benefit of a new treatment to boost the innate immune systems of patients. Because other genes conferring susceptibility to inflammatory bowel disease remain to be discovered, the NIDDK established a new multi-center Genetics Consortium to speed this search. Other NIDDK initiatives springing from portfolio management of our research into Crohn's disease include the detailed study of adult stem cells of the intestine that may ultimately lead to therapies stimulating gut regeneration. We are vigorously pursuing these research areas as we evaluate and monitor progress in attaining our goals. This example illustrates how investments in investigator-initiated basic research lead to discoveries that we can build on by implementing a strategic plan with the ultimate goal of improving outcomes of patients with Crohn's disease.

Within NIDDK, polycystic kidney disease (PKD) is another example of a disease that is the focus of intensified research through portfolio management. Like Crohn's disease, PKD represents an intersection of public health need, scientific opportunity, and input from stakeholders regarding research directions. An inherited disease in which fluid-filled cysts destroy kidney function, PKD is an important cause of end stage kidney disease, for which the only treatments are dialysis or kidney transplantation.

The discovery of two genes responsible for most cases of the disease opened up an entire new set of scientific opportunities. The NIDDK--working in conjunction with patient groups, such as the PKD Foundation, and investigator groups, such as the American Society of Nephrology--crafted a strategic plan to exploit these opportunities by supporting a wide array of molecular research and the development of new animal models. We also established four PKD Research Centers to spur additional basic and translational research. These investments produced major advances in our understanding of the function of the PKD genes. Moreover, through a serendipitous basic research discovery, the proteins encoded by the PKD genes were localized to cilia, hair-like protrusions on the surface of the cell, vital to normal cellular function. These discoveries have transformed our understanding of how a simple "spelling error" in a PKD gene can lead to the malformed, cystic kidneys characteristic of the disease.

The ultimate goal of NIDDK's agenda for PKD research is to build on these important discoveries by developing effective treatments to prevent or at least slow cyst formation. Testing such treatments will require an accurate method to monitor cyst formation and growth. For this reason, we launched the Consortium for Radiologic Imaging Studies of PKD. Its objective is to test whether non-invasive imaging techniques can provide accurate and reproducible markers of progression of renal disease in PKD. Preliminary results show promise that imaging methods will be a powerful tool to assess new therapies. We also decided to establish the PKD Clinical Trials Network to assess the best strategies for slowing progressive loss of kidney function in PKD, and thus reduce kidney failure and death. The first large trial conducted through this network, the HALT-PKD trial, will investigate the optimum target levels for blood pressure control, and whether drugs termed angiotensin-converting enzyme inhibitors offer superior benefit over other blood-pressure lowering drugs in slowing disease progression. This network will also be poised to test innovative treatments emerging from basic science discoveries. While specific drugs to treat or prevent PKD are not yet available, this example illustrates how we manage our resources to accelerate the translation of basic science discoveries toward development of such drugs.

TRANS-NIH OBESITY RESEARCH

Priority setting and portfolio management are critical, not only for research within the mission of a given institute, but also for research areas such as obesity, which are within the missions of many institutes. Obesity is a prime example of the conjunction of public health needs, scientific opportunity, and stakeholder concerns. Now an epidemic in America, obesity is a precursor to many other serious, costly diseases, such as type 2 diabetes, heart disease, stroke, and some forms of cancer. Thus, obesity has a harmful domino effect on the health of Americans and the costs of health care. The NIH recognized the impending epidemic of obesity over ten years ago, and through effective portfolio management, began to accelerate support for research.

New scientific opportunities emerged in the 1990s, when, for the first time, researchers gained important insights into the molecular underpinnings of obesity, and the essential role played by the signaling of hormones from fat and the gut to the brain. A striking example was the discovery of an obesity gene and its protein product, leptin, which when deficient, causes massive obesity in both mouse models and humans. The NIH quickly capitalized on this advance with the infusion of additional funds to understand the actions of leptin, and other newly discovered hormones that regulate appetite and metabolism. Concomitantly, behavioral research took a giant stride forward with the results of a major primary prevention clinical trial, which showed that a lifestyle intervention involving relatively modest changes in diet and exercise could reduce the incidence of type 2 diabetes by 58 percent in those at high risk of developing the disease.

To further accelerate research to combat the obesity epidemic and take advantage of new research opportunities, the NIH Director established the NIH Obesity Research Task Force in April 2003, with co-chairmanship by the Directors of the NIDDK and the National Heart, Lung, and Blood Institute. This Task Force provides a synergistic framework that promotes interactions and initiatives among the many NIH components which support pediatric, cardiovascular, neurologic, hormonal, behavioral and other avenues of research highly relevant to obesity. The Task Force has united and sparked this diverse set of Institutes and Centers to engage broadly in active portfolio planning about which areas of obesity research warrant increased resource allocation. This priority-setting process is reflected in a new Strategic Plan for NIH Obesity Research recently generated by the Task Force in conjunction with stakeholders. The NIH shared the initial draft plan for comment with approximately 70 individuals and organizations representative of the broad research and lay communities concerned about obesity. After incorporating input received, the NIH posted the plan for additional public comment on a newly established NIH obesity research Web site. The final plan will serve as an important scientific guidepost for the NIH as it develops new initiatives and manages its obesity research portfolio. The plan will contribute to the prevention and treatment of obesity by bolstering research on: (1) behavioral and environmental approaches to modify lifestyle; (2) pharmacologic, surgical, or other biological/medical approaches; and (3) ways to prevent the diseases associated with obesity. New NIH initiatives recommended in the plan are firmly rooted in scientific opportunity and public health need. We recognize that, acting alone, the NIH cannot halt or reverse obesity. However, by generating and disseminating new research knowledge through active portfolio-management, we can provide an important scientific foundation to a broad-based national effort.

The examples of portfolio management we have presented show how the NIH is using its resource base and management flexibility to respond to scientific opportunities and public health needs; to engage in planning and program development with stakeholders; and to determine budget emphases. Together with our stakeholders, the NIH is continuing to make progress in the fight against disease. We are very encouraged by the strides made during the past five years and by the power of current research momentum. We are committed to moving the research agenda forward toward the goals of developing more effective diagnosis, treatment and prevention of disease. I would be pleased to respond to any questions you may have.

DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
National Institute of Diabetes and Digestive and Kidney Diseases
Biographical Sketch

HONORS AND AWARDS:

PROFESSIONAL ORGANIZATIONS:

LICENSURE AND CERTIFICATION:

William R. Beldon
Mr. Beldon is currently serving as Acting Deputy Assistant Secretary for Budget, HHS. He has been a Division Director in the Budget Office for 16 years, most recently as Director of the Division of Discretionary Programs. Mr. Beldon started in federal service as an auditor in the Health, Education and Welfare Financial Management Intern program. Over the course of 30 years in the Budget Office, Mr. Beldon has held Program Analyst, Branch Chief and Division Director positions. Mr. Beldon received a Bachelor's Degree in History and Political Science from Marshall University and attended the University of Pittsburgh where he studied Public Administration. He resides in Fort Washington, Maryland.