    [Senate Hearing 115-277]
    [From the U.S. Government Publishing Office]

      DEPARTMENTS OF LABOR, HEALTH AND HUMAN SERVICES, AND EDUCATION, AND
              RELATED AGENCIES APPROPRIATIONS FOR FISCAL YEAR 2019

                                  ----------

                             THURSDAY, MAY 17, 2018

                                           U.S. Senate,
               Subcommittee of the Committee on Appropriations,
                                                        Washington, DC.
        The subcommittee met at 10:02 a.m. in room SD-124, Dirksen
    Senate Office Building, Hon. Roy Blunt (chairman) presiding.
        Present: Senators Blunt, Alexander, Moran, Capito, Hyde-
    Smith, Murray, Durbin, Reed, Shaheen, and Murphy.

                    DEPARTMENT OF HEALTH AND HUMAN SERVICES

                         National Institutes of Health

    STATEMENT OF FRANCIS S. COLLINS, M.D., Ph.D., DIRECTOR
    ACCOMPANIED BY:
            ANTHONY S. FAUCI, M.D., DIRECTOR, NATIONAL INSTITUTE OF ALLERGY
                AND INFECTIOUS DISEASES
            RICHARD J. HODES, M.D., DIRECTOR, NATIONAL INSTITUTE ON AGING
            WALTER J. KOROSHETZ, M.D., DIRECTOR, NATIONAL INSTITUTE OF
                NEUROLOGICAL DISORDERS AND STROKE
            NORMAN E. SHARPLESS, M.D., DIRECTOR NATIONAL CANCER INSTITUTE
            NORA VOLKOW, M.D., DIRECTOR, NATIONAL INSTITUTE ON DRUG ABUSE

                     opening statement of senator roy blunt

        Senator Blunt. The Appropriations Subcommittee on Labor,
    Health and Human Services, Education, and Related Agencies will
    come to order.
        We are glad to have our friends from NIH (National
    Institutes of Health) here today: Dr. Collins and the Institute
    Directors.
        Recent support, I think, of medical research from our
    subcommittee and the full committee and the Congress is clear.
    During the 3 years that Senator Murray and I have worked
    together on this committee, we have increased funding for the
    National Institutes of Health by 23 percent, $7 billion above
    where we were just 3 years ago. We have nearly tripled the
    Alzheimer's research amount, started the Precision Medicine
    Initiative, and targeted resources to such revolutionary
    projects as the BRAIN Initiative, the universal flu vaccine,
    and efforts to combat antibiotic resistance.
        A renewed investment in NIH has provided and can provide
    millions of Americans and their families with hope that they
    would not otherwise have. NIH-funded research has raised life
    expectancy, vastly improved the quality of life for all
    Americans. And in addition, I am hopeful that we can see ways
    to lower healthcare costs and to create economic growth by
    supporting the jobs, the research and the innovation that are
    such an important part of dealing with healthcare issues now.
        Both this administration and the last one have proposed
    cuts in NIH funding. There is rarely a straight line in
    success, but so far, we have been able to maintain an upward
    momentum in the opportunity that I think everybody on this
    subcommittee certainly sees at the moment we are in.
        In addition to that, things around the world like the West
    Africa challenge 3 years ago with the devastating outbreak of
    Ebola, the disease killed more than 11,000 people in Africa,
    became a major public health threat in the United States, and
    both NIH and CDC (Centers for Disease Control and Prevention)
    were an important part of responding to that. We see now
    another outbreak in the Democratic Republic of Congo. There was
    more news on that topic even this morning, and we need to be
    well prepared to continue to be able to do what we need to do
    to respond to those kinds of challenges.
        Earlier this month, the National Institutes of Health
    launched enrollment in the All of Us study, which will collect
    health information from 1 million Americans, an idea that Dr.
    Collins mentioned, I think, 2 years ago for the first time as
    an NIH goal. All of Us has the potential to unlock precision
    medicine for the majority of diseases that we suffer from
    today. This initiative has the potential to change our health
    system from one-size-fits-all to really understanding more
    about personalized medicine.
        We are also at a point where we see some drug repurposing
    happening. We are testing current drugs that we know are safe
    to see what other uses we might find in those drugs. There is a
    current clinical trial targeting the most common adult leukemia
    with a drug first approved to test arthritis more than 25 years
    ago. That particular work is being done at the University of
    Kansas. Certainly Senator Moran has been a real advocate for
    NIH research, and he and I hope to visit The University of
    Kansas Medical Center before too long and look at that project,
    along with others.
        The National Academy of Sciences published a report in
    February that shows that NIH funding contributed to every one
    of the 210 new drugs approved by the Food and Drug
    Administration from 2010 till 2016. That is quite a record, and
    we appreciate the fact that that work continues.
        We see increased grants among young researchers. Anything
    you have to say about that would be welcome. But this has been
    an effort that this committee has entered into together, and
    Senator Murray has been a great partner in NIH, as we hope to
    be appropriately involved in our oversight responsibilities as
    well.
        [The statement follows:]
                    Prepared Statement of Senator Roy Blunt
        Good morning. Thank you, Dr. Collins and the Institute Directors,
    for appearing before the Subcommittee today to discuss the National
    Institutes of Health's fiscal year 2019 budget request.
        My support for medical research is clear. During my time as
    Chairman of this Subcommittee, I am proud to have increased funding for
    the National Institutes of Health by 23 percent, or $7 billion, in the
    last 3 years. This investment nearly tripled funding for Alzheimer's
    research, started the Precision Medicine Initiative, and targeted
    resources to such revolutionary projects as the BRAIN Initiative, a
    universal flu vaccine, and efforts to combat antibiotic resistance.
        I stand by an investment in NIH because it has provided millions of
    Americans and their families with hope. NIH-funded research has raised
    life expectancy and vastly improved the quality of life for all
    Americans. In addition, it has lowered healthcare costs and spurred
    economic growth by supporting jobs in research and generating
    biomedical innovations.
        However, I understand that it is difficult to always quantify
    success in medical research. Both this Administration and the last one
    has proposed cuts to NIH. There is rarely a straight line to success.
    Not every grant funded will result in a breakthrough. However, this is
    not the time to abandon our commitment to medical research. The
    advances made in just the past 3 years is example enough to show why
    funding for the NIH is so important.
        Three years ago, West Africa faced one of the most devastating
    infectious disease outbreaks of the last 50 years--Ebola. This disease
    killed more than 11,000 people in Africa, and became a major public
    health threat in the United States. Now, the Democratic Republic of
    Congo faces another Ebola outbreak. In response, the World Health
    Organization will deploy an Ebola vaccine that appears to provide
    protection for 2 years. This has been made possible, in part, due to
    the support of the National Institutes of Health.
        Earlier this month, the NIH launched enrollment into the All of Us
    study which will collect health information from one million Americans.
    All of Us has the potential to unlock precision medicine for the
    majority of diseases we suffer from today. This initiative will change
    our health system from one-size-fits-all to personalized medicine.
        It is also important to point out discoveries in the revolutionary
    work of drug repurposing--testing current drugs we know are safe for
    other uses. There is a current clinical trial targeting the most common
    of adult leukemia with a drug first approved to treat arthritis more
    than 25 years ago.
        These are just a few examples of how investing in medical research
    can save lives and shows that this is not the time to back away from
    our support. As further evidence of the benefits of these investments,
    the National Academy of Sciences published a report in February that
    showed that NIH funding contributed to every one of the 210 new drugs
    approved by the Food and Drug Administration (FDA) from 2010-2016. Let
    me say that again. Every single drug approved by the FDA over a 6-year
    period had some NIH research associated with it.
        The increased funding over the past 3 years, has also allowed the
    best researchers in the country to have their research funded to
    discover the next breakthrough. I am proud to say that the number of
    grants have increased 2,200 during this period. We finally are in a
    pattern of long-term investment in medical research.
        I have worked closely with Senator Murray and other Members of the
    Subcommittee to prioritize our commitment to NIH. I know that we will
    continue to do so this year.
        Thank you for being here today.

        Senator Blunt. But let me turn to Senator Murray for her
    comments.

                       STATEMENT OF SENATOR PATTY MURRAY

        Senator Murray. Well, thank you very much, Mr. Chairman.
        Dr. Collins, it is great to see you again too and all of
    your amazing team. Thank you all for being here today. And I
    just want to say it is a pleasure to see Ann Houser back there
    as well. She has done a lot to support our subcommittee's work
    for many years. She is a great credit to the agency, and I
    wanted to recognize her back there as well.
        President Trump's budget for fiscal year 2019 once again
    seeks deep cuts across the spectrum of health activities,
    including a reduction to the National Institutes of Health that
    would cut its funding down to roughly $100 million below the
    2017 enacted level. That request is out of step with the
    sentiments of Congress and the country.
        Less than 2 months ago, Congress passed and President Trump
    signed into law a bipartisan bill that increased funding for
    NIH by $3 billion, the second largest increase in the agency's
    history. Those funds will be used to accelerate efforts to
    discover cures to Alzheimer's, cancer, and other diseases,
    tackle the opioid addiction crisis, and develop a universal flu
    vaccine, and new antibiotics and more.
        President Trump's request would undermine these efforts
    slowing their progress.
        By comparison in just the past 3 years, Congress has
    provided NIH an overall increase of $7 billion boosting its
    budget by almost a quarter. After adjusting for inflation, the
    NIH budget still falls short of its peak in 2003 and grants
    remain highly competitive, especially for our early stage
    investigators, but the numbers are trending in the right
    direction. I am hopeful in the bill our subcommittee will
    shortly begin writing, we will be able to continue closing the
    gap. I know that Chairman Blunt feels the same way, and I want
    to thank him for his work on this.
        These funding increases reflect a sustained commitment to
    invest in medical research with the goal of achieving
    breakthroughs that benefit all of us, including those who have
    been historically under-represented in clinical research, and
    preserve our Nation's leadership in biomedical research. We are
    in a time of immense promise and challenge for the research
    community, the promise of unprecedented new tools,
    technologies, and computational power balanced by the challenge
    of making the most of the staggering and ever-growing amount of
    data that NIH produces, the BRAIN Initiative efforts to cure
    Alzheimer's disease, the Cancer Moonshot, and the All of Us
    initiative to advance precision medicine that are massive
    undertakings that pose extraordinary challenges, how to manage
    and make sense of it all, allow the research community to
    leverage it as much as possible, and find that proverbial
    needle in an immense haystack, while at the same time ensuring
    each patient's data remains secure.
        I believe that much of NIH and its grantees are up to this
    task. I see the potential every time I visit the Allen
    Institute for Brain Science in Seattle, but few organizations
    have their level of sophistication.
        2 years ago, the committee tasked NIH with developing a
    strategic plan for outlining how it would manage and make the
    most of the data it is producing. NIH released that plan
    earlier this month on schedule, but the real work lies ahead. I
    am concerned there still remains no senior member of the
    leadership responsible for that portfolio. I see that NIH
    recently posted an opening for a chief data strategist and
    understand you are actively reaching out to those in the
    private sector in the hope of attracting the right person to
    public service. It is essential we find them quickly, bring
    them on board, and make sure you properly support them to
    implement your strategic plan. I look forward to hearing more
    about NIH's plans in this area when we turn to the questions.
        I am pleased the administration's fiscal year 2019 budget
    abandoned its ill-conceived proposal to drastically cut grant
    support funding that it proposed last year, but troubled that
    it now seeks to arbitrarily slash researchers' salaries by 20
    percent. The budget claims this proposal would stretch grant
    dollars to fund more research, but like the previous proposal,
    it is blindly destructive and short on details, a gimmick not
    meant to be taken seriously.
        I see the budget follows Congress' lead by preserving the
    increase we provided to address opioid addiction and spur the
    development of non-addictive pain treatments. These are
    critical investments of great importance to the members of this
    subcommittee, and I think I can speak for all of us in saying
    we expect NIH to make the most of those resources entrusted to
    address this crisis. We and those we represent are really
    counting on you on this one.
        Finally, few agencies enjoy greater trust than the National
    Institutes of Health. So it was particularly troubling that
    questions have been raised about the impartiality of a study to
    assess the health benefits of moderate alcohol consumption. Dr.
    Collins, I know you have been focused on determining the facts
    with this and ensuring the integrity of NIH's research
    practices, and hopefully you will provide us with an update on
    that.
        Thank you very much, Mr. Chairman.
        Senator Blunt. Thank you, Senator Murray.
        I am glad again to welcome Dr. Francis Collins, the
    Director of the National Institutes of Health and the Institute
    Directors that are here with him today. I think the new
    Director of the National Cancer Institute, Dr. Ned Sharpless,
    is here for his first appearance before the committee, and we
    are glad you are part of this team and look forward to the
    chance to visit with all of you later.
        But, Dr. Collins, glad to have your testimony right now.

              SUMMARY STATEMENT OF FRANCIS S. COLLINS, M.D., PH.D.

        Dr. Collins. Well, it is an honor to be here, Mr. Chairman.
        Also with me here at the table: Dr. Nora Volkow, at my
    left, your right, the Director of the National Institute on
    Drug Abuse. You mentioned Dr. Sharpless, our newbie, to my
    right. Walter Koroshetz, Director of the National Institute of
    Neurological Disorders and Stroke; next to him, Dr. Richard
    Hodes, Director of the National Institute on Aging; and over at
    the far end, somebody you know pretty well who is in his 439th
    hearing or something like that----
        [Laughter.]
        Dr. Collins [continuing]. Dr. Anthony Fauci, who is the
    Director of the National Institute of Allergy and Infectious
    Diseases.
        I just want to say to all of you, Chairman Blunt, Ranking
    Member Murray, and all the friends of NIH that are here today,
    thank you. You have gone above and beyond in your support of
    NIH research and the patients for whom it brings healing and
    hope. In behalf of all of them, I am immensely grateful for
    your consistent support, and the words you have just spoken
    give me a great sense of confidence that we are on a very good
    and strong path towards the future.
        [The graphic follows:]

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        Dr. Collins. I spend a lot of time with early stage
    researchers. I will show you a few pictures. Wherever I go, I
    set aside time to hear directly from them about their dreams,
    their ideas, and yes, their concerns. I know you too have met
    many of them, both in your home districts and sometimes in your
    much appreciated visits to NIH.

        [The graphics follow:]

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        Dr. Collins. As we move forward with implementing the
    fiscal year 2018 budget and you begin considering the fiscal
    year 2019 request, it is a good time to think about those early
    stage researchers to ask what are we doing to foster this next
    generation of discovery and what can we do to help our Nation
    remain the world leader in biomedical innovation.
        [The graphic follows:]

      [GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]

        Dr. Collins. I believe the answers could be said to lie in
    certain key areas, and I would call them the five keys to
    success in science today. They are, first and foremost, a
    stable trajectory of support, followed by a vibrant workforce,
    computational power, new technologies and facilities, and
    perhaps most important of all, scientific inspiration.
        [The graphic follows:]

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        Dr. Collins. The good news is that, thanks to you, early
    stage researchers are now beginning to see a stable trajectory
    of support. Your work over the last 3 years is helping us begin
    to reverse a distressing decade-long decline in NIH's
    purchasing power for research, which is carried out in every
    State of the Nation. Strong, stable public support lies at the
    heart of NIH science, and of course, that is absolutely vital
    to our second key to success, a vibrant workforce. Clearly
    success cannot lie simply in boosting the number of grants
    made. It must also include increasing the number of creative
    minds that are receiving those grants.
        So I want to show you a new metric we are using to evaluate
    success. This shows the trend in the number of individual
    principal investigators supported by NIH over the past 15
    years. As you can see, that number is once again growing
    nicely. Note especially the surge that occurs around 2016, a
    surge that reflects when you began to change the trajectory of
    NIH support, and shows how that investment in NIH science is
    starting to pay off.
        [The graphic follows:]

    [GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]

        Dr. Collins. The third key to success, already mentioned by
    Senator Murray, is computational power. Like so much else,
    biomedical research has been transformed by the recent
    explosion in computing power and all of the big data it is
    generating. For example, the BRAIN Initiative, which you have
    supported for the past 5 years, has created new imaging tools
    that are churning out troves of amazing data, and there is also
    data generated by structural biology and microbiome research
    and the All of Us research program supported by your precision
    medicine appropriation. Just 10 days ago in a major national
    launch event, all of us began the full scale of enrolling 1
    million Americans, building on their pilot phase that already
    enrolled over 25,000, aiming to determine how individual
    differences and lifestyle, environment, and biological makeup
    can influence health and at an unprecedented scale.
        [The graphic follows:]

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        Dr. Collins. To realize the full potential of these and
    other resources, we also must develop new technologies and
    facilities. Quite often it is the technology itself driving the
    need for equally innovative facilities. Take the case of the
    new cell-based treatments, immunotherapy and gene therapy. Many
    involve removing cells from the patient's body using technology
    to re-engineer those cells and returning them to the patient.
    The challenge is that many of our labs are not set up to handle
    these highly individualized processes, so it is crucial that we
    make upgrades to keep pace. The President's fiscal year 2019
    proposal includes a much needed increase in buildings and
    facilities to assist with that.
        [The graphic follows:]

    [GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]

        Dr. Collins. But now on to my favorite of these topics,
    scientific inspiration. I can assure you that NIH-funded
    researchers come to work every day full of innovative ideas and
    the wherewithal to see those ideas through. I could talk about
    this all day, but mindful of the clock, let me just share one
    example.
        [The graphic follows:]

    [GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]

        Dr. Collins. More than a decade ago, NIH launched a special
    project on spinal muscular atrophy, or SMA. This is a uniformly
    fatal inherited disease. As you see here, in its severe form,
    it leaves babies floppy, unable to hold their heads up, feed
    well, and eventually even to breathe. Death by 15 months is the
    tragic and almost universal result.
        10 years ago there was no treatment for SMA, but
    researchers had just discovered the DNA (deoxyribonucleic acid)
    mutations that cause it. So NIH supported more research,
    working closely with patient advocates and industry to move
    promising leads into therapeutic development. One of the most
    exciting comes from Jerry Mendell's team at Nationwide
    Children's Hospital in Columbus, Ohio, which recently tested
    gene therapy in 15 infants with severe SMA. They infused the
    viral vector designed to deliver the normal gene to the spinal
    cord and held their breath.
        And over the next few months, something truly dramatic,
    almost miraculous, happened. Like little Mateo Almeda, whom you
    see in this video, 100 percent of the infants who got the
    highest dose of the gene therapy were alive at 20 months and
    nearly all could talk and eat on their own, and some like
    Mateo, shown here at age 2 standing up on his tiptoes, were
    able to walk--and this is truly astounding--even play on the
    monkey bars with his dad. As a direct result of an NIH-inspired
    effort, we are seeing the emergence of lifesaving gene therapy
    for SMA.
        So in closing, I am proud to lead NIH at this time of
    unprecedented scientific opportunity and with such strong
    congressional support. The resources you have entrusted to us
    will be used to bring hope to untold numbers of patients and
    their families.
        [The graphic follows:]

    [GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]

        Dr. Collins. In that spirit, I would like to finish with a
    favorite quote from the poet Peter Levi. ``Hope,'' he wrote,
    ``in every sphere of life is a privilege that attaches to
    action. No action, no hope.'' At NIH our idea of action is to
    support the best investigators to apply the best science to
    find answers for those millions waiting for their hopes to be
    realized.
        Thank you, and I look forward to your questions.
        [The statement follows:]
             Prepared Statement of Francis S. Collins, M.D., Ph.D.
        Good morning, Chairman Blunt, Ranking Member Murray, and
    distinguished Members of the Subcommittee. I am Francis S. Collins,
    M.D., Ph.D., and I have served as the Director of the National
    Institutes of Health (NIH) since 2009. It is an honor to appear before
    you today.
        Before I discuss NIH's diverse investments in biomedical research
    and some of the exciting scientific opportunities on the horizon, I
    want to thank this Subcommittee for your sustained commitment to NIH to
    ensure that our Nation remains the global leader in biomedical research
    and advances in human health.
        I want to personally express gratitude to this Subcommittee and its
    leadership for its support in crafting and passing the fiscal year 2018
    Consolidated Appropriations Bill. The fiscal year 2018 Omnibus provides
    an incredible increase of $3 billion for NIH, including funding for
    opioid- and pain-related research, Alzheimer's disease, antimicrobial
    resistance, and development of a universal influenza vaccine. NIH has
    immediately set to work to invest those additional resources into
    groundbreaking research.
        As the Nation's premier biomedical research agency, NIH's mission
    is to seek fundamental knowledge about the nature and behavior of
    living systems and to apply that knowledge to enhance human health,
    lengthen life, and reduce illness and disability. As some of you have
    witnessed first-hand on your visits to NIH, our leadership and
    employees carry out our mission with passion and commitment. This
    extends equally to the hundreds of thousands of individuals whose
    research and training we support, located in every State of this great
    country, and where 81 percent of our budget is distributed.
        The fiscal year 2019 Budget provides $34.8 billion for NIH to fund
    the highest priority scientific discoveries while also maintaining
    fiscal stewardship of Federal resources. This Budget will consolidate
    research functions across the Department, optimize available grant
    dollars to fund research, invest in NIH's buildings and facilities, and
    support NIH priority areas including combatting the opioid epidemic,
    advancing Precision Medicine, and investing in translational research.
        The fiscal year 2019 Budget consolidates HHS research programs into
    three new institutes within the NIH. The Budget provides $380 million
    for the activities of the Agency for Healthcare Research and Quality
    (AHRQ), consolidated into the National Institute for Research on Safety
    and Quality. The National Institute for Occupational Safety and Health
    (NIOSH), including the Energy Employees Occupational Illness Program
    (EEOCIPA), currently administered by the Centers for Disease Control
    and Prevention, and the National Institute on Disability, Independent
    Living, and Rehabilitation Research (NIDILRR), currently administered
    by the Administration for Community Living, are also proposed for
    consolidation into the NIH.
        America's continuing leadership in conducting biomedical research
    requires infrastructure and facilities that are safe, compliant with
    all laws and regulations, and conducive to cutting edge research and
    research support. NIH owns 281 facilities, including a research
    hospital, laboratories, and offices. NIH's Backlog of Maintenance and
    Repair exceeds $1.8 billion. NIH is currently working with the National
    Academies of Sciences, Engineering and Medicine to identify NIH
    facilities and infrastructure most in need of repair. We look forward
    to providing that report to the Committee as soon as it is final.
        The fiscal year 2019 Budget makes much needed investments in NIH's
    facilities. The Budget proposes $200 million to support multiple
    biomedical research infrastructure priorities. The fiscal year 2019
    Budget will allow NIH to continue to repair and upgrade deteriorated
    infrastructure. In a recent analysis requested by this Committee, the
    condition of NIH laboratories ranks near the lowest in the Federal
    Government due to the high likelihood of floods, power outages, and
    mechanical failures. Items on the backlog list include: install steam
    and chilled water distribution systems; conduct structural repairs to
    older buildings; upgrade plumbing systems; repair elevators; upgrade
    heating, ventilating, and air conditioning systems; replace
    deteriorated electrical systems, and more. In addition, due to the age
    and use of NIH facilities, NIH must invest funds in removing
    contaminants and hazardous waste before construction or capital repairs
    can begin in most of its buildings. The Budget will allow NIH to track
    what contaminants are being cleared from each of our buildings, which
    will ultimately help NIH do a better job of anticipating the cost and
    time required to begin new projects in existing buildings.
        Truly exciting, world class science is taking place. I would like
    to provide just a few examples of the depth and breadth of the amazing
    research the fiscal year 2019 Budget supports across the Institutes and
    Centers of NIH.
        Over the past 15 years, communities across our Nation have been
    devastated by increasing prescription and illicit opioid misuse,
    addiction, and overdose. This Committee made a historic investment of
    $500 million in our work in fiscal year 2018, and the fiscal year 2019
    Budget builds on that with an investment of $850 million to support a
    range of activities to advance research on pain and addiction. NIH has
    and will continue to support cutting-edge research on pain, opioid
    misuse, addiction, and overdose. Drug addiction is a complex
    neurological condition, driven by many biological, environmental,
    social, and developmental factors. Continued research will be key to
    understanding the crisis and informing future efforts. Pain is an
    equally complex condition affecting millions of Americans. NIH will:
    explore new formulations for overdose reversal medications capable of
    combatting powerful synthetic opioids; search for new options for
    treating addiction and maintaining sobriety; continue to research how
    best to treat babies born in withdrawal through our ACT NOW trial;
    develop biomarkers to objectively measure pain; build a clinical trial
    network for pain research; and attempt to find non-addictive and non-
    pharmacological approaches to chronic pain. Thanks to your support, all
    hands are on deck at NIH for this public health crisis.
        Another exciting area of continued investment in fiscal year 2019,
    building on this Committee's long-standing support, is Precision
    Medicine. On May 6th, NIH officially launched the national roll-out of
    the All of Us Research Program. This program will partner with one
    million or more people across the United States to provide the most
    diverse biomedical data resource of its kind and gain unprecedented
    insights into the biological, environmental and behavioral influences
    of disease. The fiscal year 2019 Budget, including resources from the
    21st Century Cures Act, supports the ramp up of the program. After
    pilot testing system and forming partnerships with community
    organizations across the country, national enrollment is about to
    begin. All of Us will not focus on only one specific disease. Rather,
    it will be a national data resource to inform many research studies on
    a wide variety of health conditions. The data provided by one million
    participants will provide opportunities for researchers--including
    academics and citizen scientists--who want to understand how and why
    different people experience certain diseases and conditions while
    others do not, and why many people respond differently to treatments
    and prevention methods that will help accelerate medical breakthroughs.
        NIH is the largest funder of basic biomedical research in the
    United States, providing a critical research foundation for both the
    public and private sector. Building on that solid foundation of basic
    research, NIH also supports translational research that turns
    observations in the laboratory, clinic, and community into
    interventions that improve the health of individuals and the public,
    whether those interventions be diagnostics, therapeutics, medical
    procedures, or behavioral changes. For example, Congress created the
    Cures Acceleration Network (CAN) at the National Center for Advancing
    Translational Sciences (NCATS) to advance the development of high-need
    cures and to reduce significant barriers between research discovery and
    clinical trials. For example, CAN currently supports NCATS' Tissue Chip
    for Drug Screening program, which was designed to revolutionize the
    process for predicting drug safety. Researchers developing miniaturized
    platforms that could support miniature models of living organs--such as
    the lung, liver, and heart--that could be integrated into connected
    organ systems. New Tissue Chip initiatives were funded in fiscal year
    2017 and this support will continue into fiscal year 2019.
        CAN uses flexible research awards using the special authorization
    called other transaction authority to attract non-traditional
    government partners, and to expand, modify, and, if needed, discontinue
    activities to meet program needs. The fiscal year 2019 Budget will
    allow NCATS, through CAN, to continue to invest in high-risk, high
    reward initiatives designed to address significant scientific and
    technical challenges that hinder translational research.
        One of my personal priorities is developing the next generation of
    talented biomedical researchers. Last year, I shared with the Committee
    NIH's plans to build on our support for early-stage investigators
    through a new initiative known as the Next Generation Researchers
    Initiative. The fiscal year 2019 Budget includes a dedicated fund of
    $100 million in the Office of the Director to incentivize additional
    Institute and Center support for these researchers. NIH remains
    committed to the development, support, and retention of our next
    generation of investigators.
        We have never witnessed a time of greater promise for advances in
    medicine than right now. Your support has been critical, and will
    continue to be. Thank you again for inviting NIH to testify today. We
    look forward to answering your questions.

        Senator Blunt. Well, thank you, Dr. Collins.
        We will have 5-minute rounds of questions. There will be
    time for a second round if we are still in the hearing when we
    have the vote at 11:15. I think it is one vote. And so we will
    try to work around that and continue the hearing.

                          PUBLIC/PRIVATE PARTNERSHIPS

        One of the things that we put in the appropriations bill
    this year was an effort that, frankly, we were asked to put in
    where there would be some partnership money from pharmaceutical
    companies into opioid research, the idea being that like other
    partnerships, for example, the AMP partnerships between NIH and
    other biopharmaceutical companies, that we could deal with that
    quicker. You have decided and frankly, without consultation
    with the committee, not to do that. It might very well relate
    to the alcohol study that Senator Murray brought up. I would
    like you to respond to both of those topics, starting with why
    you decided not to do what you had asked us to put in the
    budget to allow you to do.
        Dr. Collins. Senator, I will be glad to explain that, and I
    know this is a topic that many people have been interested in
    and have been wrestling with a bit, as we have.
        We have been in deep conversations with industry partners
    for a year about ways in which we might develop a partnership
    to come up with better ways to treat addiction, to treat
    overdose, and to come up with non-addictive treatments for
    chronic pain, which are desperately needed. Working with 33
    such companies over the course of many months, we have
    identified a number of areas of opportunity which we could do
    effectively in a public-private partnership with them in ways
    that neither sector could do alone. And that includes such
    things as sharing data, sharing assets, repurposing compounds
    that might have been tried for something else or have been
    abandoned and could turn out to be valuable for pain, and
    running clinical trials together in that space.
        The good news is that partnership is very much alive and
    will, in fact, be going forward. I think we are pretty close to
    having the full plan laid out, and I would expect in the next
    few weeks to be able to say much more about exactly how we are
    going to conduct this.
        The controversy, Senator, was whether in fact, given the
    circumstances around the opioid crisis and the fact that there
    are lawsuits now filed against no less than five of these
    companies claiming that they may have played some role in the
    opioid crisis in the first place by marketing such drugs as
    OxyContin, whether it is in fact a good idea or potentially
    carries a reputational risk for NIH to receive funds from the
    company.
        And ultimately I convened an expert group of advisors from
    outside who had lots of experience in both sectors and who were
    very finely tuned to the questions of reputational risk and
    ethics. And to my surprise, they made a strong recommendation
    that we go forward with the partnership but not have actual
    cash contributions from the companies involved. Their concern
    was that that would create at least the impression, if not the
    reality that the project going forward would be in some way a
    conflict of interest, would be driven by something other than
    the best needs of the public.
        I had to accept that strong recommendation coming from
    those groups. The Foundation for NIH, by the way, which is our
    partner in all of these partnerships, also convened their board
    and came up with the same recommendation.
        And so with apologies for not having consulted, as I should
    have, with you and other members of this subcommittee, we felt
    we had to make the decision that we did.
        Again, the good news is the partnership will go forward
    very much as planned, but we are not asking the companies to
    contribute money, but we are asking them to contribute
    expertise and resources and data and assets and help with our
    clinical trials network.
        Yes, the alcohol issue was also in this particular
    discussion because we are in the midst of another place that I
    wish we were not where there is deep concerns about whether a
    study, which has really just gotten launched in the last 2 or 3
    months, which aims to look at whether there might be medical
    benefit of modest doses of alcohol in humans. And this
    particular study was set up in such a way that the funding is
    largely coming from the beverage industry, and there is
    evidence that NIH employees assisted in recruiting those funds
    for this study in a way that would violate our usual policies.
        We are in the midst of investigating that through the
    Office Management Assessment and through a working group that I
    have convened. There are sufficient concerns about that study
    that I would like to tell you that 1 week ago, we decided to
    suspend enrollment in that study of the moderate effects of
    alcohol on cardiovascular health while we continue the
    investigation and make a decision about whether the study is in
    fact still worth pursuing.
        So all of those are complicated issues and believe me, have
    caused considerable pain and stress upon the people involved.
    But again, for NIH, our reputation is so critical, and if we
    are putting ourselves in a circumstance where that could be
    called into question, I felt we had to look at that very
    seriously and come up with another strategy.
        Senator Blunt. Thank you.
        I could probably ask another question quickly and get way
    beyond my 5 minutes but I am not going to do that, and I hope
    nobody else will either. If you want to stay for a second round
    of questions, we are going to do that.
        Senator Murray.

                                    BIG DATA

        Senator Murray. Thank you very much.
        And I wanted to go back to the big data because one of the
    greatest challenges facing science today is how to manage and
    effectively use this massive amount of data that researchers
    are now producing, and without the tools to efficiently manage
    and manipulate data, the value of it is significantly reduced.
    Likewise, we do not want scientists spending time recreating
    data that already exists from other research projects. And as
    you know, the committee directed NIH in the 2017 omnibus to
    develop a strategic plan to address these issues, which you
    released last week.
        Now that you have the plan, can you tell us what the
    timeline for implementation is?
        Dr. Collins. The plan is very ambitious, Senator. And I am
    glad you had a chance to look at it. It is the product of many
    deliberations with experts both within NIH and outside and also
    responding to a request for comments from more than 800
    individuals and organizations who put forward a plan.
        Basically it does lay out what we need to be doing in the
    area of infrastructure, in the area of the data ecosystem, in
    the area of software and tools, particularly in the area of the
    workforce. We realize our bench is not as deep as it should be
    for expertise in this space, and also just sustainability, how
    do we put together something that is not here today and then in
    trouble tomorrow. All of those are laid out in the strategic
    plan in a broad and bold way.
        The way in which we are going to implement this certainly
    includes a number of things that are already underway because
    we have really been working on this issue since 2012 when a
    working group of my advisory committee made the first set of
    recommendations. We are, for instance, moving some of our
    largest datasets into the cloud in a fashion that protects the
    security and privacy of the participants but makes that data
    accessible to researchers from all over the place. And that is
    a big step forward, and most of our big datasets will need to
    be handled in that way going forward.
        And as you mentioned in your opening comments, we are
    actively recruiting for a chief data strategist, someone who we
    would ideally hope to recruit from industry and maybe from
    Silicon Valley with deep experience in how to handle big
    datasets and machine learning and artificial intelligence.

                            BARRIERS IN DATA SHARING

        Senator Murray. Are there barriers that are worrying you
    like cases where researchers face challenges sharing their data
    or delay releasing the data until they have published their
    findings, things like that?
        Dr. Collins. We are certainly attuned to the risks there of
    people hording data. I am happy to say the 21st Century CURES
    bill gave me as the NIH Director some authorities about
    requiring data access and data release from our grantees, which
    I used to have to do some cajoling, but now I have the
    opportunity to have more clout and that has helped us in that
    regard.
        I think the general ethic of the scientific community has
    shifted, though, much more in the direction of it is your
    responsibility to make your data available as soon as someone
    else might be able to use it. We have encouraged that a lot.
        Senator Murray. Okay, good.

                      DATA SHARING IN ALZHEIMER'S DISEASE

        And Dr. Hodes, I wanted to ask you. Given the scale of
    investments that we are making in Alzheimer's disease, the data
    we are generating may be used to accelerate some major
    scientific breakthroughs. Has NIA (National Institute on Aging)
    looked at its existing data sharing policies to determine how
    they are working? Do we know what percentage of grant
    recipients are fulfilling their data sharing obligations on
    this project?
        Dr. Hodes. Thank you very much for the question.
        I would echo very much what Dr. Collins has just said about
    NIH's role in general.
        I think we have had a history in the Alzheimer's research
    community of a strong willingness to share, and I think that
    has increased over past years. I think we are at a stage when
    we are dealing in part with technical feasibilities of making
    data cross-interpretable, shareable, and compatible and are
    working very hard in collaborations across Federal agencies and
    with outside groups to make that sharing more effective. But I
    think we have the culture, as well as the armamentarium to
    enforce sharing, and I think we are on an excellent trajectory
    in that regard.
        Senator Murray. Thank you.

                            MODERATE DRINKING STUDY

        Dr. Collins, just one more question on the moderate
    drinking study. NIH is a huge enterprise, and if this was
    happening in one institute, it could be happening in others.
    Are you doing anything to make sure this has not compromised
    studies elsewhere in NIH?
        Dr. Collins. I am very concerned that this might be the tip
    of a larger iceberg, and that is part of the reason that I
    pulled together this very distinguished group of experts to
    look at it. We will look closely to see if there are other
    examples of this sort because that would be very much against
    the principles that we stand for, which is separation of
    funding sources from outside with decisions about science, and
    also of course, our peer review process ought to be absolutely
    above any reproach as far as conflicts.
        I would be glad to report back to you after we have done a
    bit more digging into this. But I think this is one of my roles
    as the NIH Director. When we find something that has gone awry,
    we do not just assume that it is a little thing that you could
    put a band aid on. We make sure that it is not reflective of
    some larger issues, and then we aim to fix those too.
        Senator Murray. Thank you very much.
        And thank you, Mr. Chairman.
        Senator Blunt. Senator Alexander.
        Senator Alexander. Thank you, Mr. Chairman.
        First, let me say to Chairman Blunt and to Senator Murray,
    Senator Durbin, all the members of the committee, how much I
    appreciate their leadership and the increase in funding for the
    National Institutes of Health. And I pledge my support to do
    that for the future.
        Second, it is good to see a piece of legislation that had
    such broad bipartisan support. Senator McConnell said it was
    the most important law of 2016. Actually it would be so useful
    in its implementation. A part of that is because of the talent
    of the team we see before us and others like Dr. Gottlieb who
    know what they are doing and are leaning forward and taking
    advantage of the new authority.
        Third, we have developed quite a consensus on science and
    research. As Senator Blunt said, a 23 percent increase in
    biomedical innovation. I would add to that that in the Energy
    and Water Appropriations Subcommittee, which Senator Feinstein
    and I chair, we increase funding for the Office of Science this
    year 16 percent. That was the third straight year of record
    funding for the Office of Science that supports the national
    laboratories. So when you get 3 straight years for the National
    Institutes of Health, 3 straight years of record funding for
    the Office of Science, and you add to that in the Obama
    administration and in the first 2 years of this administration
    we have funded supercomputing at impressive levels to keep us
    first in the world in that, I think the only people not on
    board with the President's America First comments are the
    Office of Management and Budget.
        So I am going to try to talk to the President and others at
    the White House and say why do you not include this in your
    America First agenda. I mean, why not buy medical innovation,
    why not national laboratories, why not supercomputing? We need
    to lead the world in that. Congress wants to do it, both
    Republicans and Democrats. We need to get the OMB (Office of
    Management and Budget) on board.

                         NON-ADDICTIVE PAIN STRATEGIES

        Now, let me use the rest of my time to ask you about one
    area, non-addictive pain strategies. We have 25 million
    Americans who hurt badly, chronic pain, 100 million who hurt
    some, and then non-addictive treatment for opioid abuse. 95
    percent of the treatment for opioids is more opioids. It is
    medicated assisted abuse. And sometimes they say you do not
    ever get off opioids.
        So my question is in 2 minutes and a half, what progress
    are you making? Senator Murray and I have included in the
    opioids bill the transactional authority that you asked for to
    give you even more flexibility in funding. What progress are
    you making on pain, new pain strategies, and why are 95 percent
    of the treatments for opioids more opioids? Why do we not have
    more treatments like Vivitrol or some other treatment that
    helps people get away from opioids?
        Dr. Collins. So I am fortunate to have at the table two
    experts who can handle both parts of that question. Maybe we
    will go first to Dr. Volkow to talk about the treatments for
    addiction and what we might be working on in that space. And
    then I will ask Dr. Koroshetz to respond about non-addictive
    treatments for pain. We are deep into that as well.
        Dr. Volkow. Thanks, Francis.
        This is one of our priorities, how do we develop
    alternative medications for the management of opioid addiction.
    We currently only have three of them, and two of them are what
    we call agonists, opioid agonists. And Vivitrol is an
    antagonist.
        Senator Alexander. And I am right that two are about 95
    percent of the treatment. Right?
        Dr. Volkow. Correct. That is correct. Those are the
    numbers.
        And part of the problem is not all of the patients respond
    to the Vivitrol intervention, and part of the problem is it is
    very difficult to induct someone that is addicted right away
    into Vivitrol. And that is when we lose the patients. So we are
    trying to expand the alternative medications that we can give
    to patients and focusing also on strategies that are not
    involved in the opioid system so that we can help those
    individuals be able to recover and be at one point able to stay
    without opioid medications.
        Dr. Koroshetz. So I think that you are absolutely right
    that one thing that could really help in the long term stemming
    the opioid problem is developing non-addictive pain medicines
    to replace opioids in the prescription box for patients.
        Senator Alexander. And we funded $500 million in research
    this past year--Senator Blunt and Murray did--and $500 million
    more proposed by the budget for this coming year.
        Dr. Koroshetz. That is right. And so we, working with our
    industry partners, as Francis mentioned, have a plan to really
    accelerate the development of new medications. From the basic
    science point of view, we have a number of different targets
    that look very promising to develop medicines that are not
    interacting with the opioid pathway.
        One that is in current testing now is what is called anti-
    nerve growth factor therapy, which came from really very
    important basic science years ago on the intersection of that
    growth factor and the pain system. And companies are now
    developing antagonists to nerve growth factor which look
    promising in early results. So just one example, but we think
    there are many more.
        Senator Alexander. Thank you, Mr. Chairman.
        Senator Blunt. Senator Reed.
        Senator Reed. Thank you very much, Mr. Chairman.
        Thank you all. I particularly want to thank Dr. Sharpless
    for giving me an opportunity to look at the pediatric oncology
    program and meeting all the tremendous women doctors and Ph.D.s
    who lead that effort. So thank you.

                                    STAR ACT

        With the support of another tremendous woman, Senator
    Capito, we were able to pass the STAR Act. And can you give us
    an idea of how you will use this? It will pass, we hope, the
    House very soon and become law.
        Dr. Sharpless. Sure. I should not directly comment on
    pending legislation, but--and first off, thank you for the
    visit. I think it really means a lot to the pediatric
    oncologists to have the Senate come up and express an interest
    in work that they are doing and I think is really, really
    wonderful. And thank you for your support and Senator Capito's
    support of pediatric cancer research.
        The STAR Act--the intent of it is very laudable to address
    issues, some issues in pediatric oncology and childhood cancer
    that are important. So one is the issue of survivorship. The
    good news about pediatric cancer is we are curing more and more
    kids, but the problem is--well, the two problems are we are not
    curing everyone. We still have kids die of cancer. And then a
    lot of the kids we cure are left with lifelong toxicity. So the
    results from therapy can be quite debilitating, infertility,
    disfiguring surgery, and cognitive dysfunction that last for
    decades.
        So survivorship has become a major issue. There are
    probably half a million pediatric cancer survivors now in the
    United States. And trying further research to understand the
    basic science of survivorship and why these toxicities occur
    and what we can do is a really important area of pediatric
    oncology research.
        Similarly, I think we had this issue of aggregated data in
    pediatric cancer. One of the shortages of that are samples,
    biospecimens that can be sequenced and analyzed and catalogued,
    and then presented to the research community in an aggregated
    format that is de-identified and secure but usable for
    research.
        And so I think those two addressing survivorship and
    biospecimens are really important and something NCI (National
    Cancer Institute) is behind.

                    TRANS-NIH PEDIATRIC RESEARCH CONSORTIUM

        Senator Reed. Thank you very much.
        And Dr. Collins, thank you again for your hospitality on my
    visit.
        You have recently announced the creation of a trans-NIH
    pediatric research consortium. Can you give us an idea of what
    you want to accomplish with that, Doctor?
        Dr. Collins. I would be very happy to.
        We have the National Institute of Child Health and Human
    Development, which sounds like it is the place where pediatric
    research gets done and a lot does get there. But it is actually
    only about 18 percent of pediatric research across all of NIH.
    Most of the institutes--you have just heard a great example
    from the Cancer Institute--are also heavily invested in
    pediatric research.
        I have asked Diana Bianchi who is the new Director of the
    Child Health Institute to convene a trans-NIH group at a high
    level from all of the institutes that are players, which is
    essentially all of them, to see whether we could come up with a
    more coordinated strategic plan for defining where are the
    greatest priorities in pediatric research and how can we work
    together, whether it is cancer or whether it is autism, whether
    it is birth defects, whether it is development, whether it is
    behavioral issues. I believe with her leadership--and she is a
    very strong leader, indeed--that we have the chance to put
    forward a plan for pediatric research that will be quite
    exciting. That has just gotten going, and I would be glad to
    report back to you in the coming months about how this is
    leading us in new directions.

                          FOGARTY INTERNATIONAL CENTER

        Senator Reed. I would be remiss if I did not applaud the
    Fogarty Center, named after my beloved predecessor in the
    United States Congress, John Fogarty. But this is the
    international arm, if you will, of NIH, and we celebrated the
    50th anniversary. And it seems particularly important today, as
    we talk about Ebola emerging in countries like this, that we
    have this agency in very close rapport with CDC.
        Can you just comment upon the next wonderful 50 years of
    the Fogarty Center? And tell Peter Kilmarx I said hello.
        Dr. Collins. Senator, I appreciated very much your being
    there at that 50th anniversary celebration and speaking to the
    group.
        One of the things Fogarty has done that has been most
    powerful, even though it is the smallest of all of our
    institutes, is their training program for fellows.
        I am just going to quickly ask Tony Fauci to tell you a
    story or two about how those Fogarty fellows have played a
    significant role in global health challenges like Ebola and
    Zika.
        Dr. Fauci. Thank you, Dr. Collins.
        Yes, the Fogarty International Center really has been very
    important and very much interdigitated with what we do as the
    National Institute of Allergy and Infections Diseases (NIAID)
    in the area of infectious diseases. You may recall that when we
    had the Ebola outbreak in West Africa in 2014, 2015, and early
    2016, there were cases that, as you might expect, traveled not
    knowing they were infected with Ebola to other places such as
    Mali and Nigeria. And those cases did not result in outbreaks
    in those countries. Almost all the people taking care of those
    individuals infected with Ebola virus who traveled to Mali and
    Nigeria were trained as Fogarty fellows. So we had a pre-
    existing network of people there who had been trained in
    science and public health with support from the NIH. That was a
    dramatic public health example of how the Fogarty Center was a
    true partner, not only with regard Fogarty activities on our
    NIH campus in Bethesda, MD but Fogarty activities in Bamako,
    Mali and Lagos, Nigeria. It was really quite striking.
        Senator Reed. With a speech like that, you could be elected
    to Congress from the 2nd district. Thank you.
        [Laughter.]
        Senator Blunt. Senator Capito.

                              OPIOIDS PARTNERSHIP

        Senator Capito. Thank you, Mr. Chairman and the ranking
    member, and thank you all of you.
        And Dr. Collins, it is great to see you again.
        My first question is on opioids and what you are doing. And
    we have talked numerous times about this. Obviously, I live in
    an area that is highly affected here.
        Two questions. You mentioned and you said that we had put a
    $500 million historic investment into this. But you have
    mentioned in your response to questions that you have private
    partners. Could you elaborate on how the private partnership
    works, and what kind of commitment dollar-wise that private
    partnership is committing to add to the $500 million that we
    are doing in the research?
        Dr. Collins. Happy to.
        We have worked intensively since your wonderful decision to
    make $500 million available in fiscal year 2018 and to have
    that in the base so that it will be there in 2019 and beyond.
    Working with all of the institutes across NIH, we have put
    forward an opportunity for new and bold ideas to come forward,
    and we are in a place now, I think, of having a remarkable
    portfolio that we are ready to launch.
        You also graciously gave us that first year of support as
    2-year money so that we could, in fact, carry over some of the
    fiscal year 2018 funds into 2019 since it is late enough in the
    year that starting brand new things is a little challenging.
    But we have figured out how we are going to spend a significant
    fraction of that $500 million right away.
        It does include a wide variety of applications, including
    some of the things that have already been discussed by Dr.
    Volkow and Dr. Koroshetz, but also such things as what to do
    about the neonatal abstinence syndrome, which is of such deep
    concern to all of us in terms of how best to manage, what
    happens to those babies, and what is their long-term future.
        The public-private partnership, which you mentioned, is
    actually a modest part of this broad portfolio but an important
    one. Again, as we talked about earlier, the decision was made
    by me based on strong recommendations that that partnership
    should involve assets that are contributed by industry that
    have value, data, compounds, scientific expertise, but not a
    cash contribution. It is a little challenging right now to
    attach a dollar value to what their in-kind contributions are
    going to add up to, but it will be substantial.
        Senator Capito. Good.
        Dr. Collins. So putting that all together, we think we are
    in a good place to move both the public-private partnership and
    the rest of this broad portfolio together quite rapidly.

                          NEONATAL ABSTINENCE SYNDROME

        Senator Capito. Good. Thank you.
        Dr. Volkow, on the neonatal abstinence syndrome, obviously
    we are the State most highly affected by that as well. And this
    is an area of deep concern to everybody. We have got 1,000 more
    kids in foster care. A lot of these babies probably will be the
    repeat mothers. They have repeat exposure. I mean, they have
    numerous exposures to numerous drugs not just particularly one.
    And I believe you visited our Lily's Place down in Huntington
    to see what kind of care they are getting there.
        The research that you are doing and the ACT NOW trials--
    are those being conducted across the Nation, or how do you find
    the right place to conduct those kinds of--and where are you
    doing that?
        Dr. Volkow. Well, the ACT NOW is one of the programs that
    will be funded through the new money that has come for the
    opioid crisis and will allow us to actually maximize protocols
    that will enable us, for example, to determine what are the
    optimal interventions for the best outcomes on neonates. And
    that includes protocols that may not require the administration
    of medications to those neonates with abstinence.
        We have other research studies also ongoing. And I was at
    West Virginia last week and I was in Huntington. And I was
    horrified to hear that one out of five newborns had opioids on
    them. And one of the points that is highlighted is that we need
    to address the needs of the neonate, but we need to address the
    needs of the mother once the baby is born. So the outcome from
    that infant and child is not addressed. So we are working with
    research of new medications and new non-medication
    interventions to improve the outcomes of those neonates.
        And the other aspect that Francis mentioned is we are very
    interested in understanding how the brain of these newborns is
    going to have been influenced by getting exposed to opioids, as
    well as other drugs, during fetal development when the brain is
    very, very vulnerable.
        Senator Capito. Right. I am anxious to hear how we progress
    with that.
        I guess one of the points of asking my question is there a
    wealth of data all around the country with people who are hands
    on in these scenarios dealing with this right now that I think
    can feed not only good information but can help you conduct
    trials on a local level. It sounds like that is what you are
    already moving forward on.
        Dr. Volkow. Correct.

                          CLINICAL TRIALS--ALZHEIMER'S

        Senator Capito. I am really pleased to be on the STAR Act,
    the childhood cancer act. I am glad to hear about the
    survivorship. That is something of great importance to me. A
    lot of this I am very interested in, as Dr. Collins knows, but
    I do want to go over to Dr. Hodes because Alzheimer's on the
    other end of the spectrum is something that I have personally
    been touched with.
        And I would like to know, Doctor, one of the things I have
    heard is that it is hard to recruit patients for clinical
    trials for Alzheimer's. Is that the case? What are you finding
    there? I mean, I know it is hard by the time you start
    exhibiting the symptoms, you are already in it. How are you
    developing all those trials with different----
        Dr. Hodes. Senator, it is an excellent question. And it is
    a challenge to us for multiple reasons.
        As you have commented upon, for individuals who are already
    affected with symptoms, we carry out studies that are extremely
    important. But there is also a sense that in order to be most
    effective in preventing the appearance of symptoms that we need
    to intervene earlier before irreparable damage is done.
        This means that we need to recruit people who are not
    coming through a normal process where they see a clinician who
    suggests they participate in a clinical trial. These are people
    who are at high risk but show no symptoms. So we need to
    develop and are developing strategies for screening those at
    high risk and then the charge of finding people who are
    committed, dedicated to participate in studies to see if we can
    make a difference through early intervention.
        Studies such as All of Us present a unique opportunity for
    this with a million people, for example, who have signed on for
    their interest in participating in research. We can screen
    those who, by a variety of metrics, may be at high risk for
    developing symptoms years or decades later and take an
    opportunity to intervene with those now. So we are in the midst
    of a nationwide program which will be announced this summer to
    look at multiple modalities for recruiting patients into
    studies.
        Senator Capito. Good. Thank you. We want to support that.
    Thank you.
        Senator Blunt. Senator Shaheen.

                                    FENTANYL

        Senator Shaheen. Thank you, Mr. Chairman.
        And thank you to you and Senator Murray and Senator
    Alexander for your commitment to research and funding for NIH.
        And to you, Dr. Collins, and everyone there, thank you so
    much for the work that you are doing. You give hope to so many
    people across this country.
        Dr. Volkow, thank you for coming to New Hampshire. I
    especially appreciate the work that is being done to address
    the opioid epidemic. Like my colleagues on this committee, we
    have been very hard hit in New Hampshire, as you know, from
    your visit to Catholic Medical Center and other places in the
    State.
        I was interested in your discussion about new drugs that
    are in development. As you are looking at what the potential
    is, are you separating out fentanyl as a particular opioid that
    has very deadly properties and therefore requires a different
    kind of response, or are you lumping that in with everything
    else?
        Dr. Volkow. We cannot lump it with everything else because
    what we are hearing from the field and being reported in the
    literature is that when people overdose with fentanyl, the
    doses that were used of Narcan are not sufficient actually to
    reverse the overdoses. The other concern is if you get exposed
    to fentanyl, because of its potency, your risk of addiction is
    much higher.
        So as of now, we, for example, have not ever done a trial
    of how do you treat someone that is addicted to fentanyl, and
    that is one of the projects that we would like to implement as
    soon as we get the approvals.
        But also with respect to the medications, we are actually
    funding researchers who are partnering with pharmaceuticals to
    develop a stronger antagonist. So this is the nasal Narcan,
    which we actually developed, but it is not sufficient for
    fentanyl. So we are developing with companies longer lasting,
    more potent or alternative medications that may not be based on
    the same mechanism as naloxone. Because the other challenge is
    not just fentanyl, but what we are observing is people are
    overdosing with multiple medications, alcohol, benzodiazepines,
    and fentanyl. So this is not sufficient.

             CO-OCCURRING MENTAL HEALTH ISSUES AND SUBSTANCE ABUSE

        Senator Shaheen. And we see so many people who have co-
    occurring mental health issues along with their substance use
    disorder. So often they are using substances to address their
    mental health issues.
        So are you doing any research that looks at the two
    problems together that may give promise as we think about what
    the future holds?
        Dr. Volkow. We cannot do that because the comorbidity is
    many times much more frequent, the isolation. And if you
    address, for example, the depression of someone that is
    addicted to opioids, you are not going to succeed.
        Also a very important component followed by the overdose is
    we really do not know which ones are intentional, therefore
    suicide. So if you are reverting someone on an overdose that
    has suicidal behavior and you do not intervene, you are not
    going to succeed.
        So we are prioritizing. We are recognizing that the reality
    is comorbidity, comorbidity of addiction with mental illness,
    and comorbidity of addiction with pain. And those are more
    challenging than when they are in isolation.
        Senator Shaheen. So did you want to add anything to that?
        Dr. Collins. I think Dr. Volkow very accurately
    characterizes the situation.
        I think one of the things that we are most concerned about
    in terms of this crisis, just if I can show you this graph, is
    the way in which the epidemic, in terms of the overdose deaths,
    has shifted from being prescription opioids to now fentanyl
    just going straight off the chart as it gets into the heroin
    supply. And as more individuals who have fallen into addiction
    cannot find sufficient access to prescriptions, then they shift
    over.

                                     EBOLA

        Senator Shaheen. Absolutely. That is what we are seeing in
    New Hampshire where we have the highest rate of overdose deaths
    from fentanyl.
        Dr. Fauci, Senator Blunt mentioned the Ebola epidemic and
    the news report this morning that said the first case had been
    found in an urban area, a large city, in the Democratic
    Republic of Congo. And given DRC's other challenges, how
    worried are we that that epidemic is going to get out of
    control again?
        Dr. Fauci. Given our prior experience, we are on very high
    alert about this Ebola outbreak. There are some factors that
    mitigate against their having the same situation as we saw in
    West Africa, but there are also factors that actually might
    favor that. As you mentioned, the first cases that were
    reported in very early May, the first week in May, were in a
    place called Bikoro, which is on a remote area called Lake
    Tumba. The bad news is that it is very difficult to get help
    in. The good news is it is very difficult to get anybody out.
        But what you heard this morning in the report is that there
    are multiple different zones. Bikoro is one zone. Another zone
    is Mbandaka, which is an area that has a city of 1.1 million
    people. And even though there is only one case there, there is
    a total now of 44 cases. Even though only two have been
    confirmed, there are 20 that are probable and 20 that are
    suspicious. So there are probably many more cases.
        What we are doing now is shipping in with the WHO (World
    Health Organization) helping, obviously, the kinds of things
    that were the fruits of the work that we did with the support
    of this committee and others to develop countermeasures. And I
    will very briefly give you an example.
        You heard probably on the media that the WHO has authorized
    the shipping of the VSV vaccine that had its first phase one
    trial right at the Clinical Center at the NIH, and then we did
    it in Africa and that was the one that did the ring
    vaccination.
        We also have ZMapp, which is that triple combination of
    antibodies that we published in the New England Journal of
    Medicine from the intramural program at NIH that went over
    there in Liberia. That is also being shipped.
        And we have some experimental drugs, one we are partnering
    with Gilead, and some monoclonal antibodies that have been
    developed by the Vaccine Research Center.
        So although in direct answer to your question, we are on
    high alert. We are always concerned when there is Ebola. But we
    right now have a number of countermeasures that we are able to
    develop to go in and hopefully block that. So our hopes are--
    our expectations are always cautious, but the hopes are that we
    will not have the kind of outbreak that we saw in West Africa.
        Senator Shaheen. Thank you,
        Thank you, Mr. Chairman.
        Senator Blunt. Senator Durbin.
        Senator Durbin. Thanks, Mr. Chairman.
        Let me say at the outset that in a world of frustration and
    partisanship, what is happening in this room this morning is a
    welcome exception. You will find more positive feelings, more
    achievement I hope, and more bipartisanship than in almost any
    other room on Capitol Hill. And I want to salute the chairman
    of the subcommittee, Senator Blunt, his ranking member, Senator
    Murray. I told her I was going to praise her before she left.
    And certainly Senator Alexander in his work and Senator
    Shaheen. This is a great assignment because with the help of
    the folks sitting at this table, we actually feel like we are
    taking steps forward.
        And to Senator Blunt for his leadership on this, we have
    established a standard I think and I hope it is one that we can
    live by of sustainable, reliable increases in medical research
    funding in the United States of America. Dr. Collins told me
    several years ago that is what we need, and we are doing our
    best to meet that need.

                                     CRISPR

        One of the areas that I have recently learned a little bit
    about was in ``Foreign Affairs'' magazine of all places, and I
    happened to be reading it. And this liberal arts lawyer came to
    try to understand something called CRISPR, which is included in
    your publication here of promising technologies.
        And ironically--I talked to Dr. Collins about this
    earlier--a family from Illinois came to see me last week, and
    the mother, the wife, has myotonic dystrophy, and it is a
    genetic disease which she has unwittingly passed on to her
    children, a son and daughter, whose circumstances are even more
    challenging than her own, and of course, their future is really
    unknown. I mentioned CRISPR to them, and they lit up. They said
    this is the one area where we feel like there is a chance.
        Please, Dr. Collins or one of your colleagues here, give us
    a moment about CRISPR and what we are doing.
        Dr. Collins. I am happy to because I agree that this is one
    of the most exciting things that has happened in a long time in
    terms of providing tools both for basic science and for
    therapeutic applications. It opens up entirely new vistas
    particularly for individuals with genetic disorders where we
    know there is a misspelling in the DNA. This provides an
    opportunity to go and fix that in a very precise fashion.
        So it is also a great story about basic science because
    this particular enzyme called Cas9 was discovered in a very
    obscure area of people trying to understand how bacteria can
    fight off their own viruses. Bacteria have their own viruses
    and somehow they manage to survive. And it is a very elegant
    system where the bacteria have an enzyme that basically
    recognizes a foreign DNA sequence and goes and snips it and
    inactivates it. But it is programmable.
        And so Jennifer Doudna and her colleagues and Feng Zhang
    and his colleagues and a few other people who are arguing about
    who gets the credit basically came up with a way to take that
    bacterial system and make it work in all kinds of cells,
    including human cells.
        It is very precise. You program it. It can find in a 3
    billion letter instruction book--that is our DNA genome-- the
    one that you want to alter and zero in on it and very precisely
    make a cut or make a substitution.
        Now, of course, in the basic science lab, this is
    fantastic. Every laboratory that is doing molecular biology is
    using CRISPR Cas9, including mine, including all the people at
    this table who have active laboratories. But therapeutically
    the promise here is what I think has us particularly excited.
        As I mentioned to you earlier, sickle cell disease may well
    be the first success of this because for sickle cell disease,
    the problem is in the bone marrow stem cells. You can take them
    out. You can purify them. You can utilize this enzyme system to
    fix the sickle mutation and then put them back. And that should
    be not just a treatment but a cure for people with this
    disease, 100,000 of them in the U.S. I think that is going to
    happen in the next 5 years. The first clinical trials are
    probably going to start this year.

                                     VAPING

        Senator Durbin. I hate to interrupt you because this is
    important. I have one other topic I want to mention. And I hope
    that this subcommittee can zero in on the CRISPR technology and
    what is happening there. I think there is so much promise.
        But I wanted to mention one other thing that is important
    to most of us. 27 percent of the high school students in the
    State of Illinois have something in common. 27 percent of them
    are now using e-cigarettes and vaping. It used to be 28 percent
    using tobacco cigarettes. Now they are into e-cigarettes and
    vaping. And the people who are peddling these products that
    they inhale with nicotine are putting them in candy flavors.
    Here is one. The brand is Lung Candy and the flavoring is Cake
    Batter. In this listing here--it is a long listing of flavors
    for children to see opportunities for vaping. We see exactly
    what is happening.
        Can I get a comment from any of you about what you consider
    to be the perils or danger of this type of addiction?
        Dr. Collins. Dr. Volkow.
        Dr. Volkow. Indeed, we are very concerned because one of
    the issues why 50 percent of teenagers say that they are
    starting to vape only with flavors, 30 percent of them are
    starting to vape with nicotine and are becoming addicted to
    nicotine.
        And in studies that have been already published, it has
    been shown that if you start to vape, you are much more likely
    to then go into nicotine vaping, and then if you got into
    nicotine vaping, then to go into smoking tobacco. So a major
    concern is that we will be losing a lot of the advances that we
    did on prevention of smoking among teenagers.
        Another aspect that people do not really recognize is that
    nicotine acts as a priming. So anything that you take when you
    have nicotine on board becomes much more reinforcing. And as a
    result of that, if you get exposed to drugs while you are
    having nicotine on board, you are much more likely to become
    addicted. So the concern is not only that these teenagers will
    become cigarette smokers, as the data has already shown--the
    risk goes up--but also by doing this, their brain becomes
    primed to the addictiveness of other substances.
        Senator Durbin. Thank you.
        Thanks, Mr. Chairman.

                                      ZIKA

        Senator Blunt. Thank you, Senator Durbin.
        Dr. Fauci, let me give you a couple minutes to talk about
    two things. First, Zika. I was at St. Louis University during
    the Zika crisis where they were working on Zika vaccine
    research and felt like they were coming to conclusions. So are
    we going to have something available next time? And second,
    flu, specifically universal flu, or whatever you want to talk
    about on your research on those two topics.
        Dr. Fauci. Thank you, Mr. Chairman.
        First, we will take Zika. As you know, as I reported to
    this committee on more than one occasion, we have progressed in
    our vaccine trial from the phase 1 trial that we originally did
    at the NIH to now deploying a phase 2b trial, 2b being
    relatively advanced to not only ask is it safe, but does it
    induce the kind of response that you would predict would be
    effective.
        And I am pleased to report to you that today we have
    ongoing a phase 2b trial in several countries in South America,
    in Mexico, in the Caribbean, Puerto Rico, in Texas, and in
    Florida to determine if the vaccine is safe and if it does
    induce that response. It is scheduled to have between 2,400 and
    5,000 people in the study. We are recruiting very rapidly. We
    anticipate--and I am pretty cautiously optimistic about that--
    that we will have it fully accrued by the end of 2018. And then
    if in fact there is an outbreak, we could get an efficacy
    signal.
        And if there is not, then we are working very closely with
    the FDA (Food and Drug Administration) if we can get enough of
    what we call immunogenicity data--namely, it shows that it does
    induce the kind of response that you want--and bridge that to
    the animal data, which are very convincing that this is a
    vaccine that can induce a good response--we are working with
    the FDA to determine if in fact we can get an accelerated
    approval. You never anticipate what their decision will be, but
    they are being very cooperative.

                             UNIVERSAL FLU VACCINE

        Next, universal flu vaccine. Again, we are very grateful to
    the committee for supporting the addition of the $40 million in
    the 2018 omnibus for a universal influenza vaccine. So let me
    report where we are with that.
        We had a meeting in Rockville in June of 2017 in which we
    developed, in association with experts from all over the world
    and in the United States in influenza, what we call a strategic
    plan and a research agenda, which we published in the Journal
    of Infectious Diseases in February of this year.
        We are now implementing that plan both from a basic science
    standpoint but also with candidates that are at various stages
    of development, namely either preclinical in animal study or a
    phase 1 or phase 2.
        And I might just close by saying you may have read just a
    couple of days ago an NIAID-sponsored phase 2 trial with the
    universal flu vaccine candidate in association with the company
    BiondVax has been initiated. And we started a few months ago
    one of the trials from our vaccine Research Center.
        So things are on track. Obviously, as I mentioned to this
    committee, it is not going to be an overnight type of a thing,
    but we are well on the road at various iterations of going
    towards a universal flu vaccine.
        Senator Blunt. And do you see a point, if we got there--I
    am assuming what we are trying to get is for every year we
    would not have to try to calculate what that year's flu was
    like and, more often than not, be slightly off target.
        Dr. Fauci. You are absolutely correct, Mr. Chairman.
        The perfect--and that is going to be difficult to do. A
    universal flu vaccine would be one that would cover all
    versions of seasonal and any potential pandemic. But the road
    we are taking now is to go step by step. I tend to refer to it
    as universal flu vaccine 1.0, which means that we will not have
    to worry about any H3. The H3N2 that we do each year and we
    have to change it a little from season to season, which is the
    reason why we need to get vaccinated every year, the first
    version will cover all of the H3N2's. The next one will cover
    very likely an H1N1. There are two major groups of influenza
    viruses that have multiple viruses in each group. Getting one
    that covers both groups is getting close to the perfect one.
        So the answer is the end game is that you and I, but most
    likely our children, will be able to get a vaccine early on in
    life, a boost, and then maybe every 10 years or so and not have
    to worry about each year guessing what the next iteration is
    going to be. It is the guess that is the problem because
    sometimes you do not get it right, and even when you do, it
    changes enough that it evades the vaccine. And that is what we
    are trying to avoid.
        Senator Blunt. Well, I may have unlimited time here, and I
    may exceed that. Who knows what may happen?
        [Laughter.]

                           FUTURE OF CANCER RESEARCH

        Senator Blunt. Dr. Sharpless, so I think in the United
    States today there are 15.5 million cancer survivors. In 1971,
    there were 3 million cancer survivors. An incredibly exciting
    time. Immunotherapy, the BRAIN Initiative, and, that I assume
    will have a significant cancer-looking element to it, CRISPR.
        You and I have some time here. Could you take just a few
    minutes, a couple of minutes maybe, and talk about your vision
    of what you hope and believe can happen over the next handful
    of years in the Cancer Institute based on what we see happening
    already?
        Dr. Sharpless. Sure. I think you are really right about
    that. It is a very exciting time in cancer research. I recently
    had a colleague email me. It is like I picked the perfect time
    to lead the National Cancer Institute because there are all
    these exciting things going on. In fact, today is the release
    of the ASCO abstracts. It is sort of like Christmas in our
    field where all the new advances come out and a number of
    exciting advances in a variety of different cancers.
        So I think there really are a lot of opportunities that
    cash in on this observation that cancer is not only one disease
    or 10 diseases but hundreds or thousands of diseases, and each
    one of them needs its own specific treatment.
        So the good news is there is a lot of excitement going on.
    There are a lot of new technologies and new approaches, and a
    lot of that research has been empowered by the funding from
    this committee.
        But I think the bad news about it is that problem is
    somewhat different from what we used to imagine. So we used to
    think of cancer is like one disease and we had the cardiology
    paradigm where we put 800 people on one arm of the trial and
    800 people on the other arm of the trial. That sort of clinical
    trials framework no longer really works. So the modern approach
    to cancer I think has to be somewhat different.
        So the things I thought the NCI should focus on are
    training the workforce so that we have the right kinds of
    cancer researchers. So we need cancer biologists who really
    understand basic immunology because it is excessive
    immunotherapy, and we need cancer researchers who understand
    big data because we are aggregating data at such a furious pace
    to try and use that information to treat cancer patients.
        We need to recommit to basic science. You know, it is not
    enough to make progress against some cancers. We really have to
    make progress against all cancers, and that requires a basic
    biological understanding of all cancers.
        We need to fix the problem of clinical trials. The
    structure of clinical trials in cancer has led them to become
    smaller and more fragmented and much more expensive. And so we
    need to sort of rethink how we do clinical trials. A very
    interesting development there is the NCI-MATCH Trial, which
    will be presented this year at meetings about how we sequence
    patients and identify the mutations in their tumor and then
    allocate them to therapy based on the genetic driver, the
    personalized event that makes their cancer relevant.
        And then lastly, we really need to get serious in cancer
    about organizing our data and aggregating it and linking it so
    that we have the genomic data, the radiology data, the
    histology data, the clinical information--we have that all
    available in a way that is safe and secure, available to the
    research community so we can understand what mutations cause
    what patient to respond to this drug and why they lived that
    long and really get a handle on these bins of rare cancers that
    we have to treat.

                              GENETICS AND CANCER

        Senator Blunt. I was out at FDA not too long ago. They have
    put a cancer team together that I know you are aware of that is
    looking at all they are doing. You know, the thought in that
    discussion came up that within the foreseeable future, there
    just may be something that each individual is prescribed that
    amps up, if you will, whatever their unique fighting capacity
    needs to be on their unique attack that is likely to happen to
    them. That is one look.
        The other look is--I am not sure how the genetic--the
    CRISPR effort works there. But it is an incredibly exciting
    time. Even with immunology, I would think that 5 years ago an
    observation made in passing would not have been made at all.
    This is what we are doing. And there I am sure you are going to
    continue to work on why this does not work on some cancers and
    what you need to find. It may not be possible ever, but right
    now--Dr. Collins, do you want to talk about that?
        Dr. Collins. I appreciate your raising this, why does it
    not work when it does not work.
        And we talked earlier about partnerships, and I wanted to
    point to this as a very successful public-private partnership
    called PACT, the Partnership for Advancing Cancer Therapies.
    Now 12 biotechnology pharmaceutical companies have partnered
    with NIH to ask that question. What are the biomarkers that
    actually tell you that immunotherapy is going to work or it is
    not? Because we have these dramatic success stories. Emily
    Whitehead, this little girl that had failed to respond to the
    traditional treatment for leukemia and who was very much near
    the end, and who with CAR T-cell therapy was not just
    successfully treated, she was cured. She is 5 years out now.
    She looks great and wonderful.
        But it does not work for solid tumors nearly as well. Why
    does it not work for pancreatic cancer? Why does it not work
    for prostate and breast and brain tumors? We need to figure
    that out, and that is what this partnership aims to do. In this
    case no concern about, I think, conflict of interest. It is all
    pre-competitive. It is all out there in public. So in this case
    pharma is contributing both expertise and resources but also
    cash, and it is pretty exciting to see this taking shape under
    the leadership of Dr. Sharpless and his colleagues.
        Dr. Sharpless. Yes. I think that is one of the initiatives
    to really sort of--you know, each of these therapies requires a
    really detailed understanding of how they work to make them
    work in everyone. But it is just leaps and bounds. Every day
    now we are seeing some new area where we have a drug that used
    to work and we are making it work better for a whole new class
    of therapies. And so a lot of good stuff going on.
        However, I think it is also important to note that we do
    still have some cancers, some even reasonably common cancers,
    where we have not made much progress. So glioma, for example,
    glioblastoma, brain cancer, is still a real problem, and I
    think that we really as the NCI have to not only focus on the
    cancers where we are having successes but also perhaps even
    more so on the ones that have been recalcitrant and refractory
    to therapy to date. And so that is an important part of our
    mission as well.

                            ALZHEIMER'S AND DEMENTIA

        Senator Blunt. I think the area of greatest spending,
    certainly the quickest growing spending of Federal health
    dollars would be Alzheimer's and dementia. And Dr. Hodes, if
    you and maybe Dr. Koroshetz both would talk about what we are
    finding there. We have made big investments here. You have
    probably eliminated a lot of things we know do not work. Now,
    how are we doing on the other end of that and the dementia
    impact, too, Dr. Koroshetz, when it comes to you on that? And
    then when you are done, we will go to Senator Hyde-Smith as she
    settles in here.
        Dr. Hodes. Thank you.
        I first want to thank the committee, Congress for the
    increased appropriation of resources towards Alzheimer's
    disease and related dementias. It has had an enormous impact.
    For example, in 2015, we funded 152 awards supporting research
    in this area. 2 years later in 2017, that had increased to 442.
        And importantly, this is reflected with confidence and
    excitement that we heard about across the research community
    seeing the national commitment to sustained resources, a
    renewed energy on the part of new and early stage
    investigators. So of all these new awards we have seen, more
    than a quarter, 27 percent, were to the categories of early
    stage and new investigators who had not received any NIH major
    support previously. An even larger number than that, more than
    a third, 36 percent, had never had any support for Alzheimer's
    and related dementias research. So we are bringing into the
    community not just more dollars and opportunities but the
    energy that comes with new people willing to commit their
    careers and to bring new disciplines into the field.
        This has included an expansion of the number of clinical
    trials currently supported to over 140. And equally important,
    using new techniques of looking at gene expression patterns,
    proteomics, metabolomics, and an amazingly effective
    consortium, AMP, Accelerating Medicines Partnership, around
    Alzheimer's disease to bring public and private science,
    clinical expertise, and financial support together to fund new
    discoveries that have identified the so-called wall of targets
    now--there had been a consensus to find new molecular targets
    not appreciated before that might lead to entirely new
    approaches much needed, in addition to the directions we
    currently take for translation into clinical trials.
        So it is an incredible excitement I think you can
    appreciate. The numbers are only meant to illustrate the
    intensity of excitement there is now. Sustained funding has now
    convinced investigators this is an area in which we can make
    progress, and the pace has increased exponentially.
        Senator Blunt. I think at Washington University they are
    feeling more and more positive about a blood test. Things like
    that that would begin to early identify what was happening with
    amyloids in the brain would be a big step in the right
    direction. Hopefully, we can go out there together and look at
    that sometime.
        Dr. Hodes. Yes.
        Senator Blunt. Dr. Koroshetz.
        Dr. Koroshetz. Thanks to the wisdom of the Congress for
    including what we call the Alzheimer Disease-related dementias
    in this major effort to decrease the public health problem of
    dementia in our country. Most patients who have dementia are
    diagnosed with Alzheimer's disease. Especially in the elderly,
    when one looks at the brain, one more often than not will find
    multiple different things going on. And one of the two areas
    that are most common is the finding of what we call Lewy body
    disease in people who have dementia diagnosed as Alzheimer's.
    They have Alzheimer's changes but also have the signature of
    Parkinson disease, which is synuclein aggregates. So
    understanding the contribution of these synuclein aggregates
    not just to Alzheimer's dementia but also to the dementia that
    occurs in Parkinson's patients who have it for a long time is a
    focus that we have been able to really pursue much more
    aggressively.
        The other area, which is even more common, is the
    combination of vascular disease in people who are diagnosed
    with Alzheimer's disease. And this is, I think, incredibly
    important to understand because we have made strong progress
    over the last 70 years in decreasing the risk of stroke, which
    is the most common consequence of vascular disease in the
    brain, and also incredibly common in people who have dementia
    diagnosed as Alzheimer's.
        So we have been working with the National Institute on
    Aging on projects to be able to track the health of the
    cerebrovascular system in the brain and its contribution to
    dementia with the hope that the things we already know about,
    if we can be more aggressive about them, may actually prevent
    people from going on to develop dementia because we can block
    this contribution of the vascular component.
        Senator Blunt. Exactly.
        Senator Hyde-Smith.
        Senator Hyde-Smith. Thank you, Chairman Blunt.
        And thank you, Dr. Collins, for testifying today and all of
    you for testifying today.

                 EXPANDING CLINICAL TRIALS TO UNDERSERVED AREAS

        I have been involved as a volunteer with the American
    Cancer Society for many, many years in Mississippi. So I have
    seen firsthand how new treatments and therapies have
    transformed the prognosis for so many different types of
    cancers. And I am grateful for the role that you have played,
    that NIH has played in so many of those discoveries. What you
    are all doing is so important, and I truly see it changing and
    saving lives. And I am grateful to you for that.
        However, despite these recent innovations in cancer care,
    my State of Mississippi continues to have one of the highest
    cancer mortality rates of any State. For many Mississippians,
    receiving the cutting-edge treatments and participating in a
    clinical trial would mean traveling hundreds of miles from home
    to a cancer center in another State, which is not possible for
    so many of our patients.
        But, Dr. Sharpless, how is the National Cancer Institute
    working to ensure that patients in States like mine, which do
    not have an NCI-designated cancer center, are able to
    participate in clinical trials and benefit from the newest
    discoveries?
        Dr. Sharpless. Senator, thanks for the question.
        I think you raise a really important issue, which is that
    it is in some ways great news we are making all this progress
    against cancer and having those new therapies and new
    approaches, but if we then cannot disseminate them into the
    broader community and implement those therapies in sort of the
    real world, then are we helping people to the extent that we
    could do so?
        So the National Cancer Institute is very concerned about
    how we assure that our advances translate beyond just the NCI-
    designated cancer centers, which are a great program but there
    are only 70 of them, and their range is limited.
        One program we have to address this is called the National
    Community Oncology Research Program, or NCORP, which is 50
    NCORP sites that then have each several satellite sites. So
    there are sort of 900 NCORP sites across the country. Between
    the cancer centers and NCORP, we reach virtually the entire
    country. And these sites, in addition to being able to do
    clinical trials, also have catchment areas that have patients
    that are more likely to be rural patients as opposed to urban
    patients and more likely to be underserved minorities. So it is
    a way that we can enroll a demographic that looks more like the
    United States in general. So it is a great program. We have
    just decided to expand its scope somewhat. It is successful and
    we want to build on that.
        And it is also important to note that we can do clinical
    trials in the NCORP program. For example, the NCI MATCH trial
    enrolled 6,000 patients at 1,100 sites. It was the fastest
    accruing trial in the history of the National Cancer Institute,
    and it allowed us to do accrual in the community, which is also
    a real need in cancer research because 5 percent of adult
    oncology patients go on clinical trials. That number needs to
    be higher, and we need to take the trials to them through like
    the NCORP program. So it is one way that we are working to
    address this important issue.

                            ALL OF US PILOT TESTING

        Senator Hyde-Smith. Wonderful, very good.
        And also, I am proud that The University of Mississippi
    Medical Center and the Jackson-Hinds Comprehensive Health
    Center were both chosen as sites in the All of Us research
    program in Mississippi. This program, which seeks to enroll 1
    million American volunteers, will no doubt lead to important
    discoveries that will help doctors identify treatments and
    personalized to patients' lifestyles, individual's environments
    and genetic biology. Jackson-Hinds was only one of only six
    community health centers nationwide chosen to help pilot the
    project beginning in 2016.
        Dr. Collins, as the NIH rolls this program out nationwide
    this year, how have you incorporated lessons learned through
    the pilot at Jackson-Hinds that participated in this?
        Dr. Collins. That is a great question. We did spend the
    last year in a pilot phase of ramping up All of Us, recognizing
    this is probably one of the most ambitious projects that NIH
    has ever mounted, and we needed to have great attention paid to
    the needs of the participants and particularly for their
    security and privacy. And we also made a commitment that this
    was going to be a project that was truly national and it would
    include people who were traditionally not invited to take part.
    People in community health centers oftentimes have not been so
    engaged in research. We wanted to reach out. And Jackson-Hinds
    was in a particularly powerful place to be one of the first
    ones to try and see how this would go.
        I think we have been very encouraged. In the pilot projects
    for All of Us, we enrolled over 26,000 people. That makes it
    one of the biggest studies NIH has done in a long time. And
    that was just the pilot on the way to our million.
        And from the community health centers like Jackson-Hinds,
    we were gratified to hear a lot of interest on the part of
    people who came there for their medical care in getting engaged
    in this kind of research and being included. They wanted to be
    counted too. They wanted the results of this study to be about
    them and therefore, provide information that they could use.
        So I think it has been a wonderful experience. It has been
    a kind of outreach we have not necessarily tried at quite this
    scale before. And now, as of May 6th, we have done the full
    launch, and anybody in the United States can join up,
    joinallofus.org. That is all you need to know.
        Senator Hyde-Smith. Great. Well, we certainly appreciate
    it. All of you.
        Senator Blunt. Thank you, Senator Hyde-Smith.
        Senator Shaheen.

                                TYPE 1 DIABETES

        Senator Shaheen. Thank you, Mr. Chairman.
        I came back because I did not want to go home and tell my
    family that I had this whole panel from NIH in front of me and
    I did not ask you about the prospects of research into a cure
    for type 1 diabetes. I have a granddaughter who has type 1. I
    also co-chair the Diabetes Caucus in the Senate with Senator
    Collins and know how devastating the potential is in this
    country if we do not figure out a cure for this disease. One in
    three by 2050 will have diabetes, and it is one of the most
    expensive, if not the most expensive, chronic diseases that we
    have.
        So can you give me an update on where we are with research?
        Dr. Collins. Senator, I would be happy to and appreciate
    your leadership in this.
        This is another one of these very exciting areas where
    things are now moving very quickly for both type 1 and for type
    2. Much of the excitement surrounds the potential of developing
    an artificial pancreas that would take care of the production
    of insulin when the body has failed to do so at the level it
    needs to. And you already have seen, of course, the FDA
    approving the very first example of an artificial pancreas in
    sort of a closed loop where there is a sensor of what the
    levels of glucose are and then it administers insulin
    accordingly. But this is just the beginning of what I think is
    going to be a remarkable series of advances.
        Ultimately the whole stem cell area is going to be critical
    here as well. We have, after much hard work through the work of
    people like Doug Melton at Harvard, figured out how you can
    take a skin cell from somebody, convince it to become what you
    would call pluripotent and then give it the appropriate set of
    cocktails to convince it to go down the pathway to be a cell
    that makes insulin. But it is your own cell. And so ultimately
    in the view of many of us, that is where we are headed, the
    opportunity to make an artificial pancreas that does not have
    silicon in. It actually has your cells that have been
    reprogrammed to make up for what the other cells that should
    have been doing this were able to do.
        On top of that, I think in terms of prevention particularly
    of type 2 diabetes where we know that this is tightly connected
    to obesity and insulin resistance, increasingly trying out the
    efforts to reduce weight and increase exercise are looking very
    promising over the long term to keep people who are tipping
    over into diabetes from actually getting there.
        A lot of research as well on gestational diabetes and what
    kind of information we can learn when this seems to happen
    during pregnancy. What should be the follow-up to that because
    that clearly indicates a risk for future illness.
        So it is a very exciting time. I could go on much longer,
    but I wanted to reassure you that NIH is deeply in the middle
    of all this and the progress is quite gratifying.

                              ARTIFICIAL PANCREAS

        Senator Shaheen. Well, I appreciate that. And I am excited
    about some of the new developments. I think we need to think
    about how we can reverse the incentives in our healthcare
    system to do more for prevention with type 2 where it really
    makes a difference. And unfortunately, I think we are not
    providing the resources that we need there, and in the long
    term, it is going to cost us more money.
        But I wanted to ask a follow-up because one of the things I
    have heard from the diabetes community is their frustration
    with how long it has taken the FDA to approve an artificial
    pancreas and further developments on that. So we are seeing
    people in the community who are doing what they call bootleg--
    and that is probably not a good term--but are basically making
    their own artificial pancreas and feel like that provides more
    relief than they are getting currently, given the system that
    we have and the dependence on insulin and the way that works.
        So can you speak to that? Is that something that you have
    heard about, and are you concerned about what the risk might be
    from that?
        Dr. Collins. I do think there are reasons to be very
    careful about putting in place an artificial pancreas system
    without being absolutely confident that it has the appropriate
    safety mechanisms because we all know that an overdose of
    insulin can put you into a coma and can ultimately lead to
    death. So this needs to be a system that is really well worked
    out. So I understand why the FDA, therefore, has to be pretty
    rigorous in terms of their evaluation of such things.
        I do think, though, that in Scott Gottlieb you have an FDA
    Commissioner who really is dedicated to moving things along as
    soon as the data makes it possible.
        Senator Shaheen. Yes, he has said that. I appreciate that.
        Dr. Collins. We work very closely with FDA under his
    leadership. And some of the things that we can do in terms of
    providing that data is a part of that partnership that we are
    pushing pretty hard right now.
        Senator Shaheen. Well, thank you. Thank you all very much
    for the great work that you are doing.

                         SOCIAL MEDIA AND SOCIALIZATION

        Senator Blunt. Dr. Koroshetz, do you have anybody looking
    at the socialization challenges of the constant exposure to
    social media or the screens as something--the impact that that
    may have on adolescents and others?
        Dr. Koroshetz. So certainly social media is taking over our
    country, and the consequences, whether they are pros or cons,
    are still yet to be determined.
        I think at NIH there are a lot of grantees that are
    actually using social media to advance health research. I think
    it would probably be the National Institute of Mental Health,
    which is looking at the effects on adolescents. But Dr. Volkow
    can mention a really innovative project which will look at this
    and other exposures on the development of children that she has
    just recently--well, almost half finished I guess.
        Senator Blunt. I had a 50-50 shot there I thought.
        [Laughter.]
        Senator Blunt. And I missed it.
        Dr. Volkow. For us, it is important because drug taking and
    experimentation appears in adolescents, and it is a very social
    behavior. And many times it follows peer pressure. And one of
    the things that we have actually tried to understand is how the
    dramatic changes that have happened in the way that teenagers
    are interacting with one another may be influencing their
    behaviors, including drug taking.
        But most importantly, our brains are very neuroplastic and
    they are developing during childhood and adolescence to
    maximize your ability to respond to your environment. So we are
    interested to know if you as an adolescent or as a child get
    exposed massively to the social communication as opposed to the
    one-to-one, how does that influence the development of the
    brain.
        So in September of 2016, we started a study with many of
    our partners at the NIH called the ABCD, Adolescent Brain
    Cognitive Development, where we are aiming to recruit 10,000
    children. We have already recruited 9,500, and we will be
    finishing in September. But to monitor them on the next 10
    years to actually do brain imaging, characterize them
    cognitively, characterize them socially, and measure how
    exposure to social media ultimately influences the development
    of the brain. So this is probably the most notable study that
    we have because it will allow us to understand how this very
    dramatic change on how people are interacting with one another
    may influence the brain.
        We also have research to understand how social media is
    used to actually change the perspectives of teenagers with
    respect to getting exposed to drugs, the likelihood that they
    will take a drug when they see it in social media. So the
    vaping device and the electronic cigarettes, to what extent
    they are being frequently mentioned in social media are
    influencing the probability that a teenager will use them. And
    the same thing with marijuana and the same thing with alcohol.
        So this is a completely new world for all of us, and we do
    not actually, as of now, have an understanding about how it is
    going to influence the human brain and behavior.
        Senator Blunt. Thank you.
        Senator Moran.
        Senator Moran. Chairman, thank you. I am glad the meeting
    is still going. I do not know that you are pleased with my
    arrival.
        [Laughter.]
        Senator Moran. But I am honored to be here. Thank you.
        Senator Blunt. I am always pleased with your arrival.
        Senator Moran. Thank you, Chairman.

                       BIOMARKERS AND ALZHEIMER'S DISEASE

        Dr. Hodes, I am not exactly sure what has been asked and
    answered, but I want to pursue a couple of concepts that are
    now developing in regard to Alzheimer's.
        We have talked about detection and the efforts to use
    biomarkers to identify someone who is at risk or has
    Alzheimer's before they begin showing symptoms. The National
    Institute on Aging just coordinated to propose a biological
    construct which looks at the use of measurable changes in the
    brain to better understand the earliest biological signs that
    lead to symptoms.
        How will this new framework help to drive research forward?
    Does it represent a new understanding of the beginning of the
    disease?
        Dr. Hodes. Thank you.
        The importance of being able to identify the changes that
    accompany Alzheimer's disease and related dementias early, as
    you have emphasized, is critical where we think that the best
    opportunity to intervene at an early point and be able to track
    success or failure of interventions by measuring biomarkers is
    going to be absolutely critical.
        The definition that you refer to is a publication which
    suggested that for the pathologic definition of Alzheimer's
    disease, based on plaques, tangles, and neurodegeneration,
    there is a set of biomarkers that have standardized, would
    allow us to assess across studies both longitudinal studies and
    clinical trials, and in doing so, rigorously harmonize the
    results of multiple efforts, so more quickly understand which
    biomarkers are best predictive of disease and importantly,
    predictive of a response to intervention to treatment or not.
        So the studies that Senator Blunt referred to at Wash U are
    among those. Right now, the biomarkers that are most accessible
    and most widely used are either imaging, which works extremely
    well but is cumbersome and expensive, or cerebrospinal fluid
    analyses which works. But the goal of many now is to establish
    so-called fluid biomarkers that can take the advantage of blood
    and serum and identify either a single molecule or a pattern of
    molecules that will allow us to screen many people, more than
    we currently can through longitudinal studies and through
    interventions.
        Senator Moran. Doctor, thank you.

                  RETURN ON INVESTMENT IN BIOMEDICAL RESEARCH

        Let me address this question to Dr. Collins. With the
    leadership of Senator Blunt and others, we have had success in
    large part, I would say, because you all have made a case for
    additional resources within each of your institutes in which
    the public good is demonstrated and the advancements that are
    being made are sufficient for American people to feel
    comfortable that progress is happening and that we are on the
    cusp of developments that will make a difference in their
    lives.
        In the last year since you were here, Dr. Collins, in this
    setting, what can I tell my constituents that has transpired to
    reassure them that their tax dollars are being wisely spent? I
    sometimes head down the track in a town hall meeting explaining
    that there are things that we should spend no money on, things
    we should reduce spending on, and there are things we should
    spend more money on. And by the time I say that sentence, I am
    wondering what my constituents are thinking about a Senator
    from their State who is interested in spending more money on
    anything. Then I use NIH as the example.
        And one of the things that we have been able to do in this
    subcommittee and the Senate is to prioritize our spending. So
    it is making decisions about where to spend more money, not
    just always the thing that I think many Kansans might think
    happens around here, just spending more money on everything.
        So, Dr. Collins, give me the town hall description of how
    successful our spending has been in the year since we last met.
        Dr. Collins. I love to give that description. Thank you for
    the opportunity.
        One thing that I would say is maybe the most important
    discovery that happened in the last year is one we do not know
    about yet because it was a basic science discovery that sort of
    seemed at the time interesting, but we did not realize until
    maybe a year or 2 from now just how profound it might be. We
    talked about CRISPR Cas earlier. When that was discovered,
    nobody had it on their list of the big deal from that year.
        Another big discovery that probably we could mention for
    anybody across this table would be something that has just
    happened in the more therapeutic applications. In my opening
    statement, I told the story of a little boy who should not be
    alive who is walking around and hanging on the monkey bars
    after being diagnosed with spinal muscular atrophy, a fatal
    disease, and which with gene therapy now appears to have had a
    dramatic response.
        I could say, well, let us talk about drug abuse. Just
    yesterday, approval by the FDA of lofexidine, the first non-
    opioid way to help people withdraw from opioids, which is an
    effort that NIDA and their colleagues had put together with
    industry.
        With cancer, the advances in cancer immunotherapy, which
    was already pretty good stuff a year ago--oh, my gosh, it has
    gotten so much more exciting now with the additional advances,
    as Ned could no doubt tell you.
        In terms of neurological diseases and advances in aging,
    some of the basic science of aging has also had some
    interesting findings in the last year about the normal process,
    not just when it goes awry.
        And certainly Dr. Fauci would say, well, goodness, where
    were we a year ago in terms of Zika and Ebola and where are we
    now when it comes to such things as a vaccine for the flu, a
    vaccine for HIV, and maybe also ways to deal with that
    antimicrobial resistance problem, which have come a long way in
    that last year.
        So my town hall speech has already gone on too long, but I
    think you get the sense there is a long list of things we could
    point to in just this last year.
        And in case anybody thinks, well, that is fine but is it
    really worth the money, it is also the greatest return on
    investment of anything that the government spends money on,
    $8.38 of return in 5 years from every dollar that you all
    allocate to NIH because of what happens in terms of its
    economic impact.
        Senator Moran. You do, Dr. Collins, what I do in my town
    hall meetings in wrapping up and concluding and then I have
    another few paragraphs as well.
        Dr. Collins. Guilty.
        Senator Moran. But you have a great story to tell and I
    appreciate you reminding us of those successes. Thank you.
        Senator Blunt. Thank you, Dr. Collins and the Institute
    directors with you today.

                         ADDITIONAL COMMITTEE QUESTIONS

        The record will stay open for 1 week for additional
    questions.
        [The following questions were not asked at the hearing, but
    were submitted to the Department for response subsequent to the
    hearing:]
             Questions Submitted to Francis S. Collins, M.D., Ph.D.
                    Questions Submitted by Senator Roy Blunt
                             personalized medicine
        Question. Dr. Collins, over the past 3 years, this Subcommittee has
    provided $650 million in funding for personalized medicine initiatives,
    including the recently launched ``All of Us'' program. At the same
    time, the National Human Genome Research Institute has continued other
    important genomics research efforts. As the NIH advances the ``All of
    Us'' program, which is a large personalized medicine initiative, how
    are you ensuring that you continue to leverage and support the genomics
    expertise and facilities currently in place across the country?
        Answer. The NIH thanks the Subcommittee for its support of
    personalized medicine initiatives overall, and for its support of the
    All of Us Research Program in particular. The field of precision
    medicine is a major area of growth across the U.S., and the All of Us
    Research Program will dramatically advance the fields of personalized
    medicine and precision health through integrating a wide variety of
    environmental, behavioral, and biological information at an
    unprecedented scale. The program launched nationally on May 6, 2018,
    after establishing a major consortium of academic researcher
    institutions, healthcare provider organizations, technology experts,
    community partners, and participants. The program leveraged the
    expertise of the genomics community through the Genomics Working Group
    of the All of Us Research Program Advisory Panel which issued a report
    in December 2017.\1\ This Working Group included expertise from
    academia, industry, and NIH, including the National Human Genome
    Research Institute. The report provides information on the pros and
    cons of different approaches and options for corresponding
    implementation plans, and encompasses effective strategies to generate,
    analyze, and manage genomic data at the scale of All of Us. The program
    recently issued a funding announcement for Genome Centers to generate
    genotype and whole genome sequence data from participants' biosamples.
    The program anticipates funding up to two Genome Center awards in
    fiscal year 2018, with analyses to begin this fall with a goal of
    ramping up to 200,000 genotypes and whole genome sequences annually.
    This is a scale only feasible because of the outstanding achievements
    of the U.S. genomics research community. The program has been able to
    make major advances in its genomics approach not only through the
    world-class genomics expertise in its consortium and Advisory Panel,
    but also through the on-going interactions of its senior leadership
    with the broader community through frequent participation in events and
    workshops held by organizations across the country, as well as its
    strong relationships with Institutes and Centers across NIH, including
    leveraging the expertise within the National Human Genome Research
    Institute.
    ---------------------------------------------------------------------------
        \1\ Considerations Toward a Comprehensive Genomics Strategy.
    Available at: https://allofus.nih.gov/sites/default/files/
    gwg_final_report.pdf.
    ---------------------------------------------------------------------------
                                opioids vaccine
        Question. The fiscal year 2019 budget proposes a coordinated
    strategy with two primary aims to combat the opioid epidemic in our
    country. One of those aims is to accelerate the development of new,
    non-addictive pain therapies with the goal of making a wide-range of
    therapeutics accessible to those who need them as quickly as possible.
    Can you describe what types of non-addictive pain therapies are
    currently in the NIH research pipeline, and how quickly can these
    therapies can be developed and distributed to the market?
        Are there any vaccine candidates being considered?
        Answer. NIH is particularly excited about the new Helping to End
    Addiction Long-term (HEAL) Initiative. HEAL will bolster research
    across NIH in an effort to improve the treatment of chronic pain by (1)
    exploring biomarkers that predict the transition from acute to chronic
    pain, (2) identifying new targets for treating chronic pain using
    neurotechnologies developed through the Brain Research through
    Advancing Innovative Neurotechnologies (BRAIN) Initiative and the
    Stimulating Peripheral Activity to Relieve Conditions (SPARC) program,
    and (3) building the evidence base on the effectiveness of nondrug and
    integrated pain treatments. In addition, the Initiative will pursue
    public-private partnerships to develop new non-addictive pain medicines
    by sharing data on past and present research projects, and matching
    researchers with a selection of potentially promising but abandoned
    pharmaceutical industry compounds to explore their effectiveness for
    the treatment of pain. Finally, NIH will develop a clinical trials
    network for pain, allowing multiple new and repurposed compounds to be
    tested for effectiveness simultaneously.
        The Initiative will tap into the expertise of the NIH Pain
    Consortium,\2\ a trans-NIH consortium made up of NIH institutes that
    fund pain research. Funded projects are investigating the entire range
    of therapeutics development- from preclinical safety and efficacy
    testing and early phase human trials to health services research.
    Currently, the consortium members are working on developing more
    effective and less addictive treatments for chronic pain. For example,
    a study using a molecular imaging technology called x-ray
    crystallography has revealed the molecular structure of the receptors
    that mediate drugs' effects; this information is already leading to the
    development of safer medications to treat pain.
    ---------------------------------------------------------------------------
        \2\ https://www.painconsortium.nih.gov/About/Members.
    ---------------------------------------------------------------------------
        NIH-funded research is developing medications with properties that
    affect opioid receptors to produce analgesia with reduced risk of
    addiction and misuse. Some of these exhibit novel properties as a
    result of their combined activity at different opioid receptors (mu,
    delta, and kappa). Compounds with combined activity at the mu and delta
    receptors or at all three receptors can induce strong analgesia without
    producing tolerance or dependence in animal models. In addition, the
    discovery of adjunct medications that can be combined with opioids to
    reduce the needed dose has the potential to result in lower potential
    for dependence and addiction. Innovative methods are being explored for
    drug delivery to increase specificity and efficacy and to reduce
    analgesic side effects, as well as modified formulations to enhance
    delivery.
        NIH supports an initiative called the Blueprint Neurotherapeutics
    Program for small molecule drug discovery and development. For example,
    NINDS funds studies through this program that aim to develop non-
    addictive kappa opioid receptor antagonists for migraine and a safe,
    non-opioid analgesic that can be taken orally to reduce diabetic nerve
    pain.
        NIDA continues to fund development of anti-opioid vaccines capable
    of generating an immune response that would prevent opioids from
    entering the brain, thereby blocking both their euphoric effects and
    their dangerous respiratory depressant properties. Current projects
    include:
      --Optimization and preclinical testing of a practical heroin-HIV
            vaccine \3\
    ---------------------------------------------------------------------------
        \3\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9110917&icde=39707102
    &ddparam=&ddvalue=&ddsub=&cr=20&csb=default&cs=ASC&pball=.
    ---------------------------------------------------------------------------
      --Preclinical development of vaccines against heroin, oxycodone,
            hydrocodone, and fentanyl \4,5,6,7\
    ---------------------------------------------------------------------------
        \4\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9444613&icde=39707102
    &ddparam=&ddvalue=&ddsub=&cr=11&csb=default&cs=ASC&pball=.
        \5\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9330137&icde=39707102
    &ddparam=&ddvalue=&ddsub=&cr=26&csb=default&cs=ASC&pball=.
        \6\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9461410&icde=39707102.
        \7\ Olson ME, Janda KD. Vaccines to combat the opioid crisis:
    Vaccines that prevent opioids and other substances of abuse from
    entering the brain could effectively treat addiction and abuse. EMBO
    Rep. 2018 Jan;19(1):5-9.
    ---------------------------------------------------------------------------
        Results from preclinical models thus far have shown that these
    vaccine candidates are capable of producing an immune response that
    blocks opioid effects.32 While none have yet advanced to clinical
    trials, the heroin vaccine candidate developed by the Walter Reed Army
    Institute of Research in collaboration with NIDA has been in-licensed
    by Opiant Pharmaceuticals for further development.\8\
    ---------------------------------------------------------------------------
        \8\ https://www.opiant.com/pipeline/heroin-vaccine/.
    ---------------------------------------------------------------------------
                                     ______

                 Questions Submitted by Senator Lamar Alexander
                            fda enforcement actions
        Question. In April 2018, at my request, the Federation of State
    Medical Boards issued a report on regenerative and stem cell therapy
    practices. The report included information on the regulatory history of
    regenerative medicine and recommendations for state medical boards.
        The report described how ``some clinics . . .  are engaged in the
    provision of treatment modalities that lack evidence . . .  or use what
    have been described as `tokens of scientific legitimacy' to lend
    credence to treatments offered or the quality of a clinic and its
    associated professionals.'' According to the report, these tokens
    include ``patient or celebrity testimonials and endorsements, clinician
    affiliations or memberships in academic or professional societies, and
    registrations in clinical trials, among others.''
        Last week, the Food & Drug Administration (FDA) filed two
    complaints in Federal court seeking permanent injunctions to stop two
    stem cell clinics from marketing products without FDA approval. The
    National Institutes of Health runs clinicaltrials.gov and includes a
    disclaimer that not all studies on the website have been evaluated by
    the U.S. Federal Government.
        What steps can NIH take to make sure patients visiting
    clinicaltrials.gov are aware of any enforcement or regulatory actions
    taken by FDA? Is there any other legislative action Congress can take
    to help NIH address this issue?
        Answer. Research participant safety is of utmost importance to NIH.
    The ClinicalTrials.gov website currently includes information to help
    potential participants learn more about the potential benefits and
    risks of participating in a trial and always recommends talking with
    trusted healthcare professional before starting a trial. NIH is taking
    several steps to increase transparency and clarify information on
    clinicaltrials.gov including:
      --Adding more prominent disclaimers explaining that listing a study
            does not mean it has been evaluated by the U.S. Federal
            Government
      --Adding a question about whether the product being tested is under
            FDA oversight
      --Continuing to evaluate and improve other resources to help
            potential participants identify questions they may want to
            consider when deciding whether to participate in research and
            encouraging them to consult with their healthcare provider on
            such decisions
        NIH is committed to continuing to improve these resources to help
    ensure people understand important issues to consider before
    participating in a clinical trial and working closely with FDA to
    determine best strategies for educating the public on FDA activities
    and providing information on FDA oversight of clinical research.
        NIH does not believe additional legislative action is needed at
    this time. As noted, NIH is committed to working with FDA to identify
    ways to improve communication about FDA actions, including enforcement
    or regulatory actions that may be relevant to information on
    ClinicalTrials.gov.
                                     ______

                 Questions Submitted by Senator James Lankford
                                   stem cells
        Question. As you know, despite years of research and use of tax
    dollars, there is currently no validated, successful patient treatment
    from embryonic stem cells. Additionally, alternatives to embryonic stem
    cell research exist. In 2012, the Nobel Prize in Physiology or Medicine
    was awarded to two researchers for their discovery of induced
    pluripotent stem (iPS) cells, which mimic the qualities of embryonic
    stem cells but do not use embryos in any way. Similarly, NIH has had
    great success in treating and curing more than 70 diseases using adult
    stems cells and iPS cells.
        Despite that, in 2009, President Obama issued E.O. 13505, which
    gave HHS and NIH authority to use human stem cells, including embryonic
    stem cells, in research. E.O. 13505 revoked a previous EO from
    President Bush that outlined ethical principles for stem cell research.
        Because the research has yet to yield positive results, have you
    considered a plan to stop embryonic stem cell research or limit such
    research if the cell line is not already included on the NIH Human
    Embryonic Stem Cell Registry?
        Answer. NIH funds a range of stem cell research, using human and
    non-human adult stem cells, induced pluripotent stem cells (iPSCs), and
    since 2001, human embryonic stem cells (hESCs). NIH stem cell research
    must be conducted in accordance with the NIH Guidelines for Human Stem
    Cell Research, which detail stringent criteria for voluntary informed
    consent by which the NIH Director determines the eligibility for use of
    specific hESC lines in NIH-funded research. NIH-funded stem cell
    research is exploring applications in regenerative medicine, drug
    screening, and the study of the molecular pathways in biological
    development and human disease. Projects studying how undifferentiated
    stem cells become specialized cells with specific functions in the body
    have produced knowledge that is essential for developing regenerative
    medicine treatments. For example, NIH-supported researchers have
    established protocols for development of specific cell type from hESCs:
    e.g., pancreatic beta cells (which were effective in a mouse type 1
    diabetes model), dopaminergic neurons (tested in a mouse Parkinson's
    model), liver hepatocytes, and cardiomyocytes. NIH-supported
    researchers are using hESCs to study cells with particular diseases,
    such as neurons with a Niemann Pick type C1 mutation, which causes a
    progressive neurological disease. NIH-supported researchers have also
    used hESCs to develop organoids, including intestine, colon, and
    kidney, to model organ-specific diseases.
        Several investigational cell therapies developed from hESCs are
    currently in FDA-regulated clinical trials for spinal cord injury,
    macular degeneration, and type 1 diabetes. The first trial using an
    investigational cell therapy from iPSCs is taking place in Japan for
    macular degeneration; an NIH intramural investigator also plans to file
    an IND this year for using a product from human iPSCs for macular
    degeneration.
        One can never be certain where the next cure or treatment will come
    from, and maximizing researchers' access to diverse tools, methods, and
    experimental systems is critical for enhancing the likelihood of
    success in advancing the NIH mission. Therefore NIH will continue to
    support highly meritorious research with NIH-approved hESCs.
                                     ______

                  Questions Submitted by Senator Patty Murray
                                    big data
        Question. The Committee directed NIH in the fiscal year 2017
    omnibus to develop a strategic plan to address these issues, which was
    recently released. Now that NIH has a plan, what's the timeline for its
    implementation?
        Answer. The NIH Strategic Plan for Data Science \9\ (subsequently
    referred to as ``the Plan'') describes NIH's Overarching Goals,
    Strategic Objectives, and Implementation Tactics for modernizing the
    NIH-funded biomedical data-resource ecosystem. The Plan was developed
    by the NIH Scientific Data Council, and reflects input from HHS,
    scientists, policymakers, scientific and professional societies, the
    general public, and leadership and staff from NIH and its constituent
    Institutes and Centers.
    ---------------------------------------------------------------------------
        \9\ https://datascience.nih.gov/sites/default/files/
    NIH_Strategic_Plan_for_Data_Science_ Final_508.pdf.
    ---------------------------------------------------------------------------
        NIH is mapping out the Plan's implementation and expects activities
    will intensify over the next year. Implementation of key areas are
    already underway, including the NIH Data Commons Pilot and NIH's cloud-
    marketplace initiative. In addition, targeted training and career
    development opportunities to enhance the biomedical data science
    workforce are in preparation, such as data science fellowships. NIH
    also is in the process of aligning data science-related funding
    opportunity announcements to help ensure support for databases,
    knowledgebases, and tools development are addressed in the most
    efficient and cost-effective way. Other Plan goals, such as developing
    data standards, are in early discussion and will require additional
    research, planning, and interaction with the community to determine the
    scope and context of future guidance.
        As NIH moves forward, the Scientific Data Council, a sub-committee
    of the NIH Steering Committee composed of Institute and Center
    directors and deputy directors, as well as key NIH subject matter
    experts, will have an active role in overseeing execution of the Plan.
    The NIH Chief Data Strategist, currently being recruited, will
    collaborate closely with the Scientific Data Council, Data Science
    Policy Council, and other key NIH stakeholders to lead implementation
    of the NIH Strategic Plan for Data Science. We anticipate that full
    implementation plans will be in place within the next year, with a
    majority of Implementation Tactics launched in the same timeframe.
        Question. Given the scale of this undertaking, what does NIH see as
    the biggest potential barriers to achieving the plan's vision?
        Answer. During development of the Plan, a number of data science
    challenges for NIH were characterized (see pages 4-5 of the Plan). Some
    of the most pressing barriers to achieving the Plan's vision are
    summarized below:
      --The exponential expansion of data quantity and complexity is
            increasing costs of data infrastructure, storage and
            management, including data access, integrity, and privacy
            considerations.
      --The siloed nature of the current data ecosystem is a challenge for
            data integration, standardization, and interoperability.
            Implementation of FAIR (Findable, Accessible, Interoperable,
            and Reusable) principles will enhance stewardship by improving
            the sustainability of data resources supported through NIH
            investments.
      --The funding mechanisms currently used by NIH incentivize tool
            development and primary analysis of data but are less
            compatible with data resource maintenance and sharing. A key
            objective of the Plan is to tailor the funding mechanisms to
            the desired outcomes for NIH-supported data resources.
      --Novel bridges between academic research institutions, NIH, and the
            technology industry are needed to enhance development and
            dissemination of efficient and effective data resources and
            analytical tools. Flexible funding strategies, including
            expanded use of Other Transaction Authority, would assist in
            building these bridges.
      --A new generation of trained biomedical data science experts will be
            essential to bringing the vision elaborated in the Plan to
            fruition. However, the discrepancy in pay scales between the
            technology industry on the one hand and academics and
            government on the other presents a challenge for recruiting and
            retaining talent in data science for biomedical research.
        As noted in the response to Question 1, NIH is working to overcome
    these challenges and implementing new programs and initiatives to
    address these barriers.
        Question. Are there cases where researchers are reluctant or face
    challenges sharing their data, or they delay releasing that data for
    years until they've published their findings? What do you do in these
    situations? Do you see an opportunity to revise policy to address this
    issue?
        Answer. The current culture of data sharing is moving towards
    openness and transparency. Consistent with these efforts, the NIH
    encourages and expects the sharing of data from supported research
    through policies and practices. For example, under the NIH Genomic Data
    Sharing \10\ (GDS) Policy, investigators seeking NIH funding for
    genomics projects are expected to submit a Genomic Data Sharing Plan as
    part of the application for funding, which includes the data submission
    and release timeline. NIH recognizes that different types of genomic
    data undergo different levels of processing, and the expectations for
    data submission and data release are based on those levels. However, in
    general, data are released to NIH-designated data repositories for
    access by other investigators no later than 6 months after the initial
    data submission begins, or at the time of acceptance of the first
    publication, whichever occurs first, without restrictions on
    publication or other dissemination.
    ---------------------------------------------------------------------------
        \10\ https://osp.od.nih.gov/wp-content/uploads/NIH_GDS_Policy.pdf.
    ---------------------------------------------------------------------------
        In some cases, restrictions or limitations on the data may exist
    that prevent broadly sharing the data. For example, based on the
    informed consent provided by the research participants, there may be
    limits on who may use the data or for what purposes the data may be
    used. Other restrictions may stem from legal issues or limitations
    placed on downstream data use by the study populations who participated
    in the research, for example tribal populations. In some cases, it may
    not be appropriate for researchers to share genomic data. In such
    cases, NIH may grant an exception to the typical data sharing
    expectations and allow for an alternative genomic data sharing plan. An
    example of an alternative data sharing plan might be the sharing of
    summary-level information only. Summary-level information is study data
    that has been aggregated across the study population (as opposed to
    sharing data at the level of each individual study participant).
        NIH recognizes that investigators often do not want to share their
    data until they have had the opportunity to publish their own findings.
    However, at the same time, NIH has a strong interest in increasing the
    impact and rigor of research studies it funds. Therefore, the NIH
    officially announced in March 2017 \11\ that researchers may cite their
    interim research products and claim them as products of NIH funding in
    order to increase the impact and rigor of a research study. Interim
    research products can be cited anywhere other research products are
    cited in the NIH grant application. An example of such a product is a
    preprint publication, which is a complete and public draft of a
    scientific document that typically has not yet undergone peer review.
    NIH encourages investigators to use interim research products, such as
    preprints, to speed dissemination and enhance the rigor of the
    research.
    ---------------------------------------------------------------------------
        \11\ https://grants.nih.gov/grants/guide/notice-files/NOT-OD-17-
    050.html.
    ---------------------------------------------------------------------------
        NIH also has addressed specific data sharing challenges through
    targeted policy development. For example, the NIH Policy on the
    Dissemination of NIH-Funded Clinical Trial Information \12\ promotes
    broad dissemination of summary-level results from NIH-funded clinical
    trials by establishing the expectation that researchers will register
    the trials in and submit the results information to ClinicalTrials.gov.
    Under this Policy, NIH expects the results information to be submitted
    no later than 1 year after the trial's primary completion date.
    ---------------------------------------------------------------------------
        \12\ https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-
    149.html.
    ---------------------------------------------------------------------------
        Another example policy is the NIH 2003 Data Sharing Policy, which
    expects that investigators submitting a research application requesting
    $500,000 or more of direct costs in any single year include a plan for
    sharing their final research data or state why they cannot. In this
    Policy, NIH expects the timely release and sharing of data to be no
    later than the acceptance for publication of the main findings from the
    final dataset. The specific time will be influenced by the nature of
    the data collected. However, despite guidance on implementation, there
    is not a structured format for the plans, and policy compliance has
    been inconsistent.
        The NIH is evaluating its existing data sharing policies with an
    eye on furthering the current culture of data sharing. From November
    2016 to January 2017, NIH sought public comment on how scientific data
    generated from NIH-funded research should be managed, and to the
    fullest extent possible, made publicly available through a Request for
    Information: Strategies for NIH Data Management, Sharing, and
    Citation.\13\ This public comment solicitation also specifically asked
    the public for the greatest barriers and challenges associated with
    data sharing. Input \14\ from the public, which included universities,
    associations, companies, and publishers, noted specific barriers to
    data sharing, such as establishing a culture of sharing that would
    appropriately incentivize and encourage data sharing, the need for
    community-based standards for long-term preservation or sustainability
    of data, data preparation and submission, and the costs and resources
    associated with data management and sharing, e.g., data curation,
    personnel, infrastructure. Suggestions to resolve some of these
    barriers included providing incentives (e.g., citation of datasets and
    attribution for sharing data) to help to change the culture of data
    sharing. Respondents felt that the use of community-based standards, as
    well as the ability to budget for data management and sharing in NIH
    funding applications and proposals, would help mitigate some of the
    resource barriers associated with data management and sharing.
    ---------------------------------------------------------------------------
        \13\ https://grants.nih.gov/grants/guide/notice-files/NOT-OD-17-
    015.html.
        \14\ https://osp.od.nih.gov/wp-content/uploads/
    Public_Comments_Data_Managment_
    Sharing_ Citation.pdf.
    ---------------------------------------------------------------------------
        The NIH intends to continue ongoing outreach and community
    engagement on existing policies and practices to refine the
    implementation of existing policies and to develop new policies when
    warranted to achieve the goal of encouraging a culture of data sharing.
        Question. Given the scale of investments Congress is making in
    Alzheimer's disease, the data we are generating may be used to
    accelerate major scientific breakthroughs. Has NIA looked at its
    existing data sharing policies to determine how they are working? Do we
    know what percentage of grant recipients fulfil their data sharing
    obligations at the end of their projects?
        Answer. NIA does not currently keep an overall tally of compliance
    with data-sharing plans. With that said, a number of NIA initiatives
    related to Alzheimer's disease (AD) and related dementias have data-
    sharing plans built in, and in those situations sharing of data is used
    as a criterion for continued funding from year to year. Major programs
    that operate under these terms include the Accelerating Medicines
    Partnership for AD initiative (AMP-AD); the Model Organism Development
    and Evaluation for Late-Onset AD (MODEL-AD) initiative; and the
    Alzheimer's Disease Neuroimaging Initiative (ADNI). We are currently
    exploring the feasibility of and possible mechanisms for tracking
    compliance more globally across research project grants.
        Question. The committee has prioritized a biomedical research
    ecosystem that is amplified by sustainable, interoperable, accessible,
    and usable research data, including Alzheimer's research data. How do
    you ensure that data sharing is prioritized at the start of the NIH
    grant process? Is there a process to make sure researchers are
    preparing to share their data from the start? What are the most
    frequent comments you hear from researchers about why they can't share
    their data?
        Answer. Effective data sharing relies upon appropriate
    identification, adoption, and crediting of good data management and
    sharing practices. Thus, NIH encourages data sharing consistent with
    the FAIR (Findable, Accessible, Interoperable, Re-usable) data
    principles. For example, in order to facilitate access by qualified
    investigators to genomic data for the study of Alzheimer's disease, NIH
    funded the creation of The National Institute on Aging Genetics of
    Alzheimer's Disease Data Storage Site \15\ (NIAGADS), currently
    maintained at the University of Pennsylvania. NIAGADS along with other
    National Institute for Aging (NIA) approved sites make genomic data and
    associated phenotypic data available to qualified investigators in the
    scientific community for secondary analysis in accordance with
    standards established by the NIA and the NIH Genomic Data Sharing (GDS)
    Policy.
    ---------------------------------------------------------------------------
        \15\ https://www.niagads.org/.
    ---------------------------------------------------------------------------
        NIH policies on data sharing typically expect that a plan is
    submitted with a funding application, indicating for example what data
    will be shared, and how, when, and where it is expected to be shared.
    These policy expectations suggest that researchers and institutions
    should be thinking through these issues during the planning phases of
    their applications.
        For example, the implementation of the NIH GDS Policy sets the
    expectation that applications for funding that propose the generation
    of large-scale human or non-human genomic data include a Genomic Data
    Sharing Plan in the Resource Sharing Plan section of the grant
    application. Applicants are expected to describe the data type(s) and
    repository for data deposition. Applicants proposing to generate human
    data should also provide information addressing data submission and
    release timelines, Institutional Review Board assurance of the genomic
    data sharing plan, the appropriate uses of the data, and if
    appropriate, a request for a data sharing exception, prior to award.
    Those proposing to generate non-human data also need to address the
    data submission and release timelines prior to award. The Genomic Data
    Sharing Plan is approved by the funding NIH Institute or Center. In
    addition, for the NIH Policy on the Dissemination of NIH-Funded
    Clinical Trial Information, applicants proposing to conduct clinical
    trials must submit a plan for the dissemination of the trial
    information.
        NIH continues to discuss, with public input, the value of data
    sharing and what information is most helpful to include in a plan for
    managing and sharing data that ensures shared data are findable,
    accessible, interoperable, and reusable (the FAIR principles).\16\ NIH
    and the National Science Foundation held a joint workshop on the Value
    of Data Sharing in October 2017.\17\ Some consistent themes included in
    plans for data management and sharing among various Federal funders
    include describing the types of data to be shared; what tools may be
    needed to analyze shared data; what standards apply to the collected
    data; how, where, and for how long data will be available; and whether
    any barriers to data sharing exist.
    ---------------------------------------------------------------------------
        \16\ https://www.force11.org/group/fairgroup/fairprinciples.
        \17\ https://osp.od.nih.gov/2017/12/18/data-destiny-debrief-nih-
    nsf-workshop/.
    ---------------------------------------------------------------------------
        Through responses to the Request for Information: Strategies for
    NIH Data Management, Sharing, and Citation,\18\ the public indicated
    that barriers to data sharing include the resources and repositories
    needed to manage and share data, the need for data standards to ensure
    that data is reusable and reproducible, and incentives. NIH continues
    to gauge ways to address these barriers in the process of evaluating
    its existing data sharing policies and practices.
    ---------------------------------------------------------------------------
        \18\ https://grants.nih.gov/grants/guide/notice-files/NOT-OD-17-
    015.html.
    ---------------------------------------------------------------------------
                              alzheimer's vaccine
        Question. In 2000, the NIH set aside $50 million over 5 years to
    support research on new ways to treat Alzheimer's disease with a
    special emphasis on the development of a vaccine to prevent the
    disease. While the first generation of Alzheimer's vaccines were
    developed shortly thereafter, in 2008 these studies were halted due to
    patient safety concerns. Can you describe what the NIH has done in
    recent years--or plans to do in the future--to support development of a
    vaccine to treat the more than 5 million Americans currently living
    with Alzheimer's?
        With the most recent omnibus funding bill bringing total 2018
    funding to $1.8 billion, does the NIH plan to fund research for an
    Alzheimer's vaccine in fiscal year 2019?
        The Alzheimer's Association has made a commitment to prevent or
    effectively treat Alzheimer's disease by 2025. We're less than 6 years
    away from that target, and in spite of continued Congressional
    increases to the NIH budget, safe and effective treatments are still
    out of reach. Can you describe the current research being done, and if
    you believe there are any gaps in research that could be addressed in
    fiscal year 2019?
        Vaccines have been one of the most effective and impactful
    medicines in history. Is vaccine research a priority for NIH's
    Alzheimer's research goals, and if not, why?
        Answer. Vaccination is one of many treatment modalities currently
    under study for both prevention and treatment of Alzheimer's disease
    and related dementias (AD/ADRD). For example, the Alzheimer's
    Prevention Initiative Autosomal Dominant Alzheimer's Disease (API-ADAD)
    study is exploring ``preventive immunotherapy'' among members of an
    extended Colombian family that carries a genetic mutation placing many
    members at greatly increased risk of developing the disease. Another
    study, the Dominantly Inherited Alzheimer's Network (DIAN) trial,
    evaluates the safety, tolerability, and effectiveness of several drugs,
    including two vaccines, and will determine if they can prevent, delay,
    or even reverse Alzheimer's disease changes in the brain. NIA also
    supports a large cooperative agreement to complete preclinical safety
    and efficacy testing for AV-1959D, a cutting-edge DNA vaccine. DNA
    vaccines use pieces of DNA from specific pathogenic proteins to
    stimulate an immune response and offer potential technical and safety
    advantages over conventional protein/adjuvant vaccines. All of these
    studies remain important priorities within our AD/ADRD portfolio and
    will remain active in fiscal year 2019.
        With respect to current AD/ADRD research and gaps, NIA has
    leveraged the extraordinary influx of funding directed at these
    diseases to build a series of bold and innovative research programs,
    infrastructure, and new partnerships that are enabling some of the
    Nation's leading scientists to tackle the problem of AD/ADRD at an
    unprecedented scale and pace. High-priority research and infrastructure
    programs that are currently underway include:
      --Alzheimer's Clinical Trial Consortium (ACTC), to accelerate and
            expand trials of AD/ADRD therapies;
      --Resilience-AD, a new program bringing together experts from
            multiple disciplines to understand why some high-risk
            individuals remain dementia free;
      --Molecular Mechanisms of the Vascular Etiology of Alzheimer's
            Disease (M\2\OVE-AD) Initiative, exploring how metabolic and
            vascular risk factors such influence brain aging and AD
            pathology and identifying blood-based markers of the disease;
      --Alzheimer's Biomarker Consortium--Down Syndrome (ABC-DS), in which
            researchers use biomarkers to track disease progression in
            people with DS, a uniquely vulnerable population at high risk
            for developing AD;
      --The Model Organism Development and Evaluation for Late-onset AD
            (MODEL-AD) project to develop better animal models of late-
            onset AD;
      --Approximately 140 active clinical trials of interventions to
            prevent, treat, or manage symptoms of AD/ADRD and to enhance
            caregiver well-being;
      --Development of new therapeutics, including some that target
            molecules other than beta-amyloid; and
      --Harnessing the power of big data to identify existing drugs or
            combinations currently used to treat other conditions that
            could be effective for the treatment of AD/ADRD.
        Gaps continue to exist around development of caregiver support
    interventions; implementation of a national recruitment strategy that
    ensures inclusion of diverse populations in AD/ADRD research;
    understanding gene-environment interactions that increase risk or
    confer resilience against AD/ADRD; infrastructure development,
    including big data infrastructure; workforce training across the
    spectrum of research; and harmonization and distribution of data from
    large datasets. NIH considers each of these a priority area for fiscal
    year 2019, and NIA has begun to implement strategies to fill these
    gaps, with a number of relevant Funding Opportunity Announcements
    issued or approved in concept by the National Advisory Council on
    Aging.
                          next generation researchers
        Question. Ensuring a strong pipeline of the best and brightest U.S.
    scientists is of paramount importance. To this end, the Fred Hutchinson
    Cancer Research Center in Seattle participates in the Coalition for
    Next Generation Life Science, which seeks to increase transparency of
    life science career prospects by providing new data and information to
    help students make informed choices about their science careers. What
    steps is the NIH taking to ensure young and mid-career investigators
    remain engaged in academic research?
        The National Academies of Sciences, Engineering, and Medicine
    released a report in April on the next generation of biomedical and
    behavioral researchers and recommended that NIH increase by five-fold
    the number of individual research fellowship (F) awards and career
    development (K) awards available to support postdoctoral researchers.
    It also recommended that NIH create a Next Generation Researcher
    Innovation Fund to support innovative pilot projects that seek to
    improve and accelerate transitions into independent careers. Which of
    these recommendations or others in the report, do you anticipate NIH
    adopting or considering?
        Answer. NIH is currently assessing the recommendations of the
    National Academies Next Generation Researchers Initiative (NGRI)
    committee, convened in early 2017, to study and recommend solutions to
    any barriers that may extend periods of training, time to independence,
    or impede sustained success in research. As you noted, a final report
    titled, ``Next Generation of Biomedical and Behavioral Sciences
    Researchers: Breaking Through'' was released in April 2018. As these
    recommendations are being considered, NIH is also awaiting a related
    report from a working group of the Advisory Committee to the Director
    focused on the next generation of researchers, expected in June 2018.
    NIH expects to incorporate guidance from both groups to prioritize
    further actions to bolster the careers of early-stage investigators.
        Within the NIH Office of the Director, the Office of Extramural
    Research's Division of Biomedical Research Workforce conducts regular
    evaluations of outcomes of NIH training and career development
    programs. These activities help us assess strategies that are
    successful in promoting continued engagement in academic research. NIH
    has, and continues to grow, an evidence-base to support positive
    impacts of individual postdoctoral fellowship (F) awards and individual
    career development (K) awards on subsequent, sustained research
    careers. NIH is currently considering how to optimize the benefits and
    outcomes of these awards for early stage researchers.
        NIH appreciates the recommendation to increase the number of F and
    K awards. NIH will carefully consider the cost to benefit ratio of
    increasing their numbers as well as other options, such as enhancing
    stipends, salary, or research support offered with each award, to
    maximize their impact on successful research careers.
        In addition, as we consider the National Academies' and Advisory
    Committee to the Director Working Group's recommendations, we will work
    with the NIH Institutes and Centers to consider expansion of other
    programs that have been particularly successful for early stage
    investigators, including:
      --NIH Director's New Innovator Award Program (DP2), which supports
            early-stage investigators of exceptional creativity who propose
            bold and highly innovative new research approaches with the
            potential to have a major impact on broad, important problems
            in biomedical and behavioral research.
      --The Maximizing Investigators' Research Award (R35) supports early-
            stage investigators to enhance their ability to take on
            ambitious scientific projects, spend time on research, and
            reduce the time spent writing grant applications.
      --The NIH Pathway to Independence Award (K99/R00) program to
            facilitate a timely transition of outstanding postdoctoral
            researchers to independent, tenure-track, or equivalent faculty
            positions and help researchers to launch competitive,
            independent research careers.
      --The Director's Early Independence award (DP5), as part of the NIH
            Common Fund's high-risk high reward initiative, aims to support
            more bold and innovative research activities with the
            opportunity for rapid progress. Specifically, this program
            accelerates the entry of exceptional junior scientists into an
            independent research career by forgoing the traditional post-
            doctoral training period. These select investigators have
            established a record of scientific innovation and research
            productivity as well as demonstrated unusual leadership, drive,
            and maturity,
      --The High Priority, Short-Term Project/Bridge Awards (R56) supports
            early-stage investigators by providing limited, interim
            research support to gather additional data for revised grant
            applications.
                                   salary cap
        Question. The Administration's fiscal year 2019 budget request
    proposes limiting the percentage of an investigator's salary that can
    be paid with grant funds at 90 percent of total salary. Like the fiscal
    year 2018 proposal to cap facilities and administrative costs, limiting
    salary support is proposed under the guise of identifying
    ``efficiencies.'' Congress firmly rejected the proposal to cap F&A in
    the final fiscal year 2018 omnibus because these infrastructure costs
    are integral to conducting successful research. Perhaps to an even
    greater degree, researchers who develop ideas, articulate research
    questions, design studies, and conduct experiments and clinical trials
    are essential to quality research and the pursuit of life-saving
    treatments and cures. Would NIH agree that if Federal support for
    principal investigators' salaries is cut, in addition to resources
    being redirected from other activities to cover salaries, wouldn't this
    send a message to those interested in entering academic research that
    they may not be fully supported?
        Answer. Because Federal research funds are limited, reductions in
    the NIH contributions to the salary of researchers on NIH grants leaves
    more funds for additional scientists along with the equipment and
    resources they need to carry out their critically important work. This
    may also provide funds that may be used to fund additional grants.
        NIH is aware of varying degrees of salary support for its funded
    scientists. In some institutions, scientists are expected to seek
    external grant funds to support most of their salaries. Other
    institutions provide most, if not all, of the salary support.
        Based on a NIH enumeration study,\19\ the NIH supports
    approximately 313,049 full-time and part-time positions, or the
    equivalent of 121,465 full-time employed individuals each year. We
    believe that approximately half of these full-time researchers are
    affected by the salary cap. Institutions may choose to increase
    tuition, utilize funds from their endowments, or solicit state level
    support to absorb some of the costs engendered by the salary cap. Some
    stakeholders have voiced concern that stringent salary caps may lead to
    disincentives for certain highly-skilled clinician scientists who may
    be well-positioned to conduct the kind of science solicited by NIH. The
    selective pressures on such individuals may lead to a lower number of
    them willing to engage in NIH-funded research. The NIH is cognizant of
    these potential effects, but in no way intends for the policies
    included in the President's Budget to hinder the critically important
    biomedical research funded by NIH.
    ---------------------------------------------------------------------------
        \19\ Pool, Lindsay R., et al. ``Size and characteristics of the
    biomedical research workforce associated with U.S. National Institutes
    of Health extramural grants.'' The FASEB Journal30.3 (2015): 1023-1036.
    ---------------------------------------------------------------------------
                          national academy of medicine
        Question. According to the 2015 National Academy of Medicine report
    Improving Diagnosis in Healthcare, eliminating diagnostic errors is a
    ``moral, professional, and public health imperative.'' Are there steps
    that NIH can take to invest in basic research on improving diagnosis in
    medicine, consistent with the findings of the National Academy of
    Medicine report? Given NIH's disease-specific institute missions, are
    there structural barriers, either administrative or legislative, that
    would need to be addressed for successful advancement of basic research
    by NIH in improving diagnosis in medicine?
        Answer. NIH invests in basic research on improving diagnosis in
    medicine, primarily through the National Library of Medicine (NLM). Of
    the approximately $30 million NLM expects to spend on extramural
    research projects in fiscal year 2018, about 1/3 supports investigator-
    initiated research projects in clinical/healthcare informatics and
    data. NLM-funded researchers have examined safety-related issues such
    as the unintended consequences of physician order entry, data mining of
    clinical data repositories, and tools for inpatient monitoring using
    evidence from the electronic health record (EHR). Current NLM research
    projects which are consistent with the recommendations of the National
    Academies study are: ways to monitor clinical workflow to detect
    adverse events, workflow capture to improve trauma resuscitation
    outcomes, terminology services to make orders consistent and reduce
    avoidable CT imaging, extraction of typical and atypical disease
    progression patterns from multi-site EHRs, and patient medical history
    representation, extraction and inference from EHRs. NLM's intramural
    research program also emphasizes analysis of large health data sets to
    enable discoveries that can inform diagnosis. In addition, the
    intramural research program supports work on health information/data
    standards and text processing that can improve the consistency of the
    terminology used in EHRs to support large scale analysis and extract
    meaning from narrative text, such as clinical notes, to support
    research on diagnosis. NLM's expanding portfolio of data science
    research will emphasize needs of precision medicine initiatives and
    organizations like OHDSI (Observational Health Data Sciences and
    Informatics) to characterize completeness, assure accuracy, and
    mitigate bias in large heterogeneous data sets. One challenging area is
    the need for large data sets of personal health data from individuals
    for fundamental research. Restrictions and concerns about access,
    confidentiality, permissions and bias in the data remain a challenge
    and are important areas for future research.
                                     ______

                    Questions Submitted by Senator Jack Reed
                               bioethical issues
        Question. Gene editing research such as the NIH's Somatic Cell
    Genomic Editing program holds the potential for curing diseases and
    significantly improving lives; however, we will need to contend with
    serious bioethical concerns as we continue to make advances in this
    research. Can you explain how NIH is staying ahead of bioethical issues
    as the research continues to progress? How is NIH coordinating these
    efforts with other Federal agencies, both within and outside of HHS?
        Answer. Gene editing technologies are powerful tools that enable a
    broad range of applications, including investigating gene function,
    developing better animal models to study specific human diseases, and
    developing new strategies to reduce the spread of malaria and other
    infectious diseases by vectors such as mosquitoes (through an
    application called a gene drive). Gene editing technologies are also
    already being used in clinical trials to potentially treat genetic or
    acquired diseases, ranging from infectious diseases to cancer.
        The bioethical issues associated with gene editing depend on the
    specific application of the technology, that is, how the gene editing
    technology is being used and for what purpose. Applications such as
    somatic gene therapy, human germline modification, and gene drives to
    eradicate disease all have different bioethical considerations. In many
    cases, the bioethical concerns raised by these technologies are similar
    to those first raised at the advent of recombinant DNA technology and
    human gene therapy and are well explored and integrated into current
    oversight structures. For instance, NIH supports gene therapy research,
    including gene editing approaches, in somatic cells in humans. Somatic
    cells are not involved in reproduction, so changes in somatic cells are
    not inherited by subsequent generations. The well-established oversight
    frameworks and FDA regulatory authority over human gene therapy trials
    would apply to clinical research involving gene editing. In fact, gene
    editing applications have already been in the clinic for several years
    in trials involving different types of technologies targeting such
    diseases as HIV infection, cancer, and several genetic disorders such
    as Hemophilia B.
        The potential use of gene editing to modify the human germline such
    that changes would not only affect an individual, but subsequent
    generations, has been a subject of ethical debate. NIH has participated
    in multiple activities of the National Academies of Sciences,
    Engineering, and Medicine (NASEM) focused on issues related to gene
    editing. The 2017 NASEM report, Human Genome Editing: Science, Ethics,
    and Governance,\20\ supported basic research and gene therapy in
    somatic cells but recommended a cautious approach to heritable gene
    editing in clinical studies.\21\ Given the ongoing concerns in this
    space, NIH will not fund any use of gene editing technologies in human
    embryos (NIH Director's statement, April 28, 2015).\22\ There are also
    legislative and regulatory prohibitions including the ``Dickey-Wicker''
    amendment attached to the annual appropriations bill for the Department
    of Health and Human Services, which prohibits the use of NIH funds for
    ``(1) the creation of a human embryo or embryos for research purposes;
    or (2) research in which a human embryo or embryos are destroyed,
    discarded, or knowingly subjected to risk of injury or death greater
    than that allowed for research under applicable Federal regulations.''
    ---------------------------------------------------------------------------
        \20\ https://www.nap.edu/catalog/24623/human-genome-editing-
    science-ethics-and-governance.
        \21\ https://www.nap.edu/catalog/24623/human-genome-editing-
    science-ethics-and-governance.
        \22\ https://www.nih.gov/about-nih/who-we-are/nih-director/
    statements/statement-nih-funding-
    research-using-gene-editing-technologies-human-embryos.
    ---------------------------------------------------------------------------
        Potential bioethical issues exist for gene drive technology, which
    allows for the spread of desired traits through populations of
    organisms at a faster rate than what typically occurs in nature. This
    approach could potentially provide a means to address environmental or
    public health problems (e.g., control of invasive species or vector-
    borne infectious diseases like malaria), but there are potential
    ethical concerns, especially related to possible effects on the
    environment. To engage in a robust conversation and to address ethical,
    scientific, and safety issues, NIH funded in part a 2016 NASEM study
    \23\ on responsible conduct of gene drive research. In a Director's
    Statement (June 7, 2016), NIH accepted the report, which included
    support for continuing basic and applied research in gene drives while
    holding off on release of gene drive modified organisms into the
    environment at this time.\24\
    ---------------------------------------------------------------------------
        \23\ http://nas-sites.org/gene-drives/.
        \24\ https://www.nih.gov/about-nih/who-we-are/nih-director/
    statements/statement-national-academy-sciences-report-gene-drives-non-
    human-organisms.
    ---------------------------------------------------------------------------
        As new gene editing technologies come to fruition, NIH continues to
    be prepared to investigate their ethical, legal, and social
    implications (ELSI). For example, the National Human Genome Research
    Institute (NHGRI), has a Congressionally-mandated, 5 percent set-aside
    in its extramural budget to fund ELSI research. In anticipation of
    myriad bioethical issues, NHGRI's ELSI portfolio covers research to
    explore the downstream implications of emerging genomic technologies.
        How is NIH coordinating these efforts with other Federal agencies,
    both within and outside of HHS?
        Answer. NIH has been closely engaged with other Federal agencies,
    both inside and outside of HHS, on bioethical issues associated with
    gene editing. NIH works closely with the Food and Drug Administration
    (FDA) on issues related to gene editing through fora such as the NIH/
    FDA Joint Leadership Council, in which there is a dedicated effort to
    coordinate gene editing activities.
        NIH continues to participate in many NASEM activities, including
    the ongoing Human Genome Editing Initiative, which involves many
    components across the U.S. Government and beyond.\25\ As noted above,
    NIH also supported a NASEM study on gene drives, which involved other
    funders including the Defense Advanced Research Projects Agency, the
    Foundation for the National Institutes of Health, and the Bill &
    Melinda Gates Foundation. NIH continues to coordinate with these
    funders to promote the safe and ethical conduct of gene drives
    research.
    ---------------------------------------------------------------------------
        \25\ http://nationalacademies.org/gene-editing/index.htm.
    ---------------------------------------------------------------------------
        NIH also engages in bioethics conversations in international fora,
    including discussions of the ethics of gene editing at the fourth
    ``Unite to Cure Conference'' in April 2018, which was hosted at the
    Vatican to discuss the bioethics of gene editing and other
    biotechnologies with physicians, researchers, and religious thought
    leaders from across the globe. NIH will continue to engage in such
    discussions, both inside and outside the government, and both
    domestically and internationally.
                                     ______

               Questions Submitted by Senator Christopher Murphy
                   center for excellence in genomic sciences
        Question. As you know, I represent a State that has two significant
    academic medical research institutions--Yale University and the
    University of Connecticut. The University of Connecticut, via a
    collaboration with the Jackson Labs, has in recent years made
    significant investments in genomics research, a field that Yale has
    done work in as well. As the technology and tools to do genomics
    research and screening have become more widespread, more universities
    like UConn have aspired compete for Federal funding.
        As you know, the largest of such awards at the National Human
    Genome Research Institute is called the Center for Excellence in
    Genomic Sciences (CEGS) program. Each 5-year CEGS grant supports a
    multi-investigator, interdisciplinary team to develop innovative
    genomic approaches to address a particular biomedical problem and is
    funded at up to $1.75 million annually.
        The CEGS program was launched back in 2001 with two awards.
    Additional rounds of awards in subsequent years eventually expanded
    that number to 10 centers. However, at present there are only 8 CEGS
    awards active in the U.S. spread among only 7 research institutions.
    Furthermore, only 20 institutions total have ever received one of these
    awards in the past 17 years. I understand the importance of
    institutional knowledge at these universities but am also concerned
    that the same players may get these awards while other universities,
    like UConn, are left with little chance to compete for these larger
    awards.
        Do you have any suggestions on how NIH might address this problem?
        Answer. The Centers of Excellence in Genomic Science (CEGS) were
    established in 2001. Three CEGS awards were made that year, including
    one to Yale University. NHGRI generally makes one to two CEGS awards
    per year, although in 3 years we made three or four awards. In the 18
    years that the program has existed, NHGRI has issued 23 awards, to 20
    institutions. The group of 20 institutions that has benefited from the
    CEGS program is quite geographically and institutionally diverse.
        The CEGS program generally makes awards for 5 years, and only eight
    institutions have renewed for another 5 years. Awards currently in
    their first 5 years of funding are located at Harvard Medical School,
    Stanford University, the University of Washington/Altius Institute for
    Biomedical Sciences, the University of Chicago, the University of
    California Berkeley, and the University of Pennsylvania. Those in
    renewals are located at Yale University, the University of Washington/
    Arizona State University, Tempe, Stanford University, the University of
    Southern California, Harvard Medical School, Johns Hopkins University,
    and the Dana Farber Cancer Institute. NIH recognizes the importance of
    allowing as many different institutions as possible to benefit from
    such funding, and, as referenced below, institutions in Connecticut
    have received various awards from NHGRI. As stated in the CEGS Funding
    Announcement \26\ ``The total length of support for any Center under
    this program will not exceed 10 years''. This limit was put in place to
    encourage diversity of funding recipients.
    ---------------------------------------------------------------------------
        \26\ https://grants.nih.gov/grants/guide/pa-files/PAR-16-436.html.
    ---------------------------------------------------------------------------
        Applications to renew enter the same competitive pool as
    applications from institutions applying for CEGS funding for the first
    time, and not all requests to renew are successful. NHGRI encourages
    all eligible institutions to consider submitting CEGS applications.
    NHGRI also strongly recommends that applicants contact program staff
    early in the application development process, to increase their chances
    of success.
        Research institutions interested in receiving grant money for
    genomics research are not limited to applying to the CEGS program; they
    may also choose from a range of funding opportunities with varying
    award sizes provided by NHGRI and other NIH institutes. Outside of the
    CEGS program, NHGRI in recent years has issued awards comparable in
    size to a CEGS award to genomics researchers from Yale University, the
    University of Connecticut, and Jackson Laboratory for Genomic Medicine
    in Farmington, Connecticut. The total NHGRI dollars going to Yale and
    the University of Connecticut in each fiscal year 2017 and fiscal year
    2018 are $7 million per fiscal year, and at least $5.6 million will be
    awarded in fiscal year 2019. A few examples of awards to those
    institutions are listed below. Several smaller awards have also been
    awarded to Yale University and the University of Connecticut.
      --In fiscal year 2018, Brenton Graveley at the University of
            Connecticut School of Medicine was awarded $1,815,769
            ($8,624,902 total for fiscal year 2018-fiscal year 2021) for a
            Genomic Community Resource Award to develop A Comprehensive
            Functional Map of Human Protein-RNA Interactions.
      --In fiscal year 2016, Richard Lifton at Yale University received a
            renewal of a Center for Mendelian Genomics Award, which is part
            of NHGRI's largest funding program, the Genome Sequencing
            program. This award started in 2011; the current 4-year renewal
            award is co-funded by NHGRI and the National Heart, Lung, and
            Blood Institute (NHLBI). In fiscal year 2018, NHGRI is
            contributing $1,947,043, and will contribute another $2,425,542
            in fiscal year 2019.
      --In fiscal year 2017, Charles Lee at the Jackson Laboratory for
            Genomic Medicine in Farmington, CT, received $2,868,077 for
            fiscal year 2017 and $1,986,604 for fiscal year 2018, for An
            Integrative Analysis of Structural Variation for the 1000
            Genomes Project, which NHGRI has funded since 2013.
        Examples of other NHGRI programs (in order from largest to smallest
    budgets) include the Genome Sequencing Program (GSP), the Genomic
    Community Resources Program, the Electronic Medical Records and
    Genomics (eMERGE) program, and general investigator-initiated (R01 and
    R21) research grants. These programs include geographically diverse
    grantees pursuing work on both the basic and clinical sides of the
    research spectrum. Additionally, NHGRI is not the only, or even the
    largest, funder of genomic research at NIH. The National Institute on
    Aging (NIA), the National Cancer Institute (NCI), and the National
    Institute of Mental Health (NIMH) are examples of other institutes that
    provide funding for this type of research. Some other non-NHGRI
    programs that offer funding for large scale genome sequencing are the
    Gabriella Miller Kids First Pediatric Research Program (GMKF) (Common
    Fund) and the Trans-Omics for Precision Medicine (TOPMed) program
    (NHLBI). Interested parties may look to these and other institutes/
    programs as possible sources of funding as well.
              national institute on occupational health and safety
        Question. As you mentioned in your testimony, the administration's
    budget request proposes to move the National Institute on Occupational
    Health and Safety (NIOSH), which is currently located in the Centers
    for Disease Control and Prevention, into the National Institutes of
    Health. The 2019 budget also proposes a significant reduction in
    funding for NIOSH activities from $335 million to $200 million.
        As you know, NIOSH currently has multiple responsibilities in the
    areas of occupational health, including research, training of
    occupational health professions and professionals, and implementing
    research into practice with our Nation's businesses, manufacturers,
    forestry, and agricultural sectors.
        Could you provide a list of NIH's current research or training
    activities in the field of occupational health and safety, and provide
    the NIH's underlying statutory authorities that would enable NIH to
    implement NIOSH's core mission and its activities?
        Statutory authority for NIH activities is found in section 301 and
    title IV of the Public Health Services Act
        Answer. The fiscal year 2019 Budget proposes consolidating certain
    HHS research programs into three new institutes within the NIH. The
    Budget provides $380 million for the activities of the Agency for
    Healthcare Research and Quality (AHRQ), which would be renamed the
    National Institute for Research on Safety and Quality. The National
    Institute for Occupational Safety and Health (NIOSH), including the
    Energy Employees Occupational Illness Program (EEOCIPA), currently
    administered by the Centers for Disease Control and Prevention, and the
    National Institute on Disability, Independent Living, and
    Rehabilitation Research (NIDILRR), currently administered by the
    Administration for Community Living, are also proposed for
    consolidation into the NIH.
        NIH currently does not track its research or training activities in
    the field of occupational health and safety but could do so in the
    event of a consolidation. The Budget proposal assumes that existing
    statutory authorities for NIOSH's core mission and activities would be
    amended to make them available to NIH along with the necessary funding.
        Consolidating targeted research programs from across HHS--AHRQ/
    NIRSQ, NIOSH, NIDILRR--into NIH allows high priority research programs
    to benefit from focused resources and NIH research infrastructure. NIH
    will continue to implement strategies to increase operational
    efficiencies and administrative reforms.
                           clinical trials definition
        Question. NIH has expanded the definition of clinical trials
    through a set of case studies to include both fundamental basic and
    health-related research, which will have a significant impact on and
    consequences for principal investigators and research projects.
    Although there were a number of revisions in response to concerns from
    research universities and associations, issues remain unresolved.
    Congress included language in the fiscal year 2018 Omnibus to suspend
    NIH's new definition of clinical trials and called on NIH to revamp the
    policy with input from the scientific community. With that in mind,
    could you answer the following questions:
        What steps has NIH taken to satisfy the requirement in the fiscal
    year 2018 Omnibus bill that directs NIH to consult with the basic
    science research community about the implementation of the new clinical
    trials definition?
        Has NIH considered creating a new or alternative framework to
    ClinicalTrials.gov for reporting basic science research involving human
    subjects?
        The new clinical trials definition will include small-scale
    mechanistically driven clinical studies involving human subjects. These
    studies cannot inform a change in clinical practice, and yet the new
    definition will impose tremendous costs associated with registration,
    training, continuing education, record keeping, and special reports
    under the assumption that these are clinical trials. Is NIH concerned
    that the new policy will provide a disincentive for this type of
    research with human subjects?
        Answer. As the largest public funder of clinical trials in the
    United States, currently investing more than $3 billion each year, the
    National Institutes of Health (NIH) takes its stewardship of the
    nation's clinical trial enterprise very seriously. Therefore, NIH must
    ensure that supported trials investigate a mission-relevant question
    that is of high priority, do not needlessly duplicate previously
    conducted trials (in contrast to providing needed replication), and
    have the highest likelihood to advance knowledge and improve health. To
    achieve this goal, several challenges in the design, efficiency, and
    reporting of clinical trials need to be addressed. In combination,
    these targeted reforms are intended to ensure stewardship and
    transparency in the scientific enterprise. The NIH definition of a
    clinical trial, is focused on fostering this stewardship and
    transparency to assure the public that scientists will report the
    results of research with human participants--in a timely manner--
    regardless of how different scientists might classify them.
        NIH recognizes the concerns expressed by the research community and
    has spent the past few years continuing to solicit input and work with
    the community to chart the best path forward for achieving the aims
    outlined in NIH's stewardship reforms. Moreover, NIH has taken several
    steps to satisfy the requirement in the fiscal year 2018 Omnibus bill
    that directs NIH to consult with the basic science research community
    regarding its policy on the Dissemination of NIH-Funded Clinical Trial
    Information.\27\ For example, NIH leadership met with interested
    stakeholders on May 2 to discuss their concerns, and NIH leadership met
    with Senate and House staff to review those discussions and propose
    plans, including:
    ---------------------------------------------------------------------------
        \27\ https://Federalregister.gov/d/2016-22379.
    ---------------------------------------------------------------------------
      --Issuing a Guide Notice stating that for basic science trials that
            meet the October 2014 NIH definition of a clinical trial NIH
            will delay enforcement of the NIH policy \28\ on registration
            and reporting posted in the Federal Register on September 16,
            2016.
    ---------------------------------------------------------------------------
        \28\ https://www.Federalregister.gov/documents/2016/09/21/2016-
    22379/nih-policy-on-the-dissemination-of-nih-funded-clinical-trial-
    information.
    ---------------------------------------------------------------------------
      --Issuing a Guide Notice describing flexible, lenient implementation
            of other clinical stewardship and transparency policies as they
            apply to basic science studies that meet the October 2014 NIH
            definition of a clinical trial.\29\
    ---------------------------------------------------------------------------
        \29\ https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-
    015.html.
    ---------------------------------------------------------------------------
      --Issuing a basic science parent Funding Opportunity Announcement
            (FOA) in early fiscal year 2019 for fundamental human studies
            that meet the NIH definition of clinical trials. This enables
            the agency to combine the transparency we all agree on with the
            recognition that these types of studies often occur outside of
            the clinic.
      --Issuing a targeted Request for Information (RFI) to consult with
            researchers and the public to determine the reporting standards
            best suited to fundamental research with human participants.
            NIH is also interested in soliciting comments to consider
            alternative frameworks for reporting basic science research
            involving human subjects.
        As stated in the policy issued on September 16, 2016,\30\ NIH
    recognizes that additional effort is required to register and report
    the results of research studies. Nonetheless, reporting the results of
    scientific work is integral to the scientific method. The benefits of
    timely registration and reporting will, in the long run, accrue to the
    investigators as well as to the public, patients, and the enterprise
    because transparency will improve future research designs and maximize
    the public's investment--and their trust--in research. Equally
    important, it will help investigators fulfill the ethical obligation
    they have to research participants, namely to ensure that the findings
    from their participation contribute to generalizable knowledge and the
    advancement of public health.
    ---------------------------------------------------------------------------
        \30\ https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-
    149.html.
    ---------------------------------------------------------------------------
                               pulmonary fibrosis
        Question. Unfortunately, like many Americans, my family was touched
    by pulmonary fibrosis years ago when my uncle passed away from this
    devastating disease. Estimates are that about 200,000 people are
    affected in the United States, there are 50,000 new cases each year,
    and 40,000 people die from the disease each year.
        In this era of precision medicine, is the NIH and the National
    Heart, Lung and Blood Institute applying precision medicine approaches
    to tackling this disease? How can patient registry's, such as the
    registry created by the Pulmonary Fibrosis Foundation, play a role in
    NIH precision medicine efforts relating to this group of diseases?
        Answer. Pulmonary fibrosis, which causes progressive scarring of
    lung tissue, can run in families, but the exact cause of the disease is
    not well understood. The National Heart, Lung, and Blood Institute
    (NHLBI) supports a vigorous research program on pulmonary fibrosis to
    improve understanding of the disease and identify better treatments. In
    2014, a NHLBI workshop report, ``Future Directions in Idiopathic
    Pulmonary Fibrosis'' recommended continued support for precision
    medicine efforts including genomic and molecular studies.\31\ Examples
    of NHLBI efforts include:
    ---------------------------------------------------------------------------
        \31\ https://www.ncbi.nlm.nih.gov/pubmed/24160862.
    ---------------------------------------------------------------------------
      --NHLBI-funded researchers have used whole-exome sequencing--scanning
            all of the protein-coding genes in the genome--to better
            understand genetic factors involved in idiopathic pulmonary
            fibrosis (IPF). They analyzed data from >250 patients who had
            pulmonary fibrosis with little or no family history, and found
            that variation in three genes (TERT, RTEL1 and PARN) is
            associated with a risk of IPF.\32\ All three genes had
            previously been implicated in familial PF and are involved in
            the maintenance of telomeres (a region at the end of
            chromosomes that protects the ends chromosome from damage).
            Shorter telomere length also has been associated with higher
            mortality in three IPF patient cohorts.\33\
    ---------------------------------------------------------------------------
        \32\ https://www.atsjournals.org/doi/abs/10.1164/rccm.201610-
    2088OC.
        \33\ https://www.ncbi.nlm.nih.gov/pubmed/24948432.
    ---------------------------------------------------------------------------
      --The NHLBI-funded IPF Clinical Research Network (IPFnet) conducted a
            trial to investigate whether the antioxidant N-Acetylcysteine,
            when used in combination or with immunosuppressant drugs, is
            effective in patients with IPF. Analysis of the trial results,
            combined with genetic data from the participants, showed that
            N-acetylcysteine monotherapy improved clinical outcomes in
            patients who carry a particular mutation in the Toll-
            interacting protein (TOLLIP) gene.\34\
    ---------------------------------------------------------------------------
        \34\ https://www.ncbi.nlm.nih.gov/pubmed/26331942.
    ---------------------------------------------------------------------------
      --Genomic and molecular studies have revealed small bits of RNA,
            called microRNAs, as a potential form of therapy. MicroRNA-29
            appears to play a key role in preventing fibrosis in the lung.
            Researchers at Yale are collaborating with industry to create a
            similar--but more stable--version of microRNA-29 that can
            potentially be used as a therapy for IPF. Their current efforts
            to develop such a therapy have shown promise in mouse models.
            The same researchers \35\ also have identified a 52-gene
            signature \36\ in the blood that can be used to develop a risk
            profile for recently diagnosed IPF patients, which may help
            identify IPF patients who will benefit most from a given
            therapy.
    ---------------------------------------------------------------------------
        \35\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9270067.
        \36\ https://www.ncbi.nlm.nih.gov/pubmed/28942086.
    ---------------------------------------------------------------------------
      --In research funded through NHLBI's LungMAP \37\ and Lung Repair and
            Regeneration Consortium, as well as a program project
            grant,\38\ researchers performed the first single-cell RNA
            sequencing analysis of epithelial cells in pulmonary
            fibrosis.\39\ This revealed aberrant lung epithelial cells that
            appear to be in an ``indeterminate'' state of differentiation
            (cell fate) not seen in normal lung development. This work also
            provides sequencing data that can be utilized by other
            researchers conducting future IPF research.
    ---------------------------------------------------------------------------
        \37\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9062494.
        \38\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9111936.
        \39\ https://www.ncbi.nlm.nih.gov/pubmed/27942595.
    ---------------------------------------------------------------------------
        NHLBI encourages IPF investigators to utilize existing clinical
    resources, including the Pulmonary Fibrosis Foundation's patient
    registry and NHLBI's lung tissue repository,\40\ when submitting grant
    applications. By leveraging these longitudinal patient data and
    biosample repositories, alongside the collection of additional genetic
    and genomic information, clinical researchers have a greater potential
    to predict risk, disease progression, and response to therapy--
    information that is necessary to develop precision medicine approaches
    to treating IPF.
    ---------------------------------------------------------------------------
        \40\ https://www.nhlbi.nih.gov/science/lung-tissue-research-
    consortium-ltrc.
    ---------------------------------------------------------------------------
                              psychotic disorders
        Question. Despite advancements for many diseases, I continue to
    hear from constituents frustrated by the slow pace of development of
    new medicines to treat psychotic disorders such as schizophrenia. The
    absence of biomarkers and specific molecular targets, as well as the
    complexity of the brain, create enormous challenges for drug discovery.
        What steps can the National Institute of Mental Health (NIMH) be
    taking to spur development of innovative therapies to treat these
    devastating disorders? Is NIMH examining the viability of a public-
    private partnership to advance discovery of new medicines?
        Answer. NIMH supports innovative approaches aimed at improving
    treatment for individuals living with schizophrenia and other psychotic
    disorders through research on novel therapeutics, biomarkers to inform
    therapeutics development and treatment, and services and interventions
    to optimize existing evidence-based treatments.
        NIMH supports early-stage therapeutic discovery and development for
    the treatment of mental illnesses across the drug development pipeline,
    including first-in-human and early efficacy trials.\41\ The NIMH Drug
    Discovery and Clinical Therapeutics Program supports research to design
    and develop novel therapeutics agents for the treatment of mental
    illnesses and supports the NIH National Cooperative Drug/Discovery/
    Development Groups (NCDDG) program for the Treatment of Mental
    Disorders.\42\ The NCDDG encourages public-private partnerships to:
    accelerate the discovery of pharmacological agents targeting novel
    molecular processes implicated in the pathophysiology of mental
    illnesses; facilitate the development and validation of predictive
    assays for developing novel therapeutics for mental illnesses; support
    early phase human clinical testing to rapidly assess the safety and
    efficacy of promising drug candidates; and, facilitate the development
    and validation of new clinical measures or biomarkers suitable for use
    in human proof of concept trials of novel therapeutics. As an example,
    the NIMH Psychoactive Drug Screening Program provides the research
    community with access to broad screening capabilities in the form of
    pharmacological and functional assays to stimulate innovative research
    and development efforts including potential therapeutic agents for the
    treatment of psychiatric disorders.\43\ In addition, NIMH supports
    research on the development and testing of novel drug compounds for
    their potential to improve cognition in people with schizophrenia.
    These compounds modulate cholinergic signaling in the brain, which
    plays an important role in arousal, attention, memory, and motivation.
    Two of these compounds are at the stage of safety and tolerability
    testing in human subjects.\44,45\ This line of research aims to
    ameliorate neurocognitive dysfunction, which is a hallmark of
    schizophrenia and a significant contributor to disability associated
    with schizophrenia.
    ---------------------------------------------------------------------------
        \41\ https://www.nimh.nih.gov/research-priorities/therapeutics/
    index.shtml.
        \42\ https://www.nimh.nih.gov/about/organization/dnbbs/molecular-
    cellular-and-genomic-neuroscience-research-branch/drug-discovery-and-
    clinical-therapeutics-program.shtml.
        \43\ https://www.nimh.nih.gov/funding/grant-writing-and-
    application-process/concept-clearances/2017/the-nimh-psychoactive-drug-
    screening-program-pdsp.shtml.
        \44\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9339822&icde=32296266.
        \45\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9140071&icde=32296291.
    ---------------------------------------------------------------------------
        To inform novel therapeutics development, NIMH continues to fund
    research aimed at identifying biomarkers and charting trajectories of
    psychotic disorders. Through the NIH Neuroscience Blueprint, which uses
    state-of-the-science brain imaging technologies to acquire and broadly
    share data about the structural and functional connectivity of the
    human brain, NIMH co-funds two NIH Human Connectome Projects (HCP)
    focused on psychosis. One project examines brain anatomical and
    functional connectivity in individuals with early psychosis.\46\ The
    second project tests quantitative models of local and long-range neural
    mechanisms to understand abnormal visual perception in psychosis.\47\
    These projects aim to identify neural correlates of clinical symptoms
    observed in psychosis and could pave the way for novel treatment
    development. In addition, NIMH supports the North American Prodrome
    Longitudinal Study (NAPLS), a nine-site consortium combining brain-
    based biological and clinical markers to predict the onset of psychosis
    in vulnerable populations and chart trajectories of mental illness. An
    improved predictive algorithm and better understanding of biological
    mechanisms underlying psychosis onset could inform patient
    stratification for clinical trials of novel preventive treatments.\48\
    NIMH also supports the Early Psychosis Intervention Network (EPINET) to
    create a common database of information gathered during routine
    clinical encounters to inform effective early psychosis care and
    accelerate research into psychosis risk factors, biomarkers of
    psychosis risk and onset, and pre-emptive interventions.\49\
    ---------------------------------------------------------------------------
        \46\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9108511&icde=32296915.
        \47\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9109802&icde=32296932.
        \48\ http://campuspress.yale.edu/napls/.
        \49\ https://www.nimh.nih.gov/funding/grant-writing-and-
    application-process/concept-clearances/2015/early-psychosis-
    intervention-network-epinet-a-learning-healthcare-system-for-early-
    serious-mental-illness.shtml.
    ---------------------------------------------------------------------------
        In addition to seeking pathways to novel interventions, NIMH is
    also committed to improving implementation of current evidence-based
    practices for the treatment of psychosis. Antipsychotic medications
    provide substantial benefits to many patients, and consistent
    medication use is associated with lower rates of relapse and re-
    hospitalization. Through the Small Business Innovation Research and
    Small Business Technology Transfer (SBIR/STTR) program, NIMH supports
    research to help patients maintain treatment through efforts that
    improve medication adherence, medication monitoring, and the use of
    technologies to enhance interventions.\50,51,52,53,54\ In addition, the
    Advanced Laboratories for Accelerating the Reach and Impact of
    Treatments for Youth and Adults with Mental Illness (ALACRITY) Research
    Centers aims to improve the effectiveness, delivery, and quality of
    evidence-based services in diverse settings for individuals with
    serious mental illness, including psychotic disorders.\55,56,57\
    Through the Early Psychosis Prediction and Prevention (EP3) initiative,
    NIMH supports several projects to develop and test interventions to
    improve cognitive and social skills for persons at clinical high risk
    for psychotic disorders.\58,59,60,61\ NIMH recently issued a funding
    opportunity announcement to support a large-scale initiative focused on
    testing the effectiveness of interventions that target early symptoms
    associated with clinical high risk for psychosis (i.e., problems in
    thinking, mood, and social functioning suggestive of a pre-psychosis
    risk state).\62\
    ---------------------------------------------------------------------------
        \50\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9254370&icde=39687639.
        \51\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9201433&icde=39687639.
        \52\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9128708&icde=39687639.
        \53\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9361111&icde=39687639.
        \54\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9201713&icde=39687639.
        \55\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9374695&icde=39592663.
        \56\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9485776&icde=39592663.
        \57\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9486324&icde=39592663.
        \58\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9345577&icde=22682326.
        \59\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9304884&icde=22682332.
        \60\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9302540&icde=22682334.
        \61\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9302539&icde=22682335.
        \62\ https://grants.nih.gov/grants/guide/rfa-files/RFA-MH-14-
    211.html.
    ---------------------------------------------------------------------------
        NIMH will continue to fund research on psychotic disorders to
    identify and develop the breakthrough treatments of tomorrow, as well
    as to optimize and implement the effective treatments of today. In
    pursuit of its mission to transform and understand treatment of mental
    illnesses, NIMH will continue public-private partnerships through the
    NCDDG and consider other partnerships that support excellent science
    and the NIMH mission.
                            neurological conditions
        Question. As you may know, the 21st Century Cures Act authorized
    the CDC to implement a national neurological conditions surveillance
    system. I worked on this section with Sen. Isakson because despite the
    fact that estimates indicate that one in six Americans lives with a
    neurologic condition, many condition-specific figures are severely
    outdated. For instance, the last national study of prevalence and
    incidence of Multiple sclerosis was done in 1975 and data on the
    prevalence of Parkinson's disease is based on a 1985 study.
        How would a neurological disease registry help provide a foundation
    for evaluating and understanding aspects of neurological conditions?
    How could such a surveillance system accelerate neurological research?
        Answer. For many neurological diseases, there are no recent,
    reliable data on the incidence, prevalence, geographical distribution,
    and demographics in the U.S. population, nor for changes over time.
    Such information can be useful in several ways. These data are
    essential to understand the societal burden of neurological disorders,
    which is an important factor that NIH and the research community must
    consider in setting research priorities, along with scientific
    opportunity. Such data are also crucial for designing public health
    programs. In some cases, these data may provide clues to risk factors
    and potential environmental influences that more targeted studies may
    follow up, such as reported differences in geographical distribution in
    multiple sclerosis and the association of some cases of Parkinson's
    disease with occupational exposure. Data on frequency of diseases also
    can demonstrate the effectiveness of research on public health; for
    example, in stroke, for which we do have good data, there has been a 70
    percent decline in the age adjusted death rate, reflecting the
    cumulative benefits of decades of research.
        Although potentially useful, surveillance of neurological disorders
    presents formidable challenges, especially in a healthcare system that
    does not have a single central record system. There are hundreds of
    diseases of the brain and nervous system, many of which are difficult
    to diagnose correctly. Some disorders, like chronic pain, are among the
    most common of all diseases, and the many rare genetic diseases
    collectively have an enormous burden despite being individually rare.
    Together, neurological diseases affect people of all ages, who may be
    treated via family physicians, various medical specialties, hospitals,
    nursing homes, or by self-care. All of this makes tracking very
    difficult because the optimal strategy is different for different
    diseases. The 21st Century Cures Act acknowledged the difficulty,
    noting that the surveillance system may initially address a limited
    number of neurological diseases.
                                     ______

                Questions Submitted by Senator Joe Manchin, III
                                 superfund site
        Question. Dr. Collins, as you may know, Minden, West Virginia has
    been listed as a Superfund site by the EPA since 1984 because the small
    rural community was contaminated with PCBs by an industrial facility
    related to coal mining.
        I am gravely concerned about the reports stating that cancer rates
    are significantly higher in Minden than the rest of Fayette County and
    the rest of the State.
        The National Toxicology Program ranks PCBs as ``reasonably
    anticipated to be human carcinogens'' and the EPA has classified PCBs
    as a probable human carcinogen. Both designations indicate that there
    is substantial likelihood that extended exposure to PCB contaminated
    sites could result in cancer.
        Yet, the EPA has found that PCB exposure from the superfund site is
    not responsible for these high cancer rates or for a cancer cluster in
    this small, rural Appalachia town. That is why it is so critical that
    we conduct additional research to fully understand the potential causal
    connection between PCB exposure and cancer rates.
        Dr. Collins, will you commit to directing the National Toxicology
    Program at NIH to promptly prioritize further research on PCB exposure
    and the link to cancer?
        Further, will you work with me and the other members of this
    Committee to ensure that the National Institute of Environmental Health
    Sciences has the resources needed to conduct this critical research?
        Answer. Thank you for your questions, and I appreciate your sharing
    information about the situation with the Superfund site in Minden, West
    Virginia. The National Institute of Environmental Health Sciences
    (NIEHS) is home to the National Toxicology Program (NTP), which is
    dedicated to testing and evaluating substances in the environment.
    NIEHS and NTP have a long history of funding research into the health
    effects associated with exposure to polychlorinated biphenyls (PCBs).
    NTP has conducted extensive rodent studies with component PCBs to try
    to understand how these components interact in the body to cause
    cancer. Other NIEHS investments in this area cover relationships
    between exposure to PCBs and risks of developmental disorders, immune
    responses, obesity, metabolic disorders and diabetes, and neurological
    problems. Given their current and past research activities, NIEHS and
    NTP are well positioned to advise and share information with other
    agencies involved in answering scientific questions about PCB exposure
    levels in affected populations.
                                  rural health
        Question. In 2017, the America's Health Rankings Report ranked West
    Virginia 46th in overall health. This low ranking is driven by high
    obesity rates, high rates of smoking, and high rates of drug related
    deaths. We're also 48th highest in cancer deaths and 49th highest in
    the number of West Virginians with diabetes.
        West Virginia has, in many ways, been left behind as medical
    advances have saved lives in other places. In fact, I have heard from
    West Virginians who want to participate in clinical trials, but are
    forced to leave the state to do so.
        Dr. Collins, what is NIH doing to bridge this gap in health
    outcomes?
        How do you ensure that the medical research that you do benefits
    people in poor, rural communities?
        How can we better expand access to research studies and then to
    successful treatments to rural Americans, particularly in states like
    mine where the disease burden is so high?
        Answer. NIH recognizes the unique health disparities that rural
    communities face, and as such, rural health is an important area of
    research for the agency. Through diverse collaborations and
    partnerships with communities, academic institutions, and state
    agencies, NIH supports and conducts rural health research to improve
    health outcomes and reduce rural health disparities with a special
    emphasis on populations in poor, rural communities. NIH's rural health
    research focuses on key areas of concern to you and rural residents and
    are aimed at addressing health disparities that rural populations in
    West Virginia and around the U.S. experience.
        In fiscal year 2017, NIH supported more than 500 rural health-
    related grants for approximately $259 million. NIH is committed to
    ensuring that there are opportunities for poor rural Americans to
    access the benefits of research and that research addresses the unique
    strengths and challenges of rural communities. NIH supports several
    programs focused on cancer, cardiovascular disease, and other chronic
    diseases disproportionately affecting rural communities. For example,
    Screen to Save \63\ is a colorectal cancer outreach and screening
    initiative aimed at increasing cancer screening rates for individuals
    in rural communities, particularly among racial and ethnic minority
    populations. The Heart Truth Community Action Program \64\ initiative
    engages and empowers women to learn about risk factors for heart
    disease and steps they can take to live a heart-healthy life. The
    Strong Hearts, Healthy Communities \65\ program works to reduce rural
    disparities in cardiovascular disease through community-based
    interventions (e.g., nutrition and physical activity classes) in ten
    underserved, rural towns. NIH's Healthcare for Rural Populations
    Research Initiative \66\ aims to enhance the resources and
    infrastructure underlying healthcare access and quality for rural
    populations, including methods for improving oral health in rural
    school-based cavity prevention programs.
    ---------------------------------------------------------------------------
        \63\ https://www.cancer.gov/about-nci/organization/crchd/blog/2016/
    screentosave-launch.
        \64\ https://www.nhlbi.nih.gov/health/educational/hearttruth/
    partners/grantees.htm.
        \65\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9245732&icde=34114853.
        \66\ https://www.nimhd.nih.gov/programs/extramural/resource-
    related.html#healthcare-rural.
    ---------------------------------------------------------------------------
        Recognizing the unique needs of Appalachian communities, NIH
    supports the Kids SIPsmartER \67\ project, a school-based, behavior and
    health literacy curriculum aimed at improving sugar-sweetened beverages
    (SSB) behaviors among middle school students in medically underserved
    Appalachian counties in southwest Virginia. The program uses a two-way
    short service message strategy to engage caregivers in SSB role
    modeling and supporting home SSB environment changes. The primary aim
    is to assess changes in SSB behaviors among 7th grade students at
    schools receiving Kids SIPsmartER; evaluate changes in secondary
    student outcomes such as BMI and quality of life; changes in caregiver
    outcomes; and maintenance of outcomes. The overall goal is to establish
    an effective, scalable, and sustainable multi-level strategy to improve
    SSB behaviors and reduce SSB-related health inequities and chronic
    conditions in rural Appalachia.
    ---------------------------------------------------------------------------
        \67\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9495908&icde=39783928.
    ---------------------------------------------------------------------------
        Several West Virginia institutions are also engaged in rural health
    research, including the West Virginia State Department of Health and
    Human Resources, West Virginia University, West Virginia School of
    Osteopathic Medicine, CAMC Health Research Institute, and Marshall
    University. In one West Virginia-based project for example, NIH
    supports the West Virginia University Stroke Center of Biomedical
    Research Excellence (WVU Stroke CoBRE),\68\ a part of the WVU Center
    for Basic and Translational Stroke Research, which works to identify
    and treat the known risk factors for stroke among Appalachian
    populations. Research conducted by the WVU Stroke CoBRE focuses on
    stroke prediction, causes, prevention, acute treatment and
    rehabilitation. The Stroke CoBRE also has an intensive mentoring
    program for junior investigators. The WVU Stroke CoBRE recently became
    a formal part of the StrokeNet clinical trial consortium which will
    allow the Center to conduct multi-centered clinical trials to enhance
    its rapid translation of basic research into clinical trials and
    studies.
    ---------------------------------------------------------------------------
        \68\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9313278&icde=39683671.
    ---------------------------------------------------------------------------
        The Rural West Virginia Responds to Opioid Injection Epidemics:
    From Data to Action \69\ project seeks to eliminate the opioid epidemic
    and associated infectious diseases in West Virginia through
    collaborations with communities and public health agencies. The project
    will create an evidence-based roadmap to coordinate and improve
    screening, prevention, and treatment for HIV and other insular
    injection drug use-associated diseases; develop and test a novel
    strategy to rapidly identify the emergence of HIV in rural communities;
    and deploy and evaluate an integrated service delivery model to enhance
    delivery of evidence-based services, screening strategies, and
    treatment.
    ---------------------------------------------------------------------------
        \69\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9412006&icde=39683671.
    ---------------------------------------------------------------------------
        Continued collaborations and partnerships with scientists and
    organizations from rural communities, such as many in West Virginia,
    will contribute to NIH's reach in rural communities and support our
    work to combat rural health disparities.
                        institutional development award
        Question. The Institutional Development Award (NIH IDeA) program
    has been critical for West Virginia. It brings NIH funding to help
    build the medical research programs in underserved states.
        West Virginia currently only receives about $20 million in NIH
    grant funding, but WVU estimates that the economic benefit of these
    grants in West Virginia is $180 million and the IDeA program has been
    critical for expanding access to medical research in my State.
        The IDeA program received $350 million in the bipartisan fiscal
    year 2018 Omnibus Appropriations bill, but the budget would cut funding
    for the National Institute of General Medical Sciences--which houses
    this program--by more than $935 million, and this program was not even
    specifically listed.
        I believe that we should continue to strongly support this program.
        Dr. Collins, what impact the proposed cuts to NIH funding would
    have on this important program?
        Can you tell me why this program was not specifically listed in the
    budget and what the recommended fiscal year 2019 funding level is?
        Can you please speak to the importance of funding research at a
    wide variety of institutions, particularly those in rural, underserved
    states?
        Answer. The Budget recognizes that importance of funding the
    highest priority scientific discoveries while also maintaining fiscal
    responsibility of Federal resources. The IDeA Program will continue to
    fulfill its congressional mandate of broadening the geographic
    distribution of NIH funding for biomedical research and enhancing the
    competitiveness of investigators at institutions located at eligible
    states and jurisdictions at the fiscal year 2019 funding level.
        Consistent with other NIH Institutes, the fiscal year 2019 National
    Institute of General Medical Sciences (NIGMS) Congressional
    Justification only included the total program level. Individual NIGMS
    program details were not provided, also consistent with other NIH
    Institute Congressional Justifications.
        Prior to the increase of the budget caps and the fiscal year 2018
    enacted levels, the fiscal year 2019 President's Budget was built on
    the fiscal year 2018 Annualized CR level which reduced the NIGMS budget
    by 2.29 percent. Like the overall NIGMS Program level, the fiscal year
    2019 President's Budget for the IDeA Program would be reduced by 2.29
    percent from the fiscal year 2018 Annualized CR. When comparing fiscal
    year 2019 President's Budget over the fiscal year 2018 enacted level,
    the overall NIGMS total program level and the IDeA program would be
    reduced by 7.6 percent.
        The IDeA Program managed by NIGMS is a long-term interventional
    capacity-building program targeting states and jurisdictions that have
    consistently trailed in obtaining significant NIH support. The intent
    of the program is to transform institutions with infrastructure, human
    resource, and economic challenges to become more competitive biomedical
    research enterprises through various distinct but complementary
    initiatives. Some benefits of the IDeA Program in the eligible states
    and jurisdictions include:
      --Builds active biomedical research environments in IDeA states and
            improves access to modern, state-of-the-art biomedical research
            for students, researchers, and the general public.
      --Ensures that states without medical schools have an opportunity to
            develop research capacity for conducting basic, translational,
            and clinical research.
      --Provides opportunities to address health disparities in medically
            underserved groups residing in IDeA states.
      --Promotes SBIR/STTR programs, technology transfer, entrepreneurship,
            and public-private partnerships that could lead to the
            formation of bio-related industries, potentially benefitting
            the local economy.
      --Encourages collaborations and leveraging among IDeA research
            resource centers to capitalize on each other's unique
            capabilities to solve complex research questions and encourages
            consolidation of research resources with complementary
            technologies to improve efficiency and crate economies of
            scale.
      --Enhances the competitiveness of institutions by providing
            opportunities for talented and highly motivated undergraduate
            students to participate in research training and pursue
            research careers in the biomedical sciences.
      --Develops best practices, training tools, workflows, databases, and
            analysis tools that assist clinical and translational
            researchers to develop and perform clinical and translational
            protocols to address important questions in multiple areas of
            biomedical science quickly and efficiently.
        Funding research at a wide variety of institutions is extremely
    important to ensure that a rich diversity of scientific and
    geographical perspectives is represented and that all available human
    capital is deployed in the critical work of addressing vital biomedical
    research questions and pressing health problems. Local investigators
    are often the best equipped and experienced to conduct research on
    local health concerns. Further, NIH strongly believes that scientific
    discoveries can arise anywhere where there are well-trained and
    determined investigators working in adequately resourced environments.
    Ensuring that all jurisdictions and institutions across the United
    States are afforded the opportunity to become active and significant
    contributors to this country's research agenda increases the likelihood
    of breakthroughs in science and medicine.
                  medical research can save money--alzheimer's
        Question. I am someone who is very concerned about the Federal
    debt, but I have always supported strong funding for NIH because it is
    an investment that saves lives, preserves America's role as a global
    innovator, and has the potential to save a lot more money in the future
    if we're able to reduce the costs of treating expensive diseases.
        Alzheimer's disease, for example, cost West Virginia's Medicaid
    program $394 million in 2017 and this cost is expected to increase as
    the number of people with the disease increases. The Alzheimer's
    Association estimates that the cost of caring for people with
    Alzheimer's and dementia will rise from $236 billion to $1.1 trillion
    in 2050. In short, we can't afford to not invest in medical research.
        That is why I share my colleagues concern about the President's
    budget cuts of more than $2.2 billion to NIH overall and more than $1.1
    billion to the National Institute on Aging in particular relative to
    the funding that we included in the fiscal year 2018 Omnibus.
        Dr. Hodes, as the Director of the National Institute on Aging, can
    you please speak to the research that your agency is doing on
    Alzheimer's disease?
        Do you believe that investments in this research now is a fiscally
    responsible choice given the astronomical costs that our country is
    likely to face as our Nation ages?
        Answer. NIA has leveraged the extraordinary influx of funding
    directed at Alzheimer's disease and related forms of dementia (AD/ADRD)
    to build a series of bold and innovative research programs,
    infrastructure, and new partnerships that are enabling some of the
    Nation's leading scientists to tackle the problem of AD/ADRD on an
    unprecedented scale and pace. High-priority research and infrastructure
    programs that are currently underway include:
      --Alzheimer's Clinical Trial Consortium (ACTC), to accelerate and
            expand trials of AD/ADRD therapies;
      --Resilience-AD, a new program bringing together experts from
            multiple disciplines to understand why some high-risk
            individuals remain dementia free;
      --Molecular Mechanisms of the Vascular Etiology of Alzheimer's
            Disease (M\2\OVE-AD) Initiative, exploring how metabolic and
            vascular risk factors such influence brain aging and AD
            pathology and identifying blood-based markers of the disease;
      --Alzheimer's Biomarker Consortium--Down Syndrome (ABC-DS), in which
            researchers use biomarkers to track disease progression in
            people with DS, a uniquely vulnerable population at high risk
            for developing AD;
      --The Model Organism Development and Evaluation for Late-onset AD
            (MODEL-AD) project to develop better animal models of late-
            onset AD;
      --Approximately 140 active clinical trials of interventions to
            prevent, treat, or manage symptoms of AD/ADRD and to enhance
            caregiver well-being;
      --Development of new therapeutics, including some that target
            molecules other than beta-amyloid; and
      --Harnessing the power of big data to identify existing drugs or
            combinations currently used to treat other conditions that
            could be effective for the treatment of AD/ADRD.
        Other current priorities include development of caregiver support
    interventions; implementation of a national recruitment strategy that
    ensures inclusion of diverse populations in AD/ADRD research;
    understanding gene-environment interactions that increase risk or
    confer resilience against AD/ADRD; infrastructure development,
    including big data infrastructure; workforce training across the
    spectrum of research; and harmonization and distribution of data from
    large datasets.
        The financial costs associated with AD/ADRD to affected families
    and to society are considerable. Data published by the Alzheimer's
    Association estimate total payments in 2018 for all individuals with
    AD/ADRD at $277 billion, much of which will be paid by Medicare and
    Medicaid. NIH-funded researchers found that, in the last 5 years of
    life, total health and long-term care spending for people with dementia
    was more than $250,000 per person, greater than costs associated with
    death from other major chronic diseases. Average out-of-pocket spending
    for patients with dementia was 81 percent higher than for patients
    without dementia. Caregiving costs, including loss of wage income due
    to caregiving responsibilities, are also significant.
        NIH-supported researchers estimate that delaying onset of AD for 5
    years would result in 41 percent lower prevalence and 40 percent lower
    cost of AD by 2050. Given these findings, research to ameliorate not
    only the physical and mental burdens of these diseases but also the
    economic burden is not only fiscally responsible, it is crucial to the
    health of our economy.
                                     ______

                Questions Submitted by Senator Patrick J. Leahy
        Institutional Development Award (IDeA)
        Question. The IDeA program, operated by the National Institute of
    General Medical Sciences (NIGMS) at the National Institutes of Health
    (NIH) has long been a fundamental source of support for institutions
    that participate in biomedical research. With a focus on health-related
    research, specifically in rural and medically underserved communities,
    IDeA is critical in the goal of supporting researchers' work to uncover
    lifesaving methods to combatting disease. In my home State of Vermont,
    IDeA awards have contributed to advances in genetic research, new
    medical technologies, and vaccine and drug developments.
        With the help of IDeA awards, the University of Vermont, our
    State's largest research institution, developed the Vermont Genetics
    Network, the Vermont Center for Immunology and Infectious Diseases, the
    Vermont Center for Neuroscience, and the Vermont Center on Behavior and
    Health. IDeA grants have also expanded the employment of STEM
    professionals in several other institutions of higher education across
    the State. These institutes have contributed to some of the world's
    most groundbreaking medical understanding on how to cure lung and heart
    disease and on understanding the effect of brain disorders on learning
    and development.
        I am concerned that the administration's proposed cuts to NIH and
    NIGMS will undoubtedly place pressure on the IDeA program by reducing
    the amount of grant dollars awarded for institutional biomedical
    research. This means less opportunities for our Nation's institutions
    to develop lifesaving treatments to debilitating disease.
        What are the benefits of the IDeA program in building capacity in
    states that might not otherwise receive NIH funding, including a
    description of not only how this program has benefited not just local
    communities, but also helped advance the national dialogue on
    biomedical and translational research?
        Answer. The overarching mission of the Institutional Development
    Award (IDeA) Program is inclusive Biomedical Research Capacity-
    building--to develop and strengthen biomedical science research
    programs in States/Jurisdictions of the country that are
    underrepresented in the NIH portfolio, to enable increased engagement
    and participation of these states in scientific areas that are
    supported by NIH, and to promote biomedical research capacity and
    capabilities in these states that are competitive and sustainable.
    Benefits of the IDeA program in states/jurisdictions receiving IDeA
    funding include the following:
      --Through targeted professional development efforts, the IDeA Program
            grows and nurtures the pool of next generation scientific
            leaders and innovators.
      --The IDeA program develops and enhances the research facilities and
            resources in these states/jurisdictions, thereby enabling
            investigators to expand their contributions to scientific
            discovery, innovation, and learning.
      --Inclusive and sustainable biomedical workforce development pathways
            are established and formalized that equip local human resources
            with the appropriate intellectual and technical scientific
            skills. Biomedically skilled human capital, in turn, can serve
            as the nidus or help attract the formation of bio-related
            industries, potentially benefitting the local economy.
      --Through meaningful engagement of the local community, both the
            scientific research community and the community at-large form
            important partnerships that begin to address vital and urgent
            scientific questions and regional health priorities.
        Within the past year, some of the important contributions made by
    investigators and other highlights/impacts emanating from the IDeA
    Program initiatives include the following:
      --Vermont IDeA Network of Biomedical Research Excellence (INBRE) \70\
            researchers characterized the processing of a protein in
            neurons called progranulin, a mechanism that impacts the
            neuropathology of frontotemporal dementia (FTD), a
            neurodegenerative disorder characterized by progressive changes
            in personality, behavior, and/or language. FTD is the second
            most common cause of early-onset Alzheimer's disease. This
            finding was published in the scientific journal Molecular
            Neurodegeneration.
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        \70\ The IDeA Network of Biomedical Research Excellence (INBRE)
    initiative enhances, extends, and strengthens the research capabilities
    of biomedical research faculty in IDeA states through a statewide
    program that links a research-intensive institution with primarily
    undergraduate institutions.
    ---------------------------------------------------------------------------
      --A New Mexico Centers of Biomedical Research Excellence (COBRE) \71\
            team reported on a collaborative intervention to increase
            awareness on risk of falls for Zuni Native American community.
            The innovative collaborative approach can produce dramatic
            improvements in clinical outcomes, health related quality of
            life, and reductions in healthcare costs. The Zuni Health
            Initiative (ZHI), an integrated model of community, family and
            clinic-based education, life style modification and healthcare
            will facilitate the translation of validated national
            guidelines for screening and treatment of chronic disease and
            reduce health disparities in this high-risk population of Zuni
            American Indians.
    ---------------------------------------------------------------------------
        \71\ The Centers of Biomedical Research Excellence (COBRE)
    initiative develops and strengthens institutional biomedical research
    capabilities in IDeA states through three 5-year phases of
    infrastructure and faculty development of multidisciplinary research
    centers focused on a specific biomedical science theme.
    ---------------------------------------------------------------------------
      --A report from Advances in Physiology Education reported on North
            Dakota INBRE's impact on undergraduate research at rural
            primarily undergraduate institutions (PUIs) over a 12-year
            period. Participation of the PUIs in the ND INBRE generated a
            more robust research culture at the undergraduate institutions.
            The number of faculty participating in undergraduate research
            increased two- to four-fold. The high level of student success
            (550 participants) is supportive of the concept that
            undergraduate research (350 posters presented) is a value-added
            component of the INBRE initiative that will help prime the
            pipeline for the next generation of health professionals in
            research, service, and teaching.
      --A COBRE team from Vermont carried out research on adverse effects
            associated with using commercially available cigarettes and
            explored the effects of reducing potential for addiction in
            highly vulnerable populations (socioeconomically disadvantaged
            smokers, individuals with psychiatric conditions). Three
            manuscripts were published that reported the following: (1)
            significant positive association between using commercially
            available high nicotine yield cigarettes and risk of nicotine
            dependence and continuing to smoke during pregnancy in a
            nationally representative sample of U.S. women of reproductive
            age (published in Preventive Medicine), (2) reducing the
            nicotine content of cigarettes significantly reduces the
            addiction potential of cigarette smoking in adults highly
            vulnerable to tobacco addition (smokers with psychiatric
            disorders or socioeconomic disadvantage) (published in JAMA
            Psychiatry), and (3) dependence severity has no moderating
            influence on the ability of reduced nicotine content cigarettes
            to lower the addiction potential of smoking, and minimal
            effects on relief from craving/withdrawal or smoking topography
            (published in Preventive Medicine).
      --INBRE researchers from Alaska reported on the ability of the arctic
            ground squirrel, a seasonal hibernator, to resist brain damage.
            Investigating how oxygen glucose deprivation induces tolerance
            has very important translational implications in ischemic brain
            injury in stroke patients (reported in Journal of
            Neurochemistry).
      --Investigators supported through the Kentucky INBRE elucidated the
            role of a Zika capsid (membrane) protein in brain damage and
            published their results in Nature.
      --Shayna Bennett, an alumna of Johnson State College in Vermont, was
            named an awardee of the 2018 National Science Foundation
            Graduate Research Fellowship Program (GRFP). The program
            supports graduate students with high potential to be leaders in
            STEM research. The program supports NSF's goal of developing a
            workforce that leads the world in advancing science and
            engineering research. While Shayna was an undergraduate student
            at Johnson State College, she was funded by the Vermont INBRE
            to conduct biomedical research from 2014-2015. The experience
            influenced her decision to pursue a graduate degree in a STEM
            research field. She is currently a first-year doctoral student
            in applied mathematics at the University of California Merced.
      --A report at the Advances in Physiological Education demonstrated
            how the Kansas INBRE annual symposium, a 10-institute
            collaboration, improved undergraduate education. The 16-year
            undertaking has supported 1,000 students. Survey results
            indicate that students and mentors alike find the symposium to
            be beneficial and enriching of the student experience, with
            almost 80 percent of student respondents indicated that their
            participation in the symposium fostered appreciation of
            research. The KA-INBRE symposium provides a terrific
            opportunity for students to gain experience in collecting,
            preparing, and communicating research in a professional
            environment.
      --An Arkansas COBRE team published their findings on the effects of
            radiation on normal tissues and certain age-related diseases
            vis-a-vis aging stem cells and the ability of tissues to
            regenerate and repair, drive inflammation, and oxidative
            stress. The report focused on ABT-263, a molecule initially
            developed as an anti-cancer therapy drug, which could
            effectively deplete senescent (aging) cells. The depletion
            appeared to reduce premature aging of the bone marrow due to
            irradiation and rejuvenated the function of stem cells in
            normally aged mice (reported in Nature Medicine).
      --Investigators supported through the Louisiana IDeA-Clinical and
            Translational Research (CTR) \72\ award found that Mycoplasma
            genitalium is an etiologic agent of cervicitis in HIV-infected
            women, providing a potential mechanism for enhanced HIV
            transmission to an uninfected partner. M. genitalium is an
            emerging sexually transmitted pathogen implicated in
            inflammatory syndromes of the female reproductive tract
            (reported in Journal of Infectious Disease).
    ---------------------------------------------------------------------------
        \72\ The IDeA Program Infrastructure for Clinical and Translational
    Research (IDeA-CTR) initiative develops network infrastructure and
    capacity in IDeA-eligible states to conduct clinical and translational
    research focused on health concerns that affect medically underserved
    populations and/or that are prevalent in IDeA states.
    ---------------------------------------------------------------------------
      --Montana IDeA researchers collaborated on a report on the
            transmission of a pathogen from animals to humans (zoonotic
            transmission). This work provides a foundation for
            transdisciplinary investigation of spillover and synthetic
            theory on zoonotic transmission (reported in Nature Reviews
            Microbiology).
      --A New Hampshire COBRE team reported on a plant-based nanotechnology
            that could generate an antitumor immune response. The effect
            was observed to be systemic and durable, resulting in immune-
            memory and protection from recurrence (reported in Nature
            Nanotechnology).
                              tick-borne diseases
        Question. The spread of tick-borne diseases, such as Lyme disease
    (Lyme), to humans have been increasing in Vermont and many other
    northern states. While reports of Lyme in Vermont used to be rare in
    the early 1990s, it is now common to see over 400 confirmed cases
    reported in a year. This trend has proven to be true for other
    northeastern and upper Midwestern States as well, as the number of
    reported cases of Lyme has tripled and the number of high-risk counties
    has increased by more than 300 percent since the late 1990s. Ticks, and
    thus Lyme and other tick-borne diseases, have expanded their geographic
    range and are now being found in places where there were not seen 20
    years ago. It is estimated that 20 percent of the population that live
    in areas where Lyme is common are unaware that they live in high-risk
    areas for tick-borne diseases.
        Given the ever-growing threat of tick-borne diseases, what efforts
    are NIH pursuing to better detect or cure tick-borne diseases such as
    Lyme?
        Answer. The National Institute of Allergy and Infectious Diseases
    (NIAID) maintains a diverse research portfolio on Lyme disease and
    other tick-borne diseases and encourages development of diagnostics,
    therapeutics, and vaccines to combat these infections. As part of this
    effort, NIAID engages in important collaborations with Federal
    partners, Lyme disease experts, patients, and others as a member of the
    Department of Health and Human Services Tick-Borne Diseases Working
    Group created by the 21st Century Cures Act.
        NIAID supports basic research on how Borrelia species, including B.
    burgdorferi and B. mayonii, infect the host, multiply, and ultimately
    cause Lyme disease. Basic research also is underway for a variety of
    tick-borne infections such as anaplasmosis, babesiosis, tick-borne
    encephalitis, and others. Findings of these early-stage studies will
    help to identify targets for additional diagnostic tests, treatments,
    and vaccines for these infections. For example, NIAID grantees are
    using real-time imaging to track the spread of bacteria that cause Lyme
    disease and to monitor treatment effectiveness in infected mice. NIAID
    scientists also have developed a novel tick infection model for
    flaviviruses that could be used to evaluate tools to combat the deadly
    Powassan and tick-borne encephalitis viruses.
        NIAID is committed to discovering better ways to diagnose Lyme
    disease that would enable more informed treatment decisions. In
    collaboration with the Centers for Disease Control and Prevention and
    others, NIAID is working to develop novel diagnostics including next
    generation molecular tests. NIAID-supported scientists are working to
    identify biomarkers that could allow for earlier and more rapid
    diagnosis, accurate indication of disease stage and progression,
    indications of successful treatment, and ability to distinguish between
    Lyme and other tick-borne infections. NIAID scientists and extramural
    researchers recently developed a novel tool, the TBD-Serochip, to help
    differentiate several tick-borne infections. This test is designed to
    discriminate between eight major tick-borne pathogens in the United
    States, including species of Anaplasma, Babesia, and Borrelia.
        NIAID also supports Lyme disease prevention research, including
    efforts to develop effective vaccines. NIAID is funding research
    exploring the adaptation of a successful canine Lyme disease vaccine
    for potential use in humans. Other NIAID-supported studies are pursuing
    vaccine strategies to limit Lyme disease transmission, including oral-
    bait vaccines targeting wildlife reservoirs of B. burgdorferi and
    efforts to target proteins in tick saliva that are critical for
    effective transmission of Lyme bacteria.
        NIAID is committed to supporting basic, translational, and applied
    research on tick-borne diseases, including studies on the pathogens,
    the ticks that transmit them, and their vertebrate hosts. Through
    ongoing research support, as well as collaborations with Federal and
    public partners, NIAID will continue to advance the development of
    vaccines, therapeutics, and diagnostics for Lyme and other tick-borne
    diseases.
                                     ______

                   Questions Submitted to Anthony Fauci, M.D.
                  Questions Submitted by Senator Patty Murray
                    combatting antibiotic resistant bacteria
        Question. How has the threat posed by antibiotic resistant bacteria
    changed since you helped write the National Action Plan a few years
    back? Is the situation worse, better or unchanged?
        Answer. The National Institutes of Health (NIH) continues to
    prioritize research to address the public health threat of
    antimicrobial resistance. The National Institute of Allergy and
    Infectious Diseases (NIAID), part of the NIH, plays a lead role in
    addressing the goals of the National Action Plan for Combating
    Antibiotic-Resistant Bacteria (CARB), including the development of
    diagnostics, therapeutics, and vaccines for drug-resistant bacteria.
    The Progress Report: CARB Years 1 and 2 \73\ outlines NIAID-supported
    efforts, along with those of Federal CARB partners, toward achieving
    the goals of the National Action Plan for CARB. While our understanding
    of antibiotic-resistant bacteria--and how to combat them--has improved
    since the development of the National Action Plan for CARB, the
    emergence and re-emergence of drug-resistant bacteria continue to pose
    a threat to the public health. NIH and its CARB partners are committed
    to sustaining our critical efforts to develop countermeasures and
    strategies to address the ongoing challenge of antibiotic-resistant
    pathogens.
    ---------------------------------------------------------------------------
        \73\ https://aspe.hhs.gov/system/files/pdf/258516/
    ProgressYears1and2CARBNationalActionPlan.
    pdf.
    ---------------------------------------------------------------------------
        Question. What is the status of efforts to fund clinical trials to
    test new antibiotics and diagnostics to quickly identify bacterial
    pathogens?
        Answer. NIAID supports a comprehensive research portfolio on
    antimicrobial resistance, including clinical trials to test new
    diagnostics, treatments, and vaccines. NIAID is funding highly
    meritorious research projects on antimicrobial resistance focused on
    developing: (1) clinical diagnostics; (2) tools to facilitate discovery
    of novel therapeutics; and (3) prevention strategies. These awards will
    build on successes in NIH-supported CARB research, including prior
    support for more than 35 clinical studies through the NIAID
    Antibacterial Resistance Leadership Group (ARLG), which oversees
    clinical research to reduce the public health threat of antibacterial
    resistance. The ARLG has undertaken studies investigating diagnostic
    devices, optimized treatment regimens, new drugs, and projects on
    antimicrobial stewardship. NIAID also supports basic and preclinical
    research to identify promising antibacterial products that may move
    into clinical trials. NIAID continues to collaborate with the
    Biomedical Advanced Research and Development Authority (BARDA) on CARB-
    X, a unique public-private partnership dedicated to accelerating the
    development of innovative antibacterial products from target/candidate
    identification and characterization through Phase 1 clinical trials.
    NIH also continues to partner with BARDA to support the CARB diagnostic
    challenge seeking to identify innovative, rapid point-of-need
    diagnostics to combat the development and spread of drug-resistant
    bacteria, as well as increase antibiotic stewardship. These efforts are
    critical to generating a robust pipeline of candidate antibiotics and
    diagnostics to support clinical testing of promising products against
    drug-resistant organisms.
        Question. Does NIH expect these efforts to help reduce the number
    of drug-resistant infections and deaths that occur each year, or is
    that too much to expect?
        Answer. The ultimate goals of NIAID-supported research on
    antimicrobial resistance, ranging from basic research to identify
    targets for antimicrobial products to applied research and clinical
    trials to test new diagnostics, treatments, and prevention strategies,
    are to help reduce the number of drug-resistant infections and deaths
    and to increase antibiotic stewardship. As one example, NIAID
    scientists have been using next generation sequencing to study the
    evolution of community acquired methicillin-resistant Staphylococcus
    aureus (MRSA) strains to help identify how these strains developed and
    to understand why those strains have become more prevalent. This
    research, which collected MRSA isolates from patients in many
    geographic regions, may inform new strategies to limit community
    acquired MRSA infections throughout the United States. NIAID also has
    evaluated a new drug to treat Neisseria gonorrhoeae, a bacterium that
    is increasingly resistant to currently used drugs, in clinical trials
    through the Sexually Transmitted Infections Clinical Trials Group and
    the Phase 1 Clinical Trial Units for Therapeutics. Based on these early
    studies, which found the investigational gonorrhea therapeutic to be
    well-tolerated and effective, the drug will advance to later-stage
    clinical trials. NIH anticipates that its ongoing CARB research and
    partnerships across government, as well as new activities enabled by
    increases to CARB research funding in fiscal year 2018, will continue
    to support progress against antibiotic-resistant bacterial infections.
                             universal flu vaccine
        Question. NIH recently announced the phase 2 clinical trial of a
    potential universal flu vaccine. How long is that trial expected to
    last, and does NIAID have other vaccine candidates in the pipeline? If
    so, when might we see trials for candidates begin?
        Answer. The National Institutes of Health (NIH) is prioritizing the
    development of universal influenza vaccines that would represent a
    groundbreaking advance in influenza preparedness by allowing for
    durable protection against multiple influenza strains. The National
    Institute of Allergy and Infectious Diseases (NIAID), part of the NIH,
    has outlined its research priorities for a universal influenza vaccine
    in a strategic plan published online on February 28, 2018, by The
    Journal of Infectious Diseases. As one example of research consistent
    with the strategic plan, NIAID recently launched a Phase 2 clinical
    trial of an experimental universal influenza vaccine called M-001. The
    vaccine, which was developed and produced by BiondVax Pharmaceuticals,
    is designed to stimulate an immune response against peptide sequences
    shared among many different influenza strains. The clinical study will
    be conducted at NIAID-funded Vaccine and Treatment Evaluation Units
    (VTEUs) and is estimated to be completed in early 2019. The VTEUs also
    are planning to initiate Phase 1 clinical studies to inform the
    development of universal influenza vaccines, including a study to
    evaluate whether the addition of a novel adjuvant to an existing pre-
    pandemic H5N1 influenza vaccine can enhance the breadth of the immune
    response to different influenza strains.
        NIAID is studying additional strategies to create a universal
    influenza vaccine, several of which have advanced to early-stage
    clinical trials. For example, NIAID Vaccine Research Center scientists
    have initiated Phase 1/2 studies of a universal influenza vaccine
    approach that includes an investigational DNA-based vaccine followed by
    a licensed seasonal influenza vaccine ``boost'' to improve the potency
    and durability of seasonal influenza vaccines. NIAID also developed a
    ferritin nanoparticle-based vaccine approach that showed promise in
    animal testing and is being evaluated in early-stage clinical trials.
    In another strategy, NIAID scientists developed a vaccine made from
    non-infectious virus-like particles (VLPs). This VLP-based vaccine
    candidate incorporates four subtypes of the viral hemagglutinin protein
    into one vaccine. This candidate broadly protected against multiple
    influenza virus subtypes in animal models and may advance to clinical
    trials in the future. NIAID is supporting a number of preclinical
    studies to evaluate additional universal influenza vaccine candidates.
    In addition, NIAID funds basic research to better understand how the
    immune system responds to influenza infection or vaccination, and
    efforts to develop new assays and reagents to evaluate the efficacy of
    novel influenza vaccines.
        NIAID will continue to support the development of a robust pipeline
    of candidate universal influenza vaccines that may advance to
    evaluation in clinical trials. The availability of a universal
    influenza vaccine would eliminate the need to update and administer the
    seasonal influenza vaccine each year and could provide protection
    against newly emerging influenza strains, including those with pandemic
    potential. NIAID efforts to achieve this important goal will be
    facilitated by the generous support of the Congress in providing $100
    million dedicated to research on universal influenza vaccines in NIH's
    fiscal year 2018 budget.
                                opioid epidemic
        Question. What share of NIDA's roughly $1.4 billion budget for
    fiscal year 2018 will be devoted to opioid-related efforts, be it
    prevention, clinical trials or the development of new therapeutics?
        Answer. We are unable to provide this information until fiscal year
    2018 concludes, but we will provide the information when it becomes
    available.
        Question. When can we expect to see the agency's strategic plan for
    the opioids initiative, and will it include specific targets and
    milestones for what we're trying to achieve?
        Answer. The research plan for the Helping to End Addiction Long-
    term (HEAL) Initiative \74\ is available online. Setting specific
    targets and milestones is difficult due to the unpredictable nature of
    scientific inquiry, so at this time, specific targets are not included.
    The overall goals of the HEAL Initiative are preventing addiction
    through enhanced pain management and improving treatment for opioid use
    disorder.
    ---------------------------------------------------------------------------
        \74\ https://www.nih.gov/research-training/medical-research-
    initiatives/heal-initiative/heal-initiative-research-plan.
    ---------------------------------------------------------------------------
        Question. The fiscal year 2019 budget proposes a coordinated
    strategy with two primary aims to combat the opioid epidemic in our
    country. One of those aims is to accelerate the development of new,
    non-addictive pain therapies with the goal of making a wide-range of
    therapeutics accessible to those who need them as quickly as possible.
    Can you describe what types of non-addictive pain therapies are
    currently in the NIH research pipeline, and how quickly can these
    therapies can be developed and distributed to the market?
        Answer. NIH is particularly excited about the new Helping to End
    Addiction Long-term (HEAL) Initiative. HEAL will bolster research
    across NIH in an effort to improve the treatment of chronic pain by (1)
    exploring biomarkers that predict the transition from acute to chronic
    pain, (2) identifying new targets for treating chronic pain using
    neurotechnologies developed through the Brain Research through
    Advancing Innovative Neurotechnologies (BRAIN) Initiative and the
    Stimulating Peripheral Activity to Relieve Conditions (SPARC) program,
    and (3) building the evidence base on the effectiveness of nondrug and
    integrated pain treatments. In addition, the Initiative will pursue
    public-private partnerships to develop new non-addictive pain medicines
    by sharing data on past and present research projects, and matching
    researchers with a selection of potentially promising but abandoned
    pharmaceutical industry compounds to explore their effectiveness for
    the treatment of pain. Finally, NIH will develop a clinical trials
    network for pain, allowing multiple new and repurposed compounds to be
    tested for effectiveness simultaneously.
        The Initiative will tap into the expertise of the NIH Pain
    Consortium,\75\ a trans-NIH consortium made up of NIH institutes that
    fund pain research. Funded projects are investigating the entire range
    of therapeutics development- from preclinical safety and efficacy
    testing and early phase human trials to health services research.
    Currently, the consortium members are working on developing more
    effective and less addictive treatments for chronic pain. For example,
    a study using a molecular imaging technology called x-ray
    crystallography has revealed the molecular structure of the receptors
    that mediate drugs' effects; this information is already leading to the
    development of safer medications to treat pain.
    ---------------------------------------------------------------------------
        \75\ https://www.painconsortium.nih.gov/About/Members.
    ---------------------------------------------------------------------------
        NIH-funded research is developing medications with properties that
    affect opioid receptors to produce analgesia with reduced risk of
    addiction and misuse. Some of these exhibit novel properties as a
    result of their combined activity at different types of opioid
    receptors (mu, delta, and kappa). Compounds with combined activity at
    the mu and delta receptors or at all three receptors can induce strong
    analgesia without producing tolerance or dependence in animal models.
    In addition, the discovery of adjunct medications that can be combined
    with opioids to reduce the needed dose has the potential to result in
    lower potential for dependence and addiction. Innovative methods are
    being explored for drug delivery to increase specificity and efficacy
    and to reduce analgesic side effects, as well as modified formulations
    to enhance delivery.
        NIH supports an initiative called the Blueprint Neurotherapeutics
    Program for small molecule drug discovery and development. For example,
    NINDS funds studies through this program that aim to develop non-
    addictive kappa opioid receptor antagonists for migraine and a safe,
    non-opioid analgesic that can be taken orally to reduce diabetic nerve
    pain.
        It is difficult to estimate the time to market for these various
    alternatives, but NIH is establishing a Clinical Trial Network to
    accelerate the development of novel non-addictive chronic pain
    medications and devices by optimizing analgesic trial design, targeting
    appropriate patient populations for trials, and engaging research
    expertise at existing clinical sites.
        Question. Are there any vaccine candidates being considered?
        Answer. NIDA continues to fund development of anti-opioid vaccines
    capable of generating an immune response that would prevent opioids
    from entering the brain, thereby blocking both their euphoric effects
    and their dangerous respiratory depressant properties. Current projects
    include:
      --Optimization and preclinical testing of a practical heroin-HIV
            vaccine \76\
    ---------------------------------------------------------------------------
        \76\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9110917&icde=39707102
    &ddparam=&ddvalue=&ddsub=&cr=20&csb=default&cs=ASC&pball=.
    ---------------------------------------------------------------------------
      --Preclinical development of vaccines against heroin, oxycodone,
            hydrocodone, and fentanyl \77,78,79\
    ---------------------------------------------------------------------------
        \77\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9444613&icde=39707102
    &ddparam=&ddvalue=&ddsub=&cr=11&csb=default&cs=ASC&pball=.
        \78\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9330137&icde=39707102
    &ddparam=&ddvalue=&ddsub=&cr=26&csb=default&cs=ASC&pball=.
        \79\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9461410&icde=39707102.
    ---------------------------------------------------------------------------
        Results from preclinical models thus far have shown that these
    vaccine candidates are capable of producing an immune response that
    blocks opioid effects.\80\ While none have yet advanced to clinical
    trials, the heroin vaccine candidate developed by the Walter Reed Army
    Institute of Research in collaboration with NIDA has been in-licensed
    by Opiant Pharmaceuticals for further development.\81\
    ---------------------------------------------------------------------------
        \80\ Olson ME, Janda KD. Vaccines to combat the opioid crisis:
    Vaccines that prevent opioids and other substances of abuse from
    entering the brain could effectively treat addiction and abuse. EMBO
    Rep. 2018 Jan;19(1):5-9.
        \81\ https://www.opiant.com/pipeline/heroin-vaccine/.
    ---------------------------------------------------------------------------
        Question. The budget emphasizes that the NIH will work with the FDA
    and pharmaceutical partners to build a public-private partnership to
    accelerate the development of new non-addictive pain therapies. Can you
    describe what these partnerships will look like, and how small
    biopharmaceutical companies who may be working on novel approaches
    might be able to participate?
        Answer. As part of the NIH HEAL Initiative, NIH will pursue public-
    private partnerships to accelerate the development of non-addictive
    pain medicines by sharing data on past and present research projects,
    as well as matching researchers with a selection of potentially
    promising but abandoned pharmaceutical industry compounds to explore
    their effectiveness for the treatment of pain. Companies of all sizes
    can participate in this initiative.
                                     ______

                   Questions Submitted to Richard Hodes, M.D.
                    Questions Submitted by Senator Roy Blunt
                              alzheimer's vaccine
        Question. Dr. Hodes, vaccines have been one of the most impactful
    medicines in history. Is there the scientific possibility that a
    vaccine would work in Alzheimer's?
        What is the state of the research in this area?
        Is NIA planning to fund any vaccination programs in fiscal year
    2018?
        Answer. Vaccination, a form of immunotherapy, using your body's own
    immune system to help fight disease, is one of many treatment
    modalities currently under study for both the prevention and treatment
    of Alzheimer's disease (AD). While we have every reason to hope that we
    will see positive results from these studies, our cautious optimism is
    tempered by the acknowledgement that previous vaccine trials have been
    largely unsuccessful. For example, in 2002 a trial of AN1792, the first
    vaccine to target deposition of beta-amyloid, a pathological hallmark
    of the disease, ended early because dangerous brain inflammation
    occurred in some patients. More recently, industry-supported clinical
    trials of passive immunization (i.e., direct transfer of antibodies
    that attack beta-amyloid) with the monoclonal antibodies bapineuzumab
    and solanezumab produced disappointing results.
        However, these studies were initiated in individuals who were
    already showing clinical symptoms of the disease, and more recent
    vaccine studies are targeting at-risk individuals much earlier in the
    disease course, before symptoms appear. For example, the Alzheimer's
    Prevention Initiative Autosomal Dominant Alzheimer's Disease (API-ADAD)
    study is exploring ``preventive immunotherapy'' among members of a
    large extended family that carries a genetic mutation placing many
    members at greatly increased risk of developing the disease. Another
    study, the Dominantly Inherited Alzheimer's Network trial, evaluates
    the safety, tolerability and effectiveness of several drugs, including
    two vaccines, and will determine if they can prevent, delay, or even
    reverse Alzheimer's disease changes in the brain. The Alzheimer's
    Prevention Initiative APOE4 Trial (API APOE), or Generation 1 study, is
    determining the safety and efficacy of two drugs targeting beta-
    amyloid, including an active immunotherapy injection, in older adults
    at genetic risk of the disease, while the Anti-Amyloid treatment in
    Asymptomatic AD Trial (A4 Trial) is evaluating a passive vaccine in
    clinically normal older adults with evidence of AD pathology on
    screening positron emission tomography imaging who are at risk for
    developing dementia.
        NIA also supports a large cooperative agreement to complete
    preclinical safety and efficacy testing for AV-1959D, a cutting edge
    ``DNA vaccine.'' DNA vaccines use pieces of DNA from specific
    pathogenic proteins to stimulate an immune response and offer potential
    technical and safety advantages over conventional protein/adjuvant
    vaccines.
        More broadly, NIA supports research on underlying mechanisms of the
    immune system in the brain. For example, one study is exploring immune-
    mediated mechanisms underlying clearance of beta-amyloid from the brain
    and central nervous system, while others are investigating possible
    immunotherapies targeting tau, another pathological hallmark of AD. All
    of this important work will be active in fiscal year 2018 and 2019.
                               trans-angiogenesis
        Question. In May 2013, the NIH hosted the NIH Trans-Angiogenesis
    Workshop. In March 2016, the NIH released a meeting summary, which
    included an outline of clear steps needed to bring angiogenesis
    research forward. The resources needed included:
      --Develop potential partnerships with pharmaceutical companies for
            the development of new drugs that require investigations using
            structural biology approaches and medicinal chemistry.
      --Develop cross-disciplinary NIH resources to increase research on
            the molecular understanding of angiogenesis across therapeutic
            fields, such as cancer, diabetes, obesity, and cardiovascular
            diseases.
      --Develop a biomarker identification project that moves beyond
            prognostic biomarkers to the development of validated
            predictive biomarkers of clinical benefit (or lack of benefit)
            and biomarkers of toxicity.
      --Improve the translation of basic research angiogenesis focused
            findings across disciplinary fields to clinical applications.
      --Organize a cross-disciplinary meeting of basic science,
            translational and clinical scientists and clinicians where NIH
            grantees would be required to present their research.
      --Create trans-NIH Program Project Grants and Specialized Centers of
            Clinically Oriented Research for angiogenesis research.
        Could you please provide the Subcommittee an update on the progress
    on these issues?
        Answer. Angiogenesis is the process of new blood vessel formation
    and growth that is vital for normal embryonic development, new blood
    vessel formation, and wound healing. Insufficient, excessive, or
    aberrant angiogenesis may have significant clinical consequences in
    diseases such as stroke, myocardial infarction, peripheral arterial
    disease, cancer, chronic inflammation, and retinopathy.
        Multiple NIH Institutes fund angiogenesis-related research aimed at
    improving the understanding of normal and abnormal angiogenesis and
    translating findings into therapeutic interventions.
        Because angiogenesis research applies to many diseases, the trans-
    NIH workshop was convened to provide leaders in angiogenesis research
    an opportunity to examine the diverse nature of the sciences involved
    across the field, to identify current gaps, and to explore potential
    advantages in integrating basic, translational, and clinical research
    in the prevention and treatment of angiogenesis-related diseases.\82\
    NIH has continued to address research gaps and focus on priorities
    identified by the workshop. Here are a few examples:
    ---------------------------------------------------------------------------
        \82\ https://prevention.cancer.gov/news-and-events/meetings-and-
    events/trans-nih-angiogenesis-workshop/meeting-summary.
    ---------------------------------------------------------------------------
                        basic and translational research
        Research supported by the National Heart, Lung, and Blood Institute
    (NHLBI) has contributed to a better understanding of angiogenesis
    mechanisms at the molecular and cellular level.\83\ Signaling pathways
    and regulation of angiogenesis have been better defined,\84\ as has the
    role of inflammation and metabolism of cells that line the interior
    surface of vessels in angiogenesis.\85\ For example, researchers found
    that changes in endothelial cell glucose, fatty acid, and protein
    metabolism may function as a ``metabolic switch'' for angiogenesis.
    Further investigation of these pathways is ongoing to identify
    biomarkers of endothelial cell health and disease and to discover
    potential ways to alter defective angiogenesis.
    ---------------------------------------------------------------------------
        \83\ http://circres.ahajournals.org/content/120/11/1713/tab-
    supplemental.
        \84\ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966612/.
        \85\ https://www.ncbi.nlm.nih.gov/pubmed/29795441.
    ---------------------------------------------------------------------------
        Recognizing that cancers need a blood supply to grow and spread,
    the National Cancer Institute (NCI) provides support for research on
    elucidating the cellular mechanisms that give rise to the creation of
    new blood vessels and the therapeutic potential of anti-angiogenesis
    drugs. One area of particular interest is the action of vascular
    endothelial growth factor (VEGF) and other signaling molecules that
    stimulate angiogenesis. Since the discovery of VEGF almost 30 years
    ago, these proteins have become a major target for therapy; drugs that
    inhibit VEGF have become an intensively studied--and in some cases,
    successful--approach to block abnormal angiogenesis.
        Yet, some cancers are also resistant to these inhibitors.
    Researchers are examining the basic mechanisms of resistance in
    glioblastoma, with a focus on VEGF and stromal-cell derived factor 1
    (SDF-1), a protein involved in tumor growth and metastasis.\86\ NCI
    also supports basic research into tumor microenvironments, which may
    help illuminate future therapeutic pathways. Examples include a project
    examining the role of low oxygen, acidity, and depleted nutrient levels
    in the tumor microenvironment, and the effects these factors may have
    on glioblastoma angiogenesis,\87\ as well as a study on how immune
    system activity promotes angiogenesis in melanoma tumor
    microenvironments.\88\
    ---------------------------------------------------------------------------
        \86\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=8997986.
        \87\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9274829.
        \88\ https://projectreporter.nih.gov/
    project_info_description.cfm?aid=9236367.
    ---------------------------------------------------------------------------
        Angiogenesis research is also relevant to stroke, as collateral
    blood vessels around a blocked vessel can provide an alternative path
    for blood flow to the brain. Researchers funded by the National
    Institute on Neurological Disorders and Stroke (NINDS) are exploring
    the molecular and genetic mechanisms that determine the number and size
    of collateral vessels around major arteries, as well as the remodeling
    of these vessels after a stroke. Researchers also are exploring the
    role of angiogenic pathways in brain blood vessel stability and the
    risk for hemorrhage, as well as in processes that support protection
    and recovery of brain tissue following a stroke. Additionally, NINDS-
    funded investigators are exploring avenues to improve the effectiveness
    of angiogenesis inhibitors for treating brain cancers such as
    glioblastoma. Ongoing work is investigating the molecular mechanisms
    that lead to therapeutic resistance, and tumor recurrence and
    progression.
        Angiogenesis research is also important to eye health. Diabetes and
    the most common type of age-related macular degeneration (AMD) can
    cause vision loss due to abnormal blood vessels in the retina.
    Researchers funded by the National Eye Institute (NEI) have
    demonstrated that gene therapy can be used effectively to block
    proteins in the VEGF pathway to reduce vision loss in animal
    models.\89\ This proof of concept supports a novel treatment for
    angiogenesis-related retinopathy.
    ---------------------------------------------------------------------------
        \89\ https://www.ncbi.nlm.nih.gov/pubmed/29730824.
    ---------------------------------------------------------------------------
                               clinical research
        The NCI hopes to expand the successes of angiogenesis inhibitors in
    treating cancer and currently supports clinical trials of these agents
    to treat glioblastoma, pancreatic cancer, metastatic breast cancer,
    prostate cancer, ovarian cancer, colorectal cancer, lung cancer, liver
    cancer and other solid tumors. Many of these trials involve the
    therapeutic agent bevacizumab (Avastin), a monoclonal antibody directed
    against VEGF.
        The NHLBI also funds significant clinical research relating to
    angiogenesis. This includes a planning grant for a clinical trial
    testing an anti-angiogenesis drug to treat hereditary hemorrhagic
    telangiectasia, a genetic disorder that involves abnormal blood vessel
    formation and can result in hemorrhage and stroke.
        NHLBI has also supported, research to develop pro-angiogenic
    factors to treat ischemic diseases that restrict blood supply. Such
    efforts have not yielded reproducible and sustained success in late-
    stage clinical trials.\90\ While the use of pro-angiogenic stem cells
    may offer more promise, its clinical application is still limited.\91\
    ---------------------------------------------------------------------------
        \90\ https://journals.lww.com/cardiovascularpharm/Abstract/2014/
    08000/Identifying_and_
    Overcoming_Obstacles_in_Angiogenic.1.aspx.
        \91\ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869986/.
    ---------------------------------------------------------------------------
        The Eunice Kennedy Shriver National Institute of Child Health and
    Human Development (NICHD) supports a range of intramural and extramural
    research projects on aspects of angiogenesis, specifically on
    development of the utero-placental interface, placenta formation, and
    early development of the vascular system. In addition to investigator-
    initiated research, NICHD also supports clinical research aimed at
    achieving healthier pregnancy outcomes through its Maternal Fetal
    Medicine Units network. Recently, similarities in the pathology of
    cardiovascular disease and preeclampsia, a dangerous spike in a
    pregnant woman's blood pressure, prompted NICHD-supported researchers
    to conduct a preliminary study of a commonly used cardiovascular drug
    in high-risk pregnant women in their second trimester. While the risk
    of preeclampsia was unchanged in women who received a placebo, women
    who received this drug did not develop preeclampsia.\92\
    ---------------------------------------------------------------------------
        \92\ https://www.ncbi.nlm.nih.gov/pubmed/?term=26723196.
    ---------------------------------------------------------------------------
        A noninvasive retinal imaging approach called optical coherence
    tomography (OCT) has emerged as an effective tool to view the layers of
    the retina as well as any fluid leakage--a useful biomarker for AMD and
    for responses to treatment.\93\ Over the past decade, the introduction
    of anti-angiogenesis drugs, such as Avastin, Lucentis, and Eylea has
    revolutionized treatment of AMD, slowing the disease and even reversing
    vision loss in some cases. However, monthly treatment injections are
    expensive and not always needed. OCT is also used for treatment
    decisions for other angiogenesis-related causes of blindness, such as
    diabetic retinopathy.
    ---------------------------------------------------------------------------
        \93\ https://www.ncbi.nlm.nih.gov/pubmed/29077605.
    ---------------------------------------------------------------------------
                               trans-nih efforts
        Question. Several NIH Institutes are involved in a Neuroscience
    Blueprint initiative--Neurobiology of Small Blood and Lymphatic Vessels
    in Health and Disease. This initiative will support the development of
    innovative tools and technologies to explore heterogeneity of small
    blood and lymphatic vessels in the central nervous system (CNS), as
    well as human studies to identify targets, biomarkers, and mechanisms
    specific to CNS small blood and lymphatic vessels. This initiative
    emerged from a trans-NIH scientific workshop on the role of small
    vessels in health and disease across different organ systems in the
    body.\94\ While not specifically focused on angiogenesis research, it
    may support angiogenesis projects.
    ---------------------------------------------------------------------------
        \94\ https://www.ncbi.nlm.nih.gov/pubmed/27815267.
    ---------------------------------------------------------------------------
        Because angiogenesis plays an essential role in health and is
    implicated in a wide range of diseases and disorders, the NIH will
    continue to support a full spectrum of research in this area, including
    development of pro- and anti-angiogenic therapies.
                                     ______

                 Questions Submitted to Norman Sharpless, M.D.
                    Questions Submitted by Senator Roy Blunt
                cancer research & treatment in rural communities
        Question. The network of National Cancer Institute-designated
    cancer centers and comprehensive cancer centers play an important role
    in our national efforts to prevent, diagnose, and treat cancer. As
    someone from a rural state who understands the difficulty in access to
    cancer treatments in rural and remote areas, Dr. Sharpless, can you
    describe how existing resources are used to help those Americans in
    rural and underserved communities?
        How do NCI-designated cancer centers ensure those in rural
    communities can benefit from clinical trials and breakthrough cancer
    treatments?
        Answer. Rural communities face disadvantages compared with urban
    areas, including higher poverty, lower educational attainment, and lack
    of access to health services. These challenges contribute to higher
    incidence of certain cancers and worse cancer-related outcomes in low-
    income, underserved rural populations. New data has shown that--for the
    first time--cancer death rates are higher in rural areas than in urban
    areas. This shift has been demonstrated by two studies--one by NCI
    researchers \95\ and one led by researchers from the Centers for
    Disease Control and Prevention (CDC).\96\
    ---------------------------------------------------------------------------
        \95\ https://www.ncbi.nlm.nih.gov/pubmed/28600296.
        \96\ https://www.cdc.gov/mmwr/volumes/66/ss/ss6614a1.htm.
    ---------------------------------------------------------------------------
        There are several areas where the National Cancer Institute (NCI)
    plays a significant role in advancing rural cancer prevention and
    control research. Key areas include working with NCI's Community
    Oncology Research Program (NCORP) and NCI-Designated Cancer Centers to
    build on their experience with community outreach and developing
    partnerships with local organizations. To inform NCI's efforts to
    better address cancer disparities in rural communities, NCI is also
    convening researchers, community representatives, and providers to
    discuss these important issues. In May 2018, NCI hosted a diverse group
    of speakers from across these disciplines to discuss collaboration and
    coordination for rural cancer control. The objectives of the meeting
    were to (1) identify gaps in rural cancer research and practice; (2) to
    build partnerships across the country to address challenges and
    disseminate solutions; and (3) to highlight and identify methods to
    address competing and common agendas of clinics/providers, researchers,
    and community/patients.\97\
    ---------------------------------------------------------------------------
        \97\ https://cancercontrol.cancer.gov/research-emphasis/meetings/
    arcc-meeting.html.
    ---------------------------------------------------------------------------
        NCI has a broad and growing range of research in this area and will
    continue to work with the cancer community and others to refine and
    reinvigorate our cancer control efforts in rural areas across the
    country. NCORP is a crucial part of NCI's efforts to prevent, diagnose,
    and treat cancer in rural populations.\98\ NCORP's mission is to bring
    clinical trials and cancer care delivery research to people where they
    live, with a special focus on rural communities. NCORP is comprised of
    seven research bases; 46 community sites, 12 of which are designated as
    minority/underserved; \99\ and more than 900 component sites across the
    country.\100\ NCORP community and component sites, which are comprised
    of public hospitals, physician practices, academic medical centers, and
    other groups that provide healthcare services in community settings,
    play an important role in accruing patients to NCI-supported research
    studies and clinical trials, including the groundbreaking NCI Molecular
    Analysis for Therapy Choice (NCI- MATCH) precision medicine cancer
    treatment trial.
    ---------------------------------------------------------------------------
        \98\ https://ncorp.cancer.gov/.
        \99\ NCORP minority/underserved sites have a patient population
    that is of at least 30 percent racial/ethnic minorities or rural
    residents.
        \100\ https://ncorp.cancer.gov/findasite/map.html.
    ---------------------------------------------------------------------------
        NCI-Designated Cancer Centers also play an increasingly important
    role in rural cancer control. There are currently 70 NCI-Designated
    Cancer Centers located in 36 States and the District of Columbia. These
    cancer centers develop and translate scientific knowledge from
    promising laboratory discoveries into breakthrough treatments for
    cancer patients. Each year, approximately 250,000 patients receive
    their cancer diagnosis at an NCI-Designated Cancer Center, and an even
    larger number of patients are treated for cancer and/or enrolled in a
    clinical trial at these centers.\101\ Cancer centers applying for NCI-
    designation are required to describe the geographic area they intend to
    serve, and are encouraged to describe how the center plans to extend
    its reach beyond this catchment area to bring the center's expertise to
    bear on wider populations, including rural populations.\102\
    ---------------------------------------------------------------------------
        \101\ https://www.cancer.gov/research/nci-role/cancer-centers.
        \102\ https://grants.nih.gov/grants/guide/pa-files/PAR-17-095.html.
    ---------------------------------------------------------------------------
        To incentivize cancer center engagement in rural health, NCI has
    provided supplemental funding to 15 cancer centers to collect
    additional data concerning their catchment area population and align
    local measures with national ones, enabling more direct comparisons
    across centers and with national surveillance data. To extend this
    commitment, in fiscal year 2018, NCI plans to support NCI-Designated
    Cancer Centers in further developing their rural cancer control
    research capacity.
        In addition to the programs described above, NCI recently released
    a standalone Funding Opportunity Announcement (FOA) inviting
    applications for research aimed at improving the reach and quality of
    cancer care in rural populations.\103\ Depending on receipt of
    sufficiently meritorious applications, NCI intends to fund up to 10
    awards in fiscal year 2018.
    ---------------------------------------------------------------------------
        \103\ https://grants.nih.gov/grants/guide/rfa-files/RFA-CA-18-
    026.html.
    ---------------------------------------------------------------------------
                                pediatric cancer
        Question. Dr. Sharpless, we hear a lot about the need for more
    research on childhood cancer, often from families who have lost a child
    to cancer. What is the National Cancer Institute doing to improve
    outcomes for children with cancer, and to address the factors that make
    childhood cancers unique?
        Answer. Pediatric cancer research remains a top priority for the
    National Cancer Institute (NCI), and each year the Institute identifies
    the best research opportunities to build upon the foundation of basic
    science, further develop the scientific understanding of genetic
    drivers of childhood cancers, identify effective therapies, and enhance
    the quality of life for pediatric cancer survivors.
        NCI recognizes cancers that strike infants, children, teens and
    even young adults are different from those that affect adults, and that
    they require specific research. Additionally, even when long-term
    survival is achieved, many survivors of childhood cancer experience
    serious long-term adverse effects from the disease or its treatment.
    Future discoveries made through additional research are needed so that
    new, more effective, and less toxic treatments for cancers that affect
    children and young adults can be developed.
        Recognizing that childhood cancers are distinct from adult cancers,
    NCI supports numerous targeted programs aimed at advancing research in
    pediatric oncology. These efforts include:
      --The Children's Oncology Group (COG),\104\ part of NCI's National
            Clinical Trials Network (NCTN), develops and coordinates
            pediatric clinical trials across more than 200 member
            institutions. In addition to conducting late-phase clinical
            trials, the COG receives NCI support for the Phase 1 and Pilot
            Consortium,\105\ which conducts early-phase trials and pilot
            studies to rapidly introduce new anticancer agents into
            pediatric care.
    ---------------------------------------------------------------------------
        \104\ https://www.childrensoncologygroup.org/.
        \105\ https://www.childrensoncologygroup.org/index.php/phase-1-
    home.
    ---------------------------------------------------------------------------
      --The Pediatric Oncology Branch (POB) \106\ in NCI's Center for
            Cancer Research, part of NCI's intramural research program,
            conducts high-risk, high-impact basic, translational, and
            clinical research.
    ---------------------------------------------------------------------------
        \106\ https://ccr.cancer.gov/Pediatric-Oncology-Branch.
    ---------------------------------------------------------------------------
      --The NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice)
            Trial,\107\ launched in July 2017, tests molecularly targeted
            therapies in children and adolescents with advanced cancers who
            have few other treatment options. This nationwide trial is open
            to children and adolescents from 1 to 21 years of age and
            currently has eight treatment arms.
    ---------------------------------------------------------------------------
        \107\ https://www.cancer.gov/about-cancer/treatment/clinical-
    trials/nci-supported/pediatric-match.
    ---------------------------------------------------------------------------
      --Other efforts include the Pediatric Preclinical Testing Consortium
            (PPTC),\108\ the Therapeutically Applicable Research to
            Generate Effective Treatments (TARGET) \109\ program, the NCI
            Experimental Therapeutics (NExT) Program,\110\ the Childhood
            Cancer Survivor Study (CCSS),\111\ the Pediatric Provocative
            Questions (PQ) Program,\112\ the Pediatric Brain Tumor
            Consortium (PBTC),\113\ the Pediatric Cancer Immunotherapy
            Trials Network (CITN),\114\ and the New Approaches to
            Neuroblastoma Therapy (NANT) \115\ Consortium.
    ---------------------------------------------------------------------------
        \108\ http://www.ncipptc.org/.
        \109\ https://ocg.cancer.gov/programs/target.
        \110\ https://next.cancer.gov/.
        \111\ https://www.cancer.gov/types/childhood-cancers/ccss.
        \112\ https://grants.nih.gov/grants/guide/pa-files/PAR-16-217.html.
        \113\ https://www.pbtc.org/.
        \114\ https://ctep.cancer.gov/MajorInitiatives/
    cancer_immunotherapy_trials_network.htm.
        \115\ http://www.nant.org/.
    ---------------------------------------------------------------------------
        In addition to these well-established programs, the Institute is
    enthusiastic about the scientific opportunities provided by the Cancer
    MoonshotSM to stimulate further investigation of pediatric cancers.
    Current programs supported by the Cancer MoonshotSM include the Fusion
    Oncoproteins in Childhood Cancers (FusOnC2) Consortium, which will seek
    to develop models of, and therapeutic agents for, fusion-driven
    childhood cancer; \116\ the Pediatric Immunotherapy Translational
    Science Network, which will aim to identify targets for immunotherapy
    treatments for pediatric patients; \117\ and the Rare Tumor Patient
    Engagement Network,\118\ which aims to study rare tumors, including
    pediatric tumors, and develop a network of clinical trials.
    ---------------------------------------------------------------------------
        \116\ https://grants.nih.gov/grants/guide/rfa-files/RFA-CA-17-
    049.html.
        \117\ The foundation of this initiative began in 2017, with the
    release of two FOAs to establish the Pediatric Immunotherapy Discovery
    and Development Network (PI-DDN): https://grants.nih.gov/grants/guide/
    rfa-files/RFA-CA-17-051.html; https://grants.nih.gov/grants/guide/rfa-
    files/RFA-CA-17-050.html.
        \118\ https://ccr.cancer.gov/research/cancer-moonshot.
    ---------------------------------------------------------------------------
        NCI is committed to addressing the unique scientific challenges and
    opportunities that pediatric cancers pose in ways that lead to better
    outcomes for children with cancer. NCI continues to demonstrate this
    commitment through its ongoing support for childhood and adolescent
    cancer research efforts, through a continued investment in basic
    research and other crosscutting research efforts, and through its
    collaborations with the childhood cancer community.
        NCI also encourages you to visit the ``Childhood Cancers Research''
    page on its website for additional information about current research,
    including more comprehensive descriptions of some of the programs
    mentioned above.\119\ Research on pediatric cancers will continue to be
    a top priority.
    ---------------------------------------------------------------------------
        \119\ http://www.cancer.gov/researchandfunding/areas/childhood.
    ---------------------------------------------------------------------------
                    indefinite delivery/indefinite quantity
        Question. It is my understanding that NIH is using more Indefinite
    Delivery/Indefinite Quantity (ID/IQ) awards, which can provide several
    advantages: (1) greater competition in the procurement process; (2)
    smaller well-defined program tasks; (3) tighter financial control on
    each program task; and (4) incremental milestone driven funding.
    However, many small, not-for-profit contractors have a difficult time
    justifying the large commitment of time and resources when contracts
    are small and delayed. Therefore, the return-on-investment for
    contractors is becoming harder to justify. Can you discuss the issues
    NIH faces with ID/IQ contracts and why they are not being more
    regularly awarded?
        Answer. NIH makes regular use of Indefinite Delivery/Indefinite
    Quantity (ID/IQ) contracts and continues to look for more opportunities
    to establish new or use existing ID/IQs. We carefully consider small
    business opportunities when establishing or using the ID/IQs. The
    advantages of establishing multiple award ID/IQs far outweigh the
    challenges. However, one challenge is once the contracts are awarded,
    new vendors tend to be unable to pursue NIH business for a period of
    time because so much of the ordering is limited to the existing
    contractors. Additionally, due to bid protests, NIH tends to award
    contracts to a large number of contractors rather than limiting the
    awardees to a smaller, more manageable pool. This tends to make the
    competition at the task order level less efficient. Small companies
    often feel the investment of time and energy expended when pursuing an
    ID/IQ is potentially wasted when the competition for individual task
    orders involves so many competitors and requires additional resources
    to receive the order. One last issue is the inability to award flexible
    orders when issuing task orders against multiple award ID/IQs. The firm
    nature of the orders often cause the NIH program to consider other
    arrangements such as a Blanket Purchase Agreement (BPA) against a GSA
    Schedule contract.
                                     ______

                  Questions Submitted by Senator Patty Murray
                              functional genomics
        Question. Fred Hutch researchers recently received NCI funds to
    continue work on an approach termed functional genomics, in which they
    focus directly on a patient's tumor cells. The approach can be applied
    toward different types of cancer, to pinpoint which drugs work best for
    an individual patient's tumor and identify drug resistance. With this
    new infusion of funding, researchers will have the opportunity to
    identify new drug targets in difficult to treat cancers and collaborate
    with various partners to help oncologists deliver individually tailored
    therapies to cancer patients. Can you tell me more about NCI's plans to
    support this type of highly targeted treatment?
        Answer. The National Cancer Institute (NCI) is supporting a wide
    range of cancer genomic programs focused on understanding how cancer
    develops, the molecular changes that drive cancer, and the vast tumor
    heterogeneity within and across cancers. Precision oncology is rooted
    in a deep understanding of the genetic and functional changes that
    occur in cancer cells and the tumor microenvironment. NCI is committed
    to supporting research in genomics and other disciplines to increase
    our understanding of the complexity of cancer biology to advance
    precision oncology.
        The NCI Center for Cancer Genomics (CCG) unifies NCI's activities
    in cancer genomics by aiming to synthesize research in different fields
    of cancer genomics. CCG's programs and collaborations generate cancer
    genomic and clinical data, and, importantly, make these data available
    for widespread use by the research community. Using a collaborative
    ``team science'' approach, CCG engages in three complementary sub-
    disciplines within cancer genomics: structural genomics, functional
    genomics, and computational genomics. Structural genomics identifies
    alterations in cancer that contribute to cancer growth, metastasis, and
    recurrence. Functional genomics studies the role of cancer genes,
    mutations, and pathways, and develops therapeutic strategies to target
    them. Computational genomics uses statistical and computational
    approaches to derive insight from big data on cancer. By testing
    hypotheses derived from structural genomics research, and by generating
    new ideas from experiments in cancer cells, functional genomics
    research reveals patterns in cancer biology that can be translated into
    novel therapies for precision cancer care.
        To translate genomic insights to the clinic, the findings must be
    tested in models of cancer to understand the functional impact of
    insults to the genome. In addition to supporting investigator-initiated
    grants and other extramural research in this area, NCI provides
    resources to the extramural community to support their research on the
    molecular changes that drive cancer. One example is The Cancer Genome
    Atlas (TCGA),\120\ which contains the genomes of more than 30 types of
    cancer and catalogues thousands of genetic alterations in cancer cells
    that could be targets for existing or new therapies. Another example is
    the Genomics Data Commons (GDC), a unified data system for sharing
    genomic and clinical data launched in 2016. The GDC centralizes,
    standardizes, and makes data from large-scale NCI programs more
    accessible and useful to scientists and clinicians. One measure of the
    importance of this resource is that non-profit and for-profit
    organizations are now offering their data sets for sharing through the
    GDC.
    ---------------------------------------------------------------------------
        \120\ Collaboration with the National Human Genome Research
    Institute.
    ---------------------------------------------------------------------------
        One program geared towards bridging the knowledge gap between data
    generated from large-scale genomic studies and the underlying etiology
    of cancer development, progression, and/or metastasis is the Cancer
    Target Discovery and Development (CTD) \96\ Network. The CTD \96\
    Network is accelerating the use of molecular data to speed the
    translation of basic science findings to clinical trials. Through
    validation studies that rely on bioinformatics analysis of genomic
    data, high-throughput screening of small molecules, and research that
    involves cancer models or other tools, the CTD \96\ Network supports
    research to capitalize on a growing volume of data to identify new
    cancer vulnerabilities and treatments.
        The initial phase of CTD \96\ Network generated 19 novel
    bioinformatic tools which enable the identification of therapeutic
    targets, gene and molecular networks, and driver mutations (genetic
    changes that drive the development of cancers), and chemical
    sensitivities. These tools are available to the scientific community
    and can be accessed through the CTD \96\ analytical tools page.\121\
    During the first phase, the Network has been highly successful and
    published over 60 manuscripts with preclinical and clinical
    relevance.\96\ The results from some studies have provided supporting
    evidence for the initiation of several clinical trials.\122\ Highlights
    of progress during this first phase include the discovering the
    mechanism of action of a compound that selectively inhibits the growth
    of breast cancer stem cells, and the discovery of novel, rare driver
    mutations in pancreatic cancer and confirmation of their importance
    through validation studies in model systems.
    ---------------------------------------------------------------------------
        \121\ https://ocg.cancer.gov/programs/ctd2/analytical-tools.
        \122\ https://ocg.cancer.gov/programs/ctd2/publications.
    ---------------------------------------------------------------------------
        The second phase of the CTD \96\ Network (multi-year awards funded
    in fiscal year 2017) is exploring cancer complexity in terms of various
    types of heterogeneity, that is differences in genetic characteristics
    within each patient (i.e., across tumor tissue, the tumor
    microenvironment, and normal tissue), as well as genetic differences
    within each tumor (i.e., different tumor cells may have different
    genomic characteristics and molecular drivers). Projects seek to
    understand the potential impacts of heterogeneity (i.e., acquired
    resistance to chemo and immunotherapies) and develop efficient
    strategies to overcome treatment resistance. Through active
    collaboration and the sharing of data and resources with the cancer
    research community, each of the twelve funded Centers within the CTD
    \96\ Network will utilize functional and computational genomic
    approaches to contribute to the understanding of mechanisms of cancer
    and potentially accelerate the development of clinically useful
    markers, targets, and therapeutics for precision oncology.
        Complimenting these efforts, NCI is supporting development of the
    Human Tumor Atlas Network (HTAN) as part of the Cancer Moonshot.\SM\
    The HTAN is planned to be a 5-year pilot consortium focused on
    generating comprehensive, multidimensional tumor atlases (detailed
    mapping of molecular and cellular characteristics) describing key
    transitions in the development of cancer that will inform future cancer
    research and, ultimately, clinical decisionmaking. The HTAN efforts
    build upon and extend the efforts of TCGA. The HTAN will draw upon the
    lessons learned from TCGA, address its limitations, and use evolving
    state-of-the-art information technology and other emerging technologies
    to achieve its goal. Additional efforts supported by the Cancer
    Moonshot,\SM\ such as those focused on cancer immunology and
    immunotherapy, will increase our knowledge of genetic changes that
    occur in cancer cells and the tumor microenvironment to enable use of
    precision immunotherapy for both adult and pediatric cancer patients.
        Currently ongoing Precision Oncology trials that utilize molecular
    characterization to inform treatment choice include the NCI Molecular
    Analysis for Therapy Choice (NCI-MATCH) Trial and the Pediatric MATCH
    Trial. For these trials, rather than selecting therapies based on where
    a tumor originated in the body, the focus is on evaluating the
    effectiveness of treating cancer based on specific genetic changes. In
    2017, the adult NCI-MATCH Trial achieved its enrollment goal, nearly 2
    years ahead of schedule. The trial involves more than 6,000 patients
    from all 50 States. NCI also successfully opened enrollment for the
    Pediatric MATCH Trial in 2017. Other NCI precision medicine trials
    include the Lung Cancer Master Protocol (Lung-MAP) Trial, the Adjuvant
    Lung Cancer Enrichment Marker Identification and Sequencing Trials
    (ALCHEMIST), and Molecular Profiling-Based Assignment of Cancer Therapy
    (NCI-MPACT) Trial.
        NCI's investment in cancer genomics programs such as the CTD \96\
    and the HTAN will inform future precision medicine trials and build
    upon the results of ongoing trials in this paradigm changing approach
    to precision oncology for cancer patients.
                              nci-funded research
        Question. Dr. Sharpless, cancer immunotherapy is one of the great
    success stories of NCI-funded research. After decades of basic
    research, patients today are receiving immunotherapy treatments for a
    growing number of cancers, including melanoma, lung cancer, lymphoma,
    leukemia, head-and-neck cancer, and more. Many of these patients
    previously had few other treatment options. Some who had even very
    advanced cancer are now doing extremely well. And, we are just getting
    started. What is being done to educate healthcare providers about the
    principles of immunotherapy and how to manage the toxicity? And what
    efforts is NCI taking to retrain laboratory scientists to advance the
    immunotherapy field?
        Answer. Immunotherapy, a treatment that uses a patient's own immune
    system to help fight diseases including cancer, is a major focus of
    National Cancer Institute (NCI)-supported research that spans basic
    science to clinical applications. NCI-supported researchers publish
    their research results in peer-reviewed journals, and frequently
    present their research at professional conferences, including the
    annual meetings of the American Association of Cancer Research (AACR)
    and the American Society of Clinical Oncology (ASCO). For example, at
    the June 2018 meeting of ASCO, NCI-supported researchers participated
    in a two-day seminar entitled ``Cancer Immunotherapy Today: Maximizing
    Patient Outcomes,'' co-hosted by ASCO and the Society for Immunotherapy
    of Cancer (SITC).\123\ This session provided continuing education to
    clinical oncologists, nurses, pharmacists, and the entire medical team
    on effectively providing the most up-to-date and comprehensive
    immunotherapy options to their patients, and included guidance on
    patient selection and managing toxicities.
    ---------------------------------------------------------------------------
        \123\ https://www.sitcancer.org/events/event-
    description?CalendarEventKey=796e7e32-bba9-
    4712-9491-daed98d7a3c8&Home=%2fevents%2fcalendar.
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        NCI supports training for immunotherapy investigators across the
    research spectrum, from basic to translational to clinical research.
    NCI's Center for Cancer Research (CCR) supports an Immunotherapy
    Fellowship for physicians who have completed a medical oncology
    fellowship program and who seek specialized training in immunotherapy,
    including the design and facilitation of clinical trials.\124\
    Immunotherapy researchers are encouraged to apply for NCI-supported
    training awards.\125\ Different awards are available to pre- and post-
    doctoral researchers, clinical fellows, established investigators, and
    non-tenured early-career stage faculty.
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        \124\ https://www.cc.nih.gov/training/gme/programs/
    immunotherapy.html.
        \125\ https://www.cancer.gov/grants-training/training/funding.
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        NCI's intramural Center of Excellence in Immunotherapy (CEI)
    focuses on creating opportunities for immunologists in the intramural
    and extramural communities to exchange information and to facilitate
    collaborations. To that end, CEI sponsors an annual series of meetings
    on cancer-related immunology research, with the next meeting entitled
    ``Frontiers in Basic Immunology'' \126\ planned for September 2018.
    Prior meetings included the 2017 ``Cancer and Immunology and
    Immunotherapy: From Conception to Delivery,'' meeting and the 2016
    ``Immunotherapy Biomarkers 2016: Overcoming the Barriers'' meeting.
    Videos of the presentations and discussions are freely available
    online.\127\
    ---------------------------------------------------------------------------
        \126\ https://ncif-staging.ncifcrf.gov/Events/Conferences/
    Frontiers/.
        \127\ https://ncif-staging.ncifcrf.gov/Events/Conferences/
    Frontiers/PastConferences.aspx.
    ---------------------------------------------------------------------------
        In addition to these resources, NCI plans to support new training
    and education efforts in fiscal year 2018 including supplemental
    training awards for cancer immunotherapy, and additional funding to
    support the development of a consortium. The consortium will engage
    external partners that will develop standardized educational content
    for oncology care providers and deliver the content nationwide.
        NCI will continue to encourage the dissemination of research
    advances and the career development of the immunotherapy research
    community.
                                     ______

                    Questions Submitted to Nora Volkow, M.D.
                    Question Submitted by Senator Roy Blunt
                                  chronic pain
        Question. Dr. Volkow, unfortunately, much of the opioid crisis we
    are experiencing today can be linked to opioid prescriptions to treat
    chronic pain. Your Institute has studied the effectiveness and risks
    associated with long-term opioid use for chronic pain, but what
    research is currently ongoing related to new and alternative options to
    treat chronic pain other than opioids?
        Answer. In fiscal year 2017, NIH spent $516 million on pain
    research ranging from cell and molecular mechanisms of acute and
    chronic pain to safe, effective therapy development, to large scale
    clinical trials. The portfolio includes many research projects that
    address the pressing need to develop new non-opioid, non-addictive,
    pain treatments. Research studies range from early-stage drug target
    discovery focusing on molecular pathways of pain signaling, including
    exploration of receptors and channels as potential non-addictive
    analgesic targets to testing in behavioral models. A number of targets
    identified through NIH basic science, such as nerve growth factor
    receptor and pain-related ion channels, are now being pursued in
    industry-sponsored clinical trials for non-addictive treatments. NIH
    supported early development of calcitonin receptor gene protein, a
    compound recently approved for migraine treatment.
        A tissue--based tool for screening potential migraine drugs is
    under development and a library of small molecules is being leveraged
    to screen candidates for optimization as analgesics. Tissue engineering
    and regeneration to create tissue scaffolding and microenvironments to
    promote wound healing, joint cartilage, and intervertebral disc
    replacements is being applied to relieve pain. Neural stimulation
    technologies for chronic, intractable pain are being improved. For
    example, wearable ultrasound devices and implantable micro-stimulators
    are being tested on peripheral and central nervous system targets to
    relieve pain.
        Evaluation and dissemination of complementary and integrative
    health approaches is a crucial component of quality pain management.
    NIH-supported studies include mechanism-based clinical studies on
    cognitive behavior therapy, exercise, yoga, acupuncture, massage,
    fitness, and mindfulness practices are an important component of the
    NIH Federal pain research portfolio.
                                     ______

                 Question Submitted by Senator Joe Manchin, III
                   research into alternative pain management
        Question. Dr. Volkow, communities across the country are seeing an
    alarming rise in substance abuse and addiction to prescription opioids.
    Opioids killed more than 42,000 Americans in 2016. That's 115 people
    every day. In West Virginia, we lost more than 909 people to a drug
    overdose in 2017.
        So many of these people who become addicted started taking these
    drugs because their doctor prescribed them for pain even though--
    according to the CDC--there is little evidence that opioids improve
    chronic pain.
        This is a public health crisis and we have to find a better way. I
    am proud to have worked with my colleagues to dedicate an additional
    $500 million to NIH for research on opioid addiction, the development
    of opioid alternatives, pain management, and addiction treatment.
        That is why I am so worried about the President's Budget Request to
    cut more than $500 million from the National Institute on Drug Abuse.
        Dr. Volkow, what research is being done to develop non-addictive
    alternative pain management options for patients--particularly those
    dealing with long-term, chronic pain who are currently being prescribed
    opioids despite the lack of evidence of their effectiveness?
        What impact would the proposed budget cuts have on NIDA's ability
    to do continue to do this research?
        Answer. Chronic pain is a complex neurological condition, driven by
    many biological, environmental, social, and developmental factors. To
    this end, NIH supports a range of activities to advance research on
    understanding and treating pain.
        Chronic pain is a disorder of brain circuits, and the
    neurotechnologies emanating from the trans-NIH Brain Research through
    Advancing Innovative Neurotechnologies (BRAIN) Initiative enable
    scientists to explore these circuits to advance diagnostics and
    therapeutics. Similarly, the Stimulating Peripheral Activity to Relieve
    Conditions (SPARC) program at the NIH Common Fund supports novel means
    to alter peripheral nerve pathways to relieve pelvic pain and has
    promise for application to other pain conditions.
        Complementary and integrative health approaches address the
    biopsychosocial nature of chronic pain and its treatment. NIH supports
    numerous clinical studies on cognitive behavioral therapy (CBT),
    exercise, yoga, acupuncture, massage, fitness, and mindfulness
    practices. For example, trials showed that mindfulness-based stress
    reduction with CBT and yoga improved function and reduced low back
    pain.
        The NIH Health Care Systems Research Collaboratory supports large-
    scale, pragmatic clinical trials focused on the management of patients
    with multiple chronic conditions, including pain. One study is
    evaluating multidisciplinary approaches to pain management in the
    primary care setting in patients who are currently on long-term
    opioids. This large-scale trial aims to develop integrated pain care
    approaches to reduce pain and opioid use in patients enrolled in a
    large healthcare system. The NIH, Department of Defense and Department
    of Veterans Affairs Pain Management Collaboratory's goal is to develop
    the capacity to implement cost-effective large-scale clinical research
    in military and veteran healthcare delivery organizations focusing on
    non-pharmacological approaches to pain management and other comorbid
    conditions.
        To accelerate the development of novel non-addictive chronic pain
    medications and devices, NIH is establishing a Clinical Trial Network
    to optimize analgesic trial design, target appropriate patient
    populations for trials, and engage research expertise at existing
    clinical sites. A related initiative is to pursue, through the Network,
    development and validation of biomarkers of pharmacodynamic response
    and biomarkers for treatment response to optimize patient
    stratification based on phenotyping and thus allow smaller sample size
    and improve assay sensitivity for screening novel analgesics. These
    efforts provide a valuable set of clinical research resources which
    will allow researchers to identify effective pain medications more
    quickly.
        The NIH Common Fund is currently in the planning stages of a broad
    scale clinical study to identify a set of objective biomarkers to
    predict which patients will transition to chronic pain after an acute
    pain event. This program, known as Acute to Chronic Pain Signatures
    Program, will collect longitudinal data from two large patient groups
    that have acute pain associated with a surgical procedure or an acute
    musculoskeletal trauma such as a bone fracture. Neuroimaging, genetic
    and molecular data, sensory testing, and psychosocial assessments from
    patients will be collected for months after the acute pain event and
    analyzed to explore transition or resilience characteristics to help
    predict which patients will recover and which patients will develop
    long-lasting pain. Identifying such markers will help to predict which
    people might be at risk for developing chronic pain, reducing reliance
    on opioids thereby, guide precision medicine approaches to prevent
    chronic pain, and by doing so, reducing our reliance on opioids.
        The current state of the science, emerging technologies, and
    mobilization of the research community holds great promise for advances
    in evidence-based, quality pain care.

                              SUBCOMMITTEE RECESS

        Senator Blunt. The subcommittee stands in recess.
        [Whereupon, at 11:38 a.m., Thursday, May 17, the
    subcommittee was recessed, to reconvene subject to the call of
    the Chair.]

                  MATERIAL SUBMITTED SUBSEQUENT TO THE HEARING

        [Clerk's Note.--The following outside witness testimony was
    received subsequent to the hearing for inclusion in the
    record.]
     Prepared Statement of Christopher P. Austin, M.D., Director, National
                  Center for Advancing Translational Sciences
        Mr. Chairman and Members of the Committee: I am pleased to present
    the President's fiscal year 2019 budget request for the National Center
    for Advancing Translational Sciences (NCATS) of the National Institutes
    of Health.
        NCATS is dedicated to understanding and transforming translation,
    defined as the process of turning scientific, medical, and public
    health observations in the laboratory, clinic, and community into
    interventions that improve the health of individuals and the public. At
    a time of unprecedented science discoveries, our collective ability to
    translate research findings into health benefits often is too slow and
    ineffective. Developing a new drug requires on average 10 to 15 years
    and more than $2 billion given the high prevalence of failure along the
    translational pipeline. We must deliver the promise of science to
    patients in an accelerated and more efficient manner. NCATS studies and
    supports translation on a system-wide level as a scientific and
    operational problem, addressing roadblocks that impede or preclude
    promising advances.
                       accelerating clinical translation
        The largest portion of NCATS' budget is dedicated to its Clinical
    and Translational Science Awards (CTSA) Program. Through this program,
    NCATS supports a national network of medical research centers, called
    hubs, that collaborate locally, regionally, and nationally to foster
    innovation in clinical researcher training, patient engagement, and new
    research tools and processes. There are multiple initiatives within
    this program, including the Trial Innovation Network that is composed
    of the hubs as well as Trial Innovation Centers and a Recruitment
    Innovation Center. Through this network, researchers are identifying
    and implementing ways to improve the clinical trial process, including
    participant recruitment and other aspects of clinical trial conduct.
        The process of obtaining ethics approval from multiple
    institutional review boards (IRBs) to conduct a clinical research study
    at multiple institutions is a longstanding challenge that can lead to
    significant delays in study activation. To address this problem, NCATS
    supported the development of a single IRB reliance platform for
    multisite clinical studies, enabling study sites to rely on a single
    IRB of record. The platform, known as the Streamlined, Multisite,
    Accelerated Resources for Trials (SMART) IRB, includes resources such
    as umbrella agreements, guidance documents, and consultation services
    that investigators nationwide can access to harmonize and streamline
    IRB review for their own multisite studies. SMART IRB is serving as a
    roadmap to help implement the NIH policy released in June 2016 that
    requires all NIH-funded multisite clinical studies to use a single IRB.
        Providing the resources to train, cultivate, and sustain future
    leaders of the biomedical research workforce is another key CTSA
    Program emphasis. The program supports a coordinated, national effort
    to help ensure a pipeline of trained translational investigators who
    can move basic research findings into applications for improving health
    outcomes as novel therapies, diagnostics, and preventives. Program
    grantees have developed clinical and translational sciences training
    resources, including educational core competencies, best practices for
    training mentors, and curriculum materials. These tools are freely
    available, and many institutions nationwide are using them.
        Engaging patients at all stages of translation is crucial; their
    perspectives as members of the research team provide insights, focus,
    urgency and connectivity that can be instrumental in making the
    development, testing and deployment of new interventions more
    effective. NCATS supports the Rare Diseases Clinical Research Network
    (RDCRN) and requires each consortia member to include patient groups as
    full partners on their research teams, an approach that helps achieve
    greater success. The RDCRN Coalition of Patient Advocacy Groups
    develops and shares best practices, and the RDCRN website includes a
    contact registry for patients who may be interested in participating in
    RDCRN clinical studies. Rare diseases, which cumulatively affect
    approximately one in 10 people in the U.S., are in crucial need of
    innovative translational technologies, and are thus a crucial NCATS
    focus.
        Measurable outcomes can help determine whether a new translational
    process is actually an improvement. NCATS' Discovering New Therapeutic
    Uses for Existing Molecules program matches academic investigators with
    pharmaceutical companies that have compounds that were found to be
    ineffective in treating specific diseases. Repurposing these compounds
    for potentially treating other diseases saves time in the drug
    development process because significant foundational work already has
    been completed. NCATS helps to further accelerate this process by
    providing collaboration agreement templates that now are being used
    broadly in the research community and by supporting researchers with
    new ideas for how existing compounds can be repurposed.
                    finding new therapies for clinical study
        NCATS also is dedicated to removing pre-clinical translational
    science roadblocks. Through its Therapeutics for Rare and Neglected
    Diseases (TRND) program, the Center works to ``de-risk'' potential
    therapeutics so that private sector companies may be more inclined to
    acquire them to finish their development.
        Despite promising results in clinical trials outside of the U.S.,
    work on further developing a gene therapy for the rare pediatric
    disease aromatic L-amino acid decarboxylase (AADC) deficiency was
    seemingly insurmountable. Through TRND, NCATS teamed with a private
    sector partner, Agilis Biotherapeutics, to convert promise into
    reality, jointly creating a manufacturing process for a therapy that
    complies with FDA regulations, and obtaining the required pre-clinical
    data. In addition to getting this potentially lifesaving therapy to
    patients, this project established technological and regulatory models
    that will accelerate development of other rare disease gene therapies.
        The NCATS Cures Acceleration Network (CAN) supports high-risk,
    innovative programs to advance the development of high-need cures and
    reduce significant barriers between research discovery and clinical
    trials. Through the CAN-funded Tissue Chip for Drug Screening program,
    NCATS is working on new methods for predicting both safety and efficacy
    of experimental drugs using engineered ``chips'' that contain human
    cells and model human organs. Current methods such as animal and cell
    models are not always reliably predictive and can result in wasted time
    and effort. In addition to developing these chips for testing potential
    drugs, NCATS soon will send tissue chips to the International Space
    Station (ISS) for research on the effect of microgravity on these model
    organs. Microgravity can accelerate aging and have other effects
    relevant to diseases on Earth, making the ISS a unique and significant
    research environment.
        New drug development for currently untreatable diseases has been
    greatly limited because known chemical structures affect only 10
    percent of potential drug targets within the human body. With CAN
    support, NCATS plans to launch its Automated Synthesis Platform for
    Innovative Research and Execution (ASPIRE) program to bring together
    chemistry, robotic engineering, biological activity testing, and
    artificial intelligence. Tools developed through ASPIRE will minimize
    the time chemists spend on tedious and repetitive tasks, freeing them
    up for more complicated pursuits such as designing, synthesizing, and
    testing compounds for diseases that currently have no treatment.
              adaptability to tackle emerging public health needs
        With its unique collection of programs, initiatives and resources,
    NCATS has the capacity and capability to address public health crises.
    For example, a team of researchers from NCATS and the Icahn School of
    Medicine at Mount Sinai developed a miniaturized assay for high-
    throughput screening to find compounds that block the ability of Ebola
    virus-like particles (VLPs) to enter and infect cells. A screen using
    2,816 compounds identified 53 drugs with entry-blocking activity
    against Ebola VLPs.
        In another example, investigators from Johns Hopkins University and
    Florida State University collaborated with NCATS experts on drug
    repurposing and high throughput screening to identify rapidly two
    classes of existing compounds that potentially can be used to fight
    Zika. These compounds were effective either in inhibiting the
    replication of the Zika virus or in preventing the virus from killing
    brain cells. All data have been made available through public
    databases, allowing these compounds to be further studied by the
    broader research community.
        NCATS also is well-positioned to help combat the current national
    epidemic of opioid abuse. The Center's high-throughput screening
    facility could be used to test potential opioid abuse therapeutics, and
    CTSA Program-supported researchers could help identify opioid patients
    and rapidly enroll them in multisite clinical trials.
                                   conclusion
        Through its programs and initiatives described above, and others,
    NCATS is improving health through smarter science in unprecedented
    ways, with the ultimate goal of getting more treatments to more
    patients--and to the public at large--more quickly.
                                     ______

    Prepared Statement of Dr. James F. Battey, Jr., M.D., Ph.D., Director,
       National Institutue on Deafness and Other Communication Disorders
        Mr. Chairman and Members of the Subcommittee: I am pleased to
    present the President's fiscal year 2019 budget request for the
    National Institute on Deafness and Other Communication Disorders
    (NIDCD) of the National Institutes of Health (NIH).
        NIDCD conducts and supports research and research training in the
    normal and disordered processes of hearing, balance, taste, smell,
    voice, speech, and language. NIDCD focuses on disorders that affect the
    quality of life of millions of Americans in their homes, workplaces,
    and communities. The physical, emotional, and economic impact for
    individuals living with these disorders is tremendous. NIDCD continues
    to make investments to improve our understanding of the underlying
    causes of communication disorders, as well as their treatment and
    prevention. It is a time of extraordinary promise, and I am excited to
    be able to share with you some of NIDCD's ongoing research and planned
    activities on communication disorders.
              preventing hearing loss caused by common cancer drug
        NIDCD intramural researchers have discovered why cisplatin and
    other popular and effective platinum-based chemotherapy drugs cause
    ototoxicity--damage to the delicate cells in the inner ear which can
    lead to hearing loss. In previous studies, researchers have focused on
    why the inner ear is more vulnerable to cisplatin ototoxicity than
    other areas in the body. The NIDCD research team, however, studied the
    cause of cisplatin ototoxicity from a different perspective; they
    explored if cisplatin remains in the inner ear continuing to cause
    damage for a longer time than in other areas of the body. The
    scientists found that, both in mice and humans, cisplatin remains in
    the inner ear long after it is already eliminated from other areas of
    the body. These results suggest that the inner ear readily takes up
    cisplatin, but it has little ability to remove the drug.
        In mouse and human tissues, the research team saw the highest
    accumulation of cisplatin was in a part of the inner ear called the
    stria vascularis, which is responsible for maintaining the positive
    electrical charge in inner ear fluid that certain cells need to detect
    sound. The research team determined that the accumulation of cisplatin
    in the stria vascularis portion of the inner ear contributed to
    cisplatin-related hearing loss.
        This research suggests that if we can find ways to avoid cisplatin
    from entering the stria vascularis during treatment with cisplatin, we
    might be able to prevent the hearing loss that goes along with it. As
    hearing loss is often associated with isolation, depression, and other
    conditions, helping to preserve hearing in individuals who are required
    to undergo cancer treatment with these chemotherapy drugs would greatly
    contribute to maintaining the quality of their lives.
                 treating hereditary deafness with gene editing
        Hearing problems in infants and children can delay the development
    of voice, speech, and language skills. Approximately 80 percent of
    hearing loss is due to genetic factors, and treatment options for
    genetic deafness are limited. A research team, supported in part by
    NIDCD, used a mouse model of human genetic deafness to design a
    potential treatment approach.
        Mutations in a particular gene, TMC1, are known to cause hereditary
    deafness in both humans and mice. The mutation causes the death of
    sensory hair cells in the cochlea of the inner ear. These hair cells
    transform sound waves into electrical signals that the brain recognizes
    as sound. To prevent hair cell death and the resulting progressive
    hearing loss in mice with the TMC1 mutation, the scientists used the
    CRISPR-Cas9 gene-editing system to remove the mutation and disable the
    gene.
        The researchers developed a novel approach to deliver the gene-
    editing complex into the inner ears of newborn mice. They packaged the
    gene-editing complexes in lipids (fats) that form structures called
    liposomes. The liposome-packaged complexes move readily through cell
    membranes into cells. Eight weeks later, substantially more hair cells
    survived in ears of treated compared to untreated mice. The treatment
    also significantly reduced progressive hearing loss. This novel
    strategy may help scientists develop new therapies for hearing loss
    caused by inherited genetic mutations.
           taste, balance, and more--a proton channel with many roles
        Our ability to taste helps us choose and enjoy nutritious foods and
    avoid foods that have been spoiled by bacteria. On our tongue, sensory
    taste cells respond to chemicals that are released from food and drink.
    Taste cells respond to these chemicals via protein receptors and
    channels that are specific to certain taste molecules. For instance, to
    detect sourness in food, specialized channels let protons (Hydrogen
    atoms) that are released from acidic sour-tasting foods enter proton-
    sensitive, ``sour'' taste cells on the tongue.
        The identity of this ``sour detector'' protein has been elusive.
    Now, NIDCD-supported scientists have located a protein called OTOP1 and
    determined that it forms a channel that allows protons to enter taste
    cells on the tongue. They have also confirmed that human OTOP1 forms a
    channel with properties similar to those of the mouse OTOP1 protein.
    When OTOP1 gene was altered in mice, the scientists observed that taste
    cells had significantly fewer protons going into them. This evidence,
    together with other supporting studies on OTOP1, suggests that OTOP1 is
    the long-sought after sour taste receptor. The next step to test this
    theory will be to record whether mice that lack OTOP1 respond to sour
    tastes. Studies like this one, that increase our understanding about
    how we taste, may help scientists learn to restore a sense of taste to
    those who have lost it due to disease or injury.
        This study may help us understand far more than just how we detect
    taste. OTOP1 is also required for the vestibular (balance) system in
    the inner ear to detect gravity, so it is important for helping us keep
    our balance. OTOP1 is also expressed in many other body tissues,
    including fat, heart, uterus, breast, and the nervous system. Since we
    know that OTOP1 functions as a proton-sensitive channel, what we learn
    from this taste study may help us understand cell signaling in these
    other tissues, too. When protons enter cells, they change the acid/base
    (pH) concentration. So, a better understanding of OTOP1 could also help
    us understand other body processes that involve changes in pH, such as
    pain sensation, fat metabolism, and pH changes seen in cancer cells.
          personalized voices for people with severely impaired speech
        Approximately 2.5 million Americans and millions more people
    worldwide have a severe speech impairment since birth or as a result of
    a neurological disorder that occurred later in life, such as a stroke.
    For these people, communicating is a daily challenge that relies upon
    their use of a computer to generate their voice. While these devices go
    a long way toward helping people with a voice disorder express
    themselves, the synthetic voices produced are usually a poor
    representation of a natural human voice. In addition, the lack of
    diversity in available synthetic voices means that many people must use
    the same generic voice.
        Through a Small Business Innovation Research Program grant, NIDCD
    voice scientists have moved research from the lab into real-world
    application. Researchers are in the second phase of developing a
    personalized text-to-speech augmentative and alternative communication
    (AAC) device called VocaliD. This device involves blending the speech
    of two individuals--a donor and the recipient. First, a recording is
    made of whatever vocal sounds the recipient is still able to make. The
    next step is accomplished with the help of a volunteer voice donor. For
    the best results, the donor should match the recipient in terms of
    gender, age, region of origin, and other characteristics. By
    commercializing VocaliD, NIDCD scientists have refined the technology,
    automating certain steps and making the entire process of creating
    personalized, synthetic voices faster and more efficient. These
    improvements will advance speech synthesis while humanizing machine-
    mediated spoken interaction for AAC devices and beyond.
                                     ______

    Prepared Statement of Diana W. Bianchi, M.D., Director, Eunice Kennedy
       Shriver, National Institute of Child Health and Human Development
        Mr. Chairman and Members of the Committee: I am pleased to present
    the President's fiscal year 2019 budget request for the Eunice Kennedy
    Shriver National Institute of Child Health and Human Development
    (NICHD) of the National Institutes of Health (NIH).
                           achieving lifelong health
        Understanding human development, both normative and atypical, is at
    the core of NICHD's mission. As our name reflects, NICHD supports and
    conducts a wide range of research, including but not limited to
    pediatric research, on all phases of human development to maturity,
    with the goal of achieving optimal health, cognitive, and physical
    function.
        Child Health.--The epidemic of opioid use disorder and its
    consequences is among the most serious public health threats in this
    country today. Among those exposed to opioid use are the thousands of
    infants born to women with the disorder. Every 15 minutes, a baby is
    born with Neonatal Opioid Withdrawal Syndrome (NOWS) in the United
    States; to date, NOWS has cost about $2 billion in additional costs for
    Medicaid-financed deliveries.\1\ Symptoms of NOWS, also known as
    Neonatal Abstinence Syndrome (NAS), often do not begin until after
    infants have been discharged from the hospital. Their needs are placing
    huge stresses on the healthcare and foster care systems nationwide. To
    address this problem, NIH launched a new study called the Advancing
    Clinical Trials in Neonatal Opioid Withdrawal Syndrome (ACT NOW) to
    evaluate treatment options and improve clinical care of affected
    infants. The study is a collaboration between NICHD's Neonatal Research
    Network and the new IDeA States Pediatric Clinical Trials Network
    (within the Office of the NIH Director's Environmental Influences on
    Child Health Outcomes program), with sites located in rural and
    medically underserved communities. This joint research effort will use
    the reach of both networks to assess the prevalence of NOWS, understand
    current approaches to managing these cases, and develop protocols for
    conducting large scale studies to inform clinical care, so that these
    babies may get a better start in life.
    ---------------------------------------------------------------------------
        \1\ Winkelman, T.N., Villapiano, N., Kozhimannil, K.B., Davis,
    M.M., Patrick, S.W., Incidence & Costs of Neonatal Abstinence Syndrome
    among Infants with Medicaid: 2004-2014, Pediatrics published online:
    March 23, 2018 (doi: 10.1542/peds.2017-3520).
    ---------------------------------------------------------------------------
        One of NICHD's longest standing research priorities is to improve
    the lives and health of people with intellectual and developmental
    disabilities, such as Down syndrome. NICHD leads the public-private
    Down Syndrome Consortium, which includes 11 NIH Institutes and Centers,
    13 national and international organizations whose missions focus on
    Down syndrome, and individuals with Down syndrome and family members.
    Consortium members provided valuable input to DS Directions: The NIH
    Down Syndrome Research Plan. Among the plan's major objectives is the
    call for research on the co-existing conditions commonly experienced by
    people with Down syndrome. For example, studies show that virtually all
    middle-aged adults with Down syndrome exhibit the neuropathological
    hallmarks of Alzheimer's disease, 50 percent of whom will develop this
    type of change to the brain by age 40. Funded jointly by NICHD and the
    National Institute on Aging, a new project, the Alzheimer's Biomarker
    Consortium--Down Syndrome (ABC-DS), seeks to identify biomarkers and
    use brain imaging to help us understand the progression of the disease.
    In addition, the research teams will make their data and samples freely
    available to qualified researchers worldwide, with the goal of
    accelerating the testing of potential interventions, which in turn may
    have widespread implications for Alzheimer's and other conditions. In
    fiscal year 2018, NICHD will lead a major new initiative to explore the
    risk and resilience of people with Down syndrome to common, co-existing
    conditions such as autism, cancer, and cardiovascular disease.
        NICHD's research on child health explores basic biological
    processes that control healthy or atypical development, translational
    research, behavioral and social science, and clinical studies. Basic
    research studies provide fundamental knowledge essential to
    understanding causes of structural and functional birth defects. NICHD
    has long provided the evidence base informing the panel of conditions
    included in newborn screening tests to help diagnose and treat infants
    early. Further, in collaboration with NHGRI, the Newborn Sequencing in
    Genomic Medicine and Public Health (NSIGHT) is exploring the challenges
    and opportunities associated with sequencing the entire genome of a
    newborn infant to advance our understanding of undiagnosed disorders.
    And, although it is widely recognized that children are not small
    adults, only five of the 80 drugs most frequently used in newborns and
    infants have been labeled for pediatric use to date. However, progress
    is being made under The Best Pharmaceuticals for Children Act,
    reauthorized by Congress for the fourth time in summer 2017, which
    charged NIH/NICHD with leading a trans-NIH effort on pediatric
    therapeutic needs. This year, through its Pediatric Trials Network,
    NICHD tested a commonly used combined antibiotic (piperacillin-
    tazobactam), finding the dose of this combination drug that is safe for
    infants who acquire severe infections in the hospital. NICHD-supported
    researchers also recently reported that children who are engaged during
    shared reading experience a boost in the area of the brain that is
    involved in language development, comprehension, memory, and problem
    solving; understanding how reading shapes a child's brain can help
    educators and parents develop and use effective early learning
    strategies.
        Maternal Health.--The World Health Organization defines maternal
    mortality as the death of a woman while pregnant or within 42 days
    after the pregnancy ends due to causes related to or aggravated by the
    pregnancy. Between 1987 and 2013, maternal mortality in the United
    States increased from 7.2 to 17.3 per 100,000 live births, the only
    developed nation in which the rates have been rising since 2000. NICHD
    supports a wide range of research efforts to counter this disturbing
    trend. For example, NICHD-supported researchers studying placental
    abruption (a dangerous condition that occurs when the placenta
    separates from the uterus before birth) found that women who had a
    placental abruption were about twice as likely to have abnormal levels
    of specific proteins in their blood. These results may help identify
    women at risk in the future.
        NICHD is supporting two major projects to gather unprecedented
    amounts of information about pregnancy. Its ongoing Human Placenta
    Project, designed to provide insights into placental health
    noninvasively and in real time, continues to yield new data to improve
    maternal health and pregnancy outcomes. Another effort launched this
    year, PregSource is a longitudinal, crowd-sourced, citizen science
    registry that will expand our knowledge about women's typical
    experiences during pregnancy and after birth, the effects of pregnancy
    on women's lives, and special health challenges some women face. In
    addition, many pregnant or breastfeeding women must either take
    prescription medications to ensure their own health or are urged to
    take medications to benefit the baby's health outcomes. As part of the
    21st Century Cures Act legislation, NICHD was asked to lead the newly
    mandated Federal Task Force on Research Specific to Pregnant Women and
    Lactating Women. Although pregnant women in the United States take
    between three and five prescription medications, usually for serious
    health conditions, very few of these therapies have been tested during
    pregnancy. Almost nothing is known about the transfer of medications
    into breast milk, nor the risks and benefits of breastfeeding while on
    medication. The Task Force's report and recommendations are due to the
    Secretary of Health and Human Services and Congress by September 2018,
    which will shed light on this understudied issue.
        Rehabilitation.--About 5 percent of children aged 5 to 17 in the
    United States live with disability. Conditions such as brain injury,
    cerebral palsy, or spina bifida can impede children's education and
    future potential to lead productive lives. The 2016 NIH Research Plan
    on Rehabilitation, led by the National Center for Medical
    Rehabilitation Research (NCMRR) at NICHD and the trans-NIH
    Rehabilitation Working Group, set out priority areas for medical
    rehabilitation research and assistive technologies to improve the lives
    of people of all ages. Multiple funding opportunities have been
    published to encourage scientists to submit applications on topics such
    as sleep disorders during medical rehabilitation; grants recently have
    been awarded on the biomechanics of movement and regenerative medicine.
    Another priority is to support research that will improve function for
    individuals with limb loss, yet the lack of data on the number of
    individuals who experience limb loss and the types of procedures or
    devices they receive to enable them to return to optimal function at
    home, school and work, has presented a barrier to research in this
    area. This year, NCMRR, in partnership with the Department of Defense,
    will solicit applications for a nationwide Limb Loss Registry to enable
    researchers the data they need to develop new devices and track health
    and functional outcomes.
        Helping Young Scientists.--To continue to foster groundbreaking
    health research, NICHD's commitment to investing in the next generation
    of researchers has been unwavering. For example, the Institute holds an
    annual young investigators conference to facilitate the training of
    physician scientists. The conference focuses on developing the skills
    needed by young clinician investigators who are working in any of the
    areas within NICHD's mission. We are also analyzing long-term success
    as a function of different types of training awards so that training
    resources can be directed to provide the maximum return on investment.
    To help young investigators get started with testing hypotheses and
    performing original research and to make maximum use of public
    investment, NICHD makes data and other research resources available
    through the Data and Specimen Hub (DASH), which offers de-identified
    data from clinical research on pregnancy, infant care, child health,
    HIV/AIDS, and other topics. Currently, the repository includes data
    from 63 studies, and more than 12,000 users have visited the site,
    including many young investigators who are exploring possible research
    collaborations; future plans include linking hundreds of thousands of
    residual biospecimens to the de-identified data.
                                   conclusion
        To capitalize on the many scientific areas within NICHD's mission,
    and to determine scientific priorities, the Institute is engaging in a
    new strategic planning process, with input from a wide array of
    stakeholders, and in collaboration with NIH and scientific leadership.
    As the new plan emerges, NICHD will continue its life-changing research
    efforts to improve the lives of children and families.
                                     ______

        Prepared Statement of Linda S. Birnbaum, Ph.D., D.A.B.T, A.T.S,
         Director, National Institute of Environmental Health Sciences
        Mr. Chairman and Members of the Committee: I am pleased to present
    the President's fiscal year 2019 budget request for the National
    Institute of Environmental Health Sciences of the National Institutes
    of Health (NIH).
                       team science for health solutions
        Human beings are faced with an increasingly complex environment in
    which we experience thousands of exposures--both healthy and
    hazardous--on any given day over the course of our lifetimes. Although
    advances in knowledge and technology enable individual scientists to
    delve deeper than ever into how such exposures may impact our health,
    the use of diverse, multidisciplinary teams of scientists to
    investigate complex problems offer the promise of accelerated discovery
    to prevent disease and improve health. A 2015 report by the National
    Research Council concluded that ``Several strands of research and data
    suggest that team science can rapidly advance scientific and
    technological innovation by increasing research impact, novelty,
    productivity, and reach.'' Such outcomes are directly in line with the
    imperatives of Optimize NIH and ReImagine HHS to increase efficiency,
    maximize talent, and accelerate innovation.
        Team science, in the NIEHS context, is the collaborative effort of
    researchers from diverse scientific disciplines, often in partnership
    with communities that have relevant experience or perspectives, to
    solve public health problems that arise from environmental exposures.
    NIEHS continues to build on a long tradition of interdisciplinary
    approaches that engage a range of scientific and community stakeholders
    in creating the knowledge to inform public health decisionmaking. I
    will describe some of the ways in which we implement team science
    approaches as we work to fulfill the mission of the NIEHS--to discover
    how the environment affects people in order to promote healthier lives.
                     centers, consortia, and collaborations
        NIEHS both conducts team science intramurally and supports team
    science through a variety of center, consortia, and interagency
    collaborations. We use the centers framework to capitalize on the
    diverse talent at universities and create a supportive environment for
    multidisciplinary science and community engagement. NIEHS-supported
    centers include those focusing on areas such as Environmental Health
    Sciences, Breast Cancer and the Environment, Environmental Health
    Disparities, Children's Environmental Health and Disease Prevention,
    and Oceans and Human Health. These centers provide a centralized hub to
    support research, training, and scientific exchange among investigators
    across disciplines and often in partnership with patient advocacy or
    other community organizations. Each center must also conduct research
    translation, provide information and education, and engage with
    interested patient groups and communities.
        The centers are highly productive and last year generated numerous
    significant discoveries, including how omega-3 fatty acids contained in
    fish oil could be used to treat asthma patients; that dementia is
    linked to a certain genetic variation combined with exposure to air
    pollution, and an impaired sense of smell in such persons may serve as
    an early warning sign; that children with asthma may be more likely
    become obese later in childhood or adolescence; links between exposure
    to seasonal harmful algal blooms and elevated risk of amyotrophic
    lateral sclerosis (ALS); and potentially safer alternatives to
    bisphenol A (BPA), to name just a few.
        Consortia are another way that NIEHS supports team science that
    extends beyond a single institution to create a network of linked
    expertise to focus on a complex environmental health problem or set of
    related issues. NIEHS led the Gulf Long-term Followup (GuLF) Study and
    the 5-year, $25.2-million Deepwater Horizon Research Consortia, both of
    which partnered researchers with communities to investigate health
    effects stemming from the oil spill, including the long-term mental
    health impacts of the spill on coastal residents, especially women and
    children; the resilience of individuals and communities; and whether
    seafood in the Gulf was safe for human consumption. These research
    partnerships continue to yield new insights: a 2017 study linked a
    range of health problems in workers who were exposed to dispersants
    used to clean up the oil spill.
        Research needs identified by the Deepwater Horizon consortia
    provided further momentum for the creation of the NIH Disaster Research
    Response (DR2) program, which comprises a national framework for
    research on the medical and public health aspects of disasters and
    public health emergencies. Led by the NIEHS and the National Library of
    Medicine, DR2 has rapidly grown into a Federal interagency effort with
    broad engagement in the goal of understanding how to be prepared for
    disasters and how to limit any negative disaster-related health
    effects. Examples of such research include human health studies to
    assess effects of exposures on first responders, worker volunteers, and
    community members; characterizing chemical hazards in floodwaters and
    identifying post-flood molds; and assessing risks to vulnerable people
    such as those with asthma from wildfire pollution. DR2 tools and
    trainings were used last year to enable critical data collection and
    analysis, and inform response to the devastating Hurricanes Harvey,
    Irma, and Maria. In addition, NIEHS awarded time-sensitive research
    grants specifically aimed at hurricane response research.
        NIEHS is leading the Nation's coordinated science response to
    another type of environmental threat--the potential for serious human
    health impacts from exposure to PFAS, the collective name for per- and
    polyfluoroalkyl substances, chemicals widely used over the past 50
    years in food packaging, lubricants, water-resistant coating, and fire-
    fighting foams, and other manufacturing. Although some have been phased
    out, these endocrine-disrupting chemicals continue to be found in
    drinking water supplies in multiple States, and NIEHS-funded research
    suggests links to health effects on immune and thyroid function, fetal
    growth and development, risk of cancer and obesity, and others. NIEHS
    helped to organize a recent meeting of 16 Federal agencies that focused
    on exchanging information on PFAS exposure science, health science, and
    remediation and treatment of contaminated areas, and generated
    opportunities for collaborative research. The National Toxicology
    Program Laboratory Branch, one of the NIEHS research components of this
    interagency program, is also responding to public demand for more and
    faster information on the threat posed by PFAS through its Rapid
    Evaluation and Assessment of Chemical Toxicity (REACT) program.
    Outcomes of these collaborative efforts will help to target research
    and inform decisionmaking by both government and communities.
        Perhaps the most prominent environmental hazard demanding a team
    science approach from across a broad spectrum of disciplines is lead
    exposure. NIEHS-supported science established the knowledge base for
    lead's major health impacts. But although we understand the primary
    outcomes of lead poisoning, particularly neurodevelopmental damage in
    children, the need continues for research to make clear exactly how
    lead works in the body to cause damage so that successful interventions
    can be developed. An NIEHS-funded study using lead in baby teeth as a
    marker of exposure found associations between lead levels just before
    and after birth with the risk for and severity of autism in later
    childhood. Another study of children whose mothers took multivitamins
    during pregnancy suggested they were 30 percent less likely to develop
    autism. The concerns are not just for children however; a recent study
    estimated that low-level lead exposure (<5mg/dL blood) is responsible
    for more than 400,000 deaths each year in the United States, some
    250,000 of which from cardiovascular disease in adults. Combined with
    the estimated half million children still exposed beyond the CDC
    reference level, the health, economic, and societal consequences of
    lead exposure remain great. NIEHS and our grantees are continuing to
    respond to this threat through research, training for workers involved
    in lead cleanup and remediation, and engaging with our Federal partners
    on the President's Task Force on Environmental Health Risks and Safety
    Risks to Children to develop a Federal Lead Strategy.
                           connecting the data points
        No matter what the environmental health issue is, it has become
    increasingly clear that finding solutions demands a strong commitment
    to team science--data science, sharing, and integration offer the
    promise of incredible breakthroughs in preventing disease and promoting
    health, but require unprecedented levels of engagement, coordination,
    and standardization across a rapidly evolving scientific landscape.
    NIEHS has been working to foster data collaborations through support of
    training grants in the Big Data to Knowledge (BD2K) initiative,
    partnership with the NIH Data Commons, development of an NIEHS Data
    Commons, convening of National Academies workshops, establishment of an
    Office of Cyberinfrastructure, and prioritization of data science and
    integration goals across our developing Strategic Plan.
        To conclude, environmental health problems present large, costly,
    and complex issues for our society that demand the focused attention of
    multidisciplinary teams of scientists. NIEHS will continue to provide
    the critical support and leadership necessary for such teams to succeed
    in discoveries that will prevent disease and promote the health of the
    American people.
                                     ______

      Prepared Statement of Patricia Flatley Brennan, Director, National
                              Library of Medicine
        Mr. Chairman and Members of the Committee: I am pleased to present
    the President's fiscal year 2019 budget request for the National
    Library of Medicine of the National Institutes of Health (NIH).
            accelerating biomedical discovery & data-powered health
        The National Library of Medicine (NLM) plays an essential role in
    catalyzing basic biomedical science through its cutting-edge data
    science and informatics research, comprehensive information systems,
    and extensive research training programs. As the world's largest
    biomedical library, NLM acquires, organizes, and delivers up-to-date
    biomedical information across the United States and around the globe.
    Millions of data scientists, health professionals, and members of the
    public use NLM's electronic information sources every day to translate
    research results into new treatments, products, and practices; provide
    useful decision support for health professionals and patients; and
    support disaster preparedness and response.
        Leveraging its 180-year history of organizing and disseminating
    biomedical literature, NLM is committed to the application of emerging
    data science capabilities to challenges in biomedical research and
    public health. It will do this by expanding its data and information
    resources and providing leadership in both the acquisition and analysis
    of data for discovery. It will expand its core biomedical literature
    and genomic collections to include a broad array of health, clinical,
    and biological data types and make these data findable, accessible,
    interoperable, and reusable (FAIR) for research. NLM will enhance its
    research programs to systematically characterize and curate data
    describing complex health phenomena and to devise new methods to
    uncover the knowledge held in data. It will restructure its biomedical
    informatics training programs to address data science as they continue
    to foster excellence and support a diverse workforce. NLM will develop
    an efficient organizational structure to accommodate emerging
    directions in research and services.
              research in biomedical informatics and data science
        NLM's research programs support pioneering research and development
    to advance knowledge in biomedical informatics and data science. Its
    research portfolio spans such areas as artificial intelligence,
    computational biology, clinical decision support, public health
    surveillance, visualization, and discovery mining in digital data sets.
    This research encompasses areas of high importance to NIH and society
    at large, and for audiences ranging from clinicians and scientists to
    consumers and patients.
        Research in data science produces novel analytical approaches and
    visualization tools that help scientists accelerate discovery from data
    and translate these findings to clinical solutions. It also aims to
    solve problems consumers face in accessing, storing, using, and
    understanding their own health data and to produce tools that make
    precision medicine discoveries available and more understandable to
    patients. Biomedical informatics research is yielding advanced
    analytical methods and tools for use against large scale data generated
    from clinical care, leading to fuller understanding of the effects of
    medications and procedures as well as individual factors important in
    the prevention and treatment of disease processes.
        Recognized as a leader in clinical information analytics, NLM
    conducts intramural research in areas such as medical language
    processing, high-speed access to biomedical information, analysis and
    use of high quality imaging data, advanced technology for emergency and
    disaster management, health data standards; and analysis of large
    databases of clinical and administrative data to predict patient
    outcomes and validate findings from clinical research studies.
    Leveraging extensive machine learning experience and field-based
    projects, NLM is now advancing analytical tools and deep learning
    techniques for application in image analysis research.
        NLM's biomedical informatics research also addresses issues in
    computational biology. Research creates new ways to represent and link
    together genomic and biological data and biomedical literature and
    produces analytic software tools for gaining insights in areas such as
    genetic mutational patterns and factors in disease, molecular binding,
    and protein structure and function.
             biomedical information systems for research and health
        NLM develops and operates a set of richly linked databases that
    promote scientific breakthroughs and play an essential role in all
    phases of research and innovation. Every day, NLM receives up to 12
    terabytes of new data and information, enhances their quality and
    consistency, and integrates them with other NLM information. It
    responds to millions of inquiries per day from individuals and computer
    systems, serving up some 100 terabytes of information, including
    genomic, chemical, and clinical trial data, as well as citations to
    more than 25 million journal articles in PubMed and more than 4.7
    million full-text articles in PubMed Central.
        NLM also offers sophisticated retrieval methods and analysis tools
    to mine this wealth of data, many of which grow out NLM's research and
    development programs. For example, NLM tools are used to mine journal
    articles and electronic health records (EHRs) to discover adverse drug
    reactions, analyze high throughput genomic data to identify promising
    drug targets, and detect transplant rejection earlier so interventions
    to help clinical research participants can begin more quickly. Data
    analysis tools also support complex analyses of richly annotated
    genomics data resources, yielding important molecular biology
    discoveries and health advances for applications to clinical care. Such
    applications demonstrate how the benefits of big data critically depend
    upon the existence of algorithms that can transform such data into
    information.
        As a major force in health data standards for more than 30 years,
    NLM's investments have led to major advances in the ways high volume
    research and clinical data are collected, structured, standardized,
    mined, and delivered. In close collaboration with other HHS agencies
    and the Veterans Administration, NLM develops, funds, and disseminates
    clinical terminologies designated as U.S. standards for meaningful use
    of EHRs and health information exchange. The goal is to ensure that EHR
    data created in one system can be transmitted, interpreted, and
    aggregated appropriately in other systems to support healthcare, public
    health, and research. NLM produces a range of tools to help EHR
    developers and users implement these standards and makes them available
    in multiple formats, including via application programming interfaces
    (APIs).
                  engaging the public with health information
        NLM uses multiple channels to reach the public with health
    information, including development of consumer-friendly websites,
    direct contact, and human networks that reach out to communities.
    Direct-to-consumer information is made available in lay language
    through MedlinePlus, which covers more than 1000 health topics. EHR
    systems can connect directly with MedlinePlus to deliver information to
    patients and healthcare providers at the point of need in healthcare
    systems. In collaboration with NIH Institutes and Centers (ICs) and
    other partners, NLM produces the print and online NIH MedlinePlus
    magazine, and its Spanish counterpart, NIH Salud.
        The National Network of Libraries of Medicine (NNLM) engages 6,500
    academic health sciences libraries, hospital libraries, public
    libraries, and community-based organizations as valued partners in
    conducting outreach to ensure the availability of health information,
    including from NLM services. The NNLM provides a community-level
    resource for NIH's All of Us program, ensuring a point of presence in
    almost every county in the US. NNLM partners with local, State, and
    national disaster preparedness and response efforts to promote more
    effective use of libraries and librarians and ensure access to health
    information in disasters and emergencies. NNLM also plays an important
    role in increasing the capacity of research libraries and librarians to
    support data science and improve institutional capacity in management
    and analysis of biomedical big data.
                                   conclusion
        To conclude, through its research, information systems and public
    engagement, NLM supports discovery and the clinical application of
    knowledge to improve health. Its programs provide important foundations
    for the field of biomedical informatics and data science, bringing the
    methods and concepts of computational, informational, quantitative,
    social, behavioral, and engineering sciences to bear on problems
    related to basic biomedical and behavioral research, healthcare, public
    health, and consumer use of health-related information.
                                     ______

       Prepared Statement of Anthony S. Fauci, M.D., Director, National
                  Institute of Allergy and Infectious Diseases
        Mr. Chairman and Members of the Committee: I am pleased to present
    the President's fiscal year 2019 budget request for the National
    Institute of Allergy and Infectious Diseases (NIAID) of the National
    Institutes of Health (NIH).
        NIAID has a dual mandate to maintain and grow a robust basic and
    clinical research portfolio in the areas of microbiology, infectious
    diseases, immunology, and allergy as well as to launch a swift research
    response when infectious diseases emerge and re-emerge. NIAID makes
    vital contributions to developing diagnostics, therapeutics, and
    vaccines by supporting medical countermeasures specific to single
    pathogens as well as platform technologies that can be deployed to
    target multiple pathogens. Also, NIAID research that has responded to
    ongoing public health threats has been a key component of U.S.
    biodefense preparedness.
                        research on infectious diseases
        Influenza, Including Universal Influenza Vaccine Development. NIAID
    supports basic, translational, and clinical research to address the
    constant threat of seasonal and pandemic influenza. Concerns over the
    efficacy of seasonal influenza vaccine, and the threat of pandemics
    such as posed by H7N9 influenza, highlight the need for a new
    generation of influenza vaccines. NIAID recently convened influenza
    research experts from around the world at a workshop that led to the
    development of a Strategic Plan for a Universal Influenza Vaccine.
    NIAID's Strategic Plan outlines research priorities in three areas
    important for understanding the formidable challenges posed by
    influenza and advancing the development of universal influenza
    vaccines. These research areas are: 1) transmission, natural history,
    and pathogenesis of influenza infection; 2) influenza immunity and
    factors correlated with immune protection; and 3) vaccine approaches to
    elicit broad, protective immune responses.
        NIAID is pursuing the research agenda outlined in the Strategic
    Plan, including research on cohorts of infants to determine how
    influenza vaccinations and natural influenza infections may affect
    immunity to influenza infection or immunization later in life. These
    cohort studies will provide vital information to facilitate the design
    of broadly protective influenza vaccines. NIAID also is supporting the
    development of several universal influenza vaccine candidates. One
    strategy pursued by NIAID Vaccine Research Center scientists uses a
    platform to display portions of an influenza surface protein--
    hemagglutinin--that do not easily mutate and are relatively constant
    among influenza strains. A separate NIAID-supported approach uses non-
    infectious virus-like particles that display four types of influenza
    hemagglutinin in one vaccine. Another NIAID-funded strategy employs
    several influenza fragments recognized by the immune system that are
    common to different influenza virus strains. Each of these vaccine
    strategies aims to produce broad and durable immune responses that
    would be effective against multiple influenza strains.
        Zika. NIAID research has led to the rapid development of
    diagnostics, candidate vaccines, and therapeutics to address the public
    health threat of Zika virus disease, especially Zika virus-related
    congenital abnormalities. NIAID scientists developed a DNA-based Zika
    vaccine that is now being tested in a large-scale clinical trial in
    Zika-endemic regions. NIAID is developing other candidate Zika
    vaccines, including a live, attenuated vaccine that targets both Zika
    virus and the related dengue virus. In addition, NIAID is partnering
    with other NIH Institutes and the Fiocruz Institute in Brazil to
    support the Zika in Infants and Pregnancy cohort study, which is
    assessing the risks of Zika infection in expectant mothers and tracking
    infant outcomes for at least 1 year.
        Other Vector-borne Diseases. NIAID supports research to address
    mosquito-borne diseases such as dengue, malaria, chikungunya, and
    yellow fever, and tick-borne diseases such as Lyme disease. NIAID
    scientists developed a candidate dengue vaccine, TV003, that targets
    all four sub-types of dengue virus. TV003 currently is being tested in
    a large-scale clinical trial in Brazil. An NIAID-supported malaria
    vaccine, PfSPZ, contains a weakened form of the mosquito-borne malaria
    parasite. Recent clinical trials showed PfSPZ protects people against
    multiple malaria strains and prevents infection in a malaria-endemic
    region. NIAID also is supporting a clinical trial of a vaccine designed
    to trigger an immune response to mosquito saliva. This vaccine aims to
    prevent multiple mosquito-borne diseases by blocking their transmission
    from infected mosquitoes.
        HIV/AIDS. NIAID research has led to powerful HIV treatment and
    prevention tools that improve the lives of individuals living with HIV
    and that have the potential to eventually end the HIV/AIDS pandemic.
    NIAID is supporting new HIV vaccine studies, including the Imbokodo
    trial in sub-Saharan Africa that is evaluating a vaccine candidate
    designed to protect against multiple global HIV strains. NIAID also is
    developing broadly neutralizing antibodies that can block most subtypes
    of HIV found worldwide. VRC01 is one such antibody that is currently
    being evaluated by passive infusion in two ongoing HIV prevention
    trials in individuals at high risk of HIV infection. Another broadly
    neutralizing antibody protected against infection in a monkey model of
    HIV. Further study in this model showed that a mixture of two broadly
    neutralizing antibodies could treat already infected animals. Enabled
    by the HOPE Act, NIAID also is building on its pioneering clinical
    trials of organ donation between HIV-infected individuals by launching
    a multi-site clinical trial of kidney transplantation in this
    population. NIAID continues to pursue additional methods to combat HIV,
    including microbicide-based approaches such as a vaginal ring infused
    with an anti-HIV drug, and long-acting injectable drugs to prevent and
    treat HIV.
        Tuberculosis. NIAID supports research to address tuberculosis (TB)
    including the challenges of TB/HIV co-infection and increasing drug
    resistance. NIAID also leads the research component of the National
    Action Plan for Combating Multidrug-Resistant TB. NIAID scientists and
    collaborators have developed a new diagnostic tool that detects
    resistance to key antibiotics used to treat TB and may facilitate a
    point-of-care diagnostic approach to guide TB therapy. In addition, an
    NIAID clinical trial of HIV-infected individuals demonstrated that a 1
    month course of preventive TB medication was as safe and effective as a
    nine-month regimen. Patients were more likely to complete the short
    regimen, suggesting it may be a preferred TB prevention strategy.
        Antimicrobial Resistance. NIAID plays a critical role in research
    components of the National Strategy for Combating Antibiotic-Resistant
    Bacteria (CARB). NIAID is collaborating with the Biomedical Advanced
    Research and Development Authority (BARDA) on the CARB
    Biopharmaceutical Accelerator, or CARB-X, a global public-private
    partnership to advance the preclinical and early clinical development
    of promising antibacterial drugs and other products. In addition, NIAID
    funds multiple clinical trials to evaluate novel antibiotics or
    optimize the use of current antibiotics. One recent study found that
    two common, inexpensive antibiotics can effectively treat methicillin-
    resistant Staphylococcus aureus skin abscesses. NIAID also supports
    clinical trials to develop zoliflodacin, a novel antibiotic for
    gonorrhea, an increasingly drug-resistant infection.
              research on immunology and immune-mediated disorders
        NIAID research has led to transformational advances in our
    understanding of the immune system and to new ways of treating and
    preventing immune-mediated diseases. For example, NIAID research on
    mechanisms of T-cell activation led to the development of ``checkpoint
    inhibitors,'' a new class of immunotherapy drugs for cancer.
        Food Allergy. NIAID research investments have led to important
    advances in the prevention and treatment of food allergies. NIAID
    convened an expert panel to build on the findings of pivotal food
    allergy studies by developing new clinical guidelines to help prevent
    peanut allergy in at-risk infants. NIAID-supported researchers also
    have found that combining oral immunotherapy with the asthma drug
    omalizumab may be an effective strategy to simultaneously desensitize
    children with multiple food allergies.
        Stem Cell Transplants for Treatment of Autoimmune Diseases. Two
    recent NIAID-supported clinical trials found that intensive
    immunosuppression followed by transplantation of a patient's own stem
    cells was an effective treatment for progressive and life-threatening
    autoimmune diseases. The Scleroderma: Cyclophosphamide or
    Transplantation (SCOT) trial showed that stem cell transplantation
    improves survival and quality of life for people with severe
    scleroderma when compared with routine immunosuppression. The HALT-MS
    trial demonstrated sustained remission in most people with relapsing-
    remitting multiple sclerosis for 5 years following transplantation.
                                   conclusion
        NIAID research continues to drive rapid progress in the development
    of vaccines, therapeutics, and diagnostics that improve human health
    and enhance our ability to respond rapidly to emerging and re-emerging
    infectious diseases. NIAID-supported science and innovation will
    continue to pave the way to solutions for many of the formidable health
    challenges facing the Nation and the world.
                                     ______

    Prepared Statement of Gary H. Gibbons, M.D., Director, National Heart,
                           Lung, and Blood Institute
        Mr. Chairman and Members of the Committee: I am pleased to present
    the President's fiscal year 2019 budget request for the National Heart,
    Lung, and Blood Institute (NHLBI) of the National Institutes of Health
    (NIH).
        This year, the NHLBI commemorates its 70th anniversary and a legacy
    of achievements across the broad spectrum of research--including basic
    science, epidemiology studies, implementation research, training, and
    landmark clinical trials--that have helped people all over the world
    live longer, healthier lives. Moving forward, the Institute remains
    committed to leveraging scientific opportunities and working in
    partnership with the public and private sector to prevent and treat
    heart, lung, blood, and sleep disorders.
             investing in basic research today for tomorrow's cures
        The NHLBI's continued investments in fundamental discovery science
    provide the foundation for tomorrow's medical breakthroughs. This
    includes the NHLBI's support for research on the circadian rhythm (the
    body's daily internal clock), how it is regulated, and its relationship
    to the risk of chronic disease. Well known to cardiologists, blood
    pressure rises and falls on a daily rhythm, reaching its peak in the
    early morning--which is also when the risk for heart attacks and other
    cardiovascular events is greatest. Moreover, disruption of circadian
    rhythms has been shown to contribute to obesity, diabetes, and other
    conditions that can increase the risk of heart, lung, blood, and sleep
    disorders. Recent discoveries from basic research--including work on
    fruit flies recognized with the 2017 Nobel Prize in Medicine--have
    revealed new insights on the genetic and molecular pathways underlying
    circadian rhythms that are opening new doors to prevention and
    treatment.
        To leverage these discoveries, the NHLBI has partnered with the
    National Institute of Diabetes and Digestive and Kidney Diseases on a
    program to better understand how circadian-dependent mechanisms
    contribute to obesity and to the risk of heart and lung disorders
    linked to obesity. Such research may help identify novel therapies that
    act on the circadian rhythm to prevent or manage these disorders.\2\ As
    researchers learn more about the basic pathways underlying circadian
    function, they may also gain new insights into treating sleep disorders
    such as sleep apnea.
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        \2\ https://grants.nih.gov/grants/guide/rfa-files/RFA-HL-17-
    020.html.
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                   the power of data to personalize medicine
        The goal of precision medicine is to give healthcare providers the
    tools to better predict health and preempt chronic disease, and to
    tailor treatment strategies to a patient's unique characteristics. To
    accomplish this, the NHLBI's Trans-Omics for Precision Medicine
    (TOPMed) program is integrating clinical, genomic, and other data from
    diverse cohort studies, including the NHLBI's long-standing Framingham
    Heart Study and Jackson Heart Study, which continue to help us
    understand who is vulnerable to chronic diseases and why. To date,
    TOPMed has generated whole-genome sequences from 120,000 individuals in
    these studies, which we expect will identify new genetic risk factors
    for disease and new molecular targets for therapy.
        Data from TOPMed will be included in a pilot of the new NIH Data
    Commons, a public-private partnership to bring research findings into a
    cloud-computing environment to enhance data sharing. This effort will
    give researchers access to data from hundreds of studies, creating new
    opportunities for collaborative research, innovation, and discovery.
                          reducing health disparities
        Despite declines in overall death rates from cardiovascular disease
    (CVD), many populations in the United States, whether defined by race,
    gender, geography, or other factors, continue to experience a high
    burden of CVD and other chronic diseases. Increasingly, it is clear
    that place matters. Where people live, work, and play affects their
    susceptibility to disease and their health outcomes.
        A 2017 study of more than 3,000 counties found a high burden of CVD
    throughout the U.S. heartland, from Kentucky to Oklahoma, with
    mortality rates in the highest-burden counties up to four times higher
    than in the lowest-burden counties.\3\ New CDC data also shows that
    rural Americans face a higher burden of chronic obstructive pulmonary
    disease (COPD) than urban Americans and are dying from it at higher
    rates.\4\ Many communities face economic, cultural, and geographic
    barriers to disease awareness, prevention, and treatment, reflected in
    a high burden of CVD risk factors such as high blood pressure, smoking,
    low physical activity, and high-calorie diets.
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        \3\ https://jamanetwork.com/journals/jama/fullarticle/2626571.
        \4\ttps://www.cdc.gov/mmwr/volumes/67/wr/mm6707a1.htm.
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        These data help inform efforts to reduce health disparities through
    implementation research. For example, a recent NHLBI-funded study shows
    the power of using non-traditional settings to adapt and implement
    healthcare interventions for high-risk communities. In the study, blood
    pressure screenings and pharmacist referrals at barbershops helped
    reduce high blood pressure among African American men in the Los
    Angeles area.\5\ In alignment with the comprehensive Federal COPD
    National Action Plan, other research seeks to improve COPD care in
    medically underserved areas. One recent study found that a set of
    simple affordable diagnostic tools can help primary care providers
    identify patients with COPD and follow up with appropriate
    treatment.\6\
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        \5\ https://www.ncbi.nlm.nih.gov/pubmed/29527973.
        \6\ https://www.ncbi.nlm.nih.gov/pubmed/27783539.
    ---------------------------------------------------------------------------
        The NHLBI is expanding its implementation research programs. The
    STIMULATE initiative seeks investigator-initiated proposals to overcome
    barriers to implementation of proven interventions, and DECIPHeR will
    create opportunities to integrate intervention trials into the NHLBI's
    long-running observational studies of minority populations.
             sickle cell disease: from better treatments to a cure
        While the NHLBI supports implementation research programs in sickle
    cell disease (SCD) that are helping develop and test approaches to
    improve patient outcomes, fundamental discoveries in stem cell biology
    and genomics are converging toward a cure. SCD is a genetic blood
    disorder that affects 100,000 Americans and millions worldwide. It is
    caused by a genetic mutation that causes the body's red blood cells to
    take on a sickled shape and obstruct blood flow, leading to severe
    frequent pain, organ damage, and other debilitating effects.
        More than 50 percent of adults with SCD have significant pain more
    than three days per week, and about 40 percent take opioid pain
    medications daily. The NHLBI supports research to investigate
    mechanisms of pain in SCD and the potential for non-opioid treatments.
    This research will assist in addressing the Nation's devastating opioid
    epidemic, by helping ensure that individuals with SCD and other types
    of chronic pain can acquire effective relief without over-reliance on
    opioids.
        In addition to managing pain and other complications of SCD, it is
    possible to cure SCD with a bone marrow transplant. However, this
    procedure requires that the patient have a healthy, immunologically
    matched marrow donor, which is not an option for most patients.
        Advances in gene-editing technologies, such as CRISPR, are offering
    new hope for a cure that works for all patients. By using the patient's
    own bone marrow stem cells, researchers can replace the faulty SCD gene
    or edit the misspelled gene and transplant the corrected cells back
    into the patient, without the risk of immune rejection. NHLBI
    intramural scientists are leading cutting-edge research and clinical
    trials in this area.
        Curing this disease within the decade is not something the NIH can
    do alone. The NHLBI Cure Sickle Cell initiative is bringing together
    patients, patient advocacy groups, healthcare providers, academic
    researchers, and industry to accelerate development of a widely
    available SCD cure.
                                   conclusion
        Medical breakthroughs and improvements in public health that once
    seemed impossible are now within reach due in large part to the NHLBI's
    seven decades of investing in excellent science. The Institute remains
    committed to funding investigator-initiated discovery science, training
    and building a talented diverse scientific workforce to help address an
    array of research needs, forming new strategic partnerships, and
    promoting the implementation of evidence-based care. Through these
    multi-pronged efforts, the NHLBI will continue to stimulate the
    scientific advances needed to further reduce suffering from heart,
    lung, blood, and sleep disorders.
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         Prepared Statement of Roger I. Glass, M.D., Director, Fogarty
                              International Center
        Mr. Chairman and Members of the Committee: I am pleased to present
    the President's fiscal year 2019 budget request for the Fogarty
    International Center (FIC) of the National Institutes of Health (NIH).
                                  introduction
        The idea that the U.S. could benefit from international
    collaborative research was central to the creation of the Fogarty
    International Center in 1968. Fogarty's namesake, Rhode Island
    Congressman John E. Fogarty, foresaw that U.S. citizens would reap the
    benefits of international discoveries and that global health was a
    smart investment for the U.S. and the world. Fifty years later,
    Congressman Fogarty's vision remains a guiding force as Fogarty
    continues to provide leadership in strengthening the research workforce
    here and abroad to ensure that the best and brightest minds are
    harnessed solve complex health challenges that affect us all.
        Well-trained scientists have never been more critical to protecting
    the health of Americans and populations around the world. Infectious
    diseases like Ebola and Zika have traveled across borders, and diseases
    formerly found only in other countries are now present in the U.S.
    Therefore, it is imperative that we train scientists in developing
    countries to detect pandemics at their point of origin, contain
    outbreaks, and minimize their impact. In addition, the ability to
    collaborate with scientists abroad can generate valuable knowledge
    about diseases such as Alzheimer's Disease and cancer.
        Fogarty supports research and research training programs for U.S.
    and low- and middle-income country (LMIC) scientists. These programs
    are built on long-standing partnerships between U.S. and LMIC academic
    institutions. Fogarty programs also extend the reach and
    competitiveness of U.S. universities, where there is high demand for
    international research opportunities. Currently, Fogarty supports over
    500 research and training programs involving 100 universities. Roughly
    80 percent of Fogarty grants are awarded to U.S. institutions and all
    Fogarty awards involve U.S. researchers.
                strengthen and sustain the biomedical workforce
    Global Health Security
        Emerging epidemics such as Ebola demand a critical mass of in-
    country scientists with relevant research expertise and skills. In
    2016, Fogarty initiated the Emerging Epidemic Virus Research Training
    for West African Countries with Widespread Transmission of Ebola
    program. These grants fund collaborations between U.S. and African
    research institutions in Guinea, Liberia, and/or Sierra Leone to plan
    capacity building programs for Fogarty's Global Infectious Disease
    Research Training Program, with a focus on emerging viral epidemics.
    This support enables scientists on the front lines in these countries,
    which were ground zero for Ebola, to design training programs that
    increase expertise in Ebola, Lassa fever, and other emerging viral
    diseases. For example, Yale University, in partnership with the
    University of Liberia, will develop a training program focusing on
    predictive transmission modeling and epidemiological research. Fogarty
    has also awarded a grant to Tulane University, the Vanderbilt Institute
    for Global Health, and the University of Sierra Leone. Together, these
    institutions will advance research focused on efficacy studies of novel
    and existing therapeutics for endemic viral hemorrhagic fevers like
    Lassa fever, while simultaneously building capacity on how to conduct
    higher-level clinical trial research during an epidemic like Ebola.
        An in-house team of Fogarty-supported scientists develop and use
    advanced computational models to study the emergence, evolution, and
    transmission of pathogens to help predict future pandemics, provide
    actionable information early in outbreaks, and protect the U.S.
    population from these threats. For example, these researchers and their
    collaborators recently modeled the global migration of Zika virus and
    their potential for causing large outbreaks in the U.S. They have also
    studied the transmission dynamics and evolution of influenza viruses in
    humans, domestic animals, and migratory birds to help predict future
    pandemics.
    Combatting Common Disease Threats
        Fogarty also supports training of scientists in LMICs, many of whom
    have become leaders in academic institutions and ministries of health
    in their home countries and serve as critical partners for U.S.
    scientists. Notably, many health challenges facing Americans are most
    effectively addressed through research conducted in a global context,
    where diseases are often highly prevalent or where the study of unique
    genetic predispositions can inform how we detect and prevent certain
    diseases that affect U.S. citizens.
        HIV/AIDS. Key scientific discoveries in HIV/AIDS treatment and
    prevention have been made by Fogarty-supported trainees and former
    trainees, including interventions to reduce mother-to-child
    transmission of HIV, using HIV treatment to prevent new HIV infections,
    and novel approaches to address HIV/TB coinfection. Fogarty-trained
    scientists in South Africa are now studying broadly neutralizing
    antibodies, which can kill multiple strains of the virus that causes
    AIDS. Produced by only about 20 percent of people with HIV, these
    antibodies show up too late to be able to stop disease progression in
    the people who make them. However, scientists are exploring their
    potential to prevent HIV in others--either through a vaccine that would
    coax the body to generate similar types of antibodies or via passive
    immunization in which an antibody product would be given directly.
        Alzheimer's Disease. Columbia is home to the largest known family
    with an inherited, early-onset form of Alzheimer's. Testing new
    therapies on healthy individuals who are at a high risk for the
    disease, like those in this family, is providing valuable clues for
    understanding how to prevent it. Members of this family are now
    participating in a trial to determine if a drug provided by a U.S.-
    based company can stave off the decline in memory and brain function
    associated with the disease. Fogarty-supported research training helped
    to build a strong neuroscience research community in Colombia, which
    set the stage for this potentially game-changing research.
                                    research
        Brain Disorders. Fogarty's Global Brain and Nervous Systems
    Disorders Research across the Lifespan Program supports cutting-edge
    research in LMICs on nervous system development, function, and
    impairment throughout life. The program allows U.S. investigators to
    gain experience working in LMICs, expanding the research workforce in
    these settings by developing long-lasting international partnerships.
    This research network spans over 45 countries and has contributed to
    the creation of new interventions, new tools for clinical assessment,
    and new laboratory methods.
        Hydrocephalus--excessive accumulation of fluid in the brain--is one
    of the most common birth defects in the U.S. The traditional treatment
    for hydrocephalus is the surgical placement of a shunt, which often
    involves complications like mechanical failure, obstruction, and
    infection. Global Brain-supported researchers working in Uganda
    developed a new treatment for infant hydrocephalus. They combined
    endoscopic third ventriculostomy and choroid plexus cauterization (ETV/
    CPC) into one treatment, where a small hole drains fluid from the brain
    and heat is applied to brain tissue to reduce fluid production. Both
    procedures have been practiced separately, but scarce resources in
    Uganda inspired researchers to combine the two practices. This
    combination treatment has helped to avoid shunt dependence in most
    Ugandan infants treated for this condition. Notably, ETV/CPC is now
    being practiced in the U.S.
        Influenza. The Multinational Influenza Seasonal Mortality Study
    (MISMS) is an international effort led by FIC to model the epidemiology
    and evolutionary dynamics of influenza in human, swine and avian
    populations. With funding from DHHS since 2007, MISMS has developed a
    network of over three-hundred influenza experts in forty-five countries
    and studied a broad range of topics, including: the global circulation
    of influenza virus; cross-species transmission; pandemic preparedness;
    control strategies; transmission dynamics; historical pandemics;
    disease burden; and seasonality.
        Mobile Health. Mobile technologies present exceptional
    opportunities and new tools for improving health outcomes. A mobile
    health tool conceived by a Fogarty grantee for HIV patient care in
    Uganda is now being used to help patients use their phones to adhere to
    strict medication regimen at a lower cost for conditions like opioid
    addiction, tuberculosis, and hepatitis C. Fogarty-supported researchers
    from the U.S. and Zambia are developing a simple diagnostic test for
    malaria that uses a few drops of blood and tiny magnetic beads to
    accurately detect the parasite that causes the disease. This new,
    inexpensive test improves malaria detection and reduces drug resistance
    by treating only those who have the disease.
                                   conclusion
        Fogarty investments are enabling researchers to take science to
    where the problems are most acute, conduct research, and develop
    solutions in the places where diseases are especially challenging. This
    is the unique niche that Fogarty will continue to fill in fiscal year
    2018 and beyond.
                                     ______

    Prepared Statement of Joshua A. Gordon, M.D., Ph.D., Director, National
                           Institute of Mental Health
        Mr. Chairman and Members of the Committee: I am pleased to present
    the President's fiscal year 2019 budget request for the National
    Institute of Mental Health (NIMH) of the National Institutes of Health
    (NIH). I am excited to discuss NIMH's efforts to accelerate scientific
    progress that will improve our understanding of mental illnesses,
    fueling transformative care for the greatest public health impact.
                 funding impactful science to alleviate burden
        To help millions of Americans suffering from a mental illness, NIMH
    continues to ardently pursue its mission to transform the understanding
    and treatment of mental illnesses. In 2016, approximately 44.7 million
    U.S. adults suffered from a mental illness; of these, an estimated 10.4
    million U.S. adults experienced serious mental illnesses (SMI). To
    balance the challenge of alleviating the burden of mental illnesses
    now, while supporting research that will inform future treatments and
    interventions, NIMH prioritizes excellent and impactful science and
    strives for a diverse research portfolio of short-, medium-, and long-
    term investments. For example, in the short term, efforts in suicide
    prevention research, such as screening and predicting risk in emergency
    departments, could result in significant decreases in suicide events.
    In the medium term, research on techniques to manipulate neural
    circuits could be applied to the treatment of mental illnesses in
    humans. In the long term, computational and theoretical approaches to
    psychiatry are needed to refine treatments.
                     early identification and intervention
        Each year, thousands of adolescents and young adults in the United
    States experience first episode psychosis. To explore methods for
    establishing early intervention programs to help people with psychosis,
    NIMH launched the Recovery After an Initial Schizophrenia Episode
    (RAISE) project, which clearly demonstrated that when coordinated
    specialty care was provided early in the disease, outcomes for
    individuals were superior to usual care, including symptom reduction,
    improvement in school and work functioning, and increased quality of
    life. Based on these findings, the Centers for Medicaid & Medicare
    Services extended Medicaid coverage for coordinated specialty care, and
    the Substance Abuse and Mental Health Services Administration (SAMHSA)
    set aside 10 percent of its Mental Health Block Grant allocation for
    each State to support evidence-based programs that target first episode
    psychosis. Today, over 200 CSC programs operate in 49 States.
        Suicide is a potential consequence of mental illnesses and one of
    the leading causes of mortality in the United States. Suicide rates
    have increased since 1999, and nearly 45,000 Americans died from
    suicide in 2016. Recent studies show that most individuals who die by
    suicide have had recent contact with a healthcare provider, and that
    early identification of those at risk for suicide is key to prevention.
    To address this major public health concern, NIMH partners with the
    National Action Alliance for Suicide Prevention and supports its Zero
    Suicide initiative to support healthcare systems reduce suicide events.
    Another example of NIMH-funded work in this area is the ED-SAFE
    project, which demonstrated that universal screening for suicide risk
    among adults in emergency departments (EDs) doubled the rate of
    detection, and ED-initiated interventions for high-risk adults
    decreased suicide attempts by as much as 30 percent.
        In addition, researchers in the NIMH Division of Intramural
    Research Programs developed a brief pediatric suicide risk screening
    instrument; the four-item Ask Suicide Screening Questions (ASQ) is now
    used in medical facilities around the world. Additional examples of
    NIMH-funded research include the Emergency Department Screen for Teens
    at Risk for Suicide (ED-STARS) study, which uses innovative approaches
    to suicide screening and assessment for youth in EDs. NIMH also
    supports collaborative research hubs, which aim to reduce the high
    suicide rates among American Indian and Alaska Native youth.
        Similarly, NIMH recognizes the importance of early identification
    and intervention strategies for individuals with autism spectrum
    disorder (ASD). NIH-funded research has identified ASD risk markers
    within the first 12 months of age; early signs of behavioral
    differences correspond with genetic and environmental risk for ASD that
    appear to act before birth and alter the very early stages of brain
    development. However, a critical gap exists in translating these
    methods into practical screening tools that could be widely used to
    identify ASD early in life. NIMH plans to launch an initiative aimed at
    developing and validating new screening methods for ASD for use in
    infants (0-12 months of age) which could lead to novel transformative
    treatments that improve outcomes.
         developing effective and transformative treatments of tomorrow
        NIMH supports efforts to systematically and rapidly employ `lessons
    learned' from research findings and clinical practice to improve
    patient care. To help narrow the gap between research and practice, the
    Mental Health Research Network (MHRN), a learning healthcare system
    that includes large-scale practical trials and services research, uses
    electronic health records large and diverse healthcare systems to
    improve delivery of effective treatments. The NIMH Early Psychosis
    Intervention Network (EPINET) is another learning healthcare system,
    which will focus on early psychosis treatment clinics by linking
    clinical sites. Like other learning healthcare models, the aim of
    EPINET is to share and compare data that will narrow the time gap for
    feedback and can help guide practice and ultimately improve mental
    healthcare. In addition, NIMH-funded research on mobile health
    (mHealth) technologies includes smartphone and texting approaches to
    help treat and monitor patients with mental illnesses. These methods
    are examples of how NIMH-funded research create opportunities for
    continuous evaluation and improvement of care.
        It is ever important that we continue to support research focused
    on developing tools that can be used to study and treat mental
    illnesses. For example, NIMH co-leads the cutting-edge NIH Brain
    Research through Advancing Innovative Neurotechnologies (BRAIN)
    Initiative. Maps of whole brains in action, the ability to identify
    thousands of brain cells at a time, and innovative brain scanners are
    just a few of the advances funded by this groundbreaking effort. In the
    past 3 years, research under the Initiative has advanced so rapidly
    that now many of the previously funded individual projects will receive
    expanded support to achieve the ambitious goals of the BRAIN
    Initiative.
        Specifically, NIH recently announced funding for 110 new awards for
    the BRAIN Initiative. The new round of awards includes the BRAIN
    Initiative Cell Census Network (BICCN), aimed at providing researchers
    with comprehensive references of diverse brain cell types to generate
    the knowledge necessary for understanding brain disorders, including
    mental illnesses. Additionally, new BRAIN Initiative research awards
    aim to address neuroethical issues associated with human brain
    research. Through the innovative studies supported by the BRAIN
    Initiative, researchers will be able to produce a revolutionary,
    dynamic picture of the brain that will lend to new ways to treat, cure,
    and even prevent mental illness.
        Finally, NIMH has supported successful efforts to map the genes
    that predispose individuals to schizophrenia and other SMIs. Thanks to
    these efforts, we now know of hundreds of locations in the genome
    associated with risk for SMI. Each of these locations represents an
    important clue into the neurobiology of SMIs and holds promise as a
    potential therapeutic target. Current efforts, including the
    PsychENCODE consortium, which studies the relationship between genetic
    risk and protein expression in the brain, and an initiative that uses
    convergent neuroscience approaches to elucidate how these risk factors
    alter the function of neurons and circuits in the brain, are aimed at
    translating these genetic discoveries into new knowledge and novel
    treatments.
        NIMH will continue to vigorously support research using novel
    approaches to enhance biological understanding, translation of
    evidence, services and intervention delivery, and therapeutics
    development, all aimed at reducing the tremendous burden shouldered by
    individuals and families living with mental illnesses.
                                     ______

      Prepared Statement of Patricia A. Grady, Ph.D., RN, FAAN Director,
                     National Institute of Nursing Research
        Mr. Chairman and Members of the Committee: I am pleased to present
    the President's fiscal year 2019 Budget request for the National
    Institute of Nursing Research (NINR) of the National Institutes of
    Health (NIH).
                                  introduction
        The mission of NINR is to promote and improve the health of
    individuals, families, and communities. In pursuit of this mission,
    NINR has set forth a bold, innovative scientific agenda in our
    strategic plan, ``Advancing Science, Improving Lives.'' The plan, which
    incorporates long-standing focus areas of nursing science and 21st
    century solutions for improving the Nation's health, encompasses four
    focus areas, including symptom science, wellness, self-management, and
    end-of-life and palliative care; along with continued development of a
    21st-century nurse scientist workforce, and finding ways in which
    technology and innovation can contribute across all these areas. I
    appreciate this opportunity to share some examples of NINR's research.
           symptom science: promoting personalized health strategies
        Through its focus on symptom science, NINR supports research to
    develop new knowledge in biology and behavior to improve our
    understanding of symptoms such as fatigue, pain, and sleep disturbance.
    For example, NINR-supported investigators found a potential connection
    between the use of opioids to treat pain and the rate of healing for
    chronic wounds. They found that patients who had never received opioids
    healed more rapidly, and that patients receiving higher opioid doses,
    because they had a larger wound size or painful co-occurring
    conditions, had slower wound healing in comparison with those receiving
    lower doses or no opioids. Their findings raise important
    considerations on potential connections between symptoms, biological
    factors, and clinical management of pain and chronic wounds.
               wellness: promoting health and preventing illness
        In promoting wellness, NINR strives to build the science to
    understand and prevent chronic conditions, reduce burden for patients
    and caregivers, and eliminate health disparities. A recent NINR-
    supported study found that family caregivers of persons with
    Alzheimer's and related dementias (ADRD) reported an average of seven
    new or worsening symptoms and signs in the care recipient, such as
    confusion, decreased activity, and agitation, over a six-month period.
    Understanding the range of symptoms that caregivers must respond to
    when caring for loved ones with ADRD can guide the development of
    future educational materials and interventions. Other NINR-supported
    researchers are testing: a family-focused intervention to reduce the
    risk of type 2 diabetes and cardiovascular disease in Hispanics; the
    effectiveness of an intervention to reduce the rate of obesity in rural
    Alaska Native children; and an intervention to increase physical
    activity and reduce falls in older adults.
           end-of-life and palliative care: the science of compassion
        As the lead Institute for end-of-life research at NIH, NINR
    supports research to inform high quality care for individuals and their
    caregivers, improve management of pain and other advanced symptoms, and
    facilitate decisionmaking at all stages of illness, including at the
    end of life. With our support of the Palliative Care Research
    Cooperative (PCRC) group, we continue to build the science of end-of-
    life and palliative care by expanding this extensive network of over
    400 multidisciplinary palliative care scientists to include over 160
    clinical trial research sites across the U.S. NINR recently expanded
    its Palliative Care: Conversations Matter initiative, which aims to
    raise awareness of pediatric palliative care, by developing a new Web
    feature profiling different members of the pediatric palliative care
    team, including a chaplain, a child life specialist, a nurse, a nurse-
    scientist, a pediatrician-researcher, and a social worker. This
    resource gives families insight into the array of providers and
    services available to support them and gives providers a glimpse into
    how teams work together.
              supporting a 21st century nursing science workforce
        NINR has long-recognized the importance of supporting scientists at
    all career levels, particularly those at an early career stage. NINR
    supports a variety of training opportunities for scientists and
    trainees. In addition to funding extramural trainees, NINR sponsors a
    Symptom Methodologies Research Boot Camp, focused on precision health
    methodologies and the latest advances in various `omics' such as
    genomics and microbiomics. NINR's Summer Genetics Institute provides a
    foundation in molecular genetics to improve research and clinical
    practice for graduate students, faculty, and clinicians. NINR also
    provides on-line video training resources on its website to support an
    innovative workforce, from students to early- and mid-career
    scientists.
                                   conclusion
        Thank you for this opportunity to share some of NINR's recent
    accomplishments. We look forward to continuing to support nursing
    research to advance science, improve lives, and envision new pathways
    to improve health.
                                     ______

     Prepared Statement of Eric D. Green, M.D., Ph.D., Director, National
                        Human Genome Research Institute
        Mr. Chairman and Members of the Committee: I am pleased to present
    the President's fiscal year 2019 budget request for the National Human
    Genome Research Institute (NHGRI) of the National Institutes of Health
    (NIH).
                           the forefront of genomics
        NHGRI is, and always has been, at the forefront of genomics
    research. NHGRI led the U.S. contribution to the Human Genome Project,
    which was completed in 2003, and has since embarked on evermore
    ambitious endeavors, including the dissemination of genomic
    technologies, knowledge, and expertise throughout the NIH, into the
    private sector, and around the world. NHGRI accomplished this by
    driving cutting-edge research, developing new methods and approaches,
    and studying the impact of genomics on society with the goal of
    improving the health of all humans through genomic advances. The
    current pace of genomics is breathtaking, and we are approaching a
    transitional time in which there will be rapid uptake of genomics in
    medicine for prevention, diagnosis, and treatment of disease.
        To prepare to lead the next phase of genomics, NHGRI officially
    launched a new strategic planning process in early 2018. This 2-year
    effort will generate a `2020 Vision for Genomics' and position the
    Institute to lead genomics research and its applications to human
    health into the next decade.
        Our strong tradition of audacious thinking and effective strategic
    planning has led to advances that today are enabling some of the most
    high-profile initiatives in biomedical research. Examples include the
    NIH All of Us Research Program, which seeks to build the largest, most
    diverse dataset of its kind for health researchers, and the Cancer
    Moonshot initiative, which aims to accelerate cancer research and to
    improve our ability to detect, prevent, and treat cancer. The NHGRI-
    funded Electronic Medical Records and Genomics (eMERGE) Network, now in
    its third phase, has served as an invaluable pilot for precision
    medicine research studies, like All of Us, by developing the tools and
    approaches for using genomic information coupled with data in
    electronic medical records to study human health and disease, including
    prevention. The Cancer Genome Atlas (TCGA), equally funded by NHGRI and
    the National Cancer Institute (NCI), generated comprehensive maps of
    key genomic changes in 33 types of cancer and made all the generated
    data publicly available to the research community; this program
    provided a foundation upon which the molecular bases of cancer continue
    to be defined, revealing new approaches for cancer treatments. In
    addition, efforts like TCGA and the Cancer Moonshot heavily rely on the
    dropping costs of genome sequencing, which has been greatly facilitated
    by NHGRI's technology development research programs.
        As noted earlier, the uptake of genomic medicine approaches will
    increase rapidly in the coming years, and NHGRI is committed to laying
    the groundwork for these changes. An example effort that will be
    underway in fiscal year 2019, if funding allows, is the Clinical
    Sequencing Evidence-Generating Research Program (CSER), which aims to
    generate and analyze evidence for the use of genome sequencing in
    clinical care and to address barriers to genomic medicine
    implementation. This program has a targeted focus on recruiting
    ancestrally diverse and underserved populations, recognizing that the
    full benefit of genomic medicine will not be realized unless all of the
    diverse populations in the United States benefit equitably from genomic
    advances.
        Compared to even a decade ago, genomics is now associated with a
    much greater breadth and depth of research activities. Furthermore,
    influenced by NHGRI's leadership, virtually every NIH Institute and
    Center now funds genomics research to some extent, and a significant
    amount of genomics research is funded beyond NIH. Recognizing that
    going forward, a majority of genomics research will be funded by others
    in the U.S. and internationally, NHGRI aims to identify, lead, and
    support areas of genomics that are paradigm-setting, that enable novel
    applications, and that expand the field--all with a focus on
    applications to human health and disease. In doing so, NHGRI will
    directly stimulate and achieve highly impactful and generalizable
    progress in genomics that will benefit the efforts of others for years
    to come.
                                    research
        Our foundational work in technology development, coupled with new
    approaches for elucidating genome function, is fueling discoveries of
    how genomic variation relates to human health and disease; in turn,
    this knowledge is increasingly being applied to patient care through
    pilot projects that study the implementation of genomic medicine.
        In fiscal year 2019, if funding allows, NHGRI's longstanding Genome
    Sequencing Program will continue its fundamental work to identify
    genomic variants associated with disease and to provide resources for
    the research and clinical communities to discover the genomic
    underpinnings of disease. The Centers for Common Disease Genomics
    (CCDGs) are conducting an in-depth genomics study of roughly 10 common
    diseases, including cardiovascular disease and developmental disorders,
    to identify genomic variants that either increase or decrease risk
    associated with those diseases. Using the generated data, the sites
    intend to develop improved and novel analysis methods and study designs
    across the entire program. So far, the CCDG sites have generated over
    50,000 whole-genome sequences and over 38,000 whole-exome sequences
    (the protein-coding portions of the genome); the size of such studies
    is needed to generate the statistical power that will allow reliable
    conclusions about these diseases to be derived.
        Many of NHGRI's principal accomplishments have centered on
    unraveling the complexities of the genome and giving researchers open
    access to valuable data. For example, the Encyclopedia of DNA Elements
    (ENCODE) Project is creating a catalog of all the parts of the human
    genome that are functional (i.e., that play an active biological role).
    All of the generated ENCODE data are made freely available, providing
    every scientist rapid access to this unique and valuable information
    for their research. In fact, ENCODE's value in biomedicine can be
    readily appreciated by the widespread use of these data: there are more
    than 2,000 scientific publications from research groups that have used
    ENCODE data for their published work.
        Another treasure trove of data for the biomedical research
    community was generated by the NHGRI-led Common Fund project GTEx
    (genotype-tissue expression), which began in 2008 and aimed to
    establish a database and accompanying tissue bank to allow scientists
    to study the relationship between genomic variation and gene
    expression. In October 2017, Nature published a collection of papers
    highlighting discoveries from the program. The analyses include data
    for thousands of tissue samples and demonstrated how gene regulation
    differs across individuals and tissue types.
        NHGRI has also been building its portfolio in genomic medicine,
    piloting projects that seek to explore how to integrate genome
    sequencing within clinical care and begin to build an evidence base
    demonstrating its effectiveness. One example is the Newborn Sequencing
    in Genomic Medicine and Public Health (NSIGHT) program, which began in
    2013 to study the opportunities and challenges in the use of genome
    sequencing for the care of newborns. NSIGHT has shown ways in which
    newborn sequencing can be critical for saving lives by increasing the
    speed of diagnosis. For example, one of our NSIGHT grantees, whose work
    was recently featured in Time magazine, is using genome sequencing to
    provide diagnoses and suggest treatment changes for critically ill
    infants in the neonatal intensive care unit in a timeframe that can
    make life-altering differences.\7\ Notably, this group recently set a
    Guinness World Record for the fastest genomic diagnosis--19.5 hours.
    ---------------------------------------------------------------------------
        \7\ Park, A. (2017) Genetic Testing is Providing New Hope for
    Babies Born with Mysterious Ailments. Time. http://time.com/4951200/
    genetic-testing-providing-hope-babies-ailments/.
    ---------------------------------------------------------------------------
                                   conclusion
        As is clear from our research portfolio, NHGRI does more than fund
    the discovery of knowledge and create new technology--we have catalyzed
    cultural changes across biomedical research. We have demonstrated an
    unrelenting commitment to data sharing, our `team science' approach has
    fostered a spirit of collaboration among scientists, and we have
    provided researchers with access to shared tools and data to transform
    genomic advances into health discoveries. As NHGRI delves into
    strategic planning in fiscal year 2019 and beyond, we will collaborate
    with experts in the field to identify the cutting-edge areas across our
    diverse research domains that the Institute should champion and support
    in the coming decade. We will also continue to tackle the
    underrepresentation of minorities in genomics research to be sure that
    the knowledge gained through the Federal investment in genomics
    benefits all.
        NHGRI believes that advances in genomics research are transforming
    our understanding of human health and disease, and we are excited to
    continue accelerating breakthroughs, improving patient care, and
    advancing genomics in society.
                                     ______

    Prepared Statement of Jill Heemskerk, Ph.D., Acting Director, National
               Insitute of Biomedical Imaging and Bioengineering
        Mr. Chairman and Members of the Committee: I am pleased to present
    the President's fiscal year 2019 budget request for the National
    Institute of Biomedical Imaging and Bioengineering (NIBIB) of the
    National Institutes of Health (NIH).
        The mission of NIBIB is to improve human health by leading the
    development of biomedical technologies and accelerating their
    application. NIBIB supports research that integrates engineering with
    the physical and life sciences to develop emerging technologies that
    can be applied to a broad range of biomedical and healthcare problems.
    Building partnerships with industry, academia, and other Federal
    agencies is a high priority for the institute. A few examples from the
    many exciting NIBIB-funded research efforts that are leading to better,
    faster, and less costly ways to advance public health are shared in
    this testimony.
                        on the spot food allergy testing
        Eating out can be a challenge for people with allergies. Diners
    must rely on knowing what ingredients contain the allergens they must
    avoid, and on restaurants to serve dishes that exclude them.
    Recognizing this widespread public health problem, researchers have
    developed a system called integrated exogenous antigen testing (iEAT).
    The purpose of the iEAT system is to give those who suffer from food
    allergies a rapid, accurate device that allows them to personally test
    foods in less than 10 minutes. The device is small enough to fit on a
    keychain and can test for common allergens such as gluten, milk, or
    nuts. The device contains a disposable testing chamber, so once a test
    is completed the chamber can be replaced and the device used again.
    After developing and testing a prototype of the device, the research
    team granted a license to a local start-up company to make iEAT
    commercially available. In the future the device could be adapted to
    test for other allergens or substances.
                     cuff-less blood pressuring monitoring
        A person's blood pressure is one of several key indicators of
    health, but the inflatable cuff device used to measure blood pressure
    is largely the same as it was 100 years ago. Measuring blood pressure
    while in a doctor's office gives physicians a limited view since blood
    pressure can vary throughout the day. Researchers are developing a new
    ``cuff-less'' method to accurately measure blood pressure more
    frequently and without the need for special equipment. One group is
    making progress using a modified smart phone case with built-in sensors
    and an app to capture blood pressure by pressing a finger on the
    phone's home button. The ability to monitor blood pressure on an
    ongoing basis could help alert people to potential problems and more
    consistently monitor their blood pressure if they are at risk or are
    taking medications. This could help reduce the risk of cardiovascular
    disease through improved management of blood pressure.
                            clearing out blood clots
        Blood clots that form in the deep veins of the legs are called deep
    vein thrombosis and can be quite painful, and even fatal if a clot
    dislodges from the wall of the vein and travels to the heart or lungs.
    Currently, intravascular treatments use devices inserted into the vein
    to trap clots, but they have limitations including damage to the blood
    vessel wall. In some patients, clot-thinning medication is required,
    which can have a range of side effects. A new approach to overcome
    these limitations uses a surgical tool that is inserted into a vein and
    directs ultrasound waves directly at clots to break them up into tiny
    pieces. It is targeted and therefore minimizes damage to blood vessels;
    and because the broken pieces are tiny, patients do not need to use
    blood thinning medication following the procedure. In addition to using
    ultrasound, researchers are adding injectable microbubbles that vibrate
    when exposed to the ultrasound waves. This helps to further break up
    the clot. This tool is portable and is estimated to cut the declotting
    procedure time by more than half, from 10 hours to four hours. So far,
    the tool has only been tested in synthetic blood vessels, and more
    study is needed to bring this treatment to patients.
                    nanovaccines weaponized to battle tumors
        A new vaccine designed to stimulate a multi-pronged immune response
    can stimulate the immune system to specifically attack a tumor, while
    simultaneously inhibiting the suppression of the immune system, which
    often occurs in people with cancer. The researchers also developed a
    way to shrink the vaccine molecule so that it can more easily reach the
    parts of the immune system to activate it. Using colon cancer that had
    spread to the lungs as a test case for this approach, the nanovaccine
    successfully blocked lung tumor growth in a mouse model. Further
    testing revealed that mice receiving the nanovaccine had a significant
    increase in a type of immune cell that can target cancerous cells.
    Another potential benefit of this approach is that it mounts an anti-
    tumor immune response that circulates through the system, and therefore
    is particularly valuable for finding and inhibiting metastatic tumors
    growing throughout the body.
                solving a common heart disease with engineering
        Ischemic cardiovascular disease is a result of impaired blood
    circulation to tissues and organs and is the leading cause of death and
    disability in the U.S. Damage to small blood vessels is difficult to
    treat and can result in heart failure, stroke, or other arterial
    diseases. To address this problem, researchers developed a way to grow
    new blood vessels using 3D printed patches. The specially designed
    patches are seeded with cells and implanted into damaged areas. Once
    implanted, the patches induced the growth of new blood vessels. This
    early stage, basic research is an example of interdisciplinary teams
    including engineers, biologists, and clinicians combining their
    expertise and collaborating to solve health problems.
                        advances from nibib laboratories
        While the majority of NIBIB's budget supports research projects
    throughout the U.S., NIBIB also supports a small, but robust program
    within its Intramural Research Program (IRP). These investigators are
    working to create optical imaging technologies that provide
    unprecedented high resolution and speed to study living cells in real
    time. Others create ``theranostic'' imaging probes--based on
    nanomaterials--that combine therapeutic and diagnostic capabilities to
    improve early diagnosis, monitor therapeutic responses, and guide drug
    discovery and development.
        In one example, researchers developed a new radiotracer to help
    diagnose prostate cancer. Prostate cancer is the fifth leading cause of
    death worldwide and is especially difficult to diagnose, particularly
    early on. While prostate cancer is relatively easy to treat in its
    initial stages, it is prone to metastasis and can quickly become
    deadly. The research team developed a radiotracer that could identify
    prostate cancer at all stages. This new tracer is one of the first
    dual-receptor target tracers, which target more than one biomarker, to
    be studied in humans. This new method improves on the current practice
    that can lead to many false positive results and cause the patient to
    undergo unnecessary treatments or painful biopsies. A successful Phase
    I clinical trial with a small group of patients to establish safety and
    identify any possible side effects was recently completed.
                                   conclusion
        Advances in technology are catalyzing the development of solutions
    to previously intractable disorders and improved approaches to
    biomedical research. As these examples illustrate, this type of
    research requires many disciplines to work together. This integration
    of disciplines is what defines NIBIB's approach. NIBIB is committed to
    supporting such teams of researchers to solve major biomedical
    challenges that will improve the health of all Americans.
                                     ______

       Prepared Statement of Richard J. Hodes, M.D., Director, National
                               Institute on Aging
        Mr. Chairman and Members of the Committee: I am pleased to present
    the President's fiscal year 2019 budget request for the National
    Institute on Aging (NIA) of the National Institutes of Health (NIH).
                         aging: a universal risk factor
        Each one of us is susceptible to the effects of aging, which
    remains the most powerful driver of chronic diseases and disabilities
    that affect older adults. As the number of Americans ages 65 and older
    soars in the coming decades--from an estimated 46.2 million in 2014 to
    82.3 million in just 26 years, according to projections from the U.S.
    Census Bureau--it is increasingly urgent that we pursue a comprehensive
    national effort to understand aging, to develop interventions that will
    help older adults enjoy robust health and independence, and to support
    American elders' active engagement with their families and communities.
        At the NIH, the NIA leads this effort. We support genetic,
    biological, clinical, behavioral, and social research related to the
    aging process, healthy aging, and diseases and conditions that increase
    with age. We also support training of the next generation of
    researchers in geriatrics and related fields. In addition, we are the
    lead Federal agency supporting research on Alzheimer's disease and
    related forms of dementia (AD/ADRD).
             research on alzheimer's disease and related dementias
        In a recent analysis based on 2010 data, 5.5 million Americans were
    projected to have Alzheimer's disease by 2018. It's true that several
    studies, including the long-running Framingham Heart Study, have
    identified declines in the incidence and prevalence of dementia since
    the 1970s, possibly associated with increased educational attainment
    among study populations. However, if current population trends
    continue, these numbers will increase significantly as the number of
    older Americans rises--unless we learn how to prevent or effectively
    treat the disease.
        Since passage of the National Alzheimer's Project Act in 2011, an
    extraordinary influx of funding directed at AD/ADRD has made it
    possible for NIH, led by NIA, to begin building a series of bold and
    innovative research programs, infrastructure, and new partnerships
    aimed at laying the foundation for precision medicine for AD/ADRD. NIA
    and other NIH Institutes are harnessing the tremendous power of big
    data to gain insight into the basic biology of AD/ADRD, as well as
    factors that may confer resilience to these diseases; accelerating the
    discovery of the next generation of new targets and biomarkers through
    the open science research model of the Accelerating Medicines
    Partnership for AD (AMP-AD); and establishing new translational
    infrastructure programs to enable rapid sharing of data and research
    models and enhancing research rigor and reproducibility.
        NIA currently supports over 140 active clinical trials of
    interventions to enhance cognitive health in older individuals and to
    prevent, treat, or manage symptoms of AD/ADRD. These studies range from
    studies of emerging therapeutics developed in academic centers and the
    small business community, to studies of the cognitive effects of drugs
    commonly used for other conditions, to clinical trials involving
    lifestyle interventions such as exercise, dietary change, and cognitive
    training. Investigators with AMP-AD have identified over 100 potential
    new drug targets for AD/ADRD, and over 30 projects for development of
    novel therapeutics against a variety of targets are under way in NIA's
    Alzheimer's Disease Translational Research Program. NIH has also
    established the Alzheimer's Clinical Trial Consortium (ACTC),
    consisting of 35 sites across the United States, to support trials
    across the full spectrum of AD/ADRD. The ACTC will also spur innovation
    in trial design and recruitment, with a specific focus on inclusion of
    communities underrepresented in AD research.
        We have made important progress. For example, an NIA-supported
    international research team used cryo-electron microscopy to visualize
    the structure of individual tau fibrils (a pathological hallmark of
    several forms of dementia) for the first time. The high-resolution,
    exquisitely detailed images helped explain why tau-based therapies have
    been difficult to develop--its components are so tightly bound together
    as to be impermeable--but also suggested possible new avenues for
    therapy. Other investigators analyzed Medicare data and noted an
    association between use of cholesterol-lowering statin drugs and
    reduced risk of AD. Intriguingly, the reduction in risk varied across
    sex, race, and particular statin used, suggesting that the right statin
    type for the right person at the right time may provide a relatively
    inexpensive means to lessen the burden of AD.
        Our continuing efforts have been informed by input from researchers
    and advocates worldwide through key scientific conferences, including
    periodic Summits on Alzheimer's Disease (most recent: March 2018) and
    Alzheimer's Disease-Related Dementias (most recent: 2016, with the next
    Summit planned for 2019). A Summit in October 2017 also brought
    together experts to discuss dementia care and the unique needs of
    caregivers of persons with AD/ADRD.
                            advancing aging research
        Recognizing aging as the most powerful risk factor for diverse
    diseases and frailties, NIA supports research into the underlying
    biological mechanisms of aging. For example, the trans-NIH Geroscience
    Interest Group, established by the NIA and joined by most NIH
    Institutes, promotes research on the links between aging biology and
    etiology of chronic diseases. NIA also supports research on diet and
    healthy aging, as well as two multi-investigator interventions testing
    programs to identify and validate compounds that extend life and
    improve health in laboratory animals. Ongoing collaborations with the
    National Institute of Allergy and Infectious Diseases and the National
    Cancer Institute continue to expand our understanding of the aging
    immune system and the role of aging in the etiology of cancer.
        NIA's longtime flagship studies in aging remain vibrant with
    opportunities to apply new technologies and thinking to their treasure
    troves of data. The Baltimore Longitudinal Study on Aging, 60 years old
    in 2018, continues to break new ground in identifying the longitudinal
    physical and cognitive changes that define aging; elucidating the
    factors that affect the rate of age-related change; and understanding
    the relationship between advancing age and chronic disease. BLSA
    investigators are particularly interested in ``exceptional agers''--
    those rare individuals who live well into their eighties with few
    health problems. This year the Health and Retirement Study (HRS) will
    complete 25 years of data collection and will mark the occasion with
    several enhancements, including deployment of an improved approach to
    assessing cognitive impairment and dementia and expanded collection of
    objective health measures, including blood-based assays capturing the
    aging of the immune system and related molecular and cellular age-
    related changes. This project and others are designed to reveal the
    biological pathways through which differences among social and
    demographic groups can affect health.
        NIA-supported investigators are looking at better ways to translate
    what we know into clinical practice that will help improve the health
    and well-being of older Americans. For example, starting in fiscal year
    2019, NIA will support demonstration projects leading to pragmatic
    trials--clinical trials that are conducted under ``real-world''
    conditions, as opposed to the tightly controlled conditions of a
    traditional trial--for a variety of age-related diseases and
    conditions, including care of persons with dementia in long-term
    settings. The National Advisory Council on Aging has also recently
    approved in concept a new initiative to explore ``deprescribing''
    strategies for older adults with multiple chronic health conditions.
    This research, which will begin in fiscal year 2019, will address
    inappropriate prescribing of medication, which is estimated to affect
    20 percent of older adults, one-third of individuals in long-term care
    facilities and over half of the persons with advanced dementia in
    nursing homes.
                  empowering the next generation of scientists
        As the number of older Americans continues to grow, we must foster
    the development of the next generation of scientists whose research
    will lead to improved care and more effective treatment for older
    patients with complex medical conditions. To encourage emerging
    scientists, NIA supports an advantage in pay line for new and early-
    stage investigators. The Paul Beeson Career Development Awards in Aging
    Research program, sponsored by the NIA, the National Institute of
    Neurological Disorders and Stroke, and private partners, continues to
    produce leaders in the fields of aging and geriatrics research. A
    recent Funding Opportunity Announcement led to awards for four new
    training programs for joint MD-PhDs in the social sciences relevant to
    aging. Finally, the Butler-Williams Scholars Program (formerly the NIA
    Summer Institute) remains a vibrant and vital institution at NIA.
        Thank you. I welcome your questions.
                                     ______

    Prepared Statement Of Stephen I. Katz, M.D., Ph.D., Director, National
          Institute of Arthritis and Musculoskeletal and Skin Diseases
        Mr. Chairman and Members of the Committee: I am pleased to present
    the President's fiscal year 2019 budget request for the National
    Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of
    the National Institutes of Health (NIH).
                        niams research impacts everyone
        NIAMS is the primary Federal agency for supporting medical research
    on diseases of the bones, joints, muscles, and skin. As such, our work
    touches the lives of nearly every American. A 2018 publication by the
    Centers for Disease Control and Prevention notes that an estimated 23
    percent (54 million) of Americans have been diagnosed with some form of
    arthritis, including osteoarthritis, rheumatoid arthritis, gout, and
    fibromyalgia; 24 million of whom have symptoms severe enough to hinder
    activities they want or need to do. This problem is expected to grow as
    our population ages; 78.4 million adults will have arthritis by 2040 if
    current trends continue. When arthritis is combined with other bone and
    joint conditions such as neck and low back pain, osteoporosis, and
    musculoskeletal injuries, the total cost of medical care and lost wages
    is estimated to be $874 billion annually. Diseases in the NIAMS
    research portfolio also have a global impact. In 2015, low back and
    neck pain was the leading cause of disability worldwide, while skin
    diseases such as eczema and psoriasis ranked fifth.
        NIAMS is enhancing health, lengthening life, and reducing illness
    and disability by supporting basic and translational research and
    clinical trials that will inform medical practice; training the next
    generation of bone, joint, muscle, and skin scientists; and
    disseminating health information and the findings from the studies it
    supports to all Americans. For the remainder of my statement, I will
    describe a few of the many recent research activities that are
    benefiting people today and enabling future advances.
                       research advances funded by niams
        My first two examples focus on the risks and benefits of steroids,
    which an estimated 1 percent of the entire U.S. population takes as
    chronic therapy. A team of researchers studying the effects of repeated
    steroid injections for knee pain found that people who received shots
    every twelve weeks for 2 years showed worsening joint damage and no
    long-term reduction in pain compared with those who received saline
    injections. While this study did not evaluate the benefits of steroid
    injections into the knee for short-term pain relief, it does not
    support their long-term use for treatment of symptomatic knee
    osteoarthritis. Another group of investigators looked at the mechanisms
    by which steroids preserve muscle function for boys who have Duchenne
    muscular dystrophy. Using cells and a mouse model, the team determined
    that a weekly dosing regimen increases the activity of two genes
    involved in muscle cell repair, while daily dosing activates pathways
    that cause muscle to shrink and weaken. Their discovery explains the
    seemingly contradictory results of previous studies into the drugs'
    effects. If these observations from cell cultures and mice also occur
    in patients, this study could directly inform how steroids are
    prescribed to maximize their therapeutic benefits while minimizing
    their negative effects.
        After decades of investigating Pompe disease, a rare, life-
    threatening condition that cripples the muscles, NIAMS-funded
    researchers have developed a gene-transfer approach that shows promise
    in mice. While the study's main goal was to test whether the strategy
    would prevent the animals from developing an immune response, it also
    demonstrated that this gene therapy could potentially replace standard
    care. These results directly contributed to an investigational new drug
    approval by the Food and Drug Administration to move this approach into
    clinical trials. Gene therapy also holds promise for people who have
    the rare and life-threatening skin disease recessive dystrophic
    epidermolysis bullosa, which causes fragile, blistering skin. In a
    phase 1 clinical trial, investigators collected skin biopsies from four
    patients and used a harmless virus to correct the gene for the
    defective skin protein in the patients' cells. Next, they coaxed the
    genetically modified cells to grow into sheets of skin about the size
    of a deck of playing cards. Then, the new skin was grafted back onto
    patients to speed healing of the open wounds that characterize the
    disease. After 12 months, half of the two-dozen grafts were still
    covering patients' wounds. Investigators will continue monitoring these
    patients and are recruiting people for a phase 2 clinical trial.
        NIAMS research is also developing techniques to help clinicians
    identify which patients are likely to have more severe or rapidly
    progressing disease. For example, researchers found that positron
    emission tomography (PET), a technique that can visualize the body's
    metabolic processes, could be used to distinguish between patients who
    have large vessel vasculitis or other diseases with similar symptoms.
    PET may also help clinicians predict which patients are at highest risk
    of disease relapse. Another study examined children with juvenile
    myositis, a disease where the muscles are attacked by antibodies in the
    patients' blood. The investigators found that children with a certain
    type of antibody experience worse muscle disease and more severe
    weakness. This finding also explains why these children show less
    benefit from existing therapies and opens a possibility for better
    treatments. Other researchers discovered blood markers that may
    distinguish the subset of people who have systemic sclerosis that are
    at risk of developing interstitial lung disease (the leading cause of
    death for these patients). This advance also may lead to new therapies.
        Other studies of basic cellular processes hold promise for people
    who suffer from skin diseases. Investigators determined that a
    molecular pathway involving the protein JAK1 is involved in chronic
    itch. They then tested whether an existing drug that blocks JAK
    signaling could help people who do not respond to other treatments
    (e.g., some cases of atopic dermatitis). Their results were promising
    although further clinical studies are needed to confirm the findings.
    Additional teams of researchers are examining how microbes on the skin
    may influence a person's susceptibility to atopic dermatitis. A pair of
    studies, focusing on the role of the bacterium Staphylococcus aureus in
    driving the disorder, suggest that reducing S. aureus by increasing
    beneficial skin bacteria could be an effective treatment.
        NIAMS-funded research is also having an impact beyond arthritis and
    musculoskeletal and skin diseases. For example, psoriasis has been
    linked to an increased risk of developing type 2 diabetes. A new
    finding that the risk of diabetes is highest for those with the most
    severe psoriasis sheds light on the causes of both diseases and
    provides compelling evidence that certain patients should receive
    targeted diabetes prevention strategies. Other investigators are
    showing that while early antiretroviral therapy saves HIV patients'
    lives, it also damages their bones, emphasizing the importance of
    developing bone-preserving strategies for this population. Weight loss
    due to bariatric surgery, another life-saving intervention, also is
    associated with bone loss, and researchers are beginning to understand
    the role that glucose metabolism plays in bone health. This discovery
    could lead to targeted prevention and treatment strategies for
    osteoporosis, the skeletal complications of bariatric surgery, and
    diabetic bone fragility. Still other research is explaining why muscle
    breaks down in cancer patients (a process known as cachexia). A number
    of molecular pathways and targets underlying the muscle wasting process
    have been discovered recently, and investigators are beginning to
    identify existing drugs or new targets to stop this from occurring.
                         looking to a promising future
        The wide reach of NIAMS-funded research is allowing people affected
    by diseases within our mission to benefit from large multi-agency
    programs such as the Cancer Moonshot Program and the Regenerative
    Medicine Innovation Project supported by the 21st Century Cures Act.
    Moving forward, investigators will examine connections between
    immunotherapies for cancer and autoimmune disease and will continue to
    be encouraged to apply for funding for research on bone, joint, muscle,
    and skin regeneration. NIAMS, along with the National Institute of
    Allergy and Infectious Diseases, continues to lead the Accelerating
    Medicines Partnership (AMP) in rheumatoid arthritis and lupus which is
    working to identify and validate promising biological targets for those
    diseases. With guidance from NIAMS, three other Institutes, and the NIH
    Common Fund, the trans-NIH Molecular Transducers of Physical Activity
    in Humans program continues to make progress developing a database that
    researchers can use to elucidate changes that take place in our bodies
    in response to exercise and how those changes relate to human health.
        In fiscal year 2019, NIAMS plans to continue support for its
    Research Innovations for Scientific Knowledge (RISK) funding
    opportunities, which allow investigators from around the country to
    submit cutting edge, unconventional, innovative research proposals for
    up to 3 years of funding. To help bolster the next generation of
    researchers, the Institute also continues to encourage early
    established investigators who have successfully renewed their first
    NIAMS research project grant to apply for a supplemental funding
    program to aid the transition of their individual research project into
    a broader, more robust and resilient research program.
                                     ______

        Prepared Statement of George F. Koob, Ph.D., Director, National
                   Institute on Alcohol Abuse and Alcoholism
        Mr. Chairman and Members of the Committee: I am pleased to present
    the President's fiscal year 2019 budget request for the National
    Institute on Alcohol Abuse and Alcoholism of the National Institutes of
    Health (NIH).
                 burden of alcohol misuse in the united states
        Alcohol misuse has profound effects on the health and well-being of
    individuals, families, and communities. Approximately 15 million people
    in the United States have alcohol use disorder (AUD), a chronic
    relapsing brain disease related to alcohol misuse. 88,000 lives are
    lost to alcohol-related causes annually, making alcohol the third
    leading preventable cause of death in the United States. Alcohol misuse
    cost the U.S. almost $250 billion in 2010. Guided by its 2017-2021
    strategic plan, the National Institute on Alcohol Abuse and Alcoholism
    (NIAAA) supports research and initiatives to generate and disseminate
    fundamental knowledge about the effects of alcohol on health and well-
    being, and apply that knowledge to improve the diagnosis, prevention,
    and treatment of alcohol-related problems, including AUD, across the
    lifespan.
                 advancing translational and clinical research
        For nearly five decades, NIAAA has supported cutting-edge research
    to reduce the toll that alcohol misuse takes on human health and well-
    being. The Institute's vast portfolio of translational and clinical
    research has led to more effective interventions to prevent and treat
    alcohol misuse and related conditions, provided support for integrating
    prevention and treatment services into mainstream healthcare, and paved
    the way for the development of novel strategies to address medical
    conditions associated with alcohol misuse.
    Alcohol Treatment Navigator\SM\
        In any given year, less than 10 percent of individuals diagnosed
    with AUD receive treatment. Although effective behavioral interventions
    and medication-assisted treatment are available, in addition to mutual
    help groups, people often do not know the full extent of their options
    or where to turn for help. In October 2017, NIAAA launched the Alcohol
    Treatment Navigator\SM\ (alcoholtreatment.niaaa.nih.gov), a
    comprehensive online resource to help people search for professionally-
    led, evidence-based alcohol treatment. The Navigator educates consumers
    about AUD and treatment options, provides 10 recommended questions to
    ask a potential provider, and suggests five signs of higher quality
    treatment to recognize. It also provides instructions for searching
    several existing online directories of licensed professional
    therapists, accredited alcohol treatment programs, and board-certified
    addiction medicine physicians. With the Navigator, adults searching for
    AUD treatment will be better able to find care that meets their unique
    needs, friends and family members will feel empowered to help an adult
    loved one struggling with AUD, and healthcare providers can feel more
    confident in screening their patients for AUD knowing there is a tool
    to share with those who need a referral to treatment. Given that
    treatments for AUD work better for some people than others, NIAAA will
    continue to support research on the neurobiological mechanisms that
    underlie AUD to identify novel medication targets that could ultimately
    expand the number of effective treatment options.
    Addiction Medicine in Routine Healthcare
        Many individuals with AUD often seek primary care for a health
    problem related to alcohol misuse rather than for the misuse itself,
    indicating a need for addiction medicine approaches in routine medical
    practice. NIAAA provides primary care and other healthcare providers
    with tools to help them become more proficient in conducting alcohol
    screening and evidence-based interventions, including medication-
    assisted treatment. The Institute is also partnering with the National
    Institute on Drug Abuse, the Substance Abuse and Mental Health Services
    Administration, and others to improve physician training in the
    diagnosis, prevention, and treatment of alcohol and other substance
    misuse and to expand the range of healthcare providers appropriately
    trained in identifying and addressing these problems.
    Alcohol-Associated Liver Diseases
        In the United States, about half of liver disease deaths are
    attributable to alcohol misuse. NIAAA will continue to invest in
    clinical and translational research to develop treatments for alcohol-
    associated liver diseases such as alcoholic hepatitis, a deadly form of
    liver disease for which there are no treatments approved by the Food
    and Drug Administration (FDA). The Institute aims to strengthen its
    research programs in alcoholic hepatitis through the establishment of a
    clinical and translational network to streamline the design,
    initiation, and conduct of clinical trials, reduce administrative
    redundancy, and optimize the use of scientific innovations. NIAAA is
    collaborating with the FDA to identify appropriate clinical trial
    endpoints for studies investigating novel treatments for alcohol-
    associated liver diseases as well as safe, effective therapies for AUD
    in liver disease patients.
    Fetal Alcohol Spectrum Disorders
        Prenatal alcohol exposure is a leading preventable cause of
    developmental abnormalities that contribute to a broad range of
    lifelong physical, cognitive, and behavioral challenges known as Fetal
    Alcohol Spectrum Disorders (FASD). Among NIAAA's extensive portfolio in
    FASD research are studies to establish more accurate FASD prevalence
    estimates. A new NIAAA-supported study of more than 6,000 first-graders
    across four U.S. communities (Midwest, Rocky Mountain, Southeast and
    Pacific Southwest) has found that as many as 1-5 percent of first-grade
    children have FASD. This finding provides further evidence that FASD is
    a significant public health problem in the U.S. and strategies to
    expand screening, diagnosis, prevention, and treatment in communities
    are needed to address it.
                         emerging public health issues
        Changing patterns in alcohol consumption, shifts in the burden of
    alcohol-related disease, and shifts in the demographic composition of
    the U.S. pose new challenges for alcohol prevention and treatment.
    Identifying and addressing emerging public health issues early can
    lessen the societal burden and associated costs.
    Increases in Alcohol-Related Emergency Department Visits
        A new study found that the rate of alcohol-related emergency
    department visits in the U.S. increased by nearly 50 percent between
    2006-2014, especially among women and older adults. About 15 percent of
    the visits involved substances in addition to alcohol. Alcohol
    interacts with a variety of prescription and illicit drugs, including
    opioid pain relievers, which dramatically increase the risk of overdose
    deaths and may partially explain the increased prevalence of emergency
    department visits also observed for alcohol and medication
    interactions. The relationship between alcohol and pain is another area
    of interest including how chronic alcohol misuse increases sensitivity
    to pain, and how pain drives alcohol misuse. NIAAA is supporting
    epidemiological studies to determine the associations between alcohol
    and opioid misuse as well as basic research to elucidate the
    neurobiological mechanisms through which alcohol, opioids, and pain
    interact.
    Extreme Binge Drinking
        A recent NIAAA study based on 2012-2013 data found that that nearly
    32 million adults in the U.S. (13 percent of the population aged 18 and
    older) engaged in extreme binge drinking, i.e., consuming alcohol at
    levels two or more times the binge thresholds, in the past year.
    Extreme binge drinking was associated with an elevated likelihood of
    emergency department visits and other adverse consequences. NIAAA is
    forming a working group of external experts to better understand the
    social and cultural determinants of extreme binge drinking to inform
    the development of improved interventions.
    Alcohol Misuse Among Women
        A growing body of evidence indicates that women who drink are at
    increased susceptibility to short- and long-term alcohol-related
    consequences, and alcohol use and misuse are increasing more
    significantly among women than men. NIAAA encourages basic, clinical,
    and translational research on the biological bases of sex differences
    in the development of AUD and associated consequences, factors that
    increase risks for AUD and co-occurring disorders, and improved
    diagnosis and evidence-based interventions that consider the unique
    needs of women.
    Alcohol Misuse Among Older Adults
        As people age, they tend to be more sensitive to alcohol's effects,
    and are more likely to experience health conditions exacerbated by
    alcohol misuse as well as alcohol-medication interactions. An analysis
    of data from 1997-2014 showed an increase in drinking and binge
    drinking among adults aged 60 and older, particularly among women.
    NIAAA-supported studies are focused on identifying and reducing
    unhealthy alcohol use among older adults as well as elucidating how
    alcohol contributes to age-related changes in the brain. For example, a
    recent study of older adults with AUD has shown accelerated declines in
    various brain regions and circuits, including in the frontal cortex
    which may lead to accelerated impairments in cognitive function.
                                   conclusion
        Advances in alcohol research have expanded our knowledge of the
    effects of alcohol on health and resulted in numerous evidence-based
    preventive and treatment interventions. Still, more work needs to be
    done to reduce the burden of alcohol misuse in our Nation. With its
    fiscal year 2019 budget, NIAAA will continue to invest in basic,
    clinical, and translational research to address existing and emerging
    public health concerns and cultivate the biomedical research workforce
    to harness the contributions and perspectives of the broadest range of
    investigators.
                                     ______

      Prepared Statement of Walter J. Koroshetz, M.D., Director, National
                 Institute of Neurologcial Disorders and Stroke
        Mr. Chairman and Members of the Committee: I am pleased to present
    the President's fiscal year 2019 budget request for the National
    Institute of Neurological Disorders and Stroke (NINDS) of the National
    Institutes of Health (NIH). NINDS research improves the diagnosis,
    treatment, and prevention of brain diseases and other nervous system
    disorders, and the Institute is the world's largest supporter of basic
    research to understand the normal brain, which drives progress against
    disease throughout the public and private sectors.
                    the challenge of neurological disorders
        According to the Centers for Disease Control and Prevention, in the
    United States: traumatic brain injury (TBI) is the leading cause of
    death and disability in children and young adults and a major problem
    for the elderly (falls), about 795,000 strokes occur each year,
    epilepsy affects 3 million adults plus nearly half a million children,
    dementia is a growing public health challenge, and chronic pain is
    perhaps the most common of all medical problems, and a major factor in
    the opioid crisis. Parkinson's disease, multiple sclerosis, amyotrophic
    lateral sclerosis, cerebral palsy, and hundreds of other disorders,
    common and rare, also affect the brain, spinal cord, and nerves of the
    body. Because of the multiplicity of brain disorders and the
    extraordinary complexity of the brain, neurological disorders present
    the most daunting challenges in all of medicine. For most of these
    diseases, treatments are still far from adequate.
                    progress against neurological disorders
        Historically, progress against neurological disorders has been
    slow, but the pace appears to be accelerating, with encouraging
    advances against several neurological disorders in recent years. As NIH
    has driven medical progress in general, NINDS basic research has
    provided the foundation for these recent advances against neurological
    diseases, and the Institute's translational and clinical research have
    also made major contributions. A few recent examples illustrate:
      --Stroke.--Two decades ago, NINDS-supported research showed that tPA
            therapy can restore blood flow to the brain following a stroke.
            For the first time, stroke became a treatable emergency, and
            the care system organized to take advantage. Building on NINDS
            funded research, clinical trials in 2015 showed that timely
            intervention with intravascular devices can directly clear a
            blocked brain artery in severe strokes when tPA does not
            restore blood flow, with striking clinical benefit. In 2018 the
            NINDS DEFUSE 3 clinical trial reported that a brain imaging
            method can identify people who may respond well beyond the
            current restricted time window for this intervention, now up to
            16 hours, so many more people with strokes may benefit.\8\
            These recent results again transform emergency stroke
            treatment, and stroke care systems are now making these
            catheter-based treatments available in both urban and rural
            communities.
    ---------------------------------------------------------------------------
        \8\ N Engl J Med. 378:708-718 2018.
    ---------------------------------------------------------------------------
      --TBI.--The 2018 FDA marketing authorization of the first blood test
            to help in the diagnosis of concussion exemplifies the
            extensive NIH and DoD cooperation on TBI. NINDS funded the
            foundational basic science and clinical studies to the
            successful research team, and DoD supported the subsequent
            development and testing. The test could reduce the cost and
            radiation exposure from thousands of unnecessary CT scans.
      --New Drugs.--Pioneering NIH-supported basic and translational
            research, and subsequent private sector development, led to FDA
            approval of the first disease-modifying drugs for two rare
            pediatric diseases, spinal muscular atrophy (SMA) and Batten
            disease. The FDA also approved the first drugs for primary
            progressive multiple sclerosis, for movement problems
            associated with Huntington's disease, and a drug for
            amyotrophic lateral sclerosis (ALS). And researchers reported
            promising results for migraine, adrenoleukodystrophy, Niemann-
            Pick disease, and several other disorders.
      --Dementia.--A long-term NIH study with more than 15,000 people found
            that middle aged Americans who have vascular risk factors,
            including diabetes, high blood pressure and smoking, are more
            likely to suffer from dementia later in life.\9\ The findings
            add to a growing body of evidence linking cardiovascular health
            to brain health. The hope is that managing vascular risk
            factors in middle age may slow or prevent the development of
            dementia, and there are hints that may be happening.\10\
    ---------------------------------------------------------------------------
        \9\ JAMA Neurology 74:1246-54 2017.
        \10\ New England Journal of Medicine 374:523-32, 2016.
    ---------------------------------------------------------------------------
                            driving future progress
        NINDS will continue to emphasize investigator-initiated research
    with rigorous peer review because of its proven track record.
    Complementing this core strategy, the Institute calls for research
    proposals to address unmet public health needs or exceptional
    scientific opportunities. Among the notable activities for the coming
    year:
      --The Opioid Crisis.--Through a series of workshops and discussions
            in 2017, Federal agencies, the scientific community, and
            industry forged a partnership to accelerate the development of
            safe and effective, non-addictive treatments for pain. NINDS
            leads two key priorities of the plan-- development of
            biomarkers (objective indicators) of pain and of a clinical
            trials network to use biomarkers for the development of non-
            addictive pain treatments. Together with the NIH Pain
            Consortium and the NIH Director's Common Fund, NINDS is also
            targeting the key question of why acute pain leads to chronic
            pain for some people, well after the original cause of pain has
            been resolved.
      --ADRDs.--Through the National Alzheimer's Project Act (NAPA),
            Congress recognized the impact of not just Alzheimer's, but
            also Alzheimer's disease-related dementias (ADRDs).
            Frontotemporal dementia (FTD) is the most common dementia in
            people younger than 60, and Lewy body and Parkinson's dementias
            also have a major impact. The most common ADRD, Vascular
            Cognitive Impairment and Dementia (VCID), like stroke, affects
            brain blood vessels. VCID is so intertwined with Alzheimer's
            disease that most elderly people with dementia have a
            combination of the two. NINDS leads several new and ongoing
            initiatives to understand and develop treatments for the ADRDS,
            working closely with the National Institute of Aging (NIA),
            which provides funding to a suite of these NINDS-led programs.
            NINDS also leads the ADRD summits that occur every third year,
            as mandated by NAPA.
      --AMP PD.--NINDS, Celgene, Verily, Pfizer, GlaxoSmithKline, Sanofi,
            the Michael J. Fox Foundation (MJFF), and the Foundation for
            NIH are launching the Accelerating Medicines Partnership for
            Parkinson's Disease (AMP-PD). This new addition to the NIH AMP
            program will identify and validate biomarkers and new
            therapeutic targets for Parkinson's disease, leveraging a
            treasure trove of data and resources supported over the past
            several years by NINDS, MJFF, and others.
      --Pediatric Concussion.--An NINDS initiative will develop biological
            measures of persistent symptoms following pediatric concussion,
            which addresses the highest research priority identified by a
            2016 NIH scientific workshop on pediatric concussion.
      --Biomarkers.--The lack of reliable biomarkers for most neurological
            disorders heightens the challenges of developing treatments and
            dissuades private sector investment. An NINDS initiative will
            support the advanced development and validation necessary to
            bring potential biomarkers to clinical practice, complementing
            the extensive early phase biomarkers discovery research that is
            already underway.
      --BRAIN Initiative.--NINDS is an enthusiastic leader of the Brain
            Research through Advancing Innovative Neurotechnologies (BRAIN)
            Initiative. The Initiative is developing and applying new
            technologies to understand how circuits of interconnected nerve
            cells in the brain enable us to perceive, act, think, and
            learn, and what goes wrong in brain disorders. Remarkable new
            tools now enable researchers to identify all of the individual
            brain cell types, monitor activity of thousands of cells in a
            circuit at once in real time, precisely manipulate cells'
            activity, and non-invasively monitor and stimulate the human
            brain with increasing precision. As the Initiative continues,
            engaging these new opportunities to enhance research on pain
            and addiction is a high priority.
        Finally, NINDS continues its longstanding emphasis on investigator-
    initiated basic research, which is yielding remarkable advances on many
    fronts in addition to circuits. Among the many findings this year, for
    example, research discovered unexpected links between bacteria and
    brain blood vessels, new roles of non-nerve cells in the brain,
    insights about how genes orchestrate brain development, the role of
    undetected seizure-like activity in Alzheimer's disease, how the gut
    conveys information to the nervous system, mechanisms of memory, and
    novel ways that nerve cells respond to stress. Which findings from
    basic research will launch the next advances against disease is not yet
    apparent. However, NIH basic research will surely continue to be the
    wellspring of progress for both the public and private sector.
                                     ______

    Prepared Statement of Jon R. Lorsch, Ph.D. Director, National Institute
                          of General Medical Sciences
        Mr. Chairman and Members of the Committee: I am pleased to present
    the President's fiscal year 2019 budget request for the National
    Institute of General Medical Sciences (NIGMS), a component of the
    National Institutes of Health (NIH).
        The NIGMS focuses on promoting and supporting fundamental or
    ``basic'' biomedical research that increases scientific knowledge about
    how living systems work, from individual molecules to cells, organs,
    whole organisms, and populations. The Institute's priority is to
    support investigator-initiated research, based on the principle that
    the best scientific ideas, directions, and approaches stem from
    scientists themselves. Thus, NIGMS aims to enable creative, innovative,
    and ambitious research conducted by individuals and teams of
    investigators to promote scientific discovery and medical advancement.
        One indication of the success of the Institutes' strategy is the
    number of Nobel Prizes awarded to NIGMS grantees. Of the 153 Nobels
    given for NIH-funded research, over half--87--have been for work
    supported by NIGMS. This year, the Nobel Prizes in both chemistry and
    in physiology or medicine were awarded to multiple NIGMS grantees. The
    2017 Nobel Prize in chemistry was awarded to a NIGMS grantee and two
    others for the development of cryo-electron microscopy (cryo-EM), a
    technique that simplifies and improves the imaging of biomolecules.
    Similarly, the 2017 Nobel Prize in physiology or medicine was awarded
    to three NIGMS grantees for their work on molecular mechanisms
    controlling circadian rhythms, more commonly known as ``biological
    clocks.'' Biological clocks influence a variety of physiological
    responses such as alertness, hunger, metabolism, fertility, and mood;
    clock dysfunction is associated with various disorders, including
    insomnia, diabetes, and depression. These awards serve as yet another
    testament to how investing in the study of fundamental biological
    processes can yield important insights into the principles that
    underlie human biology, health, and disease.
        Because scientific breakthroughs generally cannot be predicted in
    advance and often originate from unexpected or disparate strands of
    knowledge, a cornerstone of NIGMS' strategic plan is to support a broad
    and diverse portfolio of fundamental research. This strategy builds the
    strongest possible foundation on which breakthroughs can arise.
        nigms strategic priority: new funding approaches to accelerate
                       scientific progress and discovery
        In order to enhance the efficiency and productivity of fundamental
    biomedical research, the NIGMS has developed a new mechanism to fund
    scientists. The Maximizing Investigators' Research Award (MIRA) seeks
    to transform how fundamental biomedical research is supported by
    providing individual investigators with a heightened level of both
    scientific stability and flexibility.\11\ These awards allow
    investigators to follow new research directions and insights in real-
    time, while simultaneously providing an extra year of support as part
    of a more coordinated scientific program (versus single project) focus.
    In addition, the peer review process for MIRA applicants reviews early
    stage investigators (ESIs) independently from established investigators
    (EIs), thus allowing each group of applicants to be examined relative
    to their own peer group. Since the creation of the program, the NIGMS
    has awarded 231 MIRAs to EIs and 192 MIRAs to ESIs. The MIRA program is
    especially beneficial for ESIs, as evidenced by the increase in the
    number of ESI applications from 393 in 2015 (prior to MIRA) to 649 in
    2017. The number of ESIs funded by the Institute per year has nearly
    doubled in the same time period. The NIGMS will continue to monitor the
    progress and outcomes of the MIRA program as it evolves.
    ---------------------------------------------------------------------------
        \11\ https://www.nigms.nih.gov/research/mechanisms/MIRA/pages/
    default.aspx.
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        Because some areas of biomedical investigation require groups of
    investigators to synergistically work together to solve complex
    problems, the NIGMS recently developed and implemented a new team-
    science support mechanism known as the Collaborative Program Grant for
    Multidisciplinary Teams.\12\ This investigator-initiated funding
    opportunity supports multidisciplinary teams of researchers to work
    toward a shared goal that has the potential to have a major impact on
    one or more fields of biomedical research. Because this program only
    funds highly integrated research teams working toward a common
    objective, it will promote and enable a type of collaborative science
    that can't easily be supported through other kinds of research grants.
    Further, these new awards possess an optional component that allows for
    support of pilot projects by early-stage investigators to develop
    research in the team's area(s) of expertise with a goal of helping the
    junior researchers obtain independent funding.
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        \12\ https://grants.nih.gov/grants/guide/pa-files/PAR-17-340.html.
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        nigms strategic priority: develop and sustain a highly skilled,
             diverse, and productive biomedical research workforce
        The NIGMS plays a leading role in supporting the career development
    and training of the next generation of scientists, including the
    development of institutional research capacities in regions across the
    country in which the levels of NIH support have been historically low.
        Given the rapidly evolving landscape of science and medicine, the
    Institute is working to catalyze the modernization of graduate
    education. Recently, the NIGMS issued a new funding opportunity
    announcement (FOA) for its pre-doctoral T32 training grants \13\ that
    focuses on addressing several key issues such as: shifting the emphasis
    from simply teaching scientific ``facts'' to teaching both scientific
    and professional skills; developing the acumen needed to become
    rigorous and responsible scientists; supporting a safe, inclusive and
    diverse training environment; promoting the use of evidence-based
    teaching and mentoring practices; and enhancing student career
    development. Over the next several years, the NIGMS will work to
    implement this revised T32 program and will carefully evaluate its
    outcomes. In addition, the NIGMS is also working to ensure that
    emerging issues can be quickly incorporated and addressed in the
    training process, as appropriate. For example, the Institute has
    recently supported the development of open-access curricular training
    modules in areas related to improving the rigor and reproducibility of
    biomedical research. These modules are available on the NIGMS
    website,\14\ with more modules due to be added this year. The goal is
    to generate useful resources for graduate training programs.
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        \13\ https://grants.nih.gov/grants/guide/pa-files/PAR-17-341.html.
        \14\ https://www.nigms.nih.gov/training/pages/clearinghouse-for-
    training-modules-to-enhance-data-reproducibility.aspx.
    ---------------------------------------------------------------------------
        Through its Institutional Development Award (IDeA) program, the
    NIGMS provides targeted support to help broaden the geographic
    distribution of biomedical research funding by enhancing the
    competitiveness of investigators located at academic institutions in
    States having a historically low level of NIH support. The IDeA Centers
    of Biomedical Research Excellence (COBRE), for instance, support
    thematic, multidisciplinary centers that expand and develop faculty
    research capabilities and research infrastructure, in part through the
    development of core technology facilities needed to carry out modern
    multidisciplinary collaborative research. Another important aspect of
    the IDeA program is its support of medical research for rural and
    underserved communities. The IDeA Clinical and Translational Research
    Network (CTR), for instance, provides support for clinical and
    translational research that addresses conditions that have been
    traditionally higher among certain regions, populations or communities,
    including (but not restricted to) cancer, cardiovascular disease, and
    substance abuse disorders.
        Because developing a well-trained research workforce begins with
    early outreach and education, the NIGMS was proud to welcome the NIH
    Science Education Partnership Awards (SEPA) to the Institute in
    2017.\15\ SEPA supports diversity in the workforce by providing
    opportunities for students (specifically at the pre-kindergarten to
    grade 12 levels) from underserved communities to learn about careers in
    basic or clinical research. Ten of the fourteen SEPAs in IDeA States
    are currently in partnerships with IDeA COBREs or IDeA Networks of
    Biomedical Research Excellence (INBREs). An Institute goal is to fund
    at least one SEPA in every State.
    ---------------------------------------------------------------------------
        \15\ https://www.nigms.nih.gov/Research/DRCB/SEPA/Pages/
    default.aspx.
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       nigms strategic priority: create and share cutting-edge tools and
                                   resources
        Given that technology plays a critical role in biomedical research,
    the NIGMS continues to place a high level of significance on supporting
    the development and dissemination of innovative, new technologies that
    have the potential to transform research. To this end, the NIGMS
    supports a multi-phased funding strategy that consists of support for
    an initial proof-of-concept phase for a given technology followed by
    potential support for a second prototype refinement phase. These phases
    can then lead to the adoption and expansion of the technology via
    commercialization through small business innovation research or small
    business technology transfer (SBIR/STTR) grants. Technologies can also
    be applied toward answering specific scientific questions through their
    incorporation into regular research project grants or, once
    sufficiently mature, through their incorporation into resources
    supported by the Institute's Biomedical Technology Research Resources
    (BTRR) program.\16\ Programs such as the BTRR form an important part of
    the NIGMS' portfolio as the Institute seeks to ensure broad access
    across the research community to cutting-edge technological resources.
    For example, synchrotron-based technologies, an extremely powerful
    source of X-rays, are critical for structural biology research; more
    than 90 percent of all three-dimensional structures of biological
    molecules in the Protein Data Bank \17\ were determined using data from
    synchrotrons. The NIGMS recently shifted its support for these
    important resources from research grants to a mechanism focused on
    user-access, utility and efficiency of operations. A similar model will
    be used to support the new national cryo-electron microscopy centers.
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        \16\ https://publications.nigms.nih.gov/btrrs/searchresults.asp.
        \17\ https://www.rcsb.org/.
    ---------------------------------------------------------------------------
                                   conclusion
        Mr. Chairman, in this statement, I have tried to highlight just a
    few examples of how NIGMS' programs maximize the scientific returns on
    the taxpayers' investments in fundamental biomedical research. As the
    scientific enterprise and national clinical landscape continue to
    evolve, the NIGMS looks forward to continuing to meet and address both
    the challenges and opportunities associated with this dynamic
    environment, and in so doing, to the many more advances that will
    emerge from institutions, laboratories, research teams, and individual
    investigators across the Nation. We thank you for your continued
    support and for this opportunity to describe some of the new
    initiatives at NIGMS.
                                     ______

      Prepared Statement of Griffin P. Rodgers, M.D., M.A.C.P., Director,
        National Institute of Diabetes and Digestive and Kidney Diseases
        Mr. Chairman and Members of the Committee: I am pleased to present
    the President's fiscal year 2019 budget request for the National
    Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the
    National Institutes of Health (NIH).
               combating chronic disease to improve human health
        NIDDK supports research on diseases and conditions affecting the
    health and well-being of millions of Americans. Its mission spans
    diabetes and other endocrine and metabolic diseases; digestive and
    liver diseases; kidney and urologic diseases; blood diseases; obesity;
    and nutrition disorders. Though diverse in nature, most of these
    diseases and conditions are chronic, consequential, and costly. For
    example, diabetes, kidney disease, and digestive diseases alone run
    into hundreds of billions of dollars yearly for medical care,
    disability, loss of work or productivity, and other costs. Obesity is
    at high prevalence among U.S. adults and youth and is a risk factor for
    many of these chronic and sometimes deadly health problems. The
    challenges are vast, and the needs urgent. Through research and related
    activities, NIDDK continues to seek out ways to prevent, treat, and
    cure chronic diseases and conditions to improve human health and
    quality of life.
                                    research
        To foster discovery important to combating chronic disease, NIDDK
    supports a multi-faceted scientific portfolio spanning basic to
    translational to clinical studies, while also creating and leveraging
    partnerships that can fortify and accelerate research. For example, in
    basic research, scientists have used a specialized microscopy technique
    to develop a three-dimensional picture of a cellular protein that is a
    target for certain diabetes drugs. Because this protein is also a
    member of a protein ``family'' targeted by about 40 percent of
    pharmaceutical drugs on the market today, the intricate knowledge
    gained from this work is not only important for diabetes but will
    inform the search for new drug treatments and refinement of current
    ones for other diseases. New findings in mice may also open up new
    therapeutic avenues important to prevention of obesity and type 2
    diabetes: One research group has identified a group of brain cells
    that, upon activation, induces rapid binge eating and weight gain,
    while another has found that bones secrete a hormone that both
    suppresses appetite and regulates blood sugar levels. Studies in mice
    have also revealed a more complex view of the kidney's role in salt and
    water balance and blood pressure regulation and suggest new areas of
    investigation for human hypertension. NIDDK-supported scientists have
    also been able to produce human intestinal ``organoids''--small bundles
    of cells that model various aspects of the small intestine and its
    functioning, facilitating study of certain digestive system diseases
    and disorders and creating potential for tissue replacement therapy.
        In fiscal year 2019, NIDDK will build upon research accomplishments
    such as these and upon other research avenues and continue its support
    for basic studies of both normal and disrupted biological functions and
    systems. For example, the ReBuilding a Kidney (RBK) consortium will
    continue efforts to enable tissue repair or replacement in kidney
    disease; already, RBK scientists have found that selecting the proper
    substrate for growth and structural support is critical to creating
    blood supply in a ``kidney on a chip.'' Recent studies have shed light
    on the multiple levels of complex interactions that contribute to how
    human gut microbes affect health, from molecules produced by the
    microbes themselves to differences in human diet; a 2017 workshop on
    best practices for studies of diet and gut microbiome will help inform
    rigor and reproducibility in future efforts in this aspect of research
    on the gut microbiome, which is rapidly emerging as an important
    contributor to digestive diseases, obesity, nutrition, and many other
    chronic diseases and conditions.
        Similarly, NIDDK-supported translational and clinical studies have
    yielded fruit. For example, in the translation of genetic discovery to
    treatment, NIDDK-supported scientists developed a personalized
    treatment plan for a child suffering from a severe anemia after
    discovering that the cause was a rare mutation affecting a protein
    already available in a therapeutic form. New findings about the impact
    of being diagnosed with diabetes before age 20 include that youth with
    type 2 diabetes are more than twice as likely as peers with type 1
    diabetes to have or be at high risk of a diabetes health complication
    by age 21. The Multidisciplinary Approach to the Study of Chronic
    Pelvic Pain (MAPP) Research Network has yielded important new insights
    into the nature and course of the urologic chronic pelvic pain
    syndromes interstitial cystitis/bladder pain syndrome (IC/BPS) and
    chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), such as new
    knowledge about the prediction of and bodily patterns of pain. NIDDK-
    supported scientists have also developed the first method for
    calculating the average rate of blood filtration by the individual
    functional units in the human kidney, an important measure of kidney
    health. Discoveries such as these can now be harnessed into new
    research toward interventions or into other actions to improve health.
        NIDDK will continue its support of research that, in partnership
    with human volunteers, can elucidate causes of and treatments and cures
    for chronic diseases and conditions and ways to implement those
    findings. For example, the third phase of the Diabetes Prevention
    Program Outcomes Study, spearheaded by NIDDK with several NIH partners,
    will study outcomes that are of increasing concern in an aging
    population with a high burden of pre-diabetes and diabetes. These
    include evaluating the potential benefit of the diabetes drug metformin
    on the development of cardiovascular disease and cancer. Gestational
    diabetes has long-term health impacts for affected mothers and
    children, and NIDDK will continue to capitalize on new findings and
    efforts to better understand this condition and identify ways to
    improve outcomes. Efforts will continue in development and testing of
    artificial pancreas systems for treatment of type 1 diabetes. NIDDK
    will also continue support for many clinical research efforts to
    address overweight and obesity, including major ongoing studies to
    assess the health risks and benefits of weight-loss surgery in
    extremely obese adolescents. The new Kidney Precision Medicine Project
    will pursue innovative efforts to elucidate the heterogeneity of kidney
    disease in human study participants, which could lead to novel and
    tailored treatments for both acute and chronic kidney disease. NIDDK
    will sustain its long-term investment in the Drug-Induced Liver Injury
    Network (DILIN) so that it may continue its highly productive and
    informative efforts to characterize liver injury from herbal and
    dietary supplements and prescription and over the counter drugs.
        To help tackle complex challenges and move discovery forward, NIDDK
    continues to forge effective partnerships with other NIH ICs and
    Offices, other Federal agencies, and private organizations. For
    example, the NIH Nutrition Research Task Force chaired by NIDDK and co-
    chaired by the National Heart, Lung, and Blood Institute (NHLBI),
    National Cancer Institute (NCI), and Eunice Kennedy Shriver National
    Institute of Child Health and Human Development (NICHD) has sought
    input from across NIH and external stakeholders and is developing the
    first NIH-wide strategic plan on nutrition. The public-private
    Accelerating Medicines Partnership-Type 2 Diabetes (AMP-T2D) project,
    spearheaded by NIDDK with partners from industry and nonprofit
    organizations, continues to exceed expectations in terms of progress
    and will continue augmenting content and access to genetic and clinical
    data on diabetes and related traits made available through its
    Knowledge Portal.
                                     other
        Indivisible from research are the minds and hands that generate new
    ideas and bring forth results. NIDDK will continue to foster and grow a
    diverse biomedical research workforce that can meet, with innovation
    and creativity, the challenges posed by chronic diseases and
    conditions. NIDDK supports several special training opportunities
    spanning high school to medical school to attract students, including
    those underrepresented in science and medicine, to NIDDK research
    areas. Mentorship opportunities offered by NIDDK's Network of Minority
    Health Research Investigators, which celebrated its 15th anniversary in
    2017, focus on junior investigators and will continue to promote a
    diverse research pipeline. NIDDK will also continue efforts to help the
    new generation of biomedical researchers realize their potential, such
    as priority funding strategies for those early in their careers. NIDDK
    is also pursuing multiple efforts to enhance rigor and reproducibility
    in research. Simultaneously, NIDDK will continue disseminating health
    and scientific information through multiple venues to educate and
    inform the public, healthcare providers, and researchers about new
    developments germane to chronic diseases and conditions.
                                   conclusion
        In closing, NIDDK has a robust and vigorous commitment to research
    and related activities to combat chronic diseases and conditions. This
    is reflected in its five guiding principles: maintain a vigorous
    investigator-initiated research portfolio, support pivotal clinical
    studies and trials, preserve a stable pool of new investigators, foster
    research training and mentoring, and disseminate science-based
    knowledge through education and outreach programs. Through research,
    NIDDK hopes to advance progress toward new and improved prevention,
    treatment, and curative strategies.
                                     ______

      Prepared Statement of Norman E. Sharpless, M.D., Director, National
                                Cancer Institute
        Mr. Chairman and Members of the Committee, I am pleased to present
    the President's fiscal year 2019 budget request for the National Cancer
    Institute (NCI) of the National Institutes of Health (NIH). With the
    resources that this subcommittee provides, NCI supports a broad array
    of biomedical research to advance scientific discovery, reduce the
    burden of cancer, and help all people live longer, healthier lives.
    NCI Progress under the 21st Century Cures Act
        In the Cures Act, Congress authorized $1.8 billion across seven
    fiscal years for the Cancer Moonshot. The fiscal year 2018 Consolidated
    Appropriations Act provided the second Cures Act installment of $300
    million. Guided by the recommendations of a Blue Ribbon Panel convened
    to identify research priorities, NCI awarded fiscal year 2017 funding
    in ten promising areas of cancer research targeted for rapid
    translation into new treatment and prevention. NCI will fund all
    remaining Blue Ribbon priorities during fiscal year 2018.
        One example of NCI's commitment to the progress envisioned in the
    Cures Act is the promising area of immunotherapy--activating a
    patient's immune system to attack cancer cells. To accelerate the
    development of immunotherapy strategies for cancer patients, in the
    fall of 2017, NCI launched a public-private partnership with NIH and
    pharmaceutical companies, known as the Partnership for Accelerating
    Cancer Therapies, or PACT. The Foundation for the National Institutes
    of Health will manage and coordinate PACT, and the Food and Drug
    Administration will play an essential advisory role. Twelve
    pharmaceutical companies are now members of PACT.
        A centerpiece of PACT is NCI's $54 million investment of Cures Act
    funds across 5 fiscal years to establish four Cancer Immune Monitoring
    and Analysis Centers and a Cancer Immunologic Data Commons. Together,
    the centers and data commons will operate as a network to identify
    mechanisms of response and resistance to cancer therapy and to support
    adult and pediatric immunotherapy trials.
        NCI created the immunotherapy network to speed discovery of
    molecular signatures associated with immune response and to predict
    whether immunotherapy will benefit individual patients. The network
    will identify biological markers of disease and response to treatment
    that researchers and clinicians can use to design optimum treatment
    strategies for cancer patients. The entire cancer research community
    can access data from analysis conducted by the four centers and use
    this resource to further their research on cancer cures. Other
    priorities of the NCI immunotherapy network and the 12 PACT partners
    include establishing a set of standardized biomarkers for testing in
    research studies, harmonizing assays to strengthen data
    reproducibility, fostering data comparability across clinical trials,
    and reducing duplication of effort, thereby allowing researchers to
    conduct more high-quality clinical trials for children and adults with
    cancer.
        In addition to support for PACT, NCI also awarded Cures Act funding
    to other promising research on harnessing the immune system to attack
    cancer. The goal of this research is to expand the initial successes in
    immunotherapy to a much wider range of cancers, to a broader range of
    patients experiencing the same form of cancer, and to cancers that have
    been most resistant to cure.
    Appropriations for Other Cancer Research Priorities
        While the 21st Century Cures Act deserves prominence in any
    discussion of NCI's current cancer research priorities, as a component
    of our total budget, fiscal year 2017 Cures Act funding represented
    about 5 percent of NCI's total cancer research appropriation. It is
    therefore important to emphasize the breadth of other research that
    NCI's appropriation conducts.
        As the detailed narrative accompanying NCI's budget request
    demonstrates, sustained progress that will benefit cancer patients
    relies on many forms of research, including:
      --basic research, such as genetics, cell biology, immunology, and
            structural biology
      --translational and clinical sciences to prevent, screen, and
            diagnose cancer, and to develop and test drugs, biomarkers,
            imaging technologies, diagnostics, and radiotherapies
      --population sciences, including epidemiological, environmental, and
            behavioral studies.
        These areas constitute the bedrock of NCI cancer research.
    Continued funding across all these disciplines is essential to
    understanding the causes and mechanisms of cancer, preventing cancer,
    strengthening cancer screening, developing and refining cancer
    therapies, and improving cancer survivorship. Many of these disciplines
    will experience profound changes based on the new understanding of
    cancer that is driving precision oncology and to tailor treatments to
    individuals. Others will continue to depend on more traditional
    approaches to research.
        The research resources that NCI makes available to the cancer
    research community is another mechanism of growing importance to cancer
    science. Examples of NCI research resources include:
      --The Biopharmaceutical Development Program (BDP) produces novel
            antibodies and proteins when they cannot be manufactured
            elsewhere. For example, researchers turned to the BDP to
            manufacture a monoclonal antibody (ch14.18) necessary for a
            clinical trial to proceed. The antibody is now the standard of
            care for children with certain types of neuroblastoma.

        During fiscal year 2018, NCI will use the capability of the BDP to
            expand production of CAR T-cells for use in immunotherapy
            trials. The BDP will help meet the growing demand for
            experimental therapies to serve adult and pediatric patients in
            intramural and extramural clinical trials. CAR T-cell therapy
            is an immunotherapy treatment in which a patient's T-cells (a
            type of immune cell) are modified in the laboratory so they
            bind to cancer cells. Millions of CAR T-cells are grown in the
            laboratory and then given to the patient by infusion, where
            they bind to an antigen on cancer cells and kill them.
      --NCI's Experimental Therapeutics (NExT) program advances
            breakthroughs in new cancer therapies by shortening the
            timeline for drug discovery, development, and approval.
            Researchers with promising cancer drug development projects can
            apply to NExT for assistance to overcome the challenges they
            face along the path to drug approval.

        Vanderbilt University's recent progress developing therapies to
            inhibit a protein known as Mcl-1 is an example of the
            breakthroughs that NExT helps to foster. After engaging NExT
            scientists to resolve therapeutic development challenges,
            Vanderbilt is now collaborating with Boehringer Ingelheim to
            develop drugs to treat a range of cancers known to overexpress
            the Mcl-1 protein.
      --NCI's RAS Initiative supports the development of therapies for
            tumors that contain mutations in the RAS family of oncogenes.
            One-third of all cancers involve RAS gene mutations. Through
            the RAS Initiative, NCI generates standardized reagents,
            assays, and datasets and provides them to scientists worldwide
            to support research on RAS oncogenes.
      --The Cancer Genome Atlas (TCGA)--a collaboration between NCI and the
            National Human Genome Research Institute--is a resource of
            comprehensive, multi-dimensional maps of key genomic changes in
            33 types of cancer. The publicly-available TCGA dataset--
            containing 2.5 petabytes of data--has contributed to more than
            a thousand cancer studies. An NCI priority for fiscal year 2018
            is to update TCGA data with new details on patient therapeutic
            response, outcome, and survival, and to support additional
            clinical research based on the new data.
      --Launched in June of 2016, NCI's Genomic Data Commons (GDC) is a
            unified data system for sharing genomic and clinical data. The
            GDC centralizes and standardizes data from large-scale NCI
            programs, and makes it more accessible and useful to scientists
            and clinicians. One measure of the importance of this resource
            is that non-profit and for-profit organizations are now
            offering their data sets for sharing through the GDC.
        I also want to highlight our progress with the NCI Molecular
    Analysis for Therapy Choice (NCI-MATCH) Trial and the Pediatric MATCH
    Trial, two cornerstones of NCI's Precision Medicine Initiative. Rather
    than selecting therapies based on where a tumor originated in the body,
    these trials test the effectiveness of therapies that target specific
    genetic changes. In 2017, the adult NCI-MATCH Trial achieved its
    enrollment goal nearly 2 years ahead of schedule. The trial involves
    more than 6,000 patients from all 50 States at more than 1,000
    institutions.
        NCI opened enrollment for the Pediatric MATCH Trial during fiscal
    year 2017. This is a phase 2 clinical trial for children and
    adolescents with certain advanced solid tumors that have not responded
    to treatment or have progressed on standard therapy. The study is led
    jointly by NCI and the Children's Oncology Group, a clinical trials
    group including more than 9,000 childhood cancer experts across 3
    continents that is part of the NCI-sponsored National Clinical Trials
    Network. The Pediatric MATCH trial is taking place at 200 participating
    children's hospitals, university medical centers, and cancer centers
    across the United States.
        Thanks to support from Congress over many years, NCI research in
    these and other areas has yielded important results that have
    contributed to steady decreases in cancer mortality. Sustained
    Congressional support for NCI and the national cancer program has led
    to new diagnostics, treatments, and prevention strategies, improved our
    ability to manage the symptoms of cancer and the side effects of cancer
    treatments, and allowed us to more effectively monitor the prevalence
    of cancers and the factors associated with cancer risk.
        NCI-led cancer research on prevention and treatment is paying off:
    translating into a more than 25 percent reduction in cancer death rates
    since 1991. Yet despite steady progress, too many Americans face a
    cancer diagnosis, and far too many still die from the disease. There
    will be more than 1.6 million new cases of cancer in the United States
    in the coming year and more than 600,000 will likely die from cancer.
        Thus, much work remains to meet the needs of those suffering from
    cancer, those at risk of cancer, and the growing population of cancer
    survivors. The resources proposed in this fiscal year 2019 budget will
    allow NCI to continue to conduct our cancer research mission in ways
    that deliver important results for the patients we serve.
                                     ______

    Prepared Statement of David Shurtleff, Ph.D., Acting Director, National
                Center for Complementary and Integrative Health
        Mr. Chairman and Members of the Committee: I am pleased to present
    the President's fiscal year 2019 budget request for the National Center
    for Complementary and Integrative Health (NCCIH) of the National
    Institutes of Health (NIH).
        The mission of NCCIH is to define, through rigorous scientific
    investigation, the safety and effectiveness of complementary and
    integrative health approaches, which are a group of practices and
    products that originate outside of conventional medicine. This diverse
    group of health practices includes natural products such as dietary
    supplements, plant-based products, and probiotics, as well as mind-body
    approaches such as yoga, massage therapy, meditation, mindfulness-based
    stress reduction, spinal manipulation, and acupuncture. According to a
    2012 National Health Interview Survey (NHIS), Americans are spending
    approximately $30.2 billion a year on complementary approaches to
    improve their overall health, manage symptoms of chronic diseases, and/
    or counter the side effects of conventional medicine. However, the
    scientific research base surrounding the safety and efficacy of these
    practices is limited. Therefore, NCCIH is committed to providing the
    American public with valuable information about these practices, while
    also investigating how specific complementary approaches can be
    integrated into conventional medical care.
           exploring nonpharmacologic approaches for pain management
        NCCIH is devoting significant resources to understand the basis of
    pain and how complementary and integrative health approaches can be
    utilized in pain management. Pain is a major public health problem and
    is the most common reason Americans turn to complementary and
    integrative health practices. Data from the 2012 NHIS found that an
    estimated 25.3 million adults in the U.S. (11.2 percent) experience
    daily pain with nearly 40 million adults (17.6 percent) experiencing
    severe levels of pain. The use of highly addictive opioids as a primary
    pain management strategy in the U.S. is helping to fuel the growing
    opioid misuse epidemic. Improved strategies for pain management may
    lead to a decreased reliance on opioids for patients suffering from
    pain. NCCIH supports research to better understand the biologic
    mechanisms of pain and to identify effective nonpharmacologic
    approaches to reduce the duration and intensity of pain.
        Research supported at NCCIH is focused on understanding the role of
    the brain in perceiving, modifying, and managing pain, with the long-
    term goal of improving clinical management of chronic pain through the
    integration of pharmacologic and nonpharmacologic approaches. Recently,
    scientists discovered a new class of sensory nerve cells that respond
    to high-threshold (intense) mechanical stimuli, such as hair pulling.
    This work provides insights into how our bodies encode and transmit
    pain sensations. Another study mapped the regions of the brain
    activated during pain to establish a ``pain signature'' and found that
    specific regions of the brain respond to pain intensity, while other
    regions mediate the psychological effect, and yet another region showed
    increased activity related to pain relief. This work not only provides
    insights into how pain is interpreted but could lead to the development
    of new methods to detect, quantify, or target pain.
        NCCIH-supported research is also advancing understanding of the
    mechanisms of action of mind and body interventions and determining
    their effectiveness for treating pain. One study investigated the
    effect of acupuncture on carpal tunnel syndrome and found that it
    affected activity within brain pain centers, decreased associated pain
    symptoms, and improved overall wrist function. Mindfulness meditation
    is another promising area of research. Numerous studies have shown that
    mindfulness meditation helps relieve pain, but the mechanism through
    which meditation exerts this effect is not well known. New study
    results demonstrate that mindfulness meditation activates the same
    region of the brain as opioids; however, it reduces pain independently
    of opioid neurotransmitter mechanisms. These results suggest that
    greater pain control could be achieved through the combination of
    mindfulness meditation and opioid-signaling-induced pharmacologic
    approaches. NCCIH-supported research has also shown that mindfulness-
    based stress reduction and cognitive behavioral therapy can improve
    functioning and reduce chronic low back pain in young and middle-aged
    adults and may provide patients with skills for long-term management of
    pain. Studies have demonstrated that these approaches resulted in
    substantial cost savings over usual care.
        Based on these and other promising results, NCCIH is leading a new
    multi-agency partnership between the NIH, Department of Defense (DoD)
    and Department of Veterans Affairs (VA). This initiative, called the
    NIH-DoD-VA Pain Management Collaboratory (PMC), addresses the need to
    focus on ``advancing better practices for pain management,'' which is
    outlined in HHS's five-point strategy to combat the opioid crisis. The
    PMC will focus on developing, implementing, and testing cost-effective,
    large-scale, real-world research on nondrug approaches for pain
    management and related conditions in military and veteran healthcare
    delivery organizations. The PMC launched in fiscal year 2017 and the
    agencies plan to fund 11 two-year UG3 (Planning Phase) awards, and up
    to 10 four-year subsequent UH3 (Implementation Phase) Demonstration
    Projects, contingent upon successful completion of the short-term pilot
    and feasibility studies In addition, a PMC Coordinating Center has been
    established at Yale University and the Veteran's Administration
    Hospital in Connecticut to provide leadership and serve as a resource
    for the projects by providing innovative tools and best practices.
    Types of approaches being studied include mindfulness/meditative
    interventions, movement interventions (e.g., structured exercise, tai
    chi, yoga), manual therapies (e.g., spinal manipulation, massage,
    acupuncture), psychological and behavioral interventions (e.g.,
    cognitive behavioral therapy), integrative approaches that involve more
    than one intervention, and integrated models of multi-modal care. The
    results of these studies may inform new pain management practices
    within the DoD and VA and support the use of nondrug approaches for
    pain management in the general population
                     advancing research on natural products
        According to the 2012 NHIS, nearly one in five U.S. adults use
    botanical supplements and other non-vitamin, non-mineral dietary
    supplements, such as fish oil/omega-3 fatty acids and probiotics.
    Adverse events related to dietary supplements are estimated to
    contribute to 23,000 emergency department visits in the U.S. each year.
    To better inform consumers and their healthcare providers, NCCIH
    supports rigorous research on the biological mechanisms of the benefits
    and potential harmful effects of natural products with the goal of
    improving the body of knowledge available to healthcare providers and
    patients.
        NCCIH is supporting a Center of Excellence to determine how best to
    study potential adverse interactions between natural products and
    conventional medications. The goal is to develop a definitive approach
    to determine the clinical relevance of supplement-drug interactions to
    inform design of future research and, ultimately, decisionmaking about
    using natural products and medications together.
        In fiscal year 2015, NCCIH partnered with NIH's Office of Dietary
    Supplements (ODS) to establish the Centers for Advancing Research on
    Botanical and Other Natural Products (CARBON) Program. Through this
    program, researchers recently identified two chemicals found in grapes
    that could significantly reduce depression-like behaviors in mice. The
    systems targeted by these compounds are not the same as current
    pharmaceutical antidepressants and may provide novel insights into the
    biology of depression and could lead to new therapeutic agents. The
    program is also developing new methods for chemical characterization of
    natural product mixtures, biological profiling assays, and creating new
    informatic tools to rigorously analyze and share data.
        NCCIH is also supporting research on cytisine, a natural product
    for smoking cessation. Despite promising results from clinical trials
    conducted outside the U.S., cytisine has not yet been approved for use
    in the U.S. NCCIH supported a series of pre-clinical studies on
    cytisine through a strategic collaboration with Achieve Life Sciences,
    Inc., OncoGenex Pharmaceutical, Inc., other NIH ICs, and private
    research organizations. Phase 2 clinical studies will further assess
    cytisine as a smoking cessation treatment. This continuing public-
    private partnership may lead to the wide availability of a new option
    to address the major public health issues associated with tobacco use.
                                   conclusion
        As a responsible steward of resources, NCCIH supports
    scientifically meritorious basic, mechanistic, clinical, and
    translational research. The Center focuses on areas with the greatest
    potential impact by prioritizing research topics that show scientific
    promise and are amenable to rigorous scientific inquiry. We leverage
    strategic partnerships to build the scientific evidence needed on the
    safety and efficacy of complementary health approaches and disseminate
    evidence-based information to the American public.
                                     ______

        Prepared Statement of Dr. Paul Sieving, Director, National Eye
                                   Institute
        Mr. Chairman and Members of the Committee: I am pleased to present
    the President's fiscal year 2019 budget request for the National Eye
    Institute (NEI) of the National Institutes of Health.
                         fifty years of vision research
        It may have been a hot day on August 16, 1968, when President
    Johnson signed Public Law 489 to create the National Eye Institute, but
    on March 21, 2018, the biggest blizzard of the season threatened a
    reception hosted by Congressman Pete Sessions to celebrate NEI's 50th
    anniversary. However, snow didn't deter over 100 vision research
    stakeholders, National Institutes of Health scientists, patients, and
    members of Congress from coming out to recognize the vision-saving
    progress made in the past half century. While my statement usually
    covers the latest advances, I want to start by reflecting on some of
    our remarkable research progress, which has advanced clinical vision
    care.
        Over the past 50 years, NEI has funded research of nine Nobel Prize
    winning scientists, including discovery of the molecular mechanisms by
    which specialized neurons in the retina detect photons of light
    entering the eye and initiate biochemical and electrical signals to the
    brain that convey vision. The key light-detecting protein, rhodopsin,
    became the first cell membrane-bound protein studied by x-ray
    crystallography and imaged to reveal the protein structure in three
    dimensions. This paved the way for the study of other molecules in
    diseases in and beyond the eye. NEI-funded Nobel laureates also made
    landmark neuroscience discoveries of how brain circuits form and self-
    organize in the visual cortex. This has revolutionized treatment for
    amblyopia, a disorder in which the brain favors visual information
    coming from one eye over the other. The first use of antiviral
    chemotherapy was developed for the eye to treat herpes outbreaks on the
    cornea. In ground-breaking work, NEI scientists discovered the first
    tumor suppressor gene, retinoblastoma, which transformed all of cancer
    biology. Conversely, in the past decade, the ocular adaptation of a
    cancer drug that blocks growth of abnormal blood vessels treats two of
    the leading causes of blindness: age-related macular degeneration (AMD)
    and diabetic retinopathy, stopping disease progression, and in many
    cases, reversing vision loss for medical benefit to thousands of
    patients.
        In its early years, NEI pioneered new methodology for conducting
    placebo-controlled, multi-center clinical trials, which led to vision-
    saving laser surgery to treat diabetic retinopathy, AMD, and glaucoma.
    Large trials identified dietary supplements demonstrated to slow
    progression to end-stage AMD. Trials compared effectiveness of
    different therapies for AMD, diabetic retinopathy, and an inflammatory
    eye condition called uveitis, to inform patients and their doctors of
    options for personalized treatment. Elevated fluid pressure in the eye,
    called ocular hypertension, is a precursor for glaucoma, especially in
    African Americans who have a disproportionate burden of this disease.
    1,500 patients participated in the Ocular Hypertension Treatment Study,
    including 400 African American participants, which led to new treatment
    guidelines that can reduce incidence in African Americans by 50
    percent. A 20-year follow-up study is currently underway to assess the
    long-term impact. More recently, the first application of genomics
    methods led NEI scientists to uncover new genetic components for AMD,
    opening the door to new treatments. Before NEI was established, a major
    cause of lifelong blindness was retinopathy-of-prematurity (ROP), a
    disease caused by abnormal development of retinal blood vessels in low
    birth weight babies born very prematurely. Technology to identify and
    treat ROP has improved dramatically over the years and a recent NEI
    trial demonstrated that premature infants can be screened for ROP
    remotely via telemedicine, expanding access to specialists in rural and
    underserved communities.
                       recent progress in vision research
        NEI-supported vision research remains on the forefront of medicine,
    from regenerative medicine to replace neural tissue lost due to retinal
    degeneration; to advancing retinal prosthetics, including the Argus II
    artificial retina which was approved by FDA through the Humanitarian
    Device Exemption pathway; and pioneering the application of gene
    therapy to correct blinding disease-causing mutations. One landmark
    occurred in December 2017, when the FDA approved the first ever gene
    therapy in the U.S. to correct a retinal degeneration, Leber Congenital
    Amaurosis, which causes blindness in infants and children. The genetic
    mutation had earlier been discovered by an NEI scientist in 1993, but
    researchers had to invent the tools to turn that discovery into a gene
    therapy. Having set this precedence for all of medicine, the path from
    gene discovery to clinical trial is now being expedited with vision
    loss mutations in a dozen genes currently being addressed in pre-
    clinical and clinical studies.
        Also in December, FDA approved two new drugs for glaucoma, the
    first new medications for this disorder in 18 years. This new class of
    drugs lowers pressure in the eye through novel targets that are
    different from existing medications. An ongoing clinical trial is
    testing a combination therapy of the newer and older drugs used
    together, which may prove more effective than either drug alone. This
    research represents the culmination of over 25 years of NEI basic
    research on molecules that control the contractile machinery of cells,
    which regulate the flow of fluid out of the eye.
        Idiopathic intracranial hypertension (IIH), which primarily affects
    obese young women, causes the buildup of pressure on the optic nerve,
    leading to vision loss in nearly 10 percent of patients. The recently
    completed IIH Treatment Trial of 165 patients showed that for mild
    vision loss, intervention with acetazolamide plus diet was superior to
    diet alone for reducing vision loss and improving quality of life.
    However, neither intervention was effective for patients with moderate
    to severe vision loss. NEI is funding a new three-arm trial testing
    different surgical interventions to relieve pressure and protect the
    optic nerve in 180 IIH patients with more severe vision loss.
                             seeing into the future
        The NEI Audacious Goals Initiative (AGI) seeks to restore vision
    through neuroregeneration in the eye and visual system. This
    fundamental regenerative medicine approach was initiated in 2013 and is
    advancing rapidly. NEI has established two collaborative consortia of
    research teams working on different facets of the challenge: one on
    functional imaging, and a second for discovery science to identify new
    regeneration factors by looking in model systems. For example, unlike
    adult mammals, zebrafish can regenerate their retina after injury,
    which led NEI researchers to identify a key regeneration factor,
    present in newborn mice, and through manipulating this factor, they
    caused new neurons to form in adult mice. Scientists also found that
    exosomes secreted from stem cells protect a type of retinal cells, the
    ganglion cells, which are damaged by glaucoma. Exosomes are now being
    examined for potential therapeutic effect. Exosome-treated rats lost
    only a third of their retinal ganglion cells following optic nerve
    injury, compared with 90 percent loss in untreated rats. NEI is now
    reviewing proposals for a third AGI consortium, to develop animal model
    systems to facilitate translation of discovery research into the
    clinic.
        NEI just launched new stem cell trials for retinal vein occlusion
    (RVO)--the second leading retinal vascular cause of vision loss after
    diabetic retinopathy, and for limbal stem cell deficiency (LSCD). In
    RVO, the vessels draining blood from retinal tissue become clotted,
    leading to leaking and bleeding and ultimately starving the neurons of
    oxygen. The trial will test the safety, feasibility and efficacy of
    injecting stem cells derived from the patient's own bone marrow into
    their eyes. Corneal limbal cells, are responsible for renewing the
    front layer of the transparent cornea. In thousands of patients with
    LSCD, loss of these cells causes visual impairment from chronic
    inflammation, abnormal blood vessel growth, and opaque corneas. The
    21st Century Cures Act Regenerative Medicine Program is supporting an
    NEI project to treat LSCD. Researchers identified a limbal cell marker,
    ABCB5, which has allowed them to isolate, purify and expand limbal stem
    cells in the lab in sufficient quantities for transplantation. This
    summer, NEI scientists are about to launch the first clinical trial
    using induced pluripotent stem cells-derived retinal tissue to treat
    the dry form of AMD. Skin cells taken from AMD patients will be
    manipulated in the lab for about 3 months, then transplanted back into
    the same patients, thereby minimizing rejection of foreign tissue that
    affects many types of transplant therapies.
        In 2017, NEI launched a 3D Retina Organoid Challenge Competition
    (3D-ROC), with the goal of developing functioning ``mini-retinas'' in a
    culture dish from human adult stem cells. In September, NEI awarded the
    $90,000 prize for the Phase I Ideation Stage, to a team that developed
    the concept of building a retina by screen-printing adult neural
    progenitor-derived retinal cells in layers that mimic the structure of
    the human retina. The system is designed to be scalable, efficient, and
    reproducible, enabling high throughput screening for drug testing. In
    February 2018, NEI launched Phase II, which soon will award up to $1
    million in prizes for developing this work to the critical stage of
    functional prototypes of human retinas.
        In January, NEI announced the launch of a new strategic planning
    process, under the auspices of the National Eye Advisory Council. The
    5-year plan will be developed with significant community input,
    centered around scientific program working groups. It will also align
    with the NIH Strategic Plan and requirements laid out in the 21st
    Century Cures Act, including research to address health disparities.
                                     ______

        Prepared Statement of Martha J. Somerman, DDS, Ph.D., Director,
             National Institute of Dental and Craniofacial Research
        Mr. Chairman and Members of the Committee: I am pleased to present
    the President's fiscal year 2019 budget request for the National
    Institute of Dental and Craniofacial Research (NIDCR) of the National
    Institutes of Health (NIH).
        The mission of NIDCR is to improve dental, oral, and craniofacial
    health through research, research training, and the dissemination of
    health information. A recent study looking at personal healthcare
    spending in the United States by condition estimates that Americans
    spend $66.4 billion annually on the treatment of oral disorders and
    another $48.7 billion for general dental care and preventive services.
    Together, the total surpasses the costs of treatment related to a
    common condition among Americans--diabetes--by more than $13
    billion.\18\ NIDCR leads the effort to reduce this burden by supporting
    basic, translational, and clinical research and research training to
    improve dental, oral, and craniofacial health. By promoting the timely
    translation of those findings into practice NIDCR helps advance
    treatment and prevention strategies for all Americans.
    ---------------------------------------------------------------------------
        \18\ Dieleman J. US Spending on Personal Health Care and Public
    Health, 1996-2013. JAMA. 2016; 316(24):2627-2646.
    ---------------------------------------------------------------------------
        To prioritize emerging areas of scientific inquiry that are ripe
    for significant advances over the next decade, we launched a long-term
    strategic initiative called NIDCR 2030. As part of this bold, forward-
    looking plan, NIDCR will support research that integrates oral health
    into overall health and uncovers the common risk factors and underlying
    biological mechanisms of health and disease throughout the body. This
    knowledge will inform the development of new preventative and
    therapeutic interventions to improve dental, oral, and craniofacial
    health--as well as the health of the whole body.
              pioneering a gene therapy to treat chronic dry mouth
        For most people who survive head and neck cancers, successful
    treatment with radiation therapy comes at a high price--significant
    loss of salivary gland function, leading to chronic dry mouth and its
    adverse health effects. Radiation therapy works by killing malignant
    tumor cells, but it does not discriminate among cell types. It also
    kills saliva-producing cells, which causes saliva production to shut
    down. This can lead to problems chewing, tasting, talking, and
    swallowing food, and significantly increases the risks for dental
    decay, tooth loss, and oral infections. NIDCR supports research to
    unravel the complex molecular and cellular processes involved in
    salivary gland function and fluid secretion. These investments have
    inspired the development of a gene therapy to treat chronic dry mouth
    caused by radiation treatment. The therapy delivers specific DNA
    sequences into the surviving salivary gland cells, resulting in the
    production of specialized tube-shaped proteins called aquaporins, which
    allow water to flow out of the salivary gland cells. Studies in mouse
    models showed that the gene therapy generated enough aquaporin proteins
    to restore salivary flow. This research led to a clinical trial
    conducted on the NIH campus that is currently recruiting patients to
    test the gene therapy treatment in people whose salivary glands have
    been damaged by radiation therapy for head and neck cancer. Results
    from the first phase of the study are encouraging and suggest that this
    approach could be a promising treatment. Building on these studies,
    another clinical trial is being planned to see if the therapy can also
    be used to restore salivary function in individuals whose chronic dry
    mouth is caused by Sjogren's syndrome, an autoimmune disorder that
    damages salivary glands.
       developing innovative techniques to advance regenerative medicine
        A major priority for NIDCR is advancing regenerative medicine
    research to improve the lives of those with dental, oral, and
    craniofacial conditions or diseases. A significant challenge in
    regenerating load-bearing tissues such as joint cartilage is
    engineering and growing tissues that are as strong and flexible as the
    body's natural ones. The cartilage that makes up joints, such as the
    temporomandibular joint in the jaw, must be extremely resilient to
    withstand a lifetime of repetitive movement and mechanical stress. To
    overcome this obstacle, NIDCR-supported scientists are developing
    techniques to generate functional tissues in the laboratory for
    regenerative medicine therapies. These scientists developed a device
    that physically pulls on single layers of cartilage cells while they
    are being grown on a flat, supportive matrix, resulting in tissues with
    strength and elasticity that more closely resembles natural cartilage.
    Using this technique results in engineered cartilage that is more
    resilient to wear and tear, making it especially useful as a potential
    replacement for damaged cartilage in highly mobile joints. Future uses
    could include the development of better treatment options for
    temporomandibular joint and muscle disorders (TMD) and joints damaged
    by osteoarthritis. Further development of this novel cartilage growth
    technique, and its expansion to other cell types could open the door to
    exciting possibilities for the engineering and generation of more
    durable and flexible tissues for use throughout the body.
                    finding pain relief in unexpected places
        Chronic pain is a major health problem that affects almost one-
    quarter of the U.S. population.\19\ Opioids are often prescribed to
    alleviate chronic pain, although they carry a strong risk for
    addiction. Identifying new effective and non-addictive pain treatments
    remains a priority for NIDCR, especially in regard to TMD, a group of
    conditions that can cause severe and chronic pain in the jaw and
    muscles of the head and neck. In 2005, NIDCR launched OPPERA (Orofacial
    Pain, Prospective Evaluation and Risk Assessment)--a multi-site
    population-based study--to identify the biopsychosocial and genetic
    risk factors that cause TMD. Early OPPERA studies found an association
    between the gene for epidermal growth factor (EGFR) and the development
    of chronic pain in patients with TMD. Drugs that block the activity of
    EGFR are currently being used to inhibit tumor growth in some types of
    cancer. Strikingly, there have been case reports of cancer patients
    reporting a significant reduction in pain when treated with EGFR-
    blocking drugs. Taking these observations into the laboratory, NIDCR-
    funded investigators used a mouse model to show that EGFR-blocking
    drugs alleviate inflammatory and neuropathic pain. These drugs function
    by blocking the activity of EGFR in neurons that receive and interpret
    sensory stimuli--such as pain--in the body. This intriguing finding
    could lead to the development of more effective treatments for chronic
    pain that also reduce the risks for addiction.
    ---------------------------------------------------------------------------
        \19\ Gereau RW, et al. A pain research agenda for the 21st century.
    J Pain. 2014; 15(12):1203--1214.
    ---------------------------------------------------------------------------
     advancing treatments for hpv-positive and hpv-negative oropharyngeal
                                    cancers
        Oropharyngeal cancers form in the middle part of the throat,
    including the back of the mouth, base of the tongue, and the tonsils,
    and are often caused by HPV (human papilloma virus), the same virus
    that causes cervical cancer. These cancers are known as HPV-positive
    (HPV+) oropharyngeal cancers. Experts estimate that 60 to 70 percent of
    newly diagnosed oropharyngeal cancers in the United States are likely
    to be HPV+, especially among young men and women. Although people
    exposed to the HPV virus are more likely to develop oropharyngeal
    cancer, paradoxically, HPV+ cancers respond much more successfully to
    chemotherapy than HPV-negative (HPV-) cancers. A collaboration of
    clinicians and basic science researchers funded by NIDCR are studying
    the biomolecular reasons for this difference in treatment outcomes to
    see if there is a way to separate out the HPV+ beneficial response to
    treatment and then apply it to HPV-negative (HPV-) oropharyngeal
    cancers. To do this they looked closely at the activities of
    cisplatin--the most commonly used chemotherapy for many cancers--which
    is better at killing HPV+ cancer cells than HPV-cancer cells. The team
    discovered an HPV protein called E7 that enhances the effectiveness of
    cisplatin treatment, and then developed a small protein fragment
    (peptide) called E2F5 that mimics the HPV protein E7 without the HPV
    infection. Combining this novel peptide with cisplatin treatment in
    HPV-negative patients led to improved outcomes, similar to those of
    HPV+ patients. Next steps will be to clear the FDA requirements for
    producing the E2F5 peptide and establishing treatment protocols for
    clinical trials.
                                     ______

    Prepared Statement of Eliseo J. Perez-Stable, M.D., Director, National
              Institute on Minority Health and Health Disparities
        Mr. Chairman and Members of the Committee: I am pleased to present
    the President's fiscal year 2019 budget request for the National
    Institute on Minority Health and Health Minorities of the National
    Institutes of Health (NIH).
        advancing the science of minority health and health disparities
                                    research
        Today, revolutionary advances in biomedical science, such as the
    emergence of genomics, precision medicine, and health information
    technology hold greater promise to improve our Nation's health than has
    ever before been possible. We are on the cusp of major scientific
    advances that will change how we think about minority health and health
    disparities. The mission of the National Institute on Minority Health
    and Health Disparities (NIMHD) is to lead scientific research to
    improve minority health and reduce health disparities. To accomplish
    this, NIMHD plans, coordinates, reviews, and evaluates NIH minority
    health and health disparities research and activities; conducts and
    supports research in minority health and health disparities; promotes
    and supports the training of a diverse research workforce; translates
    and disseminates research information; and fosters innovative
    collaborations and partnerships. As part of its charge to improve
    minority health and reduce health disparities, NIMHD is currently
    developing the 2018-2022 Trans-NIH Minority Health and Health
    Disparities Strategic Plan in collaboration with the other NIH
    Institutes and Centers and with input from community partners and key
    stakeholders. Once completed, this strategic plan will provide a
    blueprint to advance the direction and goals of minority health and
    health disparities research.
        As the science of minority health and health disparities research
    evolves, a critical multidisciplinary approach is needed to focus on
    research studies that facilitate scientific advances to improve
    minority health and to reduce health disparities. Minority health
    research is the scientific investigation of distinctive health
    characteristics and attributes of minority racial and/or ethnic groups
    who are underrepresented in biomedical research in order to understand
    population health outcomes. Health disparities research is a field of
    study devoted to gaining greater scientific knowledge about the
    influence of health determinants, understanding the role of different
    pathways leading to disparities, and determining how findings
    translates into interventions to reduce health disparities. In order to
    ensure that all populations have an equal opportunity to live healthy
    and productive lives, NIMHD leads advancement in minority health and
    health disparities research and promotes a diverse scientific workforce
    reflective of the population.
                                    research
        Advancing the science of minority health and health disparities
    requires scientific vision; that means building and developing
    evidence-based information that takes into account the social
    determinants of health and the places where we live, learn, work, and
    play. To meet the demands of keeping up with biomedical advances, NIMHD
    is strengthening research in minority health and health disparities;
    increasing opportunities for investigator-initiated research;
    strengthening the evaluation and reporting of minority health and
    health disparities research; and supporting the expansion of workforce
    diversity.
        NIMHD promoted the fields of minority health and health disparities
    by developing and posting NIMHD's Research Framework, a transformative
    scientific agenda which addresses the complex influences on health and
    health disparities. Specifically, the Research Framework reflects an
    evolving conceptualization of factors relevant to the understanding and
    promotion of minority health and to the understanding and reduction of
    health disparities. The framework focuses on how these influences
    affect individuals, families, communities and society at large. It
    serves as a vehicle for encouraging NIMHD- and NIH-supported research
    that addresses the complex and multi-faceted nature of minority health
    and health disparities and guides researchers on where on the
    scientific spectrum their research fits.
        NIMHD's increased emphasis on the science of minority health and
    health disparities has evolved into the three focused areas of clinical
    and health services research, integrative biological and behavioral
    research, and community health and population sciences. The Clinical
    and Health Services Research area generates new knowledge to improve
    health outcomes and quality of healthcare for minority and underserved
    populations within the context of everyday clinical practice. It
    examines the development of preventive, diagnostic and therapeutic
    healthcare interventions that can contribute to reducing health
    disparities and how precision patient-clinician communication may
    reduce health disparities. Moreover, it supports clinical research that
    generates new knowledge to improve health outcomes and quality of
    healthcare. For example, researchers found that childhood cancer
    survivors who reported greater well-being rated religion and
    spirituality of high importance, accessed specialized cancer services
    more regularly, and expressed a greater level of healthcare self-
    efficacy.
        The Integrative Biological and Behavioral Research area examines
    research on how biological and behavioral mechanisms and pathways
    influence resilience and susceptibility to adverse health conditions
    that disproportionately affect racial and ethnic minority populations,
    persons of less privileged socioeconomic status, and other health
    disparity populations. Research examples in this area include genomic
    and epigenomic risk and protective factors; human microbiome
    contributions to health and disease; and mechanisms through which
    behavioral risk and protective factors influence the development of
    adverse health conditions by triggering adverse biological pathways.
    For example, research found that changes in DNA, as a consequence of
    environmental factors, can be used to accurately estimate gestational
    age. This novel measure of gestational age may be a useful tool in
    addressing persistent higher rates of low birth weights for some
    minority populations.
        The Community Health and Population Sciences research area focuses
    on community engaged research and large studies of populations in a
    defined geographic area that reflect overall health of minority and
    underserved population groups. Community engagement refers to the
    active participation of community members in contributing to the
    research process in a partnership with investigators. Studies within
    this area examine causes, prevention, screening, early detection, and
    management of disease such as epidemiologic studies that identify and
    describe disease burden and risk factors in disparity populations;
    behavioral, sociocultural, and environmental influences on disease
    risks and outcomes; and research integrating the multiple determinants
    of health at the biologic, behavioral, and contextual levels and their
    interactions. In a study examining the perspective of older breast
    cancer survivors toward physical activity, researchers found that
    physical activity programs should focus on cancer treatment related
    concerns and include strength training.
        Innovative partnerships and collaborations are instrumental and
    essential to improve minority health and reduce health disparities.
    NIMHD supports research partnerships across NIH and the Federal
    Government with a goal to create synergistic research approaches to
    improve public health for health disparity populations. Partnerships
    conducted and supported by the NIMHD have created innovative studies
    into how to promote screening for breast, prostate, and pancreatic
    cancers; examine how children's experiences affect brain development;
    investigate the effects of environmental exposures--including physical,
    chemical, biological, social, behavioral, natural and built
    environments--on child health and development; understand the sources
    of persistent health disparities in overall longevity, cardiovascular
    disease, and cerebrovascular disease; and to eventually eliminate
    health disparities in dental care and oral/pharyngeal cancer.
                    building a diverse biomedical workforce
        At the core of NIMHD's transformative scientific agenda is its
    commitment to building institutional research capacity and a diverse
    cadre of minority health and health disparities researchers. The
    Centers of Excellence program creates collaborative hubs for minority
    health and health disparities research among research institutions and
    local communities, which support early-career scientists as well as
    established investigators. The Research Centers in Minority
    Institutions program builds research capacity, supports a new
    generation of researchers from underrepresented populations through
    pilot funding, and funds established scientists to conduct cutting edge
    science in basic, behavioral or clinical research topics. The Research
    Endowment program provides funds to low resource academic institutions
    with a diverse student body and faculty to support endowments that will
    help to support a training or research capacity program to promote
    minority health and health disparities research.
        NIMHD is committed to supporting and developing a diverse
    biomedical workforce. We support training grants across the spectrum of
    experience from pre-doctoral awards through mid-career awards.
    Moreover, NIMHD has enhanced opportunities for early-stage
    investigators by: expanding awards to help senior postdoctoral fellows
    and junior faculty-level candidates to become competitive for major
    grant support; providing fellowships to help less experienced
    researchers to become productive, independent investigators; and
    restructuring the NIMHD Health Disparities Research Institute to
    support career development for promising early-career minority health
    and health disparities research scientists.
                                   conclusion
        NIMHD continues to advance the science of minority health and
    health disparities by building upon evidence-based research; developing
    researchers from underrepresented populations and retaining their
    diverse insights; and enhancing programs that create research
    infrastructure and train a diverse scientific workforce. Through this
    scientific research agenda, NIMHD's mission and vision will lead to
    discoveries that will promote health equity and ultimately improve
    minority health and reduce health disparities.
                                     ______

       Prepared Statement of Lawrence A. Tabak, D.D.S., Ph.D., Principal
                    Deputy Director, Office of the Director
        Mr. Chairman and Members of the Committee: I am pleased to present
    the President's fiscal year 2019 budget request for the Office of the
    Director (OD) of the National Institutes of Health (NIH).
        The OD promotes and fosters NIH research and research training
    efforts in the prevention and treatment of disease through the policy
    oversight of both the extramural grant and contract award functions,
    the Intramural Research program, and through the coordinating efforts
    of several cross-cutting program offices responsible for stimulating
    specific areas of research throughout NIH to complement the ongoing
    efforts of the Institutes and Centers. The OD also develops policies in
    response to emerging scientific opportunities employing ethical and
    legal considerations; coordinates the communication of health
    information to the public and scientific communities; provides
    oversight and management of peer review policies; and coordinates
    information technology across NIH. The OD also provides the core
    administrative and management services, such as budget, human
    resources, property management, procurement services, ethics oversight,
    committee management, and the administration of equal employment
    policies and practices.
        The fiscal year 2019 budget request will also support activities
    managed by the OD's operational offices. The OD Operations is comprised
    of several OD Offices that provide advice to the NIH Director, policy
    direction and oversight to the NIH research community, and administer
    centralized support services essential to the NIH mission. In addition
    to the Common Fund (CF) administered by the Division of Program
    Coordination, Planning, and Strategic Initiatives, two additional
    research programs, Environmental Influences on Child Health Outcomes
    (ECHO) and the All of Us Research Program, are coordinated within the
    OD. The functions and initiatives of the OD's research offices and
    programs are described in detail as follows:
     division of program coordination, planning, and strategic initiatives
        DPCPSI (Division of Program Coordination, Planning, and Strategic
    Initiatives) provides leadership for identifying, reporting, and
    funding trans-NIH research that represents important areas of emerging
    scientific opportunities, rising public health challenges, or knowledge
    gaps that merit further research and would benefit from collaboration
    between two or more ICs, or from strategic coordination and planning.
        DPCPSI includes major programmatic offices that coordinate, and
    support research and activities related to HIV/AIDS, women's health,
    behavioral and social sciences, disease prevention, dietary
    supplements, and research infrastructure. DPCPSI serves as a resource
    for the ICs and OD for portfolio analysis by developing, using, and
    disseminating data-driven approaches and computational tools. DPCPSI
    serves as the focal point for coordinating research to advance the
    health and wellbeing of sexual and gender minorities and for American
    Indians and Alaska Natives, and coordinating tribal consultation
    activities for the NIH.
        The Office of Research Infrastructure Program (ORIP) provides
    support for research into model systems of human diseases and a variety
    of research infrastructure needs. ORIP supports a number of
    repositories of animal models, biological materials, genetic stocks,
    and human biospecimens. ORIP also makes grant awards to fund the
    purchase of expensive state-of-the-art scientific instruments and to
    update animal research facilities. ORIP supports training and career
    development for veterinarian-scientists engaged in biomedical research
    and contributing to interdisciplinary research teams addressing topics
    at the intersection of human/animal populations and the environment.
        The Office of Aids Research (OAR) plays a unique role at NIH by
    serving as a model of trans-NIH planning and management, vested with
    primary responsibility for overseeing all HIV/AIDS-related research
    supported by the NIH. OAR coordinates the scientific, budgetary,
    legislative, and policy elements of the NIH HIV/AIDS research program.
    OAR's response to the HIV/AIDS epidemic requires a unique and complex
    multi-institute, multi-disciplinary, global research program. This
    diverse research portfolio demands an exceptional 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.
        The Office of Behavioral and Social Sciences Research (OBSSR)
    furthers the mission of the NIH by emphasizing the critical role that
    behavioral and social factors play in health, healthcare and well-
    being. OBSSR serves as a liaison between NIH and the extramural
    research communities, other Federal agencies, academic and scientific
    societies, national voluntary health agencies, the media, and the
    general public on matters pertaining to behavioral and social sciences
    research. OBSSR's vision is to bring together the biomedical,
    behavioral, and social science communities to work more collaboratively
    to solve the pressing health challenges facing our Nation. OBSSR also
    coordinates and helps support the NIH Basic Behavioral and Social
    Science Opportunity Network, a trans-NIH initiative to expand the
    agency's funding of basic behavioral and social sciences research.
        The Office of Research on Women's Health (ORWH) has worked to
    ensure the inclusion of women in NIH clinical research, to advance and
    expand women's health research, and to promote advancement of women in
    biomedical careers. ORWH is the focal point for NIH women's health
    research and works in partnership with the NIH ICs to incorporate a
    women's health and sex differences research perspective into the NIH
    scientific framework. ORWH activities are guided by the NIH Strategic
    Plan for Women's Health Research. This strategic plan outlines six
    goals to maximize impact of NIH research effort. The NIH strategic plan
    for women's health and sex differences research serves as a framework
    for interdisciplinary scientific approaches.
        The Office of Disease Prevention (ODP) is responsible for
    assessing, facilitating, and stimulating research in disease prevention
    and health promotion, and disseminating the results of this research to
    improve public health. In fiscal year 2019, ODP will release a new
    strategic plan which outlines the priorities that the Office will focus
    on over the next 5 years and highlights ODP's role in advancing
    prevention research at the NIH. The Office of Dietary Supplements (ODS)
    is within the ODP organizational structure. The mission of ODS is to
    strengthen knowledge and understanding of dietary supplements by
    evaluating scientific information, stimulating and supporting research,
    disseminating research results, and educating the public to foster an
    enhanced quality of life and health for the U.S. population.
        The Office of Strategic Coordination (OSC) and the Common Fund
    (CF)- OSC manages the Common Fund (CF), which functions as a ``venture
    capital'' space where high-risk, innovative endeavors with the
    potential for extraordinary impact can be supported. CF supports
    approximately 30 programs that focus on areas of emerging scientific
    opportunities, rising public health challenges, and knowledge gaps that
    deserve special emphasis; that would benefit from strategic
    coordination and planning across NIH Institutes and Centers (ICs); and
    that are designed to address specific, high-impact goals and milestones
    within a 5- to 10-year timeframe. Collectively, these programs
    represent strategic investments aimed at solving problems or building
    resources to affect research throughout the entire biomedical research
    enterprise. Most CF programs consist of a series of integrated
    initiatives that collectively address a set of goals aiming to
    transform the way research is conducted, the way that health and
    disease are understood, and/or the way that diseases are diagnosed or
    treated.
               environmental influences on child health outcomes
        Launched in fiscal year 2016, the Environmental Influences on Child
    Health Outcomes (ECHO) program supports multiple synergistic,
    longitudinal studies by leveraging, harmonizing, and combining existing
    and new data from 83 maternal/pediatric cohorts to create one ECHO-wide
    Cohort with 50,000 participants. Researchers will investigate the
    effects of a broad range of early life environmental exposures (e.g.,
    physical/chemical, societal, psychosocial, behavioral, biological) on
    five key pediatric outcomes with high public health impact: pre-, peri-
    , and postnatal outcomes; upper and lower airway conditions; obesity;
    neurodevelopment and positive health.
        The intervention component of ECHO is the IDeA States Pediatric
    Clinical Trials Network, with a goal to provide access for rural and
    medically underserved children to participate in state-of-the-art
    clinical trials. This network builds institutional capacity, provides
    professional development to researcher and their teams, and leverages
    partnerships with outside academic institutions. In fiscal year 2019,
    having built its infrastructure, ECHO Cohorts will disseminate research
    findings, and the IDeA States Pediatric Network will continue to
    conduct one or more clinical trials.
                           all of us research program
        The All of Us Research Program, launched in fiscal year 2016, is an
    ambitious effort to gather data on the biological, environmental, and
    behavioral influences on health and disease over many years from one
    million or more people living in the United States. All of Us will
    serve as a national research resource to inform thousands of studies,
    covering a wide variety of health conditions and enabling
    individualized prevention and treatment options for patients.
        Since July 2016, All of Us achieved several key implementation
    milestones, including initial study protocol approval, establishment of
    a state-of-the-art biobank to process and store biological samples from
    patients, and construction of a big data IT system to store data for
    research purposes. Working together with a consortium of Federal,
    academic, and industry partners, All of Us began participant enrollment
    for its beta testing phase in May 2017, and, as of March 25, 2018, more
    than 35,000 participants are currently enrolled, of whom over 20,000
    have completed the full protocol.
        The program will begin full-scale, nationwide participant
    enrollment in the spring of 2018.
                                     ______

    Prepared Statement of Dr. Nora Volkow, Director, National Institute on
                                   Drug Abuse
        Mr. Chairman and Members of the Committee: I am pleased to present
    the President's fiscal year 2019 budget request for the National
    Institute on Drug Abuse (NIDA) of the National Institutes of Health
    (NIH).
                   drug use and addiction research priorities
        As a part of NIH, the Nation's premier biomedical research agency,
    NIDA's mission is to advance the science on the causes and consequences
    of drug use and addiction and to apply that knowledge to improve
    individual and public health. NIDA-supported research has transformed
    our understanding of how biological, social, and environmental factors
    contribute to substance use disorders (SUD), generating new knowledge
    that fosters the development of smarter means for preventing and
    treating SUDs.
        Substance use and SUDs represent a constant and dynamic threat to
    the health and well-being of our Nation. Their combined toll is more
    than $740 billion a year in healthcare, crime, and lost productivity;
    but dollars barely capture the devastating human cost of addiction to
    individuals, families, and communities. In 2016 alone, over 63,000
    Americans died because of an unintentional drug overdose. Over 42,000
    of these deaths are attributable to opioids, due in large part to the
    spread of powerful synthetic opioids such as fentanyl and its
    analogues. Other challenges include the disconcerting rise in
    fatalities associated with cocaine and methamphetamine use, as well as
    the rise of new synthetic drugs and delivery systems, such as e-
    cigarettes, that are changing how people perceive and use drugs.
        Despite these complex challenges, this is a time of great
    opportunities. In the last few years we have seen huge technological
    advances and new research applications, from deep sequencing to precise
    gene editing tools, and from more powerful brain imaging technologies
    to mobile health platforms and electronic health records.
        NIDA's commitment to leveraging these advances through synergistic
    collaborations with Federal, community, and industry partners has been
    codified in the 2016-2020 Strategic Plan, which charts our path forward
    according to four broadly defined goals designed to:
      --Understand the complex multilevel interactions influencing drug use
            trajectories.
      --Accelerate the development of treatments for SUDs.
      --Address real-world complexities including comorbidities and poly-
            drug use.
      --Advance bi-directional translation from basic to clinical and
            applied research.
                              research highlights
        I'd like to highlight several high priority research areas that
    NIDA is pursuing, the most prominent of which is addressing the opioid
    crisis with medications development and implementation research efforts
    as well as assessing the impact of adolescent drug use on brain
    development and behavior that will build the evidence for personalized
    prevention.
                                 opioid crisis
        Millions of Americans are suffering from an opioid use disorder
    (OUD). The urgency and scale of this crisis calls for innovative
    solutions:
        Medications Development.--The Division of Therapeutics and Medical
    Consequences supports synthesis and preclinical evaluation of potential
    therapeutics, clinical trial design and execution, and preparing
    regulatory submissions of medications. While there are current
    treatments available to reverse opioid overdose and treat opioid use
    disorder, the continued epidemic underscores the need for improved
    treatment options. In addition to current projects, new projects on
    reformulating drugs are underway and supported by NIDA grants and
    contracts. For example, NIDA support is accelerating the development of
    extended release formulations of existing medications used to treat OUD
    (methadone, buprenorphine, and naltrexone), as well as new medications
    to prevent and reverse overdoses from synthetic opioids or from drug
    combination (alcohol and heroin).
        Criminal Justice.--Juvenile Justice Translational Research on
    Interventions for Adolescents in the Legal System (JJ-TRIALS) is guided
    by the philosophy that all juvenile offenders can benefit from
    evidence-based drug use and HIV-related prevention, screening, and
    treatment interventions. JJ-TRIALS builds on the strong foundation of
    our past work with criminal justice populations and includes three
    interrelated research efforts: (1) a national survey of existing
    practices within the juvenile justice system, (2) a large-scale, multi-
    site randomized study of data-driven strategies to improve justice
    systems' capacity to identify unmet substance use service needs, and
    (3) a pilot study examining the capacity to form partnerships with
    public health providers to address HIV and sexually transmitted
    infection risk behaviors.
        Rural Communities.--In rural areas, a lack of treatment
    infrastructure and poor access to care hamper efforts to stem the tide
    of opioid addiction. Together with SAMHSA, CDC, and the Appalachian
    Regional Commission (ARC), NIDA is funding research to reduce the
    adverse outcomes of injection opioid use in rural communities. Initial
    projects focused on epidemiology, infrastructure, and policy issues to
    lay foundation for future research and planning efforts throughout
    Appalachia, while subsequent projects are testing the effectiveness of
    community response models and best practices in responding to opioid
    injection epidemics that can be implemented in similar rural
    communities across the US.
        Developing Alternative Pain Treatments With Reduced Abuse
    Potential.--In addition to these strategies to reverse the opioid
    overdose epidemic, we must develop more effective and less addictive
    treatments for chronic pain; NIDA is working with the NIH Pain
    Consortium to promote research in this key area. Funded grants span the
    entire range of the therapeutics development spectrum from preclinical
    safety and efficacy testing and early phase human trials, to health
    services research. Worth highlighting in this context are new molecular
    imaging technologies like x-ray crystallography that revealed the
    molecular structure of the receptors that mediate drugs' effects,
    information that is already leading to the development of safer
    medications to treat pain including the potential for developing an
    opioid pain medication devoid of addictive effects.
                   adolescent drug use and brain development
        A deeper understanding of how biological, environmental, social,
    and developmental factors interact and contribute to SUD risk is
    critical for developing better prevention and treatment strategies.
    This is particularly true when trying to understand how early onset
    drug use impacts developmental processes. To address this high priority
    need, NIDA has launched, jointly with other NIH institutes, centers,
    and offices the Adolescent Brain and Cognitive Development (ABCD)
    study, the largest long-term study of brain development and child
    health in the United States. Approximately 10,000 children ages 9-10
    will be studied at 21 research centers across the country; they will be
    followed into early adulthood with brain-imaging, genetic,
    neuropsychological, behavioral, and other health assessments. The
    results will expand our understanding of how drugs can disrupt a young
    person's life trajectory. As of March 2018, more than 8,300
    participants were enrolled in the study and close to 30 terabytes of
    data--about three times the size of the Library of Congress
    collection--had been obtained from the first 4,500 participants.
                            prevention and treatment
        Substance use disorders present a fascinating phenomenon: they are
    wholly preventable but when they strike, they can be utterly
    catastrophic. Hence, it is important to reassess our stance vis a vis
    prevention and treatment as often as possible and in response to new
    developments including the need for prevention strategies to protect
    against opioid initiation that is rising among young adults (early
    twenties).
        Prevention and Treatment.--NIDA supports integrated approaches to
    understanding and developing strategies to addressing the interactions
    between individuals and environments that contribute to substance use
    by fielding the annual Monitoring the Future survey of adolescent
    students. NIDA also supports the National Drug Early Warning System
    (NDEWS) network to survey emerging trends related to illicit drug use.
    The Division also supports research on integrating prevention and
    treatment services into healthcare and community systems to reduce the
    burden of drug problems across the lifespan. Ongoing research is
    exploring SUD treatment in the criminal justice system, including
    studies on implementation of medication-assisted treatment (MAT) and
    seek, test, treat, and retain (STTR) strategies for people with SUDs
    who are also at risk for HIV. NIDA also funds research into the
    efficacy of screening, brief intervention, and referral to treatment
    (SBIRT) in primary care settings for reducing drug use including opioid
    use disorders. Our research also examines the implementation of
    evidence-based universal as well as tailored prevention interventions
    and treatment services in real-world settings. For instance, NIDA is
    funding researchers to partner with States as they use the State
    Targeted Response funding from the 21st Century Cures Act to test
    approaches for expanding access to MAT for opioid use disorder and
    naloxone for the reversal of opioid overdoses.
        The NIDA Clinical Trials Network (CTN) is a collaborative
    partnership with clinicians, researchers, and participating patients
    that cooperatively develops, tests, and delivers new treatment options
    to patients with SUD including opioid addiction. The CTN studies
    behavioral, pharmacological, and integrated treatment interventions in
    rigorous, multisite clinical trials across a network of community-based
    treatment settings. Current CTN-funded trials include studies on how to
    implement buprenorphine in emergency departments and by primary care
    physicians, engagement of pharmacists for prescribing and monitoring
    buprenorphine to patients with an OUD and the effectiveness of a
    combination pharmacotherapy regimen to treat methamphetamine use
    disorder, among others.
        Our efforts to develop effective addiction treatments respond to
    urgent needs while facing significant challenges. For example, despite
    remarkable advances in recent years, our menu of effective addiction
    treatments still presents critical gaps. Most notably, there continues
    to be a dire need for therapies to help treat addiction to stimulant
    drugs, like cocaine and methamphetamines or to help treat addiction to
    marijuana. As a result, NIDA is committed to evaluating the potential
    of emerging new therapies for SUDs, including pharmacological and non-
    pharmacological (e.g. psychosocial, biofeedback, brain stimulation
    technologies). For example, NIDA's IRP is collaborating with partners
    in the pharmaceutical industry to study a potential medication to
    decrease methamphetamine craving and collaborating with Italian
    researchers to test the efficacy of transcranial Magnetic Stimulation
    (TMS) for treatment of cocaine use disorders. The IRP is also exploring
    interventions to reverse the impact of prefrontal cortex deficits
    caused by cocaine or heroin use and to develop clinically useful
    indicators (biomarkers) of addiction severity or treatment efficacy
    that will support the development of more effective treatments.
                                   conclusion
        Substance use and its attending disorders are complex conditions.
    The fiscal year 2019 budget request will allow NIDA to support cutting-
    edge research that leverages the most powerful technologies and latest
    emerging opportunities to expand our understanding of drug use and
    addiction in order to enhance prevention and treatment, help address
    public health emergencies, and improve the health of the public.