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Witness appearing before the House Appropriations Subcommittee on Labor, HHS, Education, and Related Agencies

Elias A. Zerhouni, M.D.
Director, ľ¹ÏÖ±²¥

Day 1: Science Advances, NIH Roadmap, FY 2005 Budget

Good morning, Mr. Chairman and members of the Committee. Let me begin by expressing my deepest appreciation to the Congress, Secretary Thompson, President Bush, and the American people for their generous and bipartisan support of the NIH's efforts to help improve the health of all our citizens. I respect the extraordinary effort of this committee and, Mr. Chairman, your leadership as well. I thank you for it.

The year 2004 marks a sea change for the NIH and its Roadmap for Medical Research. We are refining our basic and clinical research programs to ensure that new discoveries rapidly lead to new and improved diagnostics, treatments and prevention strategies that extend the length and improve the quality of human life.

In my testimony today, I want to cover three areas: first, highlight several key research advances that took place in the last year which represent the critical contributions of NIH-funded researchers; second, give examples of how the NIH Roadmap will help shape our approach to patient-oriented research; and third, present an overview of our budget. In the course of my testimony, I will mention emerging priorities and our plans for responding to the health challenges ahead. Recognizing the utmost importance of the stewardship of our Nation's investment in medical discovery, I will devote my testimony tomorrow to the advances we are making in the area of management at the NIH.

Breakthroughs & Advances

Each year, the public investment in research yields critical scientific advances. The six I highlight here are just a sample of the many that represent the development of new and improved treatments, diagnostics, or prevention strategies that will affect the health of the entire nation.

Few viruses are feared more than the Ebola, a deadly microbe that causes outbreaks in Africa and Asia and kills up to 90 percent of those it infects. Scientists at the NIH National Institute of Allergy and Infectious Diseases Vaccine Research Center developed a single dose, fast-acting, experimental Ebola vaccine that successfully protects monkeys just one month after treatment. Human trials are now under way.

This year NIH research further elucidated the role of widely used hormone replacement therapies. The NIH halted the estrogen alone study of the Women's Health Initiative on March 1, 2004 after 5.6 years of follow-up, due to increased risk of stroke. You will recall that NIH, in 2002, stopped the combination hormone trial arm of the Women's Health Initiative early due to an increased risk of invasive breast cancer, coronary heart disease, stroke, and pulmonary embolism in study participants on estrogen plus progestin compared to women taking placebo. It indicated that healthy postmenopausal women taking combination hormone therapy also suffered twice the rate of dementia as those taking a placebo. Together, the results of these clinical studies changed conventional dogma, and provided important new evidence-based information to women who are deciding whether to begin or how long to continue menopausal hormone therapy. These trials clearly are having a major impact on the health of people we know and love — our wives, our sisters, our daughters and our mothers.

The third advance was the discovery of genes associated with schizophrenia, which is a profoundly disabling disorder that affects one percent of the adult population. It is marked by hallucinations, delusions, social withdrawal, flattened emotions, and loss of social and personal care skills.

Research like this on the genetics of mental illness was named the Number 2 scientific "Breakthrough of the Year" for 2003 by the prestigious peer-reviewed journal, Science. Most of this work was funded by NIH and included discoveries of candidate genes for schizophrenia, depression, anxiety and bipolar disorders. These discoveries bring us closer to developing new diagnostic tests, strategies for prevention, and targets for the treatment of schizophrenia and other mental disorders.

The fourth advance came only six weeks ago, when NIH announced a major new discovery, the identification of a common variation of a pancreatic "master switch" gene that increases the risk of type 2 diabetes by 30 percent. Type 2 diabetes now affects 17 million people in the U.S., and is responsible for enormous health care costs. This gene discovery opens the door to the development of new and more effective methods of prevention and treatment.

The fifth advance came in research on the SARS virus. As you recall, about a year ago we were in the grip of the SARS outbreak. Previous research investments made during the NIH doubling allowed us to identify the cause of SARS in record time. Throughout this year, NIH scientists have continued to seek ways to protect us from this new, deadly virus. Just last month, they made two advances in SARS vaccine development. In one study, they showed that the mouse immune system develops antibodies capable of neutralizing the SARS virus. In a second study, NIH researchers demonstrated that a DNA-based vaccine successfully produced these antibodies in mice infected with the virus. A Phase I clinical trial of this candidate DNA vaccine is planned for August 2004, again an unprecedented pace of progress.

The final advance I want to highlight is the sequencing of the rat genome, published on April 1st. Armed with this sequencing data, a new generation of researchers will be able to greatly improve the utility of rat models and thereby improve human health. Areas in which rat models have already helped to advance medical research include: cardiovascular diseases (hypertension); psychiatric disorders (studies of behavioral intervention and addiction); neural regeneration; diabetes; surgery; transplantation; autoimmune disorders (rheumatoid arthritis); cancer; wound and bone healing; and space motion sickness. In drug development, the rat is routinely employed to demonstrate therapeutic efficacy and assess toxicity of drug compounds prior to human clinical trials. The genome sequence will facilitate all of these studies.

NIH Roadmap

Let me now turn your attention to the NIH Roadmap for Medical Research. Last year, Mr. Chairman, this Subcommittee asked us if we are getting better at translating new knowledge into real improvements in patient care. "Is the 'bench to bedside' transition becoming more effective?" was the question. I want to tell you that we heard you, and present the Roadmap to you as a major part of the answer to your question. Let me now give you some examples of how we at NIH expect the Roadmap to change the way we do research and the practice of medicine.

One of the questions we face is: how do we successfully do our part in the battle to contain health costs? We need to address the following issues: What are the roadblocks? What are the major challenges? How can we most effectively invest the funds that the American taxpayers entrust to us to fashion the fastest track to discovery as well as translate those discoveries to the patient's bedside or the doctor's office?

In seeking answers to these questions, one thing becomes clear. The traditional paradigm of medical care-when practitioners waited for the disease to cause the patient the loss of some function — must be replaced by a paradigm where health professionals act before the individual loses any function. This has become even more critical since chronic diseases now consume about 75 percent of our fast-growing health care expenditures.

Let me present four examples of how the NIH Roadmap will transform our approach to biomedical research in specific disease areas.

The first example is schizophrenia, a disorder that — as I mentioned earlier — affects one percent of the U.S. population. The peak onset occurs between the ages of 18 and 25. Schizophrenia has the hallmarks of both a neurodevelopmental and a neurodegenerative disease. But after 100 years of neuropathological study, we still lack knowledge of the precise cause of the disorder.

Today, schizophrenia is the fifth leading cause of years lost due to disability among Americans from ages 15-44. Although we can treat the so-called "positive" symptoms, such as hallucinations and delusions, we do not yet have treatments for the "negative" symptoms, like withdrawal and cognitive deficits. And these are the largest source of disability.

Less than 30 percent of people with this illness are currently employed. And people with schizophrenia represent one of the largest groups on atypical antipsychotics as the treatment of choice. In 2001, Medicaid paid for more than 50 percent of the total spending on atypical antipsychotics, amounting to $2.7 billion, a figure which has been growing at roughly 25 percent a year for the past 3 years.

Today, we lack a diagnostic test or a strategy for preventing schizophrenia. This situation is similar to cardiovascular disease 30 years ago in that we see schizophrenic patients only after their first episode equivalent to a "heart attack," and we do not have the equivalent of cholesterol level as an identifiable risk factor.

However, what we have done recently — and what holds great promise for those who are suffering — is identify 12 genes associated with risk. Our challenge now is to move from the discovery of those genes-most of which have no known function-to understanding the role these genes play in the onset and progression of this brain disease-and doing something about it.

Our hope is to use these genes to identify what is abnormal in the brains of schizophrenics, identify it early and thus provide the psychiatric diagnostic equivalent of serum cholesterol level. To accomplish this, we must study the protein products of these genes by using molecular tools that can make their function transparent.

It is precisely here that the NIH Roadmap will help accelerate the effort to study protein products through so-called molecular libraries — databases of information on small molecule compounds like aspirin and antihistamines. These libraries will let researchers screen hundreds of thousands of small molecules to yield these tools.

For example, we know that a variation in the neuregulin gene is associated with an increased risk for schizophrenia. To understand how this gene confers risk, we need to find chemicals that mimic or inhibit the gene's function. This would give us a precise description of how alterations in the gene change the activity of brain cells. Molecular libraries will not only yield the tools to study the neuregulin gene but also provide a test for vulnerability to schizophrenia. With such tools and tests, doctors could approach risk for schizophrenia the way we currently approach risk for heart disease.

A second example where the NIH Roadmap offers promise is in pediatric diseases, through the creation of clinical research networks.

Uncommon disorders like the juvenile forms of rheumatic diseases, such as arthritis, lupus and dermatomyositis, affect 300,000 children in the United States. Not one of these diseases is common enough to be studied intensively at any one academic health center. Thus, many such centers as well as community-based pediatricians are needed to collect a sufficient group of patients who can participate in these studies to gather meaningful results.

The development of clinical research networks that focus on chronic childhood diseases — like those already established for childhood cancers — and the potential to include community physicians trained in clinical research methodology in the research process will enable clinical trials to be more efficient and effective.

Using the NIH Roadmap clinical research networks concept, this could occur without building a new, and often very expensive, infrastructure for every new trial. Including community-based pediatricians as full partners in the research will allow us to overcome some of the limitations of patient recruitment that we currently experience and enable more children to participate in these trials, and accelerate the development of new treatments.

The third example is Alzheimer's disease (AD). We have made considerable progress in understanding Alzheimer's disease. Fifteen years ago, we knew none of the genes that cause AD and we had only a limited understanding of the biological pathways involved in the development of brain pathology. Ten years ago, we could not model the disease in animals. Five years ago, we were not funding any prevention trials and had no way of identifying persons at high risk for the disease. And, as recently as one year ago, we had no way of imaging AD's characteristic amyloid plaques in a living person.

Today, we can do all of these things. And we are poised to make the discoveries that will transform our understanding of the basic and clinical aspects of AD and enable us to effectively prevent, diagnose, and treat it using several NIH Roadmap initiatives.

Through basic research in Alzheimer's disease, we identified a number of brain pathways that are potential targets for preventive interventions. These range from dysfunction and death of specific neurons to loss of the connections between neurons. Roadmap efforts to improve imaging of small molecules will let us visualize the effects of treatments more rapidly and accurately, which could make effective AD clinical trials smaller, faster and more affordable.

My fourth and final example is cardiovascular disease. One of the greatest public health success stories of the last half century is the dramatic reduction in mortality from cardiovascular diseases. Studies initiated by the NIH-the Framingham Heart Study and the Lipid Research Clinics Coronary Primary Prevention Trial-have been key to that success. They helped not only to identify risk factors that contribute to the development of cardiovascular diseases, but also to demonstrate the efficacy of therapeutic interventions to control them.

Even so, cardiovascular disease remains an enormous health burden, accounting for 38 percent of all deaths in the United States in 2001. Progress in reducing that burden will require continued efforts to refine our understanding of risk factors, such as obesity and high cholesterol level, and to identify and evaluate new prevention approaches. This means that large scale population-based studies will remain a critical component of our research effort.

The NIH Roadmap will help fashion the interactive network and involvement of many community-based practitioners. For example, we can make better use of large-scale organizations set up for single studies, such as the recently completed Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Instead of disbanding it, we can involve many or all of the investigators in other trials addressing not only cardiovascular disease but also other diseases. The National Electronic Clinical Trials and Research (NECTAR) initiative — a critical part of the Roadmap effort to re-engineer clinical research — will enable data sharing and enhance comparison and aggregation of results from multiple trials by using standard definitions of outcomes and adverse events. In the future, patients will know directly from their own community doctors, who will be equipped with the new web-based NECTAR, what medical research can do for them in terms of participation in studies, the best available therapies, and nearby advanced research centers.

Budget

The discretionary FY 2005 budget request for the NIH is $28,607 million ($28,527 million from this subcommittee and $80 million from the VA/HUD subcommittee), an increase of $729 million or 2.6 percent over the FY 2004 Enacted Level. In addition, $47.4 million is included in the budget authority request of the Public Health and Social Services Emergency Fund (PHSSEF), for NIH research in radiological/nuclear countermeasures, and $150 million in mandatory funds was previously appropriated for the Special Type 1 Diabetes Initiative, bringing NIH's program level total to $28,805 million, or a 2.7 percent increase. The budget increases funding for the NIH Roadmap (+$107 million), and biodefense research (+$74 million), an increase of 4.5 percent over FY 2004.

Another major budget initiative is in obesity. Last year we created the NIH Obesity Research Task Force to coordinate the obesity research efforts of 24 NIH components. This Task Force produced a great action plan (which is on our website at www.obesityresearch.nih.gov), and we have used the Task Force's recommendations to create a budget initiative. As a testament to how seriously we take the threat from this emerging epidemic, within the NIH budget request, which increases by 2.6 percent, we are increasing obesity research by 10 percent ($40 million) to $440 million.

Conclusion

In conclusion, I want to reemphasize the NIH commitment to help improve the health of the American people. Although we have had great success in changing acute lethal diseases like AIDS and many cancers and childhood diseases into chronic manageable diseases, there are many challenges ahead. Life expectancy has increased, and the diseases of aging and the aging population have become major priorities.

With a shift from acute to chronic diseases, health disparities and pediatric diseases also present challenges, as do emerging and re-emerging diseases, such as SARS. For many years, this Committee has demonstrated its confidence in medical research to meet these challenges and improve the lives of all Americans. We share that confidence, and thank you for your trust and investment in NIH to carry out that research.

As the NIH Director, I fully understand and embrace my role as the steward of our Nation's investment in medical discovery. And I remain vigilant to ensure that these precious resources — including over 212,000 scientists working at 2,800 institutions in the United States and overseas and the 5,000 scientists at the NIH itself-are used wisely and efficiently and produce not only new knowledge but also tangible benefits that touch the lives of every individual who reaches out for our help.

William R. Beldon, Acting Deputy Assistant Secretary for Budget, HHS