[Senate Hearing 108-218]
[From the U.S. Government Publishing Office]
DEPARTMENTS OF LABOR, HEALTH AND HUMAN SERVICES, AND EDUCATION, AND
RELATED AGENCIES APPROPRIATIONS FOR FISCAL YEAR 2004
----------
TUESDAY, APRIL 8, 2003
U.S. Senate,
Subcommittee of the Committee on Appropriations,
Washington, DC.
The subcommittee met at 10 a.m., in room SD-192, Dirksen
Senate Office Building, Hon. Arlen Specter (chairman)
presiding.
Present: Senators Specter, Cochran, Harkin, and Murray.
DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
STATEMENT OF ELIAS ZERHOUNI, M.D., DIRECTOR
ACCOMPANIED BY:
DR. DUANE ALEXANDER, DIRECTOR, NATIONAL INSTITUTE OF CHILD
HEALTH AND HUMAN DEVELOPMENT
JAMES F. BATTEY, JR., M.D., PH.D., DIRECTOR, NATIONAL INSTITUTE
ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
WILLIAM R. BELDON, ACTING DEPUTY ASSISTANT SECRETARY FOR
BUDGET, DEPARTMENT OF HEALTH AND HUMAN SERVICES
FRANCIS S. COLLINS, M.D., PH.D., DIRECTOR, NATIONAL HUMAN
GENOME RESEARCH INSTITUTE
ANDREW C. VON ESCHENBACH, M.D., DIRECTOR, NATIONAL CANCER
INSTITUTE
ANTHONY S. FAUCI, M.D., DIRECTOR, NATIONAL INSTITUTE OF ALLERGY
AND INFECTIOUS DISEASES
DR. PATRICIA A. GRADY, DIRECTOR, NATIONAL INSTITUTE OF NURSING
RESEARCH
DR. JUDITH H. GREENBERG, ACTING DIRECTOR, NATIONAL INSTITUTE OF
GENERAL MEDICAL SCIENCES
GLEN R. HANSON, PH.D., D.D.S., ACTING DIRECTOR, NATIONAL
INSTITUTE ON DRUG ABUSE
RICHARD J. HODES, M.D. DIRECTOR, NATIONAL INSTITUTE ON AGING
THOMAS R. INSEL, M.D., DIRECTOR, NATIONAL INSTITUTE OF MENTAL
HEALTH
STEPHEN I. KATZ, M.D., PH.D., DIRECTOR, NATIONAL INSTITUTE OF
ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
DR. GERALD T. KEUSCH, DIRECTOR, THE JOHN E. FOGARTY
INTERNATIONAL CENTER
RAYNARD KINGTON, DEPUTY DIRECTOR, OFFICE OF THE DIRECTOR,
NATIONAL INSTITUTES OF HEALTH
CLAUDE LENFANT, M.D., DIRECTOR, NATIONAL HEART, LUNG, AND BLOOD
INSTITUTE
TING-KAI LI, M.D., NATIONAL INSTITUTE ON ALCOHOL ABUSE AND
ALCOHOLISM
DONALD A.B. LINDBERG, M.D., DIRECTOR, NATIONAL LIBRARY OF
MEDICINE
KENNETH OLDEN, PH.D., DIRECTOR, NATIONAL INSTITUTE OF
ENVIRONMENTAL HEALTH SCIENCES
AUDREY S. PENN, M.D., ACTING DIRECTOR, NATIONAL INSTITUTE OF
NEUROLOGICAL DISORDERS AND STROKE
RODERIC I. PETTIGREW, PH.D., M.D., DIRECTOR, NATIONAL INSTITUTE
OF BIOMEDICAL IMAGING AND BIOENGINEERING
JOHN RUFFIN, PH.D., DIRECTOR, NATIONAL CENTER ON MINORITY
HEALTH AND HEALTH DISPARITIES
DR. PAUL A. SIEVING, DIRECTOR, NATIONAL EYE INSTITUTE
ALLEN M. SPIEGEL, M.D., DIRECTOR, NATIONAL INSTITUTE OF
DIABETES AND DIGESTIVE AND KIDNEY DISEASES
STEPHEN E. STRAUS, M.D., DIRECTOR, NATIONAL CENTER FOR
COMPLEMENTARY AND ALTERNATIVE MEDICINE
LAWRENCE A. TABAK, D.D.S., PH.D., NATIONAL INSTITUTE OF DENTAL
AND CRANIOFACIAL RESEARCH
JUDITH L. VAITUKAITIS, M.D., DIRECTOR, NATIONAL CENTER FOR
RESEARCH RESOURCES
KERRY N. WEEMS, ACTING ASSISTANT SECRETARY FOR BUDGET,
TECHNOLOGY AND FINANCE, DEPARTMENT OF HEALTH AND HUMAN
SERVICES
JACK WHITESCARVER, PH.D., DIRECTOR, OFFICE OF AIDS RESEARCH
OPENING STATEMENT OF SENATOR ARLEN SPECTER
Senator Specter. Good morning, ladies and gentlemen. The
Appropriations Subcommittee on Labor, Health and Human
Services, and Education will proceed.
Dr. Zerhouni, we now turn to this portion of the hearing on
the National Institutes of Health.
Dr. Gerberding, we thank you for your participation. If you
would like to be a director of the NIH or one of the
institutes, you may stay.
If you choose to retain your current position at CDC, you
are free to excuse yourself. Thank you very much for joining
us.
Dr. Gerberding. Thank you. I think I will keep to my
present job.
Dr. Zerhouni. We would not mind having her as a director at
NIH.
Dr. Gerberding. Thank you.
Senator Specter. Dr. Zerhouni, we have already introduced
you with your impressive background and credentials coming from
Algiers at a young age. We thank you for the work you are doing
at NIH. It is good to hear that you were in Mississippi with
Senator Cochran. Thank you for coming to Pennsylvania to a very
interesting forum we had a few months ago at the University of
Pennsylvania. And now we look forward to your testimony.
SUMMARY STATEMENT OF DR. ELIAS ZERHOUNI
Dr. Zerhouni. Thank you, Senator Specter. And thank you,
members of the committee.
INTRODUCTION OF NEW INSTITUTE DIRECTORS
What I would like to do first and foremost is introduce to
you four new directors of NIH who have joined us over the past
year. Dr. Thomas Insel is the new Director of the National
Institute of Mental Health. Thomas can say hi. Dr. Nora Volkow
is going to assume the directorship of the National Institute
of Drug Abuse. Dr. Rod Pettigrew is going to be, is the new
Director of the National Institute of Bioimaging and
Bioengineering. And T.K. Li is the new Director of the National
Institute of Alcoholism and Alcohol Abuse.
To my right, I would like to introduce our new Deputy
Director for NIH, Dr. Raynard Kington, who has replaced Dr.
Ruth Kirschstein, who is now serving as the senior advisor to
the directors, with us today as well and continues to help both
Dr. Kington and I with her advice.
Senator Specter. Let me just pause for just a moment to
thank Dr. Ruth Kirschstein for her outstanding service at NIH
over many years, including serving as acting director. We
salute you and are glad to see that you are still on board.
Dr. Zerhouni. Again, I would like to really extend our
thanks to the full committee and to you, Mr. Chairman, and to
you, Senator Harkin. We know that without your leadership, the
doubling of NIH would not have occurred this year in the
difficult economic and budgetary circumstances that we are
facing. And we appreciate it very much.
RESEARCH PRIORITIES
I would like to quickly go over what NIH is planning to do
with the doubling of the NIH budget and what our priorities are
going to be. First and foremost, we want to make sure that the
resources you have given us are invested with the best people
and are invested on the best ideas that can promote the health
of our people.
This is done in the context of, first of all, major
priorities that continue to be priorities, but also evolving
challenges. These evolving challenges are truly fundamental to
the way biomedical research will need to be done in the future.
CHRONIC DISEASES
First and foremost, we have experienced over the past 40
years a tremendous shift in the landscape of disease in our
country going from acute diseases that were very lethal to more
chronic diseases. Seventy-five percent of the disease burden of
the United States today is related to long-term chronic
diseases. We have made great progress in cardiac diseases when
we control acute myocardial infarction. But these patients are
now surviving longer and have different kinds of problems.
AGING POPULATION
The second challenge is that of the aging population. And
we need to tackle that proactively.
HEALTH DISPARITITIES
The third is health disparities, as I mentioned before.
EMERGING DISEASES
The fourth, as you heard today, is emerging diseases. Not
just infectious diseases, but also diseases that relate to the
change in our environment, all conditions. For example, the
rise in obesity and its implications on the incidence of
diabetes in our country. Last, but not least, is the biodefense
priorities, which we will continue to support.
STRATEGIC ROADMAP FOR NIH
Now to do so and to go forward, we wanted over the past
year to work with all the directors of NIH and all the
constituencies to define what we would call a strategic road
map for NIH and how we will invest the resources you have
placed in trust with us, and what are the priorities that we
think will make the greatest difference in terms of advancing
research, in terms of developing the best people, promoting the
best ideas, and essentially translating them to real benefits.
And there are three.
We will explore new pathways to discovery. And that is
essentially to fully exploit the unprecedented opportunity of
the genomic era. To us, this is the beginning, not the end, of
an era. The genome is allowing us today to explore completely
different ways of looking at disease than we had in the past.
Second, because of the scaling complexity of 21st century
research, we understand now that the problems cannot be tackled
by individual scientists alone. We need large multi-
disciplinary teams that are going to work together to in fact
do so.
Third, we need to re-engineer the clinical research
enterprise of our country. We need to more quickly translate
our discoveries into practice. And this will be a priority of
the NIH in the future.
Last but not least, we are submitting to you a request for
the fiscal year 2004 budget, which is a 2.6 percent change over
the enacted 2003 level. When we worked--and Senator Specter and
Senator Harkin and Senator Murray, I can tell you that we
worked very, very hard, including myself and Dr. Gerberding and
others to try to make sure that the impact on our programs in
the new budget will be as limited as possible, in terms of
critical mission areas. We did advocate internally, as you
recommended in your statement.
Research will not be affected at the 2.6 percent level, but
we will be able to maintain our research to the 7 percent
level. Excluding biodefense, we will maintain a 4.3 percent
level. And the number of grants will go 10,509.
At the bottom of the slide, you see why that is in 2004.
And the reason is because many one-time expenditures that were
related to building the infrastructure for biodefense,
buildings and facilities that were needed in 2003 have been
reinvested in the research portfolio in 2004. Now those are the
main elements of the budget we are submitting. And as you said,
Senator Specter, we are looking forward to your input in this
process. And obviously, we will provide you with all the
information that you may want us to provide you and answer all
your questions in that regard.
PREPARED STATEMENTS
But rest assured that we will and are committed and will be
committed to make sure that the return on investment of the NIH
continues to be the same it was in the past. Thank you very
much.
[The statements follow:]
Prepared Statement of Dr. Elias Zerhouni
FISCAL YEAR 2004 PRESIDENT'S BUDGET REQUEST
Good morning, Mr. Chairman and members of the Committee. Let me
begin by expressing my deepest appreciation for the generous and
bipartisan support of the Congress, Secretary Thompson, President Bush,
and the American people for the completion of the doubling of the NIH
budget this year. I recognize and appreciate the extraordinary effort
of this committee and, Mr. Chairman, your leadership as well as your
efforts, Senator Harkin--without which the doubling would not have
occurred. I thank you for it.
I also want to assure you that NIH fully understands and embraces
its role as the steward of our Nation's investment in medical
discovery. We must ensure that these precious resources are used wisely
and lead to tangible benefits that touch the lives of everyone.
The year 2003 is truly a pivotal year for medical research. It is
the year when we celebrate the 50th anniversary of the discovery of the
structure of DNA and its direct consequence--the completed sequence of
the Human Genome. We have witnessed nothing short of a revolution in
science over the past 5 years. Some may see this year as the grand
finale. I think of it more as the overture. As the 21st century begins
to unfold, we are poised to make quantum leaps in our knowledge about
how to improve people's health.
In my testimony, I will demonstrate what health benefits have
resulted from the Nation's longstanding investment in the NIH, along
with some of our most recent advances. Finally, I will outline emerging
priorities and NIH's plans for responding to the health challenges
before us.
THE NIH TRADITION
NIH-led progress in medical research is changing the landscape of
disease. For example, NIH research led to a major reduction in
mortality related to coronary heart disease and stroke. NIH contributed
to this decline in a number of ways. First, we identified
cardiovascular risk factors and the importance of behavior
modification, such as smoking cessation, dietary changes, and exercise,
to reduce risk and improve cardiovascular health. Second, we supported
the basic science that led to the development of pharmaceuticals to
control hypertension and high cholesterol levels. NIH-funded research
also led to strategies as simple and inexpensive as taking aspirin to
prevent heart disease and stroke, and life-saving procedures such as
angioplasty and coronary artery bypass grafting. We also continue to
evaluate best therapeutic strategies in medical practice, as in the
recent ALLHAT trial (Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial) that showed that hypertension can be
effectively managed with an initial choice of an inexpensive drug. Were
it not for these advances and others, the expected death toll from
coronary heart disease would have been over 1,300,000 in 2000 as
compared to the actual death toll of 514,000.
Progress has been equally remarkable for Hepatitis B (HBV) and
Hepatitis C (HCV) infections. New cases of these infections are on the
decline, in part, because of improved vaccines and the reduced risk of
infection from blood transfusion--both outcomes of NIH-funded research.
Because of changes in the criteria for donor recruitment and new and
improved approaches to testing blood, the risk of infection through
transfusion has been virtually eliminated.
The ability to screen for HIV infection--made possible by NIH
research serves as an important target for both prevention and
treatment of AIDS. The mortality rate of this devastating disease is
now one fifth of what it would have been without research on the
fundamental biology of the HIV virus. Research on behavioral
interventions to prevent HIV infection and improve its treatment also
contributed to better control of the spread of this disease in our
country.
One more dramatic example can be found in the development of the
Haemophilus Influenza B vaccine. The results of this NIH research have
led to a virtual elimination of this disease in our country and, the
disease is in the process of being eliminated worldwide. In the not too
distant past, the complications of Hib made this disease the leading
cause of acquired mental retardation in infants and children.
NEW CHALLENGES AND STRATEGIES
Due in part to research advances; the burden of disease is now
shifting from more acute and lethal forms of disease to chronic
illness. Our success in conditions like myocardial infarction and
infectious diseases is leading to better survival rates. As the result
of such prolonged survival and the aging of the population, the
incidence of chronic and long-term diseases, such as congestive heart
failure, cancer, Alzheimer's disease, Parkinson's Disease, diabetes,
and obesity, among others, is increasing.
For example, although we have witnessed reductions in acute
coronary heart disease, the burden of congestive heart failure has
increased during the last 30 years of the 20th century. As another case
in point, more people are living with cancer, as therapies transform
this once acutely fatal disease into a more chronic and manageable
condition.
Furthermore, rapid changes in our environment and lifestyle lead to
disequilibrium between our genetic make-up and our ability to adapt to
these changes. The most dramatic recent example is the rise in the
incidence of obesity, due in part to the greatly increased availability
of food and reduced daily physical energy requirements.
It is imperative that we develop more comprehensive strategies to
address such emerging challenges. In all likelihood, these strategies
will require a better understanding of: (1) the series of molecular
events that lead to disease in the hope of affecting its course before
the disease develops, so-called Molecular Prevention; (2) the
interactions between genes, the environment, and lifestyle as they
relate to the etiology and progression of disease; ways of delaying the
onset of the disease and/or ways to reduce the severity of its course
and its impact on quality of life.
All of these strategies will need to be explored simultaneously and
it is this systematic approach, from most basic to applied research,
that will produce much needed results. Several important examples of
these strategies have already proved their value.
For example, a major cause of blindness, age-related macular
degeneration (AMD), currently affects 1.75 million Americans. They have
advanced degeneration in at least one eye. Over 7 million individuals
are at substantial risk of developing AMD. Its prevalence increases
dramatically with age; for more than 15 percent of white females over
80 years of age have AMD. By the year 2020, the number of people with
AMD will increase by 50 percent to 2.95 million.
NIH is engaged in a major research program to understand the
predisposing factors, the clinical course, and the prognostic factors
of AMD. Researchers found that giving high levels of antioxidants and
zinc reduce the risk of developing advanced AMD by about 25 percent.
These nutrients also reduce the risk of advanced AMD-induced vision
loss by about 19 percent. These findings may help people who are at
high risk of developing advanced AMD keep their vision. Over the next
five years, 329,000 people in the United States (66,000 per year) could
be saved from advanced AMD. More remains to be done. We need to spread
the word to change practices, and we need to continue work to identify
the genes that control the risk of this devastating disease as well as
to develop more interventions to prevent or delay the onset of
blindness.
In another example, many doctors today who are treating patients
with rheumatoid arthritis remember all too well how challenging
treatment was not so long ago. In the early 1980s, treatment was
initiated in what was known as a therapeutic pyramid. Patients would
first be given a course of aspirin or another non-steroidal anti-
inflammatory drug (NSAID), and would be followed to see if erosions
occurred in the bone. If erosions did occur or if the patients did not
respond to the NSAIDs, the next course was anti-rheumatic drugs that
were added one-by-one as the disease progressed. Sadly, the disease-
modifying therapy was initiated only after the patient was already on
the road to disability. The root causes of the disease were not known,
but the discovery, originally made through cancer research, of the role
of Tumor Necrosis Factor (TNF), a naturally occurring protein in the
body that mediates inflammation, dramatically changed the treatment
landscape. By specifically targeting this protein with customised
antibodies, entirely new drugs were developed and approved for the
treatment of rheumatoid arthritis, including etanercept and infliximab.
These were the first biological-response modifying antibody drugs that
behave as antagonists--meaning that they work by specifically blocking
the action and decreasing the availability of TNF.
These new-targeted therapies showed substantial effectiveness in
people with rheumatoid arthritis who had not previously responded to
other treatments. The treatments are generally well tolerated, although
some concerns have been raised recently about the long-term effects of
these agents. Other studies reported that infliximab and methotrexate
used in combination not only reduced the symptoms of rheumatoid
arthritis, but also halted the progression of joint damage when
compared to the use of previous forms of therapy. Scientists involved
in this study observed that in the last 2 years, aheumatoid arthritis
research has moved further than in the previous 30 years, and that a
wealth of new treatments is now available that have the potential to
prevent and heal structural damage to the joints of people with this
debilitating disease.
THE NEED FOR A STRATEGIC ROADMAP
The change in the landscape of disease requires us to adopt new
approaches and accelerate the pace of our discoveries. The need has
never been so pressing, the opportunities have never been greater, and
challenges have never been more daunting. The NIH must simetaneously
learn from the past, act in the present, and plan for the future. It
must institute the changes necessary to improve the health of the
American people. We need to proactively define enabling initiatives--
how best to advance science as well as what science to advance. We need
to map the terrain and over the past nine months we have been engaged
in just such an effort.
Soon after I arrived at NIH, I convened a series of meetings to
develop a ``Roadmap.'' My goal was to develop a short list of the most
compelling initiatives that the NIH should pursue that would make the
biggest impact on biomedical research.
This assessment was needed because powerful and unifying concepts
of biology are emerging that hold the potential to lead to rapid
progress. For example, in the past, cancer research was considered
vastly different than heart or brain research. Today, with recent
discoveries in molecular and cell biology, we know that biological
systems obey common laws and follow similar pathways in both health and
disease. Efforts to fully understand these complex molecular events are
beyond the reach of any one laboratory or group of investigators. As we
begin to decipher the tidal wave of knowledge we have amassed, the
scope, the scale, and the complexity of 21st century science will
require us to devise even newer ways to explore biology for the sake of
improving health.
Three major themes emerged from these Roadmap meetings. First, we
must uncover new pathways to scientific discovery. For example, we must
develop a comprehensive understanding of the building blocks of the
body's cells and tissues and how complex biological systems operate.
Also, structural biology will provide vital information about the
proteins that make up the human body. Molecular libraries will give us
new tools and targets for effective therapies. Overall, these examples,
plus nanotechnology, computational biology and bioinformatics and
molecular imaging will provide the foundation upon which new
treatments, diagnostics and prevention strategies will emerge.
The second theme that emerged from our consultations is the
changing dynamics of the research teams of the future. Because of the
complexity and scope of today's scientific problems, traditional
``mentor-apprentice'' models must be replaced by integrated teams of
specialists from numerous disciplines that were considered unrelated in
the past. Imaging research, for example, requires cell biologists,
computer programmers, radiologists, and physicists to work
collaboratively on new diagnostics and treatments.
The third theme that was voiced again and again by researchers is
the need to re-engineer the national clinical research enterprise for
optimal translation of our discoveries into clinical reality. The list
of what is needed is long--it includes supporting multidisciplinary
clinical research training career paths, introducing innovations in
trial design, stimulating translational research, building clinical
resources like tissue banks, developing large clinical research
networks, and reducing regulatory hurdles. We must explore a standard
clinical research informatics strategy, which will permit the formation
of nation-wide ``communities'' of clinical researchers made up of
academic researchers, qualified community physicians, and patient
groups.
Our vision is to make sure that our citizens benefit from a vibrant
clinical research system--a system that will allow us to more
efficiently translate our breakthroughs in basic research with the goal
of improving health.
The three thematic areas that I just described, that is, new
pathways to discovery, multidisciplinary teams, and reengineering the
clinical research enterprise, focus on technologies and systems that
will enable researchers today and in the future to not only solve
problems more quickly, but also to ask questions that we have not been
able to ask before--questions so complex that without the aid of these
efforts they would be impossible to address.
Efforts to understand the building blocks of the body's cells and
tissues and to understand how complex biological systems work can lead
directly to new approaches to improving health or preventing disease. A
recently discovered biological phenomenon called RNAi--or RNA
interference--has led to the development of a new and potent research
tool, which is being used to identify the function of specific genes in
normal biological and disease processes.
A recent study, co-funded by NIH, used RNAi to identify genes
involved in the regulation of fat metabolism in the roundworm
experimental model in an effort to better understand obesity. One at a
time, each of the 17,000 genes of the round worm was turned off using
this novel method. Researchers found that inhibition of 305 genes
decreased body fat, whereas inhibition of 112 genes increased fat
storage. With this information, researchers identified new genes
involved in fat metabolism, genes common in many organisms, including
humans. These genes now give researchers multiple new opportunities for
understanding obesity and new targets for the development of therapies.
This is just one example of how these new approaches are beginning to
transform medical research.
Finally and importantly, the NIH must communicate our research
results both to the lay public and health professionals. NIH works in
partnership with many different organizations to communicate scientific
results and health information to the medical research community,
health care providers, patients, the media and the general public
across the nation. We conduct our education and outreach efforts in
collaboration with other federal agencies, state agencies, private
sector organizations and national health care organizations. We have
made progress in this area. For example, the NIH Web site is now the
most accessed of all government health and science web sites. This
aspect of our mission will continue to be a priority for NIH.
BIODEFENSE
Civilian biodefense research has become a new core priority at NIH
and a prominent component of our budget. Over the last year and a half,
we responded to the most urgent needs of biodefense, namely the
development of countermeasures such as vaccines, therapeutics, and
diagnostic tests. These will allow us to respond to and control the
intentional or unintentional release of agents of terrorism that affect
human health, including infectious disease and microbial toxins. We are
also now systematically reviewing our portfolio of biodefense research
to include radiation and chemical exposures, and mental health
preparedness research. Biodefense research will be the topic of a
separate hearing.
Mr. Chairman, I am pleased to present the President's fiscal year
2004 request for the National Institutes of Health of $27,663 million
for the programs of NIH that fall under the purview of this Committee.
This level will allow us to support our highest research priorities and
continue the momentum we gained during the historic doubling of the NIH
budget. In large part this is possible because of the very significant
amount of one-time costs supported in fiscal year 2003 that will not be
required in fiscal year 2004. Once these have been taken into account,
NIH will be able to increase the amount available for research by 7.5
percent. Even after excluding increases for the Administration's
highest priority--homeland defense--the research components of the NIH
budget will still increase by 4.3 percent. The request will allow us to
support the highest number of new and competing grants in history--
10,509 new and competing grants. At this level, we will be able to
continue to support approximately one-in-three of the research grant
applications we receive. The final enacted fiscal year 2003
appropriation is very close to the President's request. In the coming
weeks, NIH will work with appropriate staff to clarify discrepancies
between the fiscal year 2003 request and the enacted level.
Special emphasis will be placed on areas of growing concern such as
obesity and diabetes, the IDeA program, and the Best Pharmaceuticals
for Children's Act. A total of $35 million is requested through the
Director's Discretionary Fund to support our important Roadmap
activities. As the fiscal year 2004 budget is developed, NIH will work
with appropriate staff to clarify discrepancies.
In sum, the plans I have outlined here today are ambitious and
rightly so. They rise to the many scientific opportunities and
significant health challenges that lie before us. Once again, my thanks
to you and the American public for your continued investment in
biomedical research to improve the health of everyone.
BUILDINGS AND FACILITIES PROGRAM
The Buildings and Facilities (B&F) program supports the physical
infrastructure required to carry out the in-house component of the
biomedical research mission of the National Institutes of Health (NIH).
The fiscal year 2004 Buildings and Facilities budget request supports
efforts to sustain a robust, modern, safe and secure physical
infrastructure for the conduct of basic and clinical research and
research support across the spectrum of biologic systems and diseases.
The B&F budget request is the product of a deliberate, corporate
facilities planning process both within the NIH and the Office of the
Secretary, Assistant Secretary for Administration and Management, HHS.
At the NIH, the Facilities Planning Advisory Committee (FPAC) oversees
this process and provides advice to the NIH leadership and Director.
The FPAC is also instrumental in adjusting priorities as necessary to
deal with unanticipated public health challenges and changes in
national priorities. The goal of the planning process is to optimally
meet the changing facility needs of the NIH research programs in the
Washington, D.C., region and across the NIH field stations with a mix
of owned and leased facilities. The fiscal year 2004 Buildings and
Facilities (B&F) budget request supports the NIH's research
infrastructure priorities. The request includes projects and programs
to responsibly manage the repair and upkeep of the existing physical
infrastructure, and to maintain our facilities at an optimal operating
standard to meet mission as well as safety and regulatory requirements.
The NIH appreciates the support from Congress in fiscal year 2003
for NIH's Physical Security, Biodefense facilities, and the final phase
of the construction of the Mark O. Hatfield Clinical Research Center.
The fiscal year 2004 request maintains responsible funding support
for the ongoing safety, renovation and repair, and related projects
that are vital to proper stewardship of the entire portfolio of real
property assets and continues the functional integration of the
clinical research components of the existing Building 10 with the new
Mark O. Hatfield Clinical Research Center (CRC).
The fiscal year 2004 B&F budget request is organized among three
broad Program Activities: Essential Safety and Regulatory Compliance,
Repairs and Improvements, and Renovations. The fiscal year 2004 request
provides funds for specific projects in each of the program areas. The
projects and programs enumerated are the end result of the
aforementioned NIH Strategic Facilities Planning process and are the
NIH's capital facility priorities for fiscal year 2004.
FISCAL YEAR 2004 BUDGET SUMMARY
The fiscal year 2004 budget request for Buildings and Facilities is
$80 million. The B&F request includes a total of $14 million for
Essential Safety and Regulatory Compliance programs composed of $2
million for the phased removal of asbestos from NIH buildings; $5
million for the continuing upgrade of fire and life safety deficiencies
of NIH buildings; $1.5 million to systematically remove existing
barriers to persons with disabilities from the interior of NIH
buildings; $0.5 million to address indoor air quality concerns and
requirements at NIH facilities; and $5 million for the continued
support of the rehabilitation of animal research facilities. In
addition, the fiscal year 2004 request includes $60.5 million in
Repairs and Improvements for the continuing program of repairs,
improvements, and maintenance that is the vital means of maintaining
the complex research facilities infrastructure of the NIH. Finally, the
request includes $5.5 million in Renovations for the Building 10
Transition Program.
My colleagues and I will be happy to respond to any questions you
may have.
______
Prepared Statement of Dr. Duane Alexander
Mr. Chairman and Members of the Committee: I am pleased to present
the fiscal year 2004 President's budget request for the National
Institute of Child Health and Human Development (NICHD). The fiscal
year 2004 budget includes $1,245 million, an increase of $41 million
over the fiscal year 2003 enacted level of $1,205 million comparable
for transfers proposed in the President's request. The NIH budget
request includes the performance information required by the Government
Performance and Results Act (GPRA) of 1993. Prominent in the
performance data is NIH's second annual performance report which
compares our fiscal year 2002 results to the goals in our fiscal year
2002 performance plan.
Forty years ago, the U.S. Congress charged the NICHD with a broad
mandate. The Institute was asked to develop a research program to
ensure that people are able to have children when they want them; that
every child is born healthy; that women suffer no adverse consequences
from the reproductive processes; and that children experience healthy
physical, cognitive, behavioral, and social development, reaching
adulthood free of disease and disability, and able to lead productive
lives.
We have made exceptional progress toward those goals during the
last 40 years. Infant mortality has been cut by more than 70 percent,
largely due to NICHD research that has lead to new ways to treat and
prevent respiratory distress syndrome, to manage premature infants, and
to reduce Sudden Infant Death Syndrome. Mental retardation in the
United States has been significantly reduced because we have conquered
and controlled some of its leading causes: Hemophilus influenza type b
(Hib) meningitis, phenylketonuria (PKU), measles encephalitis, and
jaundice. Infertility that deprived millions of couples from conceiving
children can now be diagnosed and in many cases treated. Transmission
of HIV infection from mother to baby has been reduced from 27 percent
to less than 2 percent in the U.S. as a result of research showing the
effectiveness of administering antiretroviral drugs to the mother
during pregnancy and to the infant just after birth.
We look forward to building on 40 years of scientific achievements
and we would like to share with you recent achievements that are
improving the health of the American people.
PREMATURE BIRTH: NEW RESEARCH MAY REVERSE A TREND
The number of infants who are born prematurely is increasing. While
infant mortality rates have decreased significantly in recent years,
the number of premature low birth weight babies born has increased by
11 percent over the last two decades. The number of premature very low
birth weight infants, weighing less than 1,500 grams, has increased by
24 percent. Research supported by the NICHD has helped many premature
infants to survive. But these infants can develop neurological,
respiratory, or other conditions causing life-long disabilities.
Recently, NICHD scientists discovered that weekly injections of
progesterone, a readily available hormone, can lower premature birth by
more than one-third among women who are at risk of premature delivery.
In this study, like many clinical studies, some of the women received
the progesterone and some received a placebo injection. The results
were so dramatic that the scientists halted the study and administered
progesterone to all women enrolled in the study.
ORAL CONTRACEPTIVES AND BREAST CANCER: NO ASSOCIATION
The NICHD research has also provided reassuring evidence to women
and their physicians who may be concerned about a possible relationship
between oral contraceptive use and breast cancer. About 80 percent of
U.S. women born since 1945 have used oral contraceptives. Conflicting
studies had caused concern about the possible effect of oral
contraceptive use on breast cancer risk. The NICHD's Women's
Contraceptive and Reproductive Experiences Study found that women
between the ages of 35 and 64 who took oral contraceptives at some
point in their lives were no more likely to develop breast cancer than
other women the same age who never took oral contraceptives. Many women
who took oral contraceptives during their reproductive years are now
reaching the ages of greatest breast cancer risk. This study should
resolve the long-standing concern that oral contraceptive use might be
associated with an increased risk of breast cancer in later life.
VASECTOMY AND PROSTATE CANCER: NO ASSOCIATION
Another study supported by the NICHD answered an important question
for men who have had vasectomies. About one out of six American men
over the age of 35 has had a vasectomy. Some studies conducted in the
United States in the early 1990s reported a moderately increased risk
of prostate cancer among men who underwent vasectomy. Other studies
found no such risk. Because of this conflicting evidence, many
urologists have increased prostate cancer screening of men who had
vasectomies and have discouraged vasectomies in men with a family
history of prostate cancer. The NICHD study found that men who had a
vasectomy were no more likely to develop prostate cancer than those who
had not had a vasectomy. The study also found that men who had
vasectomies as long as 25 years ago did not have an increased risk of
prostate cancer. These results should reassure men who have had or who
are considering a vasectomy.
STROKE PATIENTS IMPROVE FUNCTION OF IMPAIRED LIMB
The results of other NICHD-supported research provide encouraging
news to some stroke victims. Until recently, therapy for stroke victims
often involved teaching patients to strengthen their less impaired limb
for several weeks after a stroke. The prevailing view among
rehabilitation professionals was that patients' motor ability reached a
plateau at about six months after a stroke. They believed that
additional therapy would provide little if any additional benefit. But
new research has shown that the use of the impaired limb can improve
significantly a year or more after a stroke. Using ``Constraint Induced
Therapy,'' researchers showed that constraining the good or less
affected limb for 10 days can help restore a great deal of mobility to
the impaired limb.
TRAUMATIC BRAIN INJURY NETWORK FOR BETTER TREATMENTS
Traumatic brain injury is one of the leading causes of death and
disability in children and adults. An estimated two million head
injuries occur in the United States each year. As a result of advances
in emergency medicine at the accident scene and the hospital, many TBI
victims are living longer. However, many will live with persistent
physical, cognitive, behavioral and social deficits that compromise
their quality of life. Research over the last two decades has
demonstrated that not all neurologic damage occurs at the moment of
injury, but evolves over the minutes, hours, and days after an
accident. Research also has dramatically improved the immediate care,
follow-on care, and rehabilitative process for TBI patients. Yet there
are many unanswered questions about the underlying damage and the
reasons for reduced functioning associated with TBI. In addition, to
determine the most appropriate therapies for children and young adults
with TBI, multiple sites are needed to evaluate various interventions
with many patients. To address this need, the NICHD recently
established the Traumatic Brain Injury Clinical Trials Network. The
Network will evaluate medical, rehabilitative, and educational
interventions to identify which ones most effectively improve the long-
term outcomes of TBI patients.
NEW FRAGILE X CENTERS WILL DEVELOP TREATMENT OPTIONS
Fragile X syndrome is the most common genetically-inherited form of
mental retardation currently known. The condition occurs in every 1 out
of 2,000 males and in 1 in 4,000 females. The syndrome is caused by a
mutation in a specific gene (FMR1) on the X chromosome. In its fully-
mutated form, the FMR1 gene interferes with normal development. In a
partially mutated (premutation) form, the FMR1 gene can cause fragile X
syndrome in the children of a carrier (a person who has the premutation
gene). Until recently, however, the premutation form was not thought to
cause symptoms in carriers. Scientists have now identified a subgroup
of premutation FMR1 carriers with symptoms that appear to be associated
with the gene. Symptoms included mild cognitive and emotional problems
and, in female carriers, premature menopause. In older male carriers,
the premutation gene is associated with a neurological syndrome.
Identifying a genetic basis could be a first step toward accurate
diagnosis and, possibly, development of new treatments for these often
overlooked symptoms. In addition, to develop improved diagnostic
techniques and treatment options, the NICHD will begin funding three
new Fragile X research centers in fiscal year 2003. Each center will
call upon the combined expertise of several researchers working in
diverse fields to investigate different aspects of the disorder. The
new Fragile X Research Centers will study issues such as how the
fragile X affects the developing brain and nervous system, how the
disorder progresses throughout an individual's life span, and effective
treatments that can improve the behavior and mental functioning of
people with fragile X syndrome.
STRATEGIC ALLIANCES WITH MINORITY GROUPS TO REDUCE SIDS
Less than ten years ago, the NICHD initiated a campaign urging
parents and care takers to place infants on their backs to sleep to
reduce the risk of Sudden Infant Death Syndrome (SIDS). Since that
time, the SIDS rate in the U.S. has declined by more than 50 percent.
This dramatic decline represents a significant public health
achievement because the SIDS rates had remained tenaciously steady
prior to the NICHD campaign. Although the SIDS rates have declined in
all populations since the campaign began, the SIDS rate among African
American infants remains double that of white infants. Among Alaska
Natives and many American Indian tribes, the rates are higher still. To
begin closing this gap, the NICHD has formed strategic alliances with
the Alpha Kappa Alpha sorority, The National Coalition of 100 Black
Women, and The Women in the NAACP. In collaboration with these
organizations, the NICHD has planned and will support a series of
``summit'' meetings in three U.S. cities with high rates of African
American SIDS deaths. These summits will enlist the resources of faith-
based and community organizations, public health officials, and service
organizations to help establish an infrastructure that will provide
information, material, and support for reducing SIDS among African
American infants. Each organization will take the lead in organizing
one of the summit meetings and will continue to serve as the catalyst
for SIDS risk reduction activity in that city and its surrounding
region.
The NICHD has also initiated a project with American Indian and
Alaska Native groups to reduce SIDS and infant mortality in these
populations. At NICHD-sponsored meetings in Minneapolis, MN and Rapid
City, SD, representatives of Tribal Chairman's Health Boards and Alaska
Native health organizations provided the NICHD with a blueprint to
support the activities of community health workers involved in SIDS
risk reduction education. The NICHD will develop and disseminate the
materials for this effort during the current year.
TESTING DRUGS TO IMPROVE HEALTH OF CHILDREN AND PREGNANT WOMEN
In fiscal year 2004, the NICHD will continue to invest in research
and programs that benefit the American people. One such investment is
the fulfillment of the Best Pharmaceuticals for Children Act (BPCA).
The immature physiology of children means that drugs approved to
prevent or treat illness in adults may have different effects in
younger patients, requiring children's physicians to prescribe
different doses and make other adjustments in drug therapies. However,
for approximately seventy-five percent of the pharmaceuticals approved
by the Food and Drug Administration (FDA) for adults, there are
inadequate safety and efficacy data to allow approval for pediatric
uses, or to guide physicians in prescribing these drugs for children.
The BPCA, signed into law in January 2002, directs the NIH to issue
contracts to test in children off-patent prescription drugs already
approved for adults. Working with the FDA and other experts, the NICHD
identified a priority list of drugs to be tested through the
Institute's Pediatric Pharmacology Research Units (PPRUs) and at other
sites. The fiscal year 2004 budget request includes an increase of $25
million, across all of the NIH Institutes and Centers (ICs), for these
studies.
Drugs prescribed to pregnant women are also a concern. Although
nearly two-thirds of all pregnant women take at least four to five
drugs during pregnancy and labor, the effects of these prescribed drugs
on a pregnant woman and her fetus remain largely unstudied. In
addition, little is known about how pregnancy-related changes in
cardiac output, blood volume, intestinal absorption, and kidney
function may influence drug absorption, distribution, utilization, and
elimination. Therefore, the NICHD will establish a new network of
Obstetric-fetal Pharmacology Research Units that will allow
investigators to conduct key pharmacologic studies of drug disposition
and effect during normal and abnormal pregnancies.
EXPANSION OF NEWBORN SCREENING THROUGH MICROARRAY TECHNOLOGY
At present, all states routinely screen all newborns for only two
disorders: phenylketonuria (PKU) and congenital hypothyroidism. These
are conditions for which effective treatments are available. In
addition, most states screen for a mix of 1 to 15 other disorders, but
some commercially available tests can screen for up to 50 conditions. A
Secretarial-level panel and the American Academy of Pediatrics have
recommended that an expanded and standardized approach to newborn
screening be developed. To address this need, the NICHD proposes to
apply the knowledge and techniques garnered from the Human Genome
Project. Using cord blood and microarray technology, there is the
potential to identify disease genes at birth for more than 200 single
gene defects associated with mental retardation, nearly 100 associated
with immunodeficiency disorders, approximately 10 causes of muscular
dystrophy, and cystic fibrosis. Although treatments are available for
many of these conditions, effective study of potential new treatments
for others requires a population who has not yet developed symptons of
the condition. Screening of newborn infants can provide this
population. This testing could be done in one procedure so that
economies of scale and simplicity may overcome one of the major
obstacles to widespread acceptance of expanded newborn screening: cost.
The NICHD will collaborate with several other ICs, research
institutions, and industry to develop the appropriate microarray chip
and associated technology for mass screening and pilot test the new
screening technology. This approach would maximize the use of newborn
screening for preventive purposes. Moreover, by developing this
translational research, NICHD will fulfill one of the objectives of the
NIH road map activities.
Mr. Chairman, I will be happy to provide answers to any questions
you have.
______
Prepared Statement of Dr. James F. Battey, Jr.
Mr. Chairman and Members of the Committee, I am pleased to present
the President's budget request for the National Institute on Deafness
and Other Communication Disorders (NIDCD). The fiscal year 2004 budget
includes $380,377,000, which reflects an increase of $10,190,000 over
the fiscal year 2003 enacted level of $370,187,000 comparable for
transfers proposed in the President's request. Disorders of human
communication exact a significant economic, social, and personal cost
for many individuals. The NIDCD supports research and research training
in the normal and disordered processes of hearing, balance, smell,
taste, voice, speech, and language. Results of NIDCD's research
investment will foster the development of more precise diagnostic
techniques, novel intervention and prevention strategies, and more
effective treatment methods for the millions of Americans with
communication disorders. My testimony will highlight some examples of
research progress in human communication sciences.
Cochlear Implants.--If Ludwig van Beethoven were able to reverse
his deafness and regain his hearing again as he reached the climax of
his career as a composer, would the world have been blessed with even
more of his music? Scientific technology has advanced significantly
since the 18th century, and assistive hearing devices are now able to
restore sound perception to deaf individuals. One such device, the
cochlear implant, has provided hope to thousands of deaf individuals
worldwide. A cochlear implant converts sound into electrical impulses,
bypassing the damaged sensory hair cells that detect sound, stimulating
the auditory nerve directly and restoring sound perception. According
to the Food and Drug Administration 2002 data, approximately 59,000
people worldwide have received cochlear implants. In the U.S., about
13,000 adults and nearly 10,000 children have received them. With over
30 years of NIH research investment, the cochlear implant has evolved
from an experimental device to a commercially available treatment to
assist those who are profoundly deaf or severely hearing impaired.
Hereditary Deafness Gene Discovery.--Within the last seven years,
over 70 different genes for hearing loss that is not associated with
other inherited characteristics (nonsyndromic hereditary hearing
impairment) have been mapped and over 25 identified. In addition,
several genes essential for normal auditory development and/or function
have been identified using mouse models. Recently, scientists have
discovered a new gene of unknown function, TMC1, in which mutations
cause deafness. NIDCD intramural scientists have identified a mutation
in the mouse Tmc1 gene which causes similar types of dominant and
recessive hearing loss found in large human family studies. In mice,
mutations in the Tmc1 gene causes defects in the function of the
specialized sensory hair cells of the inner ear. Hair cells detect and
convert the physical stimulus of sound into electrical impulses sent to
the brain via the auditory nerve. This research contributes to new
models for studying specific forms of human deafness.
Sensory Stereocilia Renewal Aid Recovery to Hearing Loss.--
Stereocilia, or hair cell bundles, are fine projections in the inner
ear that vibrate when stimulated by sound. The movement of the
stereocilia activates a molecular pathway that generates an electrical
signal from the auditory nerve to the brain, which is interpreted to be
sound. Stereocilia are located in the surface of the inner ear and are
supported by a rigid and dense core of filaments. Until recently, this
core was thought of as a stable structure whose sole function was to
serve as rigid supports for changes in the mechanical property of the
hair cells. NIDCD intramural scientists have discovered that there is a
continuous renewal of the stereocilia core every 48 hours. This process
occurs in the mature bundles during recovery from temporary noise-
induced hearing loss and suggests that the stereocilia core structure
plays an unforeseen role in this recovery process. Such a renewal
mechanism could also provide more information on the molecular basis of
genetic, environmental, and age-related inner ear disorders that
involve malformation or disruption of stereocilia.
Motor Protein Facilitates the Speed of Sound.--One important
component in the mechanical transmission of sound from the ear to the
brain is Myosin-1C, a major motor protein involved in the movement of
the stereocilia in the inner ear. It is hypothesized that motor
proteins serve as the link between the stereocilia's membrane and cell
core thereby changing the polarity of hair cells following sound
vibration. NIDCD-supported scientists are in the process of deciphering
how Myosin-1C works. Specifically, they used a chemical-genetic
approach to inhibit Myocin-1C motor protein activity in mice by
introducing a custom designed amino acid that alters the protein's
function. The designer amino acid rendered the protein susceptible to a
controllable inhibitor, thus allowing regulation of the protein's motor
function. These results demonstrate the importance of Myosin-1C in
transmitting sound to the brain, allows observation of protein function
in a controllable native environment and permits assessment of protein
function in a biological process.
Antibiotic Controls the Vertigo of Meniere's Disease.--Meniere's
disease is a distressing and often disabling disorder of inner ear
function, characterized by spontaneous attacks of vertigo, fluctuating
hearing loss, tinnitus and fullness in the ear. When vertigo cannot be
controlled by diet or medication, severing of a vestibular nerve from
the affected ear usually controls vertigo while preserving hearing.
NIDCD-supported scientists have demonstrated that a single injection of
the antibiotic, gentamycin, through the eardrum into the middle ear
space, is an alternative to surgery and is effective in diminishing
vestibular response and in controlling vertigo in individuals with
Meniere's disease. Experimental studies suggest that gentamycin reduces
vestibular responsiveness, and hence, vertigo, by causing a toxic
effect on the vestibular hair cells, the sensory receptors that detect
head motion stimuli and orientation.
Odorant Receptors Help Mosquitoes Smell Their Prey.--The sense of
smell (olfaction) plays an important role for blood-feeding female
mosquitoes in finding a host. Mosquito-borne disease is a serious world
health concern, and the mosquito is known to transmit a variety of
deadly diseases, including malaria, West Nile virus, dengue and yellow
fever. Host preference, especially to humans, in the female mosquito is
a critical component of disease transmission. NIDCD-supported
scientists are characterizing the genes that play a role in the
function of the olfactory system of Anopheles gambiae and have
identified odorant receptor-encoding genes selectively expressed in the
olfactory organs of this malaria-transmitting mosquito. Blood-feeding
and host preference selection involve only the female mosquito, so the
scientists studied the expression of odorant receptor genes, AgOr, in
the female mosquito's primary olfactory organ--its antennae. It was
observed that AgOr1 is turned off in the olfactory tissue of the female
mosquito 12 hours after a blood meal, which is consistent with
decreased host-seeking behavior. These findings suggest that AgOr1 may
detect an olfactory signal that is active in female mosquitoes before
but not after a blood meal. Developing selective antagonists to AgOr1
may help to control the transmission of malaria and other mosquito-
borne diseases, and may also represent a novel disease prevention
approach that is based on an understanding of olfactory receptor genes.
In addition, these findings may ultimately be useful in developing new
repellants and attractants that are more effective, economical and
ecologically friendly.
Discovery of an Amino Acid Taste Receptor.--Taste is responsible
not only for attraction and repulsion to various foods but is also
responsible for providing important information about the chemical
environment. The basic taste qualities are sweet, sour, salty, bitter
and umami (the taste of monosodium glutamate or the taste associated
with protein-rich foods). A major challenge in taste research is
identifying the various types of taste receptors on the tongue that
respond to different structurally diverse compounds. Recently,
scientists have identified a taste receptor dedicated to tasting amino
acids, the building blocks of proteins that are involved in the
biological processes in the body. It has been known that sweet-,
bitter- and umami-tasting substances activate G-protein-coupled
receptors in the tongue. NIDCD-supported scientists discovered that two
subunits in the T1R receptor family, T1R1 and T1R3, can combine to form
an amino acid receptor, T1R1+3, that responds to most of the 20
standard amino acids. Identification of an amino acid taste receptor
provides a new tool to help scientists decode the molecular basis for
detecting different taste qualities in mammals.
Do Stutterers Have Different Brains?--To study the brain activity
patterns in the cortical speech-language areas of the brain of
individuals who stutter, NIDCD-supported scientists performed brain
imaging studies on two groups of adults; those with or without
persistent developmental stuttering (PDS). Results of the analysis
showed that differences in the speech-language areas of the brain are
more common in adults with PDS, although no one anatomic feature
accounted for the group differences. The major anatomic finding was
that the size of the right and left planum temporale (PT) of the brain
were significantly larger in the adults with PDS. The PT is important
for higher order processing of language information. The results about
the PT size and other findings, such as variations of infolding
patterns of the brain, demonstrate that atypical size or shape of the
speech-language area may put individuals at risk for stuttering.
Speech-Sound Disorders are Risk for Later Academic Impairments.--
Children with speech-sound disorders often have difficulties in other
areas of language as well. These disorders are characterized by the
inability to use speech sounds that are normal for the individual's age
and dialect. Speech-sound disorders involve language difficulty
affecting an individual's ability to learn and organize speech sounds
into a system of sound patterns. Poor awareness of speech skills and a
weakness in vocal sound classification in verbal memory may put
children of preschool age with speech-sound disorders at risk for later
spelling difficulties. In a recent NIDCD-supported study, the spelling
errors of children with history of speech-sound disorders were analyzed
to predict the association between weaknesses in spoken language skill
in early childhood and school-age spelling abilities. The findings of
this study support previous research indicating that children with
early speech-sound disorders are at risk for later spelling
difficulties. Evidence from studying these families raises the
possibility of a common genetic cause for speech/language and written
language disorders. Although the genetic cause for these disorders is
not known, specific signs of the disorder suggest a male gender bias
since brothers were also more likely to have the disorder than sisters.
The findings of this study reveal that preschool children with speech-
sound disorders are at risk for later spelling impairments even after
productive speech disorders have resolved.
A Possible Gene for Childhood Language Disorders.--Children who
fail to develop language normally (in the absence of factors such as
neurological disorders, hearing impairments, or lack of adequate
opportunity) have specific language impairment (SLI). SLI has a
prevalence of approximately 7 percent in children entering school and
is associated with later difficulties in learning to read. Research
studies have consistently demonstrated that SLI clusters in families,
suggesting that genetic factors may be an important cause of SLI.
NIDCD-supported scientists are scanning the genome for the location of
the gene suspected of causing SLI, by studying families where multiple
members have with language/reading disorders. The study showed
significant evidence of a link between a region of chromosome 13 and
susceptibility to SLI. Further analysis also suggests two additional
gene locations on chromosomes 2 and 17 that may play a role in SLI. In
addition, mutations in the same region in chromosome 13 is implicated
in autism, and some children with autism show language deficits that
are very similar to SLI.
Mr. Chairman and Members of the Committee, these are just a few
examples of NIDCD's research advances. I would be pleased to answer any
questions you may have.
______
Prepared Statement of Dr. Francis S. Collins
Mr. Chairman and Members of the Committee: Due in great part to the
visionary leadership and commitment of Congress, this month the
International Human Genome Project (HGP), led by the National Human
Genome Research Institute (NHGRI) of the National Institutes of Health
(NIH), will have accomplished all of its original goals, ahead of
schedule and under budget. This historic achievement, in the month of
the 50th anniversary of Watson and Crick's seminal publication of the
structure of DNA, opens the genomic era of medicine. April will also
witness the publication of a bold vision for the future of genomics
research, developed by the NHGRI. This vision, the outcome of almost
two years of intense discussions with hundreds of scientists and
members of the public, has three major areas of focus: Genomics to
Biology, Genomics to Health, and Genomics to Society.
Genomics to Biology.--The human genome sequence provides
foundational information that allows development of a comprehensive
catalog of all of the genome's components, determination of the
function of all human genes, and deciphering of how genes and proteins
work together in pathways and networks.
Genomics to Health.--Completion of the human genome sequence offers
a unique opportunity to understand the role of genetic factors in
health and disease, and to apply that understanding rapidly to
prevention, diagnosis, and treatment. This opportunity will be realized
through such genomics-based approaches as identification of genes and
pathways and determining how they interact with environmental factors
in health and disease, more precise prediction of disease
susceptibility and drug response, early detection of illness, and
development of entirely new therapeutic approaches.
Genomics to Society.--Just as the HGP has spawned new areas of
research in basic biology and in health, it has created new
opportunities in exploring societal issues. These include analysis of
the impact of genomics on concepts of race, ethnicity, kinship,
individual and group identity, health, disease, and ``normality'' for
traits and behaviors, and defining policy options regarding the use of
genomic information in both medical and non-medical settings.
NEW NHGRI INITIATIVES
The NHGRI has already begun several new initiatives, and is
planning others, to meet the challenge of this new vision for the
future of genomics. Below are examples of these cutting edge programs.
The Creation of a Human Haplotype Map
Multiple genetic and environmental factors influence many common
diseases, such as diabetes, cancer, stroke, psychiatric disorders,
heart disease, and arthritis; however, relatively little is known about
the genetic basis of common diseases. The NHGRI has begun to create a
``haplotype map'' of the human genome to enable scientists to find the
genes that affect common diseases more quickly and efficiently. The
power of this map stems from the fact that each DNA variation is not
inherited independently; rather, sets of variations are inherited in
blocks. The specific pattern of particular genetic variations in a
block is called a haplotype. This new initiative, an international
public/private partnership led and managed by NHGRI, will develop a
catalog of haplotype blocks, the ``HapMap.'' The HapMap will provide a
new tool to identify genetic variations associated with disease risk or
response to environmental factors, drugs, or vaccines. Ultimately, this
powerful tool will lead to more complete understanding of, and improved
treatments for, many common diseases.
The ENCODE Project: ENCyclopedia Of DNA Elements
To utilize fully the information that the human genome sequence
contains, a comprehensive encyclopedia of all of its functional genetic
elements is needed. The identity and precise location of all
transcribed sequences, including both protein-coding and non-protein
coding genes, with their structure, transcription start sites,
polyadenylation sites, and alternative splicing variants must be
determined. The identity of other functional elements encoded in the
DNA sequence, including promoters, enhancers, and other transcriptional
regulatory sequences, and determinants of chromosome structure and
function, such as origins of replication and hot spots for
recombination, also is needed. The NHGRI has developed a public
research consortium to carry out a pilot project, focusing on a
carefully chosen set of regions of the human genome, to compare
existing and new methods for identifying functional genetic elements.
This ENCyclopedia Of DNA Elements (ENCODE) consortium, which welcomes
all academic, government, and private sector scientists interested in
facilitating the comprehensive interpretation of the human genome, will
greatly enhance use of the human genome sequence to understand the
genetic basis of human health and to stimulate the development of new
therapies to prevent and treat disease.
Chemical Genomics
One novel way that the NHGRI plans to pursue translating genomics
to human health is the development and deployment to the biomedical
research community of libraries of small organic compounds. This is a
fundamentally new approach for research in the public sector, and will
accelerate understanding of the function of the human genome and the
development of new treatments. The NHGRI proposes to use the types of
organic molecules in most marketed pharmaceuticals, ``drug-like,'' or
``small'' molecules, as a core of this resource. In collaboration with
other NIH institutes, the NHGRI is planning for a resource that
includes: (a) large libraries of chemical compounds of appropriate
structural diversity and properties; (b) assay development capacity;
(c) robotic assay capacity, also termed high throughput screening
(HTS); (d) medicinal chemistry capacity to transform ``hits''
identified by HTS into workable chemical probes; and (e) distribution
capacity to disseminate the reagents to the biomedical research
community efficiently.
Genome Technology Development
The NHGRI continues to invest in technology development that
furthers the uses of genomics. Technical advances have caused the cost
of sequencing to decline dramatically, from $10 to less than $0.09 per
base pair, but this cost must decline even further for all to benefit
from genomic advances. The NHGRI, along with many partners, will
actively pursue the development of new technologies to sequence any
individual's genome for $1,000 or less. Other areas of technology
development are also ripe for expansion and the NHGRI plans to pursue
them vigorously.
Studying the Genetic Basis of Health
Analytic methods to find genetic variants that contribute to
disease can also help find genes and genetic variants that contribute
to health. The NHGRI plans to support development of new tools and
analytical methods to discover the genetic components of resistance to
diseases, disorders, toxins, and drug reactions. By finding genetic
variants that convey reduced susceptibility, researchers will better
understand disease processes and how to slow, or even prevent, them.
Promising approaches for identifying disease-resistant gene variants
include studying people at high risk for a disease who do not develop
it, relatives of people with disease who do not themselves have the
disease, or individuals who reach extreme old age without serious
illness.
RECENT SCIENTIFIC ADVANCES IN GENOMICS
Progress in Sequencing Model Organisms
From the Human Genome Project's outset, the NHGRI and its partners
have included, among their research goals, mapping and sequencing the
genomes of several non-human organisms, since they would be of great
value in understanding the biological data encoded in the human DNA
sequence and, thus, in combating human disease. Genomic sequences for a
number of important organisms, beyond those initially identified by the
HGP, have been determined. Primary among these is the laboratory mouse.
In December 2002, an analysis of an advanced draft of the mouse genome
was published and provided a key tool for interpreting the human
sequence. The first assembly of the rat genome sequence was announced
in the same month by the Rat Genome Sequencing Project. A peer review
process now selects new genomes to sequence. To champion an organism,
scientists write a ``white paper'' that presents arguments for
prioritizing their proposed target for sequencing. After two rounds of
white papers, this process determined the highest priority as: chicken,
chimpanzee, cow, dog, a set of fifteen fungi, honeybee, sea urchin, and
two protozoans. Sequencing of the chicken, chimpanzee, and honeybee has
already begun.
ETHICAL, LEGAL AND SOCIAL IMPLICATIONS OF GENETIC RESEARCH
The NHGRI devotes five percent of its annual budget to research
involving the ethical, legal and social implications (ELSI) of genetics
and genomics. Below are examples of this program's important work.
Genetic Discrimination
Most Americans are optimistic about the use of genetic information
to improve health, but many are also concerned that insurers and
employers will misuse genetic information. These concerns deter
participation in important biomedical research and the clinical use of
genetic information. The NHGRI has supported research efforts to
elucidate this issue. Such research has helped inform legislative
activity; over 40 states have passed genetic nondiscrimination bills.
Reducing Health Disparities
The NHGRI recognizes the critical importance of ensuring that the
potential of genomic research benefits all racial and ethnic groups.
The NHGRI has taken steps to engage and empower minority communities in
genomic research. The rewards of genomic research will be realized only
with active participation of all racial and ethnic groups. An important
area of genomic research is investigating how DNA sequence variation
affects differing susceptibility to disease among various populations.
The significant societal ramifications of this research also need
attention. Genomic research affects all populations; thus, all groups
need to set the research agenda and examine the broader issues it
raises. The NHGRI has intensified its efforts to address health
disparities by developing a strategic plan that identifies goals in
areas such as research projects, information sharing, development of
partnerships, and increasing diversity of the research workforce.
Effects of Gene Patents and Licenses on Genetic Testing and Research
The NHGRI continues to be concerned about the issues of gene
patenting and licensing. To gain a better understanding of these
issues, it has funded case studies and surveys to describe and analyze
the effects of patents that award proprietary claims to the use of DNA
sequences. The NHGRI held a roundtable discussion in December 2002 with
outside experts in gene patenting to explore the ramifications on
healthcare delivery and research of patenting and licensing genetic
sequence data and single nucleotide polymorphisms. The NHGRI will
utilize the insights provided at this roundtable to define further
research to inform the policy process.
CONCLUSION
This year marks a very exciting transition in the field of
genomics, with the full sequencing of the human genome marking the
successful achievement of all of the HGP's original goals, and thus the
advent of the genomics era. When Congress decided to fund the HGP it
did so with the justifiable belief that this work would lead to
improved health for all. The ability to accelerate the realization of
this vision now lies before us. At the same time, we must be sure that
all our citizens have access to these technological advances and that
this information is not misused. It is our sincere belief that the
newly created discipline of genomics will make a profound difference on
the health and well being of the people of this world. We are
profoundly grateful for the support the Congress has given to this
program.
Mr. Chairman, I am pleased to present the President's budget
request for the National Human Genome Research Institute. The fiscal
year 2004 budget includes $478,072,000, an increase of $13,467,000 over
the fiscal year 2003 enacted level of $464,605,000 comparable for
transfers proposed in the President's request.
______
Prepared Statement of Dr. Andrew C. von Eschenbach
The early part of the 21st century promises to be a period of
unprecedented progress in conquering our most debilitating diseases
especially cancer. The nation's unwavering support of the biomedical
research enterprise, in particular, the unified effort by this
committee, all of Congress, and the President to double the NIH budget
over the past five years, has positioned us to attack this devastating
disease more effectively. Cancer affects nearly every family in
America. In 2003, 1.4 million of our citizens will face a diagnosis of
cancer--and over 560,000 of our citizens will die from their disease
this year. Every day, 1,500 Americans lose their own battle with
cancer. These are daunting statistics, and the aging of the baby boomer
population and shifting demographics of America during the next 15-20
years represent enormous healthcare and economic challenges that we
must begin to prepare for now.
But, there is reason for optimism! Our nation's investment in basic
research has fueled the engine of discovery, thereby enabling
unparalleled advances in illuminating the genetic changes and molecular
mechanisms that ultimately produce cancer. The sequencing of the human
genome and associated progress in new areas such as functional
genomics, animal models of cancer, and proteomics, provide us with a
clearer picture of the disturbances that cause cancer to develop and
ravage the human body. For the first time, we have within our grasp the
ability to design target-specific interventions to preempt this
process. We must enrich these extraordinary advances in basic science
with equally extraordinary efforts to develop new agents and
technologies to actualize these interventions at key steps in cancer
progression. We now understand that cancer is a process--a process with
multiple opportunities to develop new, more effective interventions to
prevent, detect and treat cancer.
To capitalize on this knowledge, we must significantly accelerate
the pace of progress across the entire research continuum. The pathway
begins with discovery of knowledge that underpins the development of
new molecules and tools and ends with the delivery of diagnostics and
therapeutics to patients. Discovery, development and delivery are
interlinked, and it is crucial that we take the steps needed to ensure
that all phases of the research enterprise are functioning optimally.
I believe that we stand at an ``inflection point'' in our nation's
effort to conquer cancer. The research enterprise has delivered
remarkable scientific achievements in biomedical research over the past
decades, and we now are positioned to experience a rapid increase in
the trajectory of this research. This affords us an unprecedented
opportunity to harness strategically these achievements to confront the
challenges of cancer today and tomorrow.
We now envision a time when the suffering and the death that are
caused by cancer will be eliminated; and we believe that it is
realistic to set ourselves a challenge goal to achieve this vision by
the year 2015. I have presented the cancer research community with this
challenge and am confident that they will achieve the goal. I want to
be clear what we mean by ``reduce suffering and death from cancer,''
and to explain why I believe that this vision is achievable.
We are not saying that all cancer will be cured or eliminated. What
we are saying is that in this 12-year time-frame, many cancers will be
cured, but many more will be transformed into chronic, manageable
diseases that patients can live with--not die from. There is precedent
for this paradigm shift. In a single generation, we made enormous
strides in reducing deaths from coronary artery disease and converting
this disorder into a condition that people live with and manage.
Likewise, using our knowledge of the AIDS virus, molecular biology, and
skills in developing target-based therapy, we have developed treatments
for AIDS patients that both save lives and preserve quality of life. I
think we can do the same for cancer.
This vision presents new challenges for the NCI and for everyone
working to conquer this devastating disease. We will meet those
challenges by further strengthening basic research, especially in
advancing our understandings about the mechanisms of cancer
progression. In parallel, we will intensify our focus on developing the
clinical research and delivery systems needed to provide the promise of
everything that science can provide to everyone in need.
I discovery, we will establish a national effort to ``map'' the
critical events of the complex of integrated cancer disease pathways at
the cellular level. This ``systems biology approach'' will allow us to
dissect strategically the complex and redundant reactions and
interactions within cells, and will enhance our technical capabilities
to identify molecular targets and create new therapies. We will also
focus on the exploration of new technologies, in reas such as molecular
imaging, proteomics and genomics, and nanotechnology. These new
technologies offer the promise of developing new platforms to monitor
cells, identifying intricate molecular changes, and delivering
therapeutics to specific targets within the cell. The application of
these advanced technologies is no longer a dream. Advances in positron
emission tomography, coupled with new molecular imaging agents, now
make functional monitoring possible, permitting clinicians to
``visualize'' the biologic progress of cancer. Scientists and engineers
are working to achieve this goal through NCI's unique programs that
foster the development of innovative technologies for cancer diagnosis
and treatment.
The NCI will also place new emphasis on the development process--
the translation of basic research advances into new products that are
ultimately delivered to cancer patients. This is especially true in the
area of cancer therapeutics. It currently takes 15-20 years for a
promising new molecule to reach patients. That is just unacceptable in
the 21st century. Genomics and proteomics are providing us with
hundreds, potentially thousands, of new therapeutic targets for cancer;
but the enterprise is not optimized to develop and deliver these ``new
paradigm'' drugs. This is a systems problem and it can be solved. In
collaboration with he NIH, the Food and Drug Administration (FDA) and
other partners, we will work to ``re-engineer'' the clinical trials
infrastructure for the evaluation of new cancer interventions.
Underpinning all of these initiatives will be the deployment of a
bioinformatics infrastructure that will allow us to use artificial
intelligence to convert massive amounts of data into new knowledge that
will inform discovery, development, and delivery to benefit patients.
The NCI will undertake programs to optimize the process of
developing new drugs trough an emphasis on validating new cancer
targets. We will also work more closely with the FDA to facilitate the
science necessary to create a seamless system of drug discovery,
development, and delivery. To achieve these goals, the NCI will create
novel partnerships with all of the sectors involved in developing and
delivering these new drugs. In all that we do, we will encourage the
removal of barriers that separate us by creating a new environment that
encourages and rewards multi-disciplinary research.
The emerging field of proteomics provides us with unimagined
opportunities to apply these new targeted therapies and preventive
strategies by detecting cancer early enough to stop, slow, or possibly
reverse disease progression. Novel disease biomarkers are finally
providing us with new screening tools to detect early-stage cancer in
populations and individuals; and the NCI will utilize its enormous
strength in molecular epidemiology to provide rational strategies for
cancer prevention and disruption of progression within populations.
All of these tactics will be directed to reducing suffering and
death from cancer. That does not mean that we will lessen our emphasis
on curing cancer--quite the opposite--but that will no longer be our
only defining goal. We will also embrace the vision of changing the
course of cancer by reducing its morbidity and mortality through the
application of technologies and knowledge that were only a dream just a
few short years ago. Those dreams can become reality.
Finally, I believe we stand at a pivotal crossroads--a defining
moment in the history of this nation's effort to prevent and cure
cancer. We now embark on a new course that will enable patients to live
with cancer as a chronic, non-debilitating disease that doesn't
threaten their vitality, careers, and families. An ever increasing body
of scientific knowledge and an array of advanced technologies provide
us with the opportunity to detect cancer early and preempt the
progression of the disease. We will be able to remove the fear of
cancer for many more people, but more importantly for those who must
live with their disease, life will take on new meaning. We have within
our grasp the power to eliminate the suffering and death from cancer--
and we will succeed.
BUDGET STATEMENT
The fiscal year 2004 budget includes $4,770 million, an increase of
$183 million over the fiscal year 2003 enacted level of $4,587 million
comparable for transfers proposed in the President's request.
______
Prepared Statement of Dr. Anthony S. Fauci
Mr. Chairman and Members of the Committee: I am pleased to present
the President's budget request for the National Institute of Allergy
and Infectious Diseases (NIAID) of the National Institutes of Health
(NIH). The fiscal year 2004 budget includes $4,335,255,000, an increase
of $631,126,000 over the fiscal year 2003 enacted level of
$3,704,129,000 comparable for transfers proposed in the President's
request. The NIAID budget request includes the performance information
required by the Government Performance and Results Act (GPRA) of 1993.
Prominent in the performance data is NIAID's third annual performance
report, which compares our fiscal year 2002 results to the goals in our
fiscal year 2002 performance plan.
NIAID: AN OVERVIEW
Since 1948, NIAID has conducted and supported basic research into
the etiology and pathogenesis of allergic, immunologic, and infectious
diseases, as well as targeted research to develop new and improved
interventions to prevent, diagnose, and treat these illnesses. Over the
past half century, and in the past decade in particular, progress in
the core disciplines of the Institute--immunology, microbiology, and
infectious diseases--has been extraordinary. The rapid growth in
scientific knowledge and the availability of new research tools has
facilitated the development of numerous vaccines, therapies and other
interventions that have saved or improved the lives of millions of
individuals. For example, NIAID-supported scientists helped develop
many of our most useful vaccines, including new or improved vaccines
that protect against invasive Haemophilus influenzae type b (Hib)
disease, pneumonia and meningitis caused by pneumococcal bacteria,
pertussis, influenza, measles, mumps, rubella, chickenpox, and
hepatitis A and B. These and other vaccines helped reduce infectious
disease mortality in the Unites States more than 14-fold in the 20th
century.
The scientific advances realized during 55 years of NAID research
have been applied to long-standing global health problems such as
asthma, autoimmune diseases, diarrheal diseases, malaria, and
tuberculosis, as well as to diseases and pathogens that have recently
emerged or re-emerged. Examples of the latter include the acquired
immunodeficiency syndrome (AIDS), highly virulent influenza viruses,
West Nile virus, drug-resistant microbes, severe acute respiratory
syndrome (SARS), and a new kind of emerging disease--one spread
deliberately by bioterrorists. As has been the case with AIDS and other
emerging health crises, the NIAID response to the threat of
bioterrorism has been swift and comprehensive, resulting already in
important progress both in basic science and in the development of
biodefense countermeasures.
NIAID BIODEFENSE RESEARCH
The anthrax attacks in the fall of 2001, which occurred soon after
the horror of the September 11 terrorist assaults on the World Trade
Center and the Pentagon, starkly exposed the vulnerability of the
United States and the rest of the world to bioterrorism. Since the fall
of 2001, NIAID has rapidly accelerated basic and clinical research
devoted to the prevention, diagnosis, and treatment of diseases caused
by potential agents of bioterrorism. Indeed, biodefense research
spending now accounts for approximately one-third of the NIAID research
portfolio. Our efforts have focused both on ``Category A'' agents
considered to be the worst bioterror threats (smallpox, anthrax,
botulinum toxin, plague, tularemia, and hemorrhagic fever viruses such
as Ebola), as well as on a longer list of Category B and C priority
pathogens agents that also pose significant threats to human health.
The NIAID biodefense program is guided by the NIAID Strategic Plan for
Biodefense Research, as well as by detailed research agendas for
Category A agents and Category B and C priority pathogens. Each of
these documents was prepared in consultation with blue-ribbon panels of
experts, and delineates immediate, intermediate, and long-range NIAID
plans for biodefense research and countermeasures development. Using
the roadmap outlined in these agendas, NIAID has developed a total of
46 biodefense initiatives to stimulate research in fiscal years 2002
and 2003: 30 are new initiatives and 16 are significant expansions.
During this same time period, NIAID has seen a 30 percent increase in
the number of grant applications; the vast majority of these are in
response to our biodefense initiatives.
The NIAID biodefense research program is anchored in the
traditional NIH processes of basic biomedical research; concurrently,
we are aggressively pursuing the goal of translating the findings of
basic research into definable and quantifiable endpoints such as
diagnostics, therapeutics, and vaccines. NIAID historically has sought
to translate basic research findings into ``real-world'' interventions,
as with the vaccines noted above. Until now, however, the path to
product development has not been central to our research strategy. The
attacks of September 11, 2001, and the subsequent anthrax incidents
have compelled us to modify somewhat the way we do business, with an
increased focus on translational research and product development. This
applied research is based on the strongest possible foundation of
fundamental knowledge of pathogenic microbes and the host immune
response.
As we pursue innovative biodefense countermeasures, we have
strengthened our interactions with the private sector, including
biotechnology companies and pharmaceutical manufacturers. Many
biodefense products do not provide sufficient incentives for industry
to develop them on their own, because a profitable market for these
products cannot be guaranteed. Therefore, NIAID has developed public-
private partnerships with industry to overcome such obstacles so that
new and improved interventions against bioterror threats can quickly be
developed.
A number of significant advances in understanding, treating, and
preventing potential agents of bioterror already have been realized.
For example, NIAID-supported scientists have identified antivirals that
may play a role in treating smallpox or the complications of smallpox
vaccination, as well as new antibiotics and antitoxins against other
major bioterror threats. Investigators have demonstrated that existing
stores of smallpox vaccine can be diluted five-fold and still retain
their potency, greatly increasing the Nation's available stock of
smallpox vaccine. These studies of diluted smallpox vaccine helped
fulfill an immediate goal delineated in our strategic plan for
biodefense. In the intermediate-term, new and improved vaccines against
smallpox, anthrax, and other potential bioterror agents are being
developed and evaluated at NIAID intramural facilities, as well as by
our grantees and contractors in academia and industry. One of these is
a smallpox vaccine based on a strain of the vaccinia virus that
replicates less robustly than the traditional smallpox vaccine virus,
and is known to be less reactogenic than the current smallpox vaccine.
In the long-term, we will develop even safer vaccines against smallpox
virus and other pathogens.
Advances in biodefense, as well in other areas of infectious
diseases research, are being facilitated by the detailed information
about pathogens that now can be rapidly gleaned by determining their
genomic sequence. The field of pathogen genomics has made remarkable
progress: sequencing of the genomes of more than 100 pathogens is
complete or nearing completion. Among them are approximately 30
different Category A, B and C agents, including multiple strains of the
anthrax bacterium. This genomic information is being used to inform the
development of new antimicrobials, vaccines, and diagnostics.
Progress in biodefense research depends on the availability of
research resources, such as animal models, standardized reagents, and
appropriate laboratory facilities, as well as on human capital, that
is, well-trained investigators. Among many initiatives to improve the
biodefense research infrastructure, NIAID will establish in fiscal year
2003 a nationwide network of Regional Centers of Excellence for
Biodefense and Emerging Infectious Disease Research, and design, build,
and renovate a system of Regional and National Biocontainment
Laboratories. These facilities will include a small number of Biosafety
Level-4 (BSL-4) laboratories, which have the containment safeguards
necessary to study highly pathogenic organisms. The new Centers and
laboratories will serve as national resources for biodefense research
and product development, as well as for the study of other emerging
diseases such as influenza and West Nile virus.
The many new NIAID initiatives in biodefense research will provide
benefits far beyond protection from deliberate acts of bioterrorism.
After all, the general philosophy and strategy of biodefense is
essentially the same as that for defense against naturally emerging and
re-emerging infectious diseases that threaten global public health.
With the careful NIAID planning process, new biodefense resources will
unquestionably have enormous benefits in our struggle against other
diseases, endemic and emerging, that far transcend the specter of
bioterrorism.
ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS)
Another major focus of the Institute, accounting for approximately
one-third of NIAID spending, is research devoted to finding
interventions to slow the pandemic of the human immunodeficiency virus
(HIV), the cause of AIDS. HIV/AIDS is the defining health crisis of our
generation, having claimed well over 20 million lives since the
beginning of the pandemic. Another 42 million people worldwide are
living with the virus. Most of the world's HIV-infected people live in
resource-poor countries, where HIV frequently is superimposed on other
significant health challenges, including endemic diseases such as
malaria and tuberculosis, and malnutrition. By 2010, more than 45
million new infections will occur, for a cumulative total of 105
million infections, according to estimates of the Joint United Nations
Programme on HIV/AIDS.
Despite these grim numbers, significant progress has been made
against the HIV/AIDS, much of it due to the research and prevention
efforts of NIAID and other NIH Institutes, the Centers for Diseases
Control and Prevention, and other agencies of the Department of Health
and Human Services. In this country, prevention efforts have reduced
the annual number of new HIV infections in the United States from
approximately 150,000 per year to about 40,000 annually. In recent
years, we have seen the positive impact of advances in HIV therapeutics
for many living with HIV/AIDS in the United States and other western
countries, and more recently the promise these medicines offer for
those in the developing world. All but one of the 19 antiretroviral
drugs licensed in the United States target one of two viral targets:
the HIV protease enzyme or the HIV reverse transcriptase enzyme. Over
the past few years, NIAID-supported scientists and their collaborators
have identified new targets for HIV therapy and novel drugs that block
other stages of the virus replication cycle. Among them are agents that
block viral genes from entering the host cell nucleus, and drugs that
keep the virus from attaching to or entering the cell in the first
place. In the latter category, a drug known as Fuzeon or T-20 that
blocks the fusion of HIV to the host cell membrane was recently
approved and holds great promise for the many HIV-infected patients who
harbor HIV that is resistant to current therapies.
To help turn the tide of the global HIV/AIDS pandemic, NIAID has
established research collaborations with international colleagues to
develop comprehensive approaches to the HIV pandemic in poor countries,
encompassing prevention activities, antiretroviral therapy when
feasible, and care of the HIV-infected person. These collaborations
have yielded extraordinary results, notably in developing methods to
reduce mother-to-child transmission of HIV. However, a rate-limiting
factor in HIV/AIDS research efforts in developing countries has been a
lack of funds for the purchase of antiretroviral drugs and for
improving existing healthcare infrastructure. In January 2003, the
Institute's international AIDS program received a substantial boost
with the announcement of the President's Emergency Plan for AIDS
Relief. This plan commits $15 billion over 5 years ($10 billion of
which is new money), starting with $2 billion in fiscal year 2004, for
HIV/AIDS prevention, treatment, and care in 14 of the hardest-hit
countries in sub-Saharan Africa and the Caribbean. This lifesaving
effort will not only reduce the suffering caused by HIV/AIDS in
countries that account for 50 percent of the world's HIV infections,
but will provide a framework that will facilitate NIAID research
efforts to develop new and improved tools of treatment and prevention.
Many approaches to HIV prevention are being developed or refined,
but the ``holy grail'' of HIV prevention remains the development of a
safe and effective HIV vaccine. Numerous vaccine candidates have shown
promise in monkey models of HIV infection, and the most promising ones
are rapidly being moved into human trials on the NIH campus and in the
domestic and international sites of the NIAID HIV Vaccine Trials
Network.
OTHER VACCINES
In addition to developing HIV and biodefense vaccines, NIAID
continues to make significant progress in the quest for new and
improved vaccines for other diseases of global health importance. The
NIH has three broad goals in vaccine research: identifying new vaccine
candidates to prevent diseases for which no vaccines currently exist;
improving the safety and efficacy of existing vaccines; and designing
novel vaccine approaches, such as new vectors and adjuvants, substances
that improve vaccine performance.
More than 100 vaccines currently are being developed by NIAID-
funded researchers, including promising candidates against emerging
diseases such as Ebola virus, West Nile virus, dengue, and dangerous
strains of influenza virus. Of particular note are novel tuberculosis
vaccines, which soon will enter clinical trials. These trials will mark
the first time in more than 60 years that new approaches to TB
vaccination have been assessed in humans. These vaccines are a tangible
``payoff'' of research funded by NIAID and others that led to the
availability of the complete genomic sequence of the tuberculosis
bacterium. The quest for a malaria vaccine received a significant boost
in 2002 when researchers funded by NIAID and others published the
genomic sequences of the malaria parasite Plasmodium falciparum, and
one of its main mosquito vectors, Anopheles gambiae. Together, these
projects are probably the most significant pathogen genome sequencing
effort to date. With the availability of the human genome sequence,
scientists now have detailed genomic information for each of the
organisms involved in human malaria: the human host, the mosquito
vector and the malaria parasite itself. This groundbreaking malaria
research promises to provide new targets for vaccine development and
other interventions against a disease that claims the lives of more
than a million people each year, most of them children in sub-Saharan
Africa.
IMMUNE-MEDIATED DISEASES
Immune-mediated diseases such as autoimmune diseases, allergic
diseases, and asthma are important health challenges here and abroad.
Autoimmune diseases, for instance, afflict 5 to 8 percent of the U.S.
population; asthma and allergic diseases combined represent the sixth
leading cause of chronic illness and disability in the United States.
The past two decades of fundamental research in immunology have
resulted in a wealth of new information and extraordinary growth in our
conceptual understanding of the immune system and the pathogenesis of
immune-mediated diseases. Researchers now know a great deal about the
effector molecules that contribute to many immunological conditions,
knowledge that has led to the design and discovery of drugs to block
those molecules. For instance, we now have powerful treatments that
selectively target several of the immune system molecules that cause
inflammation, a hallmark of many autoimmune diseases. Blockers of an
immune system molecule called tumor necrosis factor-alpha are now
routinely used in patients with rheumatoid arthritis and other
immunologic conditions.
A relatively new avenue of research suggests that it may be
possible to interrupt deleterious immune responses, without dampening
protective ones, and provide patients with long-term clinical benefit.
The ability to induce ``immune tolerance'' by selectively blocking
deleterious immune response holds great promise for treatment of many
immune- mediated conditions, including type 1 diabetes, rheumatoid
arthritis and multiple sclerosis, as well as asthma and allergic
diseases. For example, researchers have shown in a small trial
conducted by the NIAID-sponsored Immune Tolerance Network (ITN) that
antibodies to the CD3 molecule on T-cells, given for two weeks soon
after patients were diagnosed with type 1 diabetes, appeared to halt
the destruction of the patients' insulin- producing cells for at least
a year, preserving their ability to produce some of their own insulin.
Further follow-up is underway to determine the long-term benefits of
this experimental therapy; a larger trial is currently recruiting
patients.
Induction of immune tolerance is also one our highest priorities in
organ transplantation research. The ability to selectively block the
immune response to a transplanted organ would diminish or eradicate the
risk of rejection, as well as the risks and morbidities associated with
current methods of immunosuppression. A trial currently underway in the
ITN is using a unique approach involving simultaneous bone marrow and
kidney transplantation in patients with multiple myeloma. Although only
a very small number of patients have undergone the procedure, early
results are encouraging, as they have tolerated their transplanted
kidneys without immunosuppressive medications for up to 3 years.
Another important NIAID research focus is the development of new
interventions to reduce the burden of asthma. NIAID has long been at
the forefront of discoveries leading to the characterization of asthma
and allergic diseases and is now vigorously pursing the translation of
basic knowledge into more effective treatment and prevention
strategies. The NIAID-sponsored Inner-City Asthma Study, completed in
2002, evaluated the effects of a home-based environmental intervention
on asthma symptoms and health care utilization in inner-city children
with moderate to severe asthma. The intervention led to an additional
three weeks of symptom-free days and a 14 percent reduction in
unscheduled emergency room or clinic visits in the first year of the
intervention; these effects largely persisted for a year following the
intervention phase. The improvement in symptoms was correlated with a
reduction in levels of key allergens in the home. Building on these
results, the NIAID in 2002 launched the Inner-City Asthma Consortium,
to conduct clinical trials of novel immune-based agents to treat or
prevent asthma.
CONCLUSION
The role of NIAID in fighting infectious and immunologic diseases
has never been more important, particularly in the post 9-11 world.
Working with our many collaborators in the public and private sectors,
we hope to further reduce the burden of diseases endemic in the United
States and abroad, to enhance our preparedness against bioterrorism,
and to continue to prepare for new threats to public health that will
inevitably emerge in the future.
______
Prepared Statement of Dr. Patricia A. Grady
Mr. Chairman and Members of the Committee: The fiscal year 2004
budget includes $134,579 million, an increase of $4,060 million over
the fiscal year 2003 enacted level of $130,584 million comparable for
transfers proposed in the President's request.
Nursing research and nursing practice are converging to address the
challenges of maintaining and improving health and healthcare in our
country. During this time of heightened uncertainty in many aspects of
our lives, nursing research, which informs the practice of the nation's
largest number of healthcare professionals--2.7 million nurses--is
critical to developing and testing interventions that improve health.
Increasingly there is a need for health promotion research, which is a
special strength of nursing research. This need is reflected in a
recent Department of Health and Human Services (DHHS) Fact Sheet that
attributes 40 percent of premature deaths to unhealthy behaviors, such
as smoking and poor eating habits. Conversely, of the 30-year average
gain in life expectancy in the last century, the DHHS report states
that 25 of those years came from advances in public health, principally
from health promotion. Consistent with the NIH Research Roadmap for the
future, nursing research also focuses on multidisciplinary and clinical
research. The goal is to help healthcare professionals work smarter by
capitalizing on new technologies and research-tested methodologies that
extend the reach and quality of their practice in promoting health,
managing illness, and improving care. Now let me discuss some findings.
REDUCING POSTMENOPAUSAL WOMEN'S RISKS FOR CARDIOVASCULAR DISEASE
Heart disease is the leading cause of death in women in the United
States. Even though the death rate has decreased in recent years, the
benefit is less for women than men. More needs to be known about the
effects of preventive strategies, such as exercise and diet, in
reducing risks of the disease. We know lowering total and low density
lipoprotein cholesterol (LDL-C) and raising high-density lipoprotein
cholesterol (HDL-C) reduces risk of cardiovascular disease in women.
Nurse researchers did a study that asked the question of why HDL-C, the
``good cholesterol,'' drops when post-menopausal, obese women adhere to
a low-fat diet. On a low-fat diet, weight loss occurs and the
deleterious LDL-C decreases, but the weight loss is accompanied by a
reduction of the good HDL-C. Findings of the study indicate that the
causal factor for the HDL-C reduction was not the type or amount of fat
the women consumed, but rather that they substituted simple sugars,
such as syrups and refined sugar, for fat in their diets. What the
women should have done was substitute complex sugars, such as high
fiber vegetables and starches. The current American Heart Association
guidelines recommend consuming 55 percent of energy from carbohydrates,
without specifying complex or simple. This study points out the need to
write more specific dietary guidelines that differentiate between types
of carbohydrates, in addition to types of fat. This study is especially
timely in an age where low-fat and fat-free foods often depend on
simple sugars to improve taste.
REDUCING RISK FACTORS FOR OBESITY AND HYPERTENSION IN ADOLESCENTS
Obesity continues to be a major health problem in the United
States. The Centers for Disease Control and Prevention states that
about 15 percent of children and adolescents are overweight, a 4
percent increase since the last survey in 1994. The U.S. prevalence of
obesity increased by 61 percent in the 9 years prior to 2001. Habits
formed in childhood become the lifestyles that drive this upswing.
Researchers testing an intervention in children and adolescents have
been able to decrease risk factors for hypertension and obesity. As
part of the Cardiovascular Health in Children and Youth study,
researchers tested rural, mostly African-American middle school
students in an eight-week physical activities program combining
exercise and health education. Subjects were divided into four groups--
exercise, education, or both, and controls. Those in the two exercise
groups had a lower increase in body fat, and the blood pressure of the
three intervention groups decreased compared to controls. These results
demonstrate the effectiveness of regular aerobic exercise and health
education programs for school-aged children to help reduce their risks
for cardiovascular disease later in life.
COPING WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE
People with Chronic Obstructive Pulmonary Disease (COPD), which
causes discomfort at best and severe, life-altering changes at worst,
report that there is little available to help improve their breathing.
Shortness of breath often results in inability to work, limited social
activities, and even difficulty in dressing themselves. As the nation's
fourth leading cause of death, COPD affects over 22 million people. In
confronting this issue, nurse investigators tested a ``self
management'' inspiratory muscle training technique to assist patients
in improving their own breathing and respiratory muscle strength. For
30 minutes, 5 days a week, over a 16-week period, patients used a
mouthpiece attached to a tube with openings that gradually decreased in
size to make inhalation more challenging. Following training, these
subjects' breathing, respiratory muscle strength, and endurance were
considerably improved compared to a control group, and they could once
again perform daily activities. The study also showed that subjects
were able to self-manage by performing inspiratory muscle training at
home without direct professional assistance.
IMPROVING CARE AT THE END-OF-LIFE CARE
Another important healthcare issue involves end-of-life and
palliative care. As the lead Institute at NIH for coordinating this
research, NINR supports research to improve the way the healthcare
system addresses end-of-life issues. A recent study commissioned by
Last Acts contributed more evidence of the need for change, concluding
that the United States does only a mediocre job of caring for seriously
ill and dying patients. The study also indicated that although many
would prefer to die at home or in a hospice, most die in the hospital,
where high tech efforts to prolong life and where patients' diminished
control over decisions are common.
Nurse researchers studied the outcomes for patients enrolled in the
Program for All-inclusive Care for the Elderly (PACE), a managed care
program for people 55 and older. Results showed that unlike the general
population, where 44 percent die in the hospital and 20 percent die at
home, the numbers are almost reversed in PACE, with 45 percent dying at
home and 21 percent in the hospital. Another outcome was improved
consistency and predictability of care. End-of-life care is often
fragmented, and in the case of advance directives, written instructions
may not be honored in the hospital, since staff may not have immediate
access to patient records from other care facilities. The PACE program,
however, offers consistent care, thus increasing the likelihood that
advance directives will be followed. PACE also helps older people
develop advance directives.
NEW AND EXPANDED INITIATIVES
For fiscal year 2004, NINR plans include launching a new pediatric
end-of-life initiative, stimulated by the Institute of Medicine's
report: When Children Die: Improving Palliative and End-of-Life Care
for Children and Their Families. This report concluded that pediatric
end-of-life issues have received insufficient research attention. We
will also support the development of ethnically and culturally
sensitive interventions for those near the end of life and approaches
to improve communications between care providers, patients and
families.
Research on strategies for self-management of chronic illness will
be expanded to include reducing symptoms related to high blood
pressure, diabetes, dementia and developmental disabilities. These
strategies will incorporate age, gender, and ethnic and cultural
factors.
Minority men will be targeted for interventions that promote
healthy lifestyles, since they have a shorter life span and a higher
mortality rate than Caucasian men and all subgroups of women. NINR will
stimulate research on factors that influence decision-making for
healthy choices, such as nonsmoking, exercise, and proper nutrition.
Other issues to be addressed include: How can these men improve
management of stress? How do their families and their communities
influence their health-related behaviors? Because young minority men
are often underserved, studies in this area could create an important
strategy for effective public health interventions to follow.
We continue to have a strong interest in the significant health
disparities for minority women. NINR will expand research that targets
prevention of low birthweight babies, since according to Healthy People
2010, of the Department of Health and Human Services, the incidence
rate for low birthweight African-American women is twice that of
Caucasian women. Puerto Rican women are also especially likely to have
low birthweight infants. Issues include improving early identification
and management of complications during pregnancy, such as infection,
hypertension, and diabetes.
TRAINING NURSE RESEARCHERS FOR THE FUTURE
NINR is addressing the future of nursing science--how to ensure
that sufficient, high-quality research continues to grow and play a
fundamental role in health care. In the early 90's, and again in 2000,
the National Academy of Science's National Research Council stated that
the number of nurse researchers must increase. Over the next four to
six years, our Nation is facing a critical nursing faculty shortage.
Nurse researchers form the backbone of university faculty in schools of
nursing. In rising to this workforce challenge, NINR emphasizes early
entry into research careers, including fast-track baccalaureate-to-
doctoral programs, to increase the number of nurse investigators. Other
opportunities are made available through the NINR Centers programs and
NINR/NIH research training mechanisms and career development awards.
Our centers provide an environment and infrastructure to promote
early entry into and sustained participation in research programs. NINR
funds nine Core Centers, each of which offers research and research
training opportunities to those in their geographic areas. We also fund
nine Developmental Centers that enhance emerging research programs. Our
recently-launched Nursing Partnership Centers to Reduce Health
Disparities funded 17 Centers which pair research-intensive nursing
schools with minority-serving schools of nursing. These Partnerships
are expected to expand research on health disparities and increase the
number of minority nurse investigators.
NINR is focusing on ways to integrate genetic science into nursing
research, education, and practice. Strategies include facilitating
lifestyle changes for those at risk, genetic counseling, and selecting
optimal therapeutic interventions based on genotype. The fourth NINR
Summer Genetics Institute will be offered this year. This is an
intensive, eight-week genetics training program held on the NIH campus.
Its goal is to produce graduates who develop successful research
careers and help integrate genetic information into research and
educational programs across the country.
Mr. Chairman, this concludes my remarks. I would be pleased to
answer any questions you and other members of the Committee may have.
______
Prepared Statement of Dr. Judith H. Greenberg
Mr. Chairman and Members of the Committee, good morning. I am
pleased to present the President's budget request for the National
Institute of General Medical Sciences (NIGMS). The fiscal year 2004
budget includes $1,923 million, an increase of $76 million over the
fiscal year 2003 enacted level of $1,847 million comparable for
transfers proposed in the President's request.
The NIH budget request includes the performance information
required by the Government Performance and Results Act of 1993.
Prominent in this data is NIH's fourth annual performance report, which
compared our fiscal year 2002 results to our fiscal year 2002
performance plan goals.
AN IMPRESSIVE TRACK RECORD
Since its creation more than 40 years ago, the National Institute
of General Medical Sciences has built an impressive track record as a
strategic investor in the future of basic biomedical research. Though
not a household name, NIGMS is highly respected in the scientific
community as an Institute that nurtures the nation's brightest minds in
biomedicine. Through its forward-thinking funding programs, NIGMS
supports thousands of scientists nationwide whose fundamental research
is laying the foundation for promising new advances in disease
diagnosis, treatment, and prevention.
Perhaps the most notable indicator of that track record is the
number of NIGMS-supported scientists who have won Nobel Prizes-a
remarkable 53 to date. In 2002, both the Nobel Prize in Physiology or
Medicine and the Nobel Prize in Chemistry went to long-time NIGMS
grantees, Dr. H. Robert Horvitz of the Massachusetts Institute of
Technology and Dr. John B. Fenn of Virginia Commonwealth University,
respectively. Dr. Horvitz's discovery of key genes controlling cell
death shed new light on illnesses such as AIDS, Parkinson's disease,
stroke, and cancer. And Dr. Fenn's refinement of a technique called
mass spectrometry has made it possible to analyze large molecules in
biological samples, an advance now widely used for blood testing.
Our Institute's leadership in supporting biomedical science was
also recognized in 2002 with the prestigious Albert Lasker Award for
Basic Medical Research. NIGMS grantees Dr. James E. Rothman of the
Memorial Sloan-Kettering Cancer Center and Dr. Randy W. Schekman of the
University of California, Berkeley, were honored for discovering the
universal molecular machinery that drives ``cellular trafficking.''
Their work helped explain vital processes such as how insulin is
released in pancreatic cells, how organs develop inside embryos, and
how viruses infect their hosts.
Yet another acknowledgment of NIGMS' contributions to biomedical
research came late last year when the journal Science declared the
discovery of how small RNA molecules control the behavior of genes to
be the top scientific achievement of 2002. Funded in large part by
grants from NIGMS, this ``Breakthrough of the Year'' research shows
promise as the basis for new therapies to treat cancer, AIDS, and other
diseases.
As we look ahead to fiscal year 2004 and beyond, NIGMS is poised to
help make possible even more ground-breaking advances in biomedical
science. I would like to share with you some of our strategies for
accomplishing this important mission.
UNRAVELING THE 3-D STRUCTURES OF PROTEINS
Fifty years ago, Drs. James Watson and Francis Crick made their
famous discovery of the double-helix structure of DNA. This year,
scientists will reach another milestone: the completion of a highly
accurate sequence representing the entire set of genetic instructions
encoded in human DNA. As the Human Genome Project achieves this
landmark goal, its promise to usher in a new era of molecular-based
medicine will depend on another, equally important undertaking:
discovering all the proteins our genes make and the functions these
cellular ``workhorses'' play in health and disease.
Key to this ambitious effort is the unraveling of the complex,
three-dimensional structures of proteins. Determining these structures
can in turn reveal how proteins function and help scientists tailor the
design of new drugs to treat diseases. NIGMS is the world's single
largest supporter of research in structural genomics, a field dedicated
to discovering the structures of proteins using sophisticated computer-
based methods.
In fiscal year 2000, NIGMS launched the Protein Structure
Initiative (PSI), with the goal of determining 10,000 protein
structures in 10 years. The nine pilot research centers we currently
support have made significant progress in developing tools for the
high-throughput determination of protein structures and have begun to
yield some promising results, with potential applications in
biomedicine and beyond.
In November 2002, for example, NIGMS-funded researchers at Argonne
National Laboratory determined the structure of a protein knot-one of
only a few such structures seen in nature, and the first found in a
protein from the most ancient type of single-celled organism, an
archaebacterium. The microbe that the newly discovered protein comes
from is of interest to industry for its ability to break down waste
products and produce methane gas.
NIGMS is considering additional activities to help the centers
reach their full capability, including a materials storage bank and a
database for protein production and crystallization experiments. The
production phase of the PSI, during which researchers will be rapidly
deriving protein structures, will begin in fiscal year 2005.
HARNESSING MATH & COMPUTERS TO SOLVE BIOLOGICAL PROBLEMS
In addition to leading the way in structural genomics, NIGMS is
also at another forefront: a shift in biomedical science often called
the ``mathematization'' of biology. This shift represents a broadening
of biologists' research focus from studying how individual biological
molecules behave to investigating how a large number of molecules
interact with one another. In order to model and predict these complex
interactions, biomedical scientists are increasingly partnering with
quantitative scientists, including mathematicians, physicists, computer
scientists, and engineers. Together, they are applying their combined
expertise to solve particularly challenging problems in biomedicine,
such as understanding embryonic development, metabolism, cell growth,
and cell death.
To encourage more quantitative approaches in biological studies,
NIGMS established Centers of Excellence in Complex Biomedical Systems
Research. The first awards were for two center grants and seven
planning grants to lay the groundwork for future centers, designed to
foster a multidisciplinary research environment for develop ing
innovative methods to solve biomedical problems. These centers will
also lead the way in training the next generation of computational
biologists.
A good example of this teamwork is the recent work by NIGMS-funded
researchers who have produced the first comprehensive ``script of
life,'' describing the regulation of all the genes in yeast. Reporting
in the journal Science in October 2002, Dr. Richard Young, a biologist
at the Whitehead Institute for Biomedical Research, and Dr. David
Gifford, a computer scientist at the Massachusetts Institute of
Technology, detailed how they used advanced, high-throughput biological
and computing technologies to do in weeks what would have taken years
to achieve using traditional techniques.
The mathematization of biology and its importance in modeling
complex biological systems were also major themes at our Institute's
``Visions of the Future'' meeting, held in September 2002. NIGMS
invited visionary scientific leaders to identify the most important and
emerging areas of biomedical research. A recurring topic of discussion
was the need to develop mechanisms that encourage cooperative
interactions among mathematicians, physicists, computer scientists,
engineers, and biologists. Moreover, meeting participants stressed the
need for more rigorous quantitative training of undergraduate and
graduate students who are pursuing research careers in the life
sciences.
Such interaction and training were cited as keys to realizing some
of science's grandest visions. These include the development of
``virtual'' models--of cells, tissues, disease states, and ultimately
entire organisms--as well as new imaging tools and methods for making
``molecular movies'' of cellular machinery. Such technologies will help
fill enormous gaps in our understanding of how molecules move in three
dimensions and how they interact inside living cells in real time.
Through its support of research and training in computational biology
and other areas that cross traditional academic boundaries, NIGMS is
uniquely positioned to help turn these visions into reality.
GUARDING AGAINST INFECTIOUS DISEASES & BIOTERRORISM
As concern grows over bioterrorism and the emergence of new
infectious diseases, NIGMS is designing an initiative to address this
threat using computational approaches and mathematical modeling. Such
models will help predict the spread of microbes, the rate of disease
progression in individuals, the effectiveness of different treatment or
prevention strategies, and the community response to new infectious
diseases. These predictions will, in turn, provide policymakers with
critical information that will help them respond quickly to the threat
of a new disease or bioterrorism attack.
This new initiative follows on the footsteps of another successful
NIGMS program--one dealing with the evolution of infectious diseases.
Deadly viruses and bacteria can adapt to seemingly limitless
environmental conditions by making rapid genetic changes, far outpacing
our own ability to adapt. This microbial evolution renders previously
effective drugs useless and creates a moving target for drug designers.
However, by analyzing the evolution of infectious organisms,
researchers now have a leg up on how to outwit potentially dangerous
microbes.
One application of this area of study is antibiotic resistance, an
increasing problem throughout the world. Recently, NIGMS-funded
researcher Dr. Barry G. Hall of the University of Rochester developed a
computer simulation of microbial evolution. Dr. Hall determined through
experiment which bacterial genes are most susceptible to changes that
cause resistance to commonly used antibiotics. Using this approach,
pharmaceutical companies could create drugs for which bacteria have no
evolutionary escape route.
NIGMS is also leading the way in supporting structural studies of
infectious diseases. For example, the final piece of the anthrax
puzzle--the structure of the third toxic protein responsible for the
deadly effects of the anthrax bacterium--was discovered last year by
Dr. Wei-Jen Tang of the University of Chicago. The toxin, edema factor,
causes potentially lethal swelling and fluid buildup in the body. By
completing the detailed, three-dimensional the structure of edema
factor, Dr. Tang also found that the protein appears to be an ideal
drug target, opening the door to a possible new compound to combat
anthrax infection, as well as other bacterial diseases.
BASIC RESEARCH: A VITAL RETURN ON INVESTMENT
In closing, it is worth noting that our leading efforts in
structural genomics, computational biology, complex biological systems,
and multidisciplinary collaboration give NIGMS a pivotal role to play
in the trans-NIH ``Roadmap'' initiatives. Through its partnerships with
other NIH institutes and centers, NIGMS will help forge new pathways to
discovery and research teams of the future.
It is also important to emphasize that all of the scientific
advances I have shared with you today resulted from investing in basic
research on fundamental biological processes--the central mission of
NIGMS. As administrators of federal research dollars, we are asked to
show what we have done to ensure the best possible return on that
investment, and to show how we plan to continue doing so in the future.
I hope that the examples I have mentioned--from our Nobel Prize--
winning achievements to our cutting-edge initiatives-illustrate the
tremendous value of basic biomedical research to the strength of our
scientific workforce, the security of our nation, and the health of our
people.
Thank you, Mr. Chairman. I would be pleased to answer any questions
that you may have.
______
Prepared Statement of Dr. Glen R. Hanson
Mr. Chairman and Members of the Committee: I am pleased to present
the President's budget request for the National Institute on Drug
Abuse. The fiscal year 2004 budget includes $995,614 million, an
increase of $34,496 million over fiscal year 2003 enacted level of
$961,118 million comparable for transfers proposed in the President's
request.
NIDA LEADERSHIP
I have been very fortunate and privileged to serve as the Acting
Director of the National Institute on Drug Abuse for the past year and
a half during a time of burgeoning scientific advances that have
dramatically increased our understanding of brain, behavior and
addiction. I am extremely confident that the incoming Director for
NIDA, Dr. Nora Volkow, will be a strong leader and advocate for drug
abuse research. I am pleased to have this final opportunity to showcase
some of NIDA's most exciting advances and discuss how these and other
research findings are resulting in tangible benefits that will improve
the Nation's health.
PUBLIC/PRIVATE VENTURE YIELDS NEW MEDICATION FOR ADDICTION
An important example of how NIDA-supported research is decreasing
the tremendous economic and human costs associated with drug abuse and
addiction, while meeting the national need for quality treatment, is by
bringing a new medication to the clinical toolbox of health care
professionals. Buprenorphine, approved by the Food and Drug
Administration in October 2002, is the first medication ever available
for the treatment of opiate dependence that can be prescribed and
dispensed by qualified physicians in an office setting, rather than at
a specialized addiction treatment clinic. The nearly 1 million people
who suffer from heroin addiction will benefit from the historic
collaborations that took place between legislators who passed the Drug
Addiction Treatment Act of 2000, Federal agencies, and the private
sector (Reckitt Benckiser Pharmaceuticals) to bring this new medication
to market. Buprenorphine marks the second medication to come directly
out of NIDA's relatively short investment in its Medications
Development Program. Developing medications for other drugs of abuse,
particularly stimulants like cocaine and methamphetamine, is a top
priority for the Institute, as is our commitment to develop practical
and more effective science-based behavioral therapies.
NEW TARGETS FOR MEDICATIONS DEVELOPMENT
Building on a series of discoveries regarding the effects of
marijuana on the brain, researchers discovered a new neuromodulatory
called the cannabinoid system, which is involved in pain regulation,
memory, appetite, and addiction. This system was named after the active
ingredient in marijuana, tetrahydrocannabinol. Researchers from NIDA's
own intramural program have used a compound that blocks cannabinoid
receptors to demonstrate that the mood altering and cardiac effects of
marijuana in humans can be suppressed. Additionally, they discovered
that the cannabinoid system may also be involved in relapse to other
drug addictions. In animal models, this same blocking compound
prevented drug-seeking for cocaine following exposure to two of the
three conditions that typically trigger relapse in human addicts. The
discovery of this new brain system has opened the door for the
development of new treatments for addiction to a variety of drugs,
including cocaine and alcohol, and may also prove useful for treating
obesity and pain. As we continue to unravel the complexity of the brain
and identify new systems, molecules, proteins, and genes that can be
exploited for therapeutic development, the need for a repository or
molecular library where this information can be stored and shared with
other scientists increases. This is the goal of the proposed Molecular
Libraries project in the trans-institute NIH Road Map Initiative. We
hope to work with the pharmaceutical companies to more rapidly develop
novel and even more effective therapeutic strategies for addiction and
other brain diseases that have historically been extremely difficult to
treat and control, and are often overlooked by pharmaceutical
companies.
STRESS AND THE BRAIN
We also are becoming increasing knowledgeable about the impact of
stress on brain function. Stress can be a major factor in both the
initiation of drug abuse and is known to be one of the most powerful
triggers to relapse to drug abuse in former addicts. Nowhere was this
more apparent than in a study published last year following the
September 11th attacks in Manhattan. Twenty-nine percent of the 1,000
respondents interviewed 1-2 months following the event reported an
increase in substance use, with the highest rates in those reporting
symptoms of Post-Traumatic Stress Disorder and/or depression. A study
released just last month in the journal, Neuron, elucidated one of the
ways in which stress and drugs of abuse produce a similar adaptation in
the brain through an effect on dopamine neurons. As we progress in our
understanding of the ways in which stress and drugs of abuse affect
common mechanisms, we can develop prevention and treatment strategies
that more effectively satisfy the needs of patients, particularly those
who suffer from comorbid substance abuse and mental disorders.
THE ROLE OF GENETICS AND THE ENVIRONMENT IN ADDICTION
Powerful new technologies, such as microarrays, 3-dimensional brain
mapping, and animal knockouts are accelerating the pace of science and
helping us to identify the roles that genes play in addiction. One gene
in particular (FAAH) produces an enzyme involved in the breakdown of
the brain's natural cannabinoid compound. A recent study showed that a
genetic variation in this gene was found more frequently in people who
abused drugs compared to those who did not. As other genes that
increase the risk of addiction are identified through NIDA's
Vulnerability to Addiction Research Initiative, it becomes even more
imperative that we understand how the environment can modify this risk.
Basic research is giving us important insight into this complex domain
of gene-environment interactions. A recent study conducted in monkeys
using brain imaging techniques found that the animal's social
environment can modify its neurobiology and ultimately its likelihood
to self administer drugs of abuse like cocaine. When monkeys were
housed together, the ones displaying dominant behavior were shown to
have altered expression of D2 receptors, which are important components
in the brain's reward pathway. They also were less prone to self
administer cocaine (a model of cocaine abuse). This illustrates that
the natural state of the dopamine system is altered by the environment,
which in turn influences the likelihood of using drugs of abuse. Future
studies which determine the interplay between genetic and environmental
factors will be important in gaining further insight into the
prevention and treatment of drug abuse and addiction.
REDUCING TOBACCO USE BY FIGHTING THE ADDICTION
Tobacco use is responsible for more that 430,000 deaths per year
among adults in the United States, making it one of the Nation's top
preventable causes of death. It is addiction to nicotine that continues
to drive the use of tobacco, and why NIDA's expertise concerning the
neurobiology of nicotine and the mechanisms of the addiction process,
is so integral to the national effort to reduce this public health
burden. NIDA supported research has already paved the way for a number
of treatments, including behavioral therapies, nicotine-replacement
approaches such as the patch and gum, and Zyban, that help people
conquer their addiction. But we must accelerate our efforts to help the
estimated 48 million people according to a 2000 Surgeon General Report
who remain addicted to this drug. Capitalizing on new knowledge about
the biological substrates and behavioral mechanisms of nicotine and
tobacco addiction, NIDA has joined with other NIH institutes to launch
a number of new activities to more rapidly translate tobacco addiction
research into new treatments. NIDA is also supporting research that
focuses on preventing adolescents from starting to smoke.
GOOD NEWS IN PREVENTION RESEARCH
There is good news in the epidemiology and prevention arena. NIDA's
long-standing annual Monitoring the Future Survey, which measures drug
use among 8th, 10th, and 12th graders, showed substantial decreases in
the overall use of all illicit drugs, as well as a reduction in the use
of cigarettes, marijuana, club drugs, and alcohol in the past year. One
of the most encouraging findings is the significant drop in the use of
MDMA (Ecstasy), the abuse of which had been rising at alarming rates in
recent years. We attribute these downward trends, in part, to our
prevention and education efforts. As a by product of our dissemination
of science-based information about all drugs of abuse, America's youth
are able to weigh the facts about drugs and are making better health
decisions. Understanding adolescent decision-making is an important
research area being addressed in NIDA's prevention portfolio. By
elucidating the cognitive expectancies of how an adolescent makes the
initial and subsequent decisions to try or not to try drugs, we will
gain new insight into how to develop interventions aimed at changing
the actual decision to use drugs. Preventing the initial use of drugs
and stopping the progression of drug use before it escalates to
addiction are two targeted objectives of NIDA's National Prevention
Research Initiative. The multi-disciplinary teams of basic researchers,
community leaders, prevention specialists, clinicians, and health
service providers who have been brought together as part of this
Initiative will use the power of science to reduce drug use in the
country.
COMBATING HIV/AIDS, HEPATITIS DOMESTICALLY AND INTERNATIONALLY
Our efforts to reduce the burden of drug abuse goes beyond our
borders. Given the growing number of countries that report HIV and
hepatitis C infection associated with drug injection behaviors, NIDA
supports a strong research program that is yielding findings that are
beneficial both domestically and internationally. In the absence of a
vaccine or cure for AIDS, comprehensive HIV prevention strategies are
the most cost effective and reliable approaches for preventing new HIV
infections, and other bloodborne infections, such as hepatitis C. NIDA-
supported researchers are making progress in curtailing the spread of
these diseases. NIDA researchers, using molecular biology techniques,
have recently shown that new outbreaks of HIV infection among injection
drug users are spreading along drug trafficking routes and spreading
from drug users to non-drug using individuals through sexual
transmission. Some of the victims of such transmission are homeless
U.S. adolescents and AIDS orphans. Understanding how drug use related
HIV transmission occurs is critical to the development of culturally
specific behavior change strategies. NIDA remains committed to work
with other Institutes and federal agencies to discover more effective
ways to stop drug abuse-related spread of these infectious diseases and
work towards transferring these evidence-based strategies to slow the
spread of HIV and other related infections.
CLINICAL TRIALS NETWORK DOES MORE THAN JUST TREAT PATIENTS
HIV prevention interventions are some of the new protocols being
developed for testing in NIDA's National Drug Abuse Treatment Clinical
Trials Network (CTN). The CTN, which was established in 1999, provides
a national infrastructure to bring science-based behavioral and
pharmacological treatments for addiction into diverse patient and
treatment settings across the country. NIDA added three new sites in
the past year, which now allows our 17 centers or nodes to better serve
patients across a wider geographic area, in fact through the 115
community treatment programs involved in this endeavor we are serving
patients in 27 states. Over 8,000 patients are expected to be enrolled
in treatment protocols that are addressing the unmet needs of diverse
populations, including adolescents, pregnant women, and women who
suffer from Post-Traumatic Stress Disorder. Clinical trial networks for
cancer and diabetes have been active for decades, but NIDA's efforts
are the first ever to establish this model for addiction. Another first
for the field, is the unprecedented efforts being taken to reduce the
lag time between translating research discovery into practice. NIDA is
working with the Substance Abuse and Mental Health Services
Administration to disseminate science-based treatments into SAMHSA-
supported Centers and activities. Blending the expertise of
researchers, practitioners, and service-oriented professionals is the
hallmark of the CTN, and why the CTN has become more than just a way to
get quality treatment. It is the conduit through which research meets
practice.
CONCLUSION
Reducing the adverse health, economic, and social consequences of
drug abuse to individuals, families, and communities is the ultimate
goal of our Nation's investment in drug abuse research. That goal is
being met by NIDA.
______
Prepared Statement of Dr. Richard J. Hodes
Mr. Chairman and Members of the Committee: I am pleased to present
the President's budget request for the National Institute on Aging
(NIA) for fiscal year 2004. The fiscal year 2004 budget includes
$994,411,000, an increase of $1,342,000 over the fiscal year 2003
enacted level of $993,069,000 comparable for transfers proposed in the
President's Request. The NIH budget request includes performance
information required by the Government Performance and Results Act
(GPRA) of 1993. Prominent in the performance data is NIH's third annual
performance report, which compared our fiscal year 2001 results to the
goals in our fiscal year 2001 performance plan.
There are today approximately 35 million Americans ages 65 and
over, according to the U.S. Bureau of the Census. Thanks to
improvements in health care, nutrition, and the overall standard of
living, these men and women are more likely than ever before to be
healthy, vigorous, and productive: A recent meta-analysis of
demographic studies confirms that disability among America's elders has
declined steadily over the past decade. More older Americans are able
to participate in ``instrumental activities of daily living,'' such as
performing household chores and managing their own medications, while
fewer are experiencing limitations in basic physical tasks such as
walking or climbing stairs. The prevalence of severe cognitive
impairment also appears to be declining, although this finding needs
verification.
At the same time, diseases of aging continue to affect many older
men and women, seriously compromising the quality of their lives. For
example, more than half of all Americans over age 65 show evidence of
osteoarthritis in at least one joint.\1\ Over half of Americans over
age 50 have osteoporosis or low bone mass.\2\ Cardiovascular disease,
cancer, and diabetes remain common among older Americans. And,
according to the Alzheimer's Association, as many as 4 million
Americans suffer from Alzheimer's disease (AD), the most common cause
of dementia among older persons.
---------------------------------------------------------------------------
\1\ See ``Handout on Health: Osteoarthritis,'' National Institute
of Arthritis and Musculoskeletal and Skin Diseases, July 2002.
\2\ See America's Bone Health: The State of Osteoporosis and Low
Bone Mass in Our Nation. National Osteoporosis Foundation, February
2002.
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CONQUERING ALZHEIMER'S DISEASE
We have made progress in several important areas of AD research.
For example:
We are improving our ability to diagnose AD early.--Scientists are
developing and refining powerful imaging techniques that target
anatomical, molecular, and functional processes in the brain. These new
techniques hold promise of earlier and more accurate diagnosis of AD,
as well as improved identification of people who are at risk of
developing the disease. For example, researchers have developed a new
method of functional magnetic resonance imaging (fMRI) based on oxygen
use by the brain during rest. This technique permits visualization of
signals from minute subregions of the hippocampus, a brain region
important for learning and memory that shows degenerative changes in
AD, and the researchers are using it to distinguish between hippocampal
changes that are related to normal aging and those that may indicate
the presence of neurodegenerative disease. Other researchers are
working to improve our ability to image AD's characteristic amyloid
plaques and neurofibrillary tangles in vivo, which will allow us to
diagnose the disease with greater accuracy and more closely follow its
progression. These and other NIA-funded neuroimaging studies support
the broader goals of the molecular imaging component of the NIH Roadmap
Initiative.
We are developing new, more effective treatments and preventive
interventions for AD.--Research into the underlying biology of AD is
suggesting new ways to treat the disease or even prevent it altogether.
For example, human stem cells, with their unique capacity to regenerate
and give rise to many tissue types, are of particular interest in AD
research because of their potential ability to generate new cells that
could renew damaged brain tissue, replace dying neurons, or enhance the
ability of the brain to respond to age-related impairments. Recent
findings suggest that both human embryonic stem cells (hES), which can
give rise to many cell types, and ``adult'' stem cells, which develop
into a specific cell type, show promise for the eventual treatment of
AD and other neurodegenerative conditions. Researchers have recently
developed a method for inducing hES cells to differentiate into
neurons. These newly-derived cells exhibit the properties of cells
ordinarily found in the brain and central nervous system, suggesting
that hES cells could provide a source for neural progenitor cells and
mature neurons for therapeutic use. Investigators have also found that
in the adult hippocampus, neural stem cells can give rise to functional
neurons that can integrate effectively into existing neural circuits.
NIA is currently supporting 18 AD clinical trials, seven of which
are large-scale prevention trials. These trials are testing agents such
as estrogen, anti-inflammatory drugs, and anti-oxidants for their
effects on slowing progress of the disease, delaying AD's onset, or
preventing the disease altogether. Other intervention trials are
assessing the effects of various compounds on the behavioral symptoms
(agitation, aggression, and sleep disorders) of people with AD. The
design and implementation of all of these clinical trials will be
carried out in the context of the NIH Roadmap initiative to enhance
clinical research infrastructure and methodology.
We are working to reduce the burden on caregivers of persons with
AD.--Most Americans with AD are cared for at home by an adult child or
in-law, a spouse, another relative, or a friend. For this reason, the
AD ``patient'' is, in a sense, not only the person with the disease,
but the entire family unit. The NIA's REACH Project (Resources for
Enhancing Alzheimer's Caregiver Health), a large, multi-site
intervention study aimed at family caregivers of AD patients, was
designed to characterize and test promising interventions for enhancing
family caregiving. Nine different social and behavioral interventions
were tested, and investigators found that the combined effect of
interventions alleviated caregiver burden, and that interventions that
enhanced caregiver behavioral skills reduced depression. The second
phase of the study, REACH II, combines elements of the diverse
interventions tested in REACH into a single multi-component
psychosocial behavioral intervention and is ongoing.
UNDERSTANDING THE BIOLOGY OF AGING
We are continuing to advance our understanding of the molecular and
cellular changes that underlie aging processes, with the goals of
identifying the factors that affect the life span of an organism and
using this information to develop interventions to extend life and
delay the onset of disease and/or disability.
Experiments in a number of animal models are providing valuable
insights into mechanisms of longevity. Investigators recently created a
transgenic mouse carrying a mutation in the Xpd gene, which codes for
an enzyme involved in both repair of DNA damage and transcription of
DNA into RNA (an important first step in gene activation). These mice
appear normal at birth but age rapidly and live only about half as long
as normal mice. This new mouse model will be useful for studying a
number of aspects of aging, including the roles of DNA damage and cell
death, as well as mechanisms by which the genome maintains itself and
how such maintenance contributes to longevity.
Researchers are also using animal models to identify interventions
that might be useful in delaying aging. For example, in one recent
study, fruit flies fed the chemical 4-phenylbutyrate throughout
adulthood lived significantly longer than expected, with no negative
effects on physical activity, stress resistance, or fertility. In
addition, last year the NIA issued a Request for Applications (RFA) for
the Aging Intervention Testing Program, a large-scale initiative to
test intervention strategies that may slow the rate of aging in animal
models. A number of unproven strategies are already in substantial and
growing use by older Americans; positive results using such strategies
in animals could lead to clinical trials to establish safety and
efficacy in humans. An important secondary goal is to identify
interventions that are not safe or are ineffective.
Work in animal models is also leading to the identification of
genes involved in regulation of the life span. In the tiny worm C.
elegans, researchers used a sophisticated genetic screen to identify
about 200 genes that cause an increase in longevity; many of these
genes were related to the worm's mitochondria (cellular energy
centers), while the exact function of many others remains unknown.
Such findings in model systems, as well as our increasing
understanding of genetic disorders such as Hutchinson-Gilford progeria
syndrome that exhibit features of premature aging, suggest important
roles for genes in human aging. Evidence for a genetic basis of human
longevity was strengthened by the recent finding that siblings of
centenarians have about half the risk of dying at every age compared
with people who do not have a centenarian sibling. In the same study,
the investigators found that brothers of centenarians were at least 17
times more likely to reach the age of 100 themselves; sisters were at
least 8 times more likely to reach 100 years of age.
REDUCING DISEASE AND DISABILITY
Evidence of the beneficial effects of exercise on older people
continues to increase. In a study last year, researchers assessed the
results of a resistive strength training program on men and women in
two age groups, 20-30 and 65-75. They found that the effects of the
program did not differ between the two groups: Participants in both age
groups increased strength and showed similar increases in muscle mass
and in resting metabolic rates, which generally decrease with age.
NIA is working to translate research findings in action through its
highly successful campaign to encourage older people to exercise. Since
the campaign was launched in 1998, NIA has distributed nearly one half-
million copies of its exercise guide and almost 60,000 copies of its
companion video to the public. A Spanish-language version of the guide
was published in January 2002, and over 50,000 copies were distributed
last year.
We are also working to reduce the troubling health disparities that
still exist among different racial and ethnic groups. In one study of
elderly heart attack patients, researchers found that black patients
did not live as long after discharge from the hospital as white
patients. Much of this disparity could be explained by the lower rate
of use of certain cardiac procedures among black patients, suggesting
that expanded use of effective procedures could substantially reduce
racial differences in long-term survival.
To address disability and disease in special populations, NIA
implemented a major new study of health disparities among different
racial, ethnic, and socioeconomic groups. The study, Healthy Aging in
Nationally Diverse Longitudinal Samples (HANDLS), focuses primarily on
cerebrovascular health, cardiovascular health, age-associated changes
in cognition, and strength and physical functioning. Through this
study, we hope to address hypotheses about aging and health disparities
in minority and poor populations to understand the significance of
environmental and genetic risk factors for disease. The pilot phase of
HANDLS, in which investigators assessed the logistics and feasibility
of this community-based study, was completed at the end of 2001, and
the larger population-based phase of this study is scheduled to begin
in late fall of 2003.
Other areas of research interest include:
Diabetes.--Last year, investigators in the multi-institutional
Diabetes Prevention Program (DPP) reported that people who are at high
risk for diabetes can sharply reduce their risk through a low-fat diet,
and a moderate exercise regimen. This effect was most pronounced among
study participants age 60 and over. Treatment with the drug metformin
(Glucophage) also reduced diabetes risk among study participants, but
for unknown reasons was less effective among older participants. With
other participating NIH Institutes, we are continuing to follow up the
DPP participants to determine long-term effectiveness of these
interventions.
Menopause.--Women approaching menopause may experience a variety of
uncomfortable symptoms, but uncertainty remains over the safety of
hormonal therapy due to reports of serious health risks related to some
combinations of hormones. NIA-supported researchers are working to find
effective treatments for the symptoms of menopause that do not increase
risk of adverse effects.
CONCLUSION
It is becoming increasingly obvious that old age need not be
associated with illness, frailty, or disability. In fact, we have made
tremendous progress against all of the major diseases and conditions of
aging. However, much work remains to be done. NIA is committed to
supporting high-quality research to address all aspects of aging, from
conditions and diseases that primarily affect older people to physical,
behavioral, and cellular characteristics of the aging process. As more
Americans live longer, NIA will meet the challenges of our rapidly
aging society by continuing and intensifying research that improves the
health and well-being of older people.
______
Prepared Statement of Dr. Thomas R. Insel
Mr. Chairman, and members of the Committee, I am pleased to present
the President's budget request for the National Institute of Mental
Health (NIMH) for fiscal year 2004, a sum of $1,382 million, which
reflects an increase of $42 million over the fiscal year 2003 enacted
level of $1,340 million comparable for transfers proposed in the
President's budget.
In my statement, I will call to your attention the immense burden
on our Nation of mental and behavioral disorders. In addition, in the
context of a brief review of our research activities and
accomplishments, I will suggest how NIMH's expertise in behavioral
science and behavioral neuroscience are contributing to the Nation's
capacity to prepare for and respond effectively to the psychological
impact of bioterrorist attack.
THE BURDEN OF MENTAL ILLNESS
Mental disorders are real illnesses that are mediated by the brain
and can be diagnosed reliably and accurately. Thanks to the Nation's
willingness to invest generously in research, highly effective
treatments exist for most mental disorders; and recovery is a realistic
and attainable goal for many people who have a mental disorder. Despite
our research progress, our society faces a pressing need to strengthen
the quality and accessibility of clinical services for mental disorders
for all those who require such services. In keeping with our public
health mission, NIMH assigns high priority to the task of moving
information gained through research into the hands of providers,
systems, patients, and families.
The Surgeon General's Report on Mental Health noted that an
estimated 5.4 percent of Americans adults have a serious mental
disorder such as schizophrenia, major depression, and bipolar in a
given year, and about 5- to 9 percent of children and adolescents
suffer from mental and behavioral disorders that are sufficiently
severe to cause academic, social, or family impairment. Research
supported and conducted by NIMH has significantly strengthened the
ability of the Nation's health care providers to treat and manage these
disorders; still, the public health challenge posed by mental illness
remains formidable, in large part because many serious mental disorders
tend to strike in childhood, adolescence and young adulthood, and to
persist across much of a person's lifetime.
THE PRESIDENT'S NEW FREEDOM COMMISSION ON MENTAL HEALTH
With the release of the final report of The President's New Freedom
Commission on Mental Health scheduled for this Spring, efforts to
translate our science into clinical service programs will assume added
importance and urgency. The Commission was charged to identify specific
examples of community-based care models that are demonstrably
successful in achieving desired outcomes. In its interim report, the
Commission noted that much can and is being done to improve the
delivery of high quality mental health care. The Commission found,
however, that the national mental health care system is hampered by
fragmentation of services and limited access to effective treatments.
We have worked closely with the Commission over the course of its
study, and look forward to helping to implement the its
recommendations.
An ongoing collaboration between NIH and the Substance Abuse and
Mental Health Services Administration (SAMHSA) anticipates the
Commission's interest in ensuring that individuals in every region of
the country have access to the best available treatments. NIMH, the
National Institute on Drug Abuse, and the National Institute on Alcohol
Abuse and Alcoholism have identified specific treatment and
preventative interventions that have a strong scientific evidence base
and we are working with SAMHSA officials as they develop plans to
assist State agencies implement these interventions. Built into this
initiative are processes designed to establish a systematic feedback
loop that will enable researchers to draw on real world experiences
with evidence-based practices in order to inform and guide future
intervention research.
Need clearly exists for NIMH to advise SAMHSA of completed research
that will improve the quality of care available immediately. Still,
opportunities have never been greater for fundamentally revamping our
approaches to developing new clinical treatments and preventive
interventions. New scientific knowledge about the brain and behavior,
as well as the emerging science of genomics, promise to yield new
treatments for mental disorders that ultimately will alter the delivery
of mental health care in far-reaching ways.
SEARCHING FOR SCHIZOPHRENIA VULNERABILITY GENES
After many years of searching, the recent discoveries of several
putative vulnerability genes for schizophrenia have been among the most
noteworthy achievements of the past year. Schizophrenia is a
genetically complex disorder, in which multiple genes are involved, but
no single one of them is sufficient or necessary to cause the disease.
Rather, multiple genes, interacting with environmental influences, lead
to illness. One newly discovered gene, called G72, plays a role in
regulating the activity of glutamate, an important excitatory
neurotransmitter in the brain. This is intriguing because decreased
glutamate activity appears to play a key role in negative, or deficit,
symptoms of schizophrenia such as social withdrawal, a lack of
motivation and expressiveness, and an inability to experience pleasure.
It is interesting that several of the recently discovered genes
believed to be associated with susceptibility for schizophrenia may
function by interfering with neurotransmitters in the prefrontal cortex
(PFC) and related brain regions. For example, another newly identified
gene encodes an enzyme that terminates the activity of dopamine in the
PFC. In work led by an NIMH scientist, this research has identified two
alleles, or variants, of this gene; one of these has been shown in
clinical studies to be associated with deficits in information
processing and memory, again symptoms central to schizophrenia. These
discoveries highlight the biological basis for schizophrenia and may
ultimately yield both diagnostic and therapeutic breakthroughs.
SCREENING FOR DRUG DISCOVERY TARGETS
One initial application of genetic discoveries will be to identify
the various molecules they encode and then design medications that act
on those molecules when they are implicated in various disorders.
Molecular processes gone awry can serve as targets for medications
designed to prevent, treat, or halt progression of a given condition.
As part of an initiative included in the NIH Roadmap, NIMH is
supporting research to generate a library of small molecules with novel
actions that will interact with particular biological targets.
Subsequent research will test these substances as candidates for the
treatment of mental disorders as well as for their utility as
diagnostic agents or research tools.
AUTISM
Autism represents an urgent and significant scientific and public
health challenge that, given scientific opportunity and public concern,
is the appropriate focus of multiple NIH Institutes. The reported
incidence and prevalence of autism appears to be rising. Over the past
two decades, estimates of prevalence have escalated from \1/10000\ to
as many as \1/250\ (for autism spectrum) to \1/400\ (classic autism). A
recent investigation by CDC in Brick Township, New Jersey, found a
prevalence rate for autism of 4.0 per 1,000 children and a rate of 6.7
per 1,000 children for the more broadly defined category of autistic
spectrum disorders.
A biologically based developmental disorder, autism is
characterized by qualitative impairments in social interaction and both
verbal and nonverbal communication and behaviors, resulting in a
markedly restricted repertoire of activities. High quality clinical
care and management of children with autism can exert a draining
financial toll on families.
Last year, NIMH accepted leadership of the internal NIH Autism
Coordinating Committee (ACC), which operates in close communication
with the larger Interagency Autism Coordinating Committee (IACC). Other
NIH Institutes retain control over their own activities, such as the
long-standing Collaborative Programs for Excellence in Autism (CPEAs),
a network of sites funded by NICHD and NIDCD. In 2002, NIMH committed
to be the primary funding source for the Studies to Advance Autism
Research and Treatment (STAART) Centers program mandated by the
Children's Health Act of 2000. The Institute awarded grants to develop
STAART Centers, with co-funding provided by NINDS, NICHD, NIDCD, and
NIEHS. Two Centers were awarded in fiscal year 2002, and six additional
Centers are slated for funding in fiscal year 2003. This will complete
establishment of the network, exceeding the mandate of at least five
centers required by the Act.
Our research is yielding significant dividends. A recent study
found risperidone, one of a newer class of anti-psychotic medications,
to be successful and well tolerated for the treatment of serious
behavioral disturbance associated with autistic disorder in children
aged 5 to 17. Also near completion is a study evaluating the safety and
efficacy of methylphenidate (Ritalin) in treating overactivity,
impulsivity, and distractibility in children with autism spectrum
disorders.
PSYCHOLOGICAL IMPACT OF BIOTERRORISM
In light of the maxim that ``the purpose of terror is to
terrorize,'' prudence dictates that we use research not only to treat
the consequences of terrorism, but also to help refine our ability to
triage those individuals likely to be most susceptible to serious
adverse neurobiological responses to a bioterroist attack and, to the
extent possible, to ``innoculate'' the population against destabilizing
or unwarranted anxiety or panic. Over many decades, NIMH has supported
a robust behavioral science research portfolio that has informed us
about many basic behavioral mechanisms, including those influencing
group processes. More recently, we have supported studies that have
examined the psychological impact of natural disasters such as floods
and tornados, and the terrorist attacks in Oklahoma City in 1995 and on
September 11, 2001. Behavioral science and clinical research not only
provide a ``top-down'' systems-level context to help us understand what
is happening at molecular and cellular levels in the brain in the face
of overwhelming fear and anxiety, but also can help us to prepare for
and treat the psychological and social consequences of such events.
A key finding of this research to date is that people are very
resilient--the vast majority of victims of mass disaster and terrorist
attack do not develop a psychiatric disorder. For those individuals who
do, the most frequent adverse outcome is post-traumatic stress
disorder, or PTSD. This is a form of anxiety disorder that occurs after
exposure to an extreme stressor in which an individual experiences,
witnesses, or is confronted with actual or threatened death or serious
injury to self or others. Given its prevalence, disabling impact,
chronicity, and treatment resistance, PTSD represents a major public
health concern. Through the research we have conducted, however, we are
gaining an increasingly clear understanding of what variety of
psychological and behavioral problems to expect in the event of an
attack and the types of services that will be needed. We know that we
should expect to see increases in requests for therapy and medications
for common and troubling symptoms of fear, anxiety, hyperarousal, and
sleep problems. We know that survivors--particularly those with PTSD
and others who may have a comorbid, or co-occurring mental disorder--
actively use mental health services. In the event of a future attack,
as we move beyond needs for first aid, housing, and food, the majority
of those people who were directly affected will have need for
supportive counseling and assistance with resuming normal activities
such as household routines, school, and work. Research that has
examined the use of mental health interventions speaks to the clinical
significance of subjective distress even in subjects without recognized
psychiatric disorders. We also have information about who is most
likely to be at risk for developing longer-term problems and, thus, as
people present to health, educational and social service programs for a
variety of physical and mental health problems, it will be important to
apply what we know with the aim of preventing such problems. I would
also note that we also are drawing on behavioral science research
involving coping in response to threat to advise individuals and
communities how to anticipate and lessen the emotional burden caused by
trauma. It is clear that the availability of accurate information,
including information about health risk, for example, blunts the
anxiety- and panic-provoking nature of unjustified speculation about
risk and permits people to decide on action that they can take.
Research on basic behavioral processes involved in decision-making,
judgment, and health risk assessment--all involved in shaping
attitudes, affect, and behavior--is very useful in shaping the messages
we convey to our citizens.
I will be pleased to answer any questions.
______
Prepared Statement of Dr. Stephen I. Katz
Mr. Chairman and Members of the Committee: I am pleased to present
the President's budget request for the National Institute of Arthritis
and Musculoskeletal and Skin Diseases (NIAMS). The fiscal year 2004
budget includes $502.778 million, an increase of $17.005 million over
the fiscal year 2003 enacted level of $485.773 million comparable for
transfers proposed in the President's request.
The budget increases over the last few years have made a tremendous
difference in the studies we have been able to launch, particularly in
clinical research including clinical trials in a wide variety of
diseases as well as the expansion of vital scientific infrastructure in
a creative way. As stewards of these funds, we have worked with a wide
range of advisers, both from the scientific community and from the lay
public, to ensure that we target areas of greatest scientific
opportunity. In addition, we worked to undertake studies that could
either be done solely or better by the Federal government. I am pleased
to be able to share highlights of some of the stories of progress and
promise that have resulted from our investments in medical research.
PUBLIC/PRIVATE PARTNERSHIPS
One of the priority areas in the new NIH Roadmap Initiative is the
development of public/private partnerships. The NIAMS has had a number
of positive experiences in this area, and I will mention two ongoing
examples. The first is the Osteoarthritis Initiative. Our Institute
partnered with the National Institute on Aging and several other NIH
components as well as with three pharmaceutical companies in launching
this public/private partnership aimed at developing clinical research
resources that support the discovery and evaluation of biomarkers and
surrogate endpoints for osteoarthritis clinical trials. This seven-year
project is being undertaken by four clinical sites and one data
coordinating center, and this consortium will likely serve as a model
for future endeavors that link the public and private sectors.
The second partnership involves the NIH and the Muscular Dystrophy
Association (MDA). The NIH has been actively engaged in implementing
the mandates of the MD-CARE Act, and has worked closely with
representatives of the muscular dystrophy (MD) research and patient
communities in this effort. Specifically, the NIAMS, NINDS, and NICHD
have partnered to issue new research solicitations for MD cooperative
research centers, and for developmental planning grants for future
centers. In addition, we are developing an initiative to support the
training of basic and clinical researchers to study muscular dystrophy.
To underscore the importance of stimulating and supporting further work
in this area, the NIH has established an MD Research Task Force, which
includes NIH scientific staff, as well as researchers, clinicians, and
patient representatives. This group will help ensure that we pursue all
promising opportunities to boost MD research and training, and it will
also complement the work of the newly established inter-agency Muscular
Dystrophy Coordinating Committee, which was called for in the MD-CARE
Act.
MUSCLE DISEASES
One of the most active and productive areas within the Institute's
research portfolio is in the muscular dystrophies--a group of genetic
diseases characterized by progressive weakness and degeneration of the
skeletal or voluntary muscles which control movement. Research advances
from NIAMS investments in this area include: (1) the finding that
people with facioscapulohumeral muscular dystrophy (FSHD) have an
exclusive association with one of the two different forms of the
chromosomal region linked to the disease. This work may lead to a
better understanding of the instability of the genetic locus associated
with FSHD. (2) the discovery of how to reverse muscle degeneration in a
mouse model of Duchenne muscular dystrophy, a genetic disorder in which
muscle cells become progressively more damaged and die. Scientists have
devised a way to revitalize wasting muscle by using a special viral
carrier to introduce the missing dystrophin gene into the diseased
muscle tissue--a finding that could eventually lead to gene therapies
for patients with Duchenne muscular dystrophy. (3) the report that a
faulty gene is key to understanding myotonic dystrophy. The genetic
defect affects the conductance of electrical signals, resulting in
delayed muscle control. (4) the isolation of muscle-generating stem
cells that can improve muscle regeneration and deliver the missing
protein dystrophin to damaged muscles in a mouse muscular dystrophy
model. These results signal that some of the major obstacles to stem
cell transplantation may be overcome, resulting in more effective
treatments for muscular dystrophy and other muscle-related diseases.
and (5) the creation of a new animal model that has been labeled a
``marathon mouse,'' which expresses an energy-metabolizing protein that
increases the proportion of particular muscle fibers that give distance
runners their muscular stamina. Further work in this area could benefit
research efforts against muscle-wasting diseases like the muscular
dystrophies.
SYSTEMIC LUPUS ERYTHEMATOSUS
Some of the most promising research results in fur mission areas
have come from the ability of researchers to apply the explosion of
information in genetics and genomics. One example of this is the very
recent research report that a particular genetic ``signature'' has been
linked to the blood of patients with severe systemic lupus
erythematosus (SLE or lupus). A team of scientists supported by the
NIAMS, other parts of the NIH, and the private sector (the Minnesota
Lupus Foundation and the Alliance for Lupus Research) has discovered a
genetic ``signature'' present in some patients with lupus who develop
such life-threatening complications as blood disorders, central nervous
system damage, and kidney failure. These researchers analyzed thousands
of genes in the blood of patients with lupus, and, surprisingly, 14 of
the thousands of genes studied were linked to a subset of lupus
patients with severe disease. These 14 genes are associated with a
complex family of proteins involved in the regulation of immune
responses, and these findings provide strong support for developing new
therapies to block the affected pathways in patients with severe lupus,
as well as for identifying patients most likely to benefit from these
new therapies.
I want to also mention an important new clinical trial that we
launched in children with lupus. The trial is designed to test the
efficacy of statins (cholesterol-lowering agents) in preventing or
delaying progression of cardiovascular disease in children with lupus.
This research study involves 20 centers from the Pediatric Rheumatology
Research Network in establishing the largest cohort of pediatric lupus
patients ever prospectively studied.
BONE AND OTHER MUSCULOSKELETAL DISEASES
One dimension of the NIH Roadmap Initiative is translational
research, and we know that translating the results of basic bone
biology research into therapies that prevent or treat musculoskeletal
diseases can have a very significant impact on public health.
Development and maintenance of a healthy skeleton depends on
interactions between bone and bone marrow, blood vessels, and even the
central nervous system. Understanding these complex interactions will
depend on studies employing genetic and genomic tools, including NIAMS-
supported efforts in animal models that are expected to translate into
insights guiding the development of new preventive and therapeutic
approaches to conditions such as osteoporosis. In recent advances, a
variety of pharmacological agents and biochemical factors, some already
familiar in other contexts, has been found to have unexpected effects
on bone mass. For example, the actions of the cholesterol-lowering
drugs called statins, the hormone leptin (originally identified as
important for controlling obesity), and nitric oxide (best known for
its effects on the heart and blood vessels) all provide clues to ways
that new therapies might improve bone health. In addition, studies of
the genetics of bone mass are increasingly productive, including
reports of a gene that was previously unsuspected of playing any role
in bone emerging as a possible key to restoring bone in cases of
osteoporosis.
Research that has direct applicability to daily life of affected
individuals has determined that limb reconstruction and amputation
after trauma to the lower leg result in similar outcomes in terms of
function. We anticipate that the findings of this study will help
surgeons and patients make better informed decisions when choosing
between reconstruction (limb salvage) or amputation of a limb that has
been severely damaged. With a look to the future, a large United
States/Canada cooperative project is now underway to resolve
differences of opinion on the best way to repair the fracture of the
tibia--the most common long bone fracture in the human body. Factors
that will be considered in determining which of the groups being
studied has a more successful outcome include how soon patients return
to work and their general health status and quality of life. Finally,
plans are underway for an NIH Consensus Development Conference on
Primary Knee Replacement in December 2003 to address the issues that
exist in this area, to review the current state of the science, and to
identify directions for future research.
SKIN DISEASES
NIAMS-supported researchers recently reported exciting and
promising results from their gene therapy studies in the recessive form
of the devastating blistering skin disease dystrophic epidermolysis
bullosa. This disease is caused by the absence of a specific gene, and
researchers used a particular enzyme as the base for gene transfer. The
researchers were successful in stably integrating the DNA from the
missing gene into genomes of cultured skin cells from four patients
with this inherited skin disease. The skin that was developed using
these cells displayed stable correction of the hallmark features of
this disease. These results establish a potential practical approach to
nonviral genetic correction of severe human genetic disorders that
require stable genomic integration of large DNA sequences.
The Institute has recently called on scientific experts and lay
representatives to help us in three particular areas of skin diseases
research: (1) In response to fiscal year 2002 Congressional language,
the NIAMS sponsored the ``Workshop on the Burden of Skin Disease'' in
September 2002, to discuss the elements that comprise the burden of
skin diseases and their impact on public health and daily living;
current knowledge and data-collection instruments, and how to access
the data more effectively; and future data needs and instruments for
facilitating the collection of the data. The recommendations from this
workshop are being reviewed by the Institute to determine the need and
path for future initiatives in this area. The lessons learned from this
workshop can serve as a paradigm for other areas--all of which share
the challenge of defining the burden of a disease on an individual, the
family, the workplace, and society as a whole. (2) The NIAMS teamed
with the National Alopecia Areata Foundation in sponsoring the Fourth
International Research Workshop on Alopecia Areata in November 2002,
bringing together investigators from around the country for an exchange
of recent findings in alopecia areata and related fields of hair
biology. Results of this workshop will guide future research in this
field. (3) The Institute is planning a workshop on immune modulation in
the treatment of skin diseases, which will include new treatments for
psoriasis, atopic dermatitis, autoimmune bullous diseases, and other
skin diseases. The workshop will focus on trying to understand how some
new treatments are actually working so that we may better understand
the mechanisms underlying these diseases.
HEALTH DISPARITIES
In research related to health disparities, there are four efforts
that I want to highlight: (1) The NIAMS continues to support the
diversity initiative it has created and developed over the last few
years--the Health Partnership Program, a collaborative community-based
effort in Washington, D.C., that is directed at developing research
programs to understand and address health disparities in rheumatic
diseases in African American and Hispanic/Latino communities. (2)
Differences have been documented in the damage caused by lupus in
studies of Hispanic, African American, and Caucasian individuals with
this disease. The proportion of patients who had any organ damage was
higher among Hispanics than among the other two groups, confirming the
greater negative impact of lupus among members of this ethnic group.
The association of organ damage with poor coping skills was reported
for the first time, and it suggests that approaches designed to modify
patients' behaviors and attitudes to their illness could reduce the
damage to the body caused by lupus. (3) Research suggests that women
with lupus are at increased risk for both clinical osteoporosis and
cardiovascular complications at a much younger age, and more aggressive
control of the risk factors for these complications is needed to
prevent these conditions in women with lupus. (4) Social experience has
been shown to influence joint replacement decisions; that is, when
people think about having a hip or knee replaced, knowing someone who
has had the surgery may influence their decision. A recent study funded
by the NIAMS and the Robert Wood Johnson Foundation suggested that one
reason African Americans may be less likely than Caucasians to seek
joint replacement surgery, a procedure that makes a significant
difference in alleviating pain and improving function of severely
affected individuals, is because they know fewer people who have had
this procedure.
CONCLUSION
We are proud of the advances that scientists supported by the NIAMS
have achieved and we are excited about initiatives that we have
launched. Patients and their families are looking to us with hope and
anticipation for answers to what causes their diseases, as well as how
their diseases can be better treated and even prevented. We are
confident that public health in general as well as daily life for
affected individuals in particular will benefit from NIAMS research in
the extensive and diverse array of chronic diseases within our mission
areas of bones, joints, muscles, and skin.
I would be happy to answer any questions.
______
Prepared Statement of Dr. Gerald T. Keusch
The fiscal year 2004 budget includes $64,266,000, an increase of
$2,073,000 over the fiscal year 2003 enacted level of $62,193,000
comparable for transfers proposed in the President's request.
SCIENCE FOR GLOBAL HEALTH
Thirty five years ago, the Fogarty International Center was
established to honor the memory of Congressman John E. Fogarty of Rhode
Island. The authorizing legislation, introduced by Representative
Melvin Laird of Wisconsin, stated ``. . . the committee has provided
funds to plan a lasting memorial to a man who for more than a quarter
of a century worked tirelessly for a healthier America in a healthier
world.'' (Congressional Record, House, May 25, 19867, p. 14062). It is
my privilege to report to you, that for the past 35 years, the Fogarty
International Center (FIC) has fulfilled this promise--Mr. Fogarty and
Mr. Laird would be proud of their legacy. Today the FIC is an essential
component of the DHHS and NIH response to global challenges in health,
representing the nexus between science and diplomacy and promoting both
at the same time. FIC is known and respected around the world for its
critical role in promoting research and capacity building for global
health.
The research and training supported by FIC is a window to a
brighter future for the low- and middle-income countries with heavy
burdens of disease. While people in these countries typically suffer
from high infant, child and maternal mortality rates, amplified
manyfold by the threats represented by AIDS, TB, malaria and other
seemingly intractable infectious diseases, increasingly these
populations are now subject to the ravages of chronic disease and
premature mortality represented by cardiovascular disease, diabetes,
and cancer. All of these conditions limit societal productivity,
economic growth, and stability. To this end FIC supports research to
better understand the impact of improving health on economic
development, political and social stability, and active participation
in the global marketplace of the 21st century. Because economic growth
invariably impacts on the environment, usually in an adverse manner,
FIC has also developed a research agenda to improve our understanding
of the impacts on population's health and individual's well-being
related to sustainable economic development. These programs are crucial
as we identify health care interventions that an improve both health
and development.
The programs of the FIC directly address five of the eight goals
outlined in the United Nations Millennium Declaration, including
eradication of extreme poverty (Goal 1), reducing child mortality and
improving maternal health (Goals 4 and 5), combating HIV/AIDS, TB and
malaria (Goal 6), and ensuring environmental sustainability (Goal 7).
These goals are daunting, but not incapacitating. As U.N. Secretary
General Kofi Annan has said, ``They are achievable, not by holding more
world conferences, but by people in every country, coming together and
taking action.'' This is precisely what FIC does every day. To maximize
and leverage the impacts of FIC programs, the Center has collaborated
extensively within the NIH, across the Department of Health and Human
Services, and beyond, including other components of the Federal
government, bilateral and multilateral agencies here and abroad,
foundations, and international organizations such as the World Health
Organization, The World Bank and the Regional Development Banks.
STRENGTHENING THE GLOBAL CULTURE OF RESEARCH
For scientists to come together and take action requires them to
share a common culture of scientific ethos and values. This can only be
accomplished in an environment in which rapid communication is
possible, wherein scientific knowledge is readily available to all, and
where research is conducted based on partnership and equity. When
American scientists work across geographic boundaries in this manner,
the beneficiaries are the collaborating scientists, science in general,
the United States and foreign partner countries.
FIC strengthens this ``global culture of research'' through a range
of programs. The FIC International Bioethics Education and Career
Development Award provides trainees with a strong background in ethics
and an understanding of research. The cadre of thoughtful and
knowledgeable people trained through this program will insure that
internationally and United States-accepted ethical principles are
upheld in studies around the world, including in poor nations. An
additional component to strengthening a global culture of science is to
ensure that technological advances made in one country are accessible
to the greatest extent in all countries.
FIC addresses the growing divide in the development and use of
genetic technologies through the International Collaborative Genetics
Research Training Program. FIC-upported training in the technology of
modern genetics research is accompanied by a strong component of
ethical, social, and legal considerations and focuses on the
mplications of performing genetics research in low- and middle-income
countries.
The third pillar in support of the global culture of science is
access to information, which is addressed by the International Training
Program in Medical Informatics. This program enables U.S. institutions
to support training in order to build the capacity of scientists in
developing countries to access, utilize and construct computer-based
tools to access and exchange information to advance biomedical research
and public health. This program will recompete in fiscal year 2004. As
a companion to this initiative, FIC in collaboration with the National
Library of Medicine is embarking on additional programs to support and
improve the editorial content of key biomedical research and health
journals in developing countries, and to improve the quality and
accuracy of reporting on medical research and health by developing
country journalists, whether they are working in print, radio or
television.
As FIC works to strengthen the global culture of science through
all its programs, to maximize the benefits of individual initiatives in
fiscal year 2004 FIC proposes to pilot innovative International Glue
Grants. These grants will provide resources to link together regional
and national institutions in developing countries with their several
U.S. partner institutions, taking advantage of the perspective of
biomedical, clinical and behavioral and social scientists in creating
new ways to explore old and emerging health problems. We expect the
``glue'' will bring investigators together in a common framework for
addressing critical issues, enabling these collaborators to work more
cost-effectively and with greater productivity on critical challenges
such as AIDS, maternal health, and impacts on health from environmental
pollution.
Support for the movement of junior researchers across borders is
the fourth pillar of the broader effort to strengthen the global
culture of research and science. FIC will continue to invest in the
Global Health Research Initiative Program (GRIP), which provides
resources for developing country scientists who trained in the United
States to obtain, on a peer-reviewed merit-based system, funding to
conduct research upon their return home and remain linked in
collaborative research with their U.S. mentors. As a corollary to this
program, FIC is also investing in career pathways in international
research for young American investigators through the FIC International
Research Scientist Development Award (IRSDA). The IRSDA supports junior
U.S. scientists as they conduct research in the developing world on
issues of global import, then provides additional opportunities and a
``safety net'' on their return home. In addition, in fiscal year 2004,
will bring the first crop of students of medicine, public health and
allied medical sciences into a new program to provide a year of
mentored clinical research training in a developing country
collaborative research program. The rationale for this new program is
to expose students as early as possible in their professional careers
to research needs and prospects in the developing world as a means to
encourage them to select global health challenges as long-term career
pursuits. A partnership with the Ellison Medical Foundation, the
Association of American Medical Colleges, the Association of Schools of
Public Health and the FIC, the program will pair a U.S. student with
one from the host country to train and participate in clinical research
under the guidance of expert mentors from the United States and the
foreign country who already work together on clinical research studies.
A previously neglected area is that of gender and global health
research. Not only may risk factors, disease progression, and response
to treatment vary by gender, but societal responses based on gender may
exclude women from accessing health care or may imbue them with stigma
that adds significantly to the burden of disease. FIC is initiating two
new programs to address these issues. First, the Stigma and Global
Health research program, expected to be funded in fiscal year 2003,
will support studies to better understand the exclusion of stigmatized
populations from the benefits of medical care and participation in
medical research. Importantly, it will identify interventions to
address the major needs. Second, FIC, the NIH Office of Research on
Women's Health, the Canadian Institutes of Health Research, and Harvard
and Yale Universities are working with experts around the world to
develop a framework for the inclusion of gender issues across the range
of global research and training programs the Center and other science
funding agencies support. Included in this initiative is an effort to
enhance career development for women scientists from the developing
world.
CONTINUING TO INVEST IN COMMUNICABLE DISEASE RESEARCH
FIC currently supports a broad program of research and training in
AIDS, tuberculosis, malaria and other emerging infectious diseases. In
fiscal year 2004 the Center will pursue these major global health
problems in three ways, first through its continuing focus on AIDS, the
greatest epidemic threat of our time, and second, through support of a
comprehensive program, the Global Infectious Disease Training and
Research Program (GLIDTR), to focus on infectious diseases that are
predominately endemic in or impact primarily upon people living in
tropical countries. Under the AIDS programs, a major new initiative
will be fully launched with the awarding of the first set of
comprehensive grants under the International Clinical, Operational and
Health Services Research and Training Award for AIDS and TB (ICOHRTA-
AIDS/TB). This program has as its major goal the promotion of excellent
clinical research in support of care of AIDS patients, along with the
necessary operational and health services research to move new
knowledge into practice as soon as possible. The GLIDTR is augmented by
FIC/NIH enlarging investments in the Ecology and Infectious Diseases
research program, a major collaboration between FIC and the National
Science Foundation. This innovative program is oriented towards
identifying predictive models for emergence of infectious diseases so
that preventive strategies can be implemented before a new global
calamity is unleashed on the world. Finally, FIC's Division of
International Epidemiology and Populations Studies is conducting and
coordinating research involving mathematical modeling of epidemic
disease, whether due to events in nature or caused by humans, in an
effort to better identify key questions and intervention points.
Working closely with NIAID, NIGMS, and the Office of Public Health
Emergency Preparedness at DHHS, FIC is coordinating work with leading
academic mathematical modeling groups in the United States and abroad.
EXPANDING INVESTMENTS IN NON-COMMUNICABLE DISEASES
With the aging of populations worldwide, including in poor nations,
along with changing ifestyle patterns and migration into cities, there
is a growing recognition that the global burden of disease will
increasingly include non-communicable diseases. FIC's current programs
in this broad field address the burden of mental illness, the broad
range of brain disorders across the life cycle, and the major epidemic
of tobacco use and the inevitable epidemic of chronic pulmonary,
cardiovascular disease and cancer that will follow. To complement this
set of critical issues, FIC intends to explore ways to address the huge
and growing burden of morbidity and mortality due to trauma and injury,
whether intentional or un-intentional, such as road-traffic accidents.
Areas of interest include training and research activities designed to
better understand the body's systemic responses to major injury,
fostering more rapid application of this knowledge to wound healing
following trauma and burns, development of innovative low-cost and low-
maintenance prosthetic devices, integration of mental and physical
rehabilitation into primary care for victims of trauma, and to develop
and test effective cost-effective interventions.
A complete description of the FIC Strategic Plan is available on
the World Wide Web at http://www.nih.fic.gov/about/plan.html.
CONCLUSION
Today, FIC, together with the Institutes and Centers at the NIH, is
exerting leadership in global health research in important new ways,
addressing critical global health problems while investing in the
training of United States and foreign researchers who can, together,
identify the solutions for tomorrow. As expressed by John E. Fogarty
before his death in 1967, ``The alternative is that the United States
will reduce its leadership role in furthering humanitarian programs,
and may become more of a responder than a leader.''
______
Prepared Statement of Dr. Raynard Kington
Mr. Chairman, Members of the Committee: I am pleased to present the
President's budget request for the Office of the Director (OD) for
fiscal year 2004, a sum of $317,983,000, which reflects an increase of
$44,031,000 over the comparable fiscal year 2003 appropriation. The OD
provides leadership, coordination, and guidance in the formulation of
policy and procedures related to biomedical research and research
training programs. The OD also is responsible for a number of special
programs and for management of centralized support services to the
operations of the entire NIH.
The OD guides and supports research by setting priorities;
allocating funding among these priorities; developing policies based on
scientific opportunities and ethical and legal considerations;
maintaining peer review processes; providing oversight of grant and
contract award functions and of intramural research; communicating
health information to the public; facilitating the transfer of
technology to the private sector; and providing fundamental management
and administrative services such as budget and financial accounting,
and personnel, property, and procurement management, administration of
equal employment practices, and plant management services, including
environmental and public safety regulations of facilities. The
principal OD offices providing these activities include the Office of
Extramural Research (OER), the Office of Intramural Research (OIR), and
the Offices of: Science Policy; Communications and Public Liaison;
Legislative Policy and Analysis; Equal Opportunity; Budget; and
Management. This request contains funds to support the functions of
these offices.
In addition, the OD also maintains several trans-NIH offices and
programs to foster and encourage research on specific, important health
needs; I will now discuss the budget request for each of these trans-
NIH offices in greater detail.
THE OFFICE OF AIDS RESEARCH
The Office of AIDS Research (OAR) coordinates the scientific,
budgetary, legislative, and policy elements of the NIH AIDS research
program. Our response to the epidemic requires a unique and complex
multi-institute, multi-disciplinary, global research program. Perhaps
no other disease so thoroughly transcends every area of clinical
medicine and basic scientific investigation, crossing the boundaries of
the NIH Institutes and Centers. This diverse research portfolio demands
an unprecedented level of scientific coordination and management of
research funds to identify the highest priority areas of scientific
opportunity, enhance collaboration, minimize duplication, and ensure
that precious research dollars are invested effectively and
efficiently, allowing NIH to pursue a united research front against the
global AIDS epidemic.
Each year, OAR oversees the development of the comprehensive NIH
AIDS-related research plan and budget, based on scientific consensus
about the most compelling scientific priorities and opportunities that
will lead to better therapies and prevention strategies for HIV
disease. The Plan serves as the framework for developing the annual
AIDS research budget for each Institute and Center; for determining the
use of AIDS-designated dollars; and for tracking and monitoring those
expenditures. OAR identifies scientific areas that require focused
attention and facilitates multi-institute activities to address those
needs. OAR coordinates, monitors and fosters plans for NIH involvement
in international AIDS research and training activities. OAR supports a
number of initiatives to enhance dissemination of research findings to
researchers, physicians, patients and communities. The fiscal year 2004
budget request for OAR is $60,942,000.
THE OFFICE OF RESEARCH ON WOMEN'S HEALTH
The Office of Research on Women's Health (ORWH) serves as the focal
point for women's health research for the Office of the Director, to
ensure that women are appropriately represented in biomedical and
biobehavioral research studies supported by the NIH, and to develop and
support biomedical careers. The report: An Agenda for Research on
Women's Health for the 21st Century, provides the basis for the ORWH to
collaborate with the scientific and advocacy communities to address
scientific initiatives about women's health and sex and gender factors
in health and disease. In fiscal year 2004, the OD budget request of
$41,231,000 includes an increase of $808,000 over the fiscal year 2003
enacted budget of $40,423,000 for the ORWH to continue stimulating new
research and to implement innovative career development programs.
Research priorities for women's health emphasize the importance of
interdisciplinary collaboration, especially for chronic, multi-systemic
conditions; prevention and elimination of high risk behaviors, such as
overeating and physical inactivity, which contribute to morbidity and
premature mortality of women; and reproductive health, including such
gynecologic conditions as uterine fibroid tumors, and further exploring
issues related to the menopausal transition, such as hormone therapy.
The ORWH continues to partner with Institutes and Centers to monitor
compliance with NIH policies for the inclusion of women and minorities
in clinical research, and to ensure that analyses by sex/gender are
addressed. The ORWH is witnessing exciting expansion of new research in
its specialized centers of interdisciplinary research in women's health
and sex and gender factors. The ORWH has also expanded its unique
interdisciplinary career development program in women's health research
that fosters the mentored development of junior faculty and assists
them in bridging advanced training for junior investigators with
research independence. In addition, the ORWH has now implemented a new
Intramural Program on Research on Women=s Health to focus on NIH
intramural women=s health and sex and gender comparison research.
THE OFFICE OF BEHAVIORAL AND SOCIAL SCIENCES RESEARCH
The NIH has a long history of funding health-related behavioral and
social sciences research, and the results of this work have contributed
significantly to our understanding, treatment, and prevention of
disease. The Office of Behavioral and Social Sciences Research (OBSSR)
furthers NIH's ability to capitalize on the scientific opportunities
that exist in behavioral and social sciences research by providing
leadership in identifying and implementing research programs in
behavioral and social sciences that are likely to improve our
understanding of the processes underlying health and disease and
provide directions for intervention. OBSSR works to integrate a
behavioral and social science approach across the programs of the NIH.
The fiscal year 2004 OD budget includes $26,179,000 for OBSSR, an
increase of $513,000 over the fiscal year 2003 appropriation.
Many exciting scientific developments are occurring at the
intersection of behavioral and social science research and biomedical
research. OBSSR and several ICs are in the process of developing new
approaches to train individuals to undertake a program of research that
extends well beyond traditional disciplinary boundaries. One such
initiative is a new postdoctoral program that would provide individuals
trained in one discipline with formal course work and hands-on training
in a second field. Collaboration between social and behavioral
scientists and biomedical investigators is still relatively uncommon,
in part, because traditionally trained social and behavioral
researchers lack sufficient expertise in the biomedical fields and vice
versa. The initiative will provide a mechanism for training
investigators to work in interdisciplinary teams to tackle some of our
most pressing health problems.
OBSSR is also developing an initiative that will encourage
investigators to expand on the current theoretical base of change
processes and intervention models, to expand our understanding of how
change, once achieved, is maintained over the long term. Maintaining
behavior change over the long term appears as challenging, if not more
so, than the initiation of behavior change. Past research efforts have
typically focused on short-term behavioral change. However, other
research indicates that relapse rates for addictive behaviors such as
substance abuse and tobacco use are very high. Additionally, while the
positive association between education and health has been well
documented, there is a paucity of scientific information on the
biological mechanisms and the causal pathways that underpin this
association. OBSSR in collaboration with other ICs issued a Request for
Applications to increase extramural research activity on this important
scientific question.
THE OFFICE OF DISEASE PREVENTION
The primary mission of the Office of Disease Prevention (ODP) is to
stimulate disease prevention research across the NIH and to coordinate
and collaborate on related activities with other federal agencies as
well as the private sector. There are several other offices within the
ODP organizational structure.
The Office of Medical Applications of Research (OMAR) has as its
mission to work with NIH Institutes, Centers, and Offices to assess,
translate and disseminate the results of biomedical research that can
be used in the delivery of important health services to the public. The
Office of Disease Prevention (ODP) has several specific programs/
offices that strive to place new emphasis on the prevention and
treatment of disease.
In fiscal year 2004, the Office of Dietary Supplements (ODS) within
ODP requests a budget of $18,778,000. It will continue to promote the
scientific study of the use of dietary supplements by supporting
investigator-initiated research in conjunction with other ICs at NIH
and stimulating research through conduct of conferences and through
presentations at national and international meetings. In its continuing
efforts to inform the public about the benefits and risks of dietary
supplements, the ODS expanded the International Bibliographic
Information on Dietary Supplements (IBIDS) database to include a
consumer-oriented search strategy. It has also disseminated a database
devoted to federal funding of dietary supplement research, called
CARDS, which is currently populated with data about the NIH investment
from fiscal year 1999-2001. ODS publishes Fact Sheets about vitamin and
mineral dietary supplements in collaboration with the NIH Clinical
Center, as well as Fact Sheets about botanical supplements in
conjunction with the National Center for Complementary and Alternative
Medicine. ODS, in collaboration with the National Heart Lung and Blood
Institute and other NIH ICs, has sponsored a systematic review of the
relationship between omega-3 fatty acids and a series of clinical
indications, particularly coronary heart disease. Several reports will
be published in fiscal year 2003 and fiscal year 2004 based upon this
review, which will serve as the basis for planning further NIH research
on omega-3 fatty acids. To determine the future research studies of
efficacy and safety of dietary supplements containing ephedra, ODS
sponsored a systematic review of ephedra efficacy and safety, which has
recently been completed. ODS has initiated work on a pre-clinical study
of ephedra by the National Toxicology Program. Congressional language
in the fiscal year 2002 and fiscal year 2003 appropriation reports
directed ODS to enhance an ongoing collaboration for the development,
validation, and dissemination of analytical methods and reference
materials for botanical dietary supplements. ODS works with other
partners in the public and private sectors to meet this objective. ODS
supports the National Health and Nutrition Examination Survey (NHANES),
conducted by the National Center for Health Statistics at the Centers
for Disease Control and Prevention, in order to provide more
information about dietary supplement use in the US population. This
will inform future research about potentially important target
populations, such as children, women, and the elderly. Funding is used
to create and populate a database of dietary supplements, as well as to
support the measurement of blood levels of key metabolites associated
with dietary supplement use. In fiscal year 2003, ODS and USDA
published the proceedings of a workshop that examined the emerging
needs for dietary assessment, including supplement use, in national
surveys such as NHANES. A key outcome has been to develop an
analytically-based database of dietary supplement ingredients.
Another component of ODP, the Office of Rare Diseases (ORD),
develops and disseminates information to patients and their families,
health care providers, patient support groups, and others and forges
links among investigators with ongoing research activities in this
area. The ORD supports workshops and symposia to stimulate research on
rare diseases.
To provide better and faster information, ORD, together with the
National Human Genome Research Institute (NHGRI), established the
Genetic and Rare Diseases Information Center to respond to requests for
information about genetic and rare disorders. The fiscal year 2004
budget request for ORD is $11,423,000.
The ORD, supports together with NIH Institutes and Centers research
on rare diseases. Approximately 25 million people in the United States
are affected by an estimated 6,000 rare diseases. A ``rare disease'' is
defined as a condition affecting fewer than 200,000 Americans. On
November 6, 2002, the President signed the Rare Diseases Act of 2002
(Public Law107-280). The purposes of this Act are to establish the
Office of Rare Diseases in statute at the National Institutes of Health
and to increase the national investment in the development of
diagnostics and treatments for patients with rare diseases and
disorders.
THE OFFICE OF SCIENCE EDUCATION
The Office of Science Education (OSE) plans, develops, and
coordinates science education programs to strengthen and enhance
efforts of the NIH to attract young people to biomedical and behavioral
science careers and to improve science literacy in both adults and
children. The office's mission is to help people understand and use new
knowledge uncovered by the NIH in pursuit of better health for
everyone. The OSE works toward this mission by: creating programs to
improve science education in schools (the NIH Curriculum Supplement
Series); creating programs that stimulate interest in health and
medical science careers (the new LifeWorks Web site); creating programs
to advance public understanding of medical science, research, and
careers; promoting NIH educational resources and programs; and advising
NIH leadership about science education issues. All office programs
target diverse populations including under-served communities, women,
and minorities, with a special emphasis on the teachers of students
from Kindergarten through grade 12. The OSE works closely with NIH
institutes, centers, and offices on science education issues, and
maintains the OSE Web site as a source of information about available
resources and programs. http://science.education.nih.gov.
The NIH Curriculum Supplements series are National Science
Education Standards-based lesson plans that are distributed free to K-
12 teachers across the country. They incorporate the best of both
science and education communities, and are intended to update science
content and allow the teacher to incorporate the latest NIH research
into classroom instructions. Life Works is a new OSE Web site created
as a source of career information for students, teachers, counselors,
and parents. The site will allow exploration of the educational
requirements, knowledge, skills, and abilities required for over 100
health and medical science careers. The fiscal year 2004 Budget request
for OSE is $3,866,000.
LOAN REPAYMENT AND SCHOLARSHIP PROGRAM
The NIH, through the Office of Loan Repayment and Scholarship
(OLRS), administers the Loan Repayment and Undergraduate Scholarship
Programs. The NIH Loan Repayment Programs (LRPs) seek to recruit and
retain highly qualified physicians, dentists, and other health
professionals with doctoral-level degrees to biomedical and behavioral
research careers by countering the growing economic disincentives to
embark on such careers, using as an incentive the repayment of
educational loans. There are loan repayment programs designed to
attract individuals to clinical research, pediatric research, health
disparities research, and contraception and infertility research, and
to attract individuals from disadvantaged backgrounds into clinical
research. The AIDS, Clinical, and General Research Loan Repayment
Programs are designed to attract investigators and physicians to the
NIH's intramural research and research training programs. The NIH
Undergraduate Scholarship Program (UGSP) is a scholarship program
designed to support the training of undergraduate students from
disadvantaged backgrounds in biomedical research careers and employment
at the NIH. The fiscal year 2004 Budget request for OLRS is $6,843,000.
NIH ROADMAP
The NIH Director is taking an innovative approach to accelerate
fundamental discovery and translation of that knowledge into effective
prevention strategies and new treatments-an effort referred to as the
NIH Roadmap. The fiscal year 2004 budget request for the Office of the
Director includes an increase of $35,000,000 for strategic ``roadmap''
initiatives. These funds will be allocated by the NIH Director to the
Institutes and Centers to address critical roadblocks and knowledge
gaps that currently constrain rapid progress in biomedical research.
Three broad initiatives will be stimulated with these funds: (1) new
pathways to discovery, which includes a comprehensive understanding of
building blocks of the body's cells and tissues and how complex
biological systems operate, regenerative medicine, structural biology,
molecular libraries, nanotechnology, bioinformatics and computational
biology, and molecular imaging; (2) research teams of the future,
including multidisciplinary research and public-private sector
partnerships; and (3) re-engineering the clinical research enterprise.
These efforts will allow the NIH to rethink the infrastructure that is
required to translate findings from the genomic era into front-line
treatments and prevention strategies that benefit people in this
country and abroad..
Thank you for giving me the opportunity to present this statement;
I will be pleased to answer questions.
______
Prepared Statement of Dr. Claude Lenfant
I am pleased to appear before this Committee once again on behalf
of the National Heart, Lung, and Blood Institute (NHLBI). We are
extremely grateful for the generous budget increases of recent years
that have enabled us to capitalize on extraordinary research
opportunities.
PROGRESS AND CHALLENGES
A recent report in The New York Times (``Gains on Heart Disease
Leave More Survivors, and Questions'') highlighted how far we have come
in the battle against heart disease--and how far we have yet to go. The
well-known good news is that heart disease death rates have been
plummeting for decades, and serious disease manifests itself much later
in life. The bad news is that an acute problem has become a chronic
problem that affects millions of Americans--this is ``the endgame of
the cardiovascular disease epidemic'' that we now confront.
CLINICAL RESEARCH AND THE NIH ROADMAP
Our vigorous research effort is rapidly uncovering new knowledge
and technologies that will undoubtedly lead to treatments undreamed of
even 10 or 20 years ago. While they are being developed and tested,
however, we must do our best to ensure that rigorous science guides
appropriate use of more conventional treatments. Indeed, clinical
research that has direct application to public health issues is a major
focus of the NIH Roadmap that is currently being drawn and refined. The
NIH investment in clinical research and, particularly, in clinical
trials is absolutely critical if we are to provide health-care givers
and their patients with science-based information to guide their
decision-making. This is a role that the NIH is uniquely able to fill;
indeed, it is a job that would never be undertaken without support from
public funds. In this light, I am very pleased to mention some findings
from recent clinical trials that have enormous practical significance
for disease prevention and treatment.
BLOOD PRESSURE MEDICATIONS
The benefits of treating hypertension are widely appreciated.
However, the choice of a means to achieve blood-pressure lowering has
been complicated in recent years by the arrival on the market of new
drugs (e.g., calcium-channel blockers, angiotensin-converting-enzyme
inhibitors, alpha blockers) that, while expensive, were thought to have
advantages over older drugs. The ALLHAT (Antihypertensive and Lipid-
Lowering to Prevent Heart Attack Trial) compared these new drugs with a
diuretic--one of a class of blood pressure-lowering drugs that has been
used for many years and can be had for mere pennies a day. It found
that the diuretic did at least as good a job as newer agents in
preventing complications of hypertension--and a better job, according
to some measures. The study was conducted in a variety of practice
settings and its participants, all aged 55 and over, included high
proportions of women, minorities, and persons with type 2 diabetes.
Thus, the results are widely applicable to Americans with hypertension,
who number about 50 million, according to the National Health and
Nutrition Examination Survey.
POSTMENOPAUSAL HORMONE THERAPY
The merit of conducting rigorous research to challenge widely held,
but unproven, assumptions about treatment and prevention is illustrated
even more starkly by recent studies of hormone therapy in
postmenopausal women. When the NIH Women's Health Initiative was
started more than a decade ago, belief in the manifold benefits of
estrogen--and particularly its benefits with respect to heart disease
prevention--was so widespread that some thought such a trial was
neither feasible nor ethical. Thus, it was major news when the trial
reported last summer that a widely used form of postmenopausal hormone
therapy (estrogen plus progestin) is ineffective in reducing
cardiovascular disease risk and appears, in fact, to be harmful.
Estimates from U.S. Census data indicate that more than 40 million
American women are postmenopausal, so the implications of this trial,
in terms of both health and costs, are potentially very great.
TREATING ATRIAL FIBRILLATION
Yet another example of a study that contradicted popular wisdom is
the AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm
Management) trial. It compared a well-regarded rhythm-management
approach to treating atrial fibrillation (an abnormal heart rhythm)
with a rate-control strategy. The trial found that the purported
benefits of the rhythm-management approach were nonexistent and,
moreover, that the approach carried an increased risk of adverse drug
effects. These findings are expected to alter fundamentally our method
for preventing complications, most notably stroke, of this arrhythmia,
which affects an estimated 2.3 million people in this country,
according to data from the American Heart Association.
PREVENTING RECURRENT BLOOD CLOTS
Finally, the PREVENT (Prevention of Recurrent Venous
Thromboembolism) trial was recently halted ahead of schedule because of
persuasive intermediate results. It found that long-term use of low-
dose warfarin (a blood thinner) to prevent the recurrence of two blood-
clotting disorders, deep vein thrombosis and pulmonary embolism,
provided major benefits without significant side effects. As was the
case with the ALLHAT study, this trial addressed a research question
that would never have been pursued by industry, and identified an
important use for an old, very inexpensive therapeutic agent.
NEW RESEARCH TO ADDRESS CRITICAL PUBLIC HEALTH ISSUES
Two of the most pressing public health priorities of today are
obesity and diabetes, conditions that have become epidemic in modern
America. Both are the object of NIH-wide multifaceted efforts; they
are, moreover, the special focus of concerted NHLBI attention because
their victims are inordinately susceptible to cardiovascular disease
complications. The NHLBI is undertaking new programs in both areas,
with the ultimate goal of reducing the toll of such complications.
OBESITY
Innovative worksite interventions for preventing and controlling
obesity in adults will be designed and tested. Although traditional
obesity-control strategies have focused on the individual, the
workplace constitutes a promising location for making positive, long-
lasting behavioral and environmental changes that may affect a broad
range of adults. It is envisioned that researchers will consider a
variety of approaches to make healthful foods available, affordable,
and desirable; promote physical activity; and establish support systems
that enable achievement and long-term maintenance of appropriate
weight.
A comprehensive research initiative on asthma and obesity will also
be undertaken. Studies have found that body mass index is strongly and
independently associated with risk of adult-onset asthma, and that
excessive weight gain in elementary school greatly increases risk of
developing asthma among young girls. Overweight also appears to
contribute to asthma exacerbations and diminished pulmonary function.
Experts from a variety of relevant disciplines believe that research
conducted collaboratively by scientists with expertise in asthma and in
body weight issues may yield important clues about hormonal, genetic,
and mechanical factors that influence the relationship between these
conditions. Stimulation of such collaboration is the goal of this new
program.
DIABETES
A major new clinical trial will test approaches to lowering risk of
cardiovascular disease in adults with type 2 diabetes. The ACCORD
(Action to Control Cardiovascular Risk in Diabetes) study will evaluate
the effects of intense blood sugar control along with very aggressive
control of blood pressure and lipids. Type 2 diabetes presents an
enormous public health challenge; its many victims are highly
susceptible to developing such serious consequences as heart attack,
stroke, and limb amputation due to impaired circulation and an
estimated 70 percent of them ultimately die of cardiovascular disease.
More than 15 million Americans have diagnosed type 2 diabetes, and the
number is expected to climb to 27 million by 2050; thus, if this new
program uncovers a better treatment approach, its impact will be
significant.
The Institute is also working to develop a program to study the
causes, prevention, and treatment of cardiovascular disease in the
generally younger population of patients with type 1 diabetes. Such
patients who have advanced microvascular complications suffer
cardiovascular disease rates 10-20 times those of the general
population, and there is an urgent need to identify effective
approaches to prevent or postpone this complication. Undoubtedly, some
common factors contribute to the risk of cardiovascular disease in both
type 1 and type 2 diabetic patients, but the differences in
pathophysiology between the two diseases suggest there may also be
different factors. It is hoped that a closer look at existing data
regarding such factors will form the basis for development of
innovative preventive interventions.
SPARK II CONFERENCE
Although this testimony has focused attention on programs and
activities of immediate and obvious clinical relevance, I want to
assure the Committee that the Institute is moving forward briskly on
all fronts. This past October, we began revisiting a process (called
SPARK, a reference to the expectation that it would ignite a new world
of ideas) which had been first undertaken in 1998 to assist us in
determining the best use of the funds that came our way as part of the
doubling of the NIH budget. First, a working group of select scientists
was assembled to assist in identifying important opportunities that the
Institute should address over the next 3 to 5 years. Subsequently, a
conference was held to obtain the views of representatives of three
major professional societies associated with the mission of the NHLBI
(i.e., the American Heart Association, the American Thoracic Society,
and the American Society of Hematology). A research schema was
developed that focused on five areas of opportunity: regenerative
biology and replacement therapy, development and embryogenesis,
immunology and inflammation, health promotion and disease prevention,
and public health applications of genomics and proteomics. I expect
that we will have much good news to report to the Committee in the
upcoming years as the recommendations of SPARK II are implemented.
BUDGET STATEMENT
The fiscal year fiscal year 2004 budget includes $2,868 million, an
increase of $76 million over the fiscal year 2003 enacted level of
$2,792 million comparable for transfers proposed in the President's
request.
I would be pleased to answer any questions that the Committee may
have.
______
Prepared Statement of Dr. Ting-Kai Li
I am pleased to present the President's budget request for the
National Institute on Alcohol Abuse and Alcoholism (NIAAA) for fiscal
year 2004. The fiscal year 2004 budget includes $430 million, an
increase of $14 million over the fiscal year 2003 enacted level of $416
million comparable for transfers proposed in the President's request.
Alcohol is the third leading preventable risk factor for premature
death in developed countries, according to the 2002 World Health
Organization report. In the United States, alcohol misuse costs society
about $185 billion each year.\1\
---------------------------------------------------------------------------
\1\ National Institute on Drug Abuse and the National Institute on
Alcohol Abuse and Alcoholism. The Economic Costs of Alcohol and Drug
Abuse in the United States, 1992. Analysis by the Lewin Group, Harwood,
H.; Fountain, D.; and Livermore, G. Bethesda, MD: DHHS, NIH, NIH
Publication No. 98-4327 (September 1998).
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The reason alcohol takes such a heavy toll is that its potential to
cause harm extends beyond alcoholism and behaviors that lead to fatal
injuries, major problems in themselves. Alcohol is not only a
psychoactive substance, but also a toxin that can damage any tissue or
organ in the body, unlike illegal drugs. Alcohol's toxic actions cause
or contribute to certain cancers, liver and pancreatic disease, brain
damage, and disturbances of the immune and endocrine systems, among
other conditions. But alcohol also presents a paradox. While heavy
drinking substantially raises the risk of heart disease and stroke,
studies suggest that moderate drinking appears to reduce them. Thus a
major contributor to disease appears to have the potential to improve
certain aspects of health.
VARIATION HOLDS THE ANSWER
The explanation for the paradox lies not only in degree of drinking
in terms of the quantity and the frequency of drinking, but also in
differences in our biological make-up. When we can answer the question
of why alcohol is harmful in some circumstances, but appears to be
beneficial in others, we'll also be likely to find answers to other
questions fundamental to our research: Why do only some of the people
who drink, but not others, develop alcoholism or tissue damage? Why
does the same medication result in sustained recovery from alcoholism
in some people, but fail completely in others?
The answers lie largely in variations in our genes and the hundreds
of biochemical activities they influence in our cells and, ultimately,
our organs and behaviors. Different individuals and different ethnic
populations can have different gene variants to yield a four-fold
difference in their metabolic and behavioral responses to alcohol.
Much of our research is aimed at identifying and understanding: (1)
the genes that influence how our organs and behaviors respond to
alcohol, (2) the association of specific variants of these genes with
specific alcohol-related outcomes, such as tissue damage or alcoholism;
(3) patterns of variation in gene activity, protein activity, and
metabolic activity with specific alcohol-related outcomes, and (4) how
environmental factors interact with these biological factors to
increase or decrease risk of alcoholism and alcohol-related problems.
Findings from this research form the basis on which we develop and
test pharmacological and behavioral strategies for prevention and
treatment. Through studies in humans as well as animals, a high-risk,
high-technology project currently underway is developing a biosensor
that will help us understand vulnerability to alcoholism and organ
pathology. This unobtrusive sensor will enable us to continuously
measure and integrate over time levels of alcohol and, simultaneously,
measure products resulting from alcohol metabolism in a number of
bodily processes.
One approach is an external skin sensor that periodically and
imperceptibly inserts a probe smaller than a human hair into an
individual subject's tissue or the fluid around it.
Another is to implant a microchip sensor subcutaneously. The
continuous data it generates will provide valuable information about
metabolic patterns of vulnerability. Clinically, alcohol levels also
will reveal whether patients are complying with treatment regimens,
providing clues about which treatment strategies are most effective.
CLINICAL IMPLICATIONS
Data from our basic research will enable us to do several crucial
things. We will be able to provide clinicians with reliable
biomarkers--laboratory tests--that will tell them which of their
patients are biologically and/or genetically at risk of becoming
alcoholic or of developing alcohol-induced tissue injury. Clinicians
also will have the potential to predict which patients are biologically
and/or genetically predisposed to respond to a specific medication for
treatment of alcoholism, and which patients will respond to another.
At the same time, this research is helping us to identify molecular
targets for new medications to treat both alcoholism and alcohol-
induced organ damage, a pressing need in the clinical setting. As we
follow the pathways from genes to physical and behavioral outcomes,
we're asking where, within the many biochemical reactions that occur
along the way, we can find the best molecular points at which to aim
pharmaceuticals that block alcohol's actions. We also are asking if
these points for intervention vary depending on variations in a
person's constellation of genes, necessitating different medications or
molecular targets for subtypes of the disorders.
One such point for intervention is about to be tested in human
clinical trials. Our scientists used several approaches to test a
hypothesis that blocking a specific receptor on brain cells--the CB1
receptor, a docking site for the brain's own version of marijuana-like
substances called endocannabinoids--reduces desire for alcohol. In each
approach, the CB1-receptor blocker (Rimonabant) reduced drinking.
Pending results of the clinical trials, Rimonabant could become an
important addition to our currently limited arsenal of effective
treatments for alcoholism. We have identified another 16 compounds that
are potential candidates for further development.
Our research also can help us isolate the biological mechanisms
that underlie alcohol's apparent beneficial effects. Since we don't yet
have clinically useful biomarkers that tell us who can benefit from
moderate alcohol use and who is at risk of alcohol-related problems,
and because alcohol carries with it so many well-documented risks, a
recommendation to drink moderately for those who do not drink would be
irresponsible at this point. If we can isolate the mechanisms that
underlie whatever benefits alcohol might have, we have a chance of
designing pharmaceuticals that mimic the actions of these mechanisms,
but don't have alcohol's many deleterious effects.
BRAIN RESEARCH
Alcohol exerts its principal actions in the brain. It is here that
heavy alcohol use results in brain-cell adaptations that lead to
alcohol addiction. We're approaching this crucial area of brain
research with our Integrative Neuroscience Initiative on Alcoholism
(INIA). This initiative is extending beyond traditional models of
collaboration to capture the potential of input from the many fields
that necessarily contribute to alcohol research, including genetics,
imaging, molecular biology, and behavior--each of which may use
different methods and attach different significance to findings.
At the scientific level, INIA has provided its investigators with
technologies and standardized animal models which ensure that the
significance of findings from each field are placed in the context of
alcohol research. INIA collaborations are occurring not only across
fields of research, but also across universities and organizations,
nationally and internationally.
More than that, INIA has created an operational structure that
enables us to pursue the most productive research, relatively
unencumbered by inflexible funding mechanisms. INIA's funding strategy
allows us to pursue productive investigations as they emerge, to
continue them, and to discontinue those that prove to be less promising
or have reached their potential. In short, INIA has removed roadblocks
to progress. This is enabling us to identify the structure and function
of neural circuits, networks of brain cells that work in concert as
intermediaries of alcohol's behavioral outcomes.
Molecular imaging techniques are permitting INIA investigators to
link alcohol-induced molecular responses with behaviors, in real time.
Through computational biology, INIA researchers are creating models
that predict how different brain structures and functions will respond
to alcohol under different scenarios. This kind of research can help us
determine optimal points for therapeutic intervention. A recent
expansion of INIA will enable us to conduct translational research, to
test whether neurobiological changes that occur in our animal models of
alcohol-related behavior also occur in humans.
UNDER-AGE DRINKING
Drinking by children and adolescents is a concern reflected not
only in our research, but also in parents and the media. Young brains
are still forming nerve-cell connections, and they appear to be more
sensitive to the deleterious effects of alcohol. Researchers are
investigating how alcohol affects this and other processes in the
developing brain, and for how long. Early indications are that
adolescents who have gone through alcohol addiction and withdrawal risk
long-term deficits in learning ability and memory. Research also shows
that people who begin drinking at young ages are much more likely than
those who begin later to become alcoholic at a later point in life.
Children and adolescents also are still developing decision-making
capabilities, so important in formulating responses to environmental
influences, such as peer pressure, that are powerful contributors to
their choices about drinking. Almost 30 percent of 9th-12th graders
surveyed report that they have had five drinks in a row at least once
in the previous month.\2\
---------------------------------------------------------------------------
\2\ Centers for Disease Control and Prevention, Youth Risk Behavior
Survey. http://www.cdc.gov/nccdphp/dash/yrbs/2001/youth01online.htm
---------------------------------------------------------------------------
An important question in alcohol research is how different drinking
patterns affect risk of developing alcohol-related problems. Heavy,
episodic drinking (sometimes referred to as ``binge drinking'') appears
to be popular among some youth--notably college students, as newspaper
headlines frequently attest. A study widely publicized in the media
last year estimated that 1,400 college students die each year from
alcohol-related causes and that 500,000 are injured.\3\
---------------------------------------------------------------------------
\3\ Hingson, R.W.; Heeren, T.; Zakocs, R.C.; Kopstein, A.;
Wechsler, H. Magnitude of alcohol-related mortality and morbidity among
U.S. college students ages 18-24. Journal of Studies on Alcohol,
63(2):136-144, 2002. (164269)
---------------------------------------------------------------------------
In addition to our investigator-initiated research in this area, we
have formed the Task Force on College Drinking, a collaboration between
college presidents and scientists. The Task Force has released
recommendations on prevention strategies, literature for various
audiences, and a website, and has organized regional workshops. The
Institute recently issued a research announcement calling for
scientists with expertise in underage drinking to form rapid-response
partnerships with colleges that request help. Episodic heavy drinking
of alcohol has been ritualized and is an accepted part of life at
certain celebratory events in our society, not only among youth, but
also among adults. Among the questions we're asking are: How does this
kind of drinking practice become ritualized in our society in spite of
its deleterious consequences? How can we change the culture that leads
to it?
Meanwhile, our initiative on the biological mechanisms of
adolescent alcohol abuse is using imaging techniques that correlate
brain structure with function and behaviors, in addition to other
techniques, to reveal how alcohol affects specific brain areas, in
human and nonhuman primate and rodent animal model studies. We're also
asking how developmental and environmental factors and the interplay
between genes and environment affect youths' choices to drink and their
physical and behavioral responses to alcohol.
PREVENTION AND RISK REDUCTION
Alcohol prevention research is aimed at reducing the causes and
consequences of alcohol abuse and alcoholism. For example, whether the
relationship between early onset of drinking and subsequent alcoholism
is one of cause and effect or the result of factors that predispose
people to both those behaviors, and others, is unclear. Our
investigators are studying this issue, and their findings will help us
understand why people become alcoholic. Meanwhile, preventing youth
from drinking and reducing the harm it causes are essential, not only
because early onset drinking predicts subsequent alcoholism, but also
because of the immediate harm that alcohol misuse can cause injury,
violence, early introduction into the criminal justice system, legal
repercussions, derailed scholastic careers, and death, to name a few.
We are conducting studies that develop and test strategies to
prevent drinking by youth of different ages and backgrounds.
Particularly important among these are longitudinal studies that can
tell us whether strategies that show promise among a given subgroup of
youth, such as rural adolescents, are successful or can be adapted for
others, such as urban youth. These studies examine the impact of a
number of factors, such as school programs, parental and family
influence, peer influence, alcohol advertisements, and community
policies and practices.
Prevention research at NIAAA also focuses on the general population
and segments with unique needs. Among them are pregnant women (and
their unborn children, who are at risk of fetal alcohol syndrome) and
the elderly, who may be prone to depression and dangerous interactions
between alcohol and prescription drugs. One of our initiatives is
determining if community-based approaches successful in preventing
alcohol-use disorders in the short-term can result in long-term
prevention at different life stages.
OUTREACH
Public and private partnerships are helping us send our prevention
messages to the community. The Leadership to Keep Children Alcohol-
Free, a prevention campaign in which the Robert Wood Johnson Foundation
has joined us, has recruited 33 governors' spouses to act as
spokespersons.
Other partners in our efforts to prevent under-age drinking include
the National Highway Traffic Safety Administration, the Department of
Justice, the Department of Education, and the Substance Abuse and
Mental Health Services Administration. Our outreach efforts also target
clinicians, including physician groups such as the National Hispanic
Medical Association, and the National Medical Association, that serve
special populations. A science-to-service program provides clinicians
with information about current research, and links them with scientists
who advise them on specific areas of practice, at the clinician's
request. We work with States to engage their treatment providers and
administrators. After exchanging information about our current research
findings and the practitioners' obstacles to providing treatment, we
place experts in temporary residencies in treatment programs that have
identified specific areas of need. Medical schools generally aren't
thorough in their coverage of alcohol-related problems, and we have
produced a physician's guide to help fill the gap. Through these
efforts, we promote the practical application of our research where
it's most needed.
______
Prepared Statement of Dr. Donald A. B. Lindberg
Mr. Chairman and Members of the Committee: I am pleased to present
the President's budget request for the National Library of Medicine
(NLM) for fiscal year 2004, a sum of $316,040,000, which reflects an
increase of $9,334,000 over the fiscal year 2003 enacted level of
$306,706,000 comparable for transfers proposed in the President's
request.
For more than 150 years one institution has been the nation's
primary source of published medical information--your National Library
of Medicine (NLM). Originally part of the Army, the Library became a
civilian organization in the 1950s and a part of the NIH in the 1960s.
Innovation in disseminating medical information has been a hallmark of
the Library since the 19th century, including the first successful
application of computers (40 years ago) to a large-scale bibliographic
system. Today NLM not only maintains the world's largest collection of
biomedical books and journals, but it has become, via the Web, a
ubiquitous source of authoritative information for scientists, health
professionals, and consumers around the world. Some half a billion
searches of the various NLM databases are done each year.
The NLM in the 21st century is distinguished especially by two
features unknown to it just two decades ago: the institution has become
the leading source of human genome information and at the same time an
important source of nontechnical health information for the public. The
proximate source of the information that makes both these features
possible is the National Institutes of Health. The NLM, through the Web
operations of its National Center for Biotechnology Information,
receives more than a quarter million visitors a day seeking molecular
biology information ranging from DNA sequences and protein structures
to the related research literature. On the other hand, the extensive
health information issued by the various NIH institutes and centers
forms the backbone of the MEDLINEplus information service offered to
the general public.
An unusual aspect of the NLM's contemporary role that there is a
direct connection between the Library's research and information
programs and the defense against bioterrorism and medical and public
health preparedness for disaster management and terrorist attack. To
cite a few examples: genomics research databases for targeted
development of drugs, vaccines, and other forms of treatment for such
diseases as smallpox, anthrax, plague, Ebola, and cholera; informatics
R & D related to terrorism and disaster management; training for health
professionals in the use of pertinent information resources; developing
experimental information resources targeted at first responders; and
improving the information infrastructure so that vital data can be
shared during a crisis. As to post-9/11 information services, NLM
quickly placed pages on its Web site about post-traumatic stress
disorder, biological and chemical warfare agents, anthrax, and other
information related to bioterrorism.
TOOLS FOR SCIENTISTS AND HEALTH PROFESSIONALS
In its role as the world's largest medical library, the National
Library of Medicine continues to provide access to the enormous
literature of the health sciences, including even priceless historical
treasures dating to the 11th century. Most medical researchers and
health professionals have, directly or indirectly, availed themselves
of the Library's services some time in their career; there are those
who access MEDLINE/PubMed (to take one popular example) almost daily.
Another heavily used information resource is GenBank (with DNA sequence
data).
MEDLINE is a database of 12 million references and abstracts to the
world's medical literature published since the 1960s; PubMed is the
Web-based retrieval system that makes this wealth of information freely
and easily searchable to health professionals and others. MEDLINE/
PubMed is an evolving system. The database expands at the rate of about
half a million records a year. Several years ago NLM introduced links
between MEDLINE references and publisher websites so users could
retrieve the full text of articles. Today, more than 3,000 of the 4,600
publications indexed for MEDLINE have such links. Another element in
the evolution of MEDLINE is converting information from the 1950s,
MEDLINE form, so that valuable research data, on smallpox and
tuberculosis to take just two pertinent examples, will be available to
today's scientists. A recent improvement is a text version of PubMed
for users who require special adaptive equipment to access the web.
This has had the additional benefit of making the system much more
friendly for those using hand-held devices.
GenBank, on the other hand, is accessed primarily by scientists--
some 50,000 of them each day. It is a collection of all publicly
available DNA sequences and is thus a key element in ensuring that the
flood of data resulting from research around the world, including the
Human Genome Project here at home, is available for further research
and for further analysis and for gene discovery. GenBank is maintained
by NLM's National Center for Biotechnology Information (NCBI) and now
contains more than 15 million sequences and 29 billion base pairs from
over 130,000 species. These are limited to chromosome maps, gene
protein products, and other relevant genetic information for human and
many smaller species.
An increasingly popular NCBI service for the scientist and health
professional is PubMedCentral. This is a digital archive of life
sciences journal literature under which publishers electronically
submit peer-reviewed research articles, essays, and editorials to be
included. NLM undertakes to guarantee free access to the material;
copyright remains with the publisher or the author. Creating ``digital
archives'' is an important NLM responsibility in this electronic age.
Electronic health data standards are also part of the information
infrastructure of the 21st century. Such standards are needed for safe
and effective health care, efficient clinical and health services
research, and timely public health and bioterrorism surveillance. NLM
plays an important role in HHS initiatives to promote standardization
of electronic patient data by supporting the maintenance, distribution,
and linking of key clinical terminologies within the Unified Medical
Language System (UMLS) Metathesaurus. As a result, these clinical
terminologies are available for use throughout the United States in
clinical research databases, patient care, and public health
surveillance. NLM is providing funding for the development,
enhancement, and distribution of several clinically specific
vocabularies. The UMLS Metathesaurus provides a common distribution
vehicle for such vocabularies and a mechanism for linking them to
HIPAA-mandated administrative code sets, basic research vocabularies,
and thesauri designed to index the scientific literature. In addition,
pilot projects for testing the use of the vocabulary in different
settings will be critical for maximizing the benefit of electronic
health data standards for improving patient safety, reducing costs, and
enhancing effective information exchange to combat bioterrorism.
INFORMATION SERVICES FOR THE PUBLIC
Since 1998, NLM has expanded its mission beyond serving health
professionals and researchers to encompass providing high quality
electronic health information services for the public. To serve this
audience, the Library developed a new information resource,
MEDLINEplus, a Web-based service that provides integrated access to the
high quality consumer health information produced by NIH and HHS
components and other reputable organizations. About 1.8 million unique
visitors obtained health information from MEDLINEplus in January 2003.
The main features of MEDLINEplus: 600 ``health topics,'' from Abdominal
Pain to Yeast Infections, consumer-friendly information about thousands
of prescription and over-the counter drugs, an illustrated medical
encyclopedia and medical dictionaries, directories of hospitals and
health professionals, a daily health news feed from the major print
media, 150 interactive and simply presented tutorials (with audio and
video) about diseases and medical procedures, and connections from the
health topics to current clinical trials.
Like MEDLINE, MEDLINEplus is a constantly evolving system. Links
are checked daily and new health topics added weekly. A completely
Spanish-language version of MEDLINEplus was introduced in 2002 and is
receiving heavy use. Early in 2003 a prototype ``MEDLINEplus Go Local''
system was introduced in North Carolina, a joint effort of the
University of North Carolina and the NLM. This system allows
MEDLINEplus users access to ``NC Health Info,'' which contains links to
local, county, and state health services in North Carolina and,
conversely, users of NC Health Info can link into the detailed,
authoritative health information about particular diseases and
conditions in MEDLINEplus.
The NLM casts a wide net in creating and promoting MEDLINEplus,
working closely with the Public Library Association and other
organizations not associated with NLM's mission, as well as with the
4,700 member institutions of the National Network of Libraries of
Medicine. Network librarians not only assist in identifying and
evaluating information to be included in MEDLINEplus, but are of
tremendous help in demonstrating MEDLINEplus locally and publicizing
it.
Another major consumer information resource, ClinicalTrials.gov,
was developed by the NLM on behalf of the entire NIH in response to a
mandate from Congress. The database provides patients and families
access to information about clinical trials and opportunities to
participate in the evaluation of new treatments. The site was launched
in February 2000 and currently contains approximately 7,200 clinical
studies sponsored by NIH, other Federal agencies, and the
pharmaceutical industry.
NLM RESEARCH AND DEVELOPMENT PROGRAMS
The Library is at the cutting edge of research and development in
medical informatics--the intersection of computer technology and the
health sciences. NLM has a program of grants and contracts to
university-based researchers and also a cadre of in-house scientists in
the Lister Hill National Center for Biomedical Communications and the
National Center for Biotechnology Information. The Lister Hill Center
sponsors many exciting communications research projects, such as those
in telemedicine and the Visible Human Project. The NLM-supported ``A
Clinic in Every Home'' is an especially promising telemedicine project
for medically underserved rural Iowa residents to provide them with
access to high quality health care. The expectation is that this system
will both raise the quality of health care and lower costs. Another
Lister Hill Center program is the initiative to fund projects that
demonstrate the medical community's technical needs in using high-speed
communications networks for critical healthcare applications, including
computing in support of disaster management.
The Visible Human Project comprises two enormous data sets, male
and female, of anatomical MRI, CT, and photographic cryosection images.
These data sets, licensed to more than 1,700 individuals and
institutions in 43 countries, are being used in a wide range of
educational, diagnostic, treatment planning, virtual reality, artistic,
mathematical, and industrial applications. Projects run the gamut from
teaching anatomy to practicing endoscopic procedures to rehearsing
surgery. NLM's AnatLine is a web-based image delivery system that
provides retrieval access (even from a home computer) to large
anatomical image files of various parts of the Visible Human male
thoracic region, such as the heart and stomach, including 3D images.
The other major NLM component involved in R & D is the National
Center for Biotechnology Information, noted above as the source of the
GenBank database of DNA sequence information. NCBI is more than just
assembler of genomic data, however. NCBI investigators have developed
sophisticated computational tools such as the BLAST suite of programs
that makes it dramatically easier for researchers to scan huge sequence
databases for similarities, and to evaluate the resulting matches.
Another NCBI product, Entrez, is an integrated database that allows
users to easily and quickly search enormous amounts of sequence and
literature information. The newest tool is the ``Reference Sequence
Collection'' that is serving as a foundation for genomic research by
providing a centralized, integrated, non-redundant set of sequences,
including genomic DNA, transcript (RNA), and proteome (protein product)
sequences, integrated with other vital information for all major
research organisms. As genomic sequence data continues to accumulate
and be made available in ingenious ways through the web, we can expect
discoveries that promise future medical breakthroughs.
NLM extramural programs have an important role in supporting R & D
in biocommunications. One timely example is the early warning public
health surveillance system developed at the University of Pittsburgh
and recently demonstrated to the President. NLM's grant program also is
a key supporter of NIH's ``Biomedical Information Science and
Technology Initiative.'' The Library has expanded its support from 12
to 18 training programs at universities across the nation to train
experts to carry out research in general informatics and in
bioinformatics. The NLM has recently augmented each of the training
programs with a ``BISTI supplement'' and has also funded two planning
grants that will eventually lead to the development of what are called
National Programs of Excellence in Biomedical Computing.
SERVING SPECIAL COMMUNITIES
The NLM has been working with the National Institute on Aging to
create NIHSeniorHealth.gov. Accessible from MEDLINEplus, the new site
contains information in a format that is especially usable by senior
citizens. At present NIHSeniorHealth.gov contains information on topics
like Alzheimer's and exercise for older adults, but it will soon be
expanded to include more topics of special interest to seniors as other
NIH institutes contribute to it. NLM is working on adapting special
software that would allow the visually impaired to exercise control and
hear Web pages read to them. This would also be a boon to some senior
citizens.
The National Network of Libraries of Medicine, noted above in
connection with MEDLINEplus, places a special emphasis on outreach to
underserved populations in an effort to reduce health disparities. For
example, there are programs to assist in remedying the disparity in
health opportunities experienced by such segments of the American
population as African Americans, Latinos, Native Americans, senior
citizens, and rural populations. One of the NN/LM outreach efforts
involves a telemedicine ``connections'' program for Native Americans in
the Pacific Northwest conducted through the Regional Medical Library at
the University of Washington.
Another highly successful NLM outreach program has been
strengthening Historically Black Colleges and Universities so that they
can train people to use information resources in dealing with
environmental and chemical hazards. Under this program, faculty and
students in more than 80 minority institutions have received such
training. Through these schools, NLM is working to promote high-quality
Internet connectivity and using technology for research and education.
There are other NLM programs targeting groups of citizens with
special health information needs. In the past several years, the
Library has made more than 50 awards to continue its HIV/AIDS-related
outreach efforts to community-based organizations, patient advocacy
groups, faith-based organizations, departments of health, and
libraries. This program supports local programs to improve information
access for AIDS patients, the affected community, and caregivers.
Emphasis is on providing information in a way meaningful to the target
community, and may include training in information retrieval, sending
interlibrary loans, and providing Internet access.
NLM's efforts to reach special populations in need are not limited
to the United States. An international partnership in which the NLM is
a key player is the Multilateral Initiative on Malaria. NLM's mandate
as leader of the Communications Working Group has been to leverage
partnerships (at 13 installations) to create a malaria research network
in Africa, enabling scientists there to have full access to the
Internet and the Web as well as access to medical literature. The aim
is to allow researchers, any time of the day or night, to have
instantaneous Internet access that will enable them to send and receive
e-mails, search for literature, interrogate databases, share files and
images with colleagues, and generally move to a new and more efficient
way of doing collaborative research.
FUTURE PROSPECTS
NLM is responsible for acquiring, indexing, cataloging, and
preserving the world's biomedical literature--in all languages and
media--and for providing reference and research assistance and document
delivery from this comprehensive collection. NLM also collects,
processes and distributes genome sequence data through NCBI. Both of
these core areas are experiencing unprecedented growth. The cost of
purchasing the biomedical literature typically increases about 10
percent per year, irrespective of general inflation, and the move to
electronic publishing has not diminished this rate of increase. NLM
uses advanced technology to improve the efficiency of its basic
operations, and contractors currently perform the majority of
activities required to provide NLM's basic services.
______
Prepared Statement of Dr. Kenneth Olden
Mr. Chairman and Members of the Committee: I am pleased to present
the President's budget for the National Institute of Environmental
Health Sciences (NIEHS). The fiscal year 2004 budget includes
$630,774,00, an increase of $17,358,000 over the fiscal year 2003
enacted level of $613,416,000 comparable for transfers proposed in the
President's request.
INTRODUCTION
Voluminous literature derived from epidemiological studies as well
as human and animal experiments has shown that environmental factors
play an important role in human health and disease. That is, most
complex diseases arise from the interplay between genetics, environment
and behavior. However, understanding of these interactions has remained
grossly descriptive and the molecular mechanisms elusive. But, thanks
to the rare confluence of technology breakthroughs in genomics and
proteomics and the rethinking and redirection of the environmental
health sciences over the past decade, the link between the environment
and human health and disease can now be investigated with more rigor
and specificity. For example, the sequencing of the human genome and
the development of high throughput technologies to monitor the
expression of genes and proteins in response to specific environmental
exposures has created an unparalleled opportunity to study gene-
environment interactions.
NEW INITIATIVES
Breast Cancer and Environment Research Centers.--There is
surprisingly little information on the development of the normal
breast. The lack of knowledge about the biological and molecular
mechanisms involved in normal breast development hinders our ability to
identify environmental triggers of breast cancer. How can we identify
early adverse changes in breast tissue if it is not known how the
tissue normally develops? To fill this research gap, NIEHS is funding a
consortium centers program that will provide new information on the
normal growth and development of the breast and reproductive systems,
evaluate the impact of environmental exposures on the breast, and
explore potential times of increased sensitivity and vulnerability of
breast tissue to environmental effects. These centers represent a
collaborative effort with the National Cancer Institute.
NIEHS is also continuing the effort to establish a cohort of
unaffected sisters of breast cancer cases to clarify the gene-
environment interactions in this disease. This cohort can be used to
examine breast cancer risk in relation to factors such as endogenous
hormones, growth factors and environmental contaminants, and to study
these factors jointly with genes to elucidate genetic modifiers of
response.
Toxicogenomics.--NIEHS developed the National Center for
Toxicogenomics (NCT) to coordinate a nationwide research effort for the
development of a toxicogenomics knowledge base. Toxicogenomics is a new
discipline that studies how genes respond to environmental stressors or
toxicants. It combines genetics (genomic-scale mRNA expression),
proteomics (cell and tissue-wide protein expression), metabonomics
(metabolite production) and bioinformatics with conventional toxicology
to investigate the role of gene-environment interactions in health and
disease. New molecular technologies, such as DNA microarray analysis
and protein chips, can be used to measure the expression of thousands
of genes and proteins, providing the potential to accelerate discovery
of toxicant pathways and specific chemical and drug targets.
When a person is exposed to a chemical, cells in the body may
respond by switching on some genes and switching off others. The on/off
pattern of various genes is different for different chemicals, creating
a characteristic pattern or ``signature,'' which scientists hope will
be useful in classifying chemicals and other stressors by their
biological activity. This signature pattern would provide a means of
predicting effects on human health from chemicals we currently know
little about. Toxicogenomics seeks to use these signature gene
expression patterns to go beyond the traditional toxicological tools of
testing animals for adverse outcomes that might indicate toxicity.
One aim of the NCT is to create a Chemical Effects in Biological
Systems (CEBS) Database. The CEBS database will contain data on global
gene expression, protein expression, metabolite profiles, and
associated chemical/stressor-induced effects in multiple species. With
such information, it will be possible to derive functional pathways and
network information based on cross-species homology. Once sufficient
high quality data have been accumulated and assimilated, it will become
possible to predict the toxicity of an unknown chemical by comparing
its gene and/or protein expression profile to compendia of expression
profiles in the database. As the field of toxicogenomics evolves,
toxicogenomics databases will begin to support predictive toxicology
and hazard assessment. This will help scientists predict the
toxicologic impact of suspected toxicants and calculate how much of a
hazard these toxicants actually represent to human and environmental
health.
The pharmaceutical industry is making huge investments in this
technology because of their interest in finding ways to speed up the
process of toxicological assessment of new research and development
products. Identifying molecular events that serve as precursors of
adverse health outcomes early in the development process would
eliminate much of the expense (estimated in the billions of dollars
annually) associated with the development of new pharmaceutical
products.
Susceptibility to Environmental Exposures.--Although reference is
made to the human genome, the concept of a single genome is misleading.
Each individual's genetic makeup, with the exception of identical
twins, is unique. While the genomes of individuals are 99.9 percent
identical, the 0.1 percent variation leaves considerable room for
individual differences among the approximately three billion nucleotide
base pairs that make up the human genome. However, it should be
emphasized that genes are not the only factors that contribute to
differences in susceptibility to environmental exposures; age or stage
of development, behavior, and general health or nutritional status can
have a spectacular influence. Both the genetic and age/stage of
development-related aspects of susceptibility are being addressed by
NIEHS.
Differences in susceptibility to environmental exposures had
received little attention until NIEHS launched the Environmental Genome
Project (EGP) and the Children's Environmental Health Research and
Prevention Centers in 1998. There is now considerable evidence that
hundreds of genes exist in the human genome that make some individuals
more or less susceptible to the effects of pollutants or other
environmental chemicals, contributing to everything from cancer to
birth defects and Parkinson's Disease. The key objective of the EGP is
to discover the alleles or genetic variants (called polymorphisms) that
confer susceptibility or resistance.
The Children's Environmental Health Research and Prevention Centers
were developed, in collaboration with the EPA, to explore the
relationship between the timing of exposure, the stage of development
and susceptibility. Because of the rapid rate of growth and development
of major organ systems (e.g., the lung, brain, and heart), children are
thought to be particularly vulnerable to environmental toxicants. They
can be more vulnerable than adults to adverse health outcomes, and the
consequences of these adverse effects are sustained throughout life,
making the reduction of childhood exposures a critical component of
environmental public policy.
We are also exploring the possibility of susceptibility studies in
seniors. For a variety of reasons, older Americans are also more
susceptible to environmental stress (e.g., the combination of poor air
quality and extreme heat during the summer months). This important
public health issue has received almost no attention, but dialogue is
ongoing with the EPA and the National Institute on Aging about ways to
include older Americans in more environmental health studies.
Parkinson's Disease Research Consortium.--NIEHS created a
Parkinson's Disease Consortium Centers Research Program in 2002 because
we believe that a collaborative, multidisciplinary, multi-institutional
approach is required to elucidate the complex interactions between
genes and environmental factors likely to be involved in the
development of this devastating disease. Collectively, the three
centers that make up the consortium have expertise in basic
neurosciences, human genetics, clinical research, and epidemiology, and
long-standing collaborative interactions with the various non-profit
organizations that represent patient advocates. These scientific
disciplines were included in the consortium because a major impediment
in Parkinson's Disease research has been that significant findings in
one field were not readily disseminated among investigators in the
other related fields. It is our intent to expand the Consortium Centers
concept in 2004 to capture some of the outstanding activities not
funded earlier.
The knowledge and technologies developed in the Institute's EGP,
the Mouse Genome Centers, and the National Center for Toxicogenomics
will also be made available to this cohort of investigators as they
become available. For example, new Parkinson's Disease susceptibility
genes and new environmental risk factors are likely to be discovered,
and new mouse models of the disease are likely to be created using gene
``knockout'' and ``knockin'' technologies. These new resources will be
invaluable to the Parkinson's Disease research community.
The Development of Multidisciplinary Research Teams and Novel
Technologies.--The solution to complex problems often requires the
collective knowledge and experience of multiple investigators and novel
approaches developed at the boundary of several disciplines. While the
individual investigator approach remains the cornerstone of innovation
of science and technology development, translation often requires a
team approach. In fact, lack of infrastructure to support the
development of multidisciplinary research teams is hampering our
ability to realize the benefits of the nation's expenditures for
biomedical research. While the NIH has invested in infrastructure to
build maps of the human genome and develop technologies for genotyping
and monitoring gene and protein expression, it is the deployment of
these data bases and technologies to prevent human illness that has
proven to be the most challenging.
Also, the inadequacy of current analytical methods to investigate
complex interactions involving genes, proteins and environmental
factors has been a bottleneck in understanding the development of
complex diseases resulting from such interactions. While high
resolution structural analysis of proteins is critical for
understanding molecular interactions between genes, or proteins and
toxic chemicals, new technologies will be needed to determine how the
latter disrupts structure and function of highly coordinated biological
pathways or networks at the level of the cell and tissue. NIEHS has
developed the Center Programs described here to catalyze the formation
of multidisciplinary research teams to investigate gene-environment
interactions using emerging expertise and technologies.
SUMMARY
The data generated by the studies I have described will allow for a
more rational approach of gauging environmental threats, and will
reduce the need to rely on default assumptions in extrapolating results
from animal models to humans and in setting exposure limits. These
studies will also lead to the development of high throughput
technologies that could both accelerate and reduce the costs of
toxicity testing of pharmaceuticals and environmental xenobiotics. This
approach to understand how genes and the environment interact shifts
the focus of disease management from symptom-based classification to
biological causation and prevention. The objective is to provide a
database that will allow for the use of precursors or molecular markers
in assessment of disease states.
______
Prepared Statement of Dr. Audrey S. Penn
Mr. Chairman and Members of the Committee, I am Audrey Penn, Acting
Director of the National Institute of Neurological Disorders and Stroke
(NINDS). I am pleased to present the President's budget request for
NINDS for fiscal year 2004. The fiscal year 2004 budget includes $1,469
million, an increase of $13 million over the fiscal year 2003 enacted
level of $1,456 million comparable for transfers proposed in the
President's request.
The mission of NINDS is to reduce the burden of neurological
disorders, that is, the many diseases that affect the brain, spinal
cord, muscles, and nerves of the body. Neurological disorders cause
enormous suffering and loss of life, often defying the best efforts of
modern medicine. However, we are making progress in prevention and in
treatment, derived from continuing advances in fundamental scientific
understanding of the nervous system, which enhance the prospects for
the future. Today I will touch on these points and concentrate on what
NINDS is doing to expedite progress.
THE BURDEN OF NEUROLOGICAL DISORDERS
Neurological disorders can compromise the complex thinking and
emotions that make us human, the routine perception and movement that
we take for granted, and even the control of bodily systems that are
normally beneath our awareness. Diseases of the nervous system strike
at every age. Some, such as stroke, chronic pain, epilepsy, and
traumatic brain injury, are among the most common of all causes of
death and disability. Hundreds of less common neurological disorders
take an incalculable toll on patients and families too. Also demanding
attention are substantial disparities in impact by ethnic group,
gender, socioeconomic status, and geography.
PROGRESS AND PROSPECTS FOR THE FUTURE
Progress in preventing and treating neurological disorders has been
notable. As Dr. Zerhouni has testified previously, this year alone
almost a quarter of a million fewer deaths from stroke will occur in
the United States than would have been expected without advances in
prevention--progress that represents the cooperative efforts of many
groups, public and private. Prevention of nervous system birth defects,
such as spina bifida, and genetic counseling for inherited disorders,
such as Tay-Sachs disease, are also having a major impact on public
health. The first acute treatments for ischemic stroke and spinal cord
injury--though still far from adequate--have proven effective for
reducing neurological damage. Immune therapies now reduce relapses and
slow the progression of disability in multiple sclerosis. Surgical
options employ implantable devices to compensate for brain circuits
unbalanced by disease in Parkinson's disease and epilepsy. Enzyme
therapies have brought the first successes in treating lipid storage
disorders. Advances in molecular genetics and brain imaging are further
augmenting clinicians' insights to diagnose and to guide therapy.
Progress is gaining momentum, with an unprecedented variety of new
treatment and prevention strategies under development: drugs to home in
on the molecules that cause disease, stem cell therapies to replace
lost nerve cells, neural prostheses to read control signals directly
from the brain, immune tolerance approaches to prevent stroke,
therapies to repair or replace defective genes, and behavioral
interventions to encourage the latent ``plasticity'' of the brain and
spinal cord toward self-repair. Each of these strategies relies upon
remarkable advances in understanding how the normal nervous system
works and what goes wrong in disease.
A few findings from the past year illustrate this progress:
Scientists studying genes discovered a mutation that causes a form of
Charcot-Marie-Tooth disorder, a common disabling disease of peripheral
nerves; pinpointed the site of a gene contributing to autism; and found
clues about how a chromosome defect causes facioscapulohumeral
dystrophy, a common form of muscular dystrophy. In animal models of
human disease, themselves often the product of gene research, gene
therapies have yielded encouraging results for neurofibromatosis, Fabry
disease and Parkinson's. Scientists on the trail of cell therapies
discovered that primitive precursor cells in the adult rat brain can
respond to experimental damage by multiplying, migrating to the site of
damage, and making new nerve cells, and that transplanted embryonic
stem cells show promise in animal models of Parkinson's disease,
stroke, and other disorders. Scientists focusing on the immune system
found that a strategy, which suppresses immune reactions, prevents
strokes in hypertensive rats; that an anti-cholesterol drug, the statin
Lipitor, reduces symptoms in an animal model of multiple sclerosis; and
that the gene defect in Batten disease may result in unexpected immune
reactions, which could contribute to the devastating consequences in
the brain. In research on drug treatments, the antibiotic minocycline
slowed progression of amyotrophic lateral sclerosis in mice; the
natural brain chemical inosine stimulated rewiring of the brain
following stroke in rats; and coenzyme Q10 may slow progression of
Parkinson's disease. Scientists studying new technologies developed a
device that enabled rats to control a robot arm just by thinking about
it; devised better ways to delivery therapeutic agents to the brain;
used microarrays to monitor the activity of thousands of genes,
yielding insights about brain tumors and multiple sclerosis; and for
the first time, recorded activity of the human fetal brain in response
to light, which may lead to better prenatal diagnostics.
EXPEDITING PROGRESS
NINDS continues to rely on the insight and ingenuity of scientists
and physicians throughout the nation to seek out scientific
opportunities, propose research studies, and advise on promising ideas.
Since Congress began the NIH budget doubling effort, the Institute has
taken a more active role in directing research. Efforts are motivated
by scientific opportunity, enabled by resources, guided by extensive
and inclusive planning efforts, and quality-assured through peer
review. Programs target specific diseases and cross-cutting
opportunities to enhance the effectiveness of research. A few examples
illustrate the wide range of activities:
The NIH Parkinson's Disease Research Agenda is the pacesetter for
disease-focused NINDS activities. The Agenda began in January 2000 with
a working group that included Parkinson's disease researchers, patient
advocates, industry representatives, and NIH scientific staff. Follow-
up meetings, most recently a July 2002 ``summit'' called by the NIH
Director, have updated priorities to reflect the changing scientific
landscape and to address roadblocks to progress. Since March 2000, the
Parkinson's effort has included more than 20 solicitations, more than a
dozen workshops, establishment of a network of Morris K. Udall Centers,
major clinical trials, and funding of the Deep Brain Stimulation
Consortium. The NINDS Office of Minority and Health Research is also
leading a major effort to implement the NINDS Five Year Strategic Plan
on Minority Health Disparities, and developing goals specific to
neuroAIDS, stroke and epilepsy. Implementation of planning efforts in
brain tumor, stroke, and epilepsy are also under way. Other initiatives
are focusing on diseases such as autism, muscular dystrophy, and spinal
muscular atrophy, and NINDS continues to support a variety of disease-
focused scientific workshops to assess current understanding, stimulate
research interest, and foster collaborations.
Re-engineering the research enterprise.--NINDS has designed and
conducted pioneering clinical trials to test the safety and
effectiveness of interventions to prevent and treat neurological
disorders. In recent years, the Institute augmented clinical trials
activities with new grant mechanisms for planning trials and for pilot
trials; developed procedures and increased professional staff to
optimize trial design and monitoring; and created a subcommittee of the
NANDS Council to provide broad advice on priorities for clinical
research, including trials. This year, NINDS is beginning to supplement
ongoing clinical trials to capture genetic samples for a newly
established DNA and cell line repository. For the future, the Institute
is exploring options to create a network of physician-investigators to
carry out clinical trials. Such a program might speed trials, minimize
costs, enhance accessibility for patients, facilitate the recruitment
of a diverse spectrum of participants, improve feasibility of trials
for rare diseases, and accelerate the transfer of results to practice
in community settings.
A highlight of the clinical trials program is an innovative trial
of neuroprotective drugs for Parkinson's disease, that is, drugs which
slow disease progression rather than just temporarily improving
symptoms. The Institute reached out widely to academia and industry,
here and abroad, for suggestions of possible drugs, and developed a
rigorous evaluation process, which has selected the most promising drug
candidates. A network of more than 40 clinical sites, with central
statistical and data coordination, has been established to carry out
the trial. NINDS is working closely with voluntary groups to recruit
patients. The first pilot studies may begin this spring.
Translational research is another major focus of cross-cutting
efforts. NINDS has a long history of translational research, which
moves fundamental discoveries about the brain and disease toward
therapies and clinical trials. Advances in neuroscience are yielding
increasing opportunities for translation, and NINDS responded in July
2002 by launching a comprehensive program to foster translational
research. Essential to this program are peer review criteria tailored
to the needs of translational research, milestone driven funding, and
training a cadre of investigators to carry out translational research.
The goal is to provide an environment where coalitions of basic
scientists and clinicians can design and carry out preclinical studies
required to bring therapeutic candidates to the point where clinical
studies can begin.
New pathways to discovery.--Several NINDS programs are exploring
new avenues for discovery. NINDS has established a goal of identifying
small molecules that are active in the nervous system and show promise
as therapeutic candidates, diagnostic agents, or research tools. In
2002, the Institute established a consortium to test more than 1000
drugs, most previously approved by the U.S. Food and Drug
Administration (FDA) for other conditions, against 29 rapid laboratory
assays (tests) related to neurodegenerative diseases. The best
candidate chemicals are moving to further testing in animal models
through an NINDS supplement program. NINDS has also awarded a contract
for a high throughput screening (HTS) center, and is soliciting
proposals for the development of assays for HTS. HTS rapidly tests
thousands of chemicals to find lead compounds for drug development. In
another effort, a contract-based approach to therapeutics development
for spinal muscular atrophy will test a new model that might apply to
other diseases. The NIH Molecular Library Roadmap Project will speed
the discovery process for drugs and chemical research tools by
providing access to information databases and to potentially useful
compounds. The Institute has also established a facility to provide
researchers access to microarray technology, which allows simultaneous
monitoring of the activity of thousands of genes in health and disease.
Stem cell research remains a high priority for the Institute. NINDS has
provided supplements for grantees to pursue stem cell research, and
joined with other components of NIH in stimulating this research and
targeting aspects critical for the nervous system. An NINDS intramural
investigator will lead a new NIH facility to characterize the available
approved lines of human embryonic stem cells.
Research teams of the future.--Increasingly, progress against
neurological disorders requires cooperation among multi-disciplinary
teams of investigators. NINDS is enhancing the opportunities for team
approaches with general programs to support common resources and
specific initiatives tailored to areas such as Parkinson's disease,
stroke, autism, muscular dystrophy, spinal cord injury and health
disparities. The Institute is also addressing critical training needs
in areas such as translational and clinical research. In the NIH
Intramural program, the John Edward Porter Neuroscience Center will
bring together scientists from ten NIH components that focus on the
brain.
CONCLUSION
Neurological disorders have always challenged the best efforts of
medicine. The intricacy of the brain is awesome, its workings are
elusive, and an extraordinary variety of disorders affect the nervous
system. Furthermore, the brain and spinal cord are difficult to access,
sensitive to intervention, and reluctant to regenerate following
damage. However, building on advances in basic science, progress is
improving peoples' lives, and prospects for the future are even more
encouraging. We are working to engage the best minds in the nation and
provide them with the resources they need to devise ways to prevent,
treat, or, ultimately, cure neurological disorders. Thank you.
______
Prepared Statement of Dr. Roderic I. Pettigrew
Mr. Chairman and Members of the Committee: I am pleased to present
the President's budget request for the National Institute of Biomedical
Imaging and Bioengineering (NIBIB). The fiscal year 2004 budget
includes $282,109,000, an increase of $3,838,000 over the fiscal year
2003 enacted level of $278,271,000 comparable for transfers proposed in
the President's request.
The NIBIB's mission is to lead the development and application of
breakthrough technologies in the physical and engineering sciences to
facilitate an improved fundamental understanding of complex biological
processes. This research agenda will dramatically advance the Nation's
health care by improving the detection, management, understanding and,
ultimately, the prevention of disease. Health care and technology have
long been linked in the United States. Today, cardiac pacemakers,
mammograms, sustained release medications, and artificial hips are but
a few examples of how biomedical imaging and bioengineering are
transforming health care.
In September 2002, I began my tenure as the first Director of the
NIBIB. I assumed my role during a time when the landscape of conducting
biomedical research is changing. It is this altered landscape, wherein
the most efficacious medical advances depend on multidisciplinary
findings obtained from researchers working together at the interface
between the biological and quantitative sciences, that led to the
creation of the NIBIB. This new environment, combined with recent
budgetary increases, visionary predecessors, the rapid pace in
technology development, and high-quality investigator-initiated
research, has allowed the NIBIB-just in its second year of operation-to
establish a strong research foundation on which to capitalize. To
illustrate these points, my testimony will highlight recently achieved
milestones, outline research plans and directions, and describe areas
of progress and opportunity.
MILESTONES TO SUCCESS
The NIBIB, the newest Institute at the National Institutes of
Health (NIH), was established by law December 29, 2000, and received
its first appropriation and grant funding authority in fiscal year
2002, just 15 months ago. Since its establishment, NIBIB staff have
achieved significant milestones. In fiscal year 2002 the NIBIB funded
approximately 300 research applications, participated in approximately
170 extramural symposia, planned 16 NIH-based symposia and workshops,
served as lead on 5 trans-NIH initiatives, and collaborated on 4 trans-
NIH programs.
Additional milestones have been achieved in fiscal year 2003. In
January, the NIBIB held the first meeting of its National Advisory
Council. The Institute has also built a solid research infrastructure
through the release of numerous basic and applied research
solicitations in promising areas of scientific investigation, including
tissue engineering, advanced biomaterials, image-guided interventions,
low-cost medical imaging modalities, biosensor technology, and cellular
and molecular imaging.
The NIBIB has successfully fostered extensive linkages and
collaborations with other NIH Institutes and Centers, Federal agencies,
academic institutions, private industry, and scientific societies. As
examples, the NIBIB administers and participates in the Bioengineering
Consortium (BECON), an NIH-wide consortium dedicated to promoting and
coordinating bioengineering research across the NIH. The NIBIB and the
National Science Foundation are collaborating with the National Academy
of Engineering-a private, independent, nonprofit institution-on a
project entitled ``Engineering and the Health Care System.'' This study
focuses on ways to harness advances in engineering applications to
improve health care delivery. The NIBIB will collaborate with the
National Institute of Diabetes and Digestive and Kidney Diseases to
develop a program for monitoring pancreatic insulin cell failure in
diabetes. This would constitute a significant advance in diabetes
research.
THE NIBIB RESEARCH PORTFOLIO
In December 2002, the NIBIB officially launched its strategic
planning process with an interactive workshop entitled ``Future
Research Directions.'' This workshop helped identify high-priority
research focus areas and associated high-impact projects and
technologies that could contribute significantly to biomedical research
and global healthcare needs. Areas identified as highly relevant to
NIBIB's mission include image-guided interventions, cellular and
molecular imaging, computational biology, biosensor technologies,
optical imaging technologies, and regenerative medicine. The Institute
is now poised to realize the promise within these areas of opportunity.
ADVANCED TECHNOLOGIES
Biomedical imaging and bioengineering are interdisciplinary fields
that require collaborations not only among imagers and engineers, but
also with biologists, chemists, mathematicians, computer scientists,
and clinicians of all specialties. Today, the imaging and engineering
sciences are essential for improved understanding of biological
systems, detecting and controlling disease, and enhancing human health.
Recent advances in these fields have enabled the diagnosis and
treatment of various diseases using increasingly less invasive
procedures. Benefits associated with minimally invasive imaging
applications include quicker and more accurate diagnoses leading to
improved patient outcomes at reduced costs. Minimally invasive image-
guided interventions now serve as powerful tools in the operating room
and can be applied to surgical procedures in urology, oncology,
neurosurgery, ophthalmology, cardiology, and orthopedics. However,
these techniques are in relatively early stages of development. A goal
of the NIBIB is to further establish and validate minimally invasive
image-guided therapies as standards for patient care and to support
additional research in therapeutic areas where minimally invasive
technologies do not yet exist. The NIBIB also has initiatives underway
to encourage investigator-initiated research for tracking anatomical
targets and instruments and for developing steerable devices, including
catheters, endoscopes, and needles. A goal is to develop theses
techniques so that they may be used to routinely identify disease at
its earliest stages, even before symptoms arise. At that point,
treatments can be instituted to cure the disease or preempt any serious
consequences.
The combination of image-guided therapies with genomics and
proteomics, has given researchers the capacity to develop new molecular
probes and targets for disease detection, and to immediately direct
treatment to the diseased site. By studying how a person's genetic
blueprint is expressed through proteins, and how these proteins differ
in healthy and diseased cells, researchers will be able to develop
therapies tailor-made for an individual. As a first step towards
``personalized medicine,'' NIBIB researchers are investigating tiny
``barcoded'' metal particles as a method for analyzing proteomes-the
complete set of an organism's proteins. Advances in miniaturized
devices not only have the potential to identify and characterize new
proteins, but to advance the rapid screening of multiple compounds in
the drug development process.
Molecular imaging provides a way to monitor cellular activities in
normal and diseased states. The development of novel imaging
technologies, combined with new or enhanced probes that bind to defined
cellular targets, will allow this technique to be more broadly applied
to biomolecules that are known indicators of a diseased state, such as
an enzyme that may be overexpressed in a specific tumor. For example,
NIBIB researchers have developed artificial fluorescent agents, called
quantum dots, that glow and act as cell markers when bound to certain
cancer cells. Further testing of these agents in animal models of
cancer will determine their utility as effective imaging agents for the
early detection of cancer in humans.
BIOINFORMATICS AND COMPUTATIONAL BIOLOGY
Advances in bioinformatics and computational biology have been
identified as one of the areas of greatest need, and one of the areas
having the greatest potential for positive impact on the universe of
medical science and health care. In recognition of the critical role
these disciplines play in biomedical imaging and bioengineering, NIBIB
supports fundamental research in computing technology, the targeted
development and application of new biocomputing tools, and technologies
that provide structural and functional data at the cellular level.
Areas of NIBIB interest include the development of high performance
computing and visualization methods applicable to the modeling of
biological systems, the utilization of medical imaging data in
computational modeling of biological systems and human physiology, the
development of algorithms and software for the manipulation and
analysis of imaging data, and computer modeling of tissue mechanics.
Our goal is to advance an understanding of the integrated function of
biological systems through the development and application of
computational models, and to apply these models to the design of novel
treatments and therapeutics. In support of this goal, a NIBIB
researcher is developing a brain-computer interface (BCI) system that
acquires and analyzes brain signals to create a communications channel
directly between a person's brain and a computer. BCI technologies can
allow people who are completely paralyzed to express wishes to
caregivers and to use computer programs.
NANOTECHNOLOGY: SENSORS FOR MEDICINE
The term nanotechnology is used to describe many types of research
at the atomic, molecular, or macromolecular level-research where the
characteristic dimensions are less than one-thousandth of the diameter
of a human hair. Biosensors are nanoscale devices that detect, monitor,
and transmit information about a physiological change, or about the
presence of various chemicals, gases, or biological materials (bacteria
and viruses). Laboratory diagnostics used in hematology, clinical
chemistry, pathology, and microbiology already employ sensor
technologies to perform simultaneous measurements for hundreds, maybe
thousands, of substances in urine, blood, saliva, sweat, and
interstitial fluids. The NIBIB has an active research program in sensor
technologies and is expanding this area of research.
Knowledge gained through NIBIB-supported advances in
nanotechnology, particularly in the areas of biosensors and molecular
imaging, will be further leveraged for the development of sensors that
can be applied to other critical research areas. For example, NIBIB
researchers are adapting highly sensitive and selective biosensor
arrays to provide a fingerprint for the identification of harmful
bacteria and environmental health hazards. Future NIBIB efforts being
planned in nanotechnology and sensors focus on the development of low-
cost, miniaturized, integrated sampling detector systems for field use,
including the development of systems that provide ``detect-to-warn''
capabilities, and that enable the rapid and accurate verification of
exposure to harmful environmental agents.
MULTIDISCIPLINARY RESEARCH TEAMS OF THE FUTURE
The era of the solo independent investigator is passing. Our
research culture must be redirected to the formation of teams that span
academic departments and scientific disciplines. Their formation is
critical to the development and validation of new technologies to aid
in disease detection, treatment, and prevention. Therefore, a major
goal of the NIBIB is to catalyze team science through initiatives that
encourage multi-organizational and multidisciplinary teams. Programs
differ from traditional NIH opportunities as they require collaborative
efforts between quantitative and biomedical researchers. These will
support institutional needs, infrastructure development, and the costs
associated with making team science viable and attractive to academic
institutions. Within a given area, specific clinical problems-such as
our current effort to image pancreatic beta cell function in diabetes-
will be identified to serve as a catalyst to drive the formation of the
research team. The value in catalyzing team science lies not only in
strengthening research capacity, but in fostering the formation of
research teams among disciplines where they previously have not
naturally formed.
In conclusion, the NIBIB is dedicated to promoting the development
of emerging technologies and establishing opportunities that will
encourage the necessary interdisciplinary collaborations to advance
biomedical and global health care priorities. I would be pleased to
respond to any questions that the Committee may have.
______
Prepared Statement of Dr. John Ruffin
Mr. Chairman and members of the Committee: I am pleased to present
the President's budget request for the National Center on Minority
Health and Health Disparities (NCMHD) for fiscal year 2004, a sum of
$192,724,000, which represents an increase of $7,010,000 over the
comparable fiscal year 2003 appropriation.
Despite improvements in the overall health of the general
population, over the past decade, African Americans, Hispanics,
American Indians, Alaska Natives, and Asians and Pacific Islanders the
fastest growing communities in this country and the urban and rural
poor, continue to suffer an unequal burden of death, disability, and
disease.
With the goal of addressing health disparities through science, the
Congress enacted Public Law 106-525, the Minority Health and Health
Disparities Research and Education Act of 2000, to establish the NCMHD.
The mission of the Center is to promote minority health and to lead,
coordinate, support, and assess the National Institutes of Health's
(NIH) effort to ultimately eliminate health disparities. I am grateful
to the Congress for its wisdom in creating the NCMHD so that America
can be more responsive to its increasingly diverse and complex health
and human services needs. And, I thank you for your ongoing support of
the Center. I also want to thank Dr. Elias Zerhouni, Director of the
NIH, and the Directors of the NIH Institutes and Centers (ICs) and
Offices for all of their cooperation and continued commitment to making
the elimination of health disparities a top priority for the NIH.
In January 2003, the NCMHD celebrated its second anniversary. The
staff at the NCMHD has been diligent, working hard to make the
priorities envisioned for the Center by the Congress a reality. Today,
I am happy to report to you the highlights of our accomplishments.
TRANS-NIH STRATEGIC PLAN AND BUDGET
The NCMHD has worked together with the Director of the NIH and the
Directors of the other ICs at the NIH, to develop the first
comprehensive NIH Strategic Research Plan and Budget to Reduce and
Ultimately Eliminate Health Disparities. This Plan, which was developed
with substantial stakeholder input from the health disparities
populations, has three main goals--research, research infrastructure,
and community outreach through information dissemination and public
health education. This is an evolving document, that will be updated
each year, and it includes current NIH activities and future plans to:
address the health disparities; build a culturally competent cadre of
biomedical and behavioral investigators; and increase the number of
minority clinical and basic medical scientists who are essential to the
success of our efforts. The Plan will be posted for public comment on
the NCMHD website at www.ncmhd.nih.gov.
nih fiscal year 2001 annual report on health disparities research
The NCMHD also collaborated with the other ICs to develop the NIH
fiscal year 2001 Annual Report on Health Disparities Research, which
highlights the NIH's activities, and describes the progress emanating
from the NIH's research strategies, structures, processes, and programs
to ultimately reduce and ultimately eliminate health disparities.
NCMHD PROGRAMS
As authorized by the Congress, the NCMHD has established its three
core programs, which have been successfully launched with substantial
assistance from the other NIH ICs. The Centers of Excellence in
Partnership for Community Outreach, Research on Health Disparities, and
Training (Project EXPORT) Program supports the conduct of research,
research training, and community outreach activities in the field of
health disparities at Centers of Excellence. The Research Endowment
Program is designed to build minority health and other health
disparities research capacity at Health Resources and Services
Administration (HRSA) Section 736 Centers of Excellence. The NCMHD has
established two distinct extramural Loan Repayment Programs to increase
the participation of health professionals in health disparities
research and to increase the participation of individuals from
disadvantaged backgrounds in clinical research. The Center also
administers the Research Infrastructure in Minority Institutions (RIMI)
Program to provide support for institutions that enroll a number of
students from minority health disparity populations to develop and
enhance their capacity and competitiveness to conduct biomedical or
behavioral research. By expanding the infrastructure of institutions
committed to health disparities research and supporting the education
and training of racial and ethnic minorities, as well as the medically
underserved, these programs will provide sustained effort aimed at
eradicating health disparities.
NCMHD CO-FUNDED RESEARCH
The NCMHD also supports research through collaborative agreements
with other NIH ICs and HHS agencies, for example the: Racial and Ethnic
Approaches to Community Health Program (REACH 2010) at the Centers for
Disease Prevention and Control (CDC); Excellence Centers to Eliminate
Ethnic/Racial Disparities Program (EXCEED) at the Agency for Healthcare
Research and Quality; Jackson Heart Study at the National Heart, Lung
and Blood Institute (NHLBI); Appalachia Cancer Network and Native
Hawaiian Cancer Awareness Research & Training Network at the National
Cancer Institute (NCI); National Latino and Asian American Study at the
National Institute of Mental Health, and Tribal Epidemiology Centers
Program at the Indian Health Service.
Through these and many other co-funded projects the NCMHD works to:
pilot new health disparities programs; improve recruitment and
retention of racial and ethnic minorities in clinical trials; and
provide competitive supplements to expand the focus of existing
research programs.
NIH HEALTH DISPARITIES RESEARCH
Along with the NCMHD, all of the ICs at the NIH actively support
health disparities research within their categorical missions. Let me
provide a few illustrative examples:
The NHLBI supports the Jackson Heart Study, co-sponsored with the
NCMHD, to address the cardiovascular health of African Americans; the
Strong Heart Study, directed at cardiovascular disease risk factors and
development in American Indians; the Multi-Ethnic Study of
Atherosclerosis, which is examining the development and progression of
subclinical disease in a multi-ethnic and predominately minority
population; the Family Blood Pressure Program, which is identifying
major genes associated with high blood pressure in a predominately
African American population; studies aimed at identifying genetic and
other biological factors that increase susceptibility to hypertension-
related injury and damage; and programs examining genetic factors
associated with asthma in minority populations.
To lead the NCI's efforts to examine the causes of cancer health
disparities, develop effective and sustainable interventions to
eliminate them, and actively facilitate their implementation across the
cancer continuum, the NCI established the Center to Reduce Cancer
Health Disparities. Among the NCI's other major initiatives are the
expansion of public, private, academic, and community-based partners to
increase enrollment of minorities in clinical treatment and prevention
trials and to investigate the socioeconomic, cultural, health system
related, and other causes of disparities in cervical cancer mortality.
The NCI also has established interdisciplinary research Centers for
Population Health and Health Disparities to better understand the
interaction of determinants of cancer and the behavioral and biologic
factors that contribute to them, and the Institute has expanded and
improved the efficiency and utility of the Surveillance Epidemiology
End Results Program on several fronts.
The National Institute of Allergy and Infectious Diseases (NIAID)
continues to focus on those research areas that have a major impact on
health disparities by supporting: the Innovation Grant Program, which
fosters exploratory investigator-initiated HIV vaccine research at the
early stages of concept development; the Legacy Donor Registry Project,
which supports efforts to increase organ donation in minority
populations; Genetic studies in African-American kidney transplant
recipients regarding tissue (organ) rejection; Autoimmunity Centers of
Excellence, which evaluate immunotherapies for Systemic Lupus
Erythematosus (SLE) and Scleroderma; the Inner City Asthma Consortium,
which evaluates the safety and efficacy of promising immune-based
therapies to reduce asthma severity and prevent disease onset in
minority children in inner city dwellings; and Hepatitis C Cooperative
Research Centers, which study factors that contribute to resistance to
treatment in African Americans and disease outcome in Alaska Natives
and Hispanics.
The National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK) has established its Office of Minority Health Research
Coordination to help implement its strategic plan for health
disparities. The Institute places high priority on supporting studies
of many diseases, including type 2 diabetes, hepatitis C, and kidney
disease, which disproportionately impact the health of minority
populations. Recently the Diabetes Prevention Program showed that
modest improvements in diet and exercise could dramatically decrease
the incidence of type 2 diabetes in those at risk, the benefits of
which extend to all racial and ethnic groups. American Indian and
Alaska Native communities have the highest rates of diabetes in the
world. Using the network of Tribal Colleges and Universities, the NIDDK
Diabetes-Based Science Education in Tribal Schools Program is
developing supplemental curricula for Tribal elementary, middle and
high schools to instruct students about lifestyle changes that can
dramatically reduce the risk of diabetes. The NIDDK also has initiated
the National Kidney Disease Education Program, initially targeting
cities with African-American populations showing high incidence of
chronic kidney disease.
Since the National Institute of Child Health and Human Development
(NICHD) launched its national ``Back to Sleep'' campaign in 1994, the
Sudden Infant Death Syndrome (SIDS) rate has fallen by more than 50
percent. Even though the death rates from SIDS have declined at about
the same rate for White and African-American infants, a
disproportionate number of African-American infants are still lost to
SIDS. To begin closing this gap, the NICHD enlisted the help of the
Alpha Kappa Alpha sorority, the National Coalition of 100 Black Women,
and the Women in the NAACP to conduct a series of ``summit'' meetings
in three U.S. cities with high rates of African-American SIDS deaths.
These summits will help develop strategies and create an infrastructure
for establishing community-based programs to further reduce SIDS among
African-American infants. The NICHD also is developing outreach
activities and products that encourage American Indian/Native American
communities to place babies on their back to sleep.
CONCLUSION
The NCMHD is working together with the other ICs at the NIH to
ensure that all Americans have an opportunity to lead long, healthy,
and productive lives. I am grateful to the Congress for giving the
Center a unique opportunity to bring together the expertise of health
professionals, researchers, businesses, communities, academia, public
health agencies, and government to eliminate health disparities. It's
going to take all of us working together to build a healthy America.
______
Prepared Statement of Dr. Paul A. Sieving
Mr. Chairman an members of the Committee: I am pleased to present
the President's budget request for the National Eye Institute (NEI) for
fiscal year 2004. This budget includes $648 million, an increase of $16
million over the fiscal year 2003 enacted level of $632 million
comparable for transfers proposed in the President's request.
It is my privilege to be here as the Director of the NEI and tell
you about progress laboratory and clinical scientists are making in
combating blindness and visual impairment and about the unique
opportunities that exist in the field of vision research.
GLAUCOMA RESEARCH
Glaucoma leads to blindness from damage to the optic nerve of the
eye. Glaucoma is often, but not always, associated with increased
pressure within the eye caused by inadequate drainage of aqueous humor,
the fluid within the eye that nourishes the cornea and lens. Results
from two important clinical trials were reported during this past year.
Investigators conducting the Ocular Hypertension Treatment Study found
that eye drops used to treat elevated pressure inside the eye can be
effective in delaying the onset of glaucoma. The study identified
several significant risk factors that were associated with the
development of glaucoma in study participants. These included personal
risk factors, such as older age and African descent, as well as ocular
risk factors, such as higher eye pressure and certain characteristics
of the optic nerve and cornea. These results mean that treating people
at higher risk for developing glaucoma may delay or possibly prevent
the disease.
In a separate study researchers conducting the Early Manifest
Glaucoma Trial, which was designed to compare the effect of immediate
therapy to reduce pressure inside the eye with late or no treatment on
the progression of newly detected open-angle glaucoma, found that
progression was less frequent in the treated group (45 percent) than in
the control group (62 percent), and occurred significantly later in
treated patients. This finding demonstrates definitively that treatment
to lower pressure inside the eye can slow glaucoma damage and
subsequent vision loss.
Continuing the progress in the genetics of glaucoma reported last
year by the finding of a new gene mutation that caused a form of adult-
onset glaucoma, scientists recently reported identification of a human
gene that is linked to a disease known as ``low-tension'' glaucoma.
This form of glaucoma has the characteristic pattern of optic nerve
degeneration but the elevation in pressure within the eye normally
associated with this pattern of damage is not evident on clinical
examination. The gene that was identified produces a protein that is
expressed in a number of tissues including the brain and retina and is
believed to have a significant neurological function. The
identification of genes associated with glaucoma provides a tool to
study the biochemical pathways leading to optic nerve degeneration, as
well as giving insight into designing neuroprotective strategies.
Additionally, NEI sponsored a meeting on ganglion cell and optic nerve
degeneration that brought together laboratory and clinical scientists
studying glaucoma and those studying other neurodegenerative diseases
to explore common mechanisms of nerve cell damage and potential methods
of protection.
RETINAL DISEASE RESEARCH
The retina is the transparent, light-sensitive tissue that lines
the back of the eye. Diseases and disorders of the retina and its blood
vessels account for much of the blindness and visual disability in this
country. An important barrier to therapeutic intervention in human
retinal disease is the identification of the gene or genes that cause
vision loss. Visual loss and the degenerative and other changes in the
retina are largely linked to rod and cone photoreceptors, the light-
sensing nerve cells in the retina.
Scientists have recently undertaken a comprehensive genetic
analysis of rod photoreceptors, the most abundant sensory neuron in the
retina, in order to identify all the possible genes expressed in these
cells. Rod cells play an essential role in the visual pathway and may
be especially vulnerable to any genetic defect involving the retina or
other visual centers. For many identified retinal disease genes, a
photoreceptor gene is mutated and its product is altered due to the
mutation. Work is progressing on completing a database that will
simplify the identification of candidate retinal disease genes, and
many new genes in rod photoreceptors have already been identified.
Scientists have identified a mutation in a gene on the X chromosome
that normally is associated with a form of retinitis pigmentosa (RP)
that causes a progressive loss of rod photoreceptors in the peripheral
retina and results in blindness in adulthood. This mutation was also
reported to cause a unique type of degeneration in the macula, in a
particular family. Further study may help us understand how this
mutation specifically targets the macula and causes this unique loss of
cones. This may lead to an understanding of the mechanisms of damage in
other forms of macular degeneration and perhaps to the development of
the means to prevent this type of damage to the macula.
The NEI is also funding studies on ocular albinism, a set of
hypomelanotic diseases and conditions that are characterized by
deficient cellular production of the pigment melanin. Deficiency in
this pigment causes a cosmetic loss of ocular and skin pigmentation,
but more importantly, it limits the development of vision in infants
and children by fundamentally altering the connections between the eye
and the brain. Recently the OA1 gene, which is associated with most
cases of the disease, was identified. The form of the disease
associated with OA1 is an X-linked or hereditary blinding eye disease
that primarily affects boys at an early age. Although the cause or
causes are unknown, misrouting of the neurons that go from the retina
to the brain is involved. Understanding the causes of the abnormal
neural cell axon guidance in ocular albinism may help us understand the
fundamental neurobiology that underlies this disease and represents an
important research initiative for the NEI.
CORNEAL DISEASE RESEARCH
NEI-supported scientists have also made progress against blinding
diseases of the cornea. The cornea is the transparent tissue at the
front of the eye that plays an important role in refracting or bending
light to focus visual images sharply on the retina. Because the cornea
is the most exposed surface of the eye, it is especially vulnerable to
damage from injury or infection. One such infection is ocular
onchocerciasis, commonly known as river blindness. Although river
blindness is rare in developed countries, it is the second leading
infectious cause of blindness in the world. This infection occurs when
a nematode worm infects the cornea. Researchers have found that
development and growth of the worm depends on a bacterium that lives
within it. They found that the blindness associated with the infection
was due to the reaction of the patient's immune system to the bacterium
and not to the worm. The scientists discovered that an antibiotic that
killed the bacterium also caused the death of the worm but without
causing blindness. Further development of this treatment could
revolutionize treatment of river blindness throughout the developing
world.
CATARACT RESEARCH
Although cataract treatment in this country is one of the most
successful of all surgical procedures, development of non-surgical
approaches to preventing or treating cataracts remains an important
area of research, because of the potential that it holds for reducing
costs to the Medicare system and improving the quality of life of our
senior citizens. A cataract is an opacity of the eye's normally clear
lens that interferes with vision. Age-related cataract formation is
believed to result from the complex effects of aging on normal
physiological processes. Because the end-result, cataract formation, is
in most cases far removed in time from the initial insult, exacting a
cause and effect relationship has been difficult. Lens transparency
results from the very high concentration of soluble proteins, the
crystallins, within a specialized lens fiber cell. During aging and
cataract formation, soluble lens crystallins tend to combine or
aggregate into large complexes that cause light to scatter. NEI-
sponsored researchers have found that alpha-crystallin, which normally
protects the lens by binding to other proteins, may itself become the
vehicle for the aggregate formation that accelerates cataract
formation. Additional research in this area may provide the means for
clinicians to intervene prior to the formation of a clinically evident
cataract.
Other scientists are attempting to determine the genes that control
one of the earliest events in the development of the eye, the
development of the lens. Scientists studying lens development have
identified a master gene that controls the expression of a number of
other critical genes. Two of these critical genes that have recently
been discovered. Without these two genes, the development of the lens
is stopped and crystallin-synthesizing cells fail to form. These
findings add to our understanding of the overall control of lens and
eye development and may ultimately enhance our knowledge of the
molecular basis of congenital diseases of the eye, thereby opening the
possibility of future interventions.
STRABISMUS, AMBLYOPIA, AND VISUAL PROCESSING RESEARCH
The most frequent causes of vision loss in our children are
strabismus, a misalignment of the eyes, and the development of
amblyopia, or lazy eye. Strabismus results in diseases in which visual
processing is abnormal. Amblyopia can result from this misalignment or
from unequal refraction between the eyes. NEI-supported scientists have
found that eye drops used to treat amblyopia work as well as the
standard treatment of patching the eye. This research finding may lead
to better compliance with treatment and improved quality of life in
children with this eye disorder. Patients continue to be followed in
this study to better assess the long term effects these treatments have
on visual acuity.
Recent work by NEI-sponsored researchers has helped our
understanding of nerve cell regeneration. Following injury or disease,
neurons in the central nervous system (CNS) have a limited regenerative
capacity, unlike nerve cells in the peripheral nervous system.
Nerve cells typically have two types of extensions that arise from
their cell bodies. Axons are normally quite long and extend over
considerable distances. Dendrites are much shorter and extend short
distances from the cell body. The inability of CNS neurons to
regenerate is due to the failure of their axons to re-grow. These
scientists found that axon growth may be due to a factor within the
nerve cell itself rather than in the surrounding environment and may be
regulated by signals from other nerve cells. Further research may allow
discovery of the signals that switch neurons back to the axonal growth
mode to repair damage to nerve tissue from injury or disease.
HEALTH DISPARITIES
Scientists recently reported the prevalence of glaucoma in a
population-based study conducted among 4,774 Mexican American adults
residing in two communities in Arizona. Glaucoma prevalence rates have
been reported previously for white and African American adults, but no
similar studies have been conducted among the U.S. Hispanic population.
The prevalence of open-angle glaucoma in this Mexican American
population was intermediate between the high rates reported for African
Americans and the lower rates reported for whites. Of those diagnosed
with glaucoma, only 38 percent were aware they had the disease. The
prevalence of glaucoma increased rapidly with age and was the leading
cause of bilateral blindness in this population. This information will
allow health educators to create additional glaucoma awareness
campaigns to increase awareness of the importance of glaucoma treatment
in the Mexican American population, thereby allowing eye care providers
to identify and treat those at greatest risk so that blindness can be
prevented.
PROGRAM INITIATIVES
Diabetic retinopathy is a potentially blinding complication of
diabetes characterized by the uncontrolled growth of fragile new blood
vessels in the retina that may leak fluid and blood threatening vision.
It is the leading cause of new cases of blindness in working age adults
in the United States. Macular edema secondary to diabetic retinopathy
is also a major cause of visual loss in patients with diabetes. The NEI
is developing a clinical research network of core centers and
participating clinics that will help satisfy the need to evaluate
promising new approaches to treat diabetes induced retinal disorders
and to investigate other approaches as they become available. This
network approach will provide a framework for rapid initiation of
important studies, efficient use of pooled clinical expertise in idea
generation and protocol development, and efficient use of central
resources for data management, quality control, and endpoint
evaluation.
The NEI is also planing to increase the pace of research in age-
related macular degeneration (AMD) prevention and treatment by
supporting a wide array of laboratory and clinical studies. AMD is the
leading cause of severe vision loss in older persons in the United
States, and it will have an increasingly important social and economic
impact as the population ages. These studies may range from pilot work
to the establishment and implementation of clinical research networks.
It is anticipated that a network approach to AMD clinical research will
hasten development of the more successful therapies for the treatment
or prevention of AMD.
The NEI is also undertaking a major effort to reinvigorate the
intramural research program and enhance resources to neurodegenerative
and genetic forms of vision loss. Ocular genetics research has
demonstrated that many common eye diseases have complex genetic and
environmental etiologies that must be understood before innovative
biological treatments can be designed. NEI is working on a new
laboratory program devoted to complex human eye disease to hasten
progress in this area.
Mr. Chairman that concludes my prepared statement. I would be
pleased to respond to any questions you or other members of the
committee may have.
______
Prepared Statement of Dr. Allen M. Spiegel
Mr. Chairman and Members of the Committee: I am pleased to present
the President's budget request for the National Institute of Diabetes
and Digestive and Kidney Diseases (NIDDK) for fiscal year 2004, a sum
of $1,670,007,000, which reflects an increase of $66,846,000 over the
comparable fiscal year 2003 appropriation. The fiscal year 2004 budget
comprises $1,820 million which includes $150 million ($100 million in
fiscal year 2003) for the Special Appropriation for Research on Type 1
Diabetes through Public Law 107-360. The NIDDK transfers some of these
to other institutes of the NIH and to the CDC. Adjusted for these
mandatory funds, this is an increase of $48 million over the fiscal
year 2003 enacted level of $1,622 million comparable for transfers
proposed in the President's request. The NIH budget request includes
the performance information required by the Government Performance and
Results Act (GPRA) of 1993. Prominent in the performance data is NIH's
second annual performance report, which compared our fiscal year 2002
results to the goals in our fiscal year 2002 performance plan.
OBESITY RESEARCH
I appreciate the opportunity to testify on behalf of the NIDDK,
which supports research on a wide range of chronic, debilitating
diseases. Many of these diseases, including type 2 diabetes,
nonalcoholic fatty liver disease, gallstones, end-stage kidney disease,
and urinary incontinence, are caused, directly or indirectly, by
obesity. Data from the Centers for Disease Control and Prevention
documents that obesity is growing at an alarming rate in both adults
and children, and that it disproportionately affects minorities. Recent
results from the Framingham Heart Study indicate that obesity cuts six
to seven years off of life, comparable to the effects of smoking. The
2001 Surgeon General's Call to Action to Prevent and Decrease
Overweight and Obesity reports that each year, it costs this country an
estimated $117 billion in health care related expenditures.
We must approach obesity, not as a cosmetic or moral problem, but
rather as a health problem. To address this problem, research is vital,
and the NIDDK and the National Institutes of Health are formulating a
bold and coordinated research plan. Obesity and its associated diseases
result from complex interactions of biologic and environmental factors.
The environmental factors include social, demographic, and economic
changes that encourage people to eat more food than necessary to meet
their energy requirements, and discourage physical activity that would
increase their energy expenditure. These environmental factors
disproportionately affect individuals who are biologically more
susceptible to becoming obese and to develop obesity-associated
diseases.
Tremendous progress has been made recently in understanding the
biologic basis of obesity, and I will cite just a few examples. We now
understand better how appetite is controlled through newly discovered
hormones such as ghrelin and PYY. They are produced by the stomach and
small intestine, and signal the brain, respectively, to increase and
decrease appetite. Blood levels of ghrelin peak just before meals, and
peaks are significantly higher in obese individuals who have lost
weight by dieting, perhaps explaining why sustaining weight loss is so
difficult. Bariatric, or gastric bypass, surgery is being increasingly
performed in the United States, and part of its effectiveness in
achieving sustained weight loss may be explained by the recent finding
that ghrelin levels are suppressed by some forms of the surgery.
Blocking the action of ghrelin is thus a potentially attractive target
for drug development
Similar advances are being made in understanding how the body
decides whether and where to metabolize or store fat. Discovery of
hormones such as leptin and adiponectin secreted by fat have shown that
fat signals to brain, liver, and muscle to regulate fuel metabolism and
response to insulin. Such discoveries help explain how obesity leads to
insulin resistance and type 2 diabetes, and offer new ways of treating
or preventing obesity-associated disorders. Epidemiologic results and
clinical studies show that differences in distribution of body fat may
also be important in determining which individuals develop obesity-
associated disorders.
Progress in behavioral research provided the basis for the
lifestyle intervention of our Diabetes Prevention Program (DPP), which
revealed that participants who lost 5 to 7 percent or more of their
body weight and who performed at least 150 minutes of physical activity
per week reduced their risk of developing type 2 diabetes by 58
percent. We are conducting a follow-up DPP Outcomes Study to assess the
durability of the DPP interventions in preventing diabetes, and to
determine whether the interventions reduce cardiovascular disease. Our
Look AHEAD: Action for Health in Diabetes clinical trial is testing the
effect of sustained weight loss on prevention of cardiovascular disease
in obese individuals who already have type 2 diabetes.
To further sharpen the NIDDK's obesity research efforts, I recently
announced creation of a new Office of Obesity Research within the NIDDK
that is bringing together expertise in our Division of Diabetes,
Endocrinology, and Metabolic Diseases, and our Division of Digestive
Diseases and Nutrition, both of which have important input to obesity
research. This new group is framing initiatives across a wide range of
obesity research areas to address the epidemic of obesity, from the
fundamental biologic aspects to the behavioral and environmental.
Examples include a study of the life cycle of the fat cell directed at
discovery of novel targets for treatment of obesity and associated
metabolic disorders. In order to address obesity-associated diseases
such as type 2 diabetes, we will expand our Diabetes Genome Anatomy
Project to include genetic analysis of all the major organ systems
affected by diabetes and its complications . We are helping re-engineer
the clinical research enterprise by creating a new Bariatric Surgery
Clinical Research Consortium (BSCRSC). The BSCRC will develop a common
data collection protocol to accelerate clinical research and progress
in understanding the development of severe obesity and its
complications, as well as understanding the risks and benefits of
bariatric surgery as a treatment method.
In behavioral research, we have begun a clinical trial to develop
effective strategies to prevent type 2 diabetes in children. This
initiative focuses on school-based primary prevention programs to
decrease risk factors for type 2 diabetes and lower the incidence of
the disorder. We are supporting research to translate the results of
the highly successful Diabetes Prevention Program, into clinical
practice for prevention of type 2 diabetes in individuals and
communities at risk. Of particular interest will be interventions that
focus on underserved and minority populations disproportionately
affected by the disease. Given the environmental influences fueling the
obesity epidemic, we are encouraging research to study promising
interventions that would target environmental factors contributing to
inappropriate weight gain in children, adolescents and adults. We are
asking investigators to partner with community organizations or
businesses, such as schools, supermarkets, restaurants, churches,
community groups, and worksites to develop interventions that could
potentially be translated into larger-scale interventions.
These are just some of the ways we are encouraging research to
combat obesity and its co-morbid conditions. We believe NIDDK and NIH
research is our best hope for stemming the tide of this epidemic. Why?
Because we stand poised, given new information about the human genome
and the advent of new research tools to determine the biologic and
genetic factors that make one person more (or less) susceptible to
obesity than another. Why is this important? Because it should allow
targeted obesity prevention and allow the development of new kinds of
drugs and therapies that should be more successful in preventing weight
gain and in helping people lose weight and to sustain weight loss. Tied
to this is improved research-based behavioral approaches to weight loss
and maintenance. In addition, NIH research ultimately will provide the
scientific basis for policy decisions on needed changes in
environmental factors that affect diet, nutrition, and physical
activity. Obesity is a complex problem requiring a multi-disciplinary
research approach if we are to reverse this ominous threat to our
nation's health.
DIABETES
Approximately one million Americans suffer from a type of diabetes
that is not obesity-related. Rather, type 1 diabetes involves immune
destruction of the insulin-producing beta cells of the pancreas. We are
vigorously pursuing cutting-edge research opportunities for prevention
of type 1 diabetes through our TrialNet, and for treatment and cure of
type 1 diabetes through support of the field of regenerative medicine.
One example of the latter is our Beta Cell Biology Consortium, which
brings together multi-disciplinary teams of investigators with
expertise in pancreatic development, beta cell biology, stem cell
biology, and bioinformatics. Through such collaborative research
programs, we are laying a solid foundation for the future development
of innovative, cell and regenerative growth factor therapies for
diabetes and other debilitating diseases. Increased understanding of
beta cell biology should also improve our ability to develop
noninvasive, functional imaging technology that would, for example,
help monitor type 1 diabetes prevention trials.
HEPATITIS C
The hepatitis C virus is the cause of the most common form of end-
stage liver disease in the United States. We recently held a Consensus
Development Conference on the management of hepatitis C that
recommended directions for future research, and led to development of
initiatives that are encouraging further basic and clinical research on
hepatitis C, research on management of hepatitis C in people with
chronic kidney disease, and research on new therapies for children with
hepatitis C. From such research should emerge more effective forms of
treatment and prevention.
GASTROINTESTINAL DISEASES
We are bolstering our research activities across the full spectrum
of gastrointestinal (GI) diseases, ranging from celiac disease, in
which a known dietary factor triggers intestinal damage in genetically
susceptible individuals, to functional GI disorders such as irritable
bowel syndrome. Our strong research portfolio in inflammatory bowel
disease (IBD) is paying dividends. A recent clinical trial reported
that a recombinant monoclonal antibody that blocked the action of
certain cell adhesion molecules could be used to reduce the symptoms
and improve quality of life of patients with Crohn's disease, an
inflammatory bowel disease. The NIDDK supported the basic research
underpinning this exciting work, providing another example of the
critical role of NIH research in the development of therapies for human
disease. Our IBD Genetics Research Consortium aims to identify genes
associated with increased risk of developing Crohn's disease and
ulcerative colitis. The long-term goal is to increase molecular
understanding of IBD so as to facilitate development of novel therapies
and new diagnostic methods.
KIDNEY DISEASE
We are addressing the sharp rise in end-stage renal disease (ESRD)
by supporting research on the causes, treatment, and prevention of the
major forms of kidney disease leading to ESRD. The discovery that the
proteins encoded by the polycystic kidney disease (PKD) genes are
localized to cilia (hair-like projections) in kidney tubular cells
demonstrates the rapid progress in understanding the pathogenesis of
the major cause of inherited ESRD. Results from some of our major
kidney disease trials have significant implications for clinical
practice. Our African American Study of Kidney Disease and Hypertension
(AASK) showed that angiotenson-converting enzyme inhibitors, compared
with calcium channel blockers, slowed kidney disease progression by 36
percent, and drastically reduced the risk of ESRD by 48 percent in
patients who had at least one gram of protein in the urine, a sign of
kidney failure.
The Institute's HEMO clinical trial recently showed that the
standard recommended hemodialysis dosage and filters are adequate for
reducing morbidity and mortality in ESRD patients, and that increasing
dialysis dose using a conventional three times per week regimen does
not provide greater benefit to patients. However, the important
question now is the duration and frequency of dialysis. We therefore
have planned clinical trials to compare conventional dialysis with more
frequent dialysis in patients with ESRD. We also have launched a
prospective epidemiological study of children with chronic kidney
disease to determine the risk factors for decline in kidney function,
and associated morbidities such as impaired neurocognitive development,
cardiovascular disease, and growth failure.
UROLOGIC DISEASES
Our major clinical trial on Medical Therapy of Prostate Symptoms
(MTOPS) recently demonstrated that two drugs commonly used to treat
benign prostatic hyperplasia (BPH), finasteride and doxasozin, are
significantly more effective at preventing symptomatic BPH incidence
and progression when given in combination. Samples collected during the
MTOPS trial will be used by our new MTOPS Prostate Samples Analysis
Consortium to discover and validate biologic markers for detection and
risk assessment of BPH.
Our Bladder Progress Review Group report provides a strategic plan
for future bladder research. We are already implementing the report's
recommendations on interstitial cystitis (IC), a debilitating, chronic
syndrome of urinary urgency, frequency, and pelvic pain, by encouraging
basic research pertinent to IC, the ultimate goal being the development
of reliable diagnostic tools, and new and effective disease treatments
and prevention.
Mr. Chairman and Members of the Committee, these are just a few
examples of our many research advances and initiatives. I would be
pleased to answer any questions.
______
Prepared Statement of Dr. Stephen E. Straus
I am pleased to present the President's fiscal year 2004 budget
request for the National Center for Complementary and Alternative
Medicine (NCCAM). The fiscal year 2004 budget includes $116,202
million, an increase of $2.9 million over the fiscal year 2003 enacted
level of $113,302 million comparable for transfers proposed in the
President's request.
INTRODUCTION
Arthritis, depression, menopause, cancer . . . for millions of
Americans, these and other health concerns are not being adequately
addressed through conventional medicine. Many are turning outside the
medical mainstream to approaches that embrace the whole person--mind,
body, and spirit. From acupuncture to dietary supplements,
complementary and alternative medicine (CAM) approaches are affordable
and accessible, but largely untested. Under NCCAM's leadership,
researchers are applying the tools of modern science to discover which
CAM practices work, why and how they work, and whether they are truly
safe. Exploring CAM through rigorous science will lead to the
integration of proven CAM practices with conventional medicine, thus
improving the lives of all Americans.
STANDARDIZATION & CHARACTERIZATION OF DIETARY SUPPLEMENTS
Dietary supplements, one of the most popular categories of CAM
practices, are used by 10 percent of American adults.\1\ Many consumers
use dietary supplements with the expectation that they are effective in
the self-treatment and prevention of disease and the promotion of
wellness and, further, with the assumption that they are safe. Under
the law, supplements are classified as foods and not held to the same
rigorous standards as drugs.
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\1\ Hanyu NI, Catherine Simile and Ann M. Hardy, ``Utilization of
Complementary and Alternative Medicine by United States Adults: Results
From the 1999 National Health Interview Survey,'' Medical Care, Vol.
40, No. 4, pp. 353-358.
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Research supported by NCCAM indicates that Americans who take
ginseng on a regular basis cannot rely on the label to accurately
reflect the product's contents. After examining 25 commercial ginseng
products, one NCCAM grantee recently reported that, the concentrations
of ginseng differed by as much as ten-fold from the label. The lack of
standardized dietary supplements is not only an issue of consumer
safety; it is also an issue for researchers who need to protect their
patients and work withwell-characterized and standardized products to
scientifically and accurately examine study their purported benefits.
NCCAM's recent experience with PC SPES, a patented mixture of eight
herbs, is an example of the other vexinganother problem with some
dietary supplements contamination. In 2001, thousands of men with
advanced prostate cancer in America tookwere taking PC SPES. Based on
encouraging early clinical results, NCCAM was supporting four research
studies, including a clinical trial, to determine the safety, efficacy,
and mechanism of action (i.e., how it works) of PC SPES. In February
2002, the California Department of Health Services and the Food and
Drug Administration reported that PC SPES was contaminated with
undeclared prescription drug ingredients. This finding led the
manufacturer to recall the product and subsequently cease its
operations. NCCAM immediately put its studies on hold and convened
meetings with scientists, prostate cancer specialists, patients, and
industry representatives to determine howif a ``cleaner'' an
uncontaminated product could be made available to the publicreenter the
marketplace and the research pipeline, allowing the research to resume.
As part of this strategya result of these meetings, NCCAM resumed its
laboratory studies of the cellular and molecular biology of PC- SPES
and pronounced declared its interest in resuming clinical trials once
an unadulterated, fully characterized, and standardized product is
available.
NCCAM is taking several steps is taking several stepsto address the
critical issue of product standardization and quality. Among the top-
selling products in the dietary supplement industry are products like
echinacea (Echinacea purpurea), taken to prevent and treat colds, milk
thistle (Silybum marianum), taken to treat chronic hepatitis and
cirrhosis, and feverfew (Tanacetum parthenium), taken to lower fevers.
All of these products have shown promise in small uncontrolled studies;
however, each has problems with standardization, precluding their full
and objective study. NCCAM is making awards under using the Small
Business Innovative Research (SBIR) program to obtain well-
characterized and standardized clinical-trial-grade materials of these
supplements. This investment in high-quality productsessential first
step will be followed by studies to define the optimal dose of each
product. To implement this second step, in 2004, NCCAM plans toplans to
establish a Dietary Supplement Standardization and Characterization
Center (DSSCC), which willto serve as a resource for the analysis of
dietary supplements, especially botanical products, before they are
used in clinical trials.
DETERMINING THE MECHANISMS OF ACTION OF CAM INTERVENTIONS
While pursuing innovative approaches to ensuring the safety of its
clinical trial products, NCCAM continues to support basic and clinical
studies NCCAM continues to support basic and clinical studies. The
central objective of many of these studies is to examine the mechanisms
of action underlying various CAM therapies. In 2002, for example,
NCCAM-supported researchers conducted an important body of research on
alternatives to conventional hormone therapy--an area of obvious
interest for millions of menopausalwomen who are seeking safe and
effective alternatives to conventional hormone therapy for relief of
menopausal symptoms and related conditions. Specifically, scientists
are using in vitro systems to examine how some popular dietary
supplements act on biochemical pathways responsive to estrogen. Others
are examining the estrogenic activity and specific mechanisms of
estrogen receptor regulation of a Chinese herbal extract; identifying
the active compounds of black cohosh (Cimifuga racemosa) and red clover
(Trifolium pratense); and investigating the range and mechanisms of
action of two plant-based estrogens, genistein and diadzein, and
extracts of soy on immune function. These studies will clarify what
biochemical effects supplements might have on women and indicate which,
if any, are worthy of testing in a clinical trial.
Building on the results of a detailed scientific review that NCCAM
conducted with the Agency for Healthcare Research and Quality on the
popular dietary supplement, S-Adenosyl-L-Methionine (SAMe), the Center
is also supporting mechanistic projects on the mechanisms of action of
SAMe that are consistent with the findings of the report associated
with key areas identified by the report. One grantee is using cultured
cells to better characterize the biochemistry of liver injury and what
role SAMe may play in preventing liver damage. Another investigator is
using a mouse model of hepatitis and liver cancer to study the role of
SAMe in regulating liver cell growth and death.
A trio of studies indicate that Ginkgo biloba may provide multiple
levels of protection to neural tissues and contribute to the body of
evidence explaining how Ginkgo may be beneficial in preventing the
onset of dementia. NCCAM-supported investigators reported that a
standardized Ginkgo extract protects cells from oxidative stress and
apoptosis (programmed cell death). Using model systems to study the
factors that regulate cell death, the investigators showed that the
Ginkgo extracts increase the lifespan of the worm, Caenorhabditis
aenorhabditis elegans, protect cultured neural cells from undergoing
programmed death, and hinder an early step in the biochemical processes
leading to neurodegeneration.
In fiscal year 2003, NCCAM made several awards as part of the
initiatives it launched with NIH partners to elucidate the underlying
biological pathways of the placebo effect and to reveal factors
important for eliciting the placebo effect in clinical practice
setting. The Center designated mind-body medicine as a priority
research area in fiscal year 2003, recognizing the potential
contributions to prevention and treatment of chronic diseases that
could be made by interventions based on evidence from innovative
psychophysiological research. NCCAM will enhance the support for
research into the mechanisms of mind-body medicine. Most recently,
NCCAM joined other NIH partners to solicit applications from
institutions poised to advance research on mind-body interactions and
health. The Center also designated mind-body medicine as a priority
research area in fiscal year 2003, recognizing the potential
contributions to prevention and treatment of chronic diseases that
could be made by interventions based on evidence from innovative
psychophysiological research.
EVALUATING CAM THERAPIES IN RIGOROUS CLINICAL TRIALS
A chief goal of the basic and preclinical research NCCAM supports
isbasic and preclinical research to test therapies for eventual use in
clinical trials with the ultimate objective being to translate safe and
effective therapies into widespread practice. Another purpose ofIn
addition, NCCAM-supported clinical trials is to test CAM products
already being widely used by the public. Ultimately, NCCAM wants to
answer the central question: ``does it work?''
In 2002, NCCAM announced the results of its first large-scale
clinical trial. The trial evaluated a one product containing St. John's
wort (Hypericum perforatum) product, a popular herbal remedy for
depression, as a treatment for major depression of moderate severity
and found it to be ineffective as compared to placebo. Although the
results of this trial were negative showed that St. John's wort is not
effective for this type of depression, the outcome provided
practitioners and patients alike with valuable data. In addition, the
outcome informed researchers who are testing St. John's wort as a
treatment for less severe forms of depression. NCCAM is following-up on
this finding by co-funding a new trial to test St. John's wort as a
treatment for minor depression, a less severe but very common type of
depressive illness. The trial begins this year and will enroll 300
patients at three sites nationwide.
Because CAM products and practices are already used by millions of
Americans, NCCAM supports relatively morea higher percentage of
clinical research than all of the other NIH Institutes and Centers. As
part of its clinical research portfolio, the NCCAM extramural research
program is already supporting 12 ongoing large-scale clinical trials
with other NIH Institutes and Centers. These trials include the largest
ever herbalstudy of Ginkgo biloba for the prevention of dementia a
critical study given the aforementioned body of evidence that exists
regarding Ginkgo's potential protective effects. The list also includes
the largest ever studieslargest ever study of dietary supplements
(selenium and vitamin E), involving 30,000 men, for the prevention of
prostate cancer. In fiscal year 2002, NCCAM cosponsored the first large
clinical trial to test chelation therapy as a treatment for coronary
artery disease. Also in fiscal year 2002, the NCCAM Intramural Research
Program initiated its first clinical trial, which is evaluating
electroacupuncture in reducing the severe nausea experienced by many
children following intensive cancer chemotherapy. NCCAM is taking
actionactive to ensure the quality and safety of NCCAM-supportedits
clinical trials.
In 2002, the Center established the Office of Clinical and
Regulatory Affairs to help plan, coordinate, and monitor NCCAM-
supported clinical trials. All of these activities reflect NCCAM's rich
investment in and commitment to clinical research.
BUILDING RESEARCH INFRASTRUCTURE AND INTELLECTUAL CAPITAL
The success of NCCAM's future research endeavors is contingent upon
depends on the availability of skilled investigators in both the
conventional and CAM research communities. Toward this end, NCCAM is
supporting dozens of mentored and independent trainees, from the pre-
doctoral level through mid-career and senior faculty members. In 2002,
NCCAM made institutional training and clinical research career awards
to CAM institutions and joined the new NIH-wide loan repayment program
with awards to two junior practitioner-investigators, marking a series
of ``firsts'' for NCCAM.
In addition to its support ofinvestment in training programs, NCCAM
continues to support a robust research centers program, providing a
critical CAM research infrastructure. In 2002, NCCAM sought to
strengthen its centers program by convening sought to strengthen its
centers program by cing an expert panel to evaluate the program's
current structure and objectives. The panel recommended a more flexible
approach to supporting future centers research. This new approach,
which employs a mix of funding and research mechanisms, will ideally
expand ideally the participation among investigators with varying
degrees of research expertise at both CAM and conventional institutions
in a multi-disciplinary fashion. Implementation of this strategy began
in fiscal year 2003 and will continue through fiscal year 2005.
CONCLUSION
NCCAM has made remarkablesignificant progress in its first 4 years.
Between fiscal year 2000 and fiscal year 2001, the number of people
enrolled in NCCAM-supported clinical research projects doubled. The
Center, in a partnership with other NIH Institutes, launched some of
some of the largest clinical studies of CAM therapies ever conducted.
NCCAM took pro-activesteps to improve the safety and efficacy of its
clinical research studies and the quality of the information
disseminated to the public about CAM therapies. Finally, the Center
increased its level of support to researchers who are applying cutting-
edge scientific tools to study the most promising CAM approaches to the
most important public health challenges facing our nation. I look
forward to keeping you and the American public apprised of NCCAM's
future activities and accomplishments.
______
Prepared Statement of Dr. Lawrence A. Tabak
Mr. Chairman and Members of the Committee: I am pleased to present
the President's budget request for the National Institute of Dental and
Craniofacial Research (NIDCR) for fiscal year 2004. The fiscal year
2004 budget includes $382,396,000, an increase of $11,254,000 over the
fiscal year 2003 enacted level of $371,142,000 comparable for transfers
proposed in the President's Request.
MOLECULAR MEDICINE ENTERS THE MOUTH
When molecular biologists discuss the future of medicine and
dentistry, many foresee a day when health care professionals will
possess the technological tools to dust a patient's cells, like a
detective dusts for fingerprints, and pull up a ``molecular
fingerprint'' of the activity inside. This fingerprint will allow them
for the first time to examine the patterns within the cells for
disease-causing abnormalities in the genes, proteins, and protein
networks. Based on these specific biological clues, doctors will have
far more detailed information at hand to make a correct diagnosis and
perhaps one day tailor a person's care to treat the specific molecular
defects that underlie the disorder.
SALIVARY DIAGNOSTICS
Scientists have long recognized that our saliva serves as a
``mirror'' of the body's health, in that it contains the full
repertoire of proteins, hormones, antibodies, and other molecular
analytes that are frequently measured in standard blood tests. The
Institute recently launched a major research effort that, in keeping
with the National Institutes of Health (NIH) Roadmap initiative, seeks
to identify and address major cross-cutting biomedical challenges, and
will further develop needed technologies and create the first
comprehensive baseline catalogue of all proteins found in oral fluids
of healthy individuals. The NIDCR envisions that this basic research
could one day translate into miniature, hi-tech tests, or so called
``labs'' on a silicon chip, that rapidly scan oral fluid for the
presence or absence of multiple proteins linked to various systemic
diseases and conditions. Ultimately, this approach could be used for
real-time health surveillance--rapidly identifying persons most at risk
at the earliest moments of detectable change in key diagnostic markers.
THE GENOMICS AND PROTEOMICS OF PERIODONTAL DISEASES
Although ``molecular medicine'' is still in its infancy, the NIDCR
continues to help lay its basic intellectual foundations. The tools of
molecular medicine offer promising new strategies for addressing oral
infectious diseases such as periodontitis. These conditions begin when
bacteria colonize a ``biofilm'' that forms on the surface of teeth.
Many of these microorganisms remain uncultivated and only recently have
some of these bacteria been identified by their molecular fingerprints.
Some of these bacteria are highly virulent; they elaborate noxious
substances that damage hard and soft tissues of the mouth. Furthermore,
oral bacteria can trigger an immune response that often proves
destructive both within the mouth and elsewhere in the body. Indeed,
recent studies with animal models and epidemiologic surveys have linked
periodontal diseases with pre-term delivery and low birth weight.
With the advent of more powerful research tools, NIDCR supported
scientists will now be able to assemble a molecular ``parts list'' of
all the genes and proteins involved in periodontal diseases. For the
first time, a detailed understanding of the microbial and host
signaling pathways that are activated or deactivated during periodontal
disease progression will be mapped. This represents an important step
in defining new therapeutic targets to overcome one of the most
prevalent infectious diseases of humankind.
TISSUE ENGINEERING
The NIDCR continues to invest heavily in regenerative medicine,
with a strong interest in engineering new bone to repair dental and
craniofacial wounds and birth defects. Of particular interest are adult
bone marrow stromal stem cells, the natural progenitors that create the
body's bone-forming cells. In recent years, scientists have envisioned
healing bone fractures by inserting these cells directly into the
wound. The adult stem cells would replicate in the wound, create
millions of new bone cells, and heal the fracture rapidly and
efficiently. As appealing as this approach is, however, technical
challenges have emerged to slow the research. One of the most
formidable obstacles is the discovery that adult bone marrow stromal
stem cells stop growing soon after they are introduced into cell
culture and quickly lose their ability to form new bone. Because
hundreds of thousands of stem cells are required to heal even a minor
bone fracture, scientists have been hard pressed to generate an
adequate supply of these precursors.
For the first time, NIDCR scientists and grantees reported that
they have more than doubled the life span of adult bone marrow stromal
stem cells, under laboratory conditions, by incorporating the
catalytic, or active, component of a much-studied enzyme called
telomerase, termed the hTERT gene, into the stem cells. This was
particularly interesting because hTERT is the catalytic, or active,
component of a much studied enzyme called telomerase. Telomerase has
been shown to counter the shortening of telomeres, the tips of
chromosomes, by triggering a chemical reaction that adds new base pairs
to them and extends the life of the cell. In follow-up animal studies,
the scientists found that the newly formed bone, generated from the
stem cells, had all of the hallmarks of normal bone--including
organized collagen fibers and various mineral components.
SJOGREN'S SYNDROME
The NIDCR is also applying tissue engineering strategies to
Sjogren's syndrome, a relatively rare condition that affects over one
million Americans. The syndrome is caused when the immune system
mistakenly attacks various parts of the body, often including cells
that produce saliva. When this occurs, people develop chronically dry
mouths, which can impair their ability to taste and swallow as well as
lead to oral disease. While studies are ongoing to pinpoint the root
cause of this condition, NIDCR continues to explore the possibility of
developing an artificial salivary gland, an approach that one day could
help to restore adequate levels of saliva for Sjogren's patients.
In studying Sjogren's syndrome, one of the major barriers always
has been logistical. People with the syndrome are scattered throughout
the country, and scientists are sometimes uncertain about how to find
them. To ensure that researchers have access to sufficient numbers of
Sjogren's patients with well defined clinical histories and relevant
biological samples, NIDCR will support the first international registry
of Sjogren's patients. The registry will be crucial in tracking the
incidence and natural history of the condition. It also will allow
NIDCR to launch more rapidly the necessary clinical trials to evaluate
promising diagnostic and therapeutic leads as they emerge. NIDCR also
plans to identify biomarkers--genes, proteins, or even protein
networks--which will allow early diagnosis, determination of disease
progression, and stratification of high risk individuals. By developing
a battery of sensitive and highly specific diagnostic and prognostic
biomarkers, critical molecular information will be available to more
accurately diagnose and treat Sjogren's syndrome, a long-held hope of
many Americans affected by this condition.
PAIN RESEARCH
For the past four decades, the NIDCR has been one of the key
players at NIH in the study of the basic biology and treatment of pain.
While current analgesic drugs help many ease discomfort, millions of
others have pain management needs that remain completely or partially
unmet. Nearly all available analgesics were developed based on overly
simplified, linear models of pain transmission. Recent advances show
that pain transmission is a far more dynamic process that often
involves multiple routes, or pathways. Each pathway integrates a
convergence of molecular signals, then relays them along their own
specific, hard-wired routes to the brain. The research challenge is to
define the molecular details of these multiple routes of pain
transmission with the aim of increasing the repertoire of pain
management strategies.
In keeping with the NIH Roadmap initiative, progress is now being
made in defining the biological pathways and networks of pain. For
example, a group of NIDCR grantees have discovered several biological
factors that influence pain perception. This multidisciplinary team
focuses its research on developing novel, real-time imaging techniques
that track the mu-opioid system, a specific type of protein receptor in
the brain that researchers have long suspected triggers a dampening of
the pain. In a seminal study published last year, the team confirmed
the role of the mu-opioid system in enhancing a person's tolerance of
pain. According to the research team, this marked the first study ever
that combined prolonged pain with simultaneous brain scan monitoring of
the mu-opioid system and self-reported pain ratings of human
volunteers.
The group found that the onset and slow release of jaw muscle pain
(that mimics, in part, the symptoms of individuals suffering from
Temporomandibular muscle and joint diseases and conditions) over 20
minutes caused a surge in the release of endorphins, naturally produced
chemicals that bind to the mu-opioid protein receptors that are
displayed on the surface of brain cells. Once the endorphins activated
the receptors, the volunteers said they felt a reduction in pain and
emotions related to the sensation. Specific brain regions--especially
those that play a role in emotional responses or that help to process
signals from the body's sensory systems--had the greatest increase in
endorphin levels. The research also revealed major variations among
volunteers in baseline and pain-induced levels of opioids. The
scientists noted that their results establish that people vary both in
their capacity to produce mu-opioid receptors and in their ability to
release the anti-pain chemicals themselves. This variability appears to
determine the emotional and sensory aspects of a painful experience and
might explain why some people react to pain differently. It may also
help to explain why some people are more prone to chronic pain
conditions or do not benefit from certain anti-pain medications.
The group and its collaborators have published two important
followup studies. In the first study, the scientists observed that, at
matched levels of pain intensity, men and women differ in the degree
and direction of the mu-opioid response in distinct areas of the brain.
In particular, men had greater activation of mu receptors in specific
regions of the brain--the anterior thalamus, ventral basal ganglia, and
amygdala. Women, conversely, had reductions in the resting levels of
these receptors when they experienced pain in the nucleus accubens, an
area of the brain previously associated with hyperalgesic responses to
the blockage of these receptors.
In the second study, the scientists focused on a gene that produces
a key enzyme involved in the mu-opiod system. The group found that
people who inherit an extremely common variation in the gene have a
lower natural threshold of pain than those who were born without the
variation. The scientists speculated that the variant gene encodes a
slightly altered enzyme that functions somewhat differently than the
normal enzyme, leading to lower brain levels of pain-killing
endorphins. This finding highlights the growing recognition that pain
treatment should be customized to meet the specific needs of individual
patients.
Because of the mouth's unique role in the human body, NIDCR is well
positioned to make key contributions to the future of molecular-based
medicine--not only in alleviating oral conditions but also toward
improving systemic health. This Institute's continued contributions
represent hope for millions of Americans today, as well as improved
health and quality of life for generations to come.
______
Prepared Statement of Dr. Judith L. Vaitukaitis
Mr. Chairman and Members of the Committee: I am pleased to present
the President's budget request for the National Center for Research
Resources (NCRR) for fiscal year 2004, a sum of $1,053,926, a decrease
of $84,738,000 from the fiscal year 2003 enacted level of $1,138,664
comparable for transfers proposed in the President's request.
Infrastructure is at the heart of NCRR. For more than 40 years, it
has been NCRR's mission to develop and support essential research
resources that strengthen and enhance research environments for health-
related studies. NCRR provides the nation's scientific community with
access to broad-ranging resources, including animal models, advanced
technologies, research facilities, and clinical research centers that
explore new approaches for diagnosing, treating, and preventing human
disease.
To be responsive to emerging needs, NCRR works in trusted
partnership with the biomedical research community, with other NIH
institutes and centers, and, in some cases, with other Federal agencies
and private sector organizations. In anticipation of emerging needs,
NCRR in recent years has funded construction of biocontainment
laboratories for the study of dangerous infectious agents; islet cell
resources to explore novel therapies for diabetes; and creation of
transgenic animals that enhance understanding of human disease.
Scientists today are exploring biomedical problems of enormous
complexity. Some of the nation's most pressing health concerns can best
be addressed through multidisciplinary research teams, which integrate
technologies and expertise from a variety of fields. NCRR, with its
cross-cutting mission, is ideally positioned to facilitate this
evolving approach. Today I will outline NCRR's plans for meeting the
ever-changing infrastructure needs and describe just a few of the
research advances enabled through NCRR-supported research
infrastructure.
ADVANCED TECHNOLOGIES
NCRR has a long history of developing and enhancing access to new
technologies. Magnetic resonance imaging, mass spectrometry,
synchrotrons for crystallography and optical imaging are just a few of
the now-indispensable tools that NCRR supported in their infancy,
primarily through the nationwide network of Biomedical Technology
Resource Centers. NCRR must remain positioned to ensure that innovative
technologies are developed and accessible before research progress is
compromised.
Novel insights into the prevention or treatment of disease will
arise from synthesis of massive amounts of molecular, genetic, and
biologic data. To take advantage of these rich sources of information,
researchers need new bioinformatics tools and approaches to selectively
retrieve, analyze, and interpret data stored in many different formats
and at different levels of aggregation in locations spread across many
sites. Tool development, including new database architecture, is needed
to manipulate large data sets with data object entries that vary
markedly in size and complexity. Seamless integration of information
across these data sources is a major research challenge.
NCRR has begun to address such issues through its Biomedical
Informatics Research Network (BIRN). The test bed encompasses diverse
locations nationwide. The initial development of BIRN focuses on
generating several robust technologies, computational tools, and
communications networks. These networks simplify and facilitate the
sharing of scientific expertise, technologies, and data. BIRN currently
provides links, via Internet2, among several General Clinical Research
Centers and Biomedical Technology Resource Centers. NCRR now plans to
extend the scope of these networked resources by connecting all NCRR-
supported research resource centers to Internet2, which will enhance
nationwide access to databases, bioinformatics tools, and enabling
resources for clinical and basic research in a second test bed that
will concentrate on infrastructure for clinical research.
In another facet of the BIRN development, NCRR will work in concert
with other NIH components to expand the advanced technologies used or
developed for BIRN and apply them to build a National Electronic
Clinical Trials and Research network, called NECTAR. This effort will
include designing a web-based approach for entering clinical data,
developing advanced tools for integrating datasets, and enabling
manipulation of complex datasets from remote sites. Initial development
of the NECTAR network will focus on therapeutic development networks,
particularly for the treatment of rare diseases. Ultimately, the tools
developed for NECTAR may be readily scaled up for larger
investigations, including collaboratories.
With today's multifaceted studies, biomedical scientists
increasingly depend on a systems approach that integrates, for example,
advanced technologies for macromolecular structures, structure-based
drug design, novel technologies to discern the gene-gene interactions
and molecular imaging. To enable such studies, NCRR proposes to develop
and support comprehensive research resource centers equipped with
state-of-the-art technologies and a team of investigators with wide-
ranging but complementary expertise. These comprehensive centers, which
may provide remote access to resources, will allow investigators to
characterize the thousands of proteins expressed by the human genome.
Scientists will be positioned to address fundamental questions that
cannot be answered by examining one protein at a time. Such
``postgenomic'' studies may provide clues to complex disease-related
processes that may be prevented or arrested with novel interventions.
MODEL DEVELOPMENT AND GENETIC MEDICINE
NCRR is also at the forefront in developing nonhuman models and
tools for genetic medicine. In recent years, numerous gene-targeting
and transgenic studies have produced a wealth of information on gene
function and their role in development, aging, and disease processes.
But the enormous volume of collected data is often unwieldy and
difficult to analyze. NCRR will enhance this promising area of research
by supporting a national network of resources to systematically
classify and characterize genetically altered animal models and to
support the development of new technologies to rapidly phenotype new
mutants. With the decoding of the human genome and development of new
technologies, biologic models may help unravel the causes and identify
cures for such complex diseases as diabetes, hypertension and cancer.
The mouse has gained new prominence in biomedical laboratories now
that scientists can readily modify the animal's genome to create
transgenic and ``knockout'' 1models of human disease. In 1999, NCRR
established the Mutant Mouse Regional Resource Centers to expand the
nation's capacity for preserving specialized mice and distributing them
to biomedical researchers. Because of the program's success and value
to the scientific community, NCRR now plans to extend the scope of the
mouse resource centers to an international level. Collaborations will
be established with Mutant Mouse Resources at sites in Europe and
Japan, thereby minimizing unplanned duplicative efforts on a global
scale.
NCRR also proposes to initiate a network of Mutant Rat Regional
Resource Centers--similar to the successful mouse network--to import,
validate, cryopreserve, and distribute mutant rats to investigators
globally. Up to three rat resource centers will be established along
with a complementary informatics center to design and maintain a
database of relevant data for each mutant rat included in the network,
and mantain a dedicated Internet linkage among the Centers to provide
investigators access the information on validated mutant rat models
within the network's collection and relevant information a centralized
web site and database.
Research using swine models has expanded significantly over the
past five years, resulting in the need for animal production,
appropriate husbandry and care, and genetic technologies related to
pigs. In 2002, an NCRR-supported research team at the University of
Missouri succeeded in creating the world's first ``knockout'' pigs--the
gene function is altered so that the gene can no longer add specific
sugars to the outer surface of liver cells, which, in turn, decreases
the immune-mediated tissue rejection response. The knockout pigs
represented a first step toward developing genetically engineered swine
suitable for cross-species transplantation, or xenotransplantation,
into humans. NCRR proposes to establish a National Swine Regional
Resource Center with the capacity to import, cryopreserve,
characterize, maintain, and distribute well-characterized specific-
pathogen-free swine strains. The Resource Center will also have an R&D
component to enhance the research scope and expertise of investigators
there.
PREVENTION, DIAGNOSIS, AND TREATMENT
NCRR is also an ardent supporter of clinical research. The
nationwide network of General Clinical Research Centers (GCRCs)
provides a collection of research resources and professional research
staffing for conducting state-of-the-art clinical research and career
development programs to develop independent investigators. GCRCs are
encouraged to reach out to investigators at nearby institutions without
GCRCs and provide access to the resources of the GCRCs. NCRR also funds
clinical research centers at minority institutions.
To address the public's concern about the safety of clinical
research, NCRR implemented the Research Subject Advocate (RSA) program
to assure that research conducted on NCRR-supported GCRCs and minority
clinical research sites are in compliance with Federal laws,
regulations and policies. Research Subject Advocates work closely with
research subjects to help them understand the research project for
which they agreed to participate and also work closely with clinical
investigators to apprise them of their ethical responsibilities to
research subjects. The RSA organizes workshops to inform investigators
about the several local and Federal regulations and policies that
relate to clinical research. Because of the enthusiastic institutional
responses to the Research Subject Advocate program, NCRR proposes to
begin phasing in support for RSAs for all NIH-supported patient-
oriented research at GCRC host institutions.
In addition, NCRR intends to support research to identify factors--
for example, biologic, economic or cultural--which lead to health
disparities and how to modulate for eliminate those factors in racial
and ethnic minority Americans. Through establishing dedicated
Comprehensive Centers for Health Disparities Research, NCRR support
will develop the clinical research skills and translational research
capacity of students, postdoctoral research fellows and faculty at
minority medical schools. NCRR also will continue to encourage
multidisciplinary collaborations among minority institutions and
institutions with established research programs to not only accelerate
the development of independent clinical research investigators but also
to enhance our understanding of the factors that contribute to health
disparities and how to negate them.
ENHANCEMENT OF RESEARCH CAPACITY
NCRR's purview is research infrastructure, in the broadest
interpretation of the term. Insight leading to novel research
approaches to prevent, treat or ameliorate disease will result from
synthesis of massive amounts of molecular, genetic, and biologic data.
Seamless integration of information across these data sources is a
major research challenge.
NCRR will expand the advanced technology used or developed for the
neuroscience testbed for BIRN to build a National Electronic Clinical
Trials and Research (NECTAR) network. This effort will include
designing a web based data entry approach for clinical trials and other
types of clinical research, development of a host of other tools,
including advanced grid technology to integrate datasets and develop
tools to manipulate these datasets at distributed sites. The NECTAR
network will generate heterogeneous data types which have distinct or
unique requirements for data collection, storage, integration, and
analysis. Initially this phase of the NECTAR network development will
focus on therapeutic development networks, particularly in rare
diseases. The tools developed at this stage may be readily scaled up to
include, for example, collaborative clinical research across wide
geographic sites, primary care physician clinical trial networks, other
provider networks, and private sector partners. This infrastructure
will constitute the foundation for a nation wide NECTAR-BIRN to
accelerate the rate for which health research advances at the bench
reach patients who are the intended benefactors of biomedical research.
The BIRN allows access to databases, bioinformatics tools, scalable
computing up to the teraflop level, research resources for clinical,
animal and basic research; it also includes federated databases, web-
based data collection for clinical trials and access to virtual
laboratories for crystallography, magnetic resonance imaging, electron
microscopy. This cyberspace-based network will be intertwined with a
``ground-based'' network of technology-based resources. The
complementary networks will continue to evolve with technologic needs
and research complexities. Similarly, technologies and resources
networked for human, animal and basic research will also evolve across
this national infrastructure for land-based and cyber-spaced networks.
In essence, as research problems become more complex, infrastructure to
facilitate that research must undergo a paradigm shift.
The Institutional Development Award (IDeA) program includes two
subprograms to strengthen the research infrastructure among 23 states
and Puerto Rico to improve their research competitiveness for NIH grant
awards. The two infrastructure-building programs--Centers of Biomedical
Research Excellence (COBRE) and the Biomedical Research Infrastructure
Network (BRIN)--have been in place for three and two years,
respectively. In that short time span, preliminary observations are
extremely encouraging. Between 1997 and 2002, the application rate for
NIH grants increased 16 percent--but the number of competitive NIH
grant awards increased 37 percent. The IDeA programs' impact has
resulted from providing support for modern laboratories and research
equipment, recruitment established investigators to lead the research
effort as well as to mentor graduate students and junior faculty to
become independent investigators. There has been a spinoff to small
industry as well. For example, a faculty member of the COBRE in West
Virginia has invented a microfludics chip (``lab on a chip'') that will
enable researchers to analyze and identify proteins more rapidly, an
innovation that may lead to new diagnostic strategies and treatments.
Both the COBRE and BRIN programs are enthusiastically embraced by
students, mentor-faculty, and institutional leadership. In fiscal year
2004 the NCRR will develop new COBRE research centers and will develop
a follow-on program to the BRIN, initially funded as a planning grant,
to capitalize on statewide networks to facilitate biomedical research
efforts at undergraduate institutions and to further enhance the
pipeline for promising baccalaureate and graduate students in fields
relevant to biomedical research.
Finally, NCRR will further strengthen institutional biomedical
research infrastructure and also design specific programs to develop
the research skills of graduate students and junior faculty in both
basic and clinical sciences at RCMI and IDeA institutions. Programs
will be designed to enhance early career scientists to transition from
a mentored research environment to an independent research career to
bolster the collective research capacities of this subset of
institutions. To continue to address the shrinking pool of clinical
investigators, NCRR plans to expand and extend the successful
Institutional Mentored Clinical Research Scholars (CRS) Program to
include a consortium of minority medical schools associated with the
Research Centers in Minority Institutions (RCMI) program. This cohort
of investigators will be included in a dedicated network to foster
their research through the Clinical Research Infrastructure initiative.
CONCLUSION
In conclusion, the health-related advances of tomorrow will depend
on the availability of essential, shared research resources, including
nonhuman models, advanced technologies, and tools for exploring new
diagnostics, therapies, and preventive strategies. NCRR is poised to
provide these essential resources to the biomedical community. As we
have for more than 40 years, NCRR remains committed to providing the
enabling tools and technologies that advance biomedical science and
improve the health of our nation's citizens. In collaboration with the
National Science Foundation, Internet2, and investigators from several
universities, NCRR has become a major supporter for upgrading the
infrastructure for health-related research focusing on development of a
bioinformatics tool box, a more efficient clinical trials system and
use Internet2 interface for the several tools and algorithms for data
visualization, efficient clinical trials networks and development of
grids for security, computation, and data storage.
My colleagues and I will be happy to respond to any questions you
may have.
______
Prepared Statement of Dr. Jack Whitescarver
Mr. Chairman and Members of the Committee, I am pleased to present
the President's budget request for the AIDS research programs of the
NIH for fiscal year 2004, a sum of $2,869,858,000 an increase of
$122,395,000 above the comparable fiscal year 2003 appropriation.
The NIH represents the largest and most significant public
investment in AIDS research in the world. It supports a comprehensive
program of basic, clinical, and behavioral research on HIV infection
and its associated opportunistic infections and malignancies that will
lead to a better understanding of the basic biology of HIV, the
development of effective therapies to treat it, and the design of
better interventions to prevent new infections. Perhaps no other
disease so thoroughly transcends every area of clinical medicine and
scientific investigation, crossing the boundaries of the NIH
institutes. The Office of AIDS Research (OAR) plays a unique role at
the NIH. OAR coordinates the scientific, budgetary, and policy elements
of the NIH AIDS program, supported by nearly every Institute and
Center; prepares an annual comprehensive trans-NIH plan and budget for
all NIH-sponsored AIDS research; facilitates NIH involvement in
international AIDS research activities; and identifies and facilitates
scientific programs for multi-institute participation in priority areas
of research.
THE WORLDWIDE PANDEMIC
HIV has already infected more than 60 million people around the
world. According to a new CIA report, ``The HIV/AIDS pandemic continues
to spread around the world at an alarming rate, and the number of
people with the disease will grow significantly by the end of the
decade, as it becomes more geographically diffuse. By 2010, we estimate
that five countries of strategic importance to the United States--
Nigeria, Ethiopia, Russia, India, and China--collectively will have the
largest number of HIV/AIDS cases on earth.'' A recent article in
Foreign Affairs magazine stated, ``The spread of HIV/AIDS through
Eurasia, in short, will assuredly qualify as a humanitarian tragedy--
but it will be much more than that. The pandemic there stands to
affect, and alter, the economic potential--and by extension, the
military power--of the region's major states . . . Over the decades
ahead, in other words, HIV/AIDS is set to be a factor in the very
balance of power within Eurasia--and thus in the relationship between
Eurasian states and the rest of the world.'' Dramatic increases in HIV
infection also are occurring in Eastern Europe, Central Asia, Latin
America, and the Caribbean. An article in the New York Times recently
reported another dimension to the epidemic: ``As a result of HIV, the
worst-hit African countries have undergone a social breakdown that is
now reaching a new level: African societies' capacity to resist famine
is fast eroding. Hunger and disease have begun reinforcing each
other.''
THE U.S. EPIDEMIC
The Centers for Disease Control and Prevention (CDC) recently
reported that more people were diagnosed with AIDS in 2001, the latest
year for which reliable statistics are available, than the previous
year, or any year since 1998. After years of sharp declines, thanks
largely to successful treatment with new antiretroviral therapies
(ART), this report indicates a reversal in cases of AIDS in the U.S.
Further, CDC reported that the rate of new HIV diagnoses, which had
remained stable since 1990, also appears to be increasing. New HIV
infections rose a striking 8 percent between 1999 and 2001, based on
data from 25 states with mandatory HIV reporting, which does not
include the two highest prevalence states of New York and California.
HIV infection rates continue to climb among women, racial and ethnic
minorities, young homosexual men, individuals with addictive disorders,
and people over 50 years of age. In addition, use of ART has now been
associated with a series of side effects and long-term complications
that may have a negative impact on mortality rates. The appearance of
multi-drug resistant strains of HIV presents an additional serious
public health concern. According to CDC reports, approximately one
quarter of the HIV-infected population in the United States also is
infected with Hepatitis C virus (HCV). AIDS affects African Americans
and Hispanics disproportionately. According to CDC figures through
December 2001, approximately 64 percent of newly infected women are
African American and 17 percent are Hispanic. Among newly infected men,
approximately 43 percent are African American and 20 percent are
Hispanic. This expanding and evolving U.S. epidemic presents new and
complex scientific challenges.
COMPREHENSIVE AIDS RESEARCH PLAN AND BUDGET
To address these compelling scientific questions, the OAR develops
an annual comprehensive trans-NIH AIDS research plan and budget, based
on the scientific priorities and opportunities that will lead to better
therapies and prevention strategies for HIV infection and AIDS. The
planning process is inclusive and collaborative, involving the NIH
Institutes, as well as eminent non-government experts from academia,
industry, foundations, and AIDS community representatives. The Plan
serves as the framework for developing the annual AIDS research budget
for each Institute and Center, for determining the use of AIDS-
designated dollars, and for tracking and monitoring those expenditures.
The Plan establishes the NIH AIDS scientific agenda in the areas
of: Natural History and Epidemiology; Etiology and Pathogenesis;
Therapeutics; Vaccines; and Behavioral and Social Science. In addition,
the plan addresses the cross-cutting areas of: Microbicides; Racial and
Ethnic Minorities; Women and Girls; Prevention Science; International
Research; Training, Infrastructure, and Capacity Building; and
Information Dissemination. In consultation with the Director of NIH,
the OAR determines the total annual AIDS research budget. Within that
total, the OAR establishes the AIDS research budgets for each NIH
Institute and Center, in accordance with the priorities and objectives
of the Plan, at each step of the budget development process up to the
Conference Committee. To accomplish this, OAR consults regularly with
the Institute and Center Directors. This process allows the OAR to
ensure that NIH AIDS research funds will be provided to the most
compelling scientific opportunities, rather than a distribution based
solely on a formula.
OAR plays a crucial role in identifying scientific areas that
require focused attention and facilitating multi-Institute activities
to address those needs. OAR fosters this research through a number of
mechanisms, such as designating funds and supplements to jump-start or
pilot program areas, sponsoring workshops or conferences to highlight a
particular research topic, and sponsoring reviews or evaluations of
research program areas to identify research needs.
The overarching priorities that continue to frame the NIH AIDS
research agenda are: prevention research to reduce HIV transmission,
including development of vaccines, microbicides, and behavioral
interventions; therapeutics research to develop simpler, less toxic,
and cheaper drugs and drug regimens to treat HIV infection and its
associated illnesses, malignancies, and other complications;
international research, particularly to address the critical needs in
developing countries; and research targeting the disproportionate
impact of AIDS on minority populations in the United States. All of
these efforts require a strong foundation of basic science, the bedrock
of our research endeavor.
NEW CHALLENGES IN THERAPEUTICS RESEARCH
While multiple ART drug combinations continue to successfully
reduce viral load and restore immune responses in many HIV-infected
individuals, these regimens also can result in serious toxicities and
side effects, single- and multiple drug-resistance, and other
complications which make them unacceptable for some individuals. These
side effects and complications appear to be increasing as HIV-infected
individuals continue on drug regimens. More deaths occurring from liver
failure, kidney disease, and cardiovascular complications are being
observed in this patient population. NIH-sponsored research efforts
continue to develop better antiretroviral drugs and treatment regimens
that demonstrate less toxicity, activity in viral and cellular
reservoirs, reduced development of drug resistant virus, improved
pharmacodynamics and pharmacokinetics, easier compliance, and lower
cost.
While the incidence of certain opportunistic infections (OIs) and
malignancies has decreased with the advent of ART, the number of cases
of TB, multiple drug resistant TB, and other coinfections such as
Hepatitis B virus and Hepatitis C virus has increased. The development
of practical and affordable treatment regimens against HIV coinfections
and endemic diseases in developed and developing nations is an NIH
priority.
PREVENTION RESEARCH
NIH supports a comprehensive approach to HIV prevention research
that includes contributions from the biomedical, behavioral, and social
sciences. Our biomedical prevention research priorities include the
development of vaccines, topical microbicides, strategies to prevent
mother-to-child transmission-including a better understanding of risk
associated with breast-feeding-and management of sexually transmitted
diseases (STDs). NIH also supports behavioral research strategies,
including interventions related to drug and alcohol use. Efforts
continue to identify the most appropriate intervention strategies for
different populations and sub-epidemics in the United States and around
the world. As a result of increased NIH funding, many new approaches to
HIV vaccines are being pursued. Although production of candidate
vaccines for clinical study has proceeded slowly, at least 10 new
candidate vaccines will enter Phase I trials in the next 2 years.
Several new combinations of products, which are expected to provide
better immune responses, also will be tested in Phase I or II trials.
The Dale and Betty Bumpers Vaccine Research Center, located on the NIH
campus, recently launched the first Phase I clinical trial of a multi-
clade, multi-gene vaccine candidate.
INTERNATIONAL RESEARCH
To address the increasing urgency of the AIDS pandemic, the OAR
established an initiative and strategic plan for global research on
HIV/AIDS and has significantly increased research efforts in the past
several years to benefit resource- and infrastructure-poor nations. NIH
supports a growing portfolio of research conducted in collaboration
with investigators in developing countries. Results of this research
benefit the people in the country where the research is conducted, as
well as people affected by HIV/AIDS worldwide. Critical to the success
of these international studies are foreign scientists who are full and
equal partners in the design and conduct of collaborative studies. To
that end, NIH also supports international training programs and
initiatives that help build infrastructure and laboratory capacity in
developing countries where the research is conducted.
women and minorities
Women experience HIV/AIDS differently from men. NIH research has
demonstrated that women progress to AIDS at lower viral load levels and
higher CD4 counts than men. Women also experience different clinical
manifestations and complications of HIV disease. These findings may
have implications for care and treatment of HIV-infected women,
particularly with ART. There are many research questions that remain
unanswered about specific characteristics of women and girls that might
play a role in transmission, acquisition, or resistance to HIV
infection during different stages of the life course.
In many U.S. urban centers, HIV seroprevalence rates mimic those
found in some developing nations. These findings, along with the
resurgence of STDs and associated high-risk behaviors, demonstrate the
need for comprehensive strategies to decrease HIV transmission in
affected vulnerable populations, and improve treatment options and
treatment outcomes. OAR is directing increased resources toward
research to develop new interventions that will have significant impact
on these groups. These include interventions that address the co-
occurrence of other STDs, hepatitis, drug abuse, and mental illness;
and interventions that consider the role of culture, family, and other
social factors in the transmission and prevention of these disorders in
minority communities. NIH is making significant investments to improve
research infrastructure and training opportunities for minorities and
will continue to ensure the participation of minorities in AIDS
clinical trials, as well as in natural history, epidemiologic, and
prevention studies. OAR has provided additional funds to projects aimed
at increasing the number of minority investigators conducting
behavioral and clinical research; targeting the links between substance
abuse, sexual behaviors, and HIV infection; increasing outreach
education programs targeting minority physicians and at-risk
populations; and expanding the portfolio of population-based research.
One of these projects is a series of Training and Career Development
Workshops that provide minority investigators with an opportunity to
learn more about available NIH funding mechanisms and to meet and
network with senior minority investigators who receive significant
levels of NIH funding.
SUMMARY
The human and economic toll of the AIDS pandemic is profound. It
requires a unique response that is complex, comprehensive, multi-
disciplinary, and global. The NIH role in this response is fundamental
and unprecedented. The diverse AIDS research portfolio demands
scientific coordination and management of research funds to enhance
collaboration, minimize duplication, and ensure that precious research
dollars are invested in the highest priority areas of scientific
opportunity. The nation's investment in AIDS research is reaping even
greater dividends, as AIDS research is unraveling the mysteries
surrounding many other infectious, malignant, neurologic, autoimmune,
and metabolic diseases.
The authorities of the Office of AIDS Research allow NIH to pursue
a united research front against the global AIDS epidemic. We are deeply
grateful for the continued support this Committee has provided to our
efforts.
ACTING DIRECTORS
Senator Specter. Thank you very much, Dr. Zerhouni.
Are there any other institutes which have acting directors
at the present time?
Dr. Zerhouni. Yes. We have three institutes this minute.
NIGMS, the General Medical Science Institute is--the Acting
Director is Dr. Judy Greenberg. And she is with us today.
Senator Specter. And when do you expect to have a permanent
director there?
Dr. Zerhouni. Senator, I have worked--the top priority for
my first year was to complete all six--I mean, to fill all six
vacancies for the six institutes that were vacant within the
year. So I expect that, I hope on my first anniversary that all
institutes will have new directors that have acting directors
today.
Senator Specter. Dr. Zerhouni, the subcommittee would
appreciate knowing a little more about your efforts there.
There is an inevitable sense that a full-time director with
that authority is necessary to move an institute along at top
speed. So would you submit to us in some detail, in writing,
your expectations and the progress and keep us informed as to
how you are doing on full-time directors for those institutes?
Dr. Zerhouni. I will certainly do. And I agree with your
views on that.
[The information follows:]
Progress on Full-Time Directors
Mr. Chairman, I consider the selection of outstanding, highly
qualified scientist-administrators as directors of the various
institutes to be among my highest priorities. Over the past eleven
months, I have filled three of the vacancies for Directors of
Institutes at NIH and have appointed:
Dr. Thomas Insel, Director, National Institute of Mental Health
Dr. T. K. Li, Director, National Institute on Alcohol Abuse and
Alcoholism
Dr. Nora Volkow, Director, National Institute and Drug Abuse
Two other vacancies remain and I and my staff are working very hard
to complete the searches so that I can make appointments:
--The search for the Director, National Institute of Neurological
Disorders and Stroke has been prolonged, unfortunately. It
started in March, 2001 and, after careful consideration, the
leading candidate withdrew and took a position at a
pharmaceutical company in November, 2001. The vacancy
announcement was re-issued and a slate of three highly
qualified candidates was sent forward, all of whom were
interviewed by the Acting Director, NIH between late February
and March, 2002. A candidate was offered the position at the
end of March, accepted verbally and subsequently, withdrew in
early April 2002.
Upon my assuming the Directorship of NIH, I discussed the
situation with my senior staff and decided to reconstitute the
search committee, and solicit applicants myself. This resulted
in several new applicants and consideration of several previous
candidates. Five candidates were interviewed and as of the time
of submission of this response, I am in active discussion with
my selectee. I anticipate that I will be able to name a
Director for NINDS within a very short time.
--The search for the Director, National Institutes of General Medical
Sciences was initiated in mid-March, 2002. The search committee
interviewed a total of ten candidates between late September,
2002 and February, 2003. Of the group, I and my senior staff
have interviewed three during March and early April and
anticipate conducting one more interview. I anticipate that a
selection will be made in the next month.
SALIVARY DIAGNOSTICS
Senator Specter. Dr. Zerhouni, one of the questions which
we characteristically ask is the question about what progress
is being made on major ailments and what could be done with
greater funding. And it is obviously a very difficult question.
It may be an impossible question when we ask when will a cure
be found for Parkinson's. I choose Parkinson's because 5 years
ago there were estimates that Parkinson's would be cured within
5 years.
Nobody can hold you to a cure time. But we would be
interested in your projection on where you see NIH heading on
the ailments to give us some projection as to what your
expectations are. We understand that it is not possible to be
scientifically precise. And then to tell us what more you can
do with increased funding, what level of funding on the
specific ailments would enable you to project an earlier time
and by how much.
Our colleagues in the Congress are very goal-oriented. And
even questions which are really not answerable with precision
are pursued. So to the extent that you could give us some ideas
on those questions, the subcommittee would be very
appreciative.
Let me turn to Dr. Lawrence Tabak of the Dental Institute
on a question which has recently come to the attention of the
subcommittee on the presence of a cancer-related protein in
saliva that could result in more acute, less costly ways to
diagnose breast cancer in women. The question, Dr. Tabak, is,
how much is being requested in the budget to pursue this line
of research? And do you have any plans to conduct clinical
trials in this area?
Dr. Tabak. Thank you for the question, Senator Specter. In
this current fiscal year, NIDCR is expending approximately $7
million in the general area of salivary diagnostics. And for
the next fiscal year, we hope to spend approximately $1.5
million more to continue in this effort.
Senator Specter. $1.5 million?
Dr. Tabak. Yes, sir, that is correct.
Senator Specter. What is the total budget of your
institute?
Dr. Tabak. Currently, it is $371 million, sir.
Senator Specter. Does this new test pose real promise to
give an easier, better diagnosis of breast cancer?
Dr. Tabak. This and other salivary diagnostic tests do
offer a great deal of promise, sir. The test to which you are
referring, as you know, was worked out at the University of
Mississippi. It is a test which recognizes a protein which can
be found both in blood and saliva. But because of the ease of
detection and the ease of sample collection in saliva, we feel
that there are certain advantages for the saliva-based test.
Senator Specter. Dr. Tabak, if you allocated more than $1.5
million, do you think you could get a faster result on this
important test?
Dr. Tabak. Certainly, sir, resources are always welcome.
But there is a point at which basic information needs to be
gathered. And until that basic information is obtained, it
would be premature to expend additional funds in a particular
area.
Senator Specter. Are you saying that is the maximum amount
that can be efficiently spent on that research?
Dr. Tabak. In terms of bringing this work to a full-blown
clinical trial, sir, I think it would be premature. What we are
now doing is termed phase-one trials to begin to understand
whether or not this test is both accurate and efficacious. Once
that base information is obtained, sir, then it would be
appropriate to go on to larger scale trials.
Senator Specter. Thank you.
Senator Murray.
Senator Murray. Thank you very much, Mr. Chairman.
PEDIATRIC RESEARCH
Dr. Zerhouni, when you were confirmed, you and I talked
about pediatric research. And I wanted to ask you today about
any progress you have made. I think we have made a lot of
progress on reducing gender bias, but I am still deeply
concerned that we have not made much progress on making sure
that we are looking at everything in terms of what happens to
children.
Can you give us an update on your pediatric research
initiative?
Dr. Zerhouni. Well, as you know, the pediatric research
initiative is guided by a major document that we have been
following in terms of implementation. There is no doubt in my
mind that pediatric research is a priority, continues to be a
priority. We have to also invest and continue to invest in the
multiple areas of pediatric research.
We are, for example, invested in terms of talent and
developing talent and training capabilities for pediatric
research. We are continuing to make investments in many of the
pediatric diseases separately. For example, we have increased
our investment in muscular dystrophy or increased our
investment in spinal muscular atrophy. And in every category we
have a disease-specific plan.
But in terms of the overall investments in pediatric
research, we need to integrate the pediatric research agenda
within not just the NICHD Institute, which is primarily
responsible for pediatric research, but all institutes.
So I think it is work in progress. I think we are making
good progress. But we will continue to consider that a
priority, realizing as well, Senator, that many of the changes
we need to make relate to these priority areas that I
described--multidisciplinary teams that should invest in
pediatric research, clinical research networks. For example,
the Office of Rare Diseases is looking at establishing networks
across the country to look at these rare diseases that tend to
affect children.
So we are looking at a multi-pronged approach and a
strategic approach in pediatric research.
FUNDING OF RESEARCH PRIORITIES
Senator Murray. Dr. Zerhouni, as you well know, there is a
lot of misunderstanding about NIH research dollars. There is
kind of this assumption out there that NIH only funds
politically correct diseases or that you have to have a high-
profile celebrity in order to secure any NIH funding. And I
know this subcommittee under Senators Specter and Harkin have
really resisted any efforts to earmark NIH dollars by disease.
We can express our thoughts through report language.
But could you explain for us how you establish the
priorities for NIH funding and what criteria is used in
evaluating research applications?
Dr. Zerhouni. Certainly, Senator. This is a question that
is a recurring theme, especially when any particular area feels
underserved. So that when we look at the decisionmaking
process, we realize that there are fundamentally several
factors that come into play. One, the first and foremost is the
burden of the disease as we know it through epidemiological
studies. And second, the predicted future burden of disease.
For example, just as a matter of example, you look at
diabetes and the rise in expenditures in diabetes, it parallels
what we predict the burden of disease in diabetes is going to
be. When you look at obesity research, we are now investing at
an accelerated pace in obesity research because of the
prediction. Even though when you look at the disease burden,
per se, you cannot really decide that this is the only factor
that you should look at, because the second factor is, have we
made enough scientific advances to invest in the particular
area with results that are likely to occur?
So we look fundamentally at the investments in terms of, A,
the burden of disease; B, the priority setting in terms of
science. And we get advice in that context for many more
sources than any. I am very impressed with the fact that NIH
receives advice from 21,000 advisors every year on every single
condition that we face.
So the process is not an easy one to consider. But clearly,
the patient advocacy groups are also interested in looking at
how we invest. And my gratitude goes to you, because I think
earmarking would not be a good direction for setting scientific
priorities at NIH. And we try to avoid that and try to not be
politically correct, as you state.
Senator Murray. Well, I think it is really important to
keep talking about how you set your criteria to the general
public, because we do have a misperception constantly that if
you get a high-profile person, that you get more funding. And
so it makes it harder on us. And, as I said, Senator Specter
has done a really good job managing that. But it is very
difficult.
I think it is important that we base it on science. So I
appreciate your comments.
Thank you, Mr. Chairman.
Senator Specter. Thank you, Senator Murray.
Dr. Zerhouni, I broach the subject of some delicacy now,
which has already been communicated to you. Last year the
Senate figure was cut by $25 million because the conference
committee concluded that to reach the doubling, which was an
astronomical figure, was more than sufficient. We have an
enormous number of complaints from other research agencies
about, candidly, the favoritism that NIH gets. And we have
fought those battles out.
We have heard from a number of people about directors of
the institutes who have said that certain grants could not be
applied or certain research could not be undertaken because the
budget was cut and have attributed the $25 million reduction,
which was not a cut at all, because there was an increase of
more than $3.7 billion to the NIH budget.
It would be amazing, I think, to many of you ladies and
gentlemen, how fast the information travels from what you may
tell someone who is applying for a grant or you may tell
someone who is concerned about more research right back to my
ears. You would be surprised.
The advent of this very, very heavy increase in funding for
NIH, which has come from this subcommittee, has had the
reverberating effect of having this subcommittee contacted by
many, many, many people, which had not been the case before we
took up the cause of increasing the NIH grant. So if you do not
want to make some allocation or you do not want to make a grant
or you do not want to undertake some research, if you say it is
because you got a cut in your budget, that is going to come
back to the Congress.
We hope you do not ever have a cut in your budget. But bear
in mind that these people--and I know you have a good sense of
this yourself--feel so very intently about these subjects,
very, very emotional, when you have a child with one of these
maladies, it is just the edge of the ledge. And I know that you
dedicated men and women are well aware of that. But I thought
it important to make a quasi-public statement. I have not said
very much on the subject in the brief remarks I have just made.
Let me turn now to the question of stem cell research. And
I would like to direct this question to Dr. James Battey of the
Deafness Institute and also to Dr. Allen Spiegel of the
Diabetes and Digestive and Kidney Institute. Last September,
this subcommittee held a hearing regarding the implementation
of the Federal stem cell policy. And as you all know, back on
August 9, 2001, President Bush articulated a modification of
Federal policy to allow Federal funding on existing stem cell
lines.
At the September 25, 2002 hearing, Dr. Curt Civin stated,
``Embryonic stem cell research is crawling like a caterpillar,
while NIH has listed eligible lines in its registry at 78. Only
a tiny fraction of these lines are accessible and only to those
persistent and patient enough to jump through a series of hoops
and endure lengthy waits. I am still waiting to receive my
first stem cell line.''
Dr. Battey and then Dr. Spiegel, what steps has NIH taken
to help people like Dr. Civin and other scientists gain access
to embryonic stem cell lines? And how many are now accessible?
ACCESS TO EMBRYONIC STEM CELL LINES
Dr. Battey. The process of scaling up an embryonic stem
cell derivation to the point where it can be distributed as a
high-quality, well-characterized cell line takes about a year
from start to finish. It is an expensive, time-consuming,
technically demanding process that requires enormous care to
maintain the cells in their state of pluripotency, which means
their ability to differentiate into many different cell types,
as well as to remain continuously self-renewing.
To facilitate this very expensive and time-consuming
process, the NIH has awarded infrastructure grants awards to
eight suppliers that have derivations on the NIH stem cell
registry. And I am pleased to tell you, Mr. Senator, that
between the September hearing and the hearing today, if you had
a research laboratory and wanted to order cell lines, in
September you could have ordered five such cell lines. And
right now, you could order 11 lines today.
That effort is continuing to expand. And we expect that
increasing numbers of cell lines will be widely available and
actively shipped to the research community over the next 6
months to a year.
Senator Specter. How many stem cells are currently
available?
Dr. Battey. You could order 11 lines today.
Senator Specter. Is that sufficient for the research which
people want to undertake?
Dr. Battey. At this point in time, the fundamental
challenge in the human embryonic stem cell research arena is a
basic research challenge. It is a challenge to understand what
growth factors, transcription factors, and other molecules
regulate the ability of embryonic stem cells to differentiate
into one cell type versus another. It is an understanding of
the interaction between the host and the transplanted cell that
allows that cell to persist for a long time within the host and
to function correctly.
It is a challenge to understand how you control the cell
cycle division of the cell, because once it is transplanted
into a host, you do not want it to continue to be self-renewing
in the same way that it was in the laboratory before it was
transplanted.
These basic research questions are readily addressable with
the cell lines that are currently available and will become
available within the next few months to a year.
Senator Specter. Do we have sufficient stem cell lines for
the research that people want to undertake?
Dr. Battey. We have sufficient cell lines to embrace the
basic research challenge that is in front of us today.
Senator Specter. Well, is there some facet besides the
``basic research challenge,'' which is in front of us today?
Dr. Battey. The major questions that confront the stem cell
research community today can be addressed with the cell lines
that are available.
STEM CELL INFRASTRUCTURE AWARDS
Senator Specter. Dr. Spiegel, would you care to amplify on
Dr. Battey's answer?
Dr. Spiegel. I would be happy to. Thank you, Senator
Specter.
Some general comments to amplify on what Dr. Battey said
would include the provision of support through so-called
infrastructure awards to the providers of these human embryonic
stem cell lines. NCRR is funding the majority of these
infrastructure awards. NIDDK is funding two of them. And this
provides support to allow the distribution of these cells
because they are very, very difficult to grow.
Several NIH institutes have combined to provide training
courses. As Dr. Battey has emphasized, one of the rate-limiting
steps here is bringing new investigators into the field. It is
not trivial to learn how to grow human embryonic stem cells.
And these training courses are directed at that.
A further example, which again comes out of the NIH Stem
Cell Task Force, for which Dr. Zerhouni appointed Dr. Battey
the Chair and on which I am pleased to serve, is an intramural
NIH facility, which will be under Dr. Ron McKay and the
Neurology Institute with extramural investigators as advisors.
This effort will be comparing and looking critically at the
different available human embryonic stem cell lines to provide
information that is critical before investigators order them to
work on in their own lab.
Let me then just briefly speak on NIDDK specifically.
NIDDK, like many of the other NIH institutes, has invested
heavily in all aspects of stem cell research. So-called adult
stem cell research, animal stem cell research, because animal
models are very important, as well as human embryonic stem cell
research. The aggregate figure for fiscal year 2002 for NIDDK
was $58.3 million.
One particular new initiative that we undertook, based on a
trans-NIDDK planning group was so-called stem cell genome
anatomy projects. These span the entire spectrum of the NIDDK
mission so that we have projects directed at understanding the
development of cells in the bone lineage, which we do with the
Arthritis Institute, in the gastrointestinal and liver lineage,
in the urology and the kidney lineage, and then so-called
hematopoietic stem cells.
One of our most important initiatives relating specifically
to Type 1 and Type 2 diabetes is the so-called beta cell
biology consortium. Of course, it is the beta cell that makes
insulin, which is lacking in Type 1 diabetes and deficient in
Type 2 diabetes. This consortium is looking at every avenue of
approach to the development of these critical cells.
Thank you.
STEM CELLS AND MOUSE FEEDER CELLS
Senator Specter. Dr. Spiegel, what about the research to
isolate stem cells without the use of mouse feeder cells?
Dr. Spiegel. Currently, to my knowledge, although there
have been reports from industry about the ability to grow human
embryonic stem cells absent mouse feeder cells, the lines that
are in use or available that Dr. Battey referred to do use
mouse feeder cells. As Dr. Battey emphasized, this is not
hampering the ability to do the basic research that we need to
do to really be able to understand how we can trigger in a very
organized and efficient way the development of these cells into
various therapeutic possibilities.
Senator Specter. Is it not true that research without the
use of mouse feeder cells is indispensable, necessary to use
those stem cells in humans?
Dr. Spiegel. I totally agree. The comment that I was going
to make is that a critical intermediate step before anyone
should contemplate--in terms of safety and every other
consideration--going into human trials, would be animal models,
from small animal models and eventually to non-human primate
models. Here, too, the mouse feeder layer issue is not rate-
limiting.
But, you are certainly correct that to go into human
trials, there would be issues that would have to be addressed
in terms of possible mouse viruses and other contaminating
proteins.
Senator Specter. Should not those issues be addressed now
by NIH?
Dr. Spiegel. I think that that is an important issue. I
think that, in terms of the available lines, there are
important technical developments that can be undertaken that
are critical to understand what the factors are that these
mouse feeder-layers are eliciting that are necessary to keep
the human embryonic stem cells from differentiating
spontaneously. That is really the critical issue for which they
are used.
I believe that the kind of research that is being done,
research that we can support, will very much address those
kinds of issues. That is, after all, the goal, to really
understand how to trigger development along a pathway that we
want, and yet to prevent spontaneously differentiation. And
such growth factor and other signaling research is being
undertaken.
Dr. Battey. If I could, Mr. Senator. Dr. Spiegel----
Senator Specter. Wait just a minute. I find that very
interesting, if not totally understandable. But what about the
basic question of having some research without the use of mouse
feeder cells? Do you not think that would be a pretty good idea
with all you are doing? How many millions did you say you were
spending?
Dr. Spiegel. The total figure for NIDDK for fiscal year
2002 was $58.3 million.
Senator Specter. Well, why not some research without the
mouse feeder cells? If they are to be used in humans, you are
going to have to move in that direction.
Ladies and gentlemen, what I want to be sure about, and I
cannot quite accomplish it in this hearing today, is that we
are not making any political decision, that you are making
scientific decisions. That is what we expect from you
scientists. That is why we are putting up $27 billion, which is
a very, very big public trust.
Do you want to say something more, Dr. Battey?
MOUSE FEEDER CELLS
Dr. Battey. I just wanted to add to what Dr. Spiegel said.
The first challenge to getting rid of the mouse feeder layer is
figuring out what the mouse feeder layer is providing to the
embryonic stem cells to render them able to differentiate into
many different cell types and be self-renewing. And there is
active research efforts to identify the factors that allow
these cells to remain in that state. And when those factors are
known and understood, we will be in a position to attempt to
grow these cells absent a mouse feeder layer.
Senator Specter. Dr. Penn, let me direct a question to you
with respect to spinal muscular atrophy, a genetic motor neuron
disease characterized by the wasting away of skeletal muscles.
It is the leading killer of infants and toddlers. Twenty-five
thousand Americans have the disease with up to 1,000 new babies
born with the disorder each year.
While there is a transitional research program, we are
concerned about how effectively it is being put into operation.
When spinal muscular atrophy was selected for this transitional
research program--when was SMA selected for this transitional
research program? And when will the first grants be awarded?
Dr. Penn.
SPINAL MUSCULAR ATROPHY RESEARCH
Dr. Penn. Yes, Senator. Spinal muscular atrophy actually is
the leading genetic cause of infant mortality. It is not always
lethal--there are three or four forms of it. In one form, it is
really deadly to babies. But in several others, adults can grow
and function and live with this disease.
Spinal muscular atrophy, we feel, is a great scientific
opportunity, because we not only know the genetic defect, but
we know something about how to try to render this disease
perhaps not cured, but to help it by dealing with the genetic
defects. And therefore, we did decide to move this disease
toward treatments, and I must say with a lot of help from the
voluntary agencies, as well as the Muscular Dystrophy
Association. And this is actually part of an institute-wide
effort to move in what we call translational research, dealing
with the basic mechanisms of a disease and then going to
treatments.
So we do have a brand-new way of pursuing working toward
trying these treatments and doing clinical trials. We will go
to the point of an investigational new drug application with
FDA. And it has taken time to do this properly. This is so new
that we have worked very hard to make it--to have a really
excellent product.
Actually what we are going to do is have a contractor issue
subcontracts. And the subcontracts will be directed at the
group of investigators out there that have done wonders to
figure out what is going on with this disease since the gene
was identified in 1995.
So we will not be issuing grants. The contractor will
actually call for subcontracts. We expect the whole group of
investigators to come in for these. There will then be let a
contract. And they will have to achieve milestones. It is not
so much reporting on what you--yes, reporting on what you have
done. You have to achieve something.
There are drugs, actually drugs, that could be used in this
disorder. And one of our intramural investigators, who is
internationally recognized in these areas, is trying one of
these drugs right now. But he is only working on cell lines
from the patients. Again, we have to be very careful about
using some of these things and moving to human beings.
It has taken time. But we are issuing--we have issued the
requests for proposals for this contract. And we expect to have
this move by the end of the summer.
Senator Specter. Dr. Penn, the question is, when was SMA
selected for this transitional research program?
Dr. Penn. Over a year ago. It took a year and a half to get
it to this point.
Senator Specter. Well, when will the first grants be
awarded?
Dr. Penn. The first subcontracts, sir, will be awarded, I
would say, this winter.
Senator Specter. When?
Dr. Penn. This winter, sir.
Senator Specter. Why is it taking so long?
Dr. Penn. To do it properly and to get our intramural
program up and running with it and to make sure that we develop
and design this whole program so that we would have a really
excellent result.
Senator Specter. Well, why does it take almost 2 years, Dr.
Penn?
Dr. Penn. As I said, sir, this is something brand-new for
us. It is a contract-based program. And it has taken 2 years.
Senator Specter. It is something brand-new, but it is a
contract-based program.
Dr. Penn. It is brand-new for us. And we have--we are going
to have a steering committee made up of the experts, both
academic and----
Senator Specter. You are going to have a search committee?
Dr. Penn. A steering committee, sir, to run----
Senator Specter. You are going to have a steering
committee?
Dr. Penn. For it to run----
Senator Specter. Has the steering committee been appointed?
Dr. Penn. It is being appointed right now.
Senator Specter. Why does that take so long?
Dr. Penn. Well, we had not gotten to that phase of the
exercise.
Senator Specter. Well, why have you not gotten to that
phase?
Dr. Penn. It just took this long to do this properly. It
took this long----
Senator Specter. Dr. Zerhouni, would you take a look at
that and submit in writing----
Dr. Zerhouni. Yes, Senator.
Senator Specter [continuing]. What has happened?
Dr. Zerhouni. I have looked----
Senator Specter. I would like to have--but I am not going
to take it up now.
Dr. Zerhouni. Fine.
Senator Specter. I would like to have precise answers as to
when the program was adopted, as you call it a translational
research program.
Dr. Zerhouni. Understood.
Senator Specter. And when a steering committee is adopted.
And this subcommittee wants to examine whether there is an
appropriate sense of urgency. It certainly has not satisfied a
lot of parents whose children have this ailment.
Dr. Zerhouni. I will respond directly to you on the record,
sir.
Senator Specter. Okay. We would appreciate it, if you
would.
[The information follows:]
Spinal Muscular Atrophy
The NIH is committed to accelerating research toward finding a
treatment for SMA, and fully appreciates the sense of urgency expressed
by the parents of children with this disease, as it does the concerns
of the parents of children affected by the scores of other neurological
disorders--many of which are genetic and are often disabling or lethal.
The NINDS recently launched a comprehensive program designed to
encourage and support translational research for all neurological
disorders. By translational research, I mean the process of applying
insights and discoveries from basic scientific inquiry to the treatment
or prevention of disease; the emphasis is on those activities focused
on bringing therapeutic strategies to readiness for clinical testing.
The specific, contract-based, SMA translational project to which
you refer is in addition to all the other funding opportunities that
are currently available for SMA research. It will use a performance-
based contract mechanism to allow rapid funding of translational
research, in a milestone-driven process, to identify treatments for
SMA. The NINDS presented the idea for this program to its National
Advisory Neurological Disorders and Stroke Council in February 2002.
The primary contract for the SMA project, which we expect to award
on or about September 30 of this year, will provide overall scientific
direction and organizational support for the program. A Steering
Committee, drawn from academia, industry, the public, and NIH, will
guide the program and play an integral oversight role for the
Contractor throughout the project. A working group of the Council,
including members of the proposed Steering Committee, will develop
detailed recommendations for a plan for research on promising
therapeutic strategies for SMA, such as drug development, gene therapy
and stem cell therapy. The plan will address all the steps required,
ultimately, to develop an IND--Investigational New Drug--application.
The implementation of the research plan will be finalized by the
Contractor, with guidance from the Steering Committee. The Steering
Committee will assist the Contractor in evaluating success in
accomplishing milestones, and in developing additional calls for
research proposals as needed. Because the role of the Steering
Committee is so integral to, and defined by, the contract, it would
have been premature to establish its membership in advance of the
publication of the statement of work in the request for proposals (RFP)
for the SMA program; this RFP was issued on April 22, 2003.
Importantly, efforts to recruit the Steering Committee are well
underway, and there will be detailed recommendations for the research
plan ready for presentation to the Council in September; calls for
research projects can be issued in October 2003, shortly after the
contract is awarded, and research projects should be underway by
February 2004.
The SMA translational program is not just a novel program for SMA,
but also for the NINDS. The aim is to develop treatments that will be
tested in people, and we hope this effort will serve as a model for
expediting therapy development for other disorders. This program will
require a significant investment of resources; the contract will be
awarded for four years, and NINDS intends to fund the research
subcontracts at a level of $4.5 million per year, which we anticipate
will fund up to approximately ten research subcontracts per year. The
NINDS intramural program will be involved throughout the process,
providing expertise in neurogenetics and SMA, and will be equipped to
rapidly initiate Phase I/II clinical trials when appropriate. For all
of these reasons, careful planning has been essential.
Senator Specter. Senator Harkin.
Senator Harkin. Thank you, Mr. Chairman. I have an interest
in SMA, also. I have met with families in Iowa about this. And
I am concerned, as Senator Specter, that the leading cause of
infant mortality is something that----
Senator Specter. You ladies and gentlemen would be amazed
with how many families we have met with with SMA and the other
ailments.
Senator Harkin. Yes. I started meeting with them maybe a
couple years ago in Iowa or something. And this is something I
had not even known about before. And now I just--now we find
out that it is the leading cause of infant mortality. And we
just have not done that much research on it. So I agree with
you, we have to push hard on that. We have to get this thing
moving. And I do not know why it has not by now. So I agree
with the chairman on this, that we have to find out about that.
Senator Specter. Well, there is one fellow who suffers from
Parkinson's, who has an hourglass. Whenever he sees me, he
turns the hourglass. And the ticking sands are going through
the hourglass on every hour of his life. And these parents come
to us with SMA and other ailments.
I am about to go through a fairly long list of questions.
We are going to take a little more time today, because we want
to know what the sense of urgency is as to how these issues are
being addressed.
These people come to us and say, you are giving NIH all the
money. What is happening? I do not like to hear talk of long
periods of time on appointing steering committees.
Senator Harkin.
Senator Harkin. Thank you again, Mr. Chairman.
I understand that you, in my absence--I was unavoidably
absent from here a little bit--that you did cover the issue of
stem cell research. And I just again want to buttress what you
have said and hope that we can move ahead aggressively in this
area, too. I understand that has been covered. So I will not go
into that.
The only thing that I just wanted to cover with you, Dr.
Zerhouni, was just basically broader picture of the funding of
NIH. We, as you know, basically just finished the doubling over
5 years. Senator Specter and I are both, with his leadership
and with my support, starting to get on another pathway of
trying to get it up to a tripling, that is, from what we
started in 1998.
To maintain that level, it seems to me we are going to have
to have somewhere in the neighborhood of about 7 or 8 percent a
year, if I am not mistaken, increases. And it is my
understanding, also, that just to maintain and kind of keep
doing what we are doing, we are going to need somewhere in that
level of funding. And yet the budget request this year is a 2.5
percent request.
So how can we keep from falling back from what we have
done? And how can we continue to move ahead with a fairly
aggressive level of expansion of NIH basic research at 2.5
percent, or 2.6 percent, I guess it is?
Dr. Zerhouni. Thank you.
Senator Harkin. I mean, my point is, you asked for 2.6
percent.
SUSTAINING RESEARCH PROGRAMS ON MODEST BUDGET INCREASES
Dr. Zerhouni. Thank you for your question. This is a very
important consideration. Because one of the issues that we have
to match with the concept of doubling is why are we doubling?
And what are we trying to accomplish? And I think one of the
issues that I raised was that we have evolving challenges. We
have in fact stimulated in our country an incredible change in
the way we do biomedical research. And we are in the transition
phase in terms of understanding the new methods of research and
the new teams that need to do this research.
When you look at the 2004 budget, I worked very hard with
the administration, with the Department, and with the Office of
Management and Budget, when you look at the 2.6 percent
overall, and we worked so that the effect on our research would
be about 7.5 percent overall. And the reason for that is
because we have essentially used one-time expenditures that
related to building the infrastructures that we needed for
biodefense research and other one-time items and reinvested it
in research.
So for 2004, the impact on the research portfolio in terms
of growth is greater than the 2.6 percent, Senator.
Senator Harkin. Well, I want to delve into that. In fiscal
year 2003, Congress funded more than $300 million for
extramural construction with allergies and infectious diseases,
bioterrorism.
Dr. Zerhouni. $375 million.
Senator Harkin. $375 million?
Dr. Zerhouni. Yes.
Senator Harkin. I think you can argue that was probably a
one-time expense.
Dr. Zerhouni. Correct.
Senator Harkin. But if I look at the extramural facilities
renovation and construction program, going back just the last
few years, this is an ongoing funding stream that this
committee has funded, under different chairmanships here. We
have all been supporting extramural construction and
renovation. We know that some of the labs around the United
States are deficient. They need to be upgraded. I am sure
Senator Specter has visited, as I have. And so we embarked on
this, also, a few years of making a funding stream every year
available.
So how can you say that this is a one-time expense? I could
see saying that the $300-and-some million that we put in last
year was a one-time expense for bioterrorism. But we have an
ongoing extramural renovation and construction program that
last year was $119 million, aside from that $300-and-some
million. It was $110 million the year before. Now it was $75
million a year for a few years before that. But then we bumped
it up, because we saw the need out there. And now in fiscal
year 2004, we are requesting zero dollars.
To me, that is not a one-time expense. It is an ongoing
commitment that we have to rebuild and modernize our laboratory
infrastructure in the United States.
FUNDING COMMITMENT TO EXTRAMURAL CONSTRUCTION
Dr. Zerhouni. For the 2004 year, what we tried to do was to
preserve and maintain the momentum in what is the most critical
resource, and that is people applying for grants and getting
support so that the teams of the scientists that we have
stimulated continue to be stimulated. So we had to make hard
choices, Senator. And that is one of them.
Senator Harkin. But if we make the choice here to continue
to fund extramural construction, then you will not have that
money for research, will you? It will be down to 2.6 percent.
Dr. Zerhouni. That is----
Senator Harkin. If we keep the level of funding----
Dr. Zerhouni. In each category the same per year, you are
correct. You are correct, Senator.
Senator Harkin. Dr. Zerhouni, are you advising us that we
should zero out all funding for renovation and building of
laboratory facilities?
Dr. Zerhouni. For the year 2004, because of the portfolio
of construction that we had to do and that we had to continue
to fund, we thought that the best strategy to maintain the
research momentum so that we can invest it in programs that
relate to diseases was to make that choice and----
Senator Harkin. For next year.
Dr. Zerhouni. For next year. Correct.
Senator Harkin. Well, then, Dr. Zerhouni, let me carry this
one step further. The President's budget documents call for a
1.9 percent increase in 2005, a 2 percent increase in 2006, and
2.2 percent in 2007. So carrying this logic forward, then for
the next 3 years, we will be asked to zero out any funding for
extramural construction and renovation, if that is the case. So
it may be so next year. We may be looking at 4 or 5 years
here----
Dr. Zerhouni. Right.
Senator Harkin [continuing]. Of zeroing out any--I do not--
I can only speak for myself, but to me that is unacceptable. We
cannot do that. And so I just--you know, this idea that somehow
we are going to squeeze out of this and get a 7 percent for
basic research and to make sure we keep the grant funding going
out at that level, it does not square with what we have to do
with extramural construction.
So I--maybe you might do it 1 year. I do not think you can.
I think we just cannot go to zero funding for 1 year. We can
cut out the $300-and-some million, because that was a one-time
expenditure for bioterrorism. But then there is the underlying
program that I do not think that we can cut out. So I just
wanted to make that point. I know what you are trying to do,
but I do not think it fits. And we are simply going to have to
come up with that extra money. And I am going to keep proposing
that the President has to put that in his budget next year.
Thank you, Dr. Zerhouni.
Thank you, Mr. Chairman.
Senator Specter. Thank you, Senator Harkin.
Dr. Zerhouni, I am going to go over a series of questions.
We have been asked to have separate hearings on many of the
institutes. And that is not possible, given all of the
difficult schedules. We have been asked to have a separate
hearing on tuberous sclerosis, where scientists have reportedly
isolated the genes responsible for this disease that affects
all of the body's organs.
I would like you to submit in writing and in some detail
how much NIH is currently investing in research on tuberous
sclerosis, and how that research is being coordinated among the
various institutes involved.
[The information follows:]
Tuberous Sclerosis Complex
The NIH reported actual funding for tuberous sclerosis research in
fiscal year 2002 was $6.1 million; the fiscal year 2003 estimated
funding is $6.4 million. While the National Institute of Neurological
Disorders and Stroke--NINDS--is the lead institute for research on
tuberous sclerosis complex, TSC, several other institutes conduct and
support TSC research, which is reflective of the multiple organs
affected. The National Cancer Institute--NCI; the National Heart, Lung,
and Blood Institute--NHLBI; and the National Institute of Diabetes and
Digestive and Kidney Diseases--NIDDK, support TSC research. Funding by
Institute is summarized in the table that follows:
----------------------------------------------------------------------------------------------------------------
Fiscal years
-----------------------------------------------------
2002 actual 2003 estimate 2004 estimate
----------------------------------------------------------------------------------------------------------------
NCI....................................................... $638,000 $657,000 $677,000
NHLBI..................................................... 2,140,000 2,279,000 2,336,000
NIDDK..................................................... 717,000 700,000 700,000
NINDS..................................................... 2,596,000 2,803,000 2,859,000
OD........................................................ 30,000 ................ ................
-----------------------------------------------------
Total............................................... 6,121,000 6,439,000 6,572,000
----------------------------------------------------------------------------------------------------------------
The systems affected in TSC are quite distinct, and therefore, much
of the research supported may be unique to a particular institute's
mission, for example, NINDS to investigate the development of epilepy
and autism in children with tuberous sclerosis; NCI for studies to
examine what causes skin tumors to develop in patients with TSC; and
NHLBI to study the molecular and cellular basis for the development of
lymphangioleiomyomatosisL--AM--a severe destructive lung disease, in
patients with tuberous sclerosis complex. However, we recognize the
value in tracking and coordinating the TSC research that NIH supports,
as well as identifying potential partnering opportunities, and on this
NINDS has the lead. Coordination is achieved in many ways, not the
least of which is regular communication among the program directors who
manage the TSC portfolio in each institute. In addition, NINDS is
coordinating input from several institutes, extramural researchers, and
the advocacy community in developing the NIH research plan for tuberous
sclerosis. For example, program staff from NIDDK and the National
Institute of Arthritis and Musculoskeletal and Skin Diseases--NIAMS--
participated in the September 2002 NINDS-sponsored workshop on TSC
research, the proceedings of which are providing the framework for the
research plan, and these institutes, along with the National Institute
of Child Health and Human Development--NICHD, NHLBI, and NCI, are being
consulted in the development of the NIH TSC research plan.
Senator Specter. There is another subject matter of
scleroderma, where there has been a tremendous amount of
interest. And there is significant vascular and autoimmune
components to scleroderma. And the question is whether there
are other institutes, aside from the National Institute of
Arthritis, Musculoskeletal, and Skin Disorders or the National
Heart, Lung, and Blood Institute, that you would recommend
scleroderma researchers pursue to find experiments aimed at
finding a cure.
Since the leading cause of death in scleroderma patients is
through pulmonary hypertension and its effects on heart
function, should grants on pulmonary hypertension that
encompass issues unique to scleroderma patients be directed
at--and this question goes to Dr. Katz and Dr. Lenfant. Should
those research grants be directed at NHLBI, instead of NIAMS?
These questions are so complicated that I have to read
them, which is not my style.
What do you think, Dr. Lenfant? Are you willing to defer
that to another agency, or should they be directed to your
agency? I would appreciate as much brevity as you can bring
here, because there are quite a few more questions. And we need
to finish this hearing by 11. Actually, we need to finish this
hearing by 10:45.
SCLERODERMA RESEARCH
Dr. Lenfant. Senator, in view of the complexity of this
condition, I think the research must be conducted by the two
institutes. And it is so happens that Dr. Katz and I work very
well on many conditions besides this one. And I am quite
confident that this cooperation, should it continue, it will be
the best way to handle that condition.
Senator Specter. How are you doing, Dr. Lenfant, on finding
a cure for scleroderma?
Dr. Lenfant. Scleroderma, or systemic sclerosis, is of
considerable interest to the NHLBI because of the lung problems
that so often accompany it. Indeed, 8 out of 10 patients with
scleroderma eventually develop some degree of lung disease, and
interstitial pulmonary fibrosis (scarring) is now the leading
cause of death among such patients. Since 1999, the NHLBI has
supported the Scleroderma Lung Study, a clinical trial to
evaluate treatment with cyclosphosphamide, a drug that has
effects on inflammation and the immune system. The goal is to
determine whether cyclophosphamide helps stabilize or improve
measures of lung function; the trial will also assess changes
in quality of life, activity, and shortness of breath. A
positive outcome of this trial would be of great importance by
offering a scientific basis for treatment. Similarly, a
negative result, demonstrating no benefit from cyclophosphamide
therapy, would provide an important basis for avoiding a
hazardous and expensive therapy that is now being used in many
patients.
SCLERODERMA
Senator Specter. Dr. Katz, how close do you think you are
coming to finding a cure for scleroderma?
Dr. Katz. We are pursuing every scientific opportunity
possible in scleroderma research and working with the community
as well as with our colleagues at NHLBI in this area, which
includes pulmonary fibrosis. We are pursuing research on blood
vessel abnormalities genetic controlled fibrosis, as well as
other genetic dimensions of scleroderma. So we are pursuing----
Senator Specter. Is it a realistic question to ask you how
close you are to a cure?
Dr. Katz. Yes, sir. It is a realistic question.
Senator Specter. Can you give me a realistic answer?
Dr. Katz. I cannot give you a date, if that is what you are
looking for. But I----
Senator Specter. Can you give me a time frame, a ballpark?
Dr. Katz. I would hope that in the next 5 years we will
have some better information on the complexity of this disease.
Senator Specter. Sometime within the next 5 years we would
have better information on the complexity of the disease.
Dr. Katz. Right.
Senator Specter. I would like you to supplement that in
writing, focusing on my question, please.
Dr. Katz. I would be happy to.
[The information follows:]
Scleroderma
I am very pleased to tell you that research on scleroderma is at a
very important and promising juncture. We have a solid foundation of
grants in our portfolio, we have very powerful research tools to apply
to scleroderma, and we are building on significant research advances in
our understanding of scleroderma. Examples of recent advances include
identifying a genetic marker for scleroderma in two populations; basic
research that identified defective microfibrils in cultured fibroblasts
from people with scleroderma; and the determination that the risk of
having scleroderma increases significantly (on the order of 10 to 27
times) if a family member has scleroderma. These are just highlights of
progress. With a look to the future, I am very optimistic that within
the next 5 years we will have much better information on the complexity
of scleroderma. My optimism is based on the multi-pronged approach that
we have taken in research on scleroderma, including the ongoing, 5-
year, multicenter clinical trial that is seeking to determine the
efficacy of oral collagen in the treatment of scleroderma; the funding
that the NIAMS provides for two Specialized Centers of Research focused
on scleroderma that will enhance translational research; support for
the National Family Registry for Scleroderma that will provide vitally
important information on the genetic/family dimensions of this
disorder; and the outcomes of the 10 new research grants that the NIAMS
funded in fiscal year 2001 as the result of a special solicitation. We
can expect that research findings will begin to emerge from these
grants over the next few years and will contribute significantly to our
understanding of the complexity of scleroderma. In addition, I would
note that scleroderma is an autoimmune disease, and the knowledge base
in this area is progressing at a rapid pace. Findings that we learn
from one autoimmune disease can be very useful in informing us about
other autoimmune diseases. So if we look broadly, advances in genetics
and autoimmunity will accelerate the pace of progress in scleroderma
and many other diseases. We know that medical research is an
investment, and I believe that the investments we have made over the
last few years will provide critical, key pieces of the multi-
dimensional, challenging puzzle that scleroderma represents.
Senator Specter. Dr. Zerhouni, we are having a lot of
comments on the Muscular Dystrophy Care Act, which called for
the creation of multiple centers of excellence, signed into law
in 2001. That was before your watch. The subcommittee on three
occasions has said that a minimum of three such centers should
be funded. A request for proposals has finally gone out to
organize the centers. But the only assurance of the scientific
community is that two centers will be funded.
I would like you to submit in writing an answer to the
question, why only two? And what funding level is projected for
these centers?
[The information follows:]
Muscular Dystrophy
The NIH has been actively engaged in implementing the mandates of
the MD-CARE Act, including efforts to establish research centers for
muscular dystrophy. Specificially, in the Fall of 2002, the NIH issued
two Requests for Applications (RFAs) in this area. The first solicited
applications for up to three awards for Muscular Dystrophy Cooperative
Research Centers, and the second solicited applications for up to five
awards for Developmental Planning Grants for future centers. During
fiscal year 2003, following peer review, we will make grant awards in
response to these two RFAs; the number of grants actually awarded, up
to the specified numbers, will depend on scientific merit. In fiscal
year 2004, we plan to re-issue the RFA for Cooperative Research
Centers, and expect to fund up to two additional meritorious centers in
fiscal year 2005. Subject to the number of applications we receive and
the results of scientific peer review, the combined solicitations could
result in funding up to a total of five MD cooperative centers.
We anticipate that the total costs for each center will be
approximately $1.5 million for 5 years. If the combined solicitations
result in funding a total of five MD cooperative centers, the total
costs of all centers for 5 years is estimated at $37.5 million.
Senator Specter. A question to the Cancer Institute to be
responded to by Dr. von Eschenbach. On June 21, 2001, we held a
hearing on blood cancers. And Dr. Klausner, then the Director
of the Cancer Institute, testified that Gleevec has shown
remarkable results in treating chronic leukemia. The question
is: Why is Gleevec only effective on this particular form of
cancer? And in what specific ways would Federal funding of stem
cell research expedite the treatment and cures of blood cancer?
GLEEVEC
Dr. von Eschenbach, would stem cells be helpful there, stem
cell research?
Dr. von Eschenbach. Thank you, Senator. As you are well
aware, there has been a great deal of research with regard to
adult stem cells, and particularly in their application
therapeutically in support of the treatment of blood cancers.
The issue of Gleevec, that is a very important story. Because
one of the wonderful things that we have seen as a result of
the progress made in using a drug like Gleevec, targeted to a
specific genetic defect in leukemias, the understanding of how
that drug works in that pathway is now being extended to a
whole variety of other cancers. Gleevec is being used in
prostate cancer and it is being used in other childhood
cancers. So the return on investment of Gleevec is going far
beyond the blood cancers.
Senator Specter. Dr. Insel, the prevalence of autism is
increasing, with the disease affecting, as we understand it,
some 500,000 people in this country at a cost of $13 billion
annually. Autism advocates are requesting the NIH expand its
research portfolio as well to finance a tissue bank program
that would enhance resources and provide centralized tracking
of research projects among all autism research participants.
What are your plans to develop a tissue bank? And how much
has autism research increased since the NIH doubling began?
AUTISM RESEARCH
Dr. Insel. Thank you, Senator. The interest in the autism
tissue bank has increased greatly in the last few months. We
held a workshop just in the last 6 weeks, bringing----
Senator Specter. Greatly? Greatly?
Dr. Insel. Yes.
Senator Specter. How much?
Dr. Insel. In terms of the interest? There is a wide----
Senator Specter. Increase in funding is the question.
Dr. Insel. I was saying interest in the tissue bank. The
workshop that we held 6 weeks ago brought in people from around
the country who are experts in autism. There is a plan to roll
out the specifics at the next Interagency Autism Coordinating
Committee meeting.
Senator Specter. Is a tissue bank now being developed?
Dr. Insel. We anticipate it will be public by July, the
first week in July.
Senator Specter. And how much has autism research
increased?
Dr. Insel. In 1998, the NIH budget for autism was
$26,889,000. In 2002, it was $73,850,000.
Senator Specter. Dr. Fauci, let us come back to smallpox
one more time. The Federal Government is not recommending
vaccination for the public. But HHS has stated that it will try
to accommodate members of the public who want to be vaccinated.
As the program is projected this year, the public has two
options. First, enrolling in ongoing clinical trials; or
second, for those who want to be vaccinated but who do not meet
the trial criteria, HHS has proposed that it will allow
vaccinations under an investigational new drug approach, which
will require informed consent.
Now this is because the new vaccine has not yet been
licensed. Once the new vaccine is licensed in 2004, concluding
that it will be at that time, the only way the public will be
able to get it is from HHS.
My question to you is, vaccination for the general public
is at the impetus of the individual. Do you think this is
sufficient, or should there be a national vaccination strategy
for the general public as opposed to waiting for the individual
to come forward?
NATIONAL VACCINATION PROGRAM
Dr. Fauci. Mr. Chairman, given the current threat
assessment, I think a national vaccine program for the general
public, beyond just someone coming and asking for it, is not
necessary at this time. The first priority, as you know, is to
vaccinate the core smallpox response team and ultimately the
first responders.
But given the current threat assessment, if we get that
core group vaccinated, which we hopefully will, then in the
event of an attack, the logistic capability of vaccinating
anyone who is within the range of a contact would be much
easier than it is right now. So the combination of the
Department of Homeland Security and HHS have come to the
judgment that we do not need to implement a pre-event program
for the general public at this time.
Senator Specter. Dr. Fauci, I hope you are right.
Dr. Fauci. I hope so.
Senator Specter. We have gone back and forth. We have had
quite a number of hearings on the subject. We have talked about
our grandchildren. There is no precise, cannot be a precise,
evaluation of what the risk is of a smallpox attack, try to use
that as a biological warfare weapon. People who have taken the
vaccine with some bad results. People do not like the risk.
Pretty tough to undertake a risk from the vaccination when
there is no identifiable risk of bioterrorism in the field.
Dr. Fauci. Right.
Senator Specter. But at the moment, the policy is sort of--
perhaps it is not drifting along, but it is pretty hard to
formulate it with precision. But I respect your conclusion that
the policy has been thought through. And you have decided to do
no more. But we all hope you are right that we do not find a
bioterrorism attack and insufficient cautions having been
taken.
Dr. Fauci. Excuse me, sir. In the event of an attack, there
is a response capability that we are building on right now that
would very likely, almost certainly, be able to protect the
country. The reason that the program has not been recommended
for the public is because the threat assessment of an attack is
balanced against the known toxicities of the currently
available Dry Vax, and it is felt that a preemptive total
vaccination of the Nation is not necessary.
This will change if one of two things happen. If the threat
assessment changes and we feel the threat is greater. And what
we are striving for in the next couple of years is a smallpox
vaccine that has many fewer toxicities or adverse events. If we
had the attenuated vaccine at the current time, I believe there
would be a good deal more flexibility in the broad general
recommendations for the general public.
Senator Specter. Well, thank you very much, ladies and
gentlemen. This is the longest hearing we have had in awhile.
We are into the third hour. And it is hard to attract the
attention of Senators for very long around here, given the
problem of the war in Iraq and what we are going to do with
North Korea and how we are going to handle the Middle East and
what we are going to do with terrorism and what we are going to
do with double taxation of dividends, probably the foremost
question on the minds of everybody in this room today. I mean,
not the foremost question on the minds of everybody in this
room today.
We appreciate what you are doing. There are going to be
questions submitted for the record. And when Senator Taylor
calls you up and brings issues to your attention, she is
speaking for the whole Congress. She does not speak for just
herself.
She does not speak just for me. She does not speak for
Senator Harkin and me or this subcommittee or the full
Appropriations Committee or the Senate. She speaks for the
whole Congress.
We have become a lightning rod for inquiries and demands.
You have no idea how many irate parents we see, or irate
children we see for interest in their parents. So if we convey
a sense that we are looking for a greater sense of urgency, if
you get that message today, you are right. But we do know that
you are in the trenches doing very, very important work. And we
have a tougher issue now than we have ever had before on
finding the money for NIH and the CDC. But we are going to plug
away. And we look for your continued success.
ADDITIONAL COMMITTEE QUESTIONS
There will be some additional questions which will be
submitted for your response in the record.
[The following questions were not asked at the hearing, but
were submitted to the Department for response subsequent to the
hearing:]
Questions Submitted to the National Institutes of Health
Questions Submitted by Senator Arlen Specter
PANCREATIC CANCER
Question. Director von Eschenbach, this Subcommittee has taken a
keen interest in the status of pancreatic cancer research at your
Institute. Pancreatic cancer is the now the 4th leading cause of cancer
death for men and women in this country. It also has the highest
mortality rate making it the cancer you are most likely to die from, if
you are diagnosed with this disease, because of the lack of reliable
diagnostics.
I would like for you to update the Subcommittee on the status of a
number of pancreatic cancer initiatives:
Last year's report expressed the strong intent of this Committee
that the NCI fund at least five Pancreatic Cancer Specialized Program
of Research Excellence (SPORE) grants by fiscal year 2004. Will you be
following the Committee's intent--as expressed in last years report
language--to fund five Pancreatic Cancer SPORE Grants by fiscal year
2004?
Answer. In fiscal year 2004 NCI expects to fund three pancreatic
cancer SPORE grants. The NCI announced a special initiative to enhance
and promote translational research in pancreatic cancer and received
fourteen pancreatic SPOREs applications. Thirteen of these applications
were reviewed by a Special Emphasis Panel following general peer-review
principles established by the NIH. Only three of these SPORE
applications were found to have sufficient scientific merit to be
considered for funding by the NCI. No definitive decisions can be
presented at this time since our funding recommendations will undergo a
second level of review by the National Cancer Advisory Board at the
next meeting in June 2003. We anticipate these three meritorious
applications will be funded as P20 Development awards. We are hopeful
these preliminary programs will jump start the field and serve as a
foundation to develop additional strong researchers and programs in
this field.
Question. How many of the meritorious individual projects from non-
funded SPORE Grants and program project applications does the NCI
intend to fund in fiscal year 2004?
Answer. Four projects from the remaining applications were
considered by the peer review as highly scientifically meritorious.
These applications will be recommended for submission to our R01 grant
mechanism for individual funding.
Question. I compliment the NCI's past efforts to increase the
paucity of researchers through extending the payline for grants that
were 100 percent relevant to pancreatic cancer. I understand that this
initiative may have been the single most important action taken by the
NCI to finally give pancreatic cancer the support that it needs, yet it
was discontinued after just one year. Why was this important payline
initiative discontinued?
Answer. Extending the payline for applications that were 100
percent relevant to pancreatic cancer enabled the NCI to fund only
three additional pancreatic cancer research projects in fiscal year
2002. The NCI discontinued the extended payline for pancreatic cancer
applications in fiscal year 2003 and agreed to use a mechanism for
exception funding to include grants that meet only 50 percent
relevancy. The NCI remains firmly committed to increasing the amount of
research focused on pancreatic cancer. Therefore, the NCI is granting
pancreatic cancer applications higher priority for exception funding,
even those with only 50 percent relevance to the disease. We are
hopeful that this mechanism will significantly increase the number of
meritorious grants that will impact on pancreatic cancer.
Question. Do you have plans to reinstate this extended payline, and
what are the estimated costs to continue it for a period of five years?
Answer. Since extending the payline for pancreatic cancer
applications reduced the number of better scoring applications that the
NCI could fund, the NCI does not intend to reinstate the extended
payline. This decision is not made on basis of cost but rather a
strategic effort to encourage meritorious research relevant to
pancreatic cancer.
Question. If not, how do you intend to develop the critical mass of
researchers needed for pancreatic cancer?
Answer. In its recently released strategic plan for addressing the
recommendations of the Pancreatic Cancer Progress Review Group (http://
prg.cancer.gov/pancreatic/pancreatic.pdf), the NCI lays out a multi-
faceted approach for developing a critical mass of pancreatic cancer
researchers. The Institute has implemented some of the strategies in
the plan already. These include:
--Granting special consideration to pancreatic cancer applications
beyond the payline, even those with only 50 percent relevance
to the disease.
--Soliciting and promoting applications for SPOREs in pancreatic
cancer. The top-scoring applications will undergo a required
second level of review by the National Cancer Advisory Board in
June.
--Informing investigators of new funding opportunities in areas of
particular relevance to pancreatic cancer, such as host-tumor
interactions, the tumor microenvironment, and nanotechnology
development for early detection.
NCI plans to put additional strategies in place in fiscal year 2003
and fiscal year 2004, but actual implementation will depend upon a
final determination that these strategies are feasible and sound, and
the receipt of high-quality applications from the research community.
These strategies include:
--Expanding the Transition Career Development Award (K22) to extend
the funding period and include all scientists.
--Increasing the number of pancreatic cancer research mentors through
the National Research Service Award program.
Question. It is my understanding that the NCI is continuing to make
good on its commitment to implement the report of the Pancreatic Cancer
Progress Review Group (PRG)--which is a national agenda for the
research needed on pancreatic cancer. I have been told that since the
PRG Report came out in February 2001, the NCI has been moving forward
to implement the suggestions raised in the report, and that most
recently the NCI has developed a ``Strategic Plan for Addressing the
Recommendations of the Pancreatic Cancer Progress Review Group'' to
further detail and prioritize the research needed on this disease. With
the President's proposed NIH increase of roughly 2.6 percent for fiscal
year 2004, how many of the strategies identified in the ``NCI Strategic
Plan'' can actually be put into place next year, and which ones do you
plan to implement?
Answer. The NCI has already implemented some of the strategies in
its pancreatic cancer plan. These strategies include:
--Granting special consideration to pancreatic cancer applications
beyond the payline, even those with only 50 percent relevance
to the disease.
--Soliciting and promoting applications for Specialized Programs of
Research Excellence (SPOREs) in pancreatic cancer.
--Funding the development of new pancreatic cancer mouse models.
--Funding phase 1 and phase 2 studies for chemoprevention of
pancreatic cancer.
--Holding a state-of-the-science meeting on management of pancreatic
cancer symptoms.
NCI plans to put additional strategies in place this year and next,
but actual implementation will depend upon a final determination that
these strategies are feasible and sound, and the receipt of high-
quality applications from the research community. These strategies
include:
--Funding the development of nanotechnologies that use small samples
for early detection of pancreatic cancer.
--Identifying markers for early detection of pancreatic cancer
through NCI's Center for Proteomics.
--Funding research on normal pancreas biology and pathogenesis of
pancreatic cancer (with NIDDK).
--Expanding NCI's cohort consortium to include pancreatic cancer.
--Supporting large case-control studies in HMOs to improve
understanding of pancreatic cancer risk factors.
Question. I know the request was made before you came to the NCI,
but in the fiscal year 2002 report, this Committee specifically
requested that the NCI develop a professional judgment budget due April
1, 2002 for research on pancreatic cancer for the next five years. The
goal here was to ascertain how much the NCI is actually spending on
pancreatic cancer and compare the current funding level to what is
actually needed to make some inroads on this disease, which has a 99
percent mortality rate, making it the cancer you are most likely to die
from, if you are diagnosed with this disease. While I am delighted to
hear that movement is being made on the findings of the Pancreatic
Cancer Progress Review Group, we have not received the Five-Year
Professional Judgment Budget to implement these recommendations. When
might we receive it?
Answer. Over the past several years, NCI has convened Progress
Review Groups (PRGs) on several types of cancer, and the reports
generated by these groups have formed the basis of expanded and
intensified research in these areas. Completed PRG reports have
identified gaps in research in breast, prostate, colo-rectal, brain,
pancreatic, hematologic, lung, and gynecologic cancers. As with all
other PRGs, NCI developed an implementation plan to move forward with
the recommendations for pancreatic cancer research in a prioritized
fashion. This was done with participation by outside scientists and
advocates who also participated in the PRG itself.
NCI announced a 10-point plan of action that allows NCI to take
immediate steps to address the gaps in pancreatic cancer research. Some
strategies have already been implemented such as granting special
consideration to pancreatic cancer applications beyond the payline and
funding Specialized Programs of Research Excellence (SPOREs) in
pancreatic research. The plan's approach involves expanding existing
programs, as well as developing new initiatives. Additional strategies
are being considered, including funding the development of mechanisms
for early detection and expanding proteomics research.
We estimate that we will spend $38 million on pancreatic cancer
research in fiscal year 2004. The preparation of a Professional
Judgement Budget will take into account the implementation of these
programs and their expected expenditures and increases over the next
five years. Subsequent initiatives will be included in a rolling
forward budget plan as reflected in our Bypass Budget.
PROTEMOMIC PATTERNS
Question. In last years report, this Committee encouraged the NCI
to ``rapidly identify predictive proteomic patterns relevant to
pancreatic cancer'' and ``to develop and implement methods for rapid
case ascertainment.'' Can you please provide us with the status of
progress in both of these areas including what has been developed and
implemented?
Answer. The body's 30,000 or so genes carry the blueprint for
making proteins, of which all living matter is made. Each protein has a
particular shape and function that determine its role in the body. NCI
has an extensive research program in proteomics, the study of protein
shape, function, and patterns of expression, in hopes of developing
better prevention, screening, and treatment options.
There has been a joint effort including the Food and Drug
Administration (FDA), the NCI Clinical Proteomics Program, and
Correlogic Systems Inc. which has brought together two scientific
disciplines: proteomics and artificial intelligence computer programs.
Last year, there was an exciting announcement that with a
preliminary diagnostic test, which could be completed in 30 minutes
using blood that can be obtained from a finger stick, researchers were
able to differentiate between serum samples taken from patients with
ovarian cancer and those from unaffected individuals. Further study is
continuing to confirm the sensitivity and accuracy of this technique as
a diagnostic tool. The hope is that by combining the proteomic approach
with other methods of ovarian cancer diagnosis, such as ultrasound, its
accuracy can be further improved. This new diagnostic concept is
potentially applicable to any type of disease and is now being tested
on pancreatic, prostate, lung and breast cancer.
NCI has made significant progress in the early detection of
pancreas cancer using serum proteomic patterns. We are pleased to have
already made progress in the application of this technology to
pancreatic cancer. Scientists tested 350 plasma samples from the
University of Minnesota. The sample groups were (a) unaffected, (b)
diabetes only, (c) pancreatitis only and (d) pancreatic cancer. NCI
researchers discovered a serum proteomic pattern that was greater than
95 percent sensitive and specific in the classification of pancreas
cancer compared to the other non cancer groups. Currently there is no
other reliable test for pancreas cancer. We are now moving forward to
validation of these preliminary results in a larger population of
patients with and without pancreatic cancer. At the same time we are
applying this technology to other cancers. If validated in larger
series serum, proteomics could constitute a new approach to the early
diagnosis of pancreatic cancer.
COMPREHENSIVE CANCER CENTER PROGRAM
Cancer is a disease that affects families of all backgrounds in all
parts of the country. However, cancer affects more families in my state
than most others. We hold the unfortunate distinction of ranking among
the top five in the nation in rates of multiple myeloma and oral,
prostate, pancreatic, and esophageal cancer. We are also not far behind
in regard to cervical and larynx cancer.
Through the significant investment this Subcommittee has made in
cancer research, we have enabled scientists from across the country to
expand our basic understanding of cell growth and death and to develop
effective forms of treatment and prevention. Much of this work was
accomplished in NCI-designated comprehensive cancer centers. I am
troubled that these centers tend to cluster in the Northeast and along
the Pacific Coast, and bear little correlation to cancer incidence or
mortality rates. In fact, only three of the fifteen states with the
highest cancer mortality rates have a comprehensive cancer center.
While we should continue to fund the best and brightest in their
efforts to find cures for cancer, I believe the current concentration
of comprehensive cancer centers deprives us of gaining valuable
knowledge in the parts of the country where cancer is most prevalent.
Question. Director Zerhouni and Director von Eschenbach, I would
like to hear your plans for how you intend to grow the comprehensive
cancer center program and how you intend to ensure that areas with high
cancer rates receive the full attention of these centers.
Answer. At the present time, NCI has 60 clinical and comprehensive
cancer centers. They have a wide geographic distribution and leverage
the extraordinary talents and resources of major medical centers. These
spheres of influence go far beyond their geographic location as a
Center of Excellence of cancer treatment.
Over the years, the NCI has worked closely with a number of smaller
institutions in underrepresented areas through the P20 planning grant
program. At the present time, six centers are recipients of planning
grants. Four of these are in states that currently have no cancer
center and a fifth serves a primarily minority population. We are
developing mechanisms to promote consortium centers in areas where one
institution does not have the capability to apply independently, with
concordant revision of NCI requirements to accommodate their unique
structure. In at least one state, such a consortium has received
legislative support and funding.
The NCI's Special Populations Network program is establishing a
robust and sustainable infrastructure to promote cancer awareness
within minority and medically underserved communities, and launching
more research and cancer control activities aimed at specific
population subgroups. The current Special Populations Networks consists
of 18 projects in 15 states across the United States. Initial projects
were begun after funding was awarded in April 2000 to groups that
addressed ways of building relationships between large institutions and
community groups. During the first year, cancer awareness projects were
implemented in the community and project plans were developed. In the
second and third years, partnerships between the project and NCI
sponsored groups should enhance minority training and minority
participation in cancer trials. In the last two years of these awards,
full-fledged investigator-initiated research grant applications will be
developed based on the initiative projects.
The NCI is also considering other options to improve access of
patients in underserved areas to the benefits of cancer research. One
such concept is that of a Regional Enhancement and Cancer Community
Health (REACH) initiative, which would pair smaller institutions in
these areas as formal partners with existing NCI designated centers for
collaborative research activities and delivery of cutting edge care. As
currently envisioned, this would involve providing small grants to the
smaller centers for encouragement of research, as well as some form of
NCI designation. An additional alternative might be to provide moderate
support for the existing affiliate networks already established by the
centers. These networks are primarily focused on clinical care but
additional support could be provided to specifically foster the more
extensive delivery of clinical trials into the community setting.
Finally, through the emphasis of the NCI on the ``Discovery,
Development, Delivery'' continuum, we anticipate that links between
existing Cancer Centers, their affiliates and partners in research, and
the state, municipal and private organizations within their communities
will continue to expand. These links, once firmly established, should
result in a more unified approach to the conquest of cancer, and a more
uniform delivery of the benefits of cancer research into the community.
NCI is actively seeking mechanisms to foster both the vertical
integration (i.e. from the cancer centers through the community layers
they serve) and the horizontal integration (i.e. across cancer centers
and a nationwide network of public and private partners) of the
benefits of cancer research.
SJOGREN'S SYNDROME
Question. Some progress has been made regarding Sjogren's syndrome
at the NIAID. However, the NIAMS conducts research on closely related
diseases such as lupus, scleroderma and rheumatoid arthritis. Are you
conducting research on Sjogren's syndrome and are you coordinating this
research with other Institutes at the NIH?
Answer. In collaboration with the NIAID and the NIDCR, the NIAMS
supports research on Sjogren's syndrome and other autoimmune diseases
that ranges from basic science investigations to genetic studies to
prevention research. The NIH Autoimmune Diseases Coordinating
Committee, of which the NIAMS is an active member, helps ensure the
coordination of effort among various Federal and private entities that
conduct autoimmunity research, education, and outreach. The NIAMS funds
work to better understand the molecular basis of autoimmune diseases
such as Sjogren's syndrome; to identify genes that predispose
individuals to autommunity; and to develop animal models which will
provide insights into the human form of diseases such as Sjogren's.
STEM CELL RESEARCH
Concerns have been raised by some in the scientific community that
not all NIH institutes are aggressively pursuing a stem cell research
agenda.
Question. Would you please submit for the record how each of your
institutes and centers has been implementing the embryonic stem cell
research policy?
Answer. In November 2001, NIH issued NOT-OD-02-005 Notice of
Criteria for Federal Funding of Research on Existing Human Embryonic
Stem Cells (hESCs) and Establishment of NIH Human Embryonic Stem Cell
Registry. This notice describes how federal funds can be used to
support research in human embryonic stem cells that meet the criteria
established by the President. This Notice also references the NIH Stem
Cell Registry--a registry that only lists those human embryonic stem
cell lines that meet the eligibility criteria. All NIH institutes
comply with points described in the Notice and for those that support
human embryonic stem cell research, only support human embryonic stem
cell research that uses cell lines listed on the NIH Stem Cell
Registry. In addition, NIH has a Stem Cell Implementation Committee
with representatives from the NIH Institutes that assists with
implementation. This Committee works in tandem with the NIH Stem Cell
Task Force to ensure that policy and major research initiatives are
communicated to all Institutes and provide a means for inter-Institute
cooperation and exchange.
Complimenting these NIH-wide implementation efforts are many
Institute-specific Program Announcements (PAs), Requests for
Applications (RFAs), scientific workshops, and outreach efforts to
encourage and support research on human embryonic stem cells. The NIH-
wide and Institute-specific initiatives are described for each
Institute with portfolios relevant to human embryonic stem cells:
The National Institute on Aging (NIA) is encouraging and supporting
research on human embryonic stem cells through a number of Program
Announcements, Requests for Applications, Requests for Proposals, and
workshops. NIA is co-sponsoring with other NIH Institutes PA 02-054
Short-Term Courses in Human Embryonic Stem Cell Culture Techniques, PAR
02-023 Human Embryonic Stem Cell Research Resource Infrastructure
Enhancement Award, and PA-02-025 Plasticity of Human Stem Cells in the
Nervous System. In addition, PAR 03-056 NIA Pilot Research Grant
Program specifically encourages stem cell research pilot projects and
NIA has issued a Request For Proposal (RFP) 260-03-16 on
Characterization of Human Embryonic Stem Cell Lines to establish a
contract to develop, maintain, and distribute data on the properties of
undifferentiated human embryonic stem cell lines. The NIA intramural
program is supporting one of the six intramural labs conducting
research on human embryonic stem cells. Within NIA, a Stem Cell Working
Group meets regularly to disseminate policy information on receipt,
tracking, review and administration of grants involving human embryonic
stem cell lines, as well as to plan and implement activities involving
support of human embryonic stem cell research. In May 2003, NIA is
hosting a meeting on Stem Cells and Aging to promote exchange and
enhance research among NIA stem cell research grantees.
The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is
encouraging research on human embryonic stem cells and has issued an
RFA 02-010 on Alcohol and Stem Cells that encompasses research
objectives that include human embryonic stem cell research.
The National Institute of Allergy and Infectious Diseases (NIAID)
is working to ensure that the scientific community has every
opportunity to advance research into the potential of human embryonic
stem cells in accordance with federal policy. NIAID is co-supporting
with other NIH institutes PA 02-054 Short-Term Courses in Human
Embryonic Stem Cell Culture Techniques and PAR 02-069 Career
Enhancement Award for Stem Cell Research. In addition, new research
grant mechanisms are available to support human embryonic stem cell
research: PA 02-038 NIAID-Investigator-Initiated Small Research Grants
(R03) and PAS-02-160 Application of Exploratory/Developmental
Technologies to NIAID-Funded Research (R21). NIAID also accepts and
supports requests for administrative supplements to add human embryonic
stem cell research to an existing NIAID grant.
The National Institute on Arthritis and Musculoskeletal and Skin
Diseases (NIAMS) is encouraging research on human embryonic stem cells
through several Program Announcements and Requests for Applications
with research objectives that could encompass the use of human
embryonic stem cells. These initiatives include: PA 03-009 High Risk
Rheumatic And Musculoskeletal And Skin Diseases Research; RFA 02-003
Basic And Applied Stem Cell Research For Arthritis And Musculoskeletal
Diseases; PA 02-136 Precursor Cells in Skeletal Muscle Repair and
Hypertrophy; and PAR 02-030 NIAMS Small Grant Program for New
Investigators. In addition, administrative supplements to an existing
NIAMS grant may be requested for the addition of studies of human
embryonic stem cells.
The National Institute of Biomedical Imaging and Bioengineering
(NIBIB) is fully aware of the policies and procedures governing the
funding and use of human embryonic stem cell research and takes the
necessary steps to keep grantees informed. Scientific workshops are
held and talks are presented to a wide variety of audiences in academia
and private industry, concerning tissue engineering, biomaterials,
sensors and other areas of research that may include human embryonic
stem cells. Recent outreach efforts included presentations at a PGH
Engineering Tissue Growth meeting and at a meeting for BEACON, a
bioengineering consortium in New England. At every appropriate outreach
opportunity, human embryonic stem cells research policy is delineated
to current and potential researchers. Training workshops for current
and potential grantees address this issue as well. The NIBIB currently
has two Requests for Applications, RFA 03-09 Development of Advanced
Biomaterials and RFA 03-010 Research Opportunities in Tissue
Engineering that request grant applications related to tissue
engineering, which may include human embryonic stem cell research.
The National Cancer Institute (NCI) actively encourages research on
human embryonic stem cells and widely disseminates NIH policies and
procedures to grantees. In addition, NCI is co-sponsoring with other
NIH institutes supporting the Program Announcement, PAR 02-054 Short-
Term Courses in Human Embryonic Stem Cell Culture Techniques, which
provides funding to develop, conduct, evaluate, and disseminate short-
term courses on laboratory research techniques for human embryonic stem
cell lines.
The National Institute of Child Health and Human Development
(NICHD) actively encourages and supports research on human embryonic
stem cells. The Institute has implemented the embryonic stem cell
research policy through the issuance of special NICHD initiatives in
the form of Requests For Applications, Program Announcements and
Notices that include embryonic stem cells as potential targets for
research. These include: RFA 02-018 Female Health and Egg Quality; RFA
02-029 Specialized Cooperative Centers Program in Reproductive
Research; PA 01-005 Reproductive Genetics; NOT 03-005 NICHD
Administrative Supplements for Human Embryonic Stem Cell Research.
NICHD is also co-sponsoring with other NIH Institutes two program
announcements: PAR 02-054 Short-Term Courses in Human Embryonic Stem
Cell Culture Techniques, and PAR 02-023 Human Embryonic Stem Cell
Research Resource Infrastructure Enhancement Awards to help build the
infrastructure and capacity to disseminate human embryonic stem cells
eligible for federal research support. In addition, NICHD funded the
first formal training course on human embryonic stem cells that was
held at the Jackson Laboratory, Bar Harbor, Maine in August 2002. NICHD
has also conducted numerous outreach presentations at scientific
meeting on opportunities for NICHD research support for human embryonic
stem cell research.
The National Institute on Drug Abuse (NIDA) sponsored a two-day
meeting ``Stem Cells--Opportunities for Drug Abuse Research'' where
developmental and general neuroscientists were brought together to
pursue the link between drug abuse research to stem cell research and
to provide input to NIDA about research directions in this area of
endeavor.
The National Institute on Deafness and Other Communication
Disorders (NIDCD) is encouraging investigator-initiated projects on
high risk/high impact research and administrative supplements to
facilitate scientists that would like to pursue preliminary work in
stem cell research. NIDCD is sponsoring RFA 02-003 on Cellular Repair
Studies of the Auditory and Vestibular Systems. In addition to these
research initiatives, the NIDCD Director currently serves as the Chair
of the NIH Stem Cell Task Force, a group of high-ranking scientists
from a number of NIH Institutes with expertise in the research area of
human embryonic stem cells. NIDCD also provides staff support to the
activities of the Task Force. The purpose of the Task Force is to
identify obstacles to moving the stem cell research agenda forward and
to develop strategies to overcoming these challenges.
The National Institute of Dental and Craniofacial Research (NIDCR)
encourages and supports research on human embryonic stem cells in
studies on oral, dental, and craniofacial development and the
development stem cell-based treatments for the repair and regeneration
of orofacial structures that have been compromised by congenital
disorders, diseases, and injuries. In addition, the Institute co-
supports PAR 02-054 Short-Term Courses in Human Embryonic Stem Cell
Culture Techniques.
The National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK) has disseminated NIH policies and procedures to
grantees through development of a web-based Investigator's Guide to
Human Embryonic Stem Cell Research. In addition to encouraging and
supporting investigator-initiated research, NIDDK has a number of RFAs
and PAs with research objectives that could encompass the use of human
embryonic stem cells. This list includes: PA 01-129 Innovative and
Exploratory Research in Digestive Diseases and Nutrition; PA 02-127
Pilot and Feasibility Program Related to the Kidney; PA 01-128 Pilot
and Feasibility Program in Hematological Diseases; PA 01-093 NIDDK
Expanded Awards for SBIR at NIDDK; and, PA 02-008 Pilot and Feasibility
Programs in Diabetes Endocrinology and Metabolism. Also, NIDDK is co-
supporting with other NIH institutes research training and
infrastructure initiatives targeting the needs of human embryonic stem
cell research. These initiatives include: PAR 02-023 Human Embryonic
Stem Cell Research Resource Infrastructure Enhancement Awards; PA 02-
054 Short-Term Courses in Human Embryonic Stem Cell Culture Techniques;
and, PAR 02-069 Career Enhancement Award for Stem Cell Research.
The National Institute of Environmental Health Sciences (NIEHS)
actively encourages research on human embryonic stem cells and has
established a stem cell research emphasis area to encourage research on
organ toxicology with potential for regenerative intervention/
prevention technologies. Also, the Institute has initiated working
discussions with biotechnology companies to promote their development
of programs in human liver stem cell research to address the major
public health organ transplantation issues leading to liver failure. In
addition, the Institute held a scientific meeting in November 2002
entitled ``Stem Cells: Scientific Progress and Future Research
Directions'' that discussed the potential of human stem cell research
both globally and with respect to the environmental health sciences
mission of NIEHS. This spring, NIEHS is co-sponsoring the ``Frontiers
in Human Embryonic Stem Cells Research Training Course and a sequel
symposium entitled ``Embryonic Cell Biomedicine: The Journey from Mice
to Patients'' both of which will be held at the University of
Pittsburgh.
The National Institute of General Medical Sciences (NIGMS)
encourages and supports research on human embryonic stem cells. In
fiscal year 2002, NIGMS supported a ``Workshop on the Basic Biology of
Mammilian Stem Cells'' that included key scientists in the field of
human embryonic stem cells. Based on this workshop, NIGMS developed the
RFA 03-003 Exploratory Center Grants for Human Embryonic Stem Cell
Research. In addition, NIGMS issued a Notice 03-002 for Administrative
Supplements for Human Embryonic Stem Cell Research and is co-supporting
with other NIH institutes the Program Announcement PAR 02-054 Short-
Term Courses in Human Embryonic Stem Cell Culture Techniques.
The National Heart, Lung, and Blood Institute (NHLBI) actively
encourages and supports research on human embryonic stem cells through
a number of Program Announcements, Requests for Proposals, and
workshops. NHLBI has invited research applications encompassing human
embryonic stem cell research through the following: PA 02-017
Innovative Concepts and Approaches to Developing Functional Tissues and
Organs for Heart, Vascular, Lung, and Blood Applications; PA 02-018
Basic Research on Mesenchymal Cell Biology; PA 02-019 Research on Stem
Cell Biology and Cell-based Therapies for Heart, Lung, Blood, and Sleep
Disorders; and PAR 03-063 NHLBI Competitive Supplements for Human
Embryonic Stem Cell Research. Also, the Institute announced NOT 02-009
NHLBI Administrative Supplements for Human Embryonic Stem Cell Research
that resulted in the support of several administrative supplements to
current grantees to include research on human embryonic stem cells. In
addition, NHLBI is co-sponsoring several initiatives with other NIH
institutes including: PA 02-025 Plasticity of Human Stem Cells in the
Environment of the Nervous System; PAR 02-069 Career Enhancement Award
for Stem Cell Research; PAR 02-023 Human Embryonic Stem Cell Research
Resource Infrastructure Enhancement Award; and, PA 02-054 Short Term
Courses in Human Embryonic Stem Cell Culture Techniques for which NHLBI
serves as the coordinator and designated administrative contact for all
resulting grants. NHLBI also is sponsoring BAA 03-06 and RFP 03-07 for
Somatic Cell Therapy Processing Facilities and Administrative Center
that could involve human embryonic stem cells and assist in preparing
the cells for clinical research. In addition, the Institute also
sponsored an ``NHLBI Working Group: Cell-Based Therapies for
Regenerative and Reparative Medicine--Vision, Scope, and Directions''
in May 2002 that addressed the area of embryonic stem cells, including
their future therapeutic potential.
The National Institute of Mental Health (NIMH) disseminates NIH
policies and procedures to grantees through development of a web page
on NIMH Support for Stem Cell Research. In addition to encouraging
investigator-initiated research on human embryonic stem cells, NIMH is
co-sponsoring two Program Announcements with other NIH Institutes: PAR
02-023 Human Embryonic Stem Cell Research Resource Infrastructure
Enhancement Award and PA-02-025 Plasticity of Human Stem Cells in the
Nervous System. In addition, NIMH sponsored a satellite symposium at
the Society for Neuroscience Meeting (November 2002) on ``Neuroscience
Opportunities in Human Embryonic Stem Cell Research: An International
Perspective'' and is co-sponsoring an up-coming scientific workshop on
``American-Swedish Network for Stem Cell Biology and Neural Repair''
currently scheduled for September 2003.
The National Institute of Neurological Disorders and Stroke (NINDS)
actively encourages and supports research on human embryonic stem
cells. The Institute has developed an NINDS Stem Cell website to update
investigators about NIH policy, funding opportunities, upcoming
meetings, and other relevant information. In addition, NINDS is
sponsoring PAR 02-139 NINDS Cooperative Program in Translational
Research and co-supporting with other NIH Institutes PA 02-025
Plasticity of Human Stem Cells in the Environment of the Nervous System
and PA 02-054 Short-Term Courses in Human Embryonic Stem Cell
Techniques. The Institute has issued several Notices requesting
applications for administrative supplements: NOT 02-007, NOT 02-010,
NOT 03-002 NINDS Administrative Supplements for Research on Human Stem
Cells. These Notices have resulted in support of several administrative
supplements that allow current grantees to include and pursue research
on human embryonic stems. Also, NINDS co-funded four conferences
focused on stem cell research: 8th International Conference on Neural
Transplantation and Repair; International Society for Stem Cell
Research Meeting; Conference on Stem Cells: Origins, Fate and
Functions; and, Gordon Research Conference on Neural Development.
The National Center for Research Resources (NCRR) actively
encourages and supports research on human embryonic stem cells. NCRR
co-supports PAR 02-023 Human Embryonic Stem Cell Research Resource
Infrastructure Enhancement Award and serves as coordinator and
designated contact for all the human embryonic stem cell infrastructure
grants. In addition, the Institute is supporting a Infrastructure
Awardees Meeting in June 2003 that will involve all current
infrastructure awardees in an exchange about obstacles and progress to
date in developing the respective eligible cells lines for distribution
to the scientific community.
The Fogarty International Center (FIC) has been active in
conducting outreach with foreign sources of eligible human embryonic
stem cell lines. FIC has coordinated the interests of the NIH with the
U.S. Department of State and respective U.S. Embassies to establish
dialogues with eligible stem cell providers in India, Israel, Sweden,
Australia, and South Korea. These efforts have significantly
contributed to the five NIH infrastructure awards made to-date to
eligible foreign sources.
Question. Please share with us the steps NIH has taken to create a
positive environment for human embryonic stem cells and the researchers
seeking cures using this promising research tool?
Answer. Over the past 20 months, the NIH has undertaken a number of
new initiatives to enable the field of human embryonic stem cell
research to move forward:
Train new investigators to culture and work with human embryonic
stem cell lines. Currently, there is a limited pool of scientists with
the hands-on experience needed to reliably perform experiments using
approved human embryonic stem cells. To address this need, the NIH
issued a Program Announcement soliciting applications for ``Short Term
Courses in Human Embryonic Stem Cell Culture Techniques.'' Five
applications were received in October 2002, subsequently reviewed and
plans are underway to make awards to all five applications. In
addition, to assist mid-career investigators in their efforts to
initiate research studies, the NIH issued the Program Announcement.
``Career Enhancement Award in Stem Cell Research.'' These grants will
provide salary support as well as some support for other research
costs, to allow scientists to join an established research group
working with approved human embryonic stem cells for six to twenty-four
months.
Provide support to scale up and characterize human embryonic stem
cells eligible for Federal funding and increasing accessibility to
these lines. In early Winter 2001, many of the 71 independent human
embryonic stem cell derivations listed on the NIH Human Embryonic Stem
Cell Registry were in the early phases of development and had not been
expanded or characterized to the point where they could be readily
distributed to the research community. Expanding and characterizing
cells derived from human embryos are time- and resource-consuming
processes. To help make these cells available to the research
community, the NIH issued a Program Announcement, ``Human Embryonic
Stem Cell Research Resource Infrastructure Enhancement Awards'' to
provide support to allowable sources of human embryonic stem cells to
scale up and distribute cell lines to investigators seeking such lines.
The first Infrastructure grant was awarded in April 2002. To date,
eight such awards have been issued. As a consequence of this support
the number of cell lines available for widespread distribution has
grown from a single cell line in Spring 2002 to eleven cell lines at
present, with more anticipated in the near future.
Provide assistance to the research community wishing to use human
embryonic stem cell lines in navigating the intellectual property
rights (IPR) and licensing agreements or material transfer agreements
that needed to be obtained with the owners of the cell lines. The human
embryonic stem cells available for Federal funding are owned by private
sources, not by the Federal Government. A U.S. patent exists for human
embryonic stem cell lines and the techniques used to develop such
lines. NIH negotiated a memorandum of understanding with the patent
holder (WiCell Research Institute) in September 2001, as well as with
several other sources for the use of their cells. While the NIH can
only develop such agreements for the NIH intramural research program,
the terms of these agreements require the provider to offer the cells
under no more stringent terms to other investigators using federal
funds to conduct non-commercial research.
Encourage established investigators to initiate research projects
involving human embryonic stem cells. In an effort to help established
investigators begin experiments using human embryonic stem cells, the
NIH announced the availability of Administrative Supplements to
existing NIH grants. These supplements are supporting collection of
preliminary data that will lead to investigator-initiated research
grant applications whose major focus is research using human embryonic
stem cells. To date, 42 supplements have been awarded. In addition to
these supplements, the NIH is currently supporting 13 investigator-
initiated grant awards and additional applications will be considered
for funding during the remainder of 2003, and in years ahead. Six NIH
Intramural laboratories are currently engaged in research using human
embryonic stem cell lines.
Establish an NIH Human Embryonic Stem Cell Characterization Unit.
The research community has expressed a need for information on the
characteristics of the available cell lines, to allow scientists to
select which lines are most suitable for their intended experiments. To
address this important need, the NIH intramural program is creating a
Stem Cell Characterization Unit. The mission of this unit is to provide
reliable and standardized data derived from assays performed on human
embryonic stem cell lines available to be shipped to the research
community. Performing these assays in a single laboratory will allow a
direct side-by-side comparison to be made among the cell lines that are
available for shipment, and will facilitate comparison with adult stem
cells. These data will arm the scientific community with peer reviewed
information about the properties of available lines, so scientists can
make an informed choice when ordering one or more of the available cell
lines. Data will be posted on a stem cell web site as soon as they have
been validated. The assays performed by this Unit will be overseen by a
Steering Committee comprised of leading stem cell biologists in both
the extramural and NIH Intramural Research community. In a
complementary effort, the Mammalian Gene Collection at NIH has
established contracts to construct cDNA libraries from several human
embryonic stem cell lines, and to perform expressed sequence tag (EST)
sample sequencing from these libraries. These libraries will be made
available to the research community, and all sequences will be
deposited into readily accessible public databases.
Provide support for multidisciplinary teams of investigators to
define the properties and potential of human embryonic stem cells. The
research community also articulated the need for multidisciplinary,
multi-investigator teams of researchers to explore the growth and
maintenance, biochemical and molecular properties, and other unique
properties of human embryonic stem cells. In response to a June 2002
workshop sponsored by the National Institute of General Medical
Sciences, a Request for Applications to support exploratory center
grants has been issued. These awards are intended to lead to Research
Centers within three years of funding the exploratory center award.
Establish NIH Stem Cell Task Force. In August 2002, the NIH Stem
Cell Task Force was established to oversee and coordinate the trans-NIH
activities involving human embryonic stem cells, as well as other types
of stem cells. Comprised of leading NIH scientists with expertise in
stem cell research, the Task Force will continue to monitor the state
of this rapidly evolving science, identifying barriers to research
progress and addressing the needs of the research community.
Update NIH Stem Cell Web Site. The NIH continues to serve as a
resource for stem cell information by hosting a web site. Scientists
have access to information on stem cell funding opportunities sponsored
by NIH. The web site also includes the NIH Human Embryonic Stem Cell
Registry, which lists the eligible cell lines that are available for
shipping to researchers.
Host NIH Stem Cell Symposium. The NIH plans to showcase its
scientific progress in human embryonic stem cell research by sponsoring
a scientific conference at NIH on June 12, 2003. The symposium will
feature a morning plenary session with presentations from NIH-supported
researchers and an afternoon session will feature workshops and poster
sessions.
Question. How many RFAs related to human embryonic stem cell
research has your institute sponsored and cosponsored?
Answer. Currently NIH has issued nine Requests for Applications
(RFAs) related to human embryonic stem cell research. One RFA invites
applications for multiple P20 Exploratory Grants that will support
multi investigator teams to conduct research using human embryonic stem
cells. Sponsored by the National Institute of General Medical Sciences
(NIGMS), this RFA encourages and enables basic biologists with little
or no prior hESC experience to work with hESC and establish the utility
of hESC as a model system by supporting the development of an
institutional infrastructure for research using hESC; encouraging
research on the growth and maintenance requirements of hESC;
identifying biochemical and molecular markers of hESC; stimulating
research that will lead to a better understanding of the unique
properties of hESC; and supporting pilot projects that exploit the
advantages of hESC as a model system to further the study of
fundamental research problems.
Additional RFAs related to hESC research include:
--Innovative Concepts and Approaches to Developing Functional Tissues
and Organs for Heart, Vascular, Lung and Blood Applications.
These exploratory and developmental grants are sponsored by the
National Heart, Lung and Blood Institute (NHLBI).
--Basic and Applied Stem Cell Research for Arthritis and
Musculoskeletal Diseases, sponsored by the National Institute
of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).
--Stem Cells in Development/Repair of Orofacial Structures, sponsored
by the National Institute of Dental and Craniofacial Research
(NIDCR).
--Basic Research on Mesenchymal Cell Biology, sponsored by the
National Institute on Aging (NIA) and National Heart, Lung, and
Blood Institute (NHLBI).
--Comprehensive Programs in Beta Cell Biology sponsored by the
National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK).
--Cellular Repair Studies of the Auditory and Vestibular System,
National Institute on Deafness and Other Communication
Disorders (NIDCD).
--Research on Stem Cell Biology and Cell-Based Therapies for Heart,
Lung, Blood, and Sleep Disorders (NHLBI)
--Stem Cell Research for Alcohol related Disorders, National
Institute on Alcohol Abuse and Alcoholism (NIAAA)
Question. How many Program Announcements related to human embryonic
stem cell research has your institute sponsored or cosponsored?
Answer. The Following Program Announcements related to hESC have
been issued by NIH:
--Short Term Courses in Human Embryonic Stem Cell Culture Techniques
are supported by 11 NIH Institutes. Five awards will be made in
Spring 2003.
The 11 Institutes supporting the short-term courses are:
--National Heart, Lung, and Blood Institute (NHLBI)
--National Cancer Institute (NCI)
--National Center for Research Resources (NCRR)
--National Institute of Allergy and Infectious Diseases (NIAID)
--National Institute of Child Health and Human Development (NICHD)
--National Institute of Dental and Craniofacial Research (NIDCR)
--National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK)
--National Institute of General Medical Sciences (NIGMS)
--National Institute of Mental Health (NIMH)
--National Institute of Neurological Disorders and Stroke (NINDS)
--National Institute on Aging (NIA)
--Career Development Awards which are sponsored by NIDDK, NIAAA,
NINR, NIAID and NHLBI. The announcement was made in March 1,
2002 and expires in June 1, 2005. The purpose of these awards
is to provide mid-career investigators with training to use
hESC in their research.
--Plasticity of Human Stem Cells in the Nervous System sponsored by
NINDS, NIA, NIMH and NHLBI. The purpose of this Program
Announcement is to study the fundamental properties of all
classes of human stem cells, and to confirm, extend, and
compare the behavior of human stem cells that are derived from
different sources and ages or exposed to different regimes in
vitro and in vivo.
Question. How much funding has been provided for human embryonic
stem cell research in each of fiscal years 2001 and 2002?
Answer. In fiscal year 2001, no funding was provided for human
embryonic stem cell research and $10.7 million was provided for fiscal
year 2002.
Question. Approximately how much funding is your institute planning
to provide for human embryonic stem cell research in fiscal year 2003?
Answer. NIH estimates $17.1 million will be provided for human
embryonic stem cell research in fiscal year 2003.
Question. Please explain your plans to expand funding within your
institutes for human embryonic stem cell research over the next three
years?
Answer. Investigator-initiated research is the foundation of grants
supported by NIH. To date, NIH is supporting only 13 investigator-
initiated research grants using human embryonic stem cells but NIH
anticipates a substantial number of applications over the next three
years as this field of research matures and more scientists receive
stem cell biology training through various training courses, such as
the NIH-supported short-term training courses mentioned above or
through training offered directly by eligible providers of human
embryonic stem cells. Upon completion of the training, it is expected
that scientists will address the basic research questions that need to
be answered for the field to move forward before being used for human
therapies: What are the molecular pathways that govern stem cell
differentiation to a specific cell type? How can stem cell growth be
regulated? How can stem cells be safely transplanted and how is cell
rejection prevented? How long will the stem cell transplant continue to
function? Can animal models be developed to test the efficacy of stem
cells?
Question. Please identify any administrative or program hurdles
that are impeding your institute from maximizing the potential of human
embryonic stem cell research in helping your institute achieve its
mission?
Answer. Currently, the rate limiting step of hESC research is the
lack of well-trained investigators. NIH has taken steps to remedy the
situation by funding five short term training courses for up to three
years starting in fiscal year 2003. In addition, career enhancement
awards to train scientists in the lab culturing techniques and growth
methods for hESC are currently being offered for mid-career scientists
who are interested in learning to work with hESCs. In addition, NIH is
supporting short-term training courses to teach scientists cell
culturing techniques. Currently, WiCell, UCSF and ES Cell International
are providing additional stem cell training, independent of the NIH-
supported short term training courses. NIH has awarded infrastructure
grants to providers of hESCs which allows them to grow and culture the
federally approved cell lines, making more cells available to the
research community. This will enable scientists to gain easier access
to the eligible stem cell lines. In June, the NIH is sponsoring a
symposium to showcase NIH supported hESC research. The symposium is
attracting worldwide interest. NIH believes that these activities will
assist in attracting new investigators to the field and alleviate the
current shortage of trained investigators.
Question. Several scientists have suggested to the Subcommittee
that NIH should create new funding mechanism to support human embryonic
stem cell research, given that this is such a new area of science. Are
you considering creating a mechanism that requires less preliminary
data?
Answer. In an effort to help established investigators begin
experiments using human embryonic stem cells, the NIH is issuing
Administrative Supplements to existing NIH grants. These supplements
are supporting collection of preliminary data that will lead to
investigator-initiated research grant applications whose major focus is
research using human embryonic stem cells. In addition, NIH is
providing other funding mechanisms that are used to support high risk/
high impact research as a means for generating preliminary data. Also,
the NIH Center for Scientific Review has implemented processes to
facilitate the peer review of human embryonic stem cell grant
applications. One example is informing scientific review administrators
about this new field of research and the preliminary data, which is
often part of an application or may be lacking in some grant
applications and should not be considered a penalty.
Question. If so, when can we expect this to be announced? If not,
how do you plan to spur this field?
Answer. NIH is currently implementing these initiatives. In
addition, NIH is undertaking other initiatives to spur this new
research field by enabling eligible stem cell providers to scale up
cells for shipping, providing easier access of stem cells to
researchers, becoming a source of information to the scientific
community on stem cell characteristics, and providing a forum for
scientists to share their data through a stem cell research symposium.
CLINICAL RESEARCH
Question. Most of this type of research takes place at academic
health centers, many of which are struggling financially. I also note
that you want to re-establish the Biomedical Research Support Grant
program to help support academic health centers. Are you requesting
funds for that purpose in this budget?
Answer. No funds are requested in fiscal year 2004 to re-establish
the Biomedical Research Support Grant (BRSG) program.
Question. For the record, would you provide the Subcommittee with a
description of how that program would work, and how much money it would
take to adequately support the program.
Answer. No funds are requested in fiscal year 2004 to re-establish
the Biomedical Research Support Grant (BRSG) program.
Question. How much does NIH devote to translating basic research
into improved health care for the patient?
Answer. An integral component of NIH's mission is to communicate
research results both to the lay public and health professionals. NIH
works in partnership with many different organizations to communicate
scientific results and health information to the medical research
community, health care providers, patients, and the general public
across the nation. NIH communicates basic research findings through
publication in professional journals and by distributing news releases
to the science and general media. NIH scientists speak to reporters to
explain the significance of the research and put it into the broader
context of making progress against disease. Some examples of the
translation of research findings from bench-to-bedside that are
provided below:
--In 2001, the National Institute of Neurological Disorders and
Stroke (NINDS) launched a multi-faceted public education
campaign to educate people about how to recognize stroke
symptoms and to call 911 to get to a hospital quickly for
treatment. Know Stroke: Know the Signs, Act in Time includes:
public service advertising for radio, television and print; as
well as consumer education materials that include an award-
winning 8-minute film, brochures, and posters. Because stroke
attacks the brain, a stroke patient often cannot act alone to
call 911 and seek medical treatment. Bystanders are integral to
acting quickly and getting stroke patients to the hospital.
To date, the campaign materials have derived excellent results.
The television PSA garnered more than 87 million viewer
impressions and hundreds of thousands of dollars worth of free
broadcast time; the radio PSAs received more than 46,000
broadcasts on 272 stations; the airport dioramas were placed in
117 airports, in cities such as Atlanta, Dallas, Denver and
Baltimore and received more than 800 million annual
impressions; billboard advertising focused in the Southeastern
United States, known as the Stroke Belt, averaged more than
800,000 daily impressions for the months they were placed; bus
side advertising placed in 10 markets resulted in more than
115,000,000 over the course of three months; a matte service
article has generated more than 2 million impressions and about
15,000 requests for Know Stroke brochures, and the consumer
education materials developed for the campaign have been
requested by thousands of nursing homes, hospitals, senior
centers and other organizations. Many of these activities have
been done in partnership with the American Stroke Association,
a division of the American Heart Association, and the National
Stroke Association, the two largest voluntary organizations
serving stroke patients and their families.
--The National Diabetes Education Program (NDEP), established in
1995, is a federally-sponsored initiative that involves public
and private partners to improve the treatment and outcomes for
people with diabetes, to promote early diagnosis, and to
prevent the onset of type 2 diabetes. The National Institute of
Diabetes and Digestive and Kidney Diseases (NIDDK) of the
National Institutes of Health (NIH) and the Division of
Diabetes Translation of the Centers for Disease Control and
Prevention (CDC) jointly sponsor the program with the
participation of over 200 partner organizations. The Program's
target audiences include people with diabetes and their
families, with special attention to Hispanics/Latinos, African
Americans, Asian Americans, Pacific Islanders, and American
Indians, people at risk for type 2 diabetes, especially those
with pre-diabetes, health care providers, health care payers,
purchasers, and policy makers. The program's main initiatives
include the ``Control the ABCs of Diabetes'' campaign to
promote the link between cardiovascular disease and diabetes
and the importance of controlling blood glucose, blood pressure
and cholesterol, and the ``Small Steps, Big Rewards. Prevent
type 2 Diabetes'' campaign, designed to promote the message
that diabetes can be prevented to the 16 million Americans with
pre-diabetes, a condition that puts them at high risk for
developing type 2 diabetes.
--Co-sponsored by NIH and organizations such as the Maternal and
Child Health Bureau, the American Academy of Pediatrics, the
SIDS Alliance, and the Association of SIDS and Infant Mortality
Programs, the ``Back to Sleep'' National Public Health
Education Campaign has resulted in a 50 percent relative
decrease in the rate of Sudden Infant Death Syndrome since its
launch in 1994. This campaign is directed at mothers and family
members of young infants, the professionals responsible for
their care, and the public in general.
--The National Eye Health Education Program (NEHEP) has established
public and professional education programs to help promote
public awareness on how to prevent vision loss. The NEHEP
comprises more than 50 public and private organizations, which
plan and implement eye health education programs. The NEHEP has
created educational kits on glaucoma and diabetic eye disease
for health professionals and community leaders. The kits
provide information and materials to educate people at high
risk about eye health and the need for regular dilated eye
exams. The NEHEP also has launched four national public service
campaigns. Materials and messages of the campaigns have been
tailored to high-risk populations.
--The National Heart, Lung, and Blood Institute supports several
long-standing national programs that rely the cooperative
efforts of its partners to educate the lay public and health
professionals about preventing and treating some of the major
chronic diseases of our time. The National High Blood Pressure
Education Program (NHBPEP) is a cooperative effort among
professional and voluntary health agencies, state health
departments, and many community groups interested in
hypertension prevention and control. At the core of the program
is the NHBPEP Coordinating Committee, composed of
representatives from 38 national professional, public, and
voluntary health organizations and 7 federal agencies. The
program aims to reduce death and disability related to high
blood pressure through programs of professional, patient, and
public education. The National Cholesterol Education Program
(NCEP) was established to raise awareness and understanding
about high blood cholesterol as a risk factor for coronary
heart disease (CHD) and the benefits of lowering cholesterol
levels as a means of preventing CHD. The NCEP Coordinating
Committee, with its membership of more than 40 partner
organizations representing major medical and health
professional associations, voluntary health organizations,
community programs, and governmental agencies, helps bring
cholesterol information to a wide audience. The National Asthma
Education and Prevention Program (NAEPP) was initiated to
address the growing problem of asthma in the United States,
particularly among children, African Americans, and the
elderly. Through its Coordinating Committee, composed of
representative from 43 partner organizations from professional
medical and health associations, public and voluntary health
organizations, and federal agencies, the NAEPP works to raise
awareness that asthma is a serious chronic disease, ensure
recognition of symptoms, and ensure appropriate diagnosis and
effective control of asthma.
CLINICAL RESEARCH
Question. I have a copy of your ``road map'' for streamlining the
process of taking research from the laboratory to the bedside. Is this
still in the planning stages or have you implemented it?
Answer. A national effort, led by NIH, to re-engineer the clinical
research enterprise is being planned at this time. In the course of
developing this key agency priority, the Director, NIH convened a two-
day meeting to develop a plan to identify the critical roadblocks and
knowledge gaps that constrain rapid advances, and to conceptualize and
develop far reaching solutions to build the sophisticated clinical
research enterprise of the future.
In January 2003, meeting participants developed a plan to re-
engineer the clinical research system over next 10 years. They
recommended creation of: (1) National Clinical Research Networks, which
would accrue data on clinical outcomes and quality of care at the point
of service; provide an infrastructure for rapid initiation of large
clinical trials; and inform patients and consumers; (2) a Translational
Research Infrastructure which would facilitate the transfer of clinical
research findings to the front lines of clinical care-and back; and (3)
a Clinical Research Workforce which is diverse, well trained, and
capable of collaborating optimally in cross-disciplinary teams.
Since that time, NIH workgroups on translational research, clinical
networks and clinical training have been reviewing, consolidating,
harmonizing, prioritizing, and determining the fiscal implications of
the myriad recommendations to NIH to emerge from the Clinical Research
Roadmap Meeting. Workgroups are actively taking into account key
national priorities, scientific opportunities, feasability, timing, and
resources. Draft suggestions for implementing the key recommendations
for streamlining and updating the clinical research enterprise are
being considered by agency leadership. The NIH Director, in
collaboration with Institute and Center Directors, will make the final
determination of which of the many key directions will be most likely
to yield the most substantial benefits to the health of the American
people over the course of the next century. Once agreement is reached
amongst the NIH Institutes and Centers, operational plans and a
timeline will be devised for implementing the new clinical research
infrastructure. We look forward to keeping you up to date as these
priorities develop.
Question. One of the items in this road map calls for establishing
``a natural home within NIH for clinical trials of medical
importance.'' Last year, the Subcommittee encouraged you to establish
an Office of Clinical Research to provide a central focus. So we seem
to be on the same wave length. Where does that stand?
Answer. NIH views clinical research, which focuses on the causes
and consequences of disease in human populations, as the key link in
the pathway from basic research to improvements in health. This area of
research includes the development of new technologies, mechanisms of
human disease, therapeutic interventions, clinical trials,
epidemiologic and behavioral studies, and outcomes and health services
research. We concur with your strong interest in ensuring the
advancement of clinical research. In recent years, the NIH appreciably
expanded its clinical research program; for example, by establishing
both intramural and extramural clinical research fellowship programs
targeted to medical and dental students at the NIH; expanding the
resources available for the diverse needs of the clinical research
community, including attention to inpatient, outpatient, and critical
care clinical research; and investing heavily in Patient-Oriented
Research Career Development Awards, Mid-Career Investigator Awards in
Patient-Oriented Research, Graduate Training in Clinical Investigation
Awards, and Clinical Research Curriculum Awards. In addition, the NIH
Loan Repayment Program has been expanded to include health
professionals engaged in clinical research funded by non-profit
support.
In an unprecedented effort to be responsive to the many and varied
research priorities advanced by different stakeholders--practicing
physicians, the pharmaceutic and biotechnology industries, researchers,
health plans, and patient groups, the NIH Director has convened a
series of Roadmap meetings with extramural and intramural scientists
and the Institute and Center Directors to explore the scientific
challenges in clinical research and the roadblocks to progress. As a
result of the recommendations to emerge from these meetings, the NIH is
moving forward to re-engineer the clinical research enterprise, and to
develop innovative solutions to ensure the promise of a viable 21st
century clinical research enterprise.
The development of any new organizational entity at this juncture
in the agency's deliberations would stimulate premature closure
pertaining to this complex issue affecting all NIH Institutes and
Centers. As we continue to develop the NIH clinical research roadmap
plan, we look forward to keeping the committee apprised of our progress
in implementing these goals as this groundbreaking process continues to
unfold.
INCREASED STIPEND LEVELS
In March 2001, NIH announced a commitment to increase stipend
levels for Kirschstein research training awards:
The NIH supports higher stipends for NRSA recipients and therefore
announces tentative targets of $25,000 for graduate and $45,000 for
entry-level postdoctoral stipends. Future budget requests will
incorporate 10 to 12 percent stipend increases until these targets are
reached. After attainment of these targets, the real value of stipends
will be maintained with annual cost-of-living adjustments.
Question. The Administration's fiscal year 2004 budget departs from
this commitment. Can you comment on the rationale for this change in
policy?
Answer. The change came about through recommendations included in a
2000 National Academy of Sciences report. In fiscal year 2003 the
Senate Appropriations Committee and the Conference Committee reports
asked NIH to comment on that report. The NIH remains committed to the
stipend targets described in our responses on that report. The request
for funds to cover a 4 percent increase in fiscal year 2004 will permit
the NIH to continue to increase stipends.
APPOINTMENT OF STUDY SECTION MEMBERS
Question. What role should the Administration have in the
appointment of NIH study section members?
Answer. NIH operates study section and appoints study section
members primarily based on the scientific expertise needed for review
of applications assigned to the specific scientific review committees.
Technical evaluation and advice regarding the scientific merit of the
proposed research requires that the advising panel has the appropriate
collective scientific expertise. The Federal Advisory Committee Act,
which regulates establishment and operation of NIH study sections, also
requires that committees be ``balanced'' and not ``inappropriately
influenced by the appointing authority.'' Trained NIH scientists who
develop these committees have the skills and experience to ensure this
balance and the presence of the appropriate scientific expertise so as
to achieve fair and rigorous reviews. In addition, NIH attempts to
ensure diversity (of race and ethnicity, gender, geographic
distribution, small and large institutional affiliation, public and
private institutional affiliation, academic and small business, etc.)
on study sections.
FULLY FUNDED GRANTS
Question. In the Administration's fiscal year 2004 budget request
for NIH, 322 new grants are ``fully-funded,'' that is, rather than
receiving funding over the 3 or 4-year lifespan of the grants, all
funding for these grants would be disbursed in fiscal year 2004. Is my
understanding is that this is a pilot or test that is being pushed by
the Office of Management and Budget correct?
Answer. Certain grant programs, such as the Academic Research
Enhancement Awards (AREA), and the James A. Shannon awards, have always
been fully funded. In fiscal year 2004, NIH will increase the number of
fully funded grants. NIH will undertake a study to determine the type
of grants that can reasonably be fully funded from both the point of
financial stewardship and scientific accountability. Other categories
of grants may also be proposed for full funding.
Question. If this is to be a test, by what criteria will the
success of full funding be judged?
Answer. Factors include ensuring grantee accountability for the use
of Federal funds and the availability of funds for new researchers with
new ideas.
Question. Currently, as grants are funded over a four-year cycle,
there is annual oversight of the research being performed as non-
competing continuations are awarded. Will there be less oversight if
the grants are fully-funded at one time?
Answer. The overall institutional compliance responsibilities are
the same for grants that are fully funded. As noted above, NIH
currently has two long-standing award programs that are ``fully
funded.'' For example, the Academic Research Enhancement Awards (AREA)
program provides for a three -year-award to AREA-eligible institutions.
AREA recipients are required to submit an annual progress report to
NIH.
Question. As a researcher and research administrator, what is your
view of fully-funded grants?
Answer. As a researcher, there are advantages with fully-funded
grants in that one can plan a research project with full knowledge and
control of the entire amount of the grant award. Thus, one can better
plan and manage the budget for personnel, equipment and resources as
these are needed to meet the milestones of the project. As a research
administrator, full funding could provide additional flexibility in
managing future year commitments made to NIH researchers.
Question. Are there upsides or downsides that OMB, the Department
or the Congress might not be aware of?
Answer. When determining the type of grants that can reasonably be
fully-funded, NIH will consider financial stewardship and scientific
accountability, NIH's goal of supporting stable numbers of new grants,
impact on research priorities supported through other mechanisms of
support, and the impact on new researchers entering the research arena.
TRAINING STIPENDS
Question. In March of 2001, NIH adopted a policy of increasing
training stipends by 10 percent a year until appropriate stipend levels
are reached. In fiscal year 2002 and fiscal year 2003, the
Administration has chosen to ignore NIH's policy and request
significantly lower increases for training stipends than are necessary,
and the Appropriations Committee has had to take action to ensure that
stipends were increased. Here we are in fiscal year 2004, and the
Administration has once again underfunded training stipends. What is
NIH's view of the need for a 10 percent increase in fiscal year 2004?
Answer. The NIH remains committed to the stipend targets of $25,000
for predoctoral and $45,000 for entry level postdoctoral Kirschstein--
NRSA recipients as identified on April 30, 2001. The 10 percent annual
increases specified in the 2001 NIH statement would have permitted us
to reach the indicated targets by fiscal year 2006. The indicated
targets could still be achieved at 4 percent annual increases, albeit
not until 2011, by which point they would need to be adjusted to
account for changes in the cost-of-living.
Question. What are the numbers of students supported and at what
levels?
Answer. Based on distribution of research training positions to
various career levels in fiscal year 2001, we estimate that the
positions funded in fiscal year 2004 will be filled according to the
following table.
REQUESTED FISCAL YEAR 2004 KIRSCHSTEIN--NRSA TRAINEES AND FELLOWS BY
LEVEL OF TRAINING
[Full-time training positions]
------------------------------------------------------------------------
Fiscal year
Number of 2004 est.
Career level positions stipend
levels
------------------------------------------------------------------------
Predoctoral................................... 10,046 $19,631
Postdoctoral:
Years of experience:
0..................................... 1,339 33,629
1..................................... 1,163 35,498
2..................................... 818 40,494
3..................................... 704 42,273
4..................................... 842 44,032
5..................................... 783 45,803
6..................................... 449 47,574
7..................................... 1,053 49,588
-------------
Total Postdocs...................... 7,151
=============
Total Full-Time Training Positions.. 17,197
------------------------------------------------------------------------
Question. Is it your view that stipends are adequate and that we
have enough high-quality students in the pipeline?
Answer. As indicated in my previous response, the NIH believes that
Kirschstein-NRSA stipends should be adjusted upward to $25,000 and
$45,000 for predoctoral students and entry-level postdoctorates,
respectively. Stipends are not being adjusted to influence the supply
or the quality of students in the pipeline. Based on recent studies,
the health-related sciences continue to attract highly motivated
students that score very well on national, standardized tests. Stipends
are being adjusted upward as recommended by the National Academy of
Sciences in recognition of increases in the cost-of-living and because
of the high level of education and professional skills involved in
biomedical research.
Looking at this budget proposal, I am reminded of those slow motion
films of crash tests for cars. My suspicion is that, under the
Administration's proposal, we are taking a $27 billion dollar research
enterprise and driving it into a brick wall at 60 miles an hour. Fiscal
year 2004 is the instant that the car's bumper hits the wall, the crash
dummies in the car are just starting to be thrown forward, and perhaps
the hood is starting to buckle. I fear that in fiscal year 2005 and
beyond we may well ``total'' the NIH. I didn't double the NIH over the
past five years so that we could drive it into a brick wall.
EMBRYONIC STEM CELL RESEARCH
Question. Please discuss how human embryonic stem cell research
fits into the mission of the NCI. Has NCI been actively encouraging
research on human embryonic stem cell research in order to advance your
mission?
Answer. Currently, NCI has not received any research grant
applications relating to human embryonic stem cell research. We do
believe that we will see basic research applications in the future.
NCI has an extensive commitment to the field of stem cell biology,
including both adult and animal embryonic stem cells. This research is
important in expanding our fund of knowledge that can be applied to
future human embryonic stem cell research. The Institute has publicized
to all of our grantees by listserv announcements the current applicable
NIH policies and procedures. In fiscal year 2002, NCI spent a total of
$95 million in both animal and human adult stem cell research. NCI has
also provided vital resources to the research infrastructure through
its Mammalian Gene Collection program. This program works with the
source of stem cells, such as the program at the University of
Wisconsin-Madison, to create public resources for full-length cDNA and
genomic libraries of human ES cell lines. In addition, NCI also
participates in the NIH task force and implementation team that are
facilitating interactions with the scientific communities.
Question. What is NCI doing to provide investigators with the
training necessary to maximize the potential of these cells?
Answer. In fiscal year 2002 NCI supported training and education
programs for investigators to acquire the skills and techniques
necessary to grow and maintain the human embryonic stem cell (hSEC)
lines. NCI provided co-funding support to NHLBI for the T15 short
courses in hESC culture techniques. The total funding provided was
$50,000 per year, divided among the five (5) successful applications.
These five awards were made to training programs to help establish the
workforce necessary to pursue this research field. These awards will
develop, conduct, evaluate, and disseminate short-term courses on
laboratory research techniques for human embryonic stem cell lines. The
courses will include hands-on experience to improve the knowledge and
skills of biomedical researchers to maintain, characterize, and utilize
human embryonic stem cells in basic research studies. The courses will
improve the skills of biomedical researchers in the maintenance of
human embryonic stem cells in culture and their application of this
research tool in basic research studies. The long-term objective of the
courses is to increase the number of researchers who have both
knowledge and skills in the use of human embryonic stem cells in basic
research.
REGENERATIVE MEDICINE
Question. Regenerative medicine is an area of research that could
be shared by government, academia and industry--a true public-private
partnership. Can you outline for the Subcommittee how regenerative
medicine fits into your plan for the NIH research agenda?
Answer. Regenerative medicine involves collaboration between
several research fields--stem cell biology, biomolecules/biomaterials,
and tissue engineering; and involves several scientific disciplines--
medicine, biology and bioengineering. NIH places a high priority on
supporting regenerative medicine research and is bringing together
several working groups to identify research obstacles and address
research opportunities for regenerative medicine especially in
application to stem cell biology and biomolecules/biomaterials. This
process will serve todevelop an NIH roadmap for regenerative medicine
with the goal of attracting more scientists to this emerging
multidisciplinary field that has the potential of revolutionizing
health and quality of life of millions of people.
Recent advances in stem cell research have spurred new interest in
the field of regenerative medicine. Before new therapies using human
embryonic stem cells (hESC) can proceed to the clinical phase, much
basic research must be conducted. There is a need for validating the
long-term stability of hESCs in culture and after transplantation,
understanding cell cycle control and cell specialization, and
evaluating cell-host interactions. In response to these needs, the NIH
Stem Cell Task Force is convening a working group with representatives
from government, academia and industry to develop recommendations about
what steps NIH could take to help improve or develop supporting
technologies and research tools in basic research of hESC biology.
Topics for discussion would include assessing the needs for supporting
supplies, materials, reagents, databases with broad public access;
assessing needs, progress, and opportunities for characterization
studies, genomic, and proteomic approaches to better define stem cell
lines; determining protocols for directed differentiation of stem
cells; and recommending needs for enhancing research tools to the Task
Force.
SALIVARY DIAGNOSTICS
Early detection offers the best hope for cure for many serious
diseases. However, many of the existing ways of diagnosing disease can
be difficult, invasive, time-consuming, and expensive, so that by the
time people have a test done, it may be already too late. I understand
that saliva as a diagnostic tool is a promising area of research for
addressing this issue.
Question. Is there, in the 2004 budget, an investment in this area
of research and if there is, how much are you budgeting for saliva
research?
Answer. We need to improve methods for detecting and diagnosing
disease in the early stages. Unfortunately, there are also many
barriers to effective diagnosis. Current methods, like blood tests and
imaging technologies, are often uncomfortable, invasive, and expensive.
Some diagnostic methods also carry risks themselves. Currently many
diagnostic tests do not allow for real time monitoring of the state of
health or disease because testing can take days or even weeks to
complete.
One of the most promising lines of research for diagnostic testing
involves the use of saliva. Like blood and urine, saliva can be used to
detect and measure many compounds in the body. Unlike blood and urine,
saliva is easy to collect in a physically non-invasive manner, and the
mouth is accessible for continuous monitoring. The science of microchip
technology is evolving so rapidly that it is possible to envision the
day when a microchip could be attached to a patient's tooth and be
capable of continuously monitoring not only specific disease conditions
but also an individual's overall health status.
NIH is using its resources to make this vision a reality. In fiscal
year 2002, NIDCR funded a series of grants to develop strategies to
measure and analyze multiple substances in saliva quickly and
simultaneously. Working in partnership with colleagues in industry and
academia, these grantees are using microchip technology to develop
diagnostic tests for a variety of conditions. As these studies are
completed, follow-up research will be conducted to determine the
efficacy of these new tools.
NIDCR will spend an estimated $9.0 million in fiscal year 2004 on
salivary diagnostics research.
Question. Is saliva being used for HIV diagnosis?
Answer. A number of companies have been working on saliva tests to
measure antibodies to HIV. However, the sensitivity and specificity is
lower than desired, mostly due to the fact that saliva contains low
levels of immunoglobulin G. Thus, two companies are using mucosal
transudate, the fluid that naturally seeps from the soft tissues of the
mouth, as a diagnostic medium. The existing systems are really
collection devices. The sample is sent to a laboratory, and the results
are obtained after a week or two. Both companies, however, have
developed rapid tests that are pending FDA approval for use in the
United States. One company received FDA approval on Jan. 31, 2003 for a
rapid test that utilizes a finger stick (i.e., blood sample) and
provides results in 20 minutes. The same company also has an
application before the FDA that uses the same technology with a sample
of oral mucosal fluid. FDA approval of the oral mucosal rapid test is
expected by the end of 2003.
Question. I hear people talk about the need to develop an ``HIV
rapid test''. Can you explain what that is and are you close to
accomplishing that?
Answer. An ``HIV rapid test'' implies that it can be conducted on
site within a very short time frame without the need for specialized
equipment or trained laboratory personnel. The NIDCR is working to make
this vision a reality. In fiscal year 2002, the Institute funded
several grants to develop technologies to measure and analyze multiple
substances, including HIV, in saliva. Working in partnership with
colleagues in industry, national laboratories and academia, these
grantees are focusing their efforts on developing ``labs on a chip'',
miniaturized systems about the size of a credit card for the detection
of HIV and other substances. These technologies will allow real-time
analysis of a large number of proteins (including antibodies to HIV),
nucleic acids (DNA, RNA) and small molecules (e.g., drugs, metabolites)
in oral fluids. The development of these technologies would permit
fast, highly sensitive and accurate diagnosis of HIV in small amounts
of saliva. To date, grantees at the University of Washington and the
University of Pennsylvania working in partnership with industry have
developed miniaturized prototypes for immunoassays of substances in
blood. This technology is currently being adapted for the rapid
diagnosis of HIV antibodies in saliva. Once these technologies are
developed, they will need to be validated prior to widespread use.
CLINICAL TRIALS RESEARCH IN DENTAL AND ORAL HEALTH
This Committee appreciates the need to support definitive, high-
quality clinical trials. We understand that such trials are especially
critical in dental and oral health, where large numbers of Americans
continue to suffer from oral diseases and disorders.
Question. Are there clinical trials in the area of oral health that
need to be conducted?
Answer. Continuing scientific progress in oral health has created
opportunities for state-of-the-art clinical trials to determine the
effectiveness of new treatment approaches and to broaden our
understanding of the link between oral health maintenance and overall
health. For example, new clinical trials are underway to assess the
effectiveness of periodontal treatment on control of systemic health
conditions such as preterm birth. The NIDCR has taken several steps to
increase the number of applications and awards for high-quality
clinical trials and to enhance the oral health research community's
capacity to conduct such trials.
Question. And what plans does NIH have to respond to this need?
Answer. As support for clinical trials in oral health has expanded
from about $10.8 million in fiscal year 2000 to nearly $18 million in
fiscal year 2002, NIDCR instituted a new process designed to better
assist investigators to develop and conduct clinical trials. The
Institute has given priority to Phase III clinical trials that are
likely to have a major impact on public health policy and/or clinical
practices, and that will provide important new information to
practitioners and consumers.
NIDCR recently reorganized its extramural programs to delineate
more clearly and to focus more prominently on the development and
management of clinical trials and recruited additional program staff
with expertise in clinical trials. Furthermore, a new, defined path for
clinical trial applications has been established, which will assist
investigators in developing and conducting trials. NIDCR has given the
highest priority to Phase III clinical trials with the potential for
high public impact. In addition, the Institute is using a variety of
funding mechanisms to strengthen the scientific workforce through
expanded training in clinical trial methods. The extramural community
has been very positive about these program enhancements, as reflected
in the increased number of applications and funding for clinical
trials.
SMA RESEARCH BUDGET
Question. What is the budget for SMA basic research for fiscal year
2003 and fiscal year 2004?
Answer. The NIH total estimated funding for Spinal Muscular Atrophy
(SMA) is $7,351,000 in fiscal year 2003 and $11,489,000 in fiscal year
2004.
SMA TRANSLATIONAL RESEARCH BUDGET
Question. As a result of promising breakthroughs in basic research
along with the severity and incidence of this disease in newborns and
infants, NIH has selected SMA as a model for translational research.
What is the budget for translational research for SMA in fiscal year
2003 and fiscal year 2004?
Answer. To enhance our current research efforts on SMA, we
anticipate awarding a contract for the SMA translational project on or
about September 30, 2003. The contract will be awarded for four years,
and the research will be conducted as subcontracts. The NINDS intends
to fund these research subcontracts at a level of $4.5 million per
year, which will support up to ten research subcontracts.
IMPLEMENTATION OF SMA TRANSLATIONAL RESEARCH PROGRAM
Question. Please provide specific details on your plan of action
for implementing SMA translational research?
Answer. The NINDS has developed a performance-based contract
approach to allow rapid funding of translational research in a
milestone-driven process to identify treatments for SMA. The members of
the steering committee, selected by the NINDS Director and drawn from
academia, industry, the public, and NIH, are in the process of being
identified and recruited; they will guide the program and play an
integral role throughout the project. During the Summer of 2003, a
working group will develop recommendations for a detailed plan for
research on promising therapeutic strategies, such as drug development,
gene therapy and stem cell therapy, which will address all steps
ultimately required to develop an IND-Investigational New Drug-
application, the formal procedure usually required before a treatment
can be tested in people. The primary contract for the SMA project will
provide overall scientific and organizational support. Subcontracts
will support individual research projects, which will be highly-
targeted and milestone-driven, as is often the case in industry. The
steering committee will evaluate progress toward the specified
milestones and prepare calls for additional subcontracts to do the next
steps along each therapy development pathway, as appropriate. The NINDS
intramural program, which has substantial expertise in SMA and other
neurogenetic disorders, will play an integral role throughout this
effort, and is capable of performing early phase clinical trials when
these become appropriate.
OVERSIGHT OF SMA TRANSLATIONAL RESEARCH
Question. Who has been appointed within the NINDS to oversee and
execute the SMA translational research project? What mechanisms are in
place to review the process of the project on an ongoing basis with NIH
leadership and Congress?
Answer. Dr. Jill Heemskerk, an NINDS Program Director, will be the
Project Officer for the SMA contract. She will receive advice from the
steering committee and other NINDS staff. To allow optimal management
and monitoring of research progress by the steering committee, projects
will be short-term, goal-directed, and milestone-driven. The steering
committee will review research progress at biannual oversight meetings;
advise the Contractor in assessment of research milestones; and advise
on strategies for overcoming difficulties in research progress.
Institute staff have briefed Dr. Zerhouni extensively about the
project and will continue to do so. We have responded to many questions
about the project, by letter and phone, from members of Congress, and
will continue to keep Congress informed.
TIMELINE AND PLAN FOR SMA TRANSLATIONAL RESEARCH
Question. Please provide a timeline and strategic plan for the
implementation of the translational research project and identify any
potential roadblocks?
Answer. In December 2002, NINDS published a notice on the
``Collaborative Program to Accelerate SMA Therapeutics Development'' in
the NIH Guide to Grants and Contracts to help develop the statement of
work and a request for proposals. A March 23, 2003 notice in Federal
Business Opportunities announced that the formal request for proposals
will be issued in April, and a similar notice appeared in the NIH Guide
on April 8th. We expect to award the primary contract on or about
September 30, 2003. Subsequently, calls for proposals for highly-
targeted research sub-projects will be issued quickly, and initial
research projects should be underway in January or February 2004.
Importantly, efforts to establish the steering committee are underway,
and a working group should have detailed recommendations for research
plans ready by the end of the summer, in time to begin issuing calls
for specific research and development projects once the contract is
awarded.
With regard to roadblocks, the project depends, of course, on
receiving proposals that are sufficiently scientifically meritorious so
that we can responsibly fund them. The most serious obstacles to
success, however, are scientific. It is important to keep in mind that
developing effective treatments for neurogenetic diseases such as SMA
is very much on the frontier of medicine. There are very substantial
scientific difficulties that must be overcome to develop a treatment
for SMA.
PROMOTING AWARENESS OF AND RESEARCH ON SMA
Question. What is NINDS doing to solicit grant applications? What
workshops and conferences have been organized this year and next year
to increase awareness of SMA and promote research funding
opportunities?
Answer. We are using both grant and contract mechanisms to enhance
research on SMA. SMA research funding at NINDS increased by 21 percent
from fiscal year 2001 to fiscal year 2002; SMA funding grew by more
than 500 percent from fiscal year 1998--$945,000--to fiscal year 2002--
$5.6 million. This reflects in part the stimulus provided by an NIH
workshop and a request for applications--RFA--on SMA and amyotrophic
lateral sclerosis--ALS--in Spring 2000. Much of the growth, however,
arises from the increased scientific opportunities, and reflects the
strength of the traditional investigator-initiated grant process in
responding to new avenues for progress. Given the state of the science,
we expect grant applications in SMA will continue to increase.
The translational project in SMA that I described is contract-
based. In December 2002, NINDS published a notice on the
``Collaborative Program to Accelerate SMA Therapeutics Development'' in
the NIH Guide for Grants and Contracts to help develop the statement of
work and Request for Proposals--RFP--for this program. On March 23,
2003 and April 8, 2003 NINDS published notices in Federal Business
Opportunities and the NIH Guide, respectively, that the RFP will be
released in April.
Other efforts include an NINDS consortium, developed through a
solicitation, to screen all FDA approved compounds for activity against
neurodegenerative diseases, which included a test specific to SMA. The
Institute has a program to rapidly provide supplemental funding for
testing candidate treatments that emerge from this, or other efforts,
in rodent models. Through a solicitation, the NINDS has also
established a high throughput drug screening facility and called for
proposals for disease assays, specifically listing SMA among those
disease assays being sought. In recent years, we have offered
solicitations in several cross-cutting areas that may provide results
that are relevant to SMA, focused on areas such as gene therapy for the
nervous system, neural stem cells, and pediatric neurological diseases.
The NINDS is also assisting voluntary groups in organizing a scientific
conference for Spring 2004 that will, among other goals, help inform
biotechnology companies and the pharmaceutical industry about
opportunities to develop therapies for SMA.
PROMOTING PROFESSIONAL AND PUBLIC AWARENESS OF SMA
Question. Please identify other NIH institutes and federal agencies
that NINDS is working with to promote professional and public awareness
of the disease. Please describe the programs that are being developed
with a timeline and list of objectives?
Answer. The NINDS has an SMA public information page with links to
advocacy organizations, relevant clinical studies, and research
literature. The National Library of Medicine also has an information
page for SMA with many useful links. In addition, scientific workshops
and the variety of research solicitations addressing or referencing
SMA, as well as program staff contacts, provide outreach to the
professional community. There are a number of voluntary health advocacy
groups focused on SMA that undertake extensive activities to inform the
public and the research community, as is appropriate to their role, and
we have cooperated with these groups in various ways.
STATUS AND COSTS OF CLINICAL TRIALS FOR SMA
Question. What is the status of clinical trials for promising SMA
treatments?
Answer. The NINDS is funding a grant to lay the groundwork for
clinical trials in SMA by developing a consortium of investigators and
by validating appropriate outcome measures. However, at this time we
need to emphasize translational research to bring potential treatments
to the point where clinical trials are warranted. The NINDS is
addressing this need in several ways. The contract-based translational
research project for SMA is, of course, an important part of that
effort.
Question. What is the estimate cost per trial?
Answer. Estimating the cost of trials and the possibilities of
partnering with industry depend on the specific drugs or other
therapies that might be tested, so we are not yet at the point
scientifically where I can give a specific answer.
Question. For FDA approved drugs, what efforts have been made to
partner with the manufacturer of these drugs?
Answer. We also support a consortium of investigators to screen FDA
approved drugs for potential use against neurodegenerative diseases,
including SMA. We have recently developed a high-throughput drug
screening facility as well, and called for proposals to develop
disease-specific tests, including those focused on SMA. In addition,
the NINDS intramural program will be capable of conducting clinical
trials on candidate therapies that emerge from these or other efforts.
ADDITIONAL RESOURCES REQUIRED FOR SMA RESEARCH
Question. What additional resources are necessary to execute the
SMA translational research project? What additional resources do you
require to increase the focus of SMA research at the NIH?
Answer. We believe we have the resources to execute the SMA
translational project at this time. This and all other efforts against
SMA depend on the response of the research community to these efforts.
The substantial increases in funded research on SMA over the last few
years reflect exciting scientific advances, which have brought
increases in the scientifically meritorious proposals we receive from
investigators, which is very encouraging. The growth also reflects our
commitment to addressing this terrible disease.
DUCHENNE MUSCULAR DYSTROPHY--NICHD INVOLVEMENT
Question. Duchenne Muscular Dystrophy is the world's most
prevalent, lethal childhood genetic disorder. Only in the past year has
the Child Health Institute at NIH had any involvement in this disease.
Has the Child Health Institute devoted any specific, significant
resources to this disease?
Answer. Since the passage of the MD-CARE Act, the NICHD has
partnered with the National Institute of Neurological Disorders and
Stroke (NINDS) and the National Institute of Arthritis and
Musculoskeletal and Skin Diseases (NIAMS) to support the Muscular
Dystrophy Cooperative Research Centers and the Developmental Planning
Grants for Muscular Dystrophy Research Centers. In addition, over the
past five years, NICHD, although it does not have primary
responsibility for muscular dystrophy research, has sponsored an active
portfolio of grants concerned with the muscular dystrophies, muscle
pathophysiology and other neuromuscular disorders. NICHD, along with
other NIH Institutes, also has an active role on both the NIH MD
Research Task Force and the MD Coordinating Committee.
In addition, through the NICHD-sponsored network of Mental
Retardation and Developmental Disabilities Research Centers, resources
created under this network have been used to conduct research in some
topics related to muscular dystrophy. The National Center for Medical
Rehabilitation Research within NICHD has also sponsored research on
muscle and neuromuscular disorders including such topics as the effect
of stress on dystrophic muscle and the role of strength on child
mobility. Finally, the Intramural research program at NICHD has for
several years had a research focus on understanding muscle
pathophysiology.
DUCHENNE MUSCULAR DYSTROPHY--CONGRESSIONAL PRIORITY
Question. Funding for DMD is approximately \1/2500\ of the NIH
budget. This committee has held a hearing on the subject; strong report
language has been attached to the Labor/HHS appropriation for three
years in a row; a comprehensive muscular dystrophy authorization bill
has been signed into law. Is the spending of NIAMS, NINDS, and other
institutes consistent with the congressional priority that has been
identified for this disease?
Answer. Yes, NIH's funding of muscular dystrophy research is
consistent with Congressional priorities. Indeed, from fiscal year 2000
to fiscal year 2002, NIH funding for muscular dystrophy--MD--research
has more than doubled. In fiscal year 2000, NIH funding for MD was
$12.6 million; NIH funding increased to $21.0 million in fiscal year
2001 and to $27.6 million in fiscal year 2002. Funding for DMD during
the same period also increased from $7.0 million in fiscal year 2000 to
$12.4 million in fiscal year 2002.
MD-CARE ACT--CENTERS OF EXCELLENCE
Question. The Muscular Dystrophy CARE Act called for the creation
of multiple Centers of Excellence, and was signed into law in 2001.
This committee on three occasions has said that a minimum of three such
Centers should be fully funded. I understand an RFP has finally gone
out to organize the Centers, but the only assurance to the scientific
community is that two Centers will be funded. Why so few? What funding
level is assumed for these Centers?
Answer. The NIH has been actively engaged in implementing the
mandates of the MD-CARE Act, including efforts to establish research
centers for muscular dystrophy; the Act did not provide for a specific
number of Centers. Specifically, in the Fall of 2002, the NIH issued
two Requests for Applications--RFAs--in this area. The first solicited
applications for up to three awards for Muscular Dystrophy Cooperative
Research Centers, and the second solicited applications for up to five
awards for Developmental Planning Grants for future centers. During
fiscal year 2003, following peer review, we will make grant awards in
response to these two RFAs; the number of centers actually funded, up
to the specified numbers, will depend on scientific merit. In fiscal
year 2004, we plan to re-issue the RFA for Cooperative Research
Centers, and expect to fund up to two additional meritorious centers in
fiscal year 2005. Subject to the number of applications we receive and
the results of scientific peer review, the combined solicitations could
result in funding up to a total of five MD cooperative centers. Direct
costs for the research centers can be a maximum of $1 million per
center per year, for five years.
MD-CARE ACT--CBO ESTIMATES
Question. The MD-CARE Act was scored by CBO two years ago to cost
$54 million over four years. Apparently there was a minor increase in
funding during the past year, but it is exceptionally difficult to see
that this Act is going to be fully funded at the current pace of NIAMS/
NINDS activity. What are the prospects for full funding of this Act?
Answer. The Congressional Budget Office--CBO--estimated that
implementing the MD-CARE Act--including aspects that are the
responsibility of other HHS components--would cost $4 million in fiscal
year 2002 and $56 million over the five year period of fiscal years
2002 through 2006. Of this amount, the costs of the NIH activities and
of the MD Coordinating Committee, which was established by the Act,
were estimated at $2 million in fiscal year 2002, and at $28 million
total over the fiscal year 2002 to fiscal year 2006 period. From fiscal
year 2001 to fiscal year 2002, NIH actual funding for muscular
dystrophy research increased from $21.0 million to $27.6 million, an
increase of $6.6 million or 31.4 percent--considerably more than the
CBO estimate for fiscal year 2002. Budget estimates for fiscal year
2003 suggest that NIH muscular dystrophy funding would increase another
13.8 percent this fiscal year to an estimated $31.4 million. While this
trend of increasing support for MD research is dependent upon future
scientific opportunities and meritorious applications, it should be
evident that the NIH is fully committed to implementing the MD-CARE
Act, and to defining and advancing the MD research agenda.
MUSCULAR DYSTROPHY--CINRG
Question. Has NIH ever funded translational research into muscular
dystrophy--in particular, has NIH ever subsidized the only human
clinical trials network (the Cooperative International Neuromuscular
Research Group, or CINRG) that is testing pharmacological approaches to
delay the progression of this disease?
Answer. The CINRG, with the Children's National Medical Center as
its coordinating center, conducts a multicenter clinical trials program
to investigate the most promising treatments for DMD and related
disorders. NIH currently funds a number of researchers who serve as
principal investigators at participating centers for these clinical
trials. In addition, NINDS has supported clinical trials on muscular
dystrophy through both its intramural and extramural programs, and
welcomes proposals for translational and clinical research aimed at
delaying the progression of MD and related neuromuscular diseases.
Translational research, by which we mean the process of applying
ideas, insights, and discoveries generated through basic scientific
inquiry to the treatment or prevention of human disease, is a high
priority for the NIH. The emphasis in translational research is
squarely on projects focused on the identification and pre-clinical
testing of new therapeutics. The Muscular Dystrophy Cooperative
Research Centers will promote side-by-side basic, translational, and
clinical research, and will be designed to accelerate the translation
of fundamental advances to the clinic. In addition, in July 2002, NINDS
initiated a comprehensive program designed to encourage and support
translational research for all neurological disorders, complemented by
specific initiatives in areas such as drug discovery, gene therapy, and
stem cells. Translational research is also an area of focus in the
ongoing NIH Roadmap initiative.
MUSCULAR DYSTROPHY--NIH COORDINATION
Question. DMD is untreatable and incurable, and has, throughout
history, taken the lives of children in their teenage years. Because of
the extraordinary burdens placed on families of children with this
disease, most of the benevolence on this affliction goes to subsidize
care, not research. While DMD is the#1 genetic child killer, it
afflicts one out of 3,500 boys, which is not a threshold high enough to
attract private drug money. Hence NIH research is the leading hope for
this generation of sufferers. Yet only in the past year has NIH created
a muscle biology study group--the only one devoted to the study of the
largest organ of the body, out of 110 study groups in all of NIH.
Scientific interest in this disease for years had been dampened and
frustrated because of this structural flaw. Congress on repeated
occasions has suggested that NIH coordinate its activities, and begin
to fund this disease commensurate with others--on the basis of
prevalence, severity, need, and scientific opportunity. Yet the process
of securing adequate funding in this area has been painfully,
tortuously slow--testing the limits of congressional patience and
willingness to entrust the Institutes alone to designate funding
priorities. What assurance can you give that this will change?
Answer. NIH has already taken numerous steps to coordinate its
activities with regard to muscular dystrophy. In early 2002, NIH formed
the Muscular Dystrophy Research Task Force to help guide efforts to
intensify research on muscular dystrophy. The Task Force is made up of
physicians, scientists, NIH professional staff, and representatives of
voluntary health organizations with a focus on muscular dystrophy. The
purpose of the group is to help NIH add new capabilities to the
national effort to understand and treat muscular dystrophies, without
duplicating existing programs. The Task Force has met twice already--in
May 2002 and January 2003.
In September 2002, NINDS, NIAMS, and NICHD jointly issued the
request for applications--RFA--``Muscular Dystrophy Cooperative
Research Centers--MDCRC,'' and in November 2002, issued another RFA,
``Developmental Planning Grants for Muscular Dystrophy Research
Centers.'' These centers will constitute a cohesive program, the MDCRC
Program, operating under guidelines for NIH cooperative agreements. The
centers will promote cooperation and coordination of activities and
resources across the entire MD research community.
Coordination of MD research and education activities across the
entire MD community will also be greatly enhanced by the formation of
the Muscular Dystrophy Coordinating Committee--MDCC, as called for in
the MD-CARE Act. The MDCC has broad representation from a number of HHS
agencies, including the CDC, FDA, and HRSA as well as other government
agencies, MD advocacy organizations, and the public, with an interest
in MD research and education. The MDCC is tasked with developing a plan
for conducting and supporting research and education on muscular
dystrophy through the national research institutes. This plan is to be
developed within a year of the establishment of the MDCC and will
further enhance the coordination of activities and funding
opportunities relevant to MD across NIH.
MUSCULAR DYSTROPHY--NIAMS EFFORTS
Question. What is the NIH doing to ensure an integrated research
approach regarding Muscular Dystrophy? What specific corporate
processes exist to ensure research synergies and research success?
Please provide for the record NIAMS efforts in these regard.
Answer. The NIH has a strong and growing interest in research on
muscular dystrophy, and a number of collaborative efforts illustrate
this commitment. Over the past few years, several NIH Institutes,
including the NIAMS and NINDS, have partnered to support scientific
meetings and research initiatives designed to advance the field of
muscular dystrophy research. Projects funded as a result of these
efforts include work on several forms of the disease, including the
Duchenne, facioscapulohumeral, myotonic, and limb-girdle dystrophies.
To underscore the importance of expanding and intensifying programs in
this field, the NIH has established a Muscular Dystrophy Research Task
Force, which includes NIH scientific staff, as well as researchers,
clinicians, and patient representatives. This group will help ensure
that we pursue all promising opportunities to enhance muscular
dystrophy research and training. It will also complement the work of
the newly established inter-agency MD Coordinating Committee, which was
mandated by the MD-CARE Act. Among other NIH Institutes, the NIAMS has
a very active role on both the Research Task Force and the Coordinating
Committee.
DUCHENNE MUSCULAR DYSTROPHY--``ROADMAPS''
Question. Are the specific Science and Technology ``roadmaps''
established for diseases such at Duchenne Muscular Dystrophy? What are
the disciplines involved? If so, for the record, please provide these,
demonstrating how they integrate multidisciplinary sciences and
technology efforts.
Answer. The ``Roadmap'' Action Plans being developed by Dr.
Zerhouni, with input from a broad range of NIH staff and extramural
scientific experts, are not disease or discipline specific, but rather
take a cross-cutting approach to identify scientific challenges and
roadblocks to progress. The ``Roadmap'' Action Plans will focus on
facilitating and accelerating multi-disciplinary aspects of basic,
translational, and clinical research. It is likely that several of
these areas will be applicable to research on DMD. With regard to
muscular dystrophy research overall, the MD Coordinating Committee--
MDCC--is tasked with developing a plan for conducting and supporting
research and education on muscular dystrophy through the national
research institutes. This plan will be developed within a year of the
establishment of the MDCC.
MUSCULAR DYSTROPHY--TRANSLATIONAL RESEARCH
Question. Has the NIH ever considered a technology maturity
assessment methodology akin to the NASA technology readiness levels or
TRLs? Outline for the record the means and process for determination of
transition from laboratory science to clinical trial?
Answer. As was mentioned before, translational research--the
transition from laboratory science to clinical trial--is the process of
applying ideas, insights, and discoveries generated through basic
scientific inquiry to the treatment or prevention of human disease.
There are rigorous criteria and procedures, which are unique to medical
science, for determining when it is appropriate to begin a clinical
trial. At the present time, the NIH is in the midst of developing
Roadmap Action Plans that will identify opportunities and roadblocks,
as well as establish goals, in cross-cutting, multidisciplinary areas
such as translational research. We expect that, as these needs are
addressed over the next several years, the rate of successful
translation of scientific advances into clinical trials will increase.
MD-CARE ACT--IMPLEMENTATION
Question. Outline the specific steps and associated timetime that
the Department of Health and Human Services and NIH have been on to
fully implement the provisions of the MD-Care Act of 2001. The
Congressional Budget office scored the MD Care Act act approximately
$54 million for implementation. What are the total resources that NIH
has dedicated to implementation of this Act currently reflected in the
fiscal year 2004 President's Budget Submission? Please provide for the
record fiscal year 2002 and fiscal year 2003 obligations and
expenditures for muscular dystrophy. Please indicate by institute by
form of MD, to include, Duchenne, Becker, Limble-Girdle etc.
Answer. In September 2002, NINDS, NIAMS, and NICHD jointly issued
two RFAs related to establishing the MD Research Centers provided for
in the Act. The RFA for ``Muscular Dystrophy Cooperative Research
Centers,'' will establish research centers, each of which will bring
together expertise, infrastructure and resources focused on major
questions about muscular dystrophy. In November 2002, another
solicitation was issued for ``Developmental Planning Grants for
Muscular Dystrophy Research Centers.'' These capacity-building grants
are targeted to investigators who are not yet ready to compete to
establish a muscular dystrophy research center, but would like to do so
eventually.
With respect to the MD Coordinating Committee called for in the
Act, the public members of the MDCC have been appointed as of April 20,
2003. Nine of the 10 Federal agency members have been designated by the
Secretary, HHS, and it has been recommended that the DOD be invited as
a member of the MDCC, based on the establishment in fiscal year 2003 of
muscular dystrophy research as a project within the DOD's Defense
Health Program. Committee members have been contacted about scheduling
the first meeting, which is expected to be held in July.
The NIH has also been expanding and intensifying its efforts in MD
research. In fiscal year 2002, NIH funding for MD was $27.6 million.
Estimated NIH funding for MD research in fiscal year 2003 is $31.4
million and $32.4 million in the President's fiscal year 2004 Budget.
The funding by institute follows:
----------------------------------------------------------------------------------------------------------------
Fiscal year
-----------------------------------------------
2002 actual 2003 estimate 2004 estimate
----------------------------------------------------------------------------------------------------------------
NHLBI........................................................... $1,099,000 $1,170,000 $1,200,000
NINDS........................................................... 9,843,000 12,327,000 12,589,000
NICHD........................................................... 599,000 600,000 600,000
NIA............................................................. 1,265,000 1,300,000 1,330,000
NIAMS........................................................... 11,081,000 12,000,000 12,450,000
NHGRI........................................................... 2,253,000 2,413,000 2,502,000
NCRR............................................................ 1,438,000 1,631,000 1,679,000
-----------------------------------------------
NIH....................................................... 27,578,000 31,441,000 32,350,000
----------------------------------------------------------------------------------------------------------------
The NIH funding for Duchenne MD was $12.4 million in fiscal year
2002, and the estimated funding for fiscal year 2003 is $13.7 million.
The reported funding for Duchenne MD in fiscal year 2002, fiscal year
2003, and fiscal year 2004, by institute follows:
----------------------------------------------------------------------------------------------------------------
Fiscal year
-----------------------------------------------
2002 actual 2003 estimate 2004 estimate
----------------------------------------------------------------------------------------------------------------
NINDS........................................................... $4,050,000 $4,373,000 $4,459,000
NIA............................................................. 1,265,000 1,360,000 1,400,000
NIAMS........................................................... 4,571,000 5,000,000 5,200,000
NHGRI........................................................... 2,160,000 2,312,000 2,398,000
NCRR............................................................ 384,000 430,000 454,000
OD............................................................. .............. 200,000 ..............
-----------------------------------------------
NIH....................................................... 12,430,000 13,675,000 13,911,000
----------------------------------------------------------------------------------------------------------------
MUSCULAR DYSTROPHY RESEARCH--INFRASTRUCTURE
Question. What are the specific NIH ``infrastructure'' shortfalls
associated with MD research? (ie. RDT&E equipment, laboratory
equipment, facilities, facility improvements) Please list any unfunded
requirements by institute.
Answer. The NIH's Muscular Dystrophy Research Task Force has
identified a number of infrastructure priorities, including the need
for multidisciplinary training programs to ensure a steady pipeline of
MD researchers; the importance of developing better animal models for
MD; the need to enhance bioinformatics and imaging resources; and the
need for tissue repositories, DNA samples, and cell lines that can be
used by the MD research community. Some of these needs will be
addressed through the Muscular Dystrophy Cooperative Research Centers
that NIH is planning to fund over the next few years, while others may
require novel partnerships with industry and MD voluntary
organizations.
MUSCULAR DYSTROPHY RESEARCH--COOPERATION WITH DOD
Question. Is there any relationship or cooperative research
activities with the Department of Defense regarding muscle or
myopathies? Between NIAMS and DOD? Or any other institute and DOD?
Answer. NIAMS is aware of the Department of Defense's (DOD)
involvement in muscular dystrophy research, as reflected in the fiscal
year 2003 DOD Appropriation for the Defense Health Program--Public Law
107-248--in that area. As a result, NIH is recommending that the
Secretary of HHS solicit a nomination for a DOD representative to the
Muscular Dystrophy Coordinating Committee. This will help to foster the
communication and cooperation between DOD and NIH with regard to MD
activities.
MYOPATHIES RESEARCH--NIAMS AND NASA
Question. In similar fashion, is there any cooperative RDT&E
between NIAMS and NASA on muscle, muscle wasting, or myopathies? Is
there any significant relationship to human physiology of flight,
especially for long-duration manned space flight? Have NIH institutes
made use of any data from NASA regarding muscle preservation with long-
duration space flight? Please provide for the record.
Answer. Research cooperation between NIAMS and NASA can be traced
at least to the early 1990's, highlighted by a 1990 meeting entitled,
``The Effects of Space Travel on the Musculoskeletal System'' and a
program announcement, which resulted in several grants. In 2000, NASA
and a number of NIH institutes--including NIAMS--collaborated on the
program announcement, ``Earth-Based Research Relevant to the Space
Environment,'' to encourage research applications related to biomedical
effects of space flight on humans, including the effects of gravity on
the musculoskeletal system. Thus far, the announcement has resulted in
the award of at least one NIAMS grant, a project which may provide
insights into the use of resistance exercise as a countermeasure to the
loss of muscle and bone that occurs during space flight.
DUCHENNE AND BECKER DYSTROPHIES--CLINICAL TRIALS
Question. What is the status of potential clinical trials on
Duchenne and Becker dystrophies? Are these efforts fully funded in the
fiscal year 2004 President's Budget Submission? Where is this in NIAMS
research priorities for fiscal year 2004 and the outyears? Please
provide for the record the current status of research on systematic
delivery of the dystrophin gene? What are the specific impediments to
gene therapy in DMD/Becker? What resources are reflected in the fiscal
year 2004 PB for these efforts? Provide a comprehensive list of the
``critical technical issues'' associated with efficiency of systemic
delivery.
Answer. Although much promising research is being done in animal
models of muscular dystrophy, significant work remains before the
science progresses to the level where major clinical trials in humans
are safe and appropriate. Recent progress in developing simple and
effective tests that detect more accurately the precise genetic defects
in forms of muscular dystrophy may help advance clinical research in
this area. By establishing a correct genetic diagnosis, we can identify
potential gene replacement strategies, and more accurately estimate
risks in families with a history of the disease. In addition, the NINDS
has recently funded a pilot clinical trial that will test whether the
common antibiotic gentamicin has therapeutic potential for patients
with both the Duchenne and limb-girdle forms of muscular dystrophy.
This trial may provide new insights that will help shape the course of
future clinical studies in this area. Other clinical trials are
currently under development.
One potential avenue to pursue, gene therapy, which uses vectors
such as viruses to deliver a replacement for the defective gene, is
seeing some success in the mouse. Current issues in muscular dystrophy
gene therapy include obtaining vectors in significant numbers,
effective gene delivery to affected muscles, and prevention of immune
reactions to the vector itself. NIH also supports promising work in
animal models on the therapeutic properties of muscle stem cells to
devise potential new approaches for treatment of MD. Discussions by the
NIH Muscular Dystrophy Research Task Force are expected to address
these issues.
DUCHENNE AND BECKER DYSTROPHIES--RESEARCH INITIATIVES
Question. What specific research initiatives exist regarding the
neuropsychological aspects of DMD/Becker? What resources and institutes
are associated with this effort?
Answer. NIH realizes the importance of studying and integrating
research on all aspects of a disease--from the physiological to the
psychological. NIH has supported research and invites proposals on the
neurocognitive and neuropsychological aspects of DMD. More broadly,
four NIH Institutes--NINR with NIAMS, NICHD, and NINDS--in May 2002,
issued a solicitation on ``Increasing Quality of Life in Mobility
Disorders.'' This initiative seeks applications for grants to study the
psychosocial aspects of conditions with limited mobility, which could
include DMD. These psychological consequences may include anxiety,
depression, social isolation, and lowered self-esteem. In February
2003, NINDS also issued a Request for Information for a contract that
NINDS is considering to develop a coordinated approach to defining and
measuring quality of life in neurological disorders. Patients' social
and psychological condition, as well as mental well-being, are among
the parameters that may be measured. In addition, NINDS funds very
basic studies on the effects of MD-related proteins in brain function.
These studies may provide the basis for developing studies on
neuropsychological aspects of MD.
The Muscular Dystrophy Coordinating Committee, which is tasked with
developing a research and education plan for muscular dystrophy, has
broad representation from a number of HHS agencies, such as the CDC,
FDA and HRSA, as well as other government agencies such as the
Department of Education. This will ensure that all aspects of MD,
including the neuropsychological aspects of the disease, are considered
in developing the research and education plan.
DUCHENNE AND BECKER DYSTROPHIES--PHARMACOLOGIC APPROACHES
Question. What specific pharmacologic approaches to DMD/Becker are
currently being pursued by NIH and NIAMS? What are the resource
implications and institutes involved?
Answer. Several years ago, NIAMS-funded scientists successfully
used the common antibiotic gentamicin to restore the function of the
missing protein dystrophin in mouse models of DMD. More recently, the
NINDS has funded a pilot clinical trial that will test whether
gentamicin has therapeutic potential for patients with both the
Duchenne and limb-girdle forms of muscular dystrophy. This trial may
provide new insights that will help shape the course of future clinical
studies in this area. The NINDS is also supporting work in mouse models
to test the efficacy of the protein biglycan as a potential therapy for
Duchenne muscular dystrophy. In addition, early advances involving
enzyme inhibitors and growth factors could eventually lead to new
pharmacologic treatments.
The NICHD has established a Pediatric Pharmacology Research Unit
Network which could prove to be a resource for developing
pharmacological approaches in this area.
DUCHENNE AND BECKER DYSTROPHIES--STEROIDS
Question. Has the NIH developed a consensus statement regarding
steroids in DMD/Becker? What is the progress here and target dates for
such a statement? How is NIAMS participating in this?
Answer. In the spring of 2000, several NIH Institutes, including
NIAMS and NINDS, sponsored a scientific workshop on ``Therapeutic
Approaches for Duchenne Muscular Dystrophy.'' The goals of this
workshop were to address key questions in improving treatments for DMD,
and identify areas of needed scientific knowledge, impediments, and
critical next steps to promote effective therapies. One of the areas
covered in the workshop was the use of steroids in treating DMD
patients, specifically the lack of guidelines for use and concerns
about side effects in children. Subsequent to this workshop, the
American Academy of Neurology--AAN--charged a Practice Parameters
Committee with looking at this treatment approach and developing
clinical guidelines. The AAN is expected to publish these guidelines in
the next few months.
MD CARE ACT--COOPERATIVE RESEARCH CENTERS
Question. The MD Care Act mandated the creation of coordinated
research centers in muscular dystrophy research, and suggested a budget
of $54 million. Would you verify for the record that the NIH has indeed
responded to this by requesting applications for ``Muscular Dystrophy
Cooperative Research Centers?'' Additionally, please detail your goal
of funding 2 to 3 centers at the cost of $1 million direct costs each
for 5 years a total of about $15-21 million over 5 years. Is this
currently reflected in the fiscal year 2004 President's Budget Submit?
Answer. The CBO estimate of $56 million for implementation of the
MD-CARE Act encompasses more than just the creation of research
centers; it is an estimate for implementing all aspects of the Act,
including those outside of NIH.
As one of the first steps in implementing the Act, NIH issued two
requests for applications related to Muscular Dystrophy Research
Centers. In September 2002, NIH issued an RFA entitled ``Muscular
Dystrophy Cooperative Research Centers,'' to establish research
centers, each of which will bring together expertise, infrastructure
and resources focused on major questions about muscular dystrophy. In
fiscal year 2003, following peer review and selection of applications
of the highest merit, NIH will fund up to three centers. In November
2002, NIH issued a second RFA for ``Developmental Planning Grants for
Muscular Dystrophy Research Centers.'' These grants, which will be
awarded in fiscal year 2003, are targeted to investigators who are not
ready to establish a muscular dystrophy research center but would like
to do so eventually. Since the President's fiscal year 2004 budget
reflects commitments from awards made in fiscal year 2003, the Centers
are reflected in the fiscal year 2004 budget.
In fiscal year 2004, we plan to reissue the RFA for Cooperative
Research Centers, and expect to fund up to two additional meritorious
centers in fiscal year 2005. Direct costs for the research centers can
be a maximum of $1 million per center per year, for five years.
MD COOPERATIVE RESEARCH CENTERS--RESOURCE CORES
Question. The committee understands that a second round of
competitive awards is anticipated in late 2004, with funding shared
between NINDS, NICHD, and NIAMS. Please outline for the record the
concept of ``Scientific Research Resource Cores.'' Does this include
the Muscular Dystrophy Cooperative Research Centers grant mechanism?
Does this initiative ensure that the very best support infrastructures
are present and enable the nation-wide muscular dystrophy research
community some advantage?
Answer. In fiscal year 2004, we plan to re-issue the RFA for
Muscular Dystrophy Cooperative Research Centers, and expect to fund up
to two additional centers in fiscal year 2005. At present, NIAMS and
NINDS are committed to funding centers of the highest scientific merit
through this follow-up initiative. The Scientific Research Resource
Cores that will be funded as part of these new centers are expected to
serve the national muscular dystrophy research community, in addition
to supporting research within the centers. These resource cores will
foster multidisciplinary collaborations across departments at a single
institution, as well as among investigators at several institutions,
through the sharing of novel research tools. Examples of scientific
cores include, but are not limited to, tissue and DNA repositories,
medical imaging, special animal facilities, and bioinformatics.
Investigators at the cooperative research centers are expected to
promote the use of the core facilities among researchers within the
parent institution and among scientists at other institutions.
MD RESEARCH RESOURCE CORES--ACCESS AND FUNDING
Question. A successful competitive clinical trial network could
accept clinical trials for promising therapeutic approaches from
muscular dystrophy investigators that are not formally part of one of
the two or three funded MDCRCs. Likewise, a successful gene vector or
stem cell core facility could produce these critical reagents for
laboratories throughout the country. Is the potential increased work
load of a successful Scientific Research Resource Cores planned to be
funded by the NIH via administrative supplements? Please outline your
plans and the funding profiles for record for fiscal year 2004 and the
outyears.
Answer. It is expected that an MDCRC will be able not only to
accommodate the research ideas and needs of participating scientists,
but also to be responsive to other muscular dystrophy research
enterprises that may not have direct connections to the center.
Cooperation is a key part of the MDCRC's name; the centers are designed
to both foster research, and to share knowledge and resources with the
muscular dystrophy community at large.
In fiscal year 2004, we plan to reissue the RFA for Cooperative
Research Centers, and expect to fund up to two additional meritorious
centers in fiscal year 2005. Direct costs for the research centers can
be a maximum of $1 million per center per year, for five years. The
Scientific Research Resource Cores will be funded as part of these
centers. In general, administrative supplements are awarded to already
funded researchers in response to identified needs and opportunities
within the scope of the original grant award. Since the center grants
have not yet been awarded, any discussion of supplements would be
premature.
MD COOPERATIVE RESEARCH CENTERS--FUNDING
Question. It appears that innovative and novel mechanisms that they
have put into place for executing the congressionally directed muscular
dystrophy cooperative research centers. Please outline for the record
the anticipated funding levels and implementation dates for three
competitive centers, and evidence of implementation of the innovative
Scientific Research Resource Cores via administrative supplements.
Answer. As stated in the recent solicitations for muscular
dystrophy cooperative research centers and for developmental planning
grants for future centers, the NIH expects to fund up to three research
centers and up to five planning grants in fiscal year 2003. In fiscal
year 2004, we plan to re-issue the RFA for Muscular Dystrophy
Cooperative Research Centers. Direct costs for the research centers can
be a maximum of $1 million per center per year, for five years. The
Scientific Research Resource Cores, which will be funded as part of
these new centers, are expected to serve the national muscular
dystrophy research community, in addition to supporting research within
the centers.
NIH TUBEROUS SCLEROSIS FUNDING
Question. How much is NIH currently investing in research on
tuberous sclerosis complex (TSC)?
Answer. The NIH reported actual funding for TSC research in fiscal
year 2002 was $6,121,000. The fiscal year 2003 estimated funding is
$6,439,000.
INVESTMENT IN TUBEROUS SCLEROSIS BY INSTITUTES
Question. Since tuberous sclerosis can affect all of the body's
organ systems, which institutes are currently supporting this research,
and how much is each institute investing?
Answer. The National Cancer Institute--NCI; National Heart, Lung,
and Blood Institute--NHLBI; National Institute of Diabetes and
Digestive and Kidney Diseases--NIDDK; and National Institute of
Neurological Disorders and Stroke--NINDS support TSC research. Funding
by Institute is summarized in the table that follows.
----------------------------------------------------------------------------------------------------------------
Fiscal year
-----------------------------------------------
2002 actual 2003 estimate 2004 estimate
----------------------------------------------------------------------------------------------------------------
NCI............................................................. $638,000 $657,000 $677,000
NHLBI........................................................... 2,140,000 2,279,000 2,336,000
NIDDK........................................................... 717,000 700,000 700,000
NINDS........................................................... 2,596,000 2,803,000 2,859,000
OD.............................................................. 30,000 .............. ..............
-----------------------------------------------
Total..................................................... 6,121,000 6,439,000 6,572,000
----------------------------------------------------------------------------------------------------------------
COORDINATION OF TUBEROUS SCLEROSIS RESEARCH
Question. Has there been any attempt to coordinate research on
tuberous sclerosis among the institutes involved?
Answer. Yes. The Program Director at NINDS who manages the TSC
research portfolio is in regular contact with his counterparts at other
Institutes. In addition, program staff from the National Institute of
Arthritis and Musculoskeletal and Skin Diseases--NIAMS and NIDDK
participated in the September 2002 NINDS-sponsored workshop on TSC
research, and these institutes, along with the National Institute of
Child Health and Human Development--NICHD, NHLBI, and NCI, are being
consulted in the development of the NIH TSC research plan.
TUBEROUS SCLEROSIS RESEARCH PLAN AND REPORT
Question. On September 19-22, 2002, NIH, the Office of Rare
Disorders and the Tuberous Sclerosis Alliance sponsored a research
conference entitled New Perspectives in Tuberous Sclerosis Complex. In
the fiscal year 2003 Senate report the Committee asked to receive a
progress report on efforts to develop a research plan. When can we
expect to receive this report, and how will it affect future research
on tuberous sclerosis?
Answer. In response to a joint resolution of Congress, passed in
2001, NIH is preparing a five-year TSC research plan. Efforts are
currently underway, led by NINDS, to craft the recommendations that
emerged from the September 2002 conference into a formal research plan.
NIH expects to finalize the plan and then submit a report to Congress
in June 2003. This plan will help guide the development of NIH
initiatives related to TSC and provide a framework that will allow the
NIH Institutes and research and advocacy communities to coordinate
their efforts to advance TSC research.
PAIN RESEARCH
Question. Chronic pain affects anywhere from 35-110 million
individuals per year, and is the most common reason consumers seek
health care, accounting for 20-30 percent of doctor visits and 10
percent of prescriptions sold.
The NIH Pain Research Consortium has been in existence since 1996.
Can you please provide this Committee with evidence of its activities
over the past three years, and its planned activities for fiscal year
2004?
Answer. The NIH Pain Research Consortium was established in 1996 to
enhance pain research and promote collaboration among researchers
across the many NIH Institutes and Centers that have programs and
activities addressing pain. Since its inception, the Consortium has
been co-chaired by the Director of the National Institute of Dental and
Craniofacial Research (NIDCR) and Director of the National Institute of
Neurological Disorders and Stroke (NINDS), and most recently the
Director of the National Institute of Nursing Research (NINR) has
joined as the third co-chair. The working membership of the Consortium
has been comprised of the key representatives of the Institutes,
Centers (ICs) and Offices conducting and sponsoring pain research and
programs at the NIH. It is designed to promote pain research and to
increase awareness in the various NIH ICs in order to stimulate
collaborative research initiatives, to coordinate both intramural and
extramural research programs, to foster and maintain contact with
research and patient communities, and to ensure that the results of
NIH-supported pain research are widely communicated.
In its first few years the Consortium:
--Sponsored the symposium ``New Directions in Pain Research,'' which
brought together scientists within the mainstream of pain
research and exposed them to the work of investigators who do
not normally focus on pain. In this way, the symposium brought
new ideas, methodologies and techniques to pain researchers,
where novel approaches to understanding and treating pain are
greatly needed. Summary reports from the meeting appeared in
the journals Neuron and Science.
--Sponsored the Symposium ``Gender and Pain,'' which covered subjects
such as the differing impact of the sex hormones testosterone
and estrogen on pain, brain imaging of nerve pathways involved
in the pain response, and efforts to identify genes that affect
pain sensitivity. This meeting received a great deal of media
attention, and thus information dissemination on the differing
responses to pain and current research.
--Established a Pain Research Consortium website on the NIH web that
included information on the consortium's mission, its
membership, activities being coordinated both intramurally and
extramurally, conference proceeding and collaborative funding
announcements, among other things.
--Developed a number of multi-institute supported Program
Announcements and Requests For Applications in the area of pain
research, that were also listed on the website.
--Gave rise on the NIH campus to the formation of the Pain Interest
Group, which sponsors seminars, informal discussions and
communication via subscription to a list accessible to members
of the NIH community.
In addition to these efforts, a number of institute-initiated
efforts have been ongoing. Examples include:
--In an effort to enhance the pain consult services within the NIH
Clinical Center, the highly successful Pain and Palliative Care
Service was established under the direction of a nationally
recognized pain clinician, Ann Berger, RN, MD.
--Similarly, the NIDCR-directed Pain Research Clinic accounts for the
vast majority of translational pain research done intramurally
at NIH and has influenced the field of pain research through
training and the scientific productivity of its senior
investigators.
--The NIH-FDA Analgesic Drug Development workshop attracted 250
registrants, resulted in a FDA Advisory Committee hearing in
July to develop new criteria for multi-dose studies and claims
structure for drugs indicated for Rheumatoid Arthritis and
Osteoarthritis, and has catalyzed the first revision of the
analgesic drug development process in nearly two decades.
--The NIAMS-led Osteoarthritis Initiative resulted in greater than
$50 million in funding, with significant contributions from the
pharmaceutical industry, to develop improved clinical trials
methods, identification of biomarkers, and an innovative format
for future clinical trials for this disease.
More recently, efforts are underway to capitalize and build upon
these above activities and to reinvigorate the Consortium. Over the
last six years, several changes of leadership in the NIDCR and the
NINDS have resulted in a number of changes in individual co-chairs,
and, as noted, NINR has joined as the third co-chair. Drs. Lawrence
Tabak, Audrey Penn, and Patricia Grady, the current co-chairs of the
Consortium, with the support of NIH Director, Dr. Elias Zerhouni, are
facilitating the necessary efforts to see the Consortium reach its full
potential to catalyze activities both intra- and extramurally in pain
research.
To this end, each Institute and Center Director, as well as the
central NIH Office Directors, have been contacted and asked to reaffirm
their commitment to the pain Consortium as members, and to update their
liaisons to the Consortium. In addition, invitations to participate in
the Consortium have been extended to NIH's sister agencies, including
the Food and Drug Administration, and to pain researchers in the
Department of Defense and the Veteran's Administration. An
organizational meeting of the revitalized Consortium has been scheduled
by the co-chairs to convene on June 10, 2003 to collectively frame the
scope and activities of this group for the future, and update the
scientific agenda for NIH pain research. Plans for the Consortium,
which will address current IC activities as well as those for fiscal
year 2004 and beyond, include catalyzing additional multi-institute
supported research efforts within both the extramural and intramural
programs, including more highly integrated, multi-institute sponsored
PAs and RFAs in the area of pain research. The website for the
Consortium will also be enhanced to make it an interactive source of
more comprehensive information on pain and pain research for its
various stakeholders, e.g., pain researchers; patients and patient
advocate groups, professional associations, the public, and the media,
among others.
Question. According to pain advocacy groups, the NIH has difficulty
in accurately accounting for its expenditures in pain and symptom
management. Past estimates indicate that the NIH spends less than 2
percent of its total budget on primary pain care research. The American
Pain Foundation maintains that in a conversation with the NIH Office of
Budget last summer, that office indicated that the NIH spent $124
million on pain-related projects in fiscal year 2000, with an increase
to $134.9 million in fiscal year 2001. However, other sources believe
that those figures may exaggerate the actual expenditures because they
included grant figures where pain was an underlying or secondary focus
in the study.
Can you prepare for this Committee an accurate accounting of the
NIH's intramural and extramural activity in pain and symptom management
research, to include detailed information and accounting on the
projects that are primarily addressing pain issues from across the
institutes and centers?
Answer. Thirteen of the NIH organizations have reported support for
pain-related research, as detailed in the following table and narrative
descriptions:
NATIONAL INSTITUTES OF HEALTH; FISCAL YEAR 2002 ACTUAL OBLIGATIONS; PAIN CONDITIONS, CHRONIC
[In millions of dollars]
----------------------------------------------------------------------------------------------------------------
Extramural Intramural Fiscal year
Participating ICs research research total
----------------------------------------------------------------------------------------------------------------
NCI............................................................. 10.6 0.4 11.0
NHLBI........................................................... 10.3 .............. 10.3
NIDCR........................................................... 21.4 5.1 26,5
NINDS........................................................... 47.7 1.4 49.1
NICHD........................................................... 4.8 1.1 5.9
NIA............................................................. 1.8 0.7 2.5
NIAMS........................................................... 6.6 .............. 6.6
NIMH............................................................ 5.9 .............. 5.9
NIDA............................................................ 22.6 0.4 23.0
NINR............................................................ 10.9 .............. 10.9
NCRR............................................................ 11.4 .............. 11.4
NCCAM........................................................... 9.0 .............. 9.0
OD.............................................................. 1.9 .............. 1.9
-----------------------------------------------
NIH....................................................... 164.9 9.1 174.0
----------------------------------------------------------------------------------------------------------------
The National Cancer Institute (NCI)
NCI supports clinical trials on secondary or indirect pain-related
research where pain alleviation is a factor in determining patient
quality of life during the patient's experimental treatment and care.
Pain assessment/pain management research grants investigate how to
overcome cultural barriers between providers and patients to better
manage cancer related pain. These studies consider gender differences
in the effectiveness of similar pain medications. NCI researchers are
also developing new methods of pain measurement that are computerized
for ease of patient use at the provider site or in the patient's home.
Other complementary and alternative medicine pain relief research
includes: hypnosis for postoperative breast surgery pain, massage for
short-term relief from pain in advanced stage cancer patients, and
acupuncture or acupressure for pain relief in advanced pancreatic
cancer patients.
Other NCI research examines the biological or molecular basis of
pain. Researchers are studying cellular proteins that may be elevated
in cancer cells to activate the pain response in humans or animal
models. NCI has several ongoing studies on the reduction of therapy-
induced pain. These include studies on reversing opioid related
constipation as well as determination of initial dosing rates to
minimize the pain associated with use of photodynamic therapy for
treatment of certain skin cancers. There are several phase II clinical
trials underway on therapy induced pain in advanced stage cancers,
including a study of radionuclides for metastatic prostate cancer
tumors ablation, arsenic trioxide for pain relief of advanced prostate
cancer, and radiation as a palliative care measure in advanced lung
cancers. NCI is also funding pharmaceutical research on new delivery
systems for natural delta-9-tertahydrocannabinol (THC) to alleviate the
marked loss of appetite and weight in cancer and AIDS patients.
Emerging evidence from several groups reveals that the capsaicin
receptor (a biologic molecule involved in pain sensation) is modulated
not only by compounds like capsaicin but also by signaling pathways
such as protein kinase C. NCI is actively investigating the regulation
of other (vanilloid) receptors by protein kinase C as well as the
design of molecules that can manipulate the protein kinase C pathway to
obtain useful therapeutic outcomes, such as modulation of pain.
The National Heart, Lung and Blood Institute (NHLBI)
NHLBI supports research on the management of painful episodes
associated with sickle cell disease (SCD). Its current portfolio
includes a study to ascertain the impact of acute and chronic pain
events on health care utilization among adults with SCD, as well as an
examination of the relationship between sickle cell pain, mood, and
stress in adolescent and adult patients. The NHLBI is also funding a 5-
year follow-up of adult patients who participated in a landmark
clinical trial that established the usefulness of the drug hydroxyurea
in preventing complications of SCD. The goal of the follow-up study is
to assess the continuing effectiveness of hydroxyurea in decreasing
rates of painful sickle cell episodes and improving quality of life.
The National Institute of Dental and Craniofacial Research (NIDCR)
The history of pain research at NIH began over five decades ago
when the NIDCR recognized many Americans' association of dentistry with
pain. Since that time, NIDCR, in conjunction with other NIH Institutes,
has built a comprehensive portfolio of pain research. Its scientists
and grantees have made important contributions to define the basic
neurocircuitry of pain, as well as translating this understanding into
improved treatments that benefit millions of Americans.
The NIDCR has established relevant research programs initiatives in
both its intra- and extra-mural components. NIDCR scientists have long
studied oral-facial pain, not only because of its importance in oral
disease, but also because it provides an accessible model of pain
elsewhere in the body. These investigations have greatly enriched our
understanding of the basic mechanisms of pain perception and modulation
and have helped delineate the complex pathways and multiple
transmitters that convey pain signals. The NIDCR recognizes that a
unique opportunity now exists, with the emergence of genomic,
proteomic, and other powerful, information-generating technologies, to
define in greater detail the genetic and molecular basis of pain. This
basic research will serve as the pipeline for new strategies in pain
management, allowing future clinicians to more selectively and
efficiently control the pain process.
NIDCR grantees are defining biological factors that might account
for differences in pain perception. Novel imaging techniques that track
the ``mu-opioid'' system, have revealed that people vary both in their
capacity to produce mu-opioid receptors and in their ability to release
the anti-pain chemicals themselves. Researchers found that at matched
levels of pain intensity, men and women differ in the degree and
direction of the mu-opioid response in distinct areas of the brain.
Variability in the mu-opioid system appears to determine the emotional
and sensory aspects of a painful experience may also help to explain
why some people are more prone to chronic pain conditions or do not
benefit from certain anti-pain medications. While the neurocircuitry
involved in each of these processes is extraordinarily complex and
inadequately understood, these initial imaging studies of pain
perception offer an important starting point to further explore human
perception and diversity.
In preliminary animal studies, NIDCR scientists have demonstrated a
treatment approach that selectively controls the chronic pain
associated with tissue damage and recurrent inflammation. This
discovery builds upon laboratory studies of the cell-surface protein
vanilloid receptor I, known by the unrelated acronym TRPV1. Researchers
have isolated a TRPV1-binding compound, which in animal studies
selectively eliminates an entire class of pain-sensing neurons from the
peripheral nervous system. This compound, known as resiniferatoxin
(RTX), killed certain neurons, and blocked inflammatory pain,
hyperalgesia, and thermal pain sensation. Importantly, the animals
maintained their ability to sense pain and remained well coordinated,
an indication that RTX did not affect proprioceptive nerves in the
muscles and joints. These NIDCR researchers have yielded in just over a
year of work a novel approach to pain management. This finding has
important implications for the field of pain research, as well as the
potential to impact American public heath. Additional studies are under
way that will move RTX and related compounds into human clinical
trials.
The National Institute of Neurological Disorders and Stroke (NINDS)
NINDS supports a broad range of research focused on both
understanding the causes and mechanisms of pain and on developing
effective treatments for pain. Our portfolio includes research on the
unique roles in processing and regulating pain that are played by
different areas of the nervous system including: the peripheral nervous
system, spinal cord, brainstem, and cerebral cortex. The portfolio also
includes research aimed at gaining a better understanding of the
different neurotransmitter systems involved in mediating pain. The
NINDS supports research on a wide variety of pain conditions,
including: neuropathic pain, visceral pain, pelvic pain, causalgia,
painful peripheral neuropathies, cancer pain, back pain, muscle pain,
migraine and other types of headache pain, post-surgical pain, and
inflammatory pain. Research on the mechanisms of anesthesia and
analgesia is another area funded by NINDS. The NINDS supports a number
of clinical studies aimed at testing the effectiveness of different
types of treatments (both drug and non-drug) for several pain
conditions. For example, one clinical trial is comparing the
effectiveness of either a drug or cognitive behavioral therapy for
treatment of chronic tension-type headaches. Another clinical study is
examining whether behavioral changes (e.g., changes in diet and
exercise) can prevent the pain associated with peripheral neuropathy in
individuals who have Impaired Glucose Tolerance, a condition of
impaired glucose metabolism. Finally, the NINDS supports training
programs at both the pre- and post-doctoral level with the goal of
giving young scientists and physician-scientists a broad experience in
the pharmacological, pathological, and molecular biological methods of
pain research.
National Institute of Child Health and Human Development (NICHD)
Chronic pain is a secondary condition in persons with disabilities.
Currently funded research on the management of chronic pain explores
the efficacy of innovative non-pharmacologic therapies, such as virtual
reality analgesia in children with cerebral palsy and burns. Cognitive
restructuring, relaxation training and hypnotic analgesia are pain-
management approaches being investigated in persons with cerebral
palsy, multiple sclerosis, acquired amputation, and spinal cord injury.
Research focused on the biomechanics of wheelchair propulsion may
reduce shoulder pain and increase the mobility of wheelchair users.
In the area of reproductive health, several investigators are
studying pharmacologic treatments for the pelvic pain associated with
vulvodynia, endometriosis, dysmenorrhea and hysterectomy. Other pain
research examines the effects of epidural analgesia, used commonly to
reduce pain in labor. There is evidence that suggests epidural
analgesia may also prolong labor, influence the position of the fetus
during labor and increase the likelihood of a high-risk cesarean
delivery. Pre-term infants are subjected to many painful procedures in
the NICU environment. The long-term neurodevelopmental effects of early
exposure to pain and the effects of the sedatives and opioid analgesics
used to reduce neonatal pain are the focus of other NICHD-supported
research.
National Institute on Aging (NIA)
It has been estimated that chronic pain affects approximately half
of older adults living at home, and may cause significant disruption of
physical, psychosocial, and cognitive function. Management of pain is
also of particular concern in older surgical patients, Alzheimer's
patients and other patients with diminished cognitive capacity, as well
as in end-of-life care. NIA extramural studies include a study of pain
management in hip fracture patients and the potential problem of
overlooking pain symptoms in patients who experience delirium as well
as an investigation of chronic low back pain and its effect on
physical, psychosocial, and cognitive function in a group of adults
over age 65. Another extramural study is examining the possible effects
of a multidisciplinary palliative care consultation on pain management,
dypsnea, and anxiety in a group of seriously ill, hospitalized older
patients. A new study will research the effect that identifying pre-
visit concerns of older adult patients has on improved health status
for the primary outcomes of pain and physical function. There is also a
study to understand the major determinants of postoperative outcomes
and improve functional recovery of elderly surgical patients, including
the relationship between improved pain management and improved daily
functioning.
NIA has two intramural studies of pain. The first is a study of
chronic musculoskeletal pain in hereditary disorders of connective
tissue, such as Ehlers-Danlos syndrome and Stickler syndrome, that
examines the efficacy of the use of the ``Mindfulness-Based Stress
Reduction Program'' in the relief of chronic pain. The second is an
epidemiologic study of the impact of pain and other symptoms of chronic
diseases on the daily lives and functioning of older disabled women,
which is specifically investigating whether musculoskeletal pain
increases the risk for falls and other adverse health outcomes and if
the risk can be reduced through the use of analgesic medications.
National Institute of Arthritis and Musculoskeletal and Skin Diseases
(NIAMS)
The mandate of the NIAMS is broad and diverse, focusing on the
whole array of diseases that affect the muscles, joints, bones, and
skin. Many of these diseases are chronic, and are also accompanied by
significant pain. The origin of pain and effective strategies for pain
management are areas of research supported by the NIAMS. The NIAMS pain
research portfolio includes a significant number of studies on
fibromyalgia, a complex and chronic disorder that is characterized by
widespread musculoskeletal pain, fatigue, and multiple tender points.
``Tender points'' refers to tenderness that occurs in localized areas,
particularly in the neck, spine, shoulders, and hips. The NIAMS
supported studies related to fibromyalgia and pain include efforts to
identify the central factors causing fibromyalgia; research on the
changes that occur in the nervous and the hormonal systems in people
with fibromyalgia; and a study that is using chronic low back pain as a
model for fibromyalgia. Additional research topics include: exploring
the roles of sex hormones, stress, and pain in fibromyalgia; work on
the employment and health status of women with fibromyalgia; and
adaptation to pain and stress in fibromyalgia. Other studies are
focusing on rheumatoid arthritis and exploring the value of coping
skills training for early rheumatoid arthritis as well as the roles of
stress and adaptation to rheumatoid arthritis. Also, the NIAMS has
teamed with the NIH Office of Research on Women's Health in funding a
new Specialized Center of Research on gender differences in sensitivity
to pain.
National Institute of Mental Health (NIMH)
In keeping with the NIMH's mission, over one-half of the pain
research NIMH supports is devoted to examining the relationship between
pain and mood states. Examples of this work include studying the
effects of anxiety on pain perception, and research evaluating
depression as a consequence of pain. The NIMH portfolio also includes
research on the basic neurophysiology of pain, including both central
and peripheral nervous system mechanisms. NIMH also supports studies of
the relevant receptors, neurons, neurotransmitters, and neuropeptides
implicated in pain. NIMH-funded work also investigates the efficacy of
psychosocial interventions in alleviating and preventing chronic pain.
Thirty percent of the pain research funded by NIMH focuses specifically
on children and elderly populations.
National Institute on Drug Abuse (NIDA)
The National Institute on Drug Abuse (NIDA) has a comprehensive
research portfolio that looks at all aspects of drug abuse and
addiction and includes a significant pain and analgesia research
program. NIDA's interest in this area stems from the fact that many
analgesics also have abuse potential and research on drug abuse and
addiction is relevant to pain issues. Thus, NIDA supports the
development of treatments for chronic pain, including the use of
opioids (e.g. morphine, oxymorphone, fentanyl, codeine) as well as
finding alternatives to opioids. Innovative research funded by NIDA
includes a device using transcutaneous electrical nerve stimulation
(TENS) that was developed through NIDA's Small Business Innovation
Research (SBIR) program. TENS stimulates certain nerves in the skin,
and this activation inhibits pain. This device is now FDA approved and
commercially available. NIDA also supports research on treating some
severe forms of pain, such as cancer pain, using transplanted cells
from the pituitary gland that produce opioids. Initial work in this
area showed that implanting these cells into the spinal cord reduces
pain in rats. Researchers are now looking at the use of this technique
in monkeys. Another technology using ``targeted neurotoxins'' is being
developed in animal models by several NIDA researchers. This technology
is expected to reduce chronic pain by eliminating specific chronic pain
fibers in the spinal cord. NIDCR has been examining specific targeted
agents acting on ion channels in pain-sensing neurons that have shown
potential as a clinical pain treatment. NIDA is partnering with NIDCR
in completing toxicology studies on this agent and getting FDA approval
for clinical trials in the treatment in cancer patients.
National Institute of Nursing Research (NINR)
Nursing research focuses on ethnically and culturally sensitive
interventions for pain prevention, assessment, management, and
treatment. Emphases include end-of-life pain management and
interventions that help people manage their own pain caused by chronic
diseases, such as arthritis. NINR also focuses on the interaction of
pain, the immune system, and illness at biological and cognitive
levels. NINR supports research on non-pharmacologic interventions to
reduce pain, including exercise, music and art therapy, and
biofeedback, as well as the improving clinicians' ability to assess
pain in those unable to express the level of pain they experience,
including infants and cognitively impaired elderly.
Research findings have set a new direction for pain research. For
the first time, the influence of gender on pain relief was
demonstrated. Study results showed that Kappa opioids, when used for
acute pain, are more effective in women than men and have fewer side
effects than stronger drugs, such as morphine. The role of hormones on
the effectiveness of treatment is currently under study. NINR also
conducts research on the importance of pain relief in improving the
immune systems response to metastasis following surgery. In an animal
model, researchers found that if morphine is provided before and after
surgery, the immune system is less depressed, which suggests that pain
relief improves resistance to the spread of cancer. Other research
findings suggest that exercise helps fibromyalgia patients, who
typically have both localized and widespread pain. Patients
participating in muscle strengthening achieved the greatest benefit
without significant exercise-induced flare-ups in pain.
National Center for Research Resources (NCRR)
NCRR develops and supports critical research technologies and
resources that underpin and advance health related research supported
by the NIH and other research organizations. Research is carried out
through support from the four NCRR divisions: Biomedical Technology,
Clinical Research, Comparative Medicine, and Research Infrastructure.
The Division of Biomedical Technology supports research resources that
enable investigators to do basic research on the biochemistry and
physiology of pain. NCRR's Division of Clinical Research supports
General Clinical Research Centers where researchers are studying the
clinical aspects of pain, including: drug testing and development,
gender differences in pain, and pain associated with specific diseases.
The Division of Comparative Medicine supports research on pain
treatments in animal models, including a mouse model of analgesic
regimens for surgery. Finally, the Division of Research Infrastructure
supports studies on musculoskeletal pain and pain in children.
National Center for Complementary and Alternative Medicine (NCCAM)
NCCAM supports an extramural pain research portfolio that involves
extensive testing of complementary and alternative (CAM) therapies,
such as acupuncture, chiropractic medicine, and yoga, to determine
their efficacy in preventing and treating pain associated with a
variety of conditions and diseases. For example, in a partnership with
the National Institute of Arthritis and Musculoskeletal and Skin
Diseases, NCCAM is supporting a large clinical trial to determine the
efficacy of acupuncture in treating pain and functional limitations
imposed by degenerative arthritis of the knee. At the Northwestern
Health Sciences University, investigators are comparing chiropractic
spinal manipulation, prescription medication, and self-care advice for
neck pain, while at Harvard University investigators are evaluating the
placebo effect and its role in treating repetitive strain injury. One
of NCCAM's major research interests is to study how alternative
therapies, primarily botanicals, interact with other medications. At
the Fred Hutchinson Cancer Research Center researchers are studying how
St. John's wort, a popular herb taken as an antidepressant, interacts
with pain relieving opioids in the context of cancer pain therapy. In
addition, NCCAM-supported researchers at the Johns Hopkins University
Center for Complementary and Alternative Medicine are developing an
animal model to study the reduction of cancer pain using herbal
medicines that appear to contain anti-inflammatory properties. To help
ensure a cadre of clinical investigators in the field of CAM research,
including pain research, NCCAM has also awarded a grant to the Palmer
Chiropractic University to develop a curriculum on research
methodologies for chiropractors.
Office of the Director (OD)
The Office of Research on Women's Health co-funded a total of $1.9
million in pain research projects in the areas of: lower back pain, sex
differences that influence pain, cellular mechanisms of neuropathic
pain, pain management in temporomandibular disorders, and chronic pain
conditions that predominantly affect women.
SCLERODERMA
Question. There is significant vascular and autoimmune component to
scleroderma, are there other institutes aside from the NIAMS at the NIH
that you would recommend scleroderma researchers pursue to fund
experiments aimed at finding a cure? For example, since the leading
cause of death in scleroderma patients is through pulmonary
hypertension and its effects on heart function, should grants on
pulmonary hypertension that encompass issues unique to scleroderma
patients be directed to the NHLBI instead of the NIAMS?
Answer. Research on scleroderma is of interest to a number of NIH
components. This is one of the strengths of the NIH--that we study
diseases from a variety of perspectives. These efforts are
complementary, not duplicative. To give an illustration, not an
comprehensive list, in the case of scleroderma, the NIAMS is the lead
Institute with interests in connective tissue and skin involvement.
Other researchers interested in particular aspects of scleroderma
include those supported by the National Heart, Lung, and Blood
Institute (for example, work on pulmonary fibrosis, pulmonary
hypertension, and vascular involvement), the National Institute of
Diabetes and Digestive and Kidney Diseases (for example, work on the
gastrointestinal tract and kidney function), the National Institute of
Allergy and Infectious Diseases (for example, work on autoimmunity),
and the NIH Office of Research on Women's Health (because scleroderma
affects more women than men). As well, the National Center on Minority
Health and Health Disparities also has an interest because of the
increased incidence of scleroderma in Native Americans. This means that
researchers interested in studying scleroderma should first consider
what particular dimension they wish to pursue and contact the relevant
Program Director within that Institute. The NIH web site includes links
to the individual web sites of each Institute, so this is an effective
way to identify the appropriate Program Director for the particular
area of interest. I do want to underscore the close collaboration and
collegial spirit that we have at the NIH--we team together to sponsor
solicitations and to support research in targeted areas as well as
jointly sponsor scientific meetings. All of this means that the NIH is
able to bring a wealth of experience and complementary interests to a
disease like scleroderma.
Question. In your opinion is there sufficient infrastructure (i.e.,
enough scientists in the field) to support a significant increase in
scleroderma funding? Aside from funding more grants specific to
scleroderma research, how would the NIH propose increasing interest in
the field?
Answer. The issue of infrastructure is of significance to all
scientific disciplines and diseases, and the NIH is actively working to
address all of the dimensions of infrastructure. When we look
specifically at scleroderma, I am pleased to tell you that this is an
area that is the focus of a broad array of research efforts, and I want
to cite highlights of several investments. First, the NIAMS made a
significant commitment to boosting research on scleroderma when the
Institute issued a special solicitation for research applications in
fiscal year 2000. This successful solicitation resulted in the funding
of ten new research grants totaling more than $2 million. These
included both basic and clinical studies, and we were joined by the NIH
Office of Research on Women's Health in co-funding two of the grants.
The NIAMS also currently funds two Specialized Centers of Research in
Scleroderma--one at the University of Texas Health Science Center and
one at the University of Tennessee. Specialized Centers of Research
(SCORs) increase the transfer of basic research findings into clinical
practice by conducting basic and clinical studies under one roof. These
SCORs focus only on scleroderma, and they serve as a national resource
for researchers studying scleroderma. In addition,, the NIAMS
established a national Scleroderma Family Registry and DNA Repository
for scleroderma in June 2001 with the goal of identifying
susceptibility genes. We believe these investments will provide
critically important information on the causes of scleroderma and help
us to develop improved treatments. In addition, through Dr. Zerhouni's
Roadmap Initiative, infrastructure will be strengthened to facilitate
clinical research across the spectrum of clinical diseases.
With regard to increasing interest in the field, scleroderma is an
autoimmune disease-a broad category of diseases in which the body's
immune system attacks the body's own tissues as if they were foreign
invaders, causing significant damage to target organs. The whole field
of autoimmunity is currently exploding with activity and newly launched
initiatives. Information that we learn from studying one autoimmune
disease will provide valuable information for all autoimmune diseases.
It is my opinion--and the goal of the NIAMS--that the significant,
ongoing work on scleroderma as well as the broad interest in
autoimmunity will be of great benefit for affected patients and their
families and care givers.
Question. There is strong scientific support for the NIH's
``roadmap'' meetings with scientists from various disciplines to
identify major cross-cutting biomedical challenges that the NIH could
help address. How can representatives from the scleroderma community
fit into one or several of these meetings to accelerate promising
clinical opportunities and better enable new pathways to discovery for
scleroderma and other illnesses?
Answer. There is great excitement at the NIH as well as in the
voluntary and professional communities about the newly launched NIH
Roadmap Initiative and what it will mean to medical research. The NIH
is committed to the participation of all of the voluntary and
professional groups in this process. Opportunities range from serving
as a member on one of the Working Groups that are just being formed, to
providing comments through other venues such as public representatives
serving on Institute National Advisory Councils or meetings of the NIH
Director's Council of Public Representatives. As well, as the Roadmap
Initiative moves forward, there will be opportunities to review draft
recommendations from the many components of the Initiative as
information is posted on the NIH Website and comments sought. I can
assure you that NIH is seeking very broad input on this new Initiative,
and will welcome the participation and thoughts of members of the
scleroderma community as well as all of the other constituent
communities.
Question. Approximately what percentage of scleroderma-related
grants or requests for funding did the NIH fund last year compared to
the last five years?
Answer. NIAMS is the lead Institute at NIH for funding research on
scleroderma, and the Institute has undertaken several initiatives over
the past 5 years to increase funding in this area. The total NIAMS
spending for scleroderma research has grown from $4 million in fiscal
year 1998 to over $10 million in fiscal year 2002-an increase of 155
percent. NIH-wide, funding for scleroderma research has grown to a
total of $15.1 million in fiscal year 2002.
As mentioned previously, the NIAMS has recently increased efforts
to expand the scleroderma portfolio including co-sponsoring a
conference on ``Emerging Opportunities in Scleroderma Research,'' which
led to the funding of a very successful special solicitation; support
for two Specialized Centers of Research on scleroderma to enhance
translational research; and support for the development of a national
scleroderma family registry and DNA repository, with the overall
objective of identifying genes that influence susceptibility to the
disease.
VASCULAR DISEASE
Question. There seems to be evidence that vascular diseases--
including stroke, high blood pressure, and diabetes--are associated
with an increased risk of Alzheimer's disease. Some promising initial
studies suggest that cholesterol-lowering drugs and changes in diet
could reduce that risk. Are you conducting any research along these
lines?
Answer. A growing body of evidence suggests that some vascular
conditions may be associated with an increased risk of cognitive
impairment and/or Alzheimer's disease (AD), and such findings suggest
that interventions to treat or prevent these conditions, particularly
cholesterol-lowering drugs or dietary changes, could also be used to
treat or prevent AD. For example, recent results from a biracial
(African American and white) population-based community study in
Chicago have suggested that dietary intake of vitamin E can decrease
the risk of cognitive impairment and AD and that intake of dietary fats
may increase or decrease risk of AD depending on the type of fat, while
several epidemiological studies have suggested that individuals who
take cholesterol-lowering drugs known as statins may have a reduced
risk of cognitive impairment or AD.
The NIA is currently conducting several clinical studies of
cholesterol-lowering drugs and dietary modifications for AD treatment
or prevention. For example, recent results from the Framingham Heart
Study indicate that high blood levels of the amino acid homocysteine, a
known risk factor for cardiovascular and cerebrovascular disease, may
also be a risk factor for AD. The Alzheimer's Disease Cooperative Study
(ADCS) will soon begin a clinical trial to determine whether lowering
homocysteine using a combination of vitamins B6 and B12 and folic acid
can modify progression of AD over a one-year period. Several other
studies using various antioxidants to prevent or treat AD are ongoing.
The NIA has also initiated a clinical trial through the ADCS to
determine whether the cholesterol-lowering drug simvastatin can slow
the progression of AD in people who have mild to moderate disease.
Studies using another statin drug, lovastatin, are ongoing or planned.
In addition, the NIA supports a number of basic studies elucidating
the mechanisms of interventions that ameliorate both vascular and
cognitive dysfunction. These include animal studies on the effects of
cholesterol and cholesterol-lowering drugs on cognition. The Institute
has provided support to several long-term cardiovascular health
studies, including the Framingham Study, the Honolulu Heart Study, and
the Cardiovascular Health Study, to explore links between vascular
disease and cognitive impairment. We are also working with the National
Heart, Lung, and Blood Institute to identify potential areas of
collaboration in both epidemiologic studies and clinical trials.
DIABETES AND HYPERTENSION
Question. Within the next 30 years, minorities will make up one-
fourth of the elderly population. (16 percent today) Some studies
suggest that the two diseases that are most common in minority
populations--namely diabetes and hypertension--are associated with an
increased risk of Alzheimer's disease. Are you pursuing any research in
this area?
Answer. The NIA supports a number of epidemiological studies that
are looking for risk and protective factors for AD, including diabetes
and cardiovascular disease, in minority populations. For example, the
Sacramento Area Latino Study on Aging (SALSA), a study of nearly 1,800
community dwelling Latinos, primarily Mexican Americans aged 60 and
above, has recently reported that risk of dementia was nearly 8 times
higher in those individuals with both type 2 diabetes mellitus and
stroke. In a community-based sample of African Americans in
Indianapolis, the investigators found that use of antihypertensive
medications was associated with preservation of cognitive function in
older adults.
The need to understand the driving factors behind persistent black-
white health disparities in cardiovascular disease, cerebrovascular
disease, and overall longevity has led to the development of the HANDLS
(Healthy Aging in Neighborhoods of Diversity across the Lifespan)
study, a community-based research effort focusing on evaluating health
disparities in socioeconomically diverse African-Americans and Whites
in Baltimore. This multidisciplinary project will assess physical,
genetic, demographic, psychosocial, and psychophysiological parameters
over a 20-year period. It will also employ novel research tools to
improve participation rates and retention. HANDLS researchers will
investigate the longitudinal effects of socioeconomic status and race
on the development of cerebrovascular disease and cardiovascular
disease, as well as changes in psychophysiology, cognitive performance,
strength and physical functioning, health services utilization, and
nutrition, and their influences on one another and on the development
of cardiovascular, cerebrovascular, and cognitive decline.
ALZHEIMER'S DISEASE
Question. In your testimony you talk about the remarkable strides
that have been made in understanding Alzheimer's disease. How quickly
can we expect some of that new information to be put into the hands of
physicians who are treating Alzheimer's patients? Along the same lines,
do you feel that there are sufficient clinical researchers trained to
translate all of this new knowledge into treatments and better patient
care?
Answer. NIA is currently conducting 18 clinical trials, seven of
which are large-scale prevention trials. These trials are testing
agents such as estrogen, anti-inflammatory drugs, and anti-oxidants for
their effects on slowing progress of the disease, delaying AD's onset,
or preventing the disease altogether. Other intervention trials are
assessing the effects of various compounds on the behavioral symptoms
(agitation, aggression, and sleep disorders) of people with AD. In
addition, the NIA has a contract in place to facilitate testing of
potential new therapeutic compounds in animals. This contract mechanism
has now been in place for 8 years and has yielded several potentially
promising compounds. So far, two of the drugs that have been tested,
AIT-082 and phenserine, have entered human clinical trials.
Although I cannot predict when potential treatments will be
available to physicians treating AD patients, I am hopeful that the
ability to support clinical trials directed at the multiple molecular
targets identified by recent research advances will lead to positive
results in the not-too-distant future.
Expanding the numbers of AD-focused clinical researchers has long
been a priority of the NIA. Opportunities for clinical research
training exist throughout NIA's 29 AD Centers, as well as through the
Alzheimer's Disease Cooperative Study. Many of our program project
grants have also provided an avenue for training young physician-
scientists. An important aspect of each of these mechanisms is the
exposure of basic scientists to clinical research; a number of these
``clinically-trained'' basic scientists are now making important
advances in the clinical arena. NIA has also initiated the Markey
Training Program, which provides support for supervised research and
study for clinically trained professionals who wish to redirect their
careers toward research on Alzheimer's disease. In fiscal year 2002,
six investigators received Markey Awards.
Efforts are ongoing to find better ways to encourage and facilitate
entry of clinicians into research careers (e.g., public/private
collaborations, Beeson scholarships for training in geriatric
research). Dr. Judy Salerno, NIA Deputy Director, has been leading a
major effort, in collaboration with members of the National Advisory
Council on Aging, to identify issues that affect the numbers of
clinicians entering or remaining in research careers. Related to this
effort, a symposium was held in November 2002 in Bethesda entitled
``Finding Synergy: Advancing the Development of Physician-Investigators
in Aging and Geriatrics'' at which experts in the field shared their
views of what would be needed to increase the numbers of clinical
researchers.
WOMEN'S HEART EDUCATION
Question. I am concerned that heart disease remains the leading
cause of death of women in the United States, yet many women do not
realize this fact. I hear that you have been working with the fashion
industry in your Women's Heart Health Campaign to increase women's
knowledge about their No. 1 killer. Please tell the Committee about
this initiative.
Answer. The NHLBI launched a new campaign, The Heart Truth, last
September to convey the message ``Heart disease is not just a man's
disease--it's the No. 1 killer of women.'' The Institute unveiled the
Red Dress Project as part of the campaign during Mercedes-Benz Fashion
Week, February 7-14, 2003, in New York. Fashion Week is a twice-yearly
event in which top fashion designers in the United States unveil their
new garment lines for the following season. It garners attention from
media in the United States and around the world, including editors from
most daily newspapers, women's magazine editors/writers, and
broadcasters such as Entertainment Tonight and local network
affiliates. The Red Dress Project provides a platform to promote the
messages of the campaign via the slogan ``heart disease doesn't care
what you wear.'' Nineteen red dresses were contributed by leading
fashion designers from either vintage or current collections and
showcased throughout Fashion Week. A Red Dress Pin, specially designed
for The Heart Truth campaign by a leading accessory designer, was
introduced as the national symbol for women and heart disease.
First Lady Laura Bush wore the Red Dress Pin during her visit to
the Red Dress Project display in New York on Valentine's Day. She
appeared on Good Morning America, Today, and The Early Show to promote
awareness of women and heart disease. On February 21, in the Great Hall
of the Hubert H. Humphrey Building, U.S. Department of Health and Human
Services Secretary Tommy G. Thompson presented The Red Dress Project
and designated the third Friday of February as Women's Heart Day. The
Red Dress Project is the cover story of the May 2003 issue of
Prevention magazine and has been featured in People magazine and
Newsweek. A national tour of the Red Dress Project is also being
developed, as well as plans to disseminate The Heart Truth messages and
Red Dress Pin through channels that will reach a diverse population of
women.
PARITY
Question. Dr. Insel, as you know there has been a lot of discussion
during the last several years concerning the issue of mental health
parity--that is, the requirement that health insurance coverage for
mental disorders be provided on the same basis as that provided for
coverage of so-called physical disorders. What is your view of that?
Answer. As you know, the President has come out in support of
parity coverage for mental disorders. Mental disorders are real and
devastating illnesses. They account for a large proportion of the
disability caused by all medical illnesses. Research supported by NIMH
shows that the increase in cost to provide parity coverage for mental
disorders can be limited, but not treating them would be very costly.
MEN AND DEPRESSION PROGRAM
Question. I note that NIMH has recently launched--with the help of
the Surgeon General of the United States--a major public campaign
focused on men and depression. Can you tell me why you've done that?
Answer. Depression is a treatable medical disorder that causes
terrible suffering for its victims and is the cause of many of the
Nation's 30,000 suicides each year. A major obstacle to getting people
into treatment, however, is the stigma that accompanies admitting that
you're depressed and that you need help--and this is especially true of
men, including men who have suffered trauma. To help men recognize the
signs of depression and to guide them toward more information and
sources of assistance, the NIMH recently launched the ``Real Men/Real
Depression'' public education campaign.
Question. Isn't it true that far more women than men develop
depression?
Answer. Yes, more women than men are diagnosed with depression, but
men do have depression and are less likely to seek treatment. One
indication of the importance of this campaign is that four times as
many men as women die by suicide. Figures from the Centers for Disease
Control and Prevention and the 2000 census show that more than 70
percent of all suicide victims are white males.
Question. What do you hope to accomplish with this?
Answer. The NIMH estimates that more than 6 million American men
suffer from depression every year. We are trying to overcome the
barriers that prevent these men from seeking help, and we are hoping to
reduce the number of suicides in this country as a result of this
effort. We already appear to be having success, based on the many
thousands of e-mails and letters asking for help or more information
that we have received to date--not only from depressed men, but from
their friends, their family members, their co-workers, and others who
care about them.
BUDGET REQUEST
Question. For fiscal year 2004, the President is proposing $1.382
billion for scientific and clinical research at NIMH. This is $41
million over the fiscal year 2003 appropriation of $1.341 billion--a 3
percent increase. This is barely enough to cover inflation and below
expected increases in the cost of conducting clinical research. The
Subcommittee is concerned that this funding request could prevent NIMH
from sustaining the ongoing multi-year research grants that have been
initiated over the past 2-3 years. What would be the impact of holding
increases at NIMH to 3 percent this year? Would NIMH be able to
continue ongoing, multi-year research programs such as the plan on mood
disorders and bipolar disorder? Can you provide us with an estimate of
the number of qualified grant proposals that you would expect to be
unable to fund if NIMH's budget is held to a 3 percent increase in
fiscal year 2004?
Answer. Under the proposed 3 percent increase for NIMH's fiscal
year 2004 budget, the Institute will honor its commitments to ongoing
grants that have been funded over the past several years. The proposed
budget provides funds to proceed on schedule in addressing the
scientific priorities identified in The Strategic Plan for Mood
Disorders Research. In fiscal year 2004, the NIMH estimates receiving a
total of 2,535 applications for research project grants (RPGs). At the
fiscal year 2004 President's Budget level, NIMH would fund an estimated
636 of these applications while the remaining 1,899 RPGs would be
unfunded. This is a success rate of 25 percent and is consistent with
NIMH success rates over the last few years
RESEARCH
Question. While steady funding increases have been achieved in the
area of severe mental illness research, research on these illnesses
remains underfunded, given the severe burden that these diseases
present to the nation's public health. A 1996 independent study by the
World Bank and World Health Organization (DALY: Disability Adjusted
Life Years) found that four of the top ten causes of disability
worldwide are severe mental illnesses: major depression, bipolar
disorder, schizophrenia, and obsessive-compulsive disorder. But using
the most recent estimates from NIH, research on mental illness lags far
behind other diseases relative to public health costs, lost
productivity, disability, etc.
What efforts are underway at NIMH to focus greater attention and
resources on promising research at the basic, clinical, and services
levels on severe mental illness such as schizophrenia, bipolar disorder
and major depression?
Answer. NIMH maintains energetic communications, public liaison/
outreach, and public education programs, all of which are designed to
draw attention to the opportunities and payoff of research on mental
and behavioral disorders. The Institute's award-winning home page
presents a wealth of information, (www.nimh.nih.gov) about mental
disorders and recent progress in NIMH sponsored research. The page
receives approximately 10 million hits per month from the public as
well as members of the scientific and clinical communities. In April,
NIMH launched a new mass media campaign, Real Men. Real Depression.,
which is focused on the leading cause of disability adjusted life years
in the United States. The campaign features real men--that is, not
actors--describing in everyday language what it felt like for them to
be depressed. They talk about their confusion and concern for their
ability to care for their families, about their jobs, about plans and
hopes that are so easily shattered by depression. They talk about the
difficulty of acknowledging that they were depressed and the struggle
to force themselves to get help--help that is available largely because
of NIMH-sponsored research.
TREATMENTS
Question. In the last decade, many new treatments and services have
been developed and proven for severe mental illnesses such as
schizophrenia. Yet most individuals with these illnesses receive
extremely poor treatment. What efforts are underway (or ongoing) to
ensure that the improved treatment interventions being developed now
will be effectively disseminated to providers and made available to the
people who so desperately need these treatments?
Answer. NIMH supports research on testing the best methods for
dissemination of knowledge, whether in the form of evidence-based
reports, algorithms, or guidelines. In addition to building a stronger
base for understanding what are the best methods for sharing
information, we also are engaged in research that seeks to determine
how information is translated into sustained practice, or more simply
put, how to get individuals, practitioners, and health care systems to
adopt effective research-based practices. Examples of some of the
grants we currently fund include studies that examine the use of
depression guidelines in primary care settings, and the use of practice
guidelines by physicians to improve care for hospitalized youth with
aggression and impulsivity. Another project examines the use of the
internet in educating families on care issues related to schizophrenia,
while another applies technology for physicians' use with decision
making in prescribing medications in community mental health clinics.
Examples of program activities that occurred during 2002 include:
--Two workshops on diffusion of evidence based practices in state
mental health systems
--Workshop on special issues in disseminating research findings for
child and adolescent mental health
--Initiation of new grants mechanisms that increase the capability of
providing centers to evaluate the delivery of their
interventions and improve their practices; and expedited
submission, review and funding of applications where evaluation
of changes being made in a delivery system requires time
sensitive research.
Question. How is NIMH collaborating with SAMHSA and the Center for
Mental Health Services (CMHS) on these efforts?
Answer. The Science to Service Initiative that involves SAMHSA
Centers and NIH institutes (NIMH, NIDA, and NIAAA) has as one of its
goals the exchange of evidence-based practices that can be implemented
by SAMHSA in natural settings, and then further researched by NIH as
treatment and services questions arise from the practice field. NIMH is
the principal source of support for mental health services research in
the DHHS. In the past 22 months, we have been able to increase the
number of services research applications by 45 percent. We are
providing technical assistance to former SAMHSA grantees through
workshops and individual consultations and working closely with CMHS
staff members. Through co-sponsored activities we are working together
to build the capacity of state mental health agencies and other
``natural treatment settings'' to conduct research on the treatment
they are providing, to evaluate its effectiveness and to examine
factors that will increase readiness for adoption of research-based
care.
SERVICES RESEARCH
Question. Administration is returning agencies to their core
mission, meaning that NIMH, rather than the Substance Abuse and Mental
Health Services Administration, will be conducting services research on
mental health issues.
To what degree is NIMH prepared to assume greater responsibility
with respect to services research?
Answer. NIMH is the principal source of support for mental health
services research in the DHHS. In the past 22 months, we have been able
to increase the number of services research applications by 45 percent.
We are providing technical assistance to former SAMHSA grantees through
workshops and individual consultations and working closely with CMHS
staff members. The Science to Service Initiative that involves SAMHSA
Centers and NIH institutes (NIMH, NIDA, and NIAAA) has as one of its
goals the exchange of evidence-based practices that can be implemented
by SAMHSA in natural settings, and then further researched by NIH as
treatment and services questions arise from the practice field.
Question. People with mental illnesses often have conditions
besides a mental health diagnosis. To reflect the real world in which
mental health services are delivered, how will NIMH services research
address people with multiple diagnosis?
Answer. To insure rigor and maximize the possibly of detecting a
treatment effect, randomized, controlled clinical trials--the
traditional ``gold standard'' for medical research--have excluded
anyone with a comorbid mental disorder, substance use disorder, general
medical illness or other conditions ranging from pregnancy to active
suicidality. Thus, the typical clinical trial for an antidepressant
would be conducted with a relatively small, highly homogenous number of
outpatients or, less frequently, inpatients, usually in an academic
health center. The major outcome criterion would be a decrement on a
behavioral rating scale such as the Hamilton Depression Scale.
In real life, of course, the patient who typically appears in a
psychiatrist's office is quite unlike the patient enrolled in the
traditional clinical trial. Accordingly, while the NIMH will continue
to fund the traditional form of clinical trial, the Institute's
researchers also are adapting to the changing nature of treatments,
patients, and the health care environment. In order to help clinicians
provide optimal care to patients, research today also involves trials
with larger sample sizes and with fewer exclusion criteria; trials are
being conducted not only in academic clinics but also in more real
world settings including managed care settings; and outcomes are
assessed not only on the basis of symptom reduction but also on
measures of functional rehabilitation, the end result that is of
greatest interest to families and patients as well as employers and
others who pay for treatment. This new type of trial--often called an
``effectiveness'' trial--need not give up any of the traditional and
indispensable emphasis on rigor. In trials of both pharmacotherapies
and psychotherapies, the information sought should be geared toward
helping clinical decision-making in real world settings and should
demonstrate compelling types of functional outcomes. From a
methodological perspective, new analytic techniques are being developed
that allow clinical investigators and services researchers to move away
from linear patterns and account for the complex interactions that
occur in the real world.
Question. Research at NIH focuses on randomized, clinical trials,
despite the fact that many other proven research methods are more
conducive to services research (such as multi-site research or analysis
of nationally representative data sets such as the Census Bureau's
Current Population Survey or the National Health Interview Survey). To
what degree will NIMH utilize these other methods?
Answer. NIMH supports a wide array of research designs and methods,
not just randomized clinical trials. Researchers have the freedom to
use the best techniques available to address the questions they are
asking. This might involve using statistics to analyze large national
data sets as in studies of risk factors for depression in children, or
the use of interviews and qualitative techniques for research questions
that require more context to understand. Other studies require control
of variables to get at causation; thus randomized clinical trials are
appropriate. Epidemiologic studies are also conducted in which surveys
are the basic tools used. In summary, no one approach is used-the
research question asked dictates the method to be used.
SCHIZOPHRENIA
Question. Schizophrenia is the most devastating mental illness,
affecting approximately 2.2 million American adults, or 1.1 percent of
the population age 18 and older. Scientists still do not know the
specific causes of schizophrenia; like many other medical illnesses
such as cancer or diabetes, schizophrenia seems to be caused by a
combination of problems including genetic vulnerability and
environmental factors that occur during a person's development. While
newer treatments for schizophrenia such as atypical anti-psychotic
medications are proving effective, these treatments are largely
palliative and help patients live with, rather than recover, from the
illness.
Given the enormous public health burden associated with
schizophrenia and the demand for new treatments, what is NIMH doing to
assure that the research base studying schizophrenia is strengthened
and expanded?
Answer. Recognizing that schizophrenia is among the most serious
public health problems facing Americans, the NIMH has increased the
proportion of it's budget devoted to this and other related
neurodevelopmental disorders from 16 percent to 23 percent in the last
five years. Reflecting the higher priority afforded this severe illness
within NIMH, new initiatives have been launched that balance the need
to focus on discovering the fundamental cause of the disease so a cure
might be possible, with the need to improve treatments for patients who
are suffering today.
Efforts to understand the etiology of schizophrenia and other
devastating mental illnesses are grounded in the neurosciences. For
example, the NIMH Human Genetics Initiative is in the process of
collecting biological materials on over 17,000 individuals to create a
national scientific resource of DNA for broad use by investigators in
the scientific community. Such samples help to identify risk genes
associated with schizophrenia and shed light on the mechanisms
malfunctioning in the brain. The Research Centers of Excellence (Silvio
Conte Centers for the Neuroscience of Mental Disorders) have been
established to develop and follow new leads generated by genetic and
other basic studies in order to clarify abnormalities in brain
functioning associated with major psychiatric illnesses. Over half of
these Centers focus on schizophrenia, including two new centers (Mt
Sinai, in New York City, and the University of North Carolina, Chapel
Hill) that have been funded in the last fiscal year.
BIOPLOAR DISORDER
Question. Bipolar disorder, or manic depression, is a serious brain
disorder that causes extreme shifts in mood, energy and functioning. It
affects 2.3 million adult Americans, or 1.2 percent of the population.
Currently, there is no cure for bipolar disorder. While it can be a
highly treatable and manageable illness, most of the approved
treatments are indications associated with medications that were
developed for other illnesses (anti-convulsants for epilepsy and anti-
depressants). In 1997, Congress requested NIMH to undertake a national
research plan on bipolar disorder. This request resulted in the current
research plan on mood disorders at NIMH. Can you please update the
Subcommittee on the mood disorders research plan and what NIMH is
learning about the causes and new treatments for bipolar disorder?
Answer. NIMH completed the Strategic Plan for Mood Disorders last
year and is now in the process of implementing the highest priority
recommendations for new research on the nature, course, treatment, and
prevention of these disorders. In addition, we are systematically
monitoring and evaluating the ongoing research activities in each of
the Divisions from neuroscience to services, to ensure movement toward
our goals.
In 1998 NIMH initiated funding of the STEP-BD program (Systematic
Treatment Enhancement Program for Bipolar Disorder), a multisite study
of bipolar disorder that is now following nearly 3,000 individuals
receiving care for bipolar disorder in 18 centers across the United
States. The budget for STEP-BD is approximately $25,000,000. This study
is providing unique information on the course of bipolar disorder and
on targets for treatment. We have learned, for example, that even under
optimized treatment conditions about 5 percent of people with bipolar
disorder will experience a relapse during the course of a year.
Significantly, and counter to expectations, 80 percent of these
relapses are depression, not mania, thus highlighting the need for safe
and effective treatments for bipolar depression. Studies have been
initiated to explore the value of rational strategies of combination
treatment targeting bipolar depression. One of the benefits of large
studies, such as STEP-BD is they provide training grounds and engender
interest for new studies in bipolar illness. In fiscal year 2003 NIMH
will be funding the first center specifically targeting interventions
in bipolar illness in adolescents and adults-this new center is
established at one of the primary sites of the STEP-BD study.
With an increased awareness that bipolar disorder also affects
children and adolescents, NIMH has recently funded two multisite trials
to study the benefits of medications for youths with this disorder.
______
Questions Submitted by Senator Tom Harkin
PARKINSON'S
Question. Dr. Zerhouni, I appreciate that you have focused some of
your attention on Parkinson's disease during your first year as
director and that you and your staff have developed a ``matrix'' that
outlines future NIH-funded research on Parkinson's. This matrix follows
the release in 2000 of the NIH Parkinson's Disease Research Agenda. As
you know, I have been concerned that funding for PD research during the
past few years has increased at a rate below the overall percentage
increase for NIH, despite the professional judgment estimates included
in the Research Agenda. Please explain what the NIH is doing to fully
implement the Research Agenda as well as the matrix.
In addition, the President's proposed budget for fiscal year 2004
includes $35 million for ``Roadmap Funding.'' The Budget describes its
purpose ``as an additional effort to accelerate fundamental discovery
and translation of that new knowledge into preventive and therapeutic
strategies.'' Will you be focusing on any particular diseases when you
implement the Roadmap, and will Parkinson's disease be one of the
diseases you will choose?
Answer. With regard to funding, NIH funding for Parkinson's disease
research has been growing much more rapidly than the growth of the
overall NIH budget, which of course has been very significant. During
the first four years of the doubling effort--fiscal years 1999 through
2002--actual NIH funding for Parkinson's disease research rose
approximately 92 percent, while the overall NIH budget rose by a very
generous 72 percent. To fully appreciate this increase, it is critical
to recognize that in fiscal year 1998--the ``base'' year of the
doubling--NIH had just increased its funding of Parkinson's disease
research by 23 percent over fiscal year 1997, while the overall NIH
budget increased only 7.2 percent in that time frame.
More importantly, the NIH Parkinson's Disease Research Agenda and
its updates encompass every research area critical to Parkinson's
disease--genetics, environmental factors, cell death and survival,
pharmacological treatments, deep brain stimulation, gene therapy, stem
cell research, and the non-motor effects of Parkinson's--and the NIH is
addressing every scientific aspect of that Agenda. This includes
hundreds of research grants and contracts, at all levels of research,
from basic through translational to clinical, including major clinical
trials. We are following all plausible strategies to develop therapies,
including drugs, surgery and cell transplantation. We have also held
several scientific meetings since the original Agenda was developed to
adjust to the changing scientific landscape, and to make sure that all
scientific opportunities are pursued. This includes a ``summit'' of
Parkinson's disease researchers that I convened in July 2002 to
identify roadblocks that might be impeding progress. The Summit was
very successful in identifying roadblocks, and NIH staff has drafted a
matrix of short-to-long term, and low-to-high risk action items
designed to target these issues. NIH is actively addressing these
action items, both through enhanced support of individual Institute and
Center efforts, and through improved coordination and collaboration
with the research and voluntary Parkinson's communities.
The Roadmap initiatives, being developed with input from a broad
range of NIH staff and extramural scientific experts, are not disease
or discipline specific, but rather take a cross-cutting approach to
identify scientific challenges and roadblocks to progress. Driven by
the enormous convergence in fundamental research approaches and
technologies across diseases, organs and biological systems, the
Roadmap will focus on facilitating and accelerating multi-disciplinary
aspects of basic, translational, and clinical research. Roadmap
initiatives will exploit new unprecedented opportunities and
technologies that will accelerate progress in disease areas across the
27 Institutes and Centers of the NIH. The exact nature of the progress
will differ with each disease depending on our current knowledge of the
disorder. Some diseases, which are in need of further basic research,
will be aided by initiatives supporting portions of the Roadmap such as
New Pathways to Discovery. Other diseases will benefit from Roadmap
efforts aimed at optimal translation of discoveries into clinical
reality, such as Clinical Trial Networks.
NATIONAL LIBRARY OF MEDICINE
Question. The NLM and its Center for Biotechnology Information have
made a major contribution to the fight against disease. To maximize
this contribution, this committee has supported the design of a new
facility. How is that going, and are you ready to initiate construction
if funds are made available?
Answer. The design of the National Center for Biotechnology
Information is expected to be complete by August-September 2003 at
which time the NIH, in consultation with the HHS Office of Facility
Management and Policy, will develop a plan for scheduling and financing
this project while considering other demands and priorities.
______
Questions Submitted by Senator Pete V. Domenici
MENTAL ILLNESS RESEARCH
Question. Dr. Zerhouni, can you please update the Subcommittee on
efforts underway at NIH and NIMH to focus greater attention and
resources on promising research at the basic, clinical, and services
levels on severe mental illness such as schizophrenia, bipolar disorder
and major depression to ensure that advances rapidly translate into
better treatment for individuals living with these illnesses?
Answer. At NIMH extensive efforts are underway to translate basic
science findings (from genetics, structural and functional brain
imaging, analysis of human post-mortem brain specimens, etc.) to an
enhanced understanding of the causes (etiology and pathophysiology) of
the major mental disorders. In the past few years significant progress
has been made in identifying risk genes, refining disease phenotypes
(characterizing more homogeneous subpopulations of patients), and
implicating particular brain molecules, cells, circuits and structures
as key players in these processes. The goal of these investigations is
to develop more specific treatments and, ultimately, curative and
preventive interventions. NIMH established a Clinical Neuroscience
Research Branch in 1999 specifically to address these issues of
translational science and, in the past several years, has significantly
expanded its ``flagship'' translational program--The Silvio Conte
Centers for the Neuroscience of Mental Disorders (currently 13 Centers
are funded at an annual cost of $24 million).
Carefully controlled, randomized, double-blind trials remain a
cornerstone of clinical research sponsored by the NIMH. As
practitioners are well aware, however, such studies cannot be the end
of treatment research but a beginning. Clinical treatment research must
adapt to the changing nature of treatments, patients, and the health
care environment. Accordingly, NIMH has launched a series of clinical
effectiveness trials that are characterized by large sample sizes and
few exclusion criteria; to ensure the generalizability of findings,
these trials occur not only in academic clinics but also in more real
world settings including primary care settings. The approach also calls
for aggressive dissemination of results. Four large-scale, multi-site
clinical effectiveness trials include: (1) Systematic Treatment
Enhancement Program for Bipolar Disorder (STEP-BD) to investigate
strategies for managing bipolar disorder, (2) Clinical Antipsychotic
Trials of Intervention Effectiveness (CATIE) to study the effectiveness
of the new atypical antipsychotics in schizophrenia and Alzheimer's
disease, (3) Sequenced Treatment Alternatives to Relieve Depression
(STAR*D) to develop algorithms for managing especially difficult to
treat depression, and (4) Treatment of Adolescents with Depression
Study (TADS). In mid-fiscal year 2003, all of these trials are well on
their way to attaining the targeted number of research participants.
Through the network of research centers participating in these
effectiveness trials, NIMH is creating an infrastructure for future
clinical research involving direct comparisons of treatments and their
benefits to different populations that can be conducted independently
of pharmaceutical companies.
Recognizing that much of the screening for mental illness and
treatment is provided in other than specialty settings, NIMH continues
to gain a better understanding of cost and financing associated with
care in three different settings: juvenile justice system, school
systems, and primary care. Use of non-traditional settings offer an
opportunity to learn new ways of treating and managing co-existing
addiction and mental illness problems through the use of non-specialty
care providers working with the less numerous specialty providers.
Research is also exploring preferences of individuals with mental
disorders or combined disorders to seek treatment in general health
care, or social services settings and determining if access to
treatment in a preferred setting improves seeking treatment, staying in
treatment, and adherence to treatment plans.
SCHIZOPHRENIA RESEARCH
Question. Schizophrenia is the most devastating mental illness,
affecting approximately 2.2 million American adults, or 1.1 percent of
the population age 18 and older. Schizophrenia interferes with a
person's ability to think clearly, make decisions, and relate to
others. Scientists still do not know the specific causes of
schizophrenia, but research has shown that the brains of people with
schizophrenia are different, as a group, from the brains of people
without the illness. While newer treatments for schizophrenia
(including atypical anti-psychotic medications) are proving much more
effective in treating both the positive and negative symptoms of
schizophrenia, these treatments are largely palliative and help
patients better live with, rather than recover from the illness.
Given the enormous public health burden associated with
schizophrenia and the need for new treatments, what is NIMH doing to
ensure that schizophrenia research becomes a higher priority within the
agency?
Answer. Recognizing that schizophrenia is among the most serious
public health problems facing Americans, the NIMH has increased the
proportion of it's budget devoted to this and other related
neurodevelopmental disorders from 16 percent to 23 percent in the last
five years. Reflecting the higher priority afforded this severe illness
within NIMH, new initiatives have been launched that balance the need
to focus on discovering the fundamental cause of the disease so a cure
might be possible, with the need to improve treatments for patients who
are suffering today.
Efforts to understand the etiology of schizophrenia and other
devastating mental illnesses are grounded in the neurosciences. For
example, the NIMH Human Genetics Initiative is in the process of
collecting biological materials on over 17,000 individuals to create a
national scientific resource of DNA for broad use by investigators in
the scientific community. Such samples help to identify risk genes
associated with schizophrenia and shed light on the mechanisms
malfunctioning in the brain. The Research Centers of Excellence (Silvio
Conte Centers for the Neuroscience of Mental Disorders) have been
established to develop and follow new leads generated by genetic and
other basic studies in order to clarify abnormalities in brain
functioning associated with major psychiatric illnesses. Over half of
these Centers focus on schizophrenia, including two new centers (Mt
Sinai and University of North Carolina, Chapel Hill) that have been
funded in the last fiscal year.
Although the delusions and hallucinations of schizophrenia are
often treated effectively by available medications, research indicates
that impairments in cognition (memory, planning, abstract thinking) are
most associated with disability in this illness. Unfortunately,
available medicines do little to reverse this aspect of schizophrenia.
To address this problem, NIMH has launched a Schizophrenia Treatment
Development Initiative focused on both developing new drug treatments
to remedy cognitive impairments. With the cooperation of the FDA, this
initiative will develop standard measures and methods to test new drugs
that target cognition in schizophrenia in order to provide the
pharmaceutical industry with guidelines for drug registration and
hence, enhanced incentives to invest in developing treatments for this
aspect of schizophrenia. To jumpstart this effort, in fiscal year 2004
NIMH will establish a new clinical trials network focused on
collaborating with industry to identify and test new agents for
cognition in schizophrenia.
In addition to the large Clinical Antipsychotic Trials of
Intervention Effectiveness (CATIE) project, which is designed to
determine the long-term effects and usefulness of antipsychotic
medications in a broad cross-section of persons with schizophrenia,
NIMH is conducting a range of studies concerned with how to best use
available treatments for schizophrenia. These include clinical trials
of combination medication strategies. Recognizing that medication
adherence is a crucial issue for many patients, active efforts to
stimulate research on this problem have yielded a series of new studies
designed to develop and test adherence-oriented intervention. Finally,
rehabilitation-oriented studies are encouraged and supported to develop
new approaches to enhancing patient skills and functioning.
FOCUS & ACCOUNTABILITY ON SEVERE MENTAL ILLNESS AT NIMH
Question. Dr. Insel, as you know, NIMH has been criticized in the
past for failing to maintain an appropriate focus on severe mental
illness in its portfolio. Over the years, concern has been expressed
that basic scientific and clinical research on schizophrenia, bipolar
disorder and other severe mental illnesses remain low priorities at
NIMH. In order to challenge and rebut these criticisms, would you
support a requirement for NIMH to provide an accounting of new and
existing research grants broken down by specific illnesses?
Answer. First, let me make clear that direct support for research
of so-called ``serious mental disorders,'' such as schizophrenia, is a
priority at NIMH. It is the lead Federal agency responsible for
supporting research on mental and behavioral disorders. The goal of
NIMH's portfolio of research on mental illness is to better understand,
treat, prevent, and ultimately cure mental illness. This requires both
direct and indirect approaches, which may not be apparent in accounting
for spending by disease.
Basic research, the relevance of which might not be immediately
apparent, can produce knowledge critical for understanding mental
illness. For example, studies of the brains of songbirds, brought the
unexpected and startling news that adult brains can regenerate new
nerve cells, a finding that completely changed scientists' thinking
about the possibility for brain repair. Similarly, in October 2000, Dr.
Eric Kandel, an NIMH grantee, won the Nobel Prize for Medicine based on
his work with sea slugs, in recognition that this research had
profoundly increased understanding of brain function and medication
effects in humans. Both scientists have accelerated our understanding
of brain processes important for mental illness.
Over the years, Congress has expressed interest that NIMH take
responsibility for many areas beyond mental illness including HIV/AIDs
risk behaviors, violence, gambling, and many others. Nevertheless, NIMH
has a strong and abiding commitment to a core focus on severe mental
illnesses. Indeed, NIMH has launched four large-scale, public health
oriented clinical trials in major disease conditions, including bipolar
(manic depressive) illness; schizophrenia/Alzheimer disease; treatment-
resistant depression; and major depression in adolescents. These trials
investigate ``real world'' effectiveness of mental health treatments,
and because they are carried out in community settings they do not
exclude people because they have a co-occurring substance abuse
disorder or other problems B unlike typical short-term pharmaceutical
trials. People with these disorders live in the community, and NIMH is
committed to assuring that treatment interventions will work where the
patient lives.
NIMH is supporting many new activities with a focus on severe
mental illnesses, and has increased the percentage of its overall
research portfolio in this area. One major new initiative, for example,
will look at the cognitive deficits associated with schizophrenia B the
deficits that make it very difficult for people affected by the disease
to be employed or otherwise function fully in society. This is an
effort to develop new insights into the neurobiology of attention,
working memory, and other fundamental cognitive processes in order to
identify and test potential therapeutic agents targeting cognitive
deficits in schizophrenia. As a part of this effort focused on
schizophrenia, NIMH is establishing an expert Schizophrenia Cognition
Measurement Development Group. Without measurement consensus, the Food
and Drug Administration cannot recognize cognition as a valid treatment
endpoint for industry-sponsored research and drug registration. Since
cognitive impairment, rather than delusions and hallucinations, may be
the major determinant of functional outcome in people with
schizophrenia, this is an extremely important effort. NIMH also will
support a Cognition Treatment Network to identify, evaluate, and
acquire pharmacological agents to treat cognitive deficits in
schizophrenia and related psychoses.
In summary, the goal of NIMH's portfolio of research on mental
illness is to better understand, treat, prevent, and ultimately cure
mental illness. While the NIMH has significantly increased the
percentage of its portfolio devoted specifically to studies related to
severe and persistent mental illnesses, it continues to honor its
mission and responsibility to support basic biomedical and behavioral
research that will elucidate the underlying causes of these disorders.
A strict focus on specific diseases would make this very difficult, if
not impossible, and would certainly hamper scientific progress.
______
Questions Submitted to the Social Security Administration
Questions Submitted by Senator Arlen Specter
Question. Commissioner, since 1997 the General Accounting Office
(GAO) has included the Supplemental Security Income program in its list
of programs that are at high risk for waste, fraud and mismanagement.
Thanks to the Agency's dedicated effort, GAO's 2003 High Risk Update
did not include the Supplemental Security Income program. However, as
indicated by your Corrective Action Plan, additional steps can be taken
to continue to strengthen program oversight and reduce the incidence of
erroneous payments.
What specific actions are supported in the fiscal year 2004 budget
request to prevent the occurrence of erroneous payments in the SSI
program and strengthen program oversight?
Answer. The President's fiscal year 2004 budget includes
appropriation language requiring the Social Security Administration
(SSA) to spend no less than $1.446 billion of the Limitation on
Administrative Expenses (LAE) for program integrity activities,
including continuing disability reviews (CDR), non-disability
redeterminations of eligibility in the Supplemental Security Income
(SSI) program, and overpayment workloads. This language will ensure
adequate resources for these three important and cost-effective
workloads that reduce erroneous payments, within the overall SSA
request of $8.53 billion. The fiscal year 2004 program integrity
investment will return lifetime program savings of more than $10
billion. The three key activities are:
--Continuing Disability Reviews.--SSA conducts periodic reviews to
ensure that only those beneficiaries who are truly disabled
continue to receive benefits.
--SSI Redeterminations.--Experience has shown that the most powerful
tool SSA has to detect and prevent improper payments in the SSI
program is to perform periodic reviews of the non-disability
factors of eligibility for SSI.
--Overpayment Collections.--Prompt processing of the Agency's debt
collection workload is an important element of sound financial
management and program stewardship. Having sufficient
administrative resources will allow SSA to process substantial
overpayment workloads and move forward as quickly as possible
to implement new tools of prevention, detection and collection.
SSA's substantial program integrity initiatives result in
significant benefits to the Government in terms of detecting and
collecting overpayments. Without these program integrity efforts, the
Agency would pay out billions of trust fund and general fund dollars in
erroneous payments. Experience has shown a $9-to-$1 return on for
investments in CDRs and a $7-to-$1 return for investments in SSI
redeterminations. Because these activities pay for themselves, many
times over, resources to support them shouldn't compete with resources
needed for service delivery; and the President's budget proposes
funding them through adjustments to discretionary spending caps.
The fiscal year 2004 budget also supports a number of initiatives
to prevent and collect erroneous payments in the SSI program and
strengthen program oversight, including piloting an automated monthly
wage reporting system using voice recognition and touch-tone phone
technology, testing electronic access to records of financial
institutions, and implementing cross program recovery, credit bureau
referrals, and Treasury Department administrative offset.
SSA's fiscal year 2004 budget also contains a legislative proposal
to apply the same requirements now in effect for reviewing title II
initial disability allowances to title XVI adult disability allowances.
Preeffectuation reviews have a high rate of return on investment, would
strengthen the integrity of the SSI program and help assure the
American people that their tax dollars are going only to individuals
who are truly disabled under the law.
Question. How will this budget request fully utilize all of the
tools provided by Congress for preventing and collecting erroneous
payments, in particular those authorized by the Foster Care
Independence Act of 1999? Also, if erroneous payment prevention and
collection authorities currently available are not being fully
utilized, is it because of a lack of resources available to the SSA? If
not, what is preventing SSA from fully utilizing these authorities and
what steps are being taken to overcome those barriers to full
implementation?
Answer. SSA has a vigorous program for developing all debt
prevention and collection tools authorized by Congress. The Agency's
program encompasses the authorities granted by the Foster Care
Independence Act (FCIA) of 1999, authorities given by other laws, and
self-initiated projects. SSA's strategy for implementing all of the
tools is to use its available resources first to develop those that
yield the most savings or that can be easily integrated into the
existing debt management framework.
The authorities granted by FCIA are: access to financial
institutions, credit bureau reporting, administrative offset,
establishing overpayments on the records of representative payees of
deceased beneficiaries, Federal salary offset, private collection
agencies, and interest charging. Authorities granted by other laws
include mandatory cross program recovery and administrative wage
garnishment.
DEBT PREVENTION
The top two reasons for SSI overpayment errors are unreported wages
and unreported bank accounts with substantial assets. In the past, SSA
has focused on the detection of errors in payments already made.
Initiatives either planned or underway offer substantial promise as a
means to preventing error.
--Automated Monthly Wage Reporting Using Voice Recognition and Touch-
Tone Phone Technology.--The Monthly Wage Reporting Pilot using
voice recognition and touch-tone phone technology is one of the
steps SSA is exploring to facilitate wage reporting and reduce
the incidence of erroneous overpayments in the SSI program.
Each year we detect approximately $500 million in overpayments
due to wages. Over half this amount is due to the failure to
report changes to SSA. SSI recipients are required to report
whenever there is a change in their income or the income of a
deemor (a spouse or parents of a child under the age of 18
living in the same household but not receiving SSI). Some
individuals report changes as required, but many do not.
Currently, few SSI recipients have access to the Internet.
Therefore, we are testing a new automated telephone reporting
system that could quickly process large numbers of wage
reports. We will ask approximately 4,000 people to use this new
system to report wages once a month for a 6-month period, May
through October 2003. We will then verify the wage amounts to
determine if they reported accurately. If this test is a
success, automated monthly wage reporting will be rolled out
nationwide.
--Access to Financial Institutions.--SSA will test a process using
authority granted by FCIA to access the records of financial
institutions. Use of this tool during the initial claims
process will provide access to information on unreported income
or assets. Similarly, use of the tool during the SSI
redetermination process and periodically throughout the life of
a SSI recipient's entitlement will provide information
regarding a recipient's assets in relationship to limits
affecting eligibility. SSA is currently working to finalize the
rules for publication, which will enable SSA to proceed with a
proof of concept to test the capability of electronic access of
financial records later this year. If the proof of concept is
successful, SSA will develop plans for a phased rollout of the
new business process.
DEBT COLLECTION
SSA is constantly striving to improve its debt management program.
Since 1992, when the Agency implemented Tax Refund Offset (TRO) to
collect delinquent title II overpayments, SSA has put in place eleven
different improvements. These improvements include two major expansions
to the TRO program, credit bureau reporting and administrative offset
for delinquent title II overpayments and a streamlined remittance
process that uses state-of-the-art equipment. In addition, SSA worked
with Treasury's Financial Management Service to implement Benefit
Payment Offset and the Federal Payment Levy Program, whereby Social
Security benefits are offset or levied as collection toward delinquent
tax and non-tax debts owed by beneficiaries to other Federal agencies.
--Recent Initiatives.--In keeping with its developmental strategy,
SSA implemented mandatory cross program recovery in 2002
because of its promise of large debt collections. In fact cross
program recovery has enabled SSA to collect over $50 million in
SSI debt in less than one year. SSA also implemented credit
bureau reporting and administrative offset in 2002 because
those tools could be integrated easily into the existing debt
management system.
--Current Initiative.--SSA also is developing administrative wage
garnishment (AWG), which was authorized by the Debt Collection
Improvement Act. We believe AWG has the potential to yield the
largest amount of collections of all the remaining tools. We
estimate this tool will yield $105 million in the first five
years of its use ($80 million in title II collections and $25
million in title XVI collections).
--Future Initiatives.--When SSA completes its work on AWG, it will
move on to a pair of debt collection tools authorized by FCIA:
establishing overpayments on the records of representative
payees of deceased beneficiaries and Federal salary offset.
Although these two tools will yield direct collections from
payment sources such as tax refunds, other Federal payments and
Federal salaries, they will not approach the collection
potential of AWG, and that is why they will be developed after
garnishment.
Implementation of interest charging and use of private collection
agencies will follow the completion of Federal salary offset and the
establishment of overpayments on the records of representative payees.
FULL UTILIZATION OF FCIA TOOLS
Debt management represents one of the many different areas
requiring resources. In fact, SSA has a multitude of initiatives
spanning all aspects of its business process. The Agency must
prioritize projects and choose the order in which they are developed.
SSA has a process for determining the priority of initiatives. This
process is manifested in SSA's Information Technology plan, where
projects are assessed based on their return on investment and other
critical factors. Based on this rigorous examination of projects, SSA
is focusing first on monthly wage reporting, access to financial
information and administrative wage garnishment.
Question. The ``Justification of Estimates for Appropriations
Committees'' for the fiscal year 2004 budget request for Social
Security Administration (SSA) states that: ``The Ticket to Work Program
is up and running in 33 States and the District of Columbia and will be
expanded to all States and U.S. territories in 2003.''
Specifically, how much funding is available within the fiscal year
2004 request for the Limitation for Administrative Expenses account to
support implementation of the Ticket to Work program and what
activities are supported?
Answer. SSA's fiscal year 2004 LAE account includes $39 million to
fund the following activities in support of the Ticket to Work program:
--Benefits Planning and Assistance Cooperative Agreements ($23
million).--Benefits planning, assistance and outreach (BPAO)
cooperative agreements are intended to ensure that these
community based services are available in every state, the
District of Columbia and every U.S. territory. The law
authorizes $23 million to be appropriated each year through
2004 for this purpose, and SSA's fiscal year 2004 budget
includes funding in this amount (including costs of related
training and technical assistance).
--Protection and Advocacy Grants ($7 million).--The 1999 Ticket to
Work Legislation authorizes $7 million to be appropriated each
year through 2004 for Protection and Advocacy (P&A) grants.
These grants will be used to provide advice to beneficiaries
and to provide an avenue for resolving disputes. Consistent
with the $7 million authorization, we plan to spend $7 million
(including costs of support services such as training and
technical assistance) for P&A in fiscal year 2004.
--Program Manager Contract ($9 million).--The Program Manager
contract was awarded to Maximus Inc. in fiscal year 2000 at a
total cost of $56 million covering the period September 29,
2000 through September 30, 2005. Maximus is a private Virginia
based organization that will help SSA manage the over-all
Ticket to Work program. Phase IV of the contract is funded in
fiscal year 2004 at $9.4 million.
In addition SSA's administrative budget supports other Return to
Work activities such as:
--The Ticket to Work and Work Incentives Advisory Panel advises the
Commissioner of SSA, the President, and Congress on issues
related to work incentives for people with disabilities.
--Other administrative costs include quality assurance contracts,
notices, miscellaneous printing costs such as public education
materials and reference guides, postage, training, travel, and
systems enhancements.
--Nationwide training and outreach efforts to build employment
support expertise in SSA's field offices. SSA also is looking
at its current incentives as they pertain to young people with
disabilities who are making the transition from school to work
and to disabled individuals with more challenging
rehabilitation issues.
Question. How much funding from other sources support the program
within the fiscal year 2004 budget request?
Answer. SSA's fiscal year 2004 budget includes program funding to
cover outcome and milestone payments made to Employment Networks (EN)
under the Ticket to Work program. Milestone payments are provided to
ENs based on a beneficiary's successful achievement of prescribed work
activity. Outcome payments are made once an individual's benefit
payments cease due to work activity and earnings. For fiscal year 2004,
we have budgeted $25 million in each program--Social Security (OASDI)
and Supplemental Security Income--to cover Ticket payments. In
addition, SSA provides reimbursement payments to State Vocational
Rehabilitation (VR) agencies, which elect to be paid under this system
and not as ENs, when they are successful in rehabilitating disability
beneficiaries. The budget includes an estimated $73 million to cover
OASDI VR reimbursement payments and $75 million to cover SSI
reimbursement payments in fiscal year 2004.
In addition, SSA's fiscal year 2004 section 1110 research budget
request, funded through the SSI appropriation, includes $5.2 million
for evaluation of the Ticket to Work and Self-Sufficiency Program. This
project will identify the most promising components of the Ticket to
Work initiative, the most efficient incentive structure for the
program, the refinements necessary to improve Ticket outcomes, and the
individuals most likely to benefit from the program. It also will
examine the adequacy of incentives in delivering services under the
program for hard-to-serve beneficiaries.
SSA's fiscal year 2004 budget for research and demonstration
projects also funds several other projects that support the return-to-
work initiative and the Ticket to Work program's goal of transitioning
disabled individuals into the workforce, including the Youth Transition
Process Demonstration, the Early Intervention Demonstration, and
evaluation of the Disability Program Navigator project with the
Department of Labor.
Question. Now that the SSA has roughly one year of experience with
Social Security and SSI disability recipients receiving Tickets for VR
services, what trends are evident in terms of the choices consumers are
making whether to utilize their ticket, the characteristics of
participating individuals, the organizational characteristics of
selected Employment Networks (including VR agencies), the way in which
such Employment Networks are paid and the employment outcomes for
participating individuals?
Answer. Our early information reveals that a fairly diverse group
of beneficiaries have made the decision to assign Tickets to providers
and to begin employment. So far, the profile of beneficiaries who have
assigned Tickets closely tracks the profile of Ticket-eligible
beneficiaries with regard to type of benefit, sex, type of disability
and time on the rolls. One interesting trend we will be watching is
that younger beneficiaries, those under age 40, are assigning Tickets
at a much higher rate than older beneficiaries are.
With respect to providers, approximately 85 percent of individuals
participating in the Ticket program have assigned their Tickets to the
State VR agencies; of these, about 60 percent are new clients to VR. VR
agencies have elected to receive payment under the traditional cost
reimbursement program for 95 percent of these beneficiaries. ENs with
Tickets assigned to them include traditional employment service
providers in the public and private sectors, and such non-traditional
providers as employers, colleges, employment agencies and job placement
services, hospitals, faith-based organizations and Department of Labor
One-Stop centers.
As of May 8, 2003, about 4 million Tickets have been mailed, and
more than 16,000 have been assigned to ENs or VR agencies. Although we
have information regarding payments to providers, it is still too early
to draw broad conclusions regarding the employment outcomes of
beneficiaries participating in the Ticket program. We will be
evaluating the Ticket program to identify its most promising
components, refinements needed to improve Ticket outcomes, and the
individuals most likely to benefit from the program, as well as to
assess the program's cost effectiveness. Nevertheless, many Ticket
participants are now working, and we are pleased to learn the success
stories from individuals whose receipt of the Ticket has provided them
the opportunity to return to productive employment.
By the end of this year, the Ticket-to-Work program will be
available in all 50 States. I truly believe that we're entering a new
era for people with disabilities--an era of new attitudes, new
possibilities, and new hopes. Many people want to work, and this
program helps them do that:
--Arizonian, Bob Q., used his Ticket, set up an appointment with an
employment network, and is now working as a marketing designer
for the real estate industry.
--Didi A. credits the Ticket-to-Work program for helping to provide
the motivation that brought her to Arizona Bridge to
Independent Living (ABIL). Using her Ticket, she met with a job
counselor who prepared her for work. Last September, Didi
accepted a position with the Arizona State Government.
--Vera L. has the longest recorded employment of the Ticket Program,
more than a year. Vera works 40 hours a week as a personal
assistant and has already received a raise.
Question. Through what means has SSA informed eligible
beneficiaries and recipients, employers, service providers and other
stakeholders about the Ticket program?
Answer. We've informed beneficiaries and recipients, employers,
service providers and other stakeholders about the Ticket program
through:
--The initial Ticket mailings, which we will complete in 2004;
--Media events to kick-off the Ticket program in several States in
the first two rounds of Ticket roll-out. I joined former
Senator Roth in Wilmington, Delaware to highlight presenting
``The First Tickets in the First State'' to individuals in
Delaware. I also hosted Ticket media events with Senator Ted
Kennedy in Boston, MA and Representative J.D. Hayworth in
Phoenix, AZ., and with Virginia State officials in Arlington,
VA;
--Partnering with the Office of Personnel Management (OPM) to promote
the Ticket program throughout the Federal government;
--Partnering with the Department of Labor's Office of Disability
Employment Policy to utilize its Employer Assistance Referral
Network and create a subunit named Ticket to Hire (TTH), which
specializes in matching employers with job-ready candidates
from the Ticket program;
--Partnering with private organizations to promote the program to a
diverse mix of employer groups;
--Recruitment fairs to educate service providers about the Ticket
program and encourage them to become ENs;
--Significant outreach to service providers and others by MAXIMUS,
our contracted program manager;
--Our Internet website, which educates and provides resources to
Ticket to Work stakeholders;
--National and regional representation, by specialized Ticket to Work
staff, at hundreds of conferences and forums that promote the
hiring of people with disabilities; and
--SSA's extensive informational materials provided in print and other
formats. SSA's Red Book on Work Incentives and a number of
other materials are used extensively in the field to inform and
train beneficiaries, advocates, service providers and others.
We are working on further enhancements to our outreach and public
information efforts. Plans include written and video presentation of
Ticket success stories, a new training effort to assist present and
potential ENs with information on potential funding sources and
analysis of emerging data on the Ticket program to target our
informational efforts.
Question. How much funding within the fiscal year 2004 Budget
supports training, technical assistance and outreach to these different
groups?
Answer. SSA's fiscal year 2004 administrative budget includes $39
million for BPAO cooperative agreements, P&A grants, and continuation
of the Program Manager contract. A large portion of that amount is used
to provide training, outreach and public information.
Question. How has SSA provided support to individuals in making
well-informed, work-related decisions, as well as in ensuring that
their legal rights are protected under new program authorities?
Answer. SSA has a multi-faceted approach to help beneficiaries with
disabilities obtain accurate and timely information and support
regarding return to work. The approach centers around continued
education and training for all direct service employees, the
establishment of partnerships with other agencies and organizations,
improved workload management and control systems, and the establishment
of a corps of full-time Area Work Incentives Coordinators (AWIC). The
AWIC will specialize in employment support workloads and services, and
serve as the Agency's ombudsman and focal point of contact for
advocates.
Two grant programs authorized by the Ticket to Work and Work
Incentives Improvement Act of 1999 provide support to individuals
regarding their participation in the Ticket program.
BENEFITS, PLANNING, ASSISTANCE AND OUTREACH (BPAO)
SSA awarded 116 cooperative agreements to a variety of community-
based organizations for BPAO projects. The goal of the BPAO program is
to enable SSA's beneficiaries with disabilities to make well-informed,
work-related decisions.
BPAO projects cover every State, Territory, and the District of
Columbia. Collectively they employ over 400 Benefits Specialists who
explain the complex interrelationship of SSA's benefits, those of other
Federal agencies and an individual's local programs. They assess the
potential impact of employment on a beneficiary's Federal and State
benefits eligibility and overall financial well being. Benefits
Specialists then develop a comprehensive framework of possible options
and projected results for each as part of the career development
process. Benefits assistance involves effective management of benefits
as well as problem-solving support as needed. It includes analysis,
reassessment, education, advisement and monitoring. Almost 50,000
beneficiaries have received direct services under the program to date.
Outreach activities by the BPAO projects are ongoing efforts to
inform beneficiaries, their families, service providers and other
stakeholders about the work incentives available. By enhancing
awareness and understanding of the supports to be had, the Benefits
Specialists alleviate the fear and uncertainty of beneficiaries
considering work. The BPAO program has become an important step on the
road to economic self-sufficiency for persons with disabilities.
SSA contracted with 3 universities to provide ongoing technical
assistance and training to BPAO projects so they may effectively and
responsibly serve clientele. Benefits Specialists must pass an
intensive 7-day orientation class and successfully complete a field
assignment before providing services under the program. In addition,
they attend refresher and follow-up courses throughout the award
period. This training is necessary to ensure dissemination of accurate
and timely information to our beneficiaries. SSA has provided an arena
in which persons with disabilities can confidently ask questions of a
trained professional who is not a federal employee.
PROTECTION AND ADVOCACY (P&A) GRANTS
The Ticket to Work and Work Incentives Improvement Act of 1999 also
granted the Commissioner authority to make payments to P&A systems for
the purpose of providing services to beneficiaries with disabilities.
Those services include providing information and advice about obtaining
vocational rehabilitation and employment services as well as providing
advocacy or other services that a beneficiary with a disability may
need to secure or regain gainful employment. Under this new program,
P&A grantees ensure that beneficiaries' legal rights are protected.
SSA awarded a total of 57 grants to each of the States as well as
the District of Columbia, Puerto Rico, the United States Virgin
Islands, Guam, American Samoa, the Commonwealth of the Northern Mariana
Islands, and one for the Native American community.
In 2002 alone, more than 10,000 beneficiaries with disabilities
received P&A services free of charge which ranged from information and
referral to legal representation. The P&As gave over two thousand
outreach presentations during this period. Through conferences,
seminars, publications, websites, and public service announcements on
television and radio, the projects made people aware of viable
approaches to overcoming employment barriers. Examples of the
assistance provided under this program include:
--Fighting discrimination by employers against persons with
disabilities;
--Obtaining reasonable accommodations in the workplace;
--Mediating disputes involving job coaches and individual plans for
employment;
--Resolving transportation issues related to work;
--Acquiring tuition assistance and accommodations at educational
institutions;
--Locating the best Employment Network for a beneficiary's specific
circumstances;
--Working to improve Employment Networks' grievance procedures;
--Educating beneficiaries regarding the employment supports and
incentives available; and
--Educating the local community regarding the legal rights of
individuals with disabilities.
OTHER INITIATIVES
In addition to these programs, SSA plans to create a new position,
the Area Work Incentives Coordinator, to provide technical information
and assistance to beneficiaries and outside groups and coordinate work
incentive-related activities within the field offices of the Area they
represent.
At the same time, we plan to provide a customized training
curriculum to accommodate training needs specific to each employee's
role in administering employment support programs. For example,
continuing education on Ticket to Work and related issues of concern to
our beneficiaries will allow our public affairs personnel, using their
communications skills and community outreach opportunities, to become
effective ambassadors for these programs. In addition, our enhanced
training will ensure that field and 800-Number personnel will maintain
expertise on work incentives and employment support programs to be
responsive to inquiries and process actions as appropriate.
SSA is enhancing systems and establishing procedural changes that
will assist field personnel in processing actions efficiently and
accurately and will provide information to beneficiaries with
disabilities who are working or want to work. SSA is also building
these systems to improve workload management control and to provide
more management information about beneficiaries with disabilities who
are able to return to the workforce. It is important that there be a
pool of experts with technical expertise in the complicated issues that
can arise with a disability recipient who is pursuing and taking
advantage of employment opportunities. But it is equally important that
we continue to change the organizational culture to make return-to-work
an integral part of the entire Agency's mission.
In addition to providing designated experts, we plan to leverage
our resources by heightening the awareness of employment support
programs internally and externally and broadening the knowledge of our
entire Operations workforce.
Question. How has SSA collaborated with other federal agencies and
partners to increase the work opportunities of individuals receiving
Social Security and SSI disability payments and what resources are
included within the fiscal year 2004 budget request to carry out such
activities?
Answer. SSA is collaborating with others in the following research
and demonstration projects to increase the work opportunities of
individuals receiving Social Security and SSI disability payments.
Amounts budgeted for these activities and evaluations in fiscal year
2004 total about $20 million.
--Youth Transition Process Demonstration.--SSA will support State
projects to test and deliver needed services to young Social
Security and SSI beneficiaries with disabilities to assist them
in achieving independence.
--Disability Research Institute.--One of the goals of this
cooperative agreement with the University of Illinois at
Urbana-Champaign is to provide research findings in critical
disability policy areas, such as return to work strategies.
--State Partnership Initiative (SPI).--States have been testing
innovative approaches to coordinating vocational planning and
support, employer and employee coaching, financial planning,
health and long-term care, and other necessary supports for
disability beneficiaries. SSA will be evaluating the
effectiveness of these approaches.
--Disability Program Navigator.--SSA has partnered with the
Department of Labor (DOL) to support Benefit Navigators at DOL
One-Stop Career Centers to provide beneficiaries with
information on the Ticket to Work program and other SSA work
incentives and well as assistance with related programs that
may affect their ability to enter and retain employment
(Medicare and Medicaid, housing, etc.).
SSA also is collaborating with the U.S. Department of Labor (DOL)
to sponsor the Ticket to Hire program. This free nationwide referral
service is designed to assist employers in locating and hiring
qualified job candidates with disabilities from the Ticket to Work
program. Ticket to Hire connects employers to ENs or State VR agencies
from SSA's Ticket to Work program with job ready candidates. Ticket to
Hire provides the employer with a referral list of ENs in their
community. The employer can then contact these organizations to find
qualified candidate(s) who are participants in the Ticket to Work
program.
Ticket to Hire is a specialized unit of Project EARN (Employer
Assistance Referral Network), which is also sponsored by DOL and SSA.
If the Ticket to Hire staff is unable to locate organizations with
qualified candidates in their database, the vacancy information is
shared with EARN. EARN staff then searches a database that includes
additional organizations that are employment service providers and may
not be participating in the Ticket to Work program.
Question. The fiscal year 2004 budget request proposes obligations
of $2 million for Medicare Savings Program Outreach to continue
outreach efforts to all new eligible individuals, as well as to a
portion of those previously notified. Specifically, what outreach
efforts will be undertaken to newly- and previously-eligible
individuals? What portion of those previously eligible will be notified
in fiscal year 2004 and subsequent years?
Answer. SSA intends to send Medicare Savings Programs outreach
letters annually to all new beneficiaries who meet the statutory income
test and are not already receiving help with their share of Medicare
expenses. SSA will mail outreach letters to two groups of Medicare
beneficiaries who were on the roles before the previous letter
selection:
--Beneficiaries who had too much income for this help before but now
meet the statutory income test (e.g., as a couple there was too
much income, but the new widow's income now meets the statutory
test); and
--One-fifth of people who received outreach letters before who
continue to meet the statutory income test and are not already
receiving help with their share of Medicare expenses.
SSA will continue to share electronic files of selected potentially
eligible beneficiaries of the Medicare Savings Programs with their
servicing Medicaid State agencies.
SSA plans to continue the letter and file-sharing activities
described above for new and previous eligibles annually. These
activities will ensure that every potentially eligible beneficiary
receives an outreach reminder letter at least once every five years and
States will receive appropriate information each year.
Question. How has the GAO evaluation of outreach efforts guided
development of your proposed fiscal year 2004 activities?
Answer. GAO has not yet shared evaluation data or results with SSA.
SSA looks forward to receiving the GAO evaluation as a potential source
of information that could be used to improve this process.
Question. Earlier this year, the General Accounting Office (GAO)
added Social Security's disability programs to its list of High-Risk
programs. Your fiscal year 2004 budget request supports making
substantial progress towards national implementation of an electronic
disability process--AeDib--by the end of fiscal year 2004 as a means to
improving the timeliness of and efficiency associated with disability
decisions.
How much funding is included in the request to support the AeDib?
GAO has stated (GAO-03-225, page 132) that the agency has had ``mixed
success in past technology investments.'' How has the agency's previous
experience with major technology investments helped guide the design
and implementation strategy for this new initiative?
Answer. The Agency will begin national implementation of the
Accelerated Electronic Disability System (AeDib) on January 1, 2004.
Over an 18-month period the system will be installed in every State
Disability Determination Services (DDS) center in the country. We
estimate an initial IT investment of about $150 million during the
budget period for AeDib planning, development and implementation. In
addition, significant SSA staff effort will be devoted to project as
well as related non-IT support costs.
A previous effort to automate the disability process at SSA was
called the Reengineered Disability System (RDS). In 1999 Booz Allen
Hamilton assessed RDS and made recommendations to the Agency concerning
the use of technology to improve future disability processing. AeDib is
based on those recommendations.
Many technological lessons were learned from RDS. For example,
while RDS was designed to create one processing system for all of the
State DDSs, AeDib will not replace the current DDS case processing
systems. Instead, each State is upgrading and enhancing its systems in
order to accommodate the Electronic Folder.
SSA is building applications that allow the public to file for
disability over the Internet. SSA also is creating a fully automated
Office of Hearings and Appeals Case Processing and Management System.
This system will automate the hearing process from initial receipt
through final disposition.
In order to evaluate our progress every step of the way and to
continue to meet the goals of the project, each project associated with
AeDib has been or will be rolled out in phases. This process allows SSA
to gain the experience it needs in order to continue to meet the
customer's needs.
To effectively enhance the capabilities of the Electronic Folder
and to provide the infrastructure needed for other initiatives, SSA has
completed an initial upgrade to its telecommunications infrastructure.
SSA also is maximizing the use of Commercial Off-the-Shelf products.
To document and ensure that we target our development work by
determining specific areas with the highest paybacks, Booz Allen
Hamilton has completed a Cost Benefit Analysis for AeDib.
Question. What actions are planned to ensure that all components,
including state disability determination services, have sufficiently
trained staff, available technical and program support and adequate
resources to implement this initiative and how much is provided within
this budget request for these activities?
Answer. AeDib will provide the infrastructure to support paperless
and electronic processing of disability claims from initial contact
through the hearing decision. To ensure success and ease implementation
activities, AeDib has been broken into several interrelated projects.
First, the American public will have the ability to complete
disability claims over the Internet. We have already successfully
implemented the adult version of the Social Security disability
application and medical form. Prior to national implementation, members
from the public came to SSA headquarters to test the disability form.
Between now and January 2004, we will be adding additional forms to the
Internet.
What the Internet provides for the public, the Electronic
Disability Collect System (EDCS) provides to field offices. EDCS is
used to electronically collect medical information previously obtained
on paper forms for initial adult and children cases. Regional trainers
from across the nation came to SSA headquarters to receive ``Train the
Trainer'' instruction on EDCS. As of February 2003, every field office
received EDCS training. Between now and January 2004, additional
functionality including hearings and continuing disability reviews will
be added to the program.
The next (and most complicated) project is the Electronic Folder. A
prototype of the Electronic Folder was completed in October 2002, and
pilots are scheduled to run from July 2003 through December 2003. One
of the major activities that SSA needed to accomplish to allow the
State Disability Determination Services (DDS) to interface with the new
Electronic Folder was to provide them with new computer hardware. We
accomplished this in September 2002. We provided the hardware training
to the DDSs. We are now in the process of upgrading the software.
Implementation of the Electronic Folder, combined with EDCS, will
significantly change the business process and reduce case processing
times.
The last project is to create an automated system known as the
Office of Hearings and Appeals Case Processing and Management System
(CPMS). Currently OHA has very limited automation. This project will
automate the process from initial receipt through the final decision,
which will improve case processing and contribute to productivity
improvements. We are working closely with our user groups to build a
successful CPMS prototype.
Our training strategy also is multifaceted. SSA has conducted AeDib
training for regional trainers at SSA headquarters. At SSA
headquarters, technical staff has been undergoing extensive training to
learn how to use and integrate new technologies.
In order to ensure a successful implementation of the Electronic
Folder, SSA will provide onsite technical training and support to the
various components. The goal is to ensure that the architecture is
operating smoothly and that SSA/DDS staffs supporting the system are
provided with expert training. SSA, working with the DDSs, will also
provide hands-on business training to all Federal and State components
working with the new Electronic Folder.
Our fiscal year 2004 budget includes approximately 300 workyears in
order to support these implementation initiatives and meet our goals.
Question. What steps have been taken to secure the privacy of
electronic information collected?
Answer. Several steps are being taken to secure the privacy of
electronic information for the AeDIB process as well as for other
projects SSA is undertaking. Specifically for AeDIB:
--Developers are following the SSA Systems Development Life Cycle,
which includes ongoing security review (access controls,
separation of duties, integrity, audit trail etc.), on an
iterative basis.
--We are currently piloting a secure transport mechanism for
disability data.
--A systems manager responsible for the overall project has been
named and is drafting a security plan for the project.
--We are in process of awarding a contract for a security risk
assessment monitored by the project officer, system manager and
security staff.
--We have implemented ongoing monitoring of Electronic Medical
Evidence and Security status meetings by Chief Security Officer
staff.
Question. What additional steps are being considered to improve the
accuracy, timeliness and cost-efficiency of the disability
determination process and what is the timeline for their
implementation?
Answer. AeDib is one of the key steps SSA is taking to improve the
disability process. AeDib rollout will begin in January 2004 and
continue for 18 months. While processing time is expected to improve
slightly in 2004, this initiative is expected to substantially reduce
processing time over the long term.
--AeDib will provide us with tools to move work seamlessly from place
to place, increasing access to agency medical and technical
expertise, maximizing agency resources, and supporting quality
adjudication. The first piece of AeDib is the electronic intake
system Electronic Disability Collect System (EDCS) which began
in October 2002. By automating data collection, the accuracy of
the information will be enhanced and more complete information
will be passed to the Disability Determination Services (DDS)
and later to the Office of Hearings and Appeals.
--We will be conducting assessments throughout start-up and rollout
of the new system and process. Additionally, we will be
conducting a post implementation review that will help
determine impacts, efficiencies and quality results based on
AeDib.
--SSA also is working with the medical community to leverage their
electronic processes in coordination with our AeDib medical
evidence activities. Our goal is to increase the electronic
exchange of medical evidence to maximize efficiencies in
alignment with Health Insurance Portability and Accountability
Act (HIPAA) regulations. On May 8, I met with representatives
from some of the nation's largest medical professional
associations to discuss SSA's medical evidence needs, the
process for obtaining evidence, the new HIPAA compliant
authorization form, and our vision of a future electronic
business process.
SSA has been engaged in a number of efforts to redesign and improve
the disability determination process by testing several initiatives
over the past several years. Based on our review of their results, we
have decided to:
--Encourage early and frequent contacts with claimants during the
development process;
--Eliminate the claimant conference at the end of the process; and
--Temporarily extend the ``elimination of reconsideration step''
feature in the Prototype States that are currently doing this,
while SSA develops an alternative approach.
The amount of time the SSA appeals process takes also has been a
major concern. SSA has made the following near-term changes to the
hearing process, based on analysis of the Hearings Process Improvements
(HPI) initiative:
--Include ALJs in early case screening to more quickly identify cases
for dismissal and possible on-the-record decisions;
--End the requirement that cases be certified as ``ready to hear'',
removing a step in the process;
--Allow ALJs to issue fully favorable decisions from the bench
immediately after a hearing; and
--Expand the use of technology in the Office of Hearings and Appeals,
including video teleconferencing, speech recognition and
digital recording of hearings.
SSA also is assessing its policies and procedures to enable
simplification of data collections and case documentation. We have
revised and consolidated data collection forms to ensure consistency
and accurate data propagation. For example, we are combining 3 forms
into a single public-use document as part of the appeals process.
SSA currently reviews at least 50 percent of all title II initial
disability allowances made by State agencies on behalf of SSA. The
fiscal year 2004 President's budget includes a proposal to apply the
same requirement for adult disability allowances in the SSI program.
That is, when fully phased in, 50 percent of initial SSI disability
allowances would be reviewed, applying consistency across both
disability programs.
We expect to make recommendations soon regarding additional steps
we can take to improve the disability process.
Question. Commissioner, you have stated that the Hearings Process
Improvements (HPI) initiative, which was implemented in 2000, has not
worked and that SSA has implemented additional changes to the process,
based on your assessment of HPI.
What lessons has SSA learned from the failure of HPI and how were
they used to develop and implement the latest changes?
Answer. What we learned during the course of HPI has yielded
insights valuable to the further refinement of our hearings processes.
We have not yet implemented our contemplated mid-term and long-term
process changes. Therefore, these responses chiefly address changes we
have made in the short-term.
We learned that the HPI processes included unnecessary case
handoffs. In our latest changes, we sought to eliminate these handoffs.
For instance, we observed that attorney and paralegal certification of
cases as ``ready to hear'' before sending those cases to Administrative
Law Judges (ALJs) for prehearing review was a step of limited value. We
have eliminated that step. Though we had initially thought that
rotating functional assignments among support staff would improve
overall hearing office performance, we discovered that rotation
actually undermined the strengths of our staff. Consequently, we
discontinued rotations and created a new position, the Case Intake
Assistant, with duties that incorporated the previously rotated
functions.
HPI taught us the importance of a strong management team in the
hearing offices. We are striving to strengthen the management structure
in the field. HPI also taught us the importance of prompt
implementation of systems support needed to support new initiatives. We
are proceeding as expeditiously as possible with the development and
implementation of new technology and applications to support the Office
of Hearings and Appeals' (OHA) business processes.
Question. Given that implementation of reforms is very costly in
terms of additional delay for individuals involved in the process, lost
production time, and staff anxiety, what steps were taken to involve
all stakeholders in the latest reform and what resources are included
in the fiscal year 2004 request for staff training and support of
implementation?
Answer. We haven't undertaken a major reform of the hearing process
since HPI. However, we recognize there are significant hearing backlogs
and we need to make every effort to move toward reducing those
backlogs. For this reason, with the proposed transfer of Medicare
hearings to the Department of Health and Human Services in fiscal year
2004, this budget redirects 478 workyears previously used to process
Medicare hearings to processing SSA disability hearings and appeals
instead. This will enable SSA to process 46,000 more SSA hearings in
fiscal year 2004 than in fiscal year 2003 and improve service by
reducing the hearings processing time.
We have focused on processing the work with incremental initiatives
that could be effectuated in the short term with little delay for
individuals involved in the process and minimal, if any, loss of
production time. We believe the nature of these changes, our candid
discussions with all of the unions representing our employees, and the
initiatives' incremental implementation over the past year have helped
to minimize any potentially adverse impact on employee morale and
productivity. And, despite additional investments in training, savings
from initiatives will increase the overall production rate for SSA
hearings from fiscal year 2003 to fiscal year 2004.
The budget continues to support base levels of ongoing and new
staff training for OHA staff, plus significant training for
technological enhancements to the business process in fiscal year 2003
and fiscal year 2004, including training related to implementation of
AeDIB. Most of the cost of staff training is the workyear cost, along
with related non-payroll expenses for instructors and travel. For
fiscal year 2004, we estimate about 250 workyears for OHA training,
including about 100 workyears related to AeDIB.
Question. How will the latest reforms improve timeliness, accuracy
and efficiency of decision making? What other changes have been
implemented to help improve productivity and increase the likelihood of
getting the right decision at the earliest possible time?
Answer. We are preparing cases for hearing more quickly and in
greater numbers with the aid of contract file assemblers, who furnish
clerical support for file preparation. As previously noted, we also
have eliminated rotational assignments for case technicians. These
actions free case technicians to concentrate their attention on more
complex case preparation tasks.
We have asked our most highly trained employees, ALJs, to join
other professional hearing office employees in early screening and
reviewing cases most likely to warrant on-the-record decisions. ALJ
participation in this process facilitates review of a higher percentage
of such cases, thus increasing the number of cases that can be decided
early, without the necessity of a hearing.
We have implemented a new decision writing program for fully
favorable decisions that is easy for ALJs and decision writers to use
and fully documents the legal basis for fully favorable decisions.
Providing the new program as a tool for their use, we have asked ALJs
to use their personal computers to draft any fully favorable decisions
they reach as a result of early screening, as well as any decisions
that they announce orally at a hearing. This eliminates case handoffs
to the decision writers and frees the decision writers to concentrate
on more complex cases.
We are providing speech recognition software to ALJs and decision
writers to facilitate decision drafting. The introduction of this
software will eliminate the need for transcription of dictated
decisions by case technicians, shortening case processing time and
freeing the case technicians for case preparation duties.
Question. The GAO Report ``Social Security Disability: Efforts to
Improve Claims Process Have Fallen Short and Further Action is Needed''
(GAO-02-826T) found that in fiscal year 2000, about 40 percent of the
applicants whose cases were denied at the initial level appealed this
decision and about two-thirds of those who appealed were awarded
benefits. What resources and activities are supported in the fiscal
year 2004 budget request to specifically address this issue and reduce
the likelihood that initial decisions are changed upon appeal?
Answer. Our goal is to make the right decision on disability claims
as early in the process as possible. We should note, however, that a
different decision during the appeals process does not necessarily mean
that the initial decision was wrong when it was issued. Unfortunately,
currently many months may elapse between the initial determination and
the various steps of the appeals process and, during that time, the
claimant's medical condition may have worsened. And, we allow a
claimant to provide additional information at any time during the
process. So a person who may not have met the criteria for disability
assistance at the first step may meet those criteria by the time a
hearing can be held. This kind of situation shows the importance of
reducing the delays and backlogs that currently make the appeals
process take so long. (We also are working on finding ways to ensure
that complete information is provided at the initial determination step
so that the decision-maker can consider all factors that may affect the
decision.) For this reason, I have made eliminating backlogs a primary
focus.
As I indicated in my testimony at the March 4, 2003 House
appropriations hearing before the Subcommittee, the President's budget
request for fiscal year 2004 demonstrates our commitment to continuing
efforts to improve service, efficiency and program integrity in the
disability program. Issues regarding the appeals process and reducing
the likelihood that initial decisions are changed upon appeal are
longstanding concerns in the disability program. We expect to make
recommendations that address those issues in the coming months, and
expect to propose changes that are cost-neutral in terms of the overall
impact on SSA's budget.
In order to effectively address the systemic issues in the
disability process, we need to get the existing disability workloads
under control. Based on the work that has been done on our Service
Delivery Assessment, it is clear that eliminating backlogs and
processing special workloads are prerequisites for providing good
service to the public. Although approximately 40 percent of disability
claims are approved within three and a half months of initial
application, for applicants who exercise all administrative appeal
rights provided under current law and current processes, an average of
1,153 days is required for a final Agency decision. Based on our
analysis, almost 50 percent of this time in the process results from
the backlog of cases.
We are taking a number of actions in the near term to reduce
processing times and increase efficiency. The fiscal year 2004 budget
request supports those actions. As indicated above, we are engaged in
review of strategies to further improve the disability program and
expect to make recommendations soon.
Question. The fiscal year 2004 President's Budget proposes to
transfer responsibility for Medicare hearings from SSA to the
Department of Health and Human Services (HHS).
What are the actual expenditures and associated workload processed
in fiscal years 2000, 2001 and 2002, as well as those estimated in
fiscal year 2003?
Answer. The chart below provides actual expenditures and associated
workloads for Medicare hearings for fiscal years 2000, 2001 and 2002 as
well as those estimated for fiscal year 2003 in the fiscal year 2004
President's budget. The estimates for fiscal year 2003 assume an
increase in receipts related to the Medicare, Medicaid and SCHIP
Benefits Improvement and Protection Act of 2000 (BIPA) and
implementation of a streamlined process for handling Medicare appeals.
Neither of these has occurred.
----------------------------------------------------------------------------------------------------------------
Actual fiscal year Estimate
Medicare hearings --------------------------------------- fiscal year
2000 2001 2002 2003
----------------------------------------------------------------------------------------------------------------
Receipts.................................................... 77,872 77,726 71,576 122,147
Processed................................................... 88,084 69,663 77,388 105,000
Pending..................................................... 35,904 43,517 37,705 54,852
Expenditure (dollars in millions)........................... $79 $74 $78 $79
----------------------------------------------------------------------------------------------------------------
Question. What planning and transition activities are being
undertaken with HHS/CMS to ensure that a timely and smooth transition
occurs, if legislation is enacted that transfers the Medicare appeals
function effective October 1, 2003 as proposed in the President's
budget?
Answer. While we have agreed with HHS/Centers for Medicare and
Medicaid Services (CMS) in principle to transfer responsibility for the
Medicare hearings function effective October 1, 2003, we are still
working out the details of the workload transfer. In January 2002, I
established an executive level position on my staff to work directly
with the CMS Administrator and his staff to provide technical
assistance in the design of a hearing process and service delivery plan
tailored to the unique needs and opportunities of Medicare appeals. SSA
and HHS/CMS have had an ongoing dialogue since that time. These
discussions focus on issues such as transfer of cases, sharing of
resources (e.g., video teleconferencing), and systems support. A
Memorandum of Agreement that will reflect these decisions is being
prepared.
Beginning with fiscal year 2004, consistent with the
Administration's plan to transfer the Medicare hearings function to the
Department of Health and Human Services, SSA's annual budget request
does not include the resources that would be needed to process Medicare
hearings. The President's budget now includes the Medicare hearings
function and related funding under the Department of Health and Human
Services, which is accountable by law for management and administration
of the Medicare program.
Question. What amount of budget authority is required in fiscal
year 2004 to process fully this workload, if legislation is not enacted
consistent with the President's budget?
Answer. Funds to process Medicare hearings are budgeted in HHS/CMS
for fiscal year 2004. Consistent with our assumption that HHS/CMS will
assume responsibility for the Medicare hearings function beginning
October 1, 2003, SSA has not included any resources in its fiscal year
2004 budget request to process this workload.
Question. In January 2001, the General Accounting Office identified
strategic human capital management as a governmentwide high-risk area.
What steps are you taking to acquire, develop, and retain an
appropriate mix of agency staffing/talent, particularly in light of the
Agency's impending retirement wave? What is the agency's plan for
creating an organizational culture that promotes high performance and
accountability and empowering and including employees in setting and
accomplishing programmatic goals? How does the fiscal year 2004 budget
support these activities?
Answer. SSA is taking a number of steps to acquire, develop, and
retain an appropriate mix of agency staff.
SSA started retirement wave analysis and planning over five years
ago. This analysis was the impetus for our Future Workforce Transition
Plan (FWTP), which positions us well to transition to the workforce of
the future. The FWTP contains milestones regarding recruitment,
retention, employee development and a satisfying work environment. It
is aligned with our mission, goals and objectives and is integrated in
budget, strategic and performance plans. Selected highlights of our
activities include:
To acquire staff, SSA:
--Created a national recruitment coordinator position with
responsibility for developing and implementing recruitment
initiatives SSA-wide;
--Uses recruitment and retention incentives, including above minimum
starting salaries, recruitment bonuses, relocation bonuses and
retention allowances;
--Uses delegated expedited methods to reduce the time it takes to
fill jobs, and continues to work with the Office of Personnel
Management to find ways to accelerate the staffing process;
--Is piloting a competency-based hiring process;
--Fills vacancies as early as possible in the fiscal year, subject to
budget and hiring authority; and
--Rehires experienced annuitants in times of critical need.
To develop and retain staff, SSA:
--Incorporates organizational values into entry level training and
new hire orientation;
--Offers extensive technical and leadership training via Interactive
Video and the Intranet. Personal development courses are also
available online and can be taken at home.
--Is restructuring curricula around identified competencies to ensure
that employees have the knowledge and skills to respond to
emerging needs;
--Has a variety of career paths for employee advancement;
--Offers career counseling services;
--Offers national Leadership Development Programs designed to build
identified leadership competencies for GS-9 through GS-14
employees, as well as a Senior Executive Service (SES) Career
Development Program designed to develop executive leadership in
the Agency's succession planning efforts. SSA's organizational
components also have a variety of development programs at
various grade levels nationwide; and
--Offers SES development opportunities outside of the formal
programs.
SSA is creating an organizational culture that promotes high
performance and accountability and empowering and including employees
in setting and accomplishing programmatic goals. SSA's revised SES
performance management system is linked to strategic goals and
distinguishes between high and low performance. A revised system for
non-bargaining unit GS-15s will be implemented October 1, 2003. An
executive level workgroup is currently developing alternative
performance systems models for all other employees, taking into account
the connection with the awards and promotion systems. Plans for all
other employees will take effect with the signing of a new labor
contract with AFGE in fiscal year 2004.
Also, SSA sets programmatic goals through our strategic planning
process. This process considers our responsibilities to the public we
serve and environmental factors such as demographics, health and
disability trends, technological advances and workforce trends. Our
employees are key to success in accomplishing these programmatic goals.
They are actively encouraged to offer suggestions through our newly
automated suggestion program. They are invited to participate on
workgroups or provide input as we develop and test new processes.
Additionally, in early fiscal year 2003 I held a series of 11
candid, interactive meetings with all supervisors, managers and
executives in the Baltimore/Washington headquarters area, discussing
leadership principles, management philosophy and the Agency's four
major performance areas. During the summer of fiscal year 2003, I plan
to discuss this same set of critical topics with the full management
cadre in each of the 10 regional office cities and from field offices
in commuting distance of those cities.
The fiscal year 2004 budget supports these activities with a
consistent level of baseline funding to accomplish many of the
activities cited. Consistent with actual spending in fiscal year 2002,
the fiscal year 2004 budget also includes approximately $4 million in
project-specific funding for the following initiatives:
--Interactive Video Teletraining
--Leadership Development Programs: Senior Executive Service, Advanced
Leadership Program, Leadership Development Program, and
Presidential Management Intern Program;
--Leadership Seminars
--Performance Management Training
SSA's budget also provides funding for participation in LEGIS
Fellows Programs, OPM Management Development Programs and Federal
Executive Institute programs. Funding to maintain the recruitment
marketing program developed in fiscal year 2002 and to advance the
competency-based recruitment initiative also is included in the budget.
Question. The Congress appropriated additional funds from fiscal
year 1996 through fiscal year 2002 to ensure that the Agency would
carry out a 7-year plan to become current in processing CDRs. The
fiscal year 2004 request includes dedicated funding of $1.4 billion,
for among other things to process continuing disability reviews.
Is the Agency on schedule to remain current with processing CDRs in
fiscal year 2003?
Answer. In fiscal year 2003, SSA is focusing on keeping up with
claims workloads so that the number of disability claims pending does
not grow. Consequently, we will not be able to process all CDRs
necessary to remain current. We began this year under a continuing
resolution and operated for four months at last year's level. In
addition, we are absorbing an across-the-board rescission of .65
percent and a higher-than-budgeted pay raise. Nevertheless, we will
continue to assess our ability to process more CDRs in fiscal year 2003
than reflected in the fiscal year 2004 President's budget, while
keeping up with claims receipts, and will increase the number of CDRs
processed to the extent that we are able.
Question. What lessons did SSA learn during this 7-year period
about efficiently using these funds to stay current with its CDR
obligations?
Answer. If SSA is adequately funded for CDRs we can stay current
with this workload. However, we also have learned that we need to work
closely with the States and balance the resources applied to CDRs with
those for processing initial claims. We have been unable to keep up
with incoming disability claims receipts since fiscal year 1997. This
situation was compounded by a recent surge in initial receipts. As a
result, DDSs entered fiscal year 2003 with the highest initial pending
level in DDS history. Currently, it is difficult to ensure adequate
funding for stewardship activities when they compete for the same
discretionary dollars. Specifically, we face two significant competing
demands: (1) the need to pay disabled claims as quickly and
proficiently as possible; and (2) the need to serve as stewards of the
public trust and perform CDRs to protect program integrity in our trust
fund and general fund programs.
The discretionary funding cap adjustments for CDRs authorized by
Congress for fiscal years 1996 through 2002 were crucial to realizing
currency for both the title II and title XVI disability review programs
at the close of fiscal year 2002. The discretionary spending cap
adjustment for CDRs and other integrity workloads that the President is
recommending in the fiscal year 2004 budget would ensure adequate
funding for the future to maintain currency with CDRs and process other
cost-effective program integrity work thereby, enabling SSA to meet
both its stewardship responsibilities and overall service demands.
The Agency would not have achieved currency at the close of fiscal
year 2002, nor will it be able to remain current in the future, without
the CDR profiling/mailer process. SSA uses highly skilled statistical
support from contractors in performing the statistical analyses that
determine who can be sent a CDR mailer, what action to take (automated
decision logic) when a CDR mailer is returned, and many of the
automated functions of both CDR mailer and full medical processing. SSA
has a wealth of data at its disposal resulting from hundreds of
thousands of CDR decisions. Over the past several years the
contractors' products have enabled SSA to perform mailer, rather than
full medical reviews, for several hundred thousand additional CDRs than
was possible in the first few years of the 7-year plan.
The CDR mailer process involves little public burden (it is
estimated to take approximately 15 minutes to read the instructions and
complete the form), and it is also cost-effective. Agency budget
documentation indicates that the unit cost of a CDR mailer in fiscal
year 2001 was $27, while the unit cost of a full medical review was
$689. In fiscal year 2001, the CDR mailer accounted for over 50 percent
(about 895,000 of 1,731,000) of reviews reported to Congress. In fiscal
year 2001 alone, even if the Agency had the workforce capacity, an
additional 895,000 full medical reviews would have cost an additional
$592 million when compared to processing the same number of CDR mailer
deferral actions. (The Agency did not have the workforce capacity that
would have allowed us to accomplish these medical reviews had there
been funding available.)
Since its inception, integrity sampling has been a key element in
assuring that the process is a legitimate alternative to a full medical
review. The CDR mailer process undergoes continuous, rigorous studies
and audits, including yearly audits by PricewaterhouseCoopers as agent
for SSA's Office of the Inspector General.
Question. What is SSA's plan for remaining current this year and in
the future for processing CDRs?
Answer. As previously indicated, in fiscal year 2003 SSA is
focusing on keeping up with claims workloads and therefore will not be
able to remain current with CDRs this year. SSA plans to include
sufficient resources in its budget requests to maintain currency with
CDR workloads. In support of that goal, the fiscal year 2004
President's budget includes earmarked funding of $1.446 billion for SSA
program integrity workloads, including CDRs, and a proposal to treat
this funding outside the discretionary spending caps.
Question. Please provide the subcommittee with a breakdown of the
administrative costs associated with legislative proposals included in
the fiscal year 2004 budget. Are these costs fully covered within the
fiscal year 2004 budget request for LAE?
Answer. The President's fiscal year 2004 budget for SSA includes
eight legislative proposals, only one of which would have significant
administrative costs for SSA. That is the proposal for implementation
of pre-effectuation reviews (PER) of SSI adult disability allowances,
similar to the reviews now in place for Social Security disability
program allowances. SSA's fiscal year 2004 LAE request includes $10
million to implement SSI PER. Generally, SSA's administrative budget
requests to Congress are based on current law. We have made an
exception to the general practice in this case, due to the likelihood
of enactment of SSI PER, based on the progress of this proposal in the
107th Congress and now in the 108th. Implementation of SSI PER will
yield substantial program savings.
The other SSA legislative proposals are as follows:
--Improved reporting of pension income from non-covered employment--
The Administration is working to determine the best way to
obtain noncovered pension information systematically from State
and local government employers, for enforcement of the Windfall
Elimination Provision (WEP) and Government Pension Offset (GPO)
provision of the law. The details of the proposal are still
being developed.
--Close the loophole that allows exemption of spouses from the GPO
based on one day in covered employment.
--Trust fund compensation for Military Service Wage Credits--This
proposal makes the trust funds whole for FICA tax equivalents
that remain unpaid by the Department of Defense for 2000 and
2001, including appropriate interest, together with adjustments
for prior years. There is no administrative impact.
--SSI Program proposals:
--Exclude from determination of individual income all interest and
dividend income earned on countable liquid resources and
revise the infrequent and irregular income exclusion.
--Remove the restriction on payment of benefits to children who are
born or who become blind or disabled after military parents
are stationed overseas.
--Treat all cash military compensation as earned income.
--Count nonrecurring income only for the month it is received
during the transition to retrospective monthly accounting
during the first three months of eligibility.
SUBCOMMITTEE RECESS
Senator Specter. Thank you all very much. The subcommittee
will stand in recess to reconvene at 9:30 a.m., Wednesday,
April 9, in room SD-138. At that time we will hear testimony
from the Honorable Elaine L. Chao, Secretary, Department of
Labor.
[Whereupon, at 11:10 a.m., Tuesday, April 8, the
subcommittee was recessed, to reconvene at 9:30 a.m.,
Wednesday, April 9.]