    [Senate Hearing 114-717]
    [From the U.S. Government Publishing Office]

                                                            S. Hrg. 114-717

            NOMINATION OF ROBERT CALIFF TO SERVE AS FDA COMMISSIONER

    =======================================================================

                                    HEARING

                                     OF THE

                        COMMITTEE ON HEALTH, EDUCATION,
                              LABOR, AND PENSIONS

                              UNITED STATES SENATE

                        ONE HUNDRED FOURTEENTH CONGRESS

                                 FIRST SESSION

                                       ON

            NOMINATION OF ROBERT CALIFF TO SERVE AS FDA COMMISSIONER

                                   __________

                               NOVEMBER 17, 2015

                                   __________

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                                    Pensions

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              COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS

                      LAMAR ALEXANDER, Tennessee, Chairman

    MICHAEL B. ENZI, Wyoming		PATTY MURRAY, Washington
    RICHARD BURR, North Carolina		BARBARA A. MIKULSKI, Maryland
    JOHNNY ISAKSON, Georgia			BERNARD SANDERS (I), Vermont
    RAND PAUL, Kentucky			ROBERT P. CASEY, JR., Pennsylvania
    SUSAN COLLINS, Maine			AL FRANKEN, Minnesota
    LISA MURKOWSKI, Alaska			MICHAEL F. BENNET, Colorado
    MARK KIRK, Illinois			SHELDON WHITEHOUSE, Rhode Island
    TIM SCOTT, South Carolina		TAMMY BALDWIN, Wisconsin
    ORRIN G. HATCH, Utah			CHRISTOPHER S. MURPHY, Connecticut
    PAT ROBERTS, Kansas			ELIZABETH WARREN, Massachusetts
    BILL CASSIDY, M.D., Louisiana

                   David P. Cleary, Republican Staff Director

                      Evan Schatz, Minority Staff Director

                  John Righter, Minority Deputy Staff Director

                                      (ii)

                                C O N T E N T S

                                   __________

                                   STATEMENTS

                           TUESDAY, NOVEMBER 17, 2015

                                                                       Page

                               Committee Members

    Alexander, Hon. Lamar, Chairman, Health, Education, Labor, and
      Pensions Committee, opening statement..........................     1
    Murray, Hon. Patty, a U.S. Senator from the State of Washington..     3
    Burr, Hon. Richard, a U.S. Senator from the State of North
      Carolina.......................................................     5
    Scott, Hon. Tim, a U.S. Senator from the State of South Carolina.     6
    Whitehouse, Hon. Sheldon, a U.S. Senator from the State of Rhode
      Island.........................................................    16
    Isakson, Hon. Johnny, a U.S. Senator from the State of Georgia...    18
    Warren, Hon. Elizabeth, a U.S. Senator from the State of
      Massachusetts..................................................    20
      Prepared statement.............................................    22
    Roberts, Hon. Pat, a U.S. Senator from the State of Kansas.......    23
    Baldwin, Hon. Tammy, a U.S. Senator from the State of Wisconsin..    25
    Cassidy, Hon. Bill, a U.S. Senator from the State of Louisiana...    27
    Franken, Hon. Al, a U.S. Senator from the State of Minnesota.....    28
    Hatch, Hon. Orrin G., a U.S. Senator from the State of Utah......    30
    Bennet, Hon. Michael F., a U.S. Senator from the State of
      Colorado.......................................................    32
    Sanders, Hon. Bernard, a U.S. Senator from the State of Vermont..    33
    Murkowski, Hon. Lisa, a U.S. Senator from the State of Alaska....    35
    Casey, Hon. Robert P., Jr., a U.S. Senator from the State of
      Pennsylvania...................................................    37

                                    Witness

    Califf, Robert M., M.D., Deputy Commissioner for Medical Products
      and Tobacco, Department of Health and Human Services, Durham,
      NC.............................................................     7
        Prepared statement...........................................     9

                              ADDITIONAL MATERIAL

    Statements, articles, publications, letters, etc.:
        Response by Robert M. Califf, M.D. to questions of:
            Senator Alexander........................................    42
            Senator Enzi.............................................    50
            Senator Burr.............................................    50
            Senator Isakson..........................................    53
            Senator Isakson and Senator Murkowski....................    56
            Senator Isakson and Senator Murphy.......................    56
            Senator Collins..........................................    57
            Senator Hatch............................................    61
            Senator Roberts..........................................    64
            Senator Cassidy..........................................    68
            Senator Murray...........................................    71
            Senator Sanders..........................................    82
            Senator Casey............................................    86
            Senator Bennet...........................................    90
            Senator Baldwin..........................................    94
            Senator Murphy...........................................    96
            Senator Warren...........................................    99
        Comprehensive Clinical Trials Conducted by Dr. Califf........   112
        Drug price comparisons in the United States and Canada.......   117

                                     (iii)

            NOMINATION OF ROBERT CALIFF TO SERVE AS FDA COMMISSIONER

                                  ----------

                           TUESDAY, NOVEMBER 17, 2015

                                           U.S. Senate,
           Committee on Health, Education, Labor, and Pensions,
                                                        Washington, DC.
        The committee met, pursuant to notice, at 10:05 a.m., in
    room SD-430, Dirksen Senate Office Building, Hon. Lamar
    Alexander, chairman of the committee, presiding.
        Present: Senators Alexander, Burr, Isakson, Collins,
    Murkowski, Kirk, Scott, Hatch, Roberts, Cassidy, Murray,
    Mikulski, Sanders, Casey, Franken, Bennet, Whitehouse, Baldwin,
    Murphy, and Warren.

                     Opening Statement of Senator Alexander

        The Chairman. The HELP Committee will come to order. Today
    we're reviewing the nomination of Dr. Robert Califf to serve as
    Commissioner of Food and Drugs.
        Dr. Califf, welcome. Congratulations on your nomination.
    Welcome to you and to your family members. We're glad they have
    been able to come up, some of them from Columbia, SC, and I
    enjoyed having the opportunity to meet with you in my office.
        If you're confirmed to lead the Food and Drug
    Administration as its Commissioner, you will be in charge of
    steering the agency responsible for the safety and
    effectiveness of our Nation's medical products and protecting
    our country's food supply. This is a huge job.
        The FDA affects nearly every single American almost every
    day and regulates about a quarter of all of our consumer
    spending in the United States, over $4 trillion annually. It is
    responsible for product areas as diverse as prescription drugs
    for humans and animals, medical devices, biologics, cosmetics,
    over-the-counter medications, food, and tobacco.
        It's a vital mission, and we all want to make sure that the
    right person is leading it. The President has nominated you to
    do that job, and like every full-time nominee, you've been
    through an exhaustive process to make sure that you don't have
    any conflicts of interest or other problems in your background.
        If you'll permit me, I had the privilege of coming before
    this committee about 24 or 25 years ago and sitting in the
    chair where you sit. It's not always a pleasant experience. One
    of the Democratic Senators said to me, ``Governor''--my family
    was sitting where yours is--said to me, ``Governor Alexander,
    I've heard some very disturbing things about you, but I don't
    think I'll bring them up this morning,'' and Senator Kassebaum
    leaned over and said, ``Well, Howard, I think you just did.''
    And then he held me up for 3 months.
        I don't expect that would be happening with you, because
    like every full-time nominee, you've been through an exhaustive
    process to make sure of the conflicts of interest, as I said.
    Before the President announced your nomination, there was an
    extensive vetting process by the White House and the FBI.
        You submitted paperwork to the Office of Government
    Ethics--that's been carefully reviewed--including your
    financial information. They found several recusals, which you
    have committed to do, so there wouldn't be any remaining
    conflicts of interest that would prevent you from doing your
    job, in the opinion of the Office of Government Ethics. The
    form you submitted is public. It includes every source of
    income over $200 and every asset worth more than $1,000 and
    every potential conflict that the Office of Government Ethics
    determined would require a recusal.
        I'm going through this so people will know that nominees
    such as yourself do this. You've answered 37 pages of questions
    from our committee, including some confidential questions on
    financial information. You've responded to written followup
    questions. Your responses included over 3,000 pages of articles
    and lectures that my staff reviewed and that any member of the
    committee may review.
        You were nominated on September 17. Our committee staff has
    spent 2 months carefully reviewing everything you submitted,
    and my staff tells me that they haven't found anything that
    would call into doubt your ability to lead the FDA fairly and
    impartially.
        You come here with impressive qualifications; a leading
    cardiologist, professor at one of the Nation's top medical
    schools. You are an expert on clinical research and you've been
    recognized as an author of medical publications. You've had
    some experience managing large organizations, and you've been
    the founding director of Duke's Clinical Research Institute.
    I'm sure Senator Burr will go into some detail about your
    background when he has a chance to introduce you in a few
    minutes.
        You've conducted scores of important clinical trials.
    That's important to me, because it helps to have people in
    government who actually know what they're talking about because
    of the experience that they've had before. You understand how
    research gets done in the real world.
        I'm eager to hear your priorities about how you intend to
    manage such a large and diverse organization. I'd like to hear
    what you'll be able to do to ensure that affordable drugs are
    available to American patients. I hope you'll agree that drugs
    are--that your job is to see that drugs are safe and effective,
    but the FDA can help market lower drug prices by approving
    generic drugs and other products as quickly as it possibly can
    so there's more choice and competition in the market.
        Approval times have gotten worse instead of better. I'll be
    asking you about that and what you intend to do about it.
    Second, there has never been a more exciting time to lead the
    agency. We know more about biology and medicine than ever
    before, and that's not likely to stop anytime soon given the
    advancement of regenerative cell therapies, 3D printing, and
    the President's Precision Medicine Initiative.
        Your job, if confirmed, will be to make sure that the FDA
    regulation is appropriate. Too much regulation could reduce
    investments. Too little could make it difficult for drugs to be
    safe and effective. There is much work to be done. Sometimes it
    takes a decade to develop a drug. Sometimes it takes billions
    of dollars, literally.
        In this committee, we're working together in a bipartisan
    way to help get safe cutting-edge drugs, medical devices, and
    treatments into American medicine cabinets and doctors' offices
    more quickly, and we hope to move that soon. We're looking
    forward to hearing what you believe needs to be done to build
    the FDA's capacity and to fix the impact of its regulations so
    that the FDA is a partner in innovation and not a barrier.
        I thank you, and I look forward to hearing your testimony
    on these important issues.
        Senator Murray.

                      Opening Statement of Senator Murray

        Senator Murray. Thank you very much, Mr. Chairman, and
    thank you to all of our colleagues for being here today.
        Dr. Califf, thanks to you and your multigenerational family
    that is here with you today. I want to express my appreciation
    to all of you for accepting this nomination and continuing to
    offer your expertise--or offer your spouse or dad--in service
    of families and communities nationwide.
        As the Chairman said, the FDA Commissioner has a critical
    role to play in supporting health and well-being in our
    country. Whether you're in a grocery store or the medicine
    cabinet or the emergency room, families depend on the FDA to
    maintain the highest standards of product safety.
        As we talk about the future of the FDA and the many health
    challenges our country faces, it is important to note that
    valuable efforts have been made in recent years to strengthen
    the FDA and improve its services for patients and families.
        Last year, the FDA approved 51 new drugs and biologics, its
    highest number in almost 20 years. The agency consistently
    approves drugs more quickly than advanced regulatory agencies
    in other countries, while maintaining the high standards of
    safety and effectiveness. The FDA has also made strides toward
    implementing the Food Safety Modernization Act, helping to
    bring our Nation's food safety system into the 21st century.
        Despite these gains, the FDA faces significant challenges
    moving forward. There are several areas, in particular, where I
    hope to see continued progress. As someone who has seen
    personally the challenges that patients and families face due
    to chronic illness, I am very interested in making sure we are
    encouraging development of safe, effective treatments and cures
    for our most challenging unmet medical needs.
        So-called super bugs are another growing threat and an
    issue Chairman Alexander and I are working on closely. As we
    have seen in my State and across the country, where medical
    devices known as duodenoscopes have been linked to tragic
    outbreaks of antibiotic-resistant infections, we have got to
    find ways to prevent these infections and respond more quickly
    and effectively when any risk arises.
        Especially as technology continues to evolve, we need to do
    more to make sure that after products reach the market, the FDA
    has the effective tools it needs to monitor their safety,
    taking full advantage of information technology.
        We need to ensure that FDA continues to strengthen its
    generic drug and biosimilar programs. I also believe there is
    much more we can do to bring patients' voices into the process
    of developing new treatments and cures and ensure their
    priorities are consistently reflected in the FDA's work.
        In addition, our country faces urgent public health
    challenges that deserve our attention. To name a few, we need
    to move forward on making sure families have access to
    nutritional information and ensuring our food supply is both
    safe and healthy. We need to put all of the agency's tools to
    work to stop tobacco companies from targeting our children. We
    must do more to tackle widespread illnesses, such as heart
    disease and diabetes, that threaten so many people in our
    country.
        Like so many of my colleagues here today, I have heard time
    and again from families that the cost of prescription drugs is
    a significant financial burden. I believe the next FDA
    Commissioner has an important role to play in ensuring all
    patients and families have access to the prescription drugs
    they need.
        Another critical priority is ensuring the FDA always puts
    science over politics. As some here will remember, several of
    my colleagues and I fought long and hard to ensure that medical
    expertise, not ideology, governed decisionmaking on the sale of
    Plan B over the counter. Women and families have to be able to
    trust the FDA not to play politics with their health.
        As Congress and the administration work together to address
    these and many other health challenges in which the FDA plays a
    significant role, we need to recognize that our efforts will
    not be successful without additional support for the FDA. We
    must make sure the FDA has the resources and authority it needs
    to hire top experts in a highly competitive field and manage
    its growing workload as it navigates our increasingly global
    supply chain.
        Many of these are issues that our committee is currently
    debating as we negotiate bipartisan legislation to advance
    medical innovation for patients and families. After careful
    consideration and review, I am confident that Dr. Califf would
    contribute leadership and expertise as we work to find new ways
    to advance medical innovation for patients and families and
    improve health and well-being across the country. He is a
    strong nominee for the FDA Commissioner.
        Dr. Califf has an impressive history of leadership and
    management experience, in particular, at Duke. He would bring
    to this new role a record of advancing medical breakthroughs on
    challenging illnesses through clinical trials. Our review of
    his record demonstrates a longstanding commitment to
    transparency in relationships with industry and to working to
    ensure academic integrity.
        Dr. Califf has made clear he will continue to uphold these
    values and prioritize a strong, independent FDA as
    Commissioner.
        I have approached this nomination focused on the best
    interests of families and communities in Washington State and
    across the country and in making sure the FDA puts them first
    in all its work, from drug and device approvals to ensuring
    that a child's peanut butter sandwich is safe to eat.
        As we work toward these goals, I believe Dr. Califf would
    be a valuable partner. I encourage my colleagues to join me in
    supporting his nomination, and I look forward to working with
    all of you to strengthen health and well-being for the families
    and communities that we serve.
        Thank you, Mr. Chairman.
        The Chairman. Thank you, Senator Murray.
        Senator Burr will introduce Dr. Califf.

                           Statement of Senator Burr

        Senator Burr. Mr. Chairman, thank you, and thank you to my
    colleagues.
        Dr. Califf, welcome. Thank you for sharing your family with
    us. Your parents are here. Your bride is here. Your children
    are here, and your granddaughter is here.
        Welcome, Brooke. Hope you get an extra credit at school for
    being here.
        Dr. Robert Califf is a North Carolinian whose career has
    been distinguished by his unwavering commitment to patients as
    a respected clinician, researcher, and advisor. I'm
    particularly pleased to have the opportunity to introduce him
    here today. Dr. Califf has been nominated to serve as the next
    Commissioner of the Food and Drug Administration, and my
    colleagues and I look forward to hearing from you today.
        Dr. Califf is currently serving as the Deputy Commissioner
    of Medical Products and Tobacco for the FDA since February of
    this year. In this role, he's responsible for overseeing and
    directing the Centers for Drug Evaluation and Research, the
    Centers for Biologics Evaluation and Research, the Centers for
    Devices and Radiological Health, the Centers for Tobacco
    Products, the Office of Special Medical Programs within the
    agency.
        Prior to his work at the FDA, Dr. Califf was a professor of
    medicine and vice chancellor for clinical and translational
    research at Duke University in Durham, NC. During his time at
    Duke, Dr. Califf held a number of positions, including the
    director of Translational Medicine Institute, the director of
    the Clinical Research Institute. He worked to move the
    promising field of translational science forward as the
    director of Clinical Trials Transformation Initiative.
        Dr. Califf is distinguished as a researcher and an author
    with over 1,200 peer-reviewed publications in biomedical
    science. He's a graduate of Duke University School of Medicine.
    He received his residency training in primary care at the
    University of California San Francisco and completed a
    residency in cardiology at Duke University.
        Dr. Califf is a great father, a great husband, a great
    granddad, and is a great doctor. I'll say to my colleagues he's
    a great man, and that stands out the most in his
    qualifications.
        How well the FDA fulfills its mission touches the lives of
    Americans each and every day, from the lifesaving treatments
    patients receive to the safety of the food we feed our
    families. The challenges facing the next Commissioner are
    great, but also the opportunities are as well.
        Dr. Califf, congratulations on your nomination to serve as
    Commissioner of the Food and Drug Administration.
        I urge my colleagues to thoroughly get your questions
    answered and expeditiously move this nomination so a permanent
    Commissioner of the FDA can get to work on some very serious
    problems within our system.
        I thank the Chair. I welcome Dr. Califf.
        The Chairman. Thank you, Senator Burr.
        Senator Scott has a point of clarification.

                           Statement of Senator Scott

        Senator Scott. Thank you, Chairman Alexander. Senator Burr
    referred to Dr. Califf as if he were from North Carolina. The
    fact of the matter, sir, is that while he could not get into
    the Medical University of South Carolina, he had to go to Duke.
    He's actually from South Carolina.
        [Laughter.]
        Understanding the generational responsibilities of
    southerners, you realize that his parents were also from South
    Carolina. Therefore, we know he's a southerner.
        He's from South Carolina. The North is a Yankee called
    North Carolina. I just wanted to make sure that that point was
    made clear, that you didn't insult his parents on the front row
    who are from Saint George, SC, which is in the low country.
        Thank you very much.
        Senator Burr. I welcome his parents and congratulate them
    on his ability to outperform the requirements for South
    Carolina education.
        [Laughter.]
        Senator Mikulski. Mr. Chairman.
        The Chairman. OK.
        Senator Mikulski. Mr. Chairman.
        The Chairman. Senator Mikulski.
        Senator Mikulski. While those guys are still doing border
    wars, I want to also just welcome Dr. Califf, because FDA is in
    my State. He'd be eminently qualified and look forward to
    supporting his nomination proceeding.
        I'm glad you're the son of South Carolina who lived in
    North Carolina, but you're our guy, too.
        I ask unanimous consent that my statement be in the record.
        The Chairman. It will be.
        [The prepared statement of Senator Mikulski was not
    available at time of press.]
        The Chairman. Dr. Califf, you can see the interest the
    committee has in the work you're about to do. Virtually every
    member is here. Each will have 5 minutes to have a conversation
    with you. I'll try to give you time to answer the questions. We
    want to stick pretty closely to the 5-minutes so everyone can
    be involved.
        As I mentioned earlier, you've answered a number of
    questions to the committee staff, and if any Senator has
    additional questions, there'll be a few days after the hearing
    that they can ask them, and we hope you'll respond promptly to
    them. We'll begin a round of questions 5 minutes in length.
        Dr. Califf, around the country and here in Congress, people
    are talking about the high cost of pharmaceutical drugs and
    what can be done to make those drugs affordable. Do you--oh,
    excuse me. I got so excited I didn't give you a chance to make
    your comments.
        [Laughter.]
        Dr. Califf. I've been well-instructed, Senator, not to
    interrupt you.
        [Laughter.]
        The Chairman. Dr. Califf, we look forward to your comments.

     STATEMENT OF ROBERT M. CALIFF, M.D., DEPUTY COMMISSIONER FOR
     MEDICAL PRODUCTS AND TOBACCO, DEPARTMENT OF HEALTH AND HUMAN
                          SERVICES, DURHAM, NC

        Dr. Califf. Mr. Chairman and Ranking Member Murray and also
    Senator Burr and Senator Mikulski, thank you for your kind
    comments. I want to thank you and the members of the committee
    for inviting me here today to discuss my nomination to be
    Commissioner of the Food and Drug Administration.
        I'm honored to be accompanied by my family today, as you've
    noted. Sitting behind me are my dad, a World War II veteran--
    and we're going to visit the monument later this afternoon--my
    mom, an activist-teacher and a 7-year survivor of multiple
    myeloma; and my wife of 42 years and high school sweetheart,
    Lydia. My three children and my granddaughter, Brooke, are also
    here with us. The support of my family and their feedback have
    been essential to my career success and sustaining my moral
    compass.
        I'm honored to have been nominated by President Obama to
    lead the FDA. Thank you for all of your willingness to share
    with me your perspectives on ways the agency can better serve
    the American people. My primary goals, if confirmed, will be to
    work with you to build on the excellent workforce, relentlessly
    focus on the completion of priority projects, and continue to
    develop the science base that we need to give consumers
    confidence that their food and medical products are safe and
    give patients and clinicians an accurate understanding of the
    benefits and risks of medical products.
        Amid ongoing revolutions in biological science and
    information technology, we must continue to strengthen the
    FDA's vital work, protecting Americans while encouraging
    innovations that hold promise. If confirmed, it would be an
    honor to lead this outstanding workforce in this remarkable
    time.
        I've dedicated my career to advancing the public health as
    a physician, leader, teacher, and researcher. Like each of you,
    my understanding of our health system was shaped by more than
    just my professional life. Our daughter was born with serious
    congenital heart disease, requiring open heart surgery as an
    infant.
        I still vividly remember the inspirational work of her
    doctors, nurses, and healthcare team and the uncertainties of
    that experience, including the discovery that one of our
    daughter's cardiologists had faked his medical credentials. We
    experienced firsthand as a family how important it is to find a
    critical balance between innovation and safeguarding patients.
        When I started in cardiology, heart attack was the leading
    cause of death in America, and our understanding of it was
    limited. It was agonizing that one of six patients that I saw
    in our intensive care unit with a heart attack died during the
    first hospitalization. The intensely personal experience
    dealing with catastrophic illness and personally witnessing the
    death of many people drove us to relentlessly invent and
    develop effective treatments.
        I had the privilege to serve as a leader of global networks
    of doctors and nurses, researchers, computer scientists, and
    statisticians who joined forces to develop and evaluate clot-
    busting drugs and lifesaving technologies, including stents and
    defibrillators, that have helped millions of Americans. These
    efforts have cut the risk of death from heart disease by more
    than half and highlight for me the importance of bringing these
    advances to patients as fast as safely possible.
        Indeed, it's not enough to develop new treatments. We must
    prove they are safe and effective and deploy them in a
    systematic way that reaches all Americans and eventually the
    global population. Our initial quality registries for bypass
    surgery, angioplasty, and heart attack have become global
    standards, including adoption by CMS as quality measures, to
    improve the public health by advancing evidence-based therapies
    and reducing medical errors.
        A successful FDA is a critical factor for better public
    health in this changing world. The FDA must be prepared to set
    policies that channel innovative technologies for safe and
    effective use. Also, I firmly believe that the best way to make
    this progress is for different sectors in today's healthcare
    ecosystem to collaborate.
        I've led efforts to help academic researchers collaborate
    with industry in a documented and transparent manner that
    retain their independence and primary role in caring for
    patients. More recently, I've had the pleasure of jointly
    leading a number of projects with patients, consumers, and
    community leaders, I believe, to the great benefit of research
    and public health.
        My first priority as Commissioner would be to strengthen
    and better support FDA's talented and dedicated workforce.
    While FDA scientists make decisions every single day about
    hundreds of products, as technology advances, these decisions
    are becoming more complex. It's essential that we keep pace.
        My next priority as Commissioner is working with you to
    fulfill the ambitious agenda that we set together. The Food
    Safety Modernization Act, for example, will help assure
    Americans their food is safe. The Deeming Rule for tobacco
    products will help us continue to reduce tobacco-related
    deaths. And, of course, the user fee programs are entering a
    period of renegotiation.
        My third and final priority among the leading ones as
    Commissioner would be to further develop the science base that
    informs FDA's decisionmaking--my real professional love. By
    taking advantage of extraordinary advances in biomedicine and
    information sciences, we can build the right infrastructure
    that will unlock greater amounts of useful evidence about food,
    tobacco, and medical products at a dramatically lower cost.
        Finally, we can't forget that health and disease fail to
    recognize national boundaries. In concert with our global
    colleagues, we must continue to develop sophisticated systems
    for monitoring the safety and quality of products produced
    outside our borders.
        The FDA is poised to leverage the acceleration in
    biomedical knowledge to a new era of enhanced safety and
    effective treatments. If confirmed, I would be honored to lead
    the agency in this exciting time.
        Thank you for allowing me to testify before you today, and
    I'm happy to take your questions.
        [The prepared statement of Dr. Califf follows:]
                  Prepared Statement of Robert M. Califf, M.D.
                                  introduction
        Mr. Chairman and Ranking Member Murray, I want to thank you and
    members of the committee for inviting me here today to discuss my
    nomination to be Commissioner of Food and Drugs in the office of the
    Food and Drug Administration (FDA). I'm honored to be accompanied by
    family today. Sitting behind me are my dad, a WWII Veteran, my mom, a
    7-year survivor of multiple myeloma and my wife of 42 years and high
    school sweetheart, Lydia. My three children and my granddaughter Brooke
    are also with us. The support of my family and their feedback have been
    essential to my career success and moral compass.
        I am honored to have been nominated by President Obama to lead the
    FDA. Thank you all for your willingness to share with me your
    perspectives on ways the FDA can better serve the American people. My
    primary goals, if confirmed, would be to work with you to build on the
    excellent workforce, relentlessly focus on the completion of priority
    projects, and continue to develop the science base needed to give
    consumers and patients even more confidence that their food is safe and
    their medical products are safe and effective. I also believe that we
    need to continue to improve our efforts to give patients and clinicians
    an accurate understanding of the benefits and risks of medical
    products.
        My service as Deputy Commissioner for Medical Products and Tobacco
    has underscored for me both the opportunity and the gravity of this
    undertaking. Amid ongoing revolutions in biological science and
    information technology, we must continue to strengthen the FDA's vital
    work in protecting the American people while encouraging innovations
    that hold promise to improve their health. If confirmed, it would be an
    honor to lead this outstanding workforce in this remarkable time.
                                   background
        My career has been dedicated to advancing the public health as a
    physician, leader, and researcher. But, like each of you, my
    understanding of our health system was shaped by more than just my
    professional life. Our first daughter was born with a serious
    congenital heart defect requiring open heart surgery as an infant. I
    still vividly remember the inspirational work of her doctors and the
    uncertainties of that experience--including the shocking discovery that
    one of our daughter's cardiologists was an imposter with faked medical
    credentials. My family has experienced firsthand how important it is to
    find a critical balance between innovative treatments and appropriate
    safeguards for patients. The American people need access to cutting
    edge treatments, but also must be able to trust the information they
    are given about that treatment.
        As a medical student, I worked with one of the first computerized
    medical databases and witnessed the potential for computer technology
    to inform decisions about health and healthcare. When I started in
    cardiology, heart attack was the leading cause of death in the United
    States and our understanding of the cause of this leading cause of
    death in America was limited. It was agonizing that one of six patients
    with a heart attack died during their first hospitalization. This
    intensely personal experience of dealing with a catastrophic illness
    and its consequences on victims of the disease and their families drove
    us to be relentless about inventing and developing effective
    treatments. Together with a global network of doctors and nurses, and
    with an extraordinary team of researchers, computer scientists, and
    statisticians, I had the privilege to serve as a leader on efforts to
    develop ``clot busting'' drugs that restore blood flow to the heart,
    improve the recovery of the heart muscle and help prevent future heart
    attacks. We also worked together to develop and evaluate life-saving
    technologies, including balloon angioplasty, cardiovascular stents, and
    implantable defibrillators, that have helped millions of Americans.
    These efforts have decreased the risk of death from heart disease by
    more than half. This condition that was once a death sentence is now
    treatable thanks to drugs and medical products, highlighting for me the
    importance of bringing these advances to patients as fast as safely
    possible. Much of my work has been at the intersection of public health
    and research, including large-scale efforts to improve our national
    clinical trial research infrastructure and innovative community-based
    projects undertaken in close collaboration with underserved patients
    and their communities.
        Indeed, it is not enough to develop new treatments. We must prove
    they are safe and effective, and deploy them in a systematic way that
    reaches all Americans, and eventually the global population. Our
    initial quality registries for bypass surgery, angioplasty and heart
    attack have become global standards, including adoption of derivatives
    of our quality measures by CMS, to improve the public health by
    advancing evidence-based therapies and reducing medical errors.
                                leading the fda
        A successful FDA is a critical factor for better public health in
    this changing world. We are currently witnessing a revolution in
    biomedical science and information technology that empowers consumers
    to make choices about their health and health care. Today our food
    safety system is undergoing the most comprehensive update since it was
    established and we are working to ensure that medications prescribed to
    animals do not reduce their effectiveness in humans. Against this
    backdrop of revolutionary change, the FDA must be prepared to set
    policies that channel these innovative technologies for safe and
    effective use--protecting the public while approving products with
    clear benefit.
        I firmly believe that the best way to make this progress is for
    different sectors in today's health care ecosystem to collaborate. I
    led efforts at Duke University Medical Center to help academic
    researchers collaborate with industry in a documented and transparent
    manner that retained their independence and primary role in caring for
    patients. Similarly, the United States, and indeed the entire world,
    depends on a strong, unbiased FDA that can work with industry to
    advance critical technologies while still making independent
    determinations to ensure that scientific potential is translated into
    safe and effective products. To advance, we must find common ground
    with industry and academia on the science without compromising this
    fundamental role of the FDA.
        More recently, I have had the pleasure of jointly leading multiple
    projects along with patients, consumers and community leaders, to the
    great benefit of research and public health. The emergence of consumers
    and patients as active participants in the process of developing
    therapies and devising protocols for evaluation is an important theme
    to improve the relevance of our work to the people we serve.
    The Importance of the Workforce and Infrastructure
        My first priority as Commissioner would be to strengthen and better
    support FDA's talented and dedicated workforce. However, the products
    we evaluate are increasingly complex. Sustaining the quality of FDA's
    scientific workforce may be more important than any particular policy
    because it is our day-to-day decisionmaking that protects the public
    without impeding technological progress. FDA scientists are making
    decisions every single day about hundreds of products--but as
    technology advances these decisions become more complex. Americans must
    be able to depend on a strong FDA workforce that keeps up with the
    rapidly changing world.
    Completion of Critical Priorities
        My next priority as Commissioner would be to carry our critical
    priorities over the finish line. With your guidance, the FDA has
    embarked on an ambitious agenda to keep pace with our changing society.
    The Food Safety Modernization Act will enhance our ability to assure
    Americans of the safety of the food supply. The Deeming Rule for
    tobacco products will be the basis for continuing our success in
    reducing tobacco-related deaths. Several high priority initiatives are
    underway, including the Combating Antibiotic Resistant Bacteria (CARB)
    initiative, medical counter measurement development, and the Precision
    Medicine Initiative to name a few. And, of course, the user fee
    programs that have been so successful in providing resources for review
    of medical products are entering a period of renegotiation.
    Focusing on the Science Base
        My third priority as Commissioner would be to further develop the
    science base that informs FDA's decisionmaking across drugs, devices,
    food safety, and more. If we build the right infrastructure, FDA can
    realize the potential of revolutionary advances in biological and
    information sciences that will unlock greater amounts of useful
    evidence about food, tobacco and medical products at dramatically lower
    cost.
        We must also take advantage of the astounding opportunity afforded
    by the fact that the majority of Americans have an electronic health
    record and smart phones. The groundbreaking Sentinel system
    demonstrates the power of evidence to inform FDA's decisionmaking and
    act quickly on safety issues and we have a similar plan for medical
    device surveillance. I am committed to the development of a national
    system for surveillance and evidence generation that will improve
    patient safety and provide a much more efficient way to understand the
    benefits and risks of medical products when used in practice.
        In addition, the proliferation of the Internet allows many
    patients, advocates, and caregivers to be reached directly, both to
    impart information and to solicit their perspectives and experiences. I
    am greatly encouraged to see that FDA expects industry to involve
    patients directly in the process of technology development and
    assessment, but recognize that we are just beginning to understand the
    science of consumer engagement. Further, as ever-growing amounts of
    information become available to consumers about the benefits and risks
    of medical products, we must ensure that it is high-quality
    information.
        Finally, we cannot forget that while the FDA has the well-being of
    Americans as its mission, we are operating in a global environment.
    Because health and disease do not recognize national boundaries, the
    FDA must be in constant communication with the global scientific and
    regulatory communities. We should continue to develop sophisticated and
    robust information systems for monitoring the safety and quality of
    medical products and food produced outside of our borders in concert
    with our global colleagues.
                                    summary
        The FDA is poised to leverage the acceleration in biomedical
    knowledge to lead to a new era of enhanced safety and effective
    therapies, and, if confirmed, I would be honored to lead the Agency in
    this exciting time. Thank you for allowing me to testify before you
    today and I am happy to take your questions.

        The Chairman. Thank you, Dr. Califf. We'll now begin a 5-
    minute round.
        Dr. Califf, around the country and in Congress, there's
    lots of talk about the high cost of pharmaceutical drugs. Do
    you believe, in terms of drugs, that it's accurate to say that
    the FDA's statutory mission is to promptly and efficiently make
    sure that drugs are safe and effective?
        Dr. Califf. Senator Alexander, that is our primary mission.
    We also can have an impact on the cost of drugs by performing
    that function effectively.
        The Chairman. Let me talk about that just a little bit. Do
    you agree that it's not your job to set the price of drugs?
        Dr. Califf. It is not our job to set the price of drugs.
        The Chairman. Let's talk about generic treatments. If
    generic treatments can move more rapidly through the FDA
    process in a safe and effective way, that would be one way to
    create more competition and presumably lower the cost of drugs.
    Despite getting about a billion dollars in new funds over the
    last 3 years, generic manufacturers estimate that the FDA's
    median approval time for generic drugs has gone from 30 months
    in 2011 to 48 months in 2014.
        Is that accurate, based on your knowledge? Or can you
    explain how the FDA, with the availability of a billion new
    dollars, could have actually presided over a situation where
    the approval of generic drugs has gone from 30 months in 2011
    to 48 months in 2014, especially since a more rapid approval,
    if safe and effective, might have had some effect of lowering
    drug prices?
        Dr. Califf. Senator Alexander, bear with me. I appreciate
    the question. Bear with me for just a second while I explain
    this. First of all, as you point out, 88 percent of American
    prescriptions now are generic. We have made tremendous
    progress. But we can do even better.
        You also know that we're well ahead of the generic drug
    User Fee Act goals that were set. We can still do better, and
    I'm all in favor of that.
        Explaining the backlog is really important, and here's the
    way to think about it. We started with a huge backlog,
    thousands of applications that were waiting until the user fees
    came in. The easy ones, the ones that were good, were well-
    written, went through quickly. The new ones, the ones that are
    pertinent to getting the first generic on the market are put in
    what we call a fast lane, and they're going through quickly.
        We have this backlog of applications that are requiring
    back-and-forth, because we want generic drugs to be just as
    safe and effective as the innovator drugs. When the
    applications are not complete, or there are questions about
    manufacturing, those get held up. I'm confident you'll see over
    the next several years as that backlog is cleared that new
    applications are going through very quickly.
        The Chairman. Thank you, Dr. Califf. This question will
    require just a short answer. Will you take a look, if you're
    confirmed, at the FDA's policy of issuing non-guidance
    documents instead of rulemaking?
        I've talked with Shaun Donovan, Director of the Budget, and
    the administration OMB had some pretty strong policies and firm
    views on the difference between rulemaking, which involves
    consultation and is legally binding, and guidances, which are
    not legally binding. Will you take a look at that? Because
    there is a bipartisan concern that agencies of the Federal
    Government, including FDA, are issuing guidances as if they
    were legally binding.
        Dr. Califf. Senator, I will commit to working with you on
    that and taking a careful look at it.
        The Chairman. I'd like, in my remaining time, to ask you to
    comment on a management issue at FDA. We hear that even when
    products are similar, experiences of applicants varies quite a
    bit. Regulated parties ought to be treated in consistent and
    predictable ways. Why do you think that even with similar
    products, the experience of some applicants is so different,
    and what could you do to make sure that regulated parties are
    treated in consistent and predictable ways?
        Dr. Califf. Senator Alexander, I appreciate the question.
    Having spent several decades on the other side of the fence,
    working on new therapies, I can appreciate people's concerns.
    The primary reason is really that each individual medical
    product is different. The clinical trials that need to be done,
    even if they're similar, can have nuances that are critical.
        Still, we are committed at the FDA, and Dr. Woodcock, who
    you know well--I'm working very closely with her, and we're
    going to do everything we can to produce a more even template
    across the FDA so that the standards are the same. I wouldn't
    want anyone to come away thinking you can take a cookie cutter
    and develop a drug or a device. You've got to treat each one
    differently.
        The Chairman. Thank you, Dr. Califf.
        Senator Murray.
        Senator Murray. Thank you, Mr. Chairman.
        Dr. Califf, in contrast to some of our previous FDA
    nominees who have come from the public health sector, you are a
    physician and a researcher with a specialty in large clinical
    trials. As a result, throughout your career, you have partnered
    extensively with pharmaceutical and other industry companies,
    and I want to just ask you some questions about that.
        During your past clinical trial and consulting work you've
    done, how have you ensured industry views have not biased your
    work, and what do you plan to do to ensure you are able to lead
    the FDA without any undue influence?
        Dr. Califf. Thank you, Senator Murray. It's important to
    really divide this into two parts. The clinical trials we do--
    that were done at Duke during my tenure and are still being
    done there--if funded by industry--remembering that many of our
    clinical trials are funded by foundations, and we're one of the
    largest NIH grantees, also--but when funded by industry, we
    have an ironclad contract, which I believe your staff has a
    copy of, that guarantees the independent right to publish,
    guarantees access to the database, and in the majority of
    cases, we actually have the database. We are running the trial,
    and we publish the papers with input from the companies, but
    they have absolutely no right to change what we say. We have
    the final right of publication.
        These trials are also done, usually, with international
    steering committees representing many countries, providing an
    independent voice that's really needed. So, yes, industry funds
    the trial, so they need to have their products evaluated. We
    have an independent voice, guaranteed by contract. I believe
    you'll find that 100 percent of the studies that I've been
    involved in have been published so that they're in the public
    record for people to view.
        Senator Murray. What do you see as the appropriate role of
    industry in working with the agency on key challenges like
    trials and the surveillance?
        Dr. Califf. It's critical here to separate the role of
    industry for individual applications versus what we call the
    precompetitive space. That is, what are the right methods--how
    do we understand, for example, how to streamline the clinical
    trial process? How do we share information as medical products
    are rolled out to the public to make sure we understand the
    risks that may only be seen in the post-market phase.
        In the individual applications, there is no role for
    industry other than to present its case, that it has a product
    that meets the criteria for safety and effectiveness, and it's
    the FDA's role to independently judge that application. The
    American public completely depends on having confidence that
    the FDA is independent in those reviews and judgments about
    individual products.
        In that precompetitive space, we've got to work together.
    Industry funds 70 percent of clinical research, for example,
    globally. NIH is a minority funder. I'm pleased to say we're
    working closely with the NIH right now, and we'll bring
    industry in into what will be a dramatically lower cost but
    much more effective clinical research system.
        Senator Murray. I very much appreciate that. I do want to
    turn to an issue that I've raised a number of times this year.
    We know that patients across the country, including in my home
    State in Seattle, got serious antibiotic-resistant infections
    from duodenoscopes. As I have investigated this issue further,
    it seems to me that we need to make significant improvements in
    how FDA monitors medical devices on the market to identify
    safety issues more quickly and prevent the tragedies that we
    have seen with this.
        What steps would you take to improve the post-market
    surveillance system for devices and better protect patients?
        Dr. Califf. Thank you for bringing that up. First, let me
    just say as a cardiologist and someone with administrative
    responsibilities at Duke Hospital, when ERCP, the procedure
    you're referring to, was first developed, it was in the United
    Kingdom, and those doctors came over to Duke and we were one of
    the first places to do it. I have firsthand experience on the
    importance of that procedure, typically in people who are
    critically ill.
        We need to really work on our post-market surveillance in
    devices, and I really hope that you'll help us with this. The
    Sentinel system that you all have helped with--industry has,
    too--but really developed by the FDA by Janet Woodcock, with
    Jeff Shuren's help, by the way, from devices--is a model in
    drugs. We have 170 million Americans' claims data, so that when
    there's a problem with a drug, we can look almost in real time.
        We need the same system on the device side. We have plans
    to do that. We're going to have to work together with you to
    figure out how to fund it and how to fold it in with that
    Sentinel system. Imagine these duodenoscopes--if there had been
    such a system, we would have seen the problem very early.
    Industry could contribute to that, but we could see it
    independently of industry and act on it much more rapidly.
        Senator Murray. I very much appreciate that. This is
    something I'm very concerned about as we move forward, so I
    appreciate your response and look forward to talking with you
    more about that.
        Thank you, Mr. Chairman.
        Dr. Califf. Thank you.
        The Chairman. Thank you, Senator Murray.
        The next four Senators are Burr, Whitehouse, Isakson, and
    Warren.
        Senator Burr.
        Senator Burr. Thank you, Mr. Chairman.
        Dr. Califf, the animal rule was finalized on October 27 of
    this year after a significant and, in my opinion, inexcusable
    delay, given the importance of the rule. I'm pleased that the
    rule has been finalized, as it will provide more certainty for
    those working to develop medical countermeasures to protect
    American people in the event of a public health emergency,
    whether it's natural or the result of a man-made attack on our
    country.
        If confirmed, how would medical countermeasures be
    prioritized within the agency, and how would you ensure that
    the FDA is advancing the development and review of these
    products toward the goal of a timely approval?
        Dr. Califf. Senator Burr, thank you for that question, and
    I'm amazed at the attention and intensity you all have today,
    given the fact that we're all worried about the issue that
    you're bringing up. It can be either man-made or something
    that's totally unanticipated, for example, with an infection.
        We're committed to working on this. I was pleased to be
    able to get the guidance out for the animal rule, which you had
    requested. It's going to take a concerted effort, not just by
    the FDA. As happened with the Ebola crisis, which we've all
    just witnessed, when the Federal agencies work together, a lot
    can be done to quell a crisis and deal with things.
        I do want to refer to the really brilliant work that's been
    done in the outside community, academia, industry, but also
    within the FDA. For those not thinking about it, the animal
    rule basically says in cases where we can't do human studies,
    but there's an emergency, what's a way in which we can
    extrapolate from animal studies to the benefit of humans in
    these catastrophic situations? We're committed. We're going to
    be there 24 by 7 if needed.
        Senator Burr. Thank you for getting that rule out. There
    have been reports that the Tobacco Deeming Rule did not change
    the grandfather date for newly regulated tobacco products. This
    means that many non-combustible tobacco products, which may
    have a public health benefit compared to the more traditional
    forms of tobacco, would not be available to consumers for at
    least some period of time, despite their potential benefits
    compared to a more traditional tobacco product.
        As Commissioner, how would you improve the performance of
    the FDA's Center for Tobacco Products with respect to the
    timely and predictable review of tobacco products?
        Dr. Califf. Senator Burr, this was a new creation just a
    few years ago, and it started with zero employees. It's now up
    in the multi-hundreds. There were no rules by which the tobacco
    applications could come in, so those have had to be developed.
        First of all, let me just say that you bring up a general
    issue of weighing the overall health risk of tobacco products,
    where they're graded from most serious to less serious. There
    is a pathway for doing that. We're committed to reviewing them
    in the timeframes that have been agreed to, and we have funding
    to carry out that activity. We're committed to get it done.
        Senator Burr. I thank you for that commitment. I often hear
    from constituents in North Carolina about the importance of
    laboratory-developed tests. For researchers, it means the next
    step in creating precise therapies. For providers, LDTs help to
    determine accurate diagnosis and the means for more targeted
    treatments and therapies on behalf of patients.
        As someone who has been on the front lines of research and
    treating patients, under your leadership, how would the agency
    collaborate with labs, other existing government structures
    such as CLIA, and the full range of stakeholders in this space
    to ensure that regulation of laboratory-developed tests is
    carried out in a workable way that moves these promising tests
    forward without inappropriate regulatory burdens or delays for
    patients and their practitioners?
        Dr. Califf. As an academician for over 30 years, I'm well
    aware of the importance of laboratory-developed tests. It's
    sort of the place where homebrews are made to make the tests
    better iteratively over time. It's an important activity. On
    the other hand, this has become a big industry with major
    implications for patients, especially with precision medicine,
    where you have a test, and it tells you what therapy to give.
    That can be either really good or really bad, depending on
    whether it's right.
        We're committed to work with the whole ecosystem, which is
    quite complicated, so that there is a standard for tests, so
    they'll have analytical validity and also clinical validity. As
    you may know, there's a hearing going on in the House right now
    about this issue that involves Jeff Shuren from FDA and also
    Pat Conway from CMS. There'll be a lot more to say soon about
    this.
        Senator Burr. Thank you.
        Mr. Chairman, I do have additional questions and would ask
    unanimous consent that those questions be allowed to be sent in
    writing to Dr. Califf.
        I would conclude by saying this--not a question. The FDA
    has over 150 outstanding guidance documents in limbo at the
    agency. Some of these guidances remain in draft form, and
    others have yet to be issued. My hope is that you will take
    that very seriously, because without guidance, I don't know how
    the downstream effects are ever going to be felt of investment
    and development if, in fact, they don't have the guidance as to
    how to move forward.
        I thank the Chair.
        The Chairman. Thank you, Senator Burr.
        Senator Whitehouse.

                        Statement of Senator Whitehouse

        Senator Whitehouse. Dr. Califf, good morning. Welcome.
        Dr. Califf. Good morning.
        Senator Whitehouse. There are increasingly products
    emerging on the market that combine a pharmaceutical component,
    a drug, and a delivery component, a device. The FDA is
    basically broken into one path for pharmaceuticals, the drug
    path, and another path for devices.
        I've spoken to the people who lead both the drug side and
    the device side about this question of the drug-device combined
    products, and both have said the same thing, which is that ``My
    pathway is not suitable for that. If we're going to do that, we
    need to create a new pathway for that drug-device
    combination.'' Could you let me know what your thoughts are
    about that pathway for the drug-device combination products,
    and what you think a reasonable timeframe would be for FDA to
    have such a proposal ready for us to consider?
        Dr. Califf. As a cardiologist, I sort of live and breathe
    this kind of work, because often we give lifesaving drugs
    systemically in acute situations. It would stand to reason in
    many cases if you could deliver them through a catheter, you
    could give them a much lower dose and do better. Maybe that's
    the best example to think about here.
        When you have a drug that's given in full dose
    systemically, and you can give it at a lower dose, you don't
    want to go through the whole thing as if it were a totally new
    dose. You can't assume that you know the risks and benefits of
    the lower dose. There's a strong view at the FDA that we need
    another pathway that will give the FDA the flexibility to
    require the data that's needed to assure the public that the
    proposed treatment is safe and effective.
        Senator Whitehouse. Do you agree that we need that other
    pathway? You said that was the opinion at the FDA. Is that your
    opinion as well?
        Dr. Califf. Yes, but----
        Senator Whitehouse. What is the timeframe for designing
    that pathway and giving us something to look at here in
    Congress?
        Dr. Califf. I feel like within the next year, the FDA's
    opinion can be adjudicated back and forth with you, and we're
    really happy to work with you. We have opinions on this now, so
    we're happy to engage and discuss with you.
        Senator Whitehouse. Great, because there is probably going
    to be legislative action that's going to be required to do
    this. Both of your sides of the house think that it can't be
    done under the existing regulatory authority, that it would
    require Congress to act. Do you agree with that?
        Dr. Califf. We need some help to get the right balance
    here.
        Senator Whitehouse. Great. The last thing that I'll mention
    is I hope that as you go forward with your responsibilities in
    the space of apps and communications technology that are
    adapted to measuring health effects that you'll recognize that,
    in many respects, this is a very valuable and robust industry
    that could well be over-regulated if the FDA's authority over
    those sorts of devices extended too far. What do you see as the
    boundary between informational apps that the FDA should and
    should not regulate?
        Dr. Califf. I had the privilege of going back to my old
    home, an American Heart Association meeting, just last week,
    and we had a whole session on this issue. I won't show the
    brand, but I'm wearing my own device here that has a number of
    apps on it that's like a whole different world than what
    existed 6 months ago.
        There's a good statement, the trilateral statement just
    last year that came out from FDA, the FCC, and the Office of
    the National Coordinator that states the full intention to
    regulate based on risk. Exactly where to draw that boundary is
    a matter that we need to keep talking and thinking about.
        For example, clearly stated in that document, a health-
    related app--we're monitoring my heart rate, and I'm healthy
    and I want to exercise more. That's not something that we want
    to be bothering with. If this was attached to my internal
    defibrillator--don't worry, I don't have one--but if I did have
    one, that would be something we would need to regulate, because
    misfiring the defibrillator could kill you.
        We've got to be able to deal with that spectrum and find
    that middle ground, where there will be adjudication as we
    learn how these things work.
        Senator Whitehouse. You'd be looking along the lines of
    regulating technologies that could actually have a direct
    physical effect on the human body, as opposed to just getting
    information that causes you to think that, ``Oh, gosh, my
    heart's better, so I'm not going to run as much.'' You need to
    regulate that because the individual is making a different
    decision based on the information.
        Dr. Califf. That's correct. Also, I would just like to add
    that we're going to learn as we go through this, because there
    may be cases where, for example, heart failure patients using
    the same app may be making more life and death decisions. What
    we don't want to do is suppress innovation.
        Senator Whitehouse. My time has expired, and I don't want
    to take--there's so many of us, and I don't want to trespass on
    other people's time. I thank the doctor, and my appreciation to
    the Chairman.
        The Chairman. Thank you. That's very courteous, Senator
    Whitehouse.
        Senator Isakson.

                          Statement of Senator Isakson

        Senator Isakson. Dr. Califf, following up on Senator
    Alexander's first statement regarding guidance letters, FDA has
    two opportunities. One is to issue guidance letters. The other
    is to do rulemaking. While there are similarities, there are
    substantial differences. Under rulemaking, you have to do a
    cost-benefit analysis. Rulemaking has the force and effect of
    law, and guidance letters do not.
        Yet FDA continues over and over again to try and implement
    policy through guidance letters. For example, and most
    recently, through a guidance letter, you're going to talk about
    regulating laboratories and bring them under the FDA. Guidance
    letters, again, don't have the rulemaking period or the comment
    period to be open. FDA continues to try and regulate parties
    more often through guidance letters than through rulemaking,
    which shuts out the open comment period and has confusing
    effects.
        I have really two questions to ask. No. 1, why has FDA
    grown so reliant on non-binding guidance documents for
    rulemaking? No. 2, Do you think that's a problem?
        Dr. Califf. Senator Isakson, I appreciate your concern with
    this, and one thing that's been really evident to me in my time
    at the FDA so far is that everybody wants to know what the FDA
    is thinking. There's a tremendous value in guidance documents
    to let people know what the FDA is thinking, and the demand for
    these is actually quite high.
        There are other situations where you need the full force of
    rulemaking. I understand there is a difference. I will have to
    work with you--and I look forward to doing it--when things come
    up where you're concerned so that we can discuss it and work
    through it.
        Senator Isakson. Specifically, to that offer, let me ask
    you the following question. Will you commit to require FDA
    staff to go through rulemaking when it intends to legally bind
    regulated parties or change their behavior in a burdensome way?
        Dr. Califf. Senator, I believe the statement about guidance
    documents says they're not legally binding. They're a statement
    about FDA's thinking, and, of course, people would be wise when
    they see a guidance to consider that thinking. Personally, in
    developing drugs with companies, I've often taken a different
    path from the FDA. I'm certainly committed to work with you to
    try to deal with this tension that you're feeling.
        Senator Isakson. Thinking is a subjective thing. Rulemaking
    is a objective thing. When you talk about the cost of
    compliance with things, you ought to have the rulemaking
    procedure, in my judgment, rather than just a guidance letter
    which could affect some and not others.
        Second, on sunscreen, November 26 is the first anniversary
    of the Sunscreen Innovation Act that this committee passed and
    President Obama signed, which was designed to expedite the
    approval of ingredients in sunscreen. As you probably know,
    there are sunscreens that have been available in Europe for
    years and, in some cases, decades that are still not available
    in the United States because FDA has refused to make decisions
    on some of those ingredients. It's been a year since we passed
    the expedited rule and, still, FDA hasn't done it.
        Will you commit to work with us to try and bring those
    ingredients forward and do the proper due diligence to get
    those products to the market?
        Dr. Califf. Senator Isakson, I really do look forward to
    working with you on this. As we discussed earlier, I have a
    family history of melanoma myself and a number of moles that
    probably should be looked at more frequently than they are.
    With Lydia sitting behind me, she would remind me of that.
        Let me also say that part of what we need to work on is
    actually developing the evidence. We've asked the companies
    involved for specific information, which I believe they can
    develop, and we're very open to moving as quickly as we can if
    we have the right evidence.
        I would just point to what's happened with people who have
    melanoma with these amazing new therapies, several of which
    have just come on the market, because the patients with
    melanoma have worked closely with the companies to get the
    clinical trials done so the effective treatments get expedited
    and the ineffective ones don't get out there.
        Preventing melanoma is in the same category. We've got to
    do better. It's a rapidly growing cause of death, and I really
    do want to work with you personally on this issue.
        Senator Isakson. At certain stages, a diagnosis is a death
    sentence for which there is no cure, and I think you know that.
    I've had melanoma myself and survived two of them, fortunately.
    Next March or April is spring break, and the kids are going to
    hit the beaches of America and, hopefully, a lot of Georgia's
    beaches, getting a lot of sun and having a lot of fun. I hope
    they'll also have the best sunscreen ingredients available to
    try and prevent melanoma from being developed.
        My last comment--I'll make it quickly because it's a long
    question, and I know my time will be up. The FDA has sent mixed
    signals to pregnant women with regard to seafood. I know you
    all were in the process of using some determination on seafood
    to make recommendations as to what was good to be eaten and not
    eaten, and you were using results from what was called your Net
    Effects Report. That seems to be abandoned now.
        If you would, when you take over and are confirmed, will
    you expedite the decisionmaking process on seafood for pregnant
    women and the recommendations the FDA makes?
        Dr. Califf. Yes, sir. I look forward to working on that.
        Senator Isakson. Thank you, Mr. Chairman.
        The Chairman. Thank you, Senator Isakson.
        Senator Warren.

                          Statement of Senator Warren

        Senator Warren. Thank you, Mr. Chairman.
        Dr. Califf, it's no secret that during your time at Duke
    University, you received significant financial support from the
    pharmaceutical industry, both for you, personally, and for your
    research. I know this is common practice for principal
    investigators of clinical trials, but it naturally raises
    questions about your relationship with the drug industry. One
    particular concern with industry funding of academic work is
    that drug companies may be able to exert influence over the
    conduct of those studies.
        Let me ask: For the clinical trials you conducted or
    oversaw while at Duke, can you detail for us exactly what input
    pharmaceutical sponsors had, did and did not have, in the
    design of the trials, the analysis of the data, and the
    publication of the results?
        Dr. Califf. I'm glad to do so. When industry funds a
    clinical trial, whether it's devices or drugs, done through our
    institute, the design of the trial is something that's done
    jointly and done very publicly, because, typically, it's done
    to try to get an indication from the FDA.
        It actually involves industry, academia, now patients
    involved in the design of the trial, and the FDA. It's a very
    public process. The protocol is developed, and it has to be
    submitted both to IRBs but also to the FDA before the trial
    starts. The design is something that is done jointly. The final
    say comes from the steering committee, of course, which is the
    academic leadership.
        The database is really the critical factor here, and all of
    our contracts require that we either have access to the
    database or we actually have the database onsite. That's been
    ironclad. I would say 70 percent of the studies I wanted to do,
    we couldn't do, because the company was unwilling to grant that
    right. We had to walk away, if that was not done.
        That leads to publications. Publications are in the purview
    of the steering committee and the authors from the steering
    committee. Industry has a right to make suggestions, but no
    right to censor and no right to change any of the writing
    that's done unless it's agreed to by the authors.
        The same holds for our public presentations, which, in the
    fields that I work in, are very important because evidence
    moves very quickly and it has a large input. Keeping that
    academic independence, we think, is a critical part of the
    effort.
        Senator Warren. Good. If I can, I just want to underline
    this because it is so important. I want to make sure I got this
    right from your question. I hear you to be saying there is no
    instance during your career or any instance involving Duke
    researchers at the Duke Clinical Research Institute during the
    time that you were supervising in which a pharmaceutical
    company provided any input into the analysis or the publication
    of the clinical trial that they paid to conduct. Is that right?
        Dr. Califf. Let me clarify one more time. By input, they
    could make suggestions. That's perfectly allowable in our
    contract----
        Senator Warren. On the analysis and on the publication?
        Dr. Califf. On the publication. On the analysis, this is
    another--I'm sorry to get into details here.
        Senator Warren. That's all right.
        Dr. Califf. The way we do our analyses--because the company
    has to submit the data to the FDA--is, typically, we'll have an
    analysis done by the company, an analysis done by our
    statisticians. Then we compare the results to see if they match
    up and resolve any discrepancies. In no case did we allow the
    company to do the analysis, and we just were recipients of what
    they said the answer was.
        Senator Warren. All right. I'll tell you what I'll do on
    this, just because I know we're pressed on time. I'll followup
    with questions for the record on this so that we can get a
    detailed written account of any such instances.
        I've also requested copies of the contracts that the
    pharmaceutical industry sponsors signed with the Duke Clinical
    Research Institute in order to get a better understanding of
    what's happening here. I look forward to reviewing them before
    this committee moves forward with your nomination.
        These agreements typically spell out in detail the
    relationship between the researchers and the funders. It will
    help us better understand what's happening here.
        In the little bit of time I have left, can I just make one
    other point? That is your financial relationship with the
    industry also raises questions about what your priorities will
    be if you're confirmed for this job. Many in the pharmaceutical
    and device industry spend a lot of time and money arguing that
    the FDA is just too tough, that we should lower the FDA
    standards on safety and effectiveness, and, unfortunately, they
    have a lot of friends in Congress.
        Dr. Califf, do you agree with these arguments and recent
    efforts by some lawmakers to lower the standards for FDA
    approval of drugs and devices?
        Dr. Califf. If you look at my record, you'll find I've
    never been a proponent of lowering standards. If anything, I've
    argued for raising standards with better studies that show the
    full gamut of risk and benefit for the time that a treatment
    might be used. That doesn't mean we couldn't potentially be
    quicker or something else, but in no case would we argue to
    lower the standards.
        Americans depend on safe drugs and devices that are also
    effective. A device or a drug that's safe and is not effective
    actually can harm someone because then they don't use what is
    effective. I've been staunch in that regard.
        Senator Warren. Thank you, Dr. Califf. We could abolish the
    FDA tomorrow and we'd see a lot of new products on the market.
    If they're not safe and effective, then no one is any better
    off.
        Thank you, Mr. Chairman.
        [The prepared statement of Senator Warren follows.]

                      Prepared Statement of Senator Warren

        The position of FDA Commissioner is critical for the
    protection of the public's health and safety and for the
    advancement of science and innovation. Since Dr. Califf 's
    nomination for this position, I have carefully reviewed a
    significant volume of information, including many of his
    published articles and work published under his direction, as
    well as confidential contracts between the Duke Clinical
    Research Institute and pharmaceutical companies governing the
    conduct of major clinical trials in which Dr. Califf has
    participated. In addition, I asked Dr. Califf detailed
    questions about his work, both in person at his HELP Committee
    nomination hearing and through subsequent written questions for
    the record. I have also had multiple meetings with Dr. Califf
    to discuss his background, his qualifications, and his plans
    for the agency should he be confirmed by the Senate, and I've
    had extensive conversations with him about concerns that have
    been raised about his professional relationship with the drug
    and medical device industries. Finally, I have consulted with
    several outside experts in these matters to better understand
    the materials I have been provided by Dr. Califf. All of this
    investigation was aimed at better understanding the focus and
    relative independence of his past work as it gives clues to his
    willingness, if he is confirmed as head of the FDA, to put the
    interests of the public first.
        After carefully examining Dr. Califf 's record and looking
    closely at his representations both to me and to the committee
    generally, I am satisfied that he has conducted himself with
    integrity as an academic researcher. For example, the language
    in the confidential contracts I have reviewed is consistent
    with what independent experts described to me as best practices
    designed to limit the influence of industry sponsors over
    academic investigators. Dr. Califf also indicated to me that
    there are no major trials in which he has participated that
    were not published, and he noted that he has repeatedly
    published negative trial results about products under
    development by the corporate sponsors that funded those trials.
    Dr. Califf also submitted a comprehensive list of the trials in
    which he played a major role. This list details the
    intervention under investigation in each trial and whether the
    trial resulted in the sponsor's preferred outcome. My staff
    conducted an independent analysis of the trials presented in
    this list, and in some instances disagreed with Dr. Califf 's
    conclusions about whether trial results clearly strengthened or
    undermined the position of a corporate sponsor. Even so, after
    re-classifying some of the studies, the totality of the data
    indicate that Dr. Califf has consistently published the results
    of his research, regardless of whether it ultimately bolstered
    the interests of that work's sponsor.
        My examination of the Califf nomination has raised serious
    questions about our current clinical trials system. I am
    particularly concerned with a lack of overall transparency,
    numerous opportunities for conflicts of interest, and a marked
    shortage of trials that are designed to determine which
    products to treat a given condition are the most effective--as
    well as cost-effective--for various patient populations. My
    examination has also raised concerns about the FDA's
    willingness to stand up to industry preferences in the design
    and conduct of clinical trials. Dr. Califf has indicated his
    clear and unequivocal commitment to work hard to address these
    policy issues as Commissioner.
        Dr. Califf and I have also discussed in some detail his
    views regarding other important policies at the FDA, including
    efforts to move the FDA's blood donation deferral policies to
    risk-based policies for all blood donors. We have also
    discussed the importance of reducing antibiotic use in animal
    agriculture to protect public health, including the development
    of meaningful metrics to evaluate the effectiveness of FDA's
    current policies to curb use and the need for strong
    enforcement of current laws and regulations. In addition, some
    Senators have raised concerns about the degree to which the FDA
    is using its current authorities to address the ongoing opioid
    crisis--and as a Senator from a region that has been hard-hit
    by this crisis, I expect Dr. Califf and the other relevant
    agencies to provide full and complete responses to these
    inquiries if this nomination is to move forward.
        The FDA needs a Commissioner who cares more about public
    health than industry profits or Washington politics. Given that
    the majority of major clinical trials are sponsored by private
    industry, it is fair to ask whether anyone with an extensive
    background in clinical research can be trusted to make
    decisions that are independent of the industry. On the other
    hand, there are substantial advantages to having a leader of
    the FDA who is a serious, front-line researcher who understands
    the importance of advancing cutting-edge work that will advance
    the health of millions of Americans--and who is sensitive to
    the conflicts of interest that can arise in industry-funded
    research. Based on the information I have reviewed and Dr.
    Califf 's representations, I am satisfied that he can be a
    strong leader for the FDA, placing the interests of patients
    and the American public above all others. Should he be
    confirmed, I plan to stay closely engaged with Dr. Califf to
    ensure that he advances the integrity and high standards of the
    FDA--and I fully intend to hold him accountable for his actions
    and decisions as the FDA Commissioner.

        The Chairman. Thank you, Senator Warren.
        The next four Senators are Senator Roberts, Senator
    Baldwin, Senator Cassidy, and Senator Mikulski.
        Senator Roberts.

                          Statement of Senator Roberts

        Senator Roberts. Thank you, Mr. Chairman.
        In the first place, thank you for coming by my office. We
    had a very nice visit. My wife is from South Carolina. I
    learned a long time ago you can take the girl out of the South,
    but not the South out of the girl.
        One of your responsibilities is to make sure the FDA is
    committing its resources to doing the most important work. For
    example, the FDA has been, in some cases, a little hesitant to
    implement key food safety goals while putting resources toward
    proposals for regulating sugar, salt, and caffeine. I would
    refer you to the new dietary guidelines that indicate now that
    an increase in salt intake is OK, and caffeine is six cups of
    coffee. This is my third one, so I've got three to go. Sugar,
    however, no.
        The FDA has proposed to expand its jurisdiction by
    regulating laboratory-developed tests in e-cigarettes and
    cigars for the first time. I just want to make sure that the
    FDA's use of resources is to make sure the agency stays focused
    on accomplishing its core objectives as directed by Congress.
    That's just a comment. You don't have to respond.
        Food Safety Modernization Act. The acronym for that is
    FSMA. That's a wonderful acronym. I wear two hats here. I'm
    chairman of the Ag Committee and a member of this distinguished
    committee. I'm concerned about potential overlap with these new
    FSMA regulations and the requirements with which farmers and
    ranchers already have to comply.
        We need to make sure the FDA is working with the Department
    of Agriculture to ensure these new regs and requirements are
    being harmonized with those already on the books. Will you
    commit to working toward that end, if confirmed?
        Dr. Califf. Yes, be glad to work with you on that.
        Senator Roberts. Thank you, sir. I want to followup on
    Senator Isakson's very concise comments with regards to draft
    guidances. I'm particularly apprehensive of the use of the
    guidances as they lack transparency and can escape the
    important cost-benefit analysis and other scrutiny.
        What are your thoughts about setting a maximum period for
    which draft guidance can be left outstanding without being
    finalized or substantially revised? And, second, when
    commenters have expressed concerns, shouldn't the agency be
    required to publicly respond to those concerns or, at least,
    how the concern has been addressed when a guidance is finalized
    or if the agency has rejected the concern?
        Dr. Califf. Senator Roberts, I'm kind of a big advocate of
    transparency, so I do appreciate what you're bringing up. It's
    been noticeable to me, the issues that you raise. It's also
    noticeable, as I mentioned earlier, that every time we give
    people an opportunity to interact with the FDA, they seem to
    want to do it more, in our user fee situations, for example.
    The number of meetings requested always greatly exceeds the
    number that we have.
        The critical thing to me is getting whatever the correct
    format is moved along as quickly as we possibly can through the
    process so that people understand what the FDA is really
    thinking, and in the case where there really needs to be a
    rule, they understand what the rule is and how to implement it.
    To get to the details here, I'd need to come by and spend some
    more time with you to completely understand how you see it, but
    I would be glad to do so.
        Senator Roberts. I appreciate that. My final question:
    Where is Duke ranked right now with regards to the basketball
    situation?
        [Laughter.]
        Dr. Califf. I'm just glad you didn't ask about football.
    Duke is somewhere around No. 4 or No. 5.
        Senator Roberts. I think they're No. 5. Would you be
    interested in knowing who's No. 4?
        [Laughter.]
        Dr. Califf. That might be that school in the Midwest that
    we often beat up on when it comes to tournament time.
        Senator Roberts. It is the University of Kansas. I just
    want to point that out. I might add that South Carolina is No.
    1, but we'll take care of that.
        Dr. Califf. Oh, you mean North Carolina is No. 1.
        Senator Roberts. Yes, that's correct.
        Dr. Califf. UNC. I would rather have Kansas No. 1,
    actually, than UNC, but that's a different story.
        [Laughter.]
        Senator Roberts. I have no further questions, Mr. Chairman.
        The Chairman. Thank you, Senator Roberts, for your
    illuminating inquiry there.
        Senator Baldwin.

                          Statement of Senator Baldwin

        Senator Baldwin. Thank you, Mr. Chairman and Ranking
    Member.
        I'm pleased to have you here today and was pleased to have
    an opportunity to meet with you prior to this. We all agree
    that it's critical for the products that are approved by the
    FDA to be of the highest safety and efficacy standards, and
    that the public must also have meaningful access to accurate
    information about treatments so that they can make the best
    healthcare decisions.
        I share some of my colleagues' concerns with the ever-
    increasing drug prices. There's been a little bit of dialog
    about that already, and we can do more and should do more to
    improve drug accessibility, affordability, and transparency. I
    want to start with transparency.
        Dr. Califf, the public still lacks comprehensive access to
    information about medical products. For example, companies do
    not consistently report clinical trial outcomes for drugs in
    the public databases, as a number of recent studies have noted.
    Generics are not yet able to initiate a change in their patient
    labeling if they learn of new safety information because the
    FDA has not yet finalized the generic labeling rule.
        In your new role, when you receive confirmation, how would
    you improve access to accurate information on drugs for
    patients, for doctors, for researchers? How would you ensure
    that the FDA maintains patient safety once these medicines
    actually reach patients?
        Dr. Califf. I'll try to be as quick as I can with this,
    because that's a very important question that you're asking.
    First, I'll just point out again that every study that I was
    involved in has been published, and I think that's a mandate.
    When you ask someone to participate in a human experiment, the
    informed consent actually says you're doing it to create
    generalizable knowledge. We have an obligation. Even if we
    don't like the study, the result was lousy, or whatever, we
    need to publish it.
        Second, just before I left Duke, I was the co-author of a
    New England Journal paper pointing out the track record of
    clinicaltrials.gov reporting. One interesting side issue there
    is that industry is actually doing better than NIH-funded
    investigators, so we have work to do there. I'm pleased to say,
    working with the NIH, they now have a policy that you won't get
    your next grant unless you put your result in
    clinicaltrials.gov. It's been very good working with Kathy
    Hudson and Francis Collins on making this happen.
        The third element, the surveillance system that we talked
    about, Sentinel, and the equivalent on the device side--this is
    really needed. We're now dealing with generic drugs that have
    been on the market for up to 40 years, and we're still learning
    about them. We can't have a system where it depends on the
    innovator company to figure all this out and somehow make it
    public.
        I give Jeff Shuren and Janet Woodcock a lot of credit. We
    have an approach--and we just had a meeting 2 weeks ago with
    other Federal agencies, and there's general agreement that we
    need to have a national evaluation system, which is really a
    public good, and if the companies can develop the best
    products, that's fine. We need to work toward this.
        Senator Baldwin. I want to switch gears, given the role of
    the FDA in food labeling. You and I had a chance to speak about
    one of Wisconsin's products. We're the No. 1 grower of
    cranberries. I know that a couple of other members of the HELP
    Committee represent States that have a robust cranberry
    industry, also.
        I'm concerned that recent FDA proposals to update food
    nutrition labels, specifically with added sugar information,
    may cause some confusion for customers and others by
    categorizing cranberry products, which are clearly highly
    nutrient dense fruits that need added sugar for palatability,
    as somehow comparable to foods that they shouldn't necessarily
    be compared with. For example, should you be comparing
    cranberry juice to other fruit juices or to soda pop? Should
    you be comparing dried cranberries, craisins, to raisins or
    candy?
        As Commissioner, how would you ensure that these and other
    FDA food policies appropriately account for the unique health
    benefits of food like cranberries and ensure that consumers are
    going to have the type of information, comprehensive and
    accurate, that will allow them to make healthy and nutritious
    decisions?
        Dr. Califf. Senator Baldwin, I appreciate that, and I've
    noticed cranberry juice has frequently been in our refrigerator
    at home. It may have something to do with some health benefits
    that are attributed to it. It's a good example of the balancing
    act the FDA has to do. We've got this terrible epidemic of
    obesity and diabetes, so huge amounts of sugar are clearly not
    good for you. I don't think there's any disagreement about
    that. We've also got to preserve nutritious foods that do need
    a little sugar to make it better.
        I talked with Senator Warren and with you a little bit
    about the fact that we need to really work on the cognitive
    psychology of labeling so that when we do take actions and put
    information out there, it's interpretable and actually helps
    people make good decisions. Ultimately, it's up to people to
    make their own decisions, but if we don't present it in a way
    that's clear to them, it could lead to the wrong decision.
        The Chairman. Thank you, Senator Baldwin.
        The next Senators are Senators Cassidy, Franken, Kirk, and
    Bennet.
        Senator Cassidy.

                          Statement of Senator Cassidy

        Senator Cassidy. I enjoyed our meeting. Thank you for
    coming by. I have several questions. First, going back to the
    drug pricing, clearly, we've seen companies like Turing and
    Valeant kind of abuse the social contract, which gives you a
    reasonable rate of return for drug marketing, and they've gone
    way beyond reasonable.
        I've been told in the case of Turing that an approval of a
    generic would take several years because clinical trials would
    be required to prove that the generic competitor was the
    equivalent to that which Turing now has as a sole source
    provider. We know this is a 60-year-old drug.
        It comes to mind because I'm reading now, on-premise, on a
    compounding component that would make the same drug available.
    Of course, compounding--a doc has to write the prescription. In
    a sense, compounding is doing what generic can't do.
        I guess my question is if we know, or I presume we know,
    that the compounded drug being sold for $1 a pill, as opposed
    to $750 from Turing--take that as an advertisement for anybody
    who wants a reasonably priced drug--if it is $1, why can we do
    this in the compounding space but not in the generic space? Why
    does it take so long to work this through the generic when we
    get--do you see what I'm saying? This is cognitive dissidence.
        Dr. Califf. I know you're a doc and you have an
    understanding of all this. Let me just point out, as I
    mentioned earlier, every drug is a little bit different, and
    the whole goal with generics, in most cases, is not to have to
    do major clinical trials. It's really just showing that you
    actually have something that's equivalent. I believe you spent
    a lot of time with Dr. Woodcock on this recently.
        Senator Cassidy. Yes.
        Dr. Califf. There's a lot we can tell about the molecular
    structure in some very simple pharmacodynamics type studies.
    We're not dependent on these large clinical trials that we have
    to do for the innovator drugs. When it comes to compounding, as
    you well know, we're working hard on the standards for
    compounding, because we had some disasters with compounding
    that have required FDA action.
        Senator Cassidy. The disasters were more related to
    infection control, fungi entering an injectable. This,
    obviously, is an oral drug, and I presume--knowing that there
    is liability involved, on-premise would not be selling it were
    it not bioequivalent.
        Dr. Califf. I'll have to get back with you on that because
    I don't know the details on that particular drug. I'll be glad
    to do that.
        Senator Cassidy. Just because I see now that these folks
    have established--the business model works. Again, I have
    something from Valeant--a fellow who was paying $566 a
    prescription. It's now $5,500 a prescription. A total
    exploitation of the system that has been a pretty good social
    contract and now is breaking down because of these folks--
    frankly, greed.
        If we're going to somehow circumvent that, we've got to
    come up with a more efficient way to do the generics. Again,
    just to make the editorial comment, it so clearly is working
    with compounding that it seems almost like it should work as
    well with generic.
        Dr. Califf. Again, I'll have to get back with you on the
    specifics. I did have a pharmacy compounding operation at Duke
    Hospital that was required for some of our intensive care unit
    medicines, and I'm very aware of the complexity of compounding.
    It's not as simple as it may sound. I'd have to really look at
    the specifics of this and get back with you.
        Senator Cassidy. That's fair. Second, which is related,
    going to the drugs which are manufactured in India and China, I
    gather that the FDA recently sent out a warning that said
    investigators went, looked, observed holes in the walls and
    roof which allowed pigeons access near production equipment in
    multiple manufacturing areas. There's evidence, or at least
    suspicion, that somebody was hiding audit trails, et cetera.
        I'll just say, again, cognitive dissidence. On the one
    hand, we're continuing to allow folks to import, even when good
    manufacturing procedures are obviously not being followed. Yet
    it seems like we're putting roadblocks up for those who are
    producing domestically, who could give us some relief from the
    exploitative pricing practices. Knowing that you're the new man
    on the job, I don't expect you to comment on that beyond just
    to make the observation.
        Dr. Califf. Yes, I understand what you're saying, and I did
    have the privilege as an academic to do a lot of work in India
    and China over the last decade, and it is going to be a focus
    that we'll have to pay a lot of attention to. A large part of
    our food and our drugs and device supplies are coming from
    India and China. We certainly don't want to disadvantage
    Americans in that regard, either.
        Senator Cassidy. If we found those GMP were not being
    followed, would we shut down those supply--those components of
    the supply chain?
        Dr. Califf. We can't shut down something in India or China,
    but we can shut down importation.
        Senator Cassidy. The ability for that to be used----
        Dr. Califf. Yes, and we do that.
        Senator Cassidy. I got you. I yield back. Thank you.
        The Chairman. Thank you, Senator Cassidy.
        Senator Franken.

                          Statement of Senator Franken

        Senator Franken. Thank you, Mr. Chairman, and I note that
    you, Senator Baldwin and Senator Cassidy have all talked about
    what we're hearing when we go back to our States about
    pharmaceutical costs, and that's something we really have to
    deal with, and the exploitation of positions that companies
    have gotten.
        Dr. Califf, I want to talk about probably the basic
    question that you will face, which is the delicate balance that
    the FDA plays in making sure that products get to people who
    need them quickly, but at the same time making sure that
    they're safe. That's what you deal with every day. I've tried
    to promote this balance in legislation I have introduced with
    Senator Burr, the FDA Device Accountability Act of 2015.
        Given your experience as an outside advisor and now as an
    internal leader at FDA, how can FDA use the tools at its
    disposal to strike this balance?
        Dr. Califf. When it comes to cost, we do have some tools we
    can use to help out. The first, we've already discussed, which
    is doing everything we can to do a good job with the generic
    drug situation. We're at 88 percent now, and that's a good
    thing.
        We now also have biologics, which--biosimilars are now
    coming up, and we've got over 50 applications in the works.
    We're going to need to do a good job with that, too, because
    that's a big expense and we want to make sure that people have
    access when it's appropriate and safe and effective. The
    criteria are stringent there.
        One other that is very important to me, which people
    wouldn't normally think about that much but it's going to come
    up more and more, is that if we really fix our evidence
    generation system, that is, streamline clinical trials, get the
    data that we need, people wouldn't spend money on expensive
    drugs when they're not needed. We need to have better
    information for people, and several Senators have brought that
    up today, and we can do that in a fairly dramatic way.
        And finally, we do keep track of shortages. We prevented
    over 100 shortages a year in each of the last 4 years. One
    year, it was all the way up over 200. There's a constant
    surveillance that goes on. There's a requirement that people
    notify us when there's going to be a shortage problem.
        The new area that we've got to work on is when someone gets
    a monopoly, which is what several of you have referred to,
    understanding who the competitors are and making sure that
    they're doing the right things to be able to compete and get
    their products on the market.
        Those are the things that we've gone through that we can
    clearly do fully within the FDA.
        Senator Franken. Quickly, I want to turn to a different
    issue, which is making sure that products continue to be safe
    once they've hit the market, once they've been approved for the
    market. You mentioned post-market surveillance. Does the FDA
    have adequate authorities here that you need to do this
    adequately, or do you need additional ones from Congress?
        Dr. Califf. I'd have to get back to you on the specifics of
    what you might be thinking. The thing we clearly need is a
    better system for post-marketing. Sentinel on the drug side is
    revolutionary and fantastic, and on the device side, we're
    doing better and better. We have a plan that I hope we can
    really enact, because I believe when we find a problem, for the
    most part, we can deal with it. We've got to have good data and
    quickly in order to identify the problems.
        Senator Franken. I want to talk about generic drug labeling
    and the generic drug labeling rule. This has to do with the
    rulemaking that you are doing on generic drug manufacturers and
    requiring them to update their warning labels and provide new
    safety information. This came out of the Supreme Court
    decision.
        What is the current plan for finalizing the FDA's generic
    drug labeling rule?
        Dr. Califf. Thank you for asking. That's a very important
    issue. As I said, we need to make sure that if there are
    problems with generic drugs that come up later--and they do--
    with better surveillance systems that there's a way of making
    sure the labels are up to date and consistent across similar
    products. We got a lot of comments on the proposed rule.
    They're under consideration. I can't talk about decisionmaking.
    We're in the middle of it. It's a very high priority to get
    this finished.
        Senator Franken. Thank you.
        Thank you, Mr. Chairman.
        The Chairman. Thank you, Senator Franken.
        The next Senators are Senator Hatch, Senator Bennet,
    Senator Scott if he returns, and then Senator Sanders.
        Senator Hatch.

                           Statement of Senator Hatch

        Senator Hatch. Thank you, Mr. Chairman.
        I'm very pleased to be able to support your nomination. I'm
    very impressed with what you've been able to do, not only with
    your life, but all the work that you've done down there at Duke
    and elsewhere. To be honest with you, you deserve a lot of
    credit, and you're going to add a great deal to the FDA.
        Let me just say this. I'm very concerned about data
    exclusivity. When we did Hatch-Waxman, we made sure there was
    enough data exclusivity time so that they could recoup the
    cost, because the average cost, according to what I've been
    told, for a pharmaceutical drug is about a billion dollars and
    up to 15 years or more because of the pace at FDA, and for a
    biological drug, about the same. The average cost is $2 billion
    to come up with a biological therapy that is approved by FDA.
        I'm very concerned about it, because if we reduce that data
    exclusivity time, especially with regard to bio, you're talking
    about having to charge a lot more, and you're talking about our
    industries subsidizing other countries all over the world and
    paying, really, so they can have these biotherapies really at
    our expense, and at the same time, in order to recoup the
    amount of money it cost to go through FDA, the cost of these
    therapies is continually rising.
        I just want to know if you feel that we can move ahead
    quicker on these matters and make it so that these companies
    have a chance to recoup their monies that they've invested.
        Dr. Califf. Senator Hatch, I do understand your concern
    that we want to make sure that if someone invests in the
    development of a drug, there's a return on investment.
    Otherwise, people won't invest in our kind of society.
        Senator Hatch. You also understand that the more it costs,
    the more difficult it is to recoup the funds, and the longer
    length it takes to recoup them as well without charging even
    more than we do now.
        Dr. Califf. The FDA doesn't set the length of data
    exclusivity.
        Senator Hatch. I know.
        Dr. Califf. What we can do that you bring up is the cost of
    development is largely driven these days now by the cost of
    clinical trials. We think we can do trials that are actually
    bigger and include more patients and are more representative
    for a much lower cost. I hope you'll work with us on that.
        Senator Hatch. I'm going to work with you on it, but that's
    an important issue, and it even becomes a major issue with
    regard to our trade promotion authority bill and also the Trans
    Pacific Partnership.
        Dr. Califf. I appreciate that.
        Senator Hatch. If we don't allow enough data exclusivity
    time, we're not going to develop these therapies, especially in
    bio, because bio is one of four or five places, four or five
    techniques, where we can actually find treatments and cures. If
    we find the cures, that, over time, will save us trillions of
    dollars. I'm very concerned about this system working very
    well.
        Dr. Califf. I've been fortunate to be a leader in the
    development of several biological therapies that have made a
    difference. So I appreciate what you're saying.
        Senator Hatch. Also, Hatch-Waxman has made a real
    difference as far as getting--I remember when we did Hatch-
    Waxman, it was like 18 years to get a generic through. Today,
    it's--and it was very, very difficult. It's kind of automatic
    because----
        Dr. Califf. We're doing better, and 88 percent of
    prescriptions are generic. It's been a tremendous success.
        Senator Hatch. One issue that significantly affects many
    entities in my home State is the FDA's October 2014 proposed
    guidance on the regulation of LDTs, laboratory-developed tests.
    There has been a robust conversation on this proposed guidance
    between stakeholders, Members of Congress, and the FDA ever
    since the announcement.
        Does the FDA intend to issue final guidance, or does the
    agency plan to allow for further comments and feedback on the
    next steps proposed?
        Dr. Califf. As you may know, this is an ecosystem issue
    where we want to have universities continue to innovate, but we
    also want to assure patients that they're getting accurate test
    results for analytical and clinical validity. We're collecting
    a lot of information, ongoing feedback.
        We just had 2 days at the FDA of all the stakeholders
    talking about next generation sequencing, which is an advanced
    form of this testing, so we're still collecting feedback. We
    want to find something that stimulates innovation but also
    assures patients.
        Senator Hatch. Mr. Chairman, may I ask just one other
    question that would just requires a yes or no answer?
        The Chairman. Sure.
        Senator Hatch. Thank you.
        Do you believe, as prior commissioners have--every one has
    told me this--that the Dietary Supplement Health and Education
    Act, DSHEA, provides adequate authority to regulate the dietary
    supplement industry and protect consumers from unsafe products?
        Dr. Califf. We're fully aware of our authorities, and
    you're going to see a lot of action where the authorities are
    pertinent in the near future.
        Senator Hatch. Do you agree you have enough authority?
        Dr. Califf. We're very well aware of our authorities and
    plan to use them as Congress has directed.
        Senator Hatch. All right. Thank you.
        The Chairman. Thank you, Senator Hatch.
        Senator Bennet.

                          Statement of Senator Bennet

        Senator Bennet. Thank you, Mr. Chairman.
        Thank you, Dr. Califf, for your willingness to serve. We're
    delighted that you're here today.
        In my view, the FDA has been extremely successful
    implementing the breakthrough therapy pathway, which has led to
    the approval of 32 lifesaving drugs and over 100 more in the
    pipeline. When I was first working on this bill with Senator
    Hatch and Senator Burr, Colorado startups were saying to me
    that all of the venture capital in this country was moving to
    Asia and moving to Europe because of the regulatory uncertainty
    at the FDA.
        All of us want to keep jobs here, and we want to give
    patients safe and effective drugs as soon as possible. It looks
    to me like this breakthrough pathway may be achieving both, and
    I wonder whether you could talk about it a little bit. What
    have we learned about regulation, and can this kind of approach
    be modeled in other places at the FDA, including at the device
    center?
        Dr. Califf. Thanks for your comment, and my two sons from
    Colorado are listening carefully, I'm sure, to your thoughts on
    this. Breakthrough is----
        Senator Bennet. Barbara Mikulski is not here, so let me say
    we would gladly move the FDA to Colorado if that would make the
    family closer together.
        [Laughter.]
        The concept of breakthrough is where things look really
    promising early on, that it's going to make a dramatic
    difference, and there's an unmet need for a life-threatening
    condition. The FDA works closely with the industry to move
    things along as quickly as possible. There have been a whole
    series of cancer issues, in particular, that have just
    delighted the cancer community and people who otherwise would
    die.
        My mom back here has multiple myeloma. She's now on her
    third or fourth chemotherapy treatment. It's been a tremendous
    success to have the community working with the FDA and with
    industry and with academia in a concerted effort. We don't need
    this for chronic common problems where there's already
    effective treatment. We want to make sure we don't rush things
    to the market that aren't safe. The real key is having the
    criteria to identify where this kind of activity is needed.
        Senator Bennet. I want to say that, at least from my
    perspective, it's fashionable to criticize the agency. This is
    a place where the FDA has really gotten it right.
        How about on the medical device side of the equation?
        Dr. Califf. There have been issues with medical devices
    moving to other parts of the world. They're beginning to come
    back, and one of the reasons is the early device research
    program that's been developed by CDRH together with the
    community that is working with the big centers that can do the
    early device work, bringing those things back.
        There's also an issue with devices that you know a lot
    about, which is, often, a device is useful in a very unusual
    disease, and it's a very niche activity where there's not an
    adequate market. We do have a program for that. It's
    successful. It's a topic that we need to think about and
    discuss more to define ongoing criteria.
        Senator Bennet. I should also say that the cancer community
    was vitally important in getting that piece of legislation
    passed to begin with. It's nice to see that some of the early
    drugs have been drugs that fight cancer.
        Switching gears, I wonder whether you would take a few
    minutes to discuss with the committee how we should think about
    investment in life science innovation, not just as a domestic
    priority, but as a global economic priority to keep us
    competitive with other nations. This is a time when we're
    seeing diminishing resources in this country applied to basic
    science, and I wonder if you could help us understand why
    that's important or whether it is.
        Dr. Califf. It's just the case that almost everyone is
    concerned about, living longer and being more functional in
    their lives, and the way we do that is through public health
    and also through medical products, and in the case of tobacco,
    reducing it, hopefully. As we go about that, the development of
    new medical products does require investment, because it's
    appropriate that there's a law that says you've got to show
    you're safe and effective before you come on the market.
        This requires time to do the development, and it requires
    that you really show that you're not producing an inferior
    product before you come on the market. It's really a critical
    issue. We've got to invest.
        On this note, in our work with the NIH, we're very focused
    on the use of biomarkers, surrogate inpoints, but also on not
    using them inappropriately when they're not going to work. This
    is really hard work to set the conditions that would excite
    investors to put money into biomedical science.
        Ultimately, the United States is saving the world through
    investment in the NIH, and I want to put in a plug for
    continuing with the NIH investment. If not for the scientists
    being funded through NIH, we wouldn't have the basic science to
    translate into effective medical products.
        Senator Bennet. Thank you. Thank you for your testimony.
        Thank you, Mr. Chairman.
        The Chairman. Thank you, Senator Bennet.
        I want to thank Senator Murkowski, who has left the
    hearing, and Senator Casey for allowing Senator Sanders to go
    next. He has been waiting patiently and he has extracurricular
    activities which he's attending to.
        Senator Sanders.

                          Statement of Senator Sanders

        Senator Sanders. Thank you, Mr. Chairman, and thank you,
    Senator Casey.
        Dr. Califf, thanks very much for being with us. You and I
    chatted a while back, and I told you that I would not support
    your nomination, because I believed you were not strong enough
    on the most important issue that the American people are
    concerned about with regard to prescription drugs. That is, in
    our country, we pay, by far, the highest prices in the world
    for prescription drugs. As I understand it, about one out of
    five Americans cannot afford to fill the prescriptions that
    their doctors are writing for them.
        Mr. Chairman, with your permission, I would put into the
    record a comparison of drug prices in the United States and
    Canada, which show that on major and important drugs, the
    prices in Canada are far, far less expensive than they are in
    the United States, and that's true all over the world.
        [The information referred to may be found in Additional
    Material]
        My concern, Mr. Chairman, is that while last year, the top
    four drug companies in this country--Pfizer, Johnson and
    Johnson, Novartis, and Hoffmann-La Roche--made $57 billion in
    profit in 1 year, I heard concern that drug companies are not
    doing well. They're doing quite well, and yet you have millions
    of Americans who cannot afford the high cost of prescription
    drugs.
        While all of us agree that, clearly, we want great new
    products out on the market to save lives, for millions of
    people, it doesn't matter what the products are. They just
    cannot afford them. We need, in my view, an FDA Commissioner
    who is going to be aggressive and understands that very simple
    principle, and I'm not clear, and what I heard today confirms
    that I don't think you get that.
        Here are some of the questions I'd like to ask to make out
    the point. It is not a coincidence that last year, the
    pharmaceutical industry spent $250 million on lobbying and
    campaign contributions and employ some 1,400 lobbyists. Do you
    think, Dr. Califf, that that type of expenditure has any impact
    on the fact that we pay, by far, the highest prices in the
    world for prescription drugs?
        Dr. Califf. Senator Sanders, the ideal situation would be
    if the money went into R&D to develop an adequate picture of
    the risks and benefits of treatment and that was made available
    to people.
        Senator Sanders. Why do we pay the highest prices in the
    world, by far, for prescription drugs?
        Dr. Califf. I'm not an expert on the price of drugs,
    Senator Sanders, but I'm certainly sensitive to the fact that
    in a field like cardiovascular medicine, my specialty, we need
    to have drugs available, because they save lives and----
        Senator Sanders. Doctors and oncologists have written to us
    that it doesn't matter what drugs are available because their
    patients can't afford them. Let me ask you this, a very simple
    question. As head of the FDA, you will oversee the importation
    of food products, vegetables, fish from all over the world. We
    can import lettuce and tomatoes--vegetables from farms all over
    the world. Somehow we cannot reimport from Canada brand name
    prescription drugs manufactured by the largest drug companies
    in the world.
        Can you explain to me, and do you support, the
    reimportation of brand name prescription drugs from major
    companies from Canada and from other major industrialized
    countries? Yes? No?
        Dr. Califf. Senator, as you're aware from our previous
    discussion, we have major concerns about reimportation. The
    system it would take to make sure that the drugs are adequate
    and safe for Americans----
        Senator Sanders. In other words, you think we can bring in
    fish products and vegetables from farms all over the world, but
    we cannot bring from across the Canadian border brand name
    drugs. You don't think we have the capability of doing that?
        Dr. Califf. We have the capability. It would add additional
    cost, and systems would have to be put in place to make it
    work.
        Senator Sanders. This is why, precisely, the American
    people are paying, by far, the highest prices in the world for
    prescription drugs. It is beyond my comprehension that you're
    sitting here saying we can bring in vegetables and fish from
    all over the world, but we cannot bring in brand name drugs
    manufactured by the largest pharmaceutical companies in the
    world from a country like Canada. I just do not accept that.
        Let me ask you another question. One of the reasons we pay
    the highest prices in the world is--today, I can walk into a
    drugstore and they can tell me the medicine I use--the price
    has doubled because we have no regulations. Do you believe, and
    will you support, the right of Medicare to negotiate drug
    prices, which is now currently not allowed by law? Shouldn't
    Medicare sit down and negotiate drug prices so we can lower the
    prices of medicine?
        Dr. Califf. You're aware, I believe, it is the
    administration's position that in certain circumstances that
    have been spelled out in the President's budget, negotiation on
    Medicare prices should be done. It's not the FDA's remit to set
    the prices, as we've already discussed. It is the
    Administration's----
        Senator Sanders. I know. But the issue of affordability is
    within your jurisdiction.
        Let me just conclude, Mr. Chairman, and let me thank,
    again, Senator Casey for jumping over him here.
        We all want great medicine to come onto the market, and I
    respect the work that you have done. At the end of the day,
    people are dying, people are not buying the food they need
    because they have to pay outrageous prices for medicine because
    we have been extraordinarily weak in taking on the
    pharmaceutical industry that is ripping off the American
    people.
        I believe that we need a Commissioner--and I know that's
    not the only responsibility of the FDA--but I believe we need a
    Commissioner who is going to stand up to the pharmaceutical
    industry and protect American consumers. I'm going to have to
    say to you, with regret, that I think you are not that person.
        Thank you very much.
        The Chairman. Thank you, Senator Sanders. Senator Murkowski
    also stepped aside as well as Senator Casey.
        Senator Murkowski, thank you for being here.

                         Statement of Senator Murkowski

        Senator Murkowski. Thank you, Senator Alexander.
        Dr. Califf, welcome. Senator Sanders has just broached very
    briefly the issue of fish. He says we can bring in fish from
    all around the world. I want to suggest to you that perhaps
    bringing in fish from all around when it is mislabeled and
    misnamed is not something that we want to do.
        I would ask you again to look at the issue that we have
    raised repeatedly before the FDA regarding the Pollock
    nomenclature. This is something where we contend that you do
    have the regulatory authority to change the acceptable market
    name from Alaska Pollock to Pollock so that we can put some
    limitation and parameters on what we're seeing from the large
    volume of Russian harvested Pollock that is sold to U.S.
    consumers as Alaska Pollock.
        I have repeatedly raised this and would ask that you would
    work to expedite this change and remove the blockade that has
    been created within the FDA's bureaucracy regarding this
    Pollock nomenclature.
        Dr. Califf. Senator Murkowski, I enjoyed my visit with you
    and I heard clearly what you said then. We are still open for
    comments and thinking about this. I will work with you to come
    to a resolution on this issue.
        Senator Murkowski. I do want to work with you. Again, this
    is something that can easily be resolved, and that's what we're
    looking to do here, to address it through the regulatory route
    as opposed to the legislative, which we will do if we have to.
    This is one that we can fix working together.
        The last question that I have for you also relates to
    seafood, and this is regarding some concerns that we're hearing
    that the forthcoming FDA seafood advice to pregnant women on
    seafood consumption may not be entirely based on science. This
    is something, of course, that is gravely concerning.
        Back in 2014, there was a statement that was released on
    the draft seafood advice that spells out pretty clearly that
    science now tells us that limiting or avoiding fish during
    pregnancy and early childhood can mean missing out on important
    nutrients that can have a positive impact on growth and
    development as well as your general health. The concern is that
    the FDA has revised that advice in a way that ignores this Net
    Effects Report.
        The question to you this morning is: What is the status of
    the FDA's seafood advice for pregnant women? I guess what I'd
    like to hear from you, specifically, is whether or not, when
    that advice is released, that final seafood advice for pregnant
    women and nursing mothers will be based in science, namely,
    using the Net Effects Report.
        Dr. Califf. I can assure you it will be based on science,
    and the recommendation will be something that will be very good
    for American people and----
        Senator Murkowski. Why would it not be based on the Net
    Effects Report?
        Dr. Califf. We're having to balance a lot of input and
    considerations here.
        Senator Murkowski. Wouldn't that input and consideration be
    based on the science that went into that report?
        Dr. Califf. We base it on all the scientific facts that can
    be brought to bear that accumulate over time. These will all be
    considered. You'll be happy with the recommendation when it
    comes out.
        Senator Murkowski. I appreciate that assurance. It doesn't
    necessarily get me to where I would like to be, which is a
    recognition that you will utilize that Net Effects Report, the
    report that very clearly outlines why it is important for the
    nutritional needs of not only the mother, but developing
    children as well.
        Dr. Califf. I'm very familiar with the concept, but the
    detail I'm going to have to come back to you on to make sure
    that----
        Senator Murkowski. Can you tell me when we might anticipate
    this report then?
        Dr. Califf. I can't give exact dates or timelines. This is
    a fairly straightforward issue, and it's a high priority, and
    we've had discussions about it recently. So it's going to move
    along.
        Senator Murkowski. I would agree that it is high priority.
    It is important, and it is overdue. Certainly, the science is
    overwhelming in its support for the recommendations, good sound
    recommendations based in science that pregnant and nursing
    women be given good advice when it comes to seafood in their
    diets.
        Thank you, Mr. Chairman.
        The Chairman. Thank you, Senator Murkowski, and thank you
    for your courtesy to Senator Sanders, even though you were
    chairing a hearing, and thanks also to Senator Casey.
        Dr. Califf, after I call on Senator Casey, I'm going to
    leave for another appointment and turn over the hearing to
    Senator Scott, who will ask his questions, and then if there
    are no other Senators, he will conclude the hearing. Thank you
    for being here.
        Senator Casey, thank you for your courtesy to Senator
    Sanders.

                           Statement of Senator Casey

        Senator Casey. Mr. Chairman, thank you. Thanks for the
    hearing.
        Doctor, we're grateful you're here, and we appreciate your
    commitment to public service and that of your family. I know,
    and we all know, that when an individual makes a commitment to
    service, it involves a sacrifice and a contribution in a
    substantial way by your family, so we're grateful for that.
        I wanted to try to cover maybe three topics, one or two of
    which I may have to do by way of written questions. The first
    is children, and that's what I'll spend most of my time on, and
    the second is food safety, and the third is this issue that's
    been raised about independence and ensuring that's the case
    going forward.
        First, with regard to kids, we're told that today is World
    Prematurity Day, so we're talking about premature babies born.
    I guess 1 in 10 born in the United States today is born
    prematurely. We've had legislation over time, obviously, that
    speaks to this. One is the recent FDA Safety and Improvement
    Act, which required, among other things, that FDA hire a
    neonatologist in the Office of Pediatric Therapeutics to work
    on implementation of the provisions of the act for neonates.
    That happened, and that hiring was done. We're grateful that
    that happened.
        One of the areas I'll be looking at more broadly as you do
    your work is to focus on the implementation of changes by the
    FDA that come as a result of both the Best Pharmaceuticals for
    Children Act and the Pediatric Research Equity Act, and we can
    amplify those later. Just with regard to treating premature
    infants, we know that more must be done to accelerate the
    development of both therapies and devices to treat infants in
    so-called NICUs, neonatal intensive care units.
        If confirmed, I guess my first question would be: How might
    you use FDA's existing authority, the regulatory authority, to
    promote the development of cutting-edge treatments for
    premature babies?
        Dr. Califf. Thanks for asking that question, Senator Casey.
    You may not be aware of this, but when the Children's Act first
    came into existence, I was one of the instigators with the
    phrase, children should not be therapeutic orphans, that is,
    doctors were forced to give treatments to children with no
    evidence about the right way to give the treatment.
        We ended up at Duke being the coordinating center for the
    NIH part of this, to take drugs that were already off patent
    and figure out the right dose. We have a neonatal intensive
    care unit network from my old institute which is focused on
    this. I've written about 20 papers on this topic. We need to
    keep moving along, and we need to move on to pregnancy, which
    is another very high priority issue where the right doses of
    drugs are just not known for the most part.
        Senator Casey. The second question--and I appreciate the
    background of what you've been doing. The second question might
    take more reflection, because it's kind of a broad-based
    question. You can certainly amplify or add to what you say here
    by way of a written response. Is there anything you would hope
    that Congress would do to increase FDA authority in this area?
        Dr. Califf. The food safety?
        Senator Casey. No, I'm sorry. On----
        Dr. Califf. On children?
        Senator Casey. Yes.
        Dr. Califf. We're in pretty good shape where we are in
    terms of authority. If you have good ideas, let me know. The
    studies could be better and could be broader. We can make that
    happen working with the community.
        Senator Casey. I'll move to one other question as it
    relates to children, so-called neonatal abstinence syndrome.
        Dr. Califf. Yes.
        Senator Casey. We're told now among other statistics that
    one baby is born every 25 minutes with opioid withdrawals,
    meaning the equivalent of neonatal abstinence syndrome. It's
    increased some fivefold in the last 12 or so years.
        The majority leader, Senator McConnell, and I just got a
    bill through both the Senate and just, I guess, yesterday, the
    House, which we hope will be signed into law to focus on this
    problem. Anything that you can tell us about either your
    previous work or work you can do leading the FDA on this
    specific issue as it relates to neonates?
        Dr. Califf. This is a terrible problem, the concept that an
    unborn child would be exposed to opiates and essentially
    addicted at birth. We had a public meeting on this recently.
    Like the opioid problem all together, this is a community
    effort. We've all got to work on it, including the FDA.
        We have a whole series of measures that we're implementing,
    including a major effort on physician education, which is
    critical. Tens of thousands of docs have now taken the required
    courses through the REMS program, the post-marketing. This is a
    huge problem. We've got a lot of work to do on this, and I look
    forward to working with you on it.
        Senator Casey. I appreciate that.
        Mr. Chairman, could I have one more minute?
        Senator Scott [presiding]. Certainly.
        Senator Casey. Thank you very much, and I know you're
    waiting.
        Part of this we can develop more in a written question. On
    food safety, one of my constituents just recently was severely
    sickened with listeria in 2012, and I guess as a result of
    ingesting ricotta salata cheese from Italy, among many other
    stories I know that constituents have with regard to food
    safety.
        I know this is a resource issue or, I should say, lack of
    resource issue as well. Can you tell us a little bit about what
    you hope to be able to do even within the confines of limited
    resources?
        Dr. Califf. It's been a real privilege getting to know Mike
    Taylor, who heads up FSMA and heads up this part of the FDA.
    He's been doing this for years. A dream of his was to get FSMA
    put together, and we're now moving to the implementation phase.
        The real key--because this is such a massive food--it's
    just a lot of things. High-quality analytics, like every other
    industry is using now, really is what we're implementing so we
    can target the inspections to where the highest risk is. We're
    even using genomics for bacteria to figure out exactly where
    they come from by doing complete genotyping, just like we do
    with people. It's really moving the science along and then
    realigning the workforce so that it's allocated to preempt and
    prevent these problems before they occur rather than just
    reacting.
        Senator Casey. I'll submit for the record a question about
    the issue that was raised about independence, and I appreciate
    what you said in your testimony about the Duke contract as well
    as your own steps you've taken since being at the FDA on
    recusal. I'll develop a broader question to send to you.
        Dr. Califf. I appreciate it, and I'm glad to respond. I
    just wanted to note in light of Senator Warren's questions that
    Duke University has graciously agreed to make the contracts
    available, and they're either in the staff 's hands or on the
    way. It'll be good for you to look at those.
        Also, just a note that the consulting money abided by these
    principles, but I also made a personal decision to donate that
    money to not-for-profit charities. It's really just a sign that
    the work is something I thought was important, not the money,
    in this case.
        Senator Casey. Thanks, Doctor.
        Thank you, Mr. Chairman, for the extra time.
        Senator Scott. Thank you, Senator Casey.
        Dr. Califf, thank you for your willingness to serve and
    thank you for allowing me to clear up the fact that you're a
    South Carolinian and not from North Carolina. That was
    important to me and----
        Dr. Califf. It's great to be here with a fellow South
    Carolinian.
        Senator Scott. Thank you, sir, especially since Senator
    Burr is now gone. We'll continue.
        [Laughter.]
        Dr. Califf, I am the co-founder of the Sickle Cell Caucus.
    We focus a lot of attention on trying to make sure that people
    understand and appreciate the devastating impact that sickle
    cell has throughout the Nation and specifically within African-
    American communities.
        Sickle cell, while rare, is devastating to communities and
    families. It is also one of the most expensive diseases to
    treat, given the high incidence of hospital re-admission. Yet
    we haven't had any new treatments introduced in the market,
    some say for 20 or 30 years. How can we address this and create
    an environment that incentivizes investment in research and
    development for diseases that affect smaller segments of the
    population?
        Dr. Califf. Thank you for asking that question. One of the
    regrets that I have about the wonderful opportunity at the
    FDA--I was glad to do it, but I left behind some things I was
    working on. One of those is the issue of diseases that affect
    minorities, particularly poor minority people, differentially.
        We had a big project going on in North Carolina, West
    Virginia, and Mississippi looking at the population base using
    electronic health records. One thing that pops right out at you
    is that sickle cell disease, while people are children, is
    pretty well covered by the Medicaid system.
        Senator Scott. Yes.
        Dr. Califf. With first-rate care, and then when people
    become adults, they're on their own. They frequently live in
    rural places. They can't get to the big centers, and this has
    created a disincentive to therapeutic development.
        The good news is NHLBI, with Gary Gibbons as the head--he's
    a good friend. I was working with him, and I think there's a
    comprehensive plan, including some of the designations for
    moving therapeutics through more quickly. I'm aware of some of
    the new things that are in development, and they look really
    good. If I wasn't here, I'd be working with those new things.
        Senator Scott. Excellent. Thank you. Two diseases that
    affect my State at a rate higher than the national average are
    heart disease and diabetes. In 2013, heart disease was the
    leading cause of death in South Carolina and accounted for $3.1
    billion in hospitalization costs. In 2013 as well, 11.3 percent
    of South Carolinians had diabetes.
        We are in desperate need for cures for these two chronic
    conditions. However, the high risk and cost of trials,
    particularly Phase 3 trials, actually seems to create an
    incentive for researchers and investors to avoid working on
    medications that could help the many Americans and South
    Carolinians suffering with these chronic diseases.
        What ideas do you have for reforming the clinical trial
    process to incentivize researchers and investors to delve into
    the high-risk but high-reward areas of medicine?
        Dr. Califf. I'm tempted to ask how many hours you have, but
    I'll keep this brief. First of all, let me just make a note
    that in the population base studies we were doing with a CMMI
    innovation grant in North Carolina--unfortunately, not South
    Carolina--West Virginia, and Mississippi, it's really a
    devastating--this was focused on diabetes. We need to get it
    under control.
        In addition to the cures that you mentioned, we also need
    to just deliver good healthcare to people close to where they
    live, and that was what our project was doing, using electronic
    health records to set up systems in neighborhoods so people got
    the care that they needed to deal with chronic disease.
        On the clinical trials front, it's a problem that's related
    to something we discussed earlier, which is that for a disease
    like heart disease, where we have a lot of effective treatments
    already, we don't want to let something on the market that's
    not going to be safe and effective. We have to do adequate
    clinical trials.
        Here's the good news. We're committed, as are all the
    Federal agencies, to work with industry and academia to develop
    a national system that delivers better clinical trial results
    with larger, more representative populations at a lower cost,
    and I would say a dramatically lower cost. The key here is
    using electronic health records that we already have. Almost
    every American has one.
        We've got to overcome the interoperability hurdles and some
    terminology. We can do this, and that would enable people to
    develop new therapies at a much lower cost, but with better
    information about safety and efficacy.
        Senator Scott. My final question. Back in September, I had
    an opportunity to ask Dr. Woodcock of the FDA about labeling of
    biosimilars. She stated that there were tradeoffs in various
    labeling decisions but did not provide any clarity as to what
    industry, physicians, and patients can expect and when they can
    expect it, which was a primary part of my question--the when.
        I continue to feel as if there's a serious risk in not
    providing notice that a product is a biosimilar, considering
    that there can be small differences between biosimilars and
    their branded counterparts, unlike with generics. Can you
    provide any update on where things stand with the labeling of
    biosimilars?
        Dr. Califf. What I can say, Senator Scott, is that we're
    working really hard on it, and it is a very tough, complicated
    issue. As I've already said, much of my career in cardiology
    was developing biological products that were highly effective.
    These molecules are complicated and difficult to work with. You
    really have to understand them.
        Dr. Woodcock is actually one of the world's authorities, so
    I have a lot of confidence in the approaches that she's taking.
    The labels ultimately have to both encourage the use of
    biosimilars where they're as good and enable providers and
    patients to understand when there are differences. We're really
    working hard to come up with--and also have to fit in with
    global standards about nomenclature that exist so that as these
    are on the market, they can be tracked. If there's a safety
    problem, we can keep up with it.
        Those are all the factors. I can't tell you exactly when
    we'll be done. Everybody is interested in this, and it's a very
    high priority.
        Senator Scott. Thank you for your time today.
        The hearing record will remain open for statements for 10
    days. I ask that Senators submit any written questions by 5
    p.m. on November 24th. Thank you for being here today.
        The next HELP Committee hearing will be on mental health on
    Wednesday, December 2d. The committee will stand adjourned.
        [Additional Material follows.]

                              ADDITIONAL MATERIAL

     Response by Robert Califf to Questions of Senator Alexander, Senator
        Enzi, Senator Burr, Senator Isakson, Senator Murkowski, Senator
       Collins, Senator Hatch, Senator Roberts, Senator Cassidy, Senator
        Murray, Senator Sanders, Senator Casey, Senator Bennet, Senator
                   Baldwin, Senator Murphy and Senator Warren
                               senator alexander
        Question 1a. The Food and Drug Administration (FDA) has been
    criticized for how it restricts what drug and medical device
    manufacturers can tell doctors and insurers about lawful uses of their
    products. In particular, current regulations are unclear and heavily
    restrict manufacturers' ability to provide truthful and non-misleading
    information to doctors and insurers, unless the information appears in
    the product's FDA-approved labeling. Often, however, this information
    relates to medically accepted treatments that doctors can--and
    frequently do--prescribe for their patients, and that the Federal
    Government will even reimburse. In some instances, such ``off-label''
    uses may even be the standard of care.
        In an era when information about medical products abounds on the
    Internet--some of it reputable, some of it not--do you think it is
    appropriate for FDA to maintain decades-old policies that block
    manufacturers from sharing factual, non-misleading information about
    lawful treatments with doctors and insurers?
        Answer 1a. It's important to remember the fundamental public health
    interests underlying the Agency's current statutory and regulatory
    framework, including the requirements related to premarket review of
    medical products before they are distributed for new uses. This
    framework was developed over time in response to public health
    tragedies, which Congress addressed by requiring independent review of
    scientific evidence of the products' safety and efficacy. The Agency is
    currently examining its rules and policies, with the goal of
    harmonizing the important public health and safety interests served by
    FDA's premarket review of new uses of medical products, with the value
    that sharing relevant scientific information regarding unapproved uses
    can have in certain contexts, and with First and Fifth Amendment
    considerations.
        I believe it is appropriate for FDA to continue examination of its
    rules and policies and to refine them as appropriate, in light of the
    important public health issues, free speech, and due process principles
    at stake.

        Question 1b. Several courts, including the U.S. Court of Appeals
    for the Second Circuit and the U.S. District Court for the southern
    district of New York, have indicated that FDA's restrictions on
    manufacturers' speech may violate the First Amendment. These decisions
    raise the possibility that many of FDA's regulations governing the
    promotion of medical products could be struck down by the courts unless
    they are substantially revised. What proactive steps will you take, if
    confirmed, to avoid that situation?
        Answer 1b. If I am confirmed, I will support FDA's efforts to
    comprehensively review its regulations and guidance documents and will
    make it a priority for the Agency to work on revising these documents
    as appropriate, in an effort to harmonize the goal of protecting the
    public health with First-Amendment interests.

        Question 2a. Before you began your current position at FDA, you
    advocated publicly for changes to certain regulations. For example, you
    gave a presentation in 2014 in which you called regulation a ``barrier
    to disruptive innovation,'' and, in 2013, you wrote in the New England
    Journal of Medicine about inefficiencies in the requirements for
    clinical trials and safety monitoring for approved drugs.
        What are the three biggest ways in which FDA poses a barrier to
    innovation? If confirmed, how would you address these problems?
        Answer 2a. I think you are referring to a slide I have used in
    multiple lectures that characterizes regulation as a barrier to
    disruptive innovation.
        This issue is a very important one for people proposing to develop
    new medical therapies. Throughout my career, I have benefited from a
    close relationship with the Fuqua School of Business at Duke and the
    many contacts it brings in the field of health economics and health
    management. Among the many brilliant people I have met is Clayton
    Christensen (``The Innovators Dilemma''), who developed the concept of
    ``disruptive innovation.''
        This concept is derived from the study of the transformation of
    industries with the base case being the conversion of radios from the
    vacuum tube to the transistor. The concept is that the new product or
    method initially is inferior but lower priced so there is a market for
    it. This enables innovators to iteratively improve their product until
    it becomes better and supplants the old product or method. My purpose
    in showing this slide in multiple lectures is to explain to audiences
    that often include students, trainees in fellowship and scientists who
    are not involved in development of medical products, why the risk and
    investment in biotechnology is higher than most other industries, i.e.,
    because it is a highly regulated industry, which is in fact a necessary
    barrier to protect public health, as discussed below. The amount of
    capital needed is lower and the time to return on investment is shorter
    in many other industries.
        I have never stated, implied, or argued that the barrier should be
    lowered or removed. In fact, I do not believe that we should be putting
    inferior medical products on the market, nor do the American people
    want inferior products to be used in medical practice. The belief that
    we should have evidence of benefits and risks before marketing in
    health care has been a driving force in my career and a motivation to
    develop more effective, efficient and unbiased ways of conducting
    generalizable clinical trials and implementing quality systems for
    learning in health care as a focus of my academic and practical work.
        In summary, the purpose of the slide is to point out an issue that
    is motivational for people who want to develop medical products that
    prevent death and reduce disability: there is a requirement to
    demonstrate that your product is safe and effective before you market
    it and that it does not put people at risk, compared to the clinical
    care that is currently accessible. This is a good thing and forms the
    basis for the benefit of a strong FDA to make these determinations, and
    it places a special responsibility on innovators to develop the
    evidence base that can ensure the FDA (on behalf of the American
    public) that the product is safe and effective.
        With these requirements (i.e., appropriate barriers) in place, it
    is reasonable to ask the question, what can FDA do to enable innovators
    to develop new approaches and technologies, maintaining the same
    standards, but reducing the cost and time so that Americans can get
    access to new technologies that are safe and effective and so that
    investors continue to invest in this enterprise, which is essential to
    our health and vital to our economy? Among a longer list, my top three
    responses would be:

         Reform the clinical trials system, using the principle of
    Quality by Design, so that a combination of small, focused trials for
    precision medicine and very large trials using electronic health
    records for inclusion of important populations can be conducted at a
    dramatically lower cost per unit of knowledge. The small precision
    medicine trials are lower cost because of lower sample size and the
    very large, inclusive trials will be lower cost because they will take
    advantage of data already collected and the novel methods of community-
    based research. FDA's Sentinel project is an excellent building block
    with claims data on over 170 million Americans available to evaluate
    the safety of drugs and biologics, but the same system with
    modifications could be used to dramatically reduce the cost of data
    collection in clinical trials. Direct involvement of patients will also
    enable us to streamline, because a more involved public, together with
    more trials relevant to the needs of patients will lead to faster
    enrollment.
         A second key approach is to continue to improve the
    communication between FDA and the scientific community. In every case
    where FDA has offered more meetings with sponsors, the opportunity has
    been over-subscribed. In addition, public-private partnerships have
    been highly successful in promoting multi-sector dialog and developing
    a common view of key issues in medical product development, including
    the Medical Device Innovation Consortium and the Clinical Trials
    Transformation Initiative.
         Finally, effective interactions between FDA and its
    Federal partners can be an important factor in maintaining the
    appropriate standard while reducing the cost of medical product
    development. The FDA-National Institutes of Health (NIH) Leadership
    Council is a successful collaboration between FDA and NIH, focused on
    clarifying the biomarker-surrogate-clinical outcome continuum and
    streamlining clinical trials.

        There are many other measures to achieve the goal of optimizing the
    efficiency of the effort to produce useful, safe, and effective medical
    products based on high-quality evidence.

        Question 2b. In your academic work, you have argued for expanding
    the size of certain clinical trials. What impact would larger clinical
    trials have on the cost and speed at which innovative new treatments
    come to market? Are there specific policies you would promote that
    would affect the size of future trials, and would those policies be
    tailored to particular types of trials?
        Answer 2b. As discussed above, the principle of Quality by Design,
    an initiative that FDA is already undertaking, will lead to some trials
    that are ``targeted,'' when the therapy is expected to have a large
    effect in a small subpopulation, and others that will need to be much
    larger to ensure that the treatment is safe and effective across the
    spectrum of patients likely to be treated. The targeted trials are made
    possible by the dramatic advances in molecular biology and precision
    medicine methods, and the larger trials are made possible by the
    ubiquity of electronic health records and social media. Quality by
    Design is a risk-based approach to pharmaceutical development and
    manufacturing that has been described in numerous FDA guidance
    documents. In recent years, this approach has been increasingly
    recognized as having significant applicability to the development of
    clinical trial protocols and is now included in an FDA guidance
    document on risk-based monitoring.
        Another consideration is that rare diseases will continue to need
    special trial considerations, especially when there is no effective
    treatment. As information and communication technologies advance,
    however, we can also develop new methods to improve enrollment in these
    trials.

        Question 3. Will you commit to requiring FDA staff to act through
    rulemaking, rather than through the guidance process, when (a) it
    intends to legally bind regulated parties or (b) it expects regulated
    parties to change their behavior in burdensome or costly ways?
        Answer 3. The Federal Food, Drug, and Cosmetic Act (FD&C Act), and
    FDA's own regulations, set forth clear criteria for determining whether
    guidance is appropriate and provide for ample opportunity for public
    consideration of, and comment on, FDA guidances. I commit to working to
    ensure that the Agency continues to follow the requirements set forth
    in these authorities and issue guidance only where appropriate.\1\
    ---------------------------------------------------------------------------
        \1\ In addition, the Administrative Procedure Act (APA) (5 U.S.C.
    551-59) prescribes procedures for an agency issuing a ``rule,'' which
    is defined as ``an agency statement of general or particular
    applicability and future effect designed to implement, interpret, or
    prescribe law or policy or describing the organization, procedure, or
    practice requirements of an agency'' (5 USC 551(4)). For legislative
    and substantive rules that create a new law, rights or duties, the APA
    requires that agencies, among other things, provide the public with
    adequate notice of a proposed rule followed by a meaningful opportunity
    to comment on the rule's content.
    ---------------------------------------------------------------------------
        When issuing guidance, FDA complies with the requirements set forth
    in the FD&C Act as well as its own good guidance practices (GGPs).
    Section 701(h)(1)(A) of the FD&C Act outlines the procedures that FDA
    must adopt when issuing guidance relating to its initial
    interpretations of a statute or regulation, changes in interpretation
    or policy, and existing practices or minor changes in policy. The FD&C
    Act requires that the Secretary develop guidance documents with public
    participation and makes clear that guidance documents ``shall not
    create or confer any rights for or on any person.''
        FDA's GGP regulation provides greater detail regarding the
    circumstances when guidance is appropriate and the procedures that must
    be employed when the Agency issues guidance. The GGP regulation
    explains that guidance documents are intended to describe the Agency's
    interpretation of policy on a regulatory issue, but are not intended to
    be binding documents or establish legally enforceable rights or
    responsibilities that bind the public or FDA (21 CFR 10.115). Guidance
    documents contain a statement of this non-binding effect.\2\
    ---------------------------------------------------------------------------
        \2\ That said, in certain instances, FDA is expressly authorized by
    statute to promulgate guidances with binding effect. In such cases FDA
    clearly explains the extent to which such guidance is binding, based on
    the requirements in the statute, in the guidance document itself. See,
    e.g., Guidance for Industry: Necessity of the Use of Food Product
    Categories in Food Facility Registrations and Updates to Food Product
    Categories (October 2012), available at http://www.fda.gov/
    RegulatoryInformation/Guidances/ucm324778.htm.
    ---------------------------------------------------------------------------
        FDA's guidance documents are a valued resource for many external
    stakeholders, including industry and patient advocacy groups, because
    they can serve as a means of conveying FDA's current thinking on
    important issues, such as the most current scientific practices related
    to product development. Often the Agency's guidance documents are
    issued in response to stakeholder requests. Guidance is a helpful tool
    that allows the Agency to inform stakeholders about its views on
    scientific and technical policy issues. Small businesses are often
    particularly interested in and reliant upon Agency guidances on such
    topics.

        Question 4a. Food and medical products regulated by FDA
    increasingly are imported from other countries into the United States.
    Currently, FDA is not able to clear many time-critical and often
    temperature-sensitive shipments quickly enough for them to arrive at
    their destinations intact and when they are needed.
        How do you think FDA can improve its ability to process time-
    sensitive shipments by commercial express carriers in a timely manner
    to minimize the expense and disruption that even short delays can
    cause?
        Answer 4a. FDA continues work on streamlining, improving,
    standardizing, and clarifying import processes and has initiated a
    number of efforts designed to process imported shipments more
    efficiently. FDA is a Participating Government Agency (PGA) involved in
    the ACE/ITDS (Automated Commercial Environment/International Trade Data
    System) project, which is designed to provide the import community with
    a single window for importing into the United States, commonly referred
    to as ``One U.S. Government at the Border,'' to streamline the entry
    process and provide improved messaging to the trade community.
        FDA is currently running a Secure Supply Chain Pilot Program
    (SSCPP) for pharmaceuticals. The SSCPP is allowing FDA to assess the
    various entities and processes involved in a repetitive-type import
    chain; and if found acceptable and if all information is accurately
    submitted at the time of entry, it would allow for more and quicker
    system-based releases of shipments (as opposed to having to manually
    verify required information). If successful, the expansion of this
    program will help expedite the admissibility process for
    pharmaceuticals originating from known sources, destined for known U.S.
    entities.
        In addition, FDA is participating with U.S. Customs and Border
    Protection (CBP) in a trusted Trader Program designed to facilitate the
    importation process for selected firms. CBP issued a Federal Register
    Notice announcing a test program on June 16, 2014. FDA has been
    involved in the review of applications. The pilot will begin after the
    applicant awardees have been notified and CBP receives confirmation of
    the intent to participate.
        FDA is in the process of implementing the Voluntary Qualified
    Importer Program (VQIP) for human and animal food to help facilitate
    the import entry of products from importers who demonstrate a high
    level of control over the safety and security of their supply chains.
    VQIP importers must offer FDA various assurances of compliance,
    including facility certifications of their foreign suppliers of VQIP
    products, in exchange for the expedited release of entries of those
    products imported into the United States. FDA continues to work on the
    operational design of VQIP; currently, IT requirements are being
    addressed and importer user fees are under development.
        To improve transparency, FDA developed and deployed the Import
    Trade Auxiliary Communication System (ITACS), which facilitates two-way
    communication with the import trade community. ITACS allows users to
    check the status of FDA-regulated entries and lines, to submit entry
    documentation, and to submit the location of goods availability for
    those lines targeted for FDA exam. The system is currently undergoing
    enhancements to allow for FDA notifications to be sent directly to
    regulated industry via electronic means, which will allow for more
    timely and efficient communications.
        FDA has conducted a centralized entry review pilot for courier
    operations. The results of this pilot are currently under review as a
    possible model for centralized entry review and staffing for all
    couriers that could expand Agency operations and better mirror the
    courier business model.
        FDA is evaluating a dashboard intended to allow real-time
    monitoring of all aspects of the import process to determine if
    backlogs are forming and if delays are occurring, so that resources can
    be allocated before an issue arises.
        In addition, FDA has proposed a request for new authority to assess
    user fees on international express courier facilities (or ``couriers'')
    that import FDA-regulated products into the United States. These fees
    would support part of the cost of certain inspection-related activities
    at courier facilities, including processing, examining, sampling, and
    analysis of FDA-regulated products by FDA to improve timeliness of
    processing. The fees will be charged in accordance with U.S.
    obligations under applicable international agreements (i.e., General
    Agreement on Tariffs and Trade (GATT), North American Free Trade
    Agreement (NAFTA), etc.).

        Question 4b. What will you do to improve FDA's ability to use its
    electronic import review system--the PREDICT system--in a risk-based
    manner that minimizes the burdens on compliant, non-harmful shipments
    so that resources are allocated efficiently to the shipments carrying
    the highest risk?
        Answer 4b. Since December 2011, FDA has been utilizing the
    Predictive Risk-based Evaluation for Dynamic Import Compliance
    Targeting (PREDICT) screening tool to provide a more dynamic and risk-
    based assessment of imported shipments. PREDICT is designed to
    calculate a customized risk score based on a wider variety of factors,
    including, but not limited to, inherent risk of the product, data
    anomalies, data quality, and the compliance history of firms (e.g.,
    manufacturer, shipper, and consignee) and the product.
        FDA is continuing to improve the capabilities of PREDICT to
    minimize the impact on imported shipments. For example, many shipments
    consist of multiple commodities. Line release is a recently implemented
    enhancement to PREDICT that will allow FDA to evaluate a higher-risk
    commodity in a shipment, independent of other products that may be
    included in the same shipment but do not have the same level of risk.
        FDA has modified the PREDICT risk evaluation process from a pool of
    all FDA-regulated products to a commodity-based approach in order to
    compare products with similar risk factors. This will improve targeting
    for medium- and higher-severity products and improve the ``May
    Proceed'' rate for lower-risk commodities. As of November 2015, this
    improvement has been implemented for medical devices and diagnostics,
    biologics, human foods, pharmaceuticals, radiation-emitting products,
    and animal foods and feeds. FDA continues to work on developing the
    same approach for a number of other commodities, including vitamins and
    supplements, cosmetics, food and color additives, infant foods, house
    wares, veterinary drugs, medicated feed, and tobacco products.

        Question 5a. In recent months, FDA has sent warning letters to
    overseas drug manufacturing facilities, particularly in India and
    China, that detailed alarming violations of current good manufacturing
    practices. These violations include not only sanitary issues--such as
    bird and lizard infestations in processing facilities--but also a
    troubling number of instances in which data were falsified or obscured,
    including an instance in which an employee grabbed a memory stick and
    fled from FDA inspectors. While it is reassuring that FDA identified
    these violations, it also raises questions about the extent to which
    similar violations in other imports are going undetected.
        Section 706 of the Food and Drug Administration Safety and
    Innovation Act, signed into law on July 9, 2012, enables FDA to request
    records in advance or in lieu of an inspection. This authority enables
    FDA to detect many data integrity issues without having to send
    inspectors onsite, thus improving FDA's ability to detect violations
    rapidly and efficiently. It is now more than 3 years since FDA was
    given this authority, but FDA still has not used it to request records
    from a particular manufacturer in advance or in lieu of an inspection.
    Why has FDA not exercised this important authority for improving its
    oversight of drug safety? When can we expect FDA to begin requesting
    records in advance or in lieu of an inspection?
        Answer 5a. FDA recognizes that the authority to request records in
    advance or in lieu of inspection under the Food and Drug Administration
    Safety and Innovation Act (FDASIA) is a potentially powerful tool for
    enhancing FDA's ability to assess drug manufacturers' compliance with
    current good manufacturing practices, and has sought to plan the use of
    this broad authority carefully via the several work streams described
    in greater detail below.
        FDA is actively engaged in projects to implement this authority,
    for example:

         Public Health Incident: Recognizing that FDASIA section
    706 represented a broad statutory authority that could potentially be
    used in many inspection contexts, FDA sought to prioritize
    implementation of the authority based on public health risk. To that
    end, in October 2014, FDA finalized procedures in the Staff Manual
    Guide (SMG) for requesting records in advance or in lieu of inspection
    in the event of a public health incident. Although FDA has not yet
    encountered a situation warranting use of a 706 request under this SMG,
    we continue to monitor appropriate opportunities for doing so.
         Pilot to Optimize On-Site Inspection: FDA is planning to
    pilot the use of the authority in advance of a small number of already-
    planned inspections in 2016, and the Agency will use the results of
    that effort to inform its strategy on a broader implementation of the
    authority. FDA believes that use of 706 in advance of an inspection
    could lead to efficiencies by allowing FDA investigators to maximize
    the use of their time while onsite. FDA is seeking to assess the best
    use of this authority by gathering data through this pilot effort to
    evaluate, for example, the appropriate scope and volume of records to
    request, and the burden of producing and reviewing those records.
         Quality Metrics: The continued existence of product
    quality issues may point to increased complexities in the supply chain,
    a lack of innovation in manufacturing, a failure to adopt modern
    manufacturing technologies and robust quality management systems, or
    other factors. In the summer of 2015, FDA announced the availability of
    draft guidance for industry entitled ``Request for Quality Metrics,''
    and held a public meeting on the Agency's plans associated with a
    quality metrics reporting program. The draft guidance and public
    meeting were intended to gain stakeholders' perspectives on various
    aspects of the development and planned implementation of a quality
    metrics program launched under the new FDASIA authority. FDA expects
    that quality metrics calculated from the data we intend to collect
    through this program will provide objective measures that, when used
    with additional internal data, can provide the Agency with indicators
    of the effectiveness of quality systems associated with pharmaceutical
    manufacturing. These indicators are expected to be a factor in risk-
    based inspection coverage, which will enable FDA to focus resources on
    facilities and products that present a greater risk to consumers.

        In addition, FDA has implemented FDASIA section 707 and issued
    guidance related to this section. Section 707 deems adulterated any
    drug that is manufactured in an establishment that delays, limits,
    denies, or refuses to permit entry or inspection. In the FDA final
    guidance issued in October 2014, we specified that under circumstances
    delaying, denying, limiting, or refusing a request for records in
    advance or in lieu of an inspection under section 707 of FDASIA may
    also result in a drug being adulterated under the FD&C Act.\3\ In such
    circumstances FDA may issue an import alert that notifies FDA's field
    staff that the Agency has enough evidence or other information to
    refuse admission of future shipments of that imported product.
    ---------------------------------------------------------------------------
        \3\ Guidance for Industry: Circumstances that Constitute Delaying,
    Denying, Limiting, or Refusing a Drug Inspection. http://www.fda.gov/
    downloads/RegulatoryInformation/Guidances/UCM360484.pdf.

        Question 5b. At your confirmation hearing, you stated that you have
    ``major concerns about reimportation'' of drugs from other countries,
    including Canada. Would you please elaborate on these concerns?
        Answer 5b. Drugs that are not FDA-approved nor manufactured in a
    facility inspected by FDA do not have the assurance of safety,
    effectiveness, and quality as do drugs subject to FDA oversight. There
    have been documented incidences of non-FDA-approved imported drugs
    found to be contaminated, counterfeit, containing varying amounts of
    active ingredients or none at all, or containing different ingredients
    than the FDA-approved product. Moreover, FDA would not be able to make
    safety and quality determinations for prescription drugs offered for
    import into the United States that have not gone through the U.S.
    regulatory process. In fact, FDA evaluation of non-FDA-approved
    imported drugs revealed that while nearly half of imported drugs
    claimed to be Canadian or from Canadian pharmacies, 85 percent of such
    drugs were actually from different countries. Typically, these products
    are smuggled into the United States after being transshipped to third-
    party countries in an effort to avoid detection and create an
    appearance of coming through countries that consumers may find
    trustworthy. Through FDASIA Title VII and the Drug Supply Chain
    Security Act, Congress has recognized the need to bolster this closed
    drug distribution system. Authorizing importation would compromise the
    closed drug distribution system in the United States and undermine
    these laws, thus making it easier for unapproved drugs, which may
    include counterfeit or other substandard drugs, to reach American
    patients putting their treatment at risk. FDA is concerned that the
    risks of unapproved products from foreign sources outweigh any
    potential cost savings. We are also concerned that adverse events
    flowing from importation of such unapproved products could lead to
    diminished confidence in FDA-approved products.

        Question 6. The Food Safety Modernization Act was signed into law
    in January 2011. It took the agency over 4 years after the law was
    enacted to finalize five of the seven regulations required under the
    law. Congress intended this law to be flexible and risk-based, taking
    into account the very diverse food industry across our country. If
    confirmed, how will you ensure that as FDA implements this law, it
    focuses on and prioritizes high-risk activities in the food supply
    chain consistent with Congress's intent to introduce a risk-based
    framework that targets areas with a history of foodborne illness, is
    flexible, and is not overly burdensome?
        Answer 6. Since the passage of the FDA Food Safety Modernization
    Act (FSMA), the Agency has pursued a transparent process, engaging all
    stakeholders, to allow FDA to craft final regulations that provide
    sufficient flexibility across the broad spectrum of food-producing
    operations. Throughout the rulemaking process, the Agency has been
    committed to developing final regulations that are practical for
    businesses and that help ensure food is safe. An unparalleled outreach
    effort followed the original proposal of the FSMA rules. As you know,
    in September 2014, FDA issued supplemental proposals with a number of
    revisions that would add flexibility and reduce burden in key areas.
    FDA proposed these changes based on extensive outreach and feedback
    received during meetings with the public, industry groups, and consumer
    groups, and in the comments submitted to the Agency on the proposed
    rules.
        In September 2015, FDA finalized preventive controls rules for
    human and animal food, which require modern preventive practices in
    food processing and storage facilities. In November 2015, the Agency
    published additional final rules, which establish enforceable safety
    standards for produce farms and make importers accountable for
    verifying that imported food meets the same food safety standards as
    domestic products. The Agency also issued a rule establishing a program
    for the accreditation of third-party certification bodies, also known
    as auditors, to conduct food safety audits and issue certifications of
    foreign food facilities and their foods. These rules will work together
    to systematically strengthen the food safety system and better protect
    public health.
        The final rules recognize the importance of providing for
    flexibility within the requirements. For example, the final produce
    safety rule enables a State, tribe, or country to request variances if
    it concludes that meeting one or more of the rule's requirements would
    be problematic in light of local growing conditions. The State, tribe,
    or foreign country must demonstrate that the requested variance is
    reasonably likely to ensure that the produce is not adulterated and
    provides the same level of public health protection as the
    corresponding requirement(s) in the rule.
        Through our sustained engagement with stakeholders, the Agency has
    been laying the foundation for effective, efficient, and collaborative
    implementation of the new standards. The Agency intends to provide
    guidance and technical assistance to industry so that they know what is
    expected and are supported in carrying out their responsibilities. For
    example, FDA, in cooperation with the Illinois Institute of
    Technology's Institute for Food Safety and Health, has established the
    Food Safety Preventive Controls Alliance, which is developing training
    courses and materials on preventing hazards for both human and animal
    food during production.\4\ These materials will help industry--
    particularly small- and medium-sized companies--comply with the new
    preventive controls rules. Our implementation strategy also calls for
    re-orienting and retraining the FDA inspection and compliance
    workforce, as well as our State food safety partners, so that we can
    provide consistent, high-quality oversight within the more preventive,
    systems-based and technically sophisticated FSMA framework.
    ---------------------------------------------------------------------------
        \4\ http://www.iit.edu/ifsh/alliance/.
    ---------------------------------------------------------------------------
        Going forward, FDA is committed to continuing to ensure that its
    FSMA efforts are risk-based and targeted in order to achieve the
    greatest health benefit, without placing an unnecessary burden on the
    regulated industry.

        Question 7a. In your role as Deputy Commissioner for Medical
    Products and Tobacco, you have overseen activities within the Center
    for Tobacco Products (CTP), including work to finalize a proposed rule
    to deem additional tobacco products subject to regulation. If that
    proposed rule is finalized and applies the same ``grandfather date''
    that was written into statute for cigarettes, it will force cigars and
    other tobacco products, including most if not all electronic cigarettes
    and e-vapor products, to go through FDA's lengthy premarket tobacco
    application (PMTA) process in order to stay on or enter the market.
    Only recently has FDA acted for the first time to authorize the
    marketing of new tobacco products through the PMTA pathway, which means
    that the agency does not have an established track record of acting
    quickly on PMTAs. As a result, this rule, if finalized, is expected to
    create significant regulatory burdens on small businesses.
        If confirmed, will you commit to ensuring that FDA reviews product
    submissions in a timely manner to prevent a delay of innovative and
    novel tobacco products from entering the market and limiting consumer
    choice, which could cause citizens to lose access to products they have
    been using as less harmful alternatives to traditional smoking? As part
    of this commitment, will you agree to dedicate as much funding as
    necessary from user fees to ensure that (a) FDA acts upon PMTAs within
    the statutory timeframe, and (b) adequate resources to assist
    applicants who previously have not been subject to FDA regulation?
        Answer 7a. FDA is committed to continuing to strengthen the process
    for reviewing tobacco products to determine if they meet the statutory
    standard for marketing, including acting on applications in a timely
    way and working with applicants who have not previously been regulated.
        As you indicated, FDA recently authorized the marketing of eight
    new tobacco products under the PMTA pathway. This action shows that the
    PMTA process is a viable pathway to market for new products, if they
    meet the statutory standard, which includes the requirement that
    permitting the product to be marketed would be ``appropriate for the
    protection of the public health.'' It took FDA 8 months to issue
    decisions on these applications. Currently, the Agency does not have
    any pending PMTAs.
        FDA has made significant progress in reviewing substantial
    equivalence (SE) applications for currently regulated products and this
    momentum will continue. The Agency has increased staffing, taken steps
    to streamline the SE review process, and established performance goals
    that include timeframes for review of regular SE reports\5\ and review
    of exemption from SE requests for currently regulated products. FDA has
    been able to develop these performance goals because of increased
    capacity, efficiency, and knowledge of the scientific evidence needed
    to adequately review SE applications.
    ---------------------------------------------------------------------------
        \5\ SE applications submitted to the Agency are divided into two
    types: ``provisional'' and ``regular.'' Products that are the subject
    of provisional applications were received prior to March 22, 2011, and
    may stay on the market unless FDA issues an order finding them not
    substantially equivalent, or NSE. Products that are the subject of
    regular applications cannot be legally marketed unless FDA issues an
    order that they are substantially equivalent to a valid predicate
    product chosen by the company.
    ---------------------------------------------------------------------------
        As of November 1, nearly 70 percent of full regular SE reports had
    been resolved by a final decision, either because FDA issued an Order
    letter, issued a Refuse-to-Accept letter, or because the submission was
    withdrawn.
        FDA continues to improve the tobacco product review program,
    including hiring and training new staff and addressing the scientific
    policy issues that result from developing a new regulatory review
    program. We will continue to advance our efforts to review and act on
    SE reports while preparing for the PMTAs that may be submitted to FDA
    once the deeming rule is finalized.
        FDA recognizes that manufacturers of newly deemed products will
    need assistance in complying with FDA regulations. The Agency is
    committed to providing this assistance. For example, the Agency intends
    to issue guidance, hold training webinars, meet with companies at their
    request, and increase staffing in the Center for Tobacco Product's
    (CTP) Office of Small Business Assistance.

        Question 7b. If FDA finalizes this rule, it will result in an
    increased workload not only for tobacco-specific offices within CTP,
    but also for other FDA components, such as the Office of Regulatory
    Affairs, which oversees inspections and other enforcement activity, and
    the Office of Chief Counsel. Will you commit to ensuring that the
    increased workload attributable to deeming does not require FDA to
    shift resources away from non-tobacco program areas? What specific
    steps will you take to ensure that such a shift in resources does not
    occur?
        Answer 7b. The workload that will result after the tobacco deeming
    rule is final will not shift resources from non-tobacco program areas.
    The TCA states that tobacco user fees are the only funds available for
    FDA activities related to tobacco regulation. The TCA specifically
    prohibits the use of funds other than tobacco user fees for tobacco
    regulation activities. The TCA user fees are used to hire the necessary
    staff in other parts of the Agency that assist CTP in the
    implementation and enforcement of the law.

        Question 8. FDA's Office of External Affairs engages in a variety
    of patient outreach programs, often through the Office of Health and
    Constituent Affairs. One such program involves a partnership with the
    National Forum for Heart Disease and Stroke Prevention to educate
    patients about heart disease and stroke, and to encourage them to
    follow their doctors' advice about lifestyle changes--such as
    improvements in diet and exercise. Although doctors' advice regarding
    lifestyle changes may be beneficial to the public health, it is not
    clear why FDA--which regulates the safety and effectiveness of medical
    products, but not the practice of medicine--is the right agency to be
    engaging in such efforts.
        Do you believe that FDA's statutory mission includes encouraging
    patients to follow their doctors' advice regarding lifestyle changes,
    such as eating better or exercising more? Or are such efforts better
    left to other public health agencies, such as the Centers for Disease
    Control?
        What do you see as FDA's proper role in the doctor-patient
    relationship?
        Answer 8. FDA believes it is important for the Agency to keep our
    many stakeholders, including health care professionals and patients,
    informed as appropriate, when we approve important products, issue
    safety announcements, and take public health actions. Occasionally
    these communications may touch on lifestyle issues. For example, when
    FDA announced its approval of a medical device to treat obesity, our
    press release pointed out that patients who use the product must follow
    a medically supervised diet and exercise plan to augment their weight
    loss; this information is contained in the product labeling approved by
    FDA. We recognize that while many people learn about FDA's products and
    announcements from their health care providers, others learn through
    FDA's website, the news media, social media, or from family or friends,
    so we make sure that our communications include a recommendation that
    patients and consumers continue to follow their doctor's advice or to
    consult their doctor if they have any questions.
                                  senator enzi
        Question. Dr. Califf, labeling of menus for chain restaurants and
    similar retail food establishments will take effect on December 1,
    2016. What steps is the FDA taking to ensure that the new uniform
    labeling standards will not be eroded by additional labeling
    requirements being added across the Nation?
        Answer. Federal law includes an express preemption provision that
    preempts

            ``any requirement for nutrition labeling of food that is not
            identical to the requirement of section 403(q) [of the FD&C
            Act] [21 U.S.C. 343(q)],''

    except that this provision does not apply

            ``to food that is offered for sale in a restaurant or similar
            retail food establishment that is not part of a chain with 20
            or more locations doing business under the same name
            (regardless of the type of ownership of the locations) and
            offering for sale substantially the same menu items unless such
            restaurant or similar retail food establishment complies with
            the voluntary provision of nutrition information requirements
            under section 403(q)(5)(H)(ix) [of the FD&C Act].''

        Therefore, State or local governments cannot have nutrition
    labeling requirements for foods sold in establishments covered by the
    final rule, unless such requirements are identical to the Federal
    requirements.
        Under the rule, consumers will have consistent nutrition
    information available to them, whenever they eat out in covered
    establishments. In addition, companies that are covered by the
    requirements won't have to display different nutrition labeling,
    depending on the geographical location.
        Restaurants and similar retail food establishments that are not
    covered under the Federal requirements would remain subject to
    applicable State or local nutrition labeling requirements, unless they
    choose to voluntarily register with FDA to comply with the Federal
    nutrition labeling requirements.
        FDA intends to work with State and local authorities, as
    appropriate, to ensure that the menu labeling requirements are
    uniformly applied.
                                  senator burr
        Question 1. The field of cellular therapies continues to show
    promise for a variety of diseases, and is moving at a rapid pace. If
    you are confirmed, how would you ensure that the potential of these
    therapies are fulfilled and that their regulation by the FDA strikes an
    appropriate balance which reflects their unique characteristics in this
    rapidly advancing area of medicine?
        Answer 1. Cellular therapies are rapidly evolving and show great
    promise. Advances in molecular and cellular biology, combined with
    developments in biomedical engineering, have made the concept of in
    vitro production of tissues, and even organs, a reality. An example of
    success in this field is the artificial trachea, which consists of live
    cells layered on a scaffold.
        Due to the breadth of product types, as well as their potentially
    inherent complexity, FDA is working with stakeholders to ensure that
    regulation of these products is appropriate. Appropriate regulation
    should encourage innovation and provide Americans with timely access to
    safe and effective cellular therapies. FDA recently announced a 1-day
    public hearing to obtain input on four recently issued draft guidance
    documents relating to the regulation of HCT/Ps. These draft guidance
    documents were issued by FDA in response to stakeholders' requests for
    guidance on FDA's current views about how manufacturers,
    establishments, and distributors of HCT/Ps and health care
    professionals can meet the criteria under the Agency's regulations that
    apply to HCT/Ps. The comment period for all of these guidances will
    remain open between now and 2 weeks following the public hearing. FDA
    will carefully consider information it obtains from responses submitted
    to the docket and from the public hearing as it works to finalize these
    four guidance documents.

        Question 2. The FDA is in the midst of initial discussions with
    industry and stakeholders for the 2017 User Fee Agreements. The Agency
    is funded by both significant taxpayer dollars through the
    appropriations process as well as the user fees collected by the
    agency. The Agency is always eager for more resources. However,
    additional funding does not always translate into a more predictable
    and timely review process, or a decrease in the total time it takes for
    products to reach patients. Any agreement submitted to Congress will be
    heavily scrutinized.
        The Agency has a responsibility to balance the priorities set forth
    in these agreements as well as those set forth in law by Congress. The
    requirements and priorities that Congress sets forth are not optional.
    The agency needs to satisfy its commitments from the last agreements,
    before making any additional promises. How would you ensure the FDA
    fulfills its current commitments?
        Answer 2. The Agency takes its responsibilities under its user fee
    agreements, as well as those set forth in law by Congress, very
    seriously. We are working toward implementing each commitment,
    including through specific implementation steering committees that have
    been established for each user fee program. FDASIA requires annual
    reports to Congress, which describe the Agency's progress in achieving
    the goals of the agreement. The most recent reports can be found from
    the main User Fee site here: http://www.fda.gov/forindustry/userfees/
    default.htm. Please refer to the legend on the left-hand side of the
    website to find reports and plans for program-specific user fees.

        Question 3. You stated during the nomination hearing that you are
    committed to working with the whole ecosystem of regulation for
    Laboratory Developed Tests (LDTs). If confirmed as Commissioner, how
    would you ensure that FDA regulation of LDTs does not cause the
    unintended stifling of innovative test development at research and
    public health labs? Is the FDA working with CMS to ensure that CMS
    policies are updated before any new policy from FDA is effective to
    avoid duplicative regulation? If so, what role does FDA see CMS's CLIA
    office keeping and what sections of CLIA's current regulation does FDA
    intend to overtake?
        Answer 3. FDA is committed to developing a final policy for
    oversight of LDTs that encourages innovation, improves patient
    outcomes, and strengthens patient confidence in the reliability of
    these products. Under the proposed LDT framework, FDA would phase in
    enforcement of premarket review requirements and the quality system
    regulation for some LDTs, with a risk-based approach. We proposed a
    framework that prioritizes attention on those tests that have the
    potential to pose the greatest risk to patients and the public health
    if they do not work as intended.
        FDA's premarket review is necessary to determine if IVDs generally,
    including LDTs, are analytically and clinically valid--that they will
    perform as claimed, and that patients and their physicians can rely
    upon their results to make major medical decisions. When conventional
    IVD manufacturers comply with FDA regulations and labs developing
    similar tests do not, this creates a lack of consistency across the
    diagnostic market. Inconsistent oversight also puts patients at
    considerable risk. Because most LDTs have not undergone premarket
    review for analytical or clinical validity, it is possible that
    patients may receive incorrect results from those LDTs. This could mean
    patients receive incorrect treatment recommendations if their physician
    or hospital is using an LDT. In addition to patient harm, incorrect
    treatment recommendations may increase our health care system costs
    through coverage of unnecessary treatments or more expensive
    treatments.
        This inconsistency also creates a disincentive to develop new and
    innovative tests. Conventional diagnostic manufacturers who have
    invested in the development of an IVD generally obtain premarket
    approval or clearance before packaging their tests into kits for use in
    multiple labs or health care facilities. They also register with FDA,
    list their devices, report adverse events and comply with good
    manufacturing practices. They are concerned that their laboratory
    competitors are currently not doing any of this, yet offer immediate
    competition to their own FDA-authorized tests.
        FDA and CMS have complementary, non-duplicative roles, and FDA does
    not intend to take over any of CMS's current responsibilities. CMS,
    under CLIA, focuses on the labs' overall performance, whereas FDA
    regulates lab tests. CLIA does not require premarket review of tests or
    a showing that a test is clinically valid.
        When FDA finalizes and implements its framework, both FDA and CMS
    will play a role in ensuring that LDTs are high quality--CMS through
    CLIA by continuing to focus on laboratory operations, and FDA by using
    its authority and expertise to ensure the analytical and clinical
    validity of the laboratory tests.
        Although the roles of the agencies are different, FDA and CMS share
    an interest in ensuring effective and efficient oversight of LDTs so
    that laboratories can offer tests to the American public with
    confidence that are accurate and provide clinically meaningful
    information, without unnecessary or duplicative agency oversight.
        To coordinate efforts across the Department, FDA, and CMS
    established an interagency task force this past April that will
    continue and expand on our collaboration related to the oversight of
    LDTs. The task force, comprised of leaders and subject matter experts
    from each agency, will work to address a range of issues, including
    those involving quality requirements for LDTs.

        Question 4. From 2010-14, the FDA spent almost $2 billion on
    external IT contracts. What are the results of these investments? Have
    these investments translated into more timely or faster review periods
    and/or resulted in an increase in the number of FDA-approved products?
    As Commissioner, how would you ensure that investments like these are
    effectively utilizing taxpayer and industry dollars?
        Answer 4. FDA is committed to securing, supporting and enhancing
    its technological capabilities in furtherance of FDA's mission to
    protect the public health, support scientific excellence, and promote
    innovation and collaboration.
        By investing and improving our information technology
    infrastructure, FDA has deployed state-of-the-art IT functionality
    through new systems and upgrades to existing systems to facilitate and
    improve the review of drugs and medical devices. These capabilities
    include electronic submissions processing, advanced search engines, and
    business intelligence capabilities. We are supporting ``media-less,''
    electronic-only submissions through dedicated client and web portal
    software for premarket and post-market information, enhanced search and
    database functionality with the use of search engines and NoSQL
    databases, and upgraded data mining and reporting for signal detection
    and trend identification.
        As FDA continuously seeks new and innovative technological
    solutions to fulfill its mission, we are working to implement state-of-
    the-art technologies and technological improvements that would further
    support and enhance the Agency's initiatives. These innovative
    capabilities include increased automation in the development,
    deployment and maintenance of FDA's information systems, using modern
    technology approaches which will allow for reduced cost and more rapid
    deployments of new systems. In addition we are expanding our data
    network capacity to provide the improved ability to transfer very large
    data files between industry and FDA, as well as internally within HHS.
    The need for expanded network infrastructure is to support and manage
    the very large data sets that enter FDA and allow us to continue to
    expand on our scientific research capabilities.
        Investments such as the FDA Electronic Submissions Gateway (ESG)
    and the Document Archiving, Reporting & Regulatory Tracking System
    (DARRTS) allow FDA to receive and review a significantly increased
    volume of applications. Without these investments, FDA would be unable
    to respond to the increased volume in a timely fashion; for example,
    within the goal timeframes outlined in FDA's user fee performance
    commitments. Additionally, through FDA's Adverse Event Reporting System
    (FAERS) and the Safety Reporting Portal (SRP), FDA is able to more
    efficiently and effectively monitor and report on safety issues in
    accordance with our mission to protect the public health. FDA will
    continue the regular review of the performance of these investments. We
    will review and prioritize funding for IT investments to prevent waste
    and ensure emerging needs are met. Further, we will closely monitor IT
    systems, such as ESG, to safeguard the confidentiality of industry's
    sensitive and protected data.

        Question 5. As you stated during your nomination hearing, the FDA
    is committed to reviewing applications in the Center for Tobacco
    Products according to the agreed upon timelines, which are set forth in
    the Family Smoking Prevention and Tobacco Control Act and require the
    agency to act within 180 days of receiving an application.
    Communication between the agency and the industry it regulates is also
    an important component of a timely review and approval process. As
    Commissioner, how would you ensure that the CTP maintains adequate
    lines of communication with the entities it regulates?
        Answer 5. FDA is committed to communicating with regulated entities
    and reviewing tobacco product applications in a timely manner. The only
    application review timeframe specified in the TCA is for Premarket
    Tobacco Applications. That timeframe is 180 days. We agree that it is
    important for FDA to make tobacco product review decisions in a timely
    manner. It is absolutely critical that these decisions are sound ones,
    grounded in the best-available science, and made in accordance with
    applicable public health standards.
        In 2009, as a new regulatory entity, FDA's CTP needed to establish
    and develop processes for the review of tobacco products that
    manufacturers wanted to bring to market. This had never been done by
    any regulatory body anywhere in the world, and initial review times
    were not as short as we would expect them to be with a more established
    program.
        FDA has made significant progress in reviewing SE applications for
    currently regulated products and this momentum will continue. The
    Agency has increased staffing, taken steps to streamline the SE review
    process, and established performance goals that include timeframes for
    review of regular SE applications and review of exemption from SE
    requests for currently regulated products. FDA has been able to develop
    these performance goals because of increased capacity, efficiency, and
    knowledge of the scientific evidence needed to adequately review SE
    applications.
        The ability to communicate with regulated entities is critical to
    the success of FDA's program to review tobacco product applications.
    FDA has provided many educational materials to help manufacturers
    complete quality product applications that the Agency will be able to
    review in a timely manner. In addition, the Agency assists
    manufacturers on an individual basis at their request. To demonstrate
    FDA's commitment to be responsive to industry and other external
    stakeholders, in October 2014, CTP implemented a performance measure
    for fiscal year 2015 to respond to 80 percent of meeting requests from
    industry and other external stakeholders within 21 calendar days. This
    performance measure increases to 90 percent in fiscal year 2017.\6\
    ---------------------------------------------------------------------------
        \6\ http://www.fda.gov/tobaccoproducts/newsevents/ucm393894.htm.
    ---------------------------------------------------------------------------
        The Agency also communicates with regulated entities by regularly
    attending their conferences and public meetings. Since spring 2014, the
    Director of CTP has spoken at the Tobacco Merchants Association, the
    Global Tobacco Network Forum, the National Association of Tobacco
    Outlets, the Smoke-Free Trade Association, and the National Association
    of Convenience Stores. This is in addition to numerous meetings held
    with industry at their request.
        FDA also looks for opportunities to proactively communicate with
    regulated entities. This will be especially important for manufacturers
    of newly deemed products who will need assistance in complying with FDA
    regulations. The Agency is committed to providing this assistance. For
    example, the Agency intends to issue guidance, hold training webinars,
    meet with companies at their request, and increase staffing in CTP's
    Office of Small Business Assistance.
                                senator isakson
        Question 1. I appreciate all the work that the FDA has done to
    implement the Drug Quality Safety Act (DQSA), and the numerous work
    streams that the Agency has had to initiate to make this important
    legislation work. However, I am concerned that the Agency's
    implementation efforts may cause some unintended consequences outside
    of the parameters that Congress intended be regulated by the law. For
    example, several months ago FDA issued a draft guidance addressing
    repackaging under the authority of the DQSA. I understand that the
    Agency's draft is sweeping in scope, and is very broad in its
    application. More specifically, I understand that the draft guidance,
    if implemented, would fundamentally and negatively change the way in
    which prescription medications are distributed to nursing home
    residents by specialized long-term care pharmacies. As you may be
    aware, long-term care pharmacies that serve nursing home residents are
    obligated by law to dispense individual patient prescriptions in unit-
    dose packaging and through emergency kits that can be prepositioned in
    the home in the case of emergencies. Yet, I am told the draft guidance
    may prevent these pharmacies from providing the needed medications to
    residents in unit dose packaging and emergency kits to meet other
    requirements of both Federal and State laws.
        What assurance can you give that the FDA will promptly address and
    correct this seemingly unintended consequence of its draft guidance,
    and how can the Agency improve stakeholder engagement before such
    Guidance is ever issued?
        Answer 1. Title I of the Drug Quality and Security Act (DQSA), the
    Compounding Quality Act, amended the FD&C Act concerning compounded
    human drugs. However, the legislation did not address repackaged drugs,
    which are generally not exempt from any of the provisions of the FD&C
    Act related to the production of drugs. Therefore, on February 13,
    2015, FDA published draft guidance, Repackaging of Certain Human Drug
    Products by Pharmacies and Outsourcing Facilities, to describe the
    conditions under which FDA does not intend to take action regarding
    violations of certain requirements of the FD&C Act, if a State-licensed
    pharmacy, a Federal facility, or an outsourcing facility repackages
    human drug products.
        In June and July 2014, prior to issuance of the draft guidance, FDA
    engaged with approximately 40 stakeholder groups during listening
    sessions regarding compounding and related activities, including
    repackaging. FDA then published the guidance in draft form to seek
    input and feedback from stakeholders regarding its proposed policies.
    The Agency received approximately 625 comments on the draft guidance,
    mostly concerning its implications for long-term care pharmacies and
    the facilities they serve. Since publishing the draft guidance, FDA has
    held listening sessions with members of approximately 60 stakeholder
    groups, including long-term care organizations, to hear their views
    regarding the draft guidance and other issues related to compounding
    and repackaging. FDA is considering all of the issues raised in the
    comments as well as the input we received during the listening
    sessions, before finalizing the draft guidance.

        Question 2a. CBER, or the Center for Biologics Research and
    Evaluation, has issued a series of Untitled Letters related to product
    classification of tissue products. FDA's Regulatory Procedures Manual
    explains that an Untitled Letter

            ``cites violations that do not meet the threshold of regulatory
            significance for a Warning Letter. Therefore, the format and
            content of an Untitled Letter should clearly distinguish it
            from a Warning Letter.''

        Unfortunately, several of these recent CBER Untitled Letters are
    not distinguishable at all from Warning Letters. Because CBER posts
    these documents on its website and they are read exactly like Warning
    letters, these Untitled Letters have caused great disruptions and
    uncertainty for industry including damage to companies.
        Why has FDA begun issuing Untitled Letters rather than trying to
    have a dialog with the company first about the product classification?
        Answer 2a. FDA's Untitled Letters often serve as the initial
    communication with regulated industry concerning regulatory violations.
    But, FDA also uses other means to communicate and resolve questions
    with manufacturers.
        For example, the Center for Biologics Evaluation and Research
    (CBER) formed the Tissue Reference Group (TRG) to assist stakeholders
    on questions regarding human cell tissues and cellular and tissue-based
    products (HCT/Ps). The purpose of the TRG is to provide a single
    reference point for product-specific questions received by FDA
    concerning jurisdiction and applicable regulation of HCT/Ps. FDA has
    publicly posted information on how manufacturers can submit inquiries
    to the TRG and publicly discloses information related to TRG
    recommendations on the CBER website.
        If FDA issued an Untitled Letter subsequent to an establishment
    inspection, the FDA investigator may have already informally discussed
    the situation, though they are not required to do so. In determining
    whether to issue an Untitled Letter, FDA officials generally consider
    whether evidence shows that a firm, product, and/or individual is in
    violation of the law or regulations. Such evidence may have been
    obtained during a routine or directed inspection, or other means of
    surveillance, such as Internet website surveillance.
        Untitled Letters should be clearly distinguishable from Warning
    Letters in their format and content. For example:

         The letter is not titled.
         The letter does not include a statement that FDA will
    advise other Federal agencies of the issuance of the letter so that
    they may take this information into account when considering the awards
    of contracts.
         The letter does not include a warning statement that
    failure to take prompt correction may result in enforcement action.
         The letter does not evoke a mandated district followup.
         The letter requests (rather than requires) a written
    response from the firm within a reasonable amount of time (e.g.,
    ``Please respond within 30 days''), unless more specific instructions
    are provided in a relevant compliance program.

        Untitled Letters are not limited to potential product
    classification issues, but are generally a mechanism to communicate and
    provide notice of a violation. These letters ordinarily provide the
    factual basis regarding the violation and serve to communicate the
    concern without committing FDA to enforcement action, if the violation
    is not corrected.

        Question 2b. Why is FDA insistent that such letters must be posted
    on their website? FDA has Center-specific policies as to whether to
    post Untitled Letters, except to the extent that it overlaps with FDA's
    approach to proactive posting under the Freedom of Information Act
    (FOIA).
        Answer 2b. FDA's posting approach under FOIA requires the posting
    of any FDA record subject to the FOIA, such as an Untitled Letter if:

        1. FDA has received three or more FOIA requests for a copy of the
    record, or
        2. If the content related to is a matter of significant public
    interest and we expect to receive multiple FOIA requests for it.

        This approach is consistent with Federal law, guidelines from the
    Department of Justice, President Obama's January 21, 2009, FOIA
    Memorandum, and Attorney General Holder's March 19, 2009, Memorandum (5
    U.S.C. Sec. 552(a)(2)(D)).

        Question 2c. In light of the above, are you willing to review your
    process for Untitled Letters, especially as it relates to product
    reclassifications, and examine ways to make issuance of these letters
    fairer, more effective and more consistent?
        What are some procedural protections the agency might consider in
    this space?
        At the hearing, you said that FDA will ``do everything we can to
    produce a more even template across the FDA so that the standards are
    the same.'' Do you believe that it is important to have consistent and
    predictable standards across the FDA governing the use of Untitled
    Letters? What specific steps will you take to improve consistency and
    predictability in this area?
        Answer 2c. We are currently reviewing processes for issuing and
    posting Untitled Letters for FDA and each of our Centers. Specifically,
    we are reviewing ways that Agency and Center policies could be made
    more accessible and transparent.
        FDA believes in transparency and consistency in our procedures. We
    recognize that some stakeholders want greater uniformity in FDA's
    practices related to posting Untitled Letters. We also recognize that
    our product centers need to maintain some specific procedures to
    address the particulars of the products they regulate.

        Question 3a. The American Association of Tissue Banks (AATB) made
    CBER aware on numerous occasions that it was preparing a homologous use
    guidance proposal for FDA's consideration. That AATB proposal was to be
    discussed at the AATB-FDA liaison meeting on October 29, 2015. Given
    the exchange of agendas and meeting materials in the weeks leading up
    to the meeting, the agency was well aware of this scheduled discussion.
    However, around 5 p.m. on October 28, FDA posted its own homologous use
    draft guidance. This had the effect of rendering any substantive
    conversation about the AATB guidance impossible, as the subject matter
    was now part of an open docket which FDA cannot discuss while the
    comment period remains open.
        Why did FDA choose to release this guidance just hours before the
    scheduled discussion with AATB, which limited the ability to have the
    ability to have a meaningful discussion?
        Answer 3a. It was FDA's intention to have this guidance released
    well in advance of this meeting with AATB. The guidance was released as
    soon as the clearance process was completed. Unfortunately, AATB did
    not have enough time to review prior to the meeting. FDA was receptive
    to the comments from AATB regarding their proposed guidance, and looks
    forward to AATB's contributions through written comments on the
    guidance at the upcoming public meeting.

        Question 3b. Will FDA evaluate AATB's proposed guidance document
    during the comment period?
        Answer 3b. FDA will evaluate all comments received regarding this
    guidance, including AATB's proposed guidance, which FDA encouraged AATB
    to submit to the docket.

        Question 3c. In what area is there alignment between the AATB
    proposed guidance and FDA's draft guidance?
        Answer 3c. Both AATB's and FDA's documents share the goal of
    developing better clarity to help facilitate the development of HCT/Ps.
    FDA will carefully review the AATB proposal, as well as other comments
    received. In addition, FDA is having an open public meeting in April
    2016, and this has been announced in the Federal Register.

        Question 4a. The medical device industry continues to strive for
    the best quality and safety record possible, and believes inspections
    are an important part of this. However, there have been a growing
    number of challenges with the lack of consistency, transparency, and
    predictability in the FDA post-market inspection process. I understand
    FDA is engaging a number of efforts to reorganize their inspections
    program, such as Program Alignment.
        Can you provide me with an update on the progress of these
    initiatives?
        Answer 4a. Work continues to advance the transition to a commodity-
    based and vertically integrated regulatory program (specialization of
    our inspection and compliance staffs). The Office of Regulatory Affairs
    (ORA) and the Center for Devices and Radiological Health (CDRH) are
    actively working on the action plan for the second year of Program
    Alignment (Fiscal Year 2016). The fiscal year 2016 action plan includes
    development of a medical device and radiological health curriculum to
    ensure that inspection and compliance staffs have the requisite
    knowledge and training for their commodity-specific duties. Fiscal year
    2016 is a transition year for ORA--operating in our current regional
    and district geographic structure, while planning for the
    implementation of program-based operations. Contingent upon appropriate
    approvals, standup is expected early in fiscal year 2017.

        Question 4b. Has FDA included industry's perspective in developing
    these initiatives?
        Answer 4b. The device program has multiple ongoing initiatives, and
    the device industry is engaged in many of these initiatives. The Agency
    has met, and will continue working with, industry to enhance
    communication channels and to assist us with identifying device program
    specialties and overall program enhancements. For example, we plan to
    share the medical device and radiological health curriculum with our
    stakeholders to ensure comprehension and identify current and emerging
    gaps. ORA and CDRH plan to work with our stakeholders to identify and
    leverage state-of-the-art training opportunities. We also welcome
    additional approaches to better engage with industry.

        Question 4c. How best can industry be a partner in addressing these
    challenges?
        Answer 4c. All medical device and radiological health stakeholder
    organizations (e.g., AdvaMed, MITA, MDIC, MDMA, etc.) should engage in
    regular dialog with ORA's program director for medical devices, as well
    as the device management teams in the device divisions.

        Question 4d. What other opportunities do you see for further
    improvements in the FDA post-market inspection process to address these
    challenges?
        Answer 4d. ORA will continue to work with its stakeholders to
    ensure awareness of advances in manufacturing technology and
    development of corresponding training for inspection staff.
        ORA also will continue to communicate with industry stakeholders
    about the inspection process; expectations, engagement opportunities,
    etc. ORA and CDRH, together with our stakeholders, will continue to
    identify opportunities to enhance and optimize the inspection method
    used for medical devices, and we will continue to develop feedback
    opportunities to use in process improvement.
                     senator isakson and senator murkowski
        Question. We believe that pregnant women should have access to the
    latest science-based nutrition advice that empowers them to make
    healthy nutrition decisions during pregnancy. The FDA's draft guidance
    has been pending since June 2014, and at that point, the release was 3
    years past the date of when Secretary Sebelius told us it would be
    issued. In April, we wrote to the current Commissioner along with many
    of our colleagues asking FDA to finalize this guidance in order to
    ensure that women have the best advice that reflecting the latest
    nutrition science about the types of seafood that is healthy and safe
    to eat during pregnancy. In addition to FDA's 2014 draft guidance on
    seafood nutrition advice to pregnant women, the agency also issued a
    comprehensive scientific study of the effects of consuming seafood
    during pregnancy, called the Net Effects Report. It is our
    understanding that FDA may be moving away from the findings of the Net
    Effects Report in order to finalize the advice, yet it is not clear to
    me why the agency would be shifting away from their most recent
    scientific study and contradicting its own scientific findings.
        If the agency is not consulting its own Net Effects Report, what
    new scientific study is FDA using as the basis for finalizing its
    current thinking on seafood advice for pregnant women?
        Furthermore, if FDA is using a different study, can you provide the
    source of funding for this new study or studies?
        If confirmed, will you ensure that pregnant women receive final
    guidance on nutrition advice for what seafood is safe and healthy to
    consume that is consistent, understandable, and based on FDA's latest
    scientific review of the net effects of seafood consumption?
        Answer. FDA shares your interest in ensuring that pregnant women
    have access to sound, science-driven, and clearly understandable
    recommendations that enable them to make informed decisions about their
    diets. The final seafood consumption advice for pregnant women is
    undergoing interagency review. We will continue to take steps to ensure
    that it is reflective of the latest nutrition science.
        In response to our 2014 draft advice, we received many comments on
    science related to the draft advice. FDA has not initiated any
    additional studies on this topic, but we have looked carefully at the
    comments, the scientific literature cited in the comments, and the
    scientific literature that continues to surface relevant to this topic.
    Based on the totality of the scientific evidence, we remain confident
    that pregnant women, breast feeding women, and women considering
    becoming pregnant should eat more fish, particularly fish lower in
    mercury. Completing the updated advice remains a priority for the
    Agency.
                       senator isakson and senator murphy
        Question. Every day over 1 million Americans are treated with
    medical gases. In 2012, this Committee and FDA worked together to enact
    historic reforms that we drafted, governing how this unique class of
    drugs are approved and regulated by FDA. The FDA is considerably behind
    in its rulemaking to implement this law, resulting in unnecessary
    confusion and disruption to the provision of medical gas. In fact,
    there have been recent enforcement actions in Iowa, New Jersey, Ohio
    and Florida trying to apply FDA regulations that the agency has
    acknowledged should not apply to medical gases, such as expiration
    dating. And as communicated by both Houses in the Appropriates Bill
    Report Language, guidance and inspector training alone is not adequate.
        If confirmed, will you commit to updating FDA's regulations to
    address the longstanding enforcement issues as to medical gas?
        Answer. As required in FDASIA, FDA reviewed Federal drug
    regulations that apply to medical gases, and submitted a Report to
    Congress in June 2015. During that process, FDA sought public comments
    through meetings and a public docket.
        As described in that report, FDA has determined that the current
    regulatory framework is adequate and flexible enough to appropriately
    regulate medical gases, with regard to most issues. FDA can work within
    the existing regulatory framework to regulate the production and
    distribution of medical gases without rulemaking, for example, through
    publication of revised guidance to industry and revisions to FDA's
    medical gas inspection program and related inspection training.
        FDA is currently engaged in a number of activities intended to
    reduce any regulatory uncertainty and clarify expectations for industry
    and the public, including additional training of inspectors, issuing an
    updated compliance guide inspection program, and updating the 2003
    draft guidance to industry on CGMPs for medical gases, with input from
    stakeholders, including industry.
        Also, as stated in FDA's Report to Congress on the regulation
    review, FDA has determined that certain regulation changes regarding
    warning label statements and adverse event reporting are or may be
    needed, and FDA will continue to evaluate the need for regulatory
    changes on an ongoing basis. FDA expects to maintain open communication
    with industry, Members of Congress, and other stakeholders as
    appropriate, and will continue to evaluate and address medical gas
    issues as needed.
                                senator collins
        Question 1. I am concerned about the sudden, aggressive price hikes
    in certain off-patent drugs where there is just one supplier. This to
    me represents a market failure that hurts patients and providers and
    increases costs for Federal and State programs too. Do you have any
    initial thoughts of what the FDA could do to bring to market generic or
    safe foreign drugs to compete with these prescriptions drugs to put
    pressure on costs?
        Answer 1. I appreciate the concerns about drug costs. FDA works as
    quickly as possible to get safe and effective generic drugs to the
    market and will continue to evaluate other steps that may be able to be
    taken to address this concern. It is important to note, however, that
    FDA's role is to review drug applications for the statutory approval
    criteria but this authority does not extend to reviewing or approving
    drug costs or pricing, which are set by manufacturers and distributors.
    That said, FDA is concerned that the prices of drugs can interfere with
    patients' access to drugs, including lifesaving therapies. By making
    safe and effective generic drugs available, there is greater price
    competition with innovator drugs, resulting in significant drug cost
    savings to the American people.
        Through GDUFA, the Agency has built up the infrastructure for a
    21st-Century generic drug program. As part of this, FDA has established
    a review prioritization policy for generic drug applications determined
    to be a priority of the Agency.
        Specifically, FDA considers certain types of ANDAs to be public
    health priorities, and expedites their review accordingly. In August
    2014, FDA's Center for Drug Evaluation and Research (CDER) updated its
    Manual of Policies and Procedures (MAPP) entitled Prioritization of the
    Review of Original ANDAs, Amendments, and Supplements. This MAPP, which
    is publicly available, describes how the review of ANDAs, ANDA
    amendments, and ANDA supplements are prioritized.
        For example, FDA considers potential ``first generic'' ANDAs to be
    a public health priority. First generics are the first generic to enter
    the market for a given branded product. Potential first generics are
    about 15 percent of our workload. All of them have been tagged as
    priorities, and their review has been expedited. This is true
    regardless of when the ANDA was submitted. In the past 3 years, we have
    approved hundreds of first generics for more than 200 new drug
    products. FDA also considers shortage-related drugs a priority, and
    expedites their review, as well as other public health priorities.
        It is important to note that regardless of FDA granting approval,
    the sponsor makes the ultimate decision whether to market the approved
    product. There are many instances of FDA granting approval and the
    sponsor, for one reason or another, deciding not to bring the product
    to the market. This has occurred even in the ``first generics'' space.
        Drugs that are not FDA-approved nor manufactured in a facility
    inspected by FDA do not have the assurance of safety, effectiveness,
    and quality as do drugs subject to FDA oversight. There have been
    documented incidences of non-FDA-approved imported drugs found to be
    contaminated, counterfeit, containing varying amounts of active
    ingredients or none at all, or containing different ingredients than
    the FDA-approved product. Moreover, FDA would not be able to make
    safety and quality determinations for prescription drugs offered for
    import into the United States that have not gone through the U.S.
    regulatory process. In fact, FDA evaluation of non-FDA-approved
    imported drugs revealed that while nearly half of imported drugs
    claimed to be Canadian or from Canadian pharmacies, 85 percent of such
    drugs were actually from different countries. Typically, these products
    are smuggled into the United States after being transshipped to third-
    party countries in an effort to avoid detection and create an
    appearance of coming through countries that consumers may find
    trustworthy. Through FDASIA Title VII and the Drug Supply Chain
    Security Act, Congress has recognized the need to bolster this closed
    drug distribution system. Authorizing importation would compromise the
    closed drug distribution system in the United States and undermine
    these laws, thus making it easier for unapproved drugs, which may
    include counterfeit or other substandard drugs, to reach American
    patients putting their treatment at risk. FDA is concerned that the
    risks of unapproved products from foreign sources outweigh any
    potential cost savings. We are also concerned that adverse events
    flowing from importation of such unapproved products could lead to
    diminished confidence in FDA-approved products.

        Question 2. Dr. Califf, I would like to relay some ongoing
    frustrations I am hearing from grocery stores regarding the FDA's
    handling of the menu labeling regulations. There are clear differences
    between chain restaurants with pre-printed menus and grocery stores
    with salad bars, yet the menu labeling rule does not reflect this fact
    and is a one-size-fits-all regulation.
        Former Commissioner Margaret Hamburg, just days before she left
    office, told the Senate Agriculture Appropriations Subcommittee, on
    which I serve, that supermarkets had legitimate concerns that required
    additional guidance and flexibility. It then took more than 10-months
    for the agency to provide ``draft'' guidance, which confused the
    situation even more.
        One point that illustrates the need for flexibility is with local
    and seasonal foods. In Maine, you will see salad bar offerings or other
    menu items that are made with local blueberries or seafood. These foods
    may be sold at one or two stores, under the same name as 20 or more
    other stores, but the ingredients or recipe may vary from store-to-
    store. Under FDA's rules, these would all be considered ``standard menu
    items,'' and require a store manager to provide a calorie-count for
    each of these locally made foods before selling them to their
    customers. Concerns have been raised that this will cause a store
    manager to move away from offering truly fresh and local items and
    instead outsource them to a central kitchen or standardized, pre-
    packaged food offerings. The date for complying with this menu labeling
    rule has been pushed out until December 2016, however, I am concerned
    that the rule is still burdensome for many who will have to follow it.
        Would you be willing to explore ways to provide additional
    flexibility for these grocery store settings before compliance begins?
        Answer 2. The final menu labeling rule applies to standard menu
    items sold at covered establishments. There is flexibility built into
    the final rule. If a food is not routinely included on a menu or menu
    board or routinely offered as a self-service food or food on display at
    a covered establishment, it is not a standard menu item and, therefore,
    is not covered by this rule. Also, if a food's ingredients and recipe
    changes daily based on food available in the store, it is likely that
    the food would not be a standard menu item but rather a daily special,
    and thus exempt from the provisions of this rule. Also, temporary menu
    items or a self-service food and food on display that is offered for
    sale for less than a total of 60 days per calendar year are exempt.
        Further, daily specials that are not listed regularly on the menu
    are also exempt from the provisions of this rule.
        If a covered establishment offers salad bar offerings or other menu
    items prepared using local or seasonal foods, and these menu items are
    standard menu items, they would be covered under the menu labeling
    requirements, even if they are not sold at every location within the
    chain. We note, however, that covered establishments have several means
    that can be used to determine the calorie and other nutrition
    information, including existing databases and cookbooks.
        FDA is committed to working collaboratively with establishments
    covered by the menu labeling final rule, including chain restaurants,
    covered grocery stores serving restaurant-type food, and others, now
    and in the future, to answer questions. In addition, we will be
    providing educational and technical assistance for covered
    establishments and for our State, local, and tribal regulatory partners
    to support consistent compliance nationwide. We will work flexibly and
    cooperatively with individual companies making a good faith effort to
    comply. FDA believes that this cooperative approach helps to improve
    the dialog surrounding the requirements and facilitates successful
    implementation in a practical way.

        Question 3. Dr. Califf, the Department of Health and Human Services
    Inspector General listed the cybersecurity of networked medical devices
    as a new priority for oversight in 2016, writing that they pose a
    growing threat to the security and privacy of personal health
    information. Moreover, the research technology firm Forrester has
    predicted that hackers will release ransomware for medical devices that
    would allow criminals to take control of a medical device and hold the
    power to hold that device's control ransom until the victims meet the
    attacker's demands.
        I understand FDA has started to take steps to address this problem,
    including releasing final guidance last year on its expectation that
    cybersecurity will be baked into the design of future medical devices.
    Many networked medical devices in use today, however, were created
    before cybersecurity was even a consideration. Dr. Califf, what role do
    you see for FDA in helping to address vulnerabilities that exist in
    these legacy medical devices?
        Answer 3. FDA is taking a proactive approach to mitigating any
    medical device cybersecurity vulnerabilities that could pose a threat
    to patient safety. The landscape of medical device cybersecurity is
    complex, and a commitment from multiple stakeholders--including device
    manufacturers, cybersecurity researchers, hospitals, and others--is
    necessary.
        FDA's approach embraces the National Institute of Standards and
    Technology (NIST) framework of ``identify, protect, detect, respond and
    recover'' in assuring the safety and effectiveness of medical devices
    and in facilitating medical device manufacturers and other stakeholders
    in the Health and Public Health Critical Infrastructure Sector to
    engage, assess, and address cybersecurity vulnerabilities before they
    are exploited. To that end, FDA's 2014 guidance addresses the Agency's
    premarket expectations to address cybersecurity vulnerabilities. FDA
    has established a Cybersecurity Working Group within the Center for
    Devices and Radiological Health to focus on Agency activities related
    to device cybersecurity. The Agency also partners with other Federal
    entities, such as the Department of Homeland Security's Industrial
    Control Systems Cyber Emergency Response Team (ICS-CERT) to quickly
    address cybersecurity vulnerabilities when they are identified and to
    facilitate communication among relevant stakeholders.
        FDA is currently working on, and plans to soon publish, draft
    guidance to address post-market concerns regarding the cybersecurity of
    medical devices. This includes ``legacy medical devices,'' some of
    which have been on the market before present-day cybersecurity concerns
    existed. In particular, the draft guidance will State FDA's
    expectations with regard to cybersecurity risk management across the
    total product life cycle. It will emphasize the need for vigilance,
    continuous monitoring and ongoing cybersecurity risk management, not
    just before commercialization or procurement, but for the entire
    lifespan of the product.
        Additionally, in the coming weeks, FDA will announce a medical
    device cybersecurity workshop to be scheduled for January 2016. As a
    followup to the previously held October 2014 workshop, this workshop
    will emphasize the total product life cycle and will bring diverse
    stakeholders together to present progress as well as persistent
    challenges in information-sharing, implementation of voluntary
    frameworks, vulnerability disclosure, and proactive vulnerability
    management.

        Question 4. Dr. Califf, I am pleased with the continued progress
    toward strengthening the role and voice of the patient in the medical
    product development process and the leadership that the FDA has shown.
    The patient voice is critical in understanding what patients value and
    the risk they are willing to accept in exchange for any potential
    benefit from any medical product.
        To ensure that patient-focused drug development tools are of a
    caliber appropriate for FDA reviewers, do you see a role for publicly
    reporting how such tools are being used in product reviews?
        Answer 4. I certainly agree that patient engagement in the drug
    development process is critical, and I look forward to continuing FDA's
    leadership in this area. In the last several years especially, the
    Agency has made significant efforts to publicly involve the patient
    community in product development in a variety of ways. Given that our
    activities have been public, I do not believe that a formal reporting
    mechanism is needed and instead would commit to continuing the Agency's
    transparency activities around these issues. Below are some examples of
    the work FDA has done to date on this important issue.
        The engagement by Parent Project Muscular Dystrophy (PPMD) in
    submitting their proposed guidance is an example of how early input
    from patients and caregivers can contribute to drug development. For
    the first time, the development of FDA guidance was preceded by the
    submission on June 25, 2014, of a proposed draft guidance independently
    prepared by PPMD. FDA values PPMD's effort and input and appreciates
    the insights provided by PPMD. PPMD's proposed draft guidance was
    posted on the web for public comment. Both the proposed guidance and
    public comments submitted to FDA were carefully considered in
    developing FDA's draft guidance. This example of collaboration between
    engaged stakeholders and FDA highlights how input from patients and
    caregivers can contribute to drug development.
        In addition, FDA has conducted a series of disease-specific public
    meetings to systematically gather patients' perspectives on their
    condition and available therapies to treat their condition. These
    meetings have been a rich source of information for the Agency, and we
    hope to continue them in the future. We also anticipate issuing
    guidances in the future to address scientific and methodological issues
    related to incorporating patients' perspectives in medical product
    development and subsequent regulatory review, and look forward to
    receiving public comment on these guidances. In sum, we believe that it
    is especially appropriate for the Agency to be transparent regarding
    its activities related to patient engagement, and we will continue to
    involve the patient community and other interested stakeholders.

        Question 5. Dr. Califf, we spoke last month about the FDA's
    proposed rule on electronic prescribing information and its implication
    for rural pharmacists. I continue to hear concerns that this rule, if
    finalized, would have an adverse effect on patient safety. This would
    be acutely felt by rural Americans who live in areas with limited
    Internet access. It would also affect patients and health care
    providers when electronic technologies are unavailable, including
    during a power outage or in the wake of a natural disaster or terrorist
    attack.
        Given that 96 percent of the public comments were in opposition to
    the proposal, are you willing to carefully evaluate the concerns before
    proceeding any further with this rulemaking?
        Answer 5. We encouraged patients, health care providers, and other
    stakeholders to submit comments to the docket for this proposed rule,
    with information or data supporting their concerns. In addition, in the
    preamble to the proposed rule, FDA specifically requested public
    comments on aspects of the proposal, including whether alternatives to
    request a paper copy of the prescribing information are adequate, and
    on alternative distribution systems in which both paper and electronic
    prescribing information would be available. As you know, FDA granted a
    request to extend the comment period for 60 days, until May 18, 2015.
    The Agency will consider all comments submitted in response to the
    proposal as we work to finalize the rule.

        Question 6. Dr. Califf, I want to switch gears for a minute to an
    issue of growing interest to many Americans, personal care products.
    The average consumer uses 10 personal care products every day, yet the
    laws governing the cosmetics and personal care products industry
    haven't been updated since 1938, and States have been acting on their
    own in the absence of a national standard. I have been working with
    Senator Feinstein on legislation that would modernize cosmetic safety
    laws and provide greater transparency for consumers and regulatory
    certainty for manufacturers.
        Would you agree that it is time to update the laws to better ensure
    the safety of personal care products?
        Answer 6. The Administration believes that the United States needs
    a modern and effective system of safety oversight for cosmetics. The
    President's fiscal year 2016 budget requests authority to require
    cosmetic firms to register their establishments and products with FDA
    and to pay a user fee. The product, ingredient, and facility
    information submitted with registration would expand FDA's information
    about the industry and better enable the Agency to develop necessary
    guidance and safety standards. With additional funding resources, FDA
    would be able to conduct priority activities that meet public health
    and industry goals. This authority would be an important step toward
    improving FDA's capacity to promote greater safety and understanding of
    cosmetic products. We would be pleased to work with you and your
    colleagues on the HELP Committee to achieve these and other meaningful
    enhancements to our cosmetics safety program.
                                 senator hatch
        Question 1a. One issue that significantly affects many entities in
    my home State is the FDA's October 2014 proposed guidance on the
    regulation of laboratory-developed tests (LDTs).
        FDA's proposal to regulate LDTs is a significant change that would
    impose considerable new burdens on regulated parties. Why was this
    proposed by guidance, when rulemaking would be more transparent,
    provide clear and binding rules, and include a better cost assessment?
        Answer 1a. The draft guidances describe FDA's proposed new
    enforcement policy for LDTs. Issuing the proposed enforcement policy
    for LDTs via guidance, rather than regulation, is appropriate because
    FDA is communicating a change in its enforcement of applicable
    requirements that already exist in statute and regulations.
        FDA is committed to a transparent and evidence-based process in the
    development of its guidance. In 2007, FDA issued a draft guidance
    proposing to no longer exercise enforcement discretion over a certain
    category of LDTs (in vitro diagnostic multivariate index assays), but
    the lab community urged FDA to address LDTs generally, rather than take
    a piecemeal approach in order to provide for greater predictability. In
    2010, FDA held a public meeting to discuss FDA oversight of LDTs and
    also opened a public docket providing additional opportunity for public
    comment. In developing the draft guidances, FDA considered and
    incorporated many of the suggestions provided by stakeholders. In
    addition, upon issuing the draft guidances, FDA provided an extended
    comment period and provided additional opportunity for comment at a 2-
    day public meeting. FDA has received 300 public comments, has met with
    numerous stakeholders, and is working to incorporate suggested changes
    into the final guidances, as appropriate.
        FDA oversight is needed to ensure that LDTs used in making major
    medical decisions are safe and effective. Due to advances in technology
    and business models, LDTs have evolved from being relatively simple
    tests that were generally only available on a limited basis to complex
    tests that have a nationwide reach and have higher risk uses, such as
    predicting breast cancer risk and directing critical treatment
    decisions, similar to those of other IVDs that have undergone FDA
    premarket review. Patients and physicians should be able to rely on the
    results of these tests to make major medical decisions.
        It is also important to note that other entities, including NIH and
    the Department of Energy in the 1990s and two advisory committees to
    the HHS Secretary after the 1990s, have been talking about the need for
    greater FDA oversight of LDTs. More recently, the Institute of Medicine
    (IOM) reinforced this as well.\7\
    ---------------------------------------------------------------------------
        \7\ National Human Genome Research Institute (1997). Promoting Safe
    and Effective Genetic Testing in the United States. See http://
    www.genome.gov/10001733.
        Secretary's Advisory Committee on Genetic Testing (2000). Enhancing
    the Oversight of Genetic Tests: Recommendations of SACGT. See http://
    www4.od.nih.gov/oba/sacgt/reports/oversight_report.pdf. Accessed
    September 16, 2010.
        Secretary's Advisory Committee on Genetics, Health, and Society
    (SACGHS). U.S. system of oversight of genetic testing: a response to
    the charge of the Secretary of Health and Human Services. Washington,
    DC: Department of Health & Human Services; 2008 Apr. 276 p. Also
    available at http://oba.od.nih.gov/oba/SACGHS/reports/SACGHS.
        Institute of Medicine. Evolution of Translational Omics: Lessons
    Learned and the Path Forward. Washington, DC: The National Academies
    Press, 2012.

        Question 1b. Many stakeholders in my State and around the country
    have shared with me concerns on the impact of this proposed guidance.
    If the FDA finalizes it, how would the agency respond to potential non-
    compliance from those impacted, given that FDA guidance documents do
    not have the force of law and are non-binding on FDA and regulated
    parties?
        Answer 1b. FDA is committed to developing a final policy for
    oversight of LDTs that encourages innovation, improves patient
    outcomes, and strengthens patient confidence in the reliability of
    these products. The Agency's premarket review is necessary to determine
    if IVDs generally, including LDTs, are analytically and clinically
    valid--that they will perform as claimed, regardless of where they are
    developed, and that patients and their physicians can rely upon their
    results to make major medical decisions.
        Under the proposed LDT framework, FDA would phase in enforcement of
    premarket review requirements and the quality system regulation for
    some LDTs using a risk-based approach. This approach will allow for a
    clear and transparent process for those clinical laboratories complying
    with premarket review requirements. We appreciate concerns from
    laboratories and others about the FDA oversight proposal, and have
    proposed a framework that prioritizes attention on those tests that
    have the potential to pose the greatest risk to patients and the public
    health, if they do not work as intended.

        Question 2. Many entities are engaging in criminal activity by
    manufacturing and marketing products that masquerade as ``dietary
    supplements'' but contain anabolic steroids, active pharmaceutical
    ingredients (APIs), or analogues of APIs. With the large number of
    legitimate dietary supplement companies who manufacture and market safe
    products to consumers, it is imperative that illegal manufacturers and
    marketers be removed to protect the public health. I was very pleased
    to see the FDA join with the Department of Justice (DOJ) and other
    Federal agencies in announcing a sweep of criminal and civil actions on
    Tuesday, November 17, 2015.
        Should you be confirmed, will you make it a priority for FDA to
    develop a plan, in conjunction with the DOJ, to take more aggressive
    action, including pursuit of both felony and misdemeanor convictions,
    against these bad actors who are threatening the public health of
    American consumers?
        During your hearing before the Senate HELP Committee, I asked
    whether you believe that the Dietary Supplement Health and Education
    Act (DSHEA) provides adequate authority to regulate the dietary
    supplement industry and protect consumers from unsafe products. In
    response, you stated that you are ``fully aware of [your] authorities
    and plan to use them as Congress has directed.'' In light of the
    sweeping enforcement actions announced by the FDA together with the DOJ
    and other agencies later that same day, it seems apparent to me that
    the FDA does have ample authority to take action in this space. Given
    these points, can you elaborate beyond your statement cited above
    whether you believe, as prior FDA commissioners have, that DSHEA
    provides adequate authority to regulate the dietary supplement industry
    and protect consumers from unsafe products?
        Answer 2. FDA is committed to fully enforcing DSHEA as vigorously
    as possible to protect the public health. Using these authorities, FDA
    has been able to take significant steps to protect the public,
    including recent Warning Letter initiatives related to products
    containing BMPEA, DMBA, DMAA and pure powdered caffeine.
        The Agency is continuing to work on better focusing our resources
    to quickly identify and act against unsafe dietary supplements. For
    instance, over the past 5 years, we have emphasized inspections and
    enforcement of our current Good Manufacturing Practice regulations
    across the entire industry, and that is helping to ensure that dietary
    supplements are manufactured safely. Also, we have implemented the
    serious adverse event reporting law for dietary supplements passed in
    2007. As we receive adverse event information under this system, our
    ability to recognize trends and patterns in adverse events is helping
    us target dangerous products or categories of products.
        As you know, DSHEA puts the burden on FDA to develop the evidence
    necessary to take action against unsafe dietary supplements. In
    addition, dietary supplement manufacturers and distributors are not
    required to inform the Agency of most products they sell prior to
    marketing. This creates enforcement challenges for FDA in discovering
    violations within a huge universe of dietary supplements, proving the
    violation, and effectively deterring future bad actors.
        FDA's dietary supplement program office is currently undergoing a
    strategic review of its structure and practices, including a review of
    the underlying statutory and regulatory authority for dietary
    supplements and how the Agency has traditionally used this authority.
    This effort is intended to ensure that we are using our full
    authorities in the most effective way possible.
        FDA works with DOJ on civil and criminal actions, such as
    injunction or seizure. For those firms demonstrating repeated or
    significant non-compliance with dietary supplement regulations, we will
    continue to pursue the most appropriate action to assure public health,
    which may include, but not be limited to, such joint actions with DOJ.

        Question 3. In September of this year, FDA's Division on Dietary
    Supplement Programs provided a Declaration to certain State attorneys
    general in response to concerns on whether a certain substance is a
    legal dietary ingredient under the Federal Food, Drug, and Cosmetic
    Act. This Declaration was then used in State enforcement activities by
    State AGs as primary evidence in cease and desist efforts against
    retailers.
        Can you shed any light on why the FDA chose to engage with State
    enforcement actions and proceed with such a Declaration, and more
    importantly why FDA took this action instead of following the usual
    transparent process, such as issuing a public statement, a warning
    letter, consumer advisory, or requesting a voluntary recall on the
    ingredient?
        I am concerned that FDA's approach of providing a Declaration
    privately to a State law enforcement agency on an issue never raised by
    the agency in a public forum or with industry could set a dangerous
    precedent. Should you be confirmed as Commissioner, will you commit to
    engaging in a more public and transparent process? Do you believe that
    FDA should clarify its position on this issue, if so, how will you
    ensure clarification? Do you believe it is appropriate and good
    regulatory practice to issue warning letters or consumer advisories
    when taking action in the future on such ingredients of concern?
        Answer 3. FDA prioritizes its enforcement actions based on
    available resources and the level of safety concern identified. The
    Agency faces the challenge of having limited resources to monitor the
    ever growing marketplace for potentially harmful dietary supplements
    and dietary ingredients. As a way of leveraging those limited
    resources, we work with outside partners, such as other Federal and
    State agencies, as well as industry stakeholders, to encourage full
    compliance with applicable statutes and regulations.
        In responding to requests from certain State attorneys general, FDA
    recognized the opportunity to work cooperatively in providing an Agency
    determination as to the validity of the purported dietary ingredient.
    This would not only assist these State agencies in exercising their
    jurisdiction over such products, but also help to conserve limited FDA
    resources while protecting the public health. FDA continues to
    investigate the marketing of products containing the ingredient in
    question, and will exercise our authority as warranted.
        FDA is committed to protecting public health through a variety of
    avenues.

        Question 4. In fiscal year 2015, FDA received around $1.9 billion
    in user fees from industry and others, and about $2.5 billion in
    appropriated funds. For the user fees, members of this committee
    receive annual financial and performance reports that are quite
    granular on the reporting of how those dollars are spent. My concern is
    that congressional dollars are not tracked as thoroughly. Programs
    without fees seem to suffer from delayed or ineffective implementation,
    including the over-the-counter drug program and food safety law. Can
    you comment to how you all currently track resources for programs
    outside of the user fee agreements, and commit to tracking taxpayer
    dollars to the same level of detail you track dollars from industry?
        Answer 4. FDA tracks the spending of all of its resources to
    include appropriated budget authority and user fees. FDA has set up its
    financial system of record to enable the Agency to track and report on
    spending by the source of funds (i.e., budget authority or user fee) as
    well as by the organization doing the spending (i.e., Center and
    Office).

        Question 5a. One of the hallmarks of the Hatch-Waxman framework
    governing generic drugs is that each generic version of a brand-name
    drug must have the same labeling as its brand-name equivalent. This
    requirement protects patients by ensuring that they have the same FDA-
    approved information no matter which version of a drug is dispensed and
    helps promote the use of lower cost generic drugs by providing public
    assurance that the products are identical. In November 2013, however,
    FDA proposed to require generic manufacturers to change the safety
    information on their drugs' labeling without prior FDA approval. If
    finalized, this proposed rule would lead to situations in which there
    are three or more different versions of the labeling of the same drug,
    with patients receiving different information depending on which
    version of the drug their pharmacists dispense.
        The labeling for a generic drug is required by statute to be ``the
    same as the labeling approved for'' its brand name equivalent. Under
    this longstanding policy, a generic drug's labeling must match the
    brand-name labeling at the time of approval, and the generic drugmaker
    must update its labeling to follow changes made by the brand-name
    manufacturer. FDA's proposal, however, would allow a generic drugmaker
    to change a drug's labeling to be different from the labeling approved
    for its brand-name equivalent. What do you believe the word ``same''
    means in this context?
        Answer 5a. In the current marketplace, approximately 80 percent of
    drugs dispensed are generic and, as we have learned, brand drug
    manufacturers may discontinue marketing after generic drug entry. The
    proposed rule, if finalized, would provide abbreviated new drug
    application (ANDA) holders with the means to update product labeling to
    reflect data obtained through post-market surveillance, even though
    this may result in temporary labeling differences among products, while
    FDA reviews the proposed labeling change. During its review of a
    generic drug manufacturer's changes being effected (CBE-0) supplement,
    FDA would consider submissions by the brand drug manufacturer and other
    generic drug manufacturers related to the safety issue, and determine
    whether the labeling update is justified and whether modifications are
    needed. FDA would make an approval decision on proposed labeling
    changes for the generic drug and the corresponding brand drug at the
    same time, so that brand and generic drug products have the same FDA-
    approved labeling.
        The proposed rule would likely reduce the variation between brand
    and generic drug labeling that currently takes place. Under current
    regulations, only brand drug manufacturers can independently update
    product labeling with certain newly acquired safety information and
    distribute revised labeling, before FDA reviews or approves the
    labeling change, by submitting a CBE-0 supplement. Under the current
    regulation, FDA generally has advised that a generic drug manufacturer
    may use the CBE-0 supplement process only to update its product
    labeling to conform to the FDA-approved labeling for the corresponding
    brand drug or to respond to FDA's specific request to submit a labeling
    change through the CBE-0 process. Accordingly, while FDA reviews a
    brand drug manufacturer's CBE-0 supplement, there currently is a
    difference between the brand drug labeling and generic drug labeling.
    Once FDA approves a change to the brand drug labeling, the generic drug
    manufacturer is required to revise its product labeling to conform to
    the approved labeling of the corresponding brand drug. FDA advises that
    this update should occur at the very earliest time possible; however,
    FDA has determined that there is often a delay, of varying lengths,
    between the date on which revised brand drug labeling is approved and
    the date on which the generic drug manufacturer submits such labeling
    updates. The proposed rule, if finalized, generally would reduce the
    time in which all generic drug manufacturers make safety-related
    labeling changes by requiring generic drug manufacturers to submit
    conforming labeling changes within a 30-day timeframe.

        Question 5b. Will you commit to considering carefully, before
    taking further action on this proposal, what impact it will have on
    public perceptions regarding the sameness of generic and brand-name
    equivalents?
        Answer 5b. The proposed rule is intended to improve the
    communication of important drug safety information to health care
    professionals and patients. FDA has received a great deal of public
    input from stakeholders during the comment period on the proposed rule
    regarding the best way to accomplish this important public health
    objective.
        FDA is carefully considering comments submitted to the public
    docket, established for the proposed rule from a diverse group of
    stakeholders including: consumers and consumer groups, academia
    (including economists), health care associations, drug and pharmacy
    associations, brand and generic drug companies, law firms, State
    governments, and Congress, including comments on how the proposed rule,
    if finalized, may affect public confidence in generic drugs and
    comments proposing alternative approaches to communicating newly
    acquired, safety-related information in a multi-source environment. FDA
    also met with the Generic Pharmaceutical Association (GPhA) on
    September 8, 2014, to listen to their comments and views regarding the
    proposed rule, and a summary of this meeting has been posted to the
    public docket (FDA-2013-N-0500). In addition, FDA held a public meeting
    at which any stakeholder had the opportunity to present or comment on
    the proposed rule, or on any alternative proposals intended to improve
    communication of important, newly acquired drug safety information to
    health care professionals and the public. In the February 18, 2015,
    notice announcing the public meeting, FDA also reopened the docket for
    the proposed rule until April 27, 2015, to allow the submissions of
    written comments concerning proposals advanced during the public
    meeting. FDA will determine next steps based on our analysis of
    comments on the proposed rule and additional information submitted as
    part of the public meeting.

        Question 5c. Under current Supreme Court precedent, FDA's proposal
    could expand generic drugmakers' potential exposure to tort lawsuits
    under State law. To what extent do you believe it is appropriate for
    FDA to consider this potential impact on the proposal's (a) cost
    assessment, and (b) policy merits?
        Answer 5c. It is appropriate for FDA to consider whether the
    proposed rule, if finalized, would result in higher costs to generic
    drug manufacturers, and also to consider information from commenters
    who support an alternative to the regulatory changes proposed by FDA in
    the proposed rule.
                                senator roberts
        Question 1. Congress was clear when it passed the Food Safety
    Modernization Act that FDA was to clearly distinguish in its
    regulations the difference between animal foods and human foods. Can
    you please explain why these rules are so similar and how the agency
    accounted for Congress' intended risk-based approach to regulating the
    supply chain for both human and animal foods? If confirmed, will you
    commit to working with inspectors to ensure the nuances between the
    animal food industry and the human food industry are taken into
    account?
        Answer 1. In the final preventive controls for animal food (PCAF)
    rule, FDA finalized baseline CGMP requirements for producing safe
    animal food. FDA recognizes that the CGMPs have to take into
    consideration the unique aspects of the animal food industry and
    provide flexibility for the wide diversity in types of animal food
    facilities. From our original proposed rule in 2013 to the supplemental
    proposal in 2014, we significantly revised the CGMPs based on feedback
    from the regulated industry. We received a number of comments from
    industry that supported the revised CGMPs in the supplemental proposal,
    but additional modifications were also requested. For the final rule,
    we revised the CGMPs, based on the comments received and existing
    industry standards. These modifications provide clarity, additional
    flexibility, and decreased prescriptiveness, while still maintaining a
    baseline to protect against animal food contamination that would be
    harmful to public health.
        FDA developed the rule with risk-based processes in mind to ensure
    that, where appropriate, the requirements for hazard analysis and risk-
    based preventive controls were the same for both the preventive
    controls for human food and the PCAF rules. Consistency in the
    regulations is beneficial for industry, especially those that
    manufacture raw material and other ingredients that may be used in both
    human food and animal food. Although the regulations are similar, the
    flexibility provided allows for the application of the regulations to
    reflect the type of facility and the type of food being processed. We
    expect the application to look different between human food facilities
    and animal food facilities, based on the expected hazards and types of
    food being processed.
        Application of the regulations will also differ across the animal
    food industry, given the great diversity of facilities, ranging from a
    small feed mill to a large pet food facility. We are committed to
    training our workforce and our State, local, and tribal regulatory
    partners to understand the flexibility built into the final rule and
    the nuances of how they may see it being applied in an animal food
    facility. We are working with both State regulatory partners and
    industry in the Food Safety Preventive Controls Alliance (FSPCA) to
    develop training that will be required for all investigators; both
    regulatory personnel and industry will receive the same base training.
    FDA is also working on development of training specific to regulators,
    which will include expectations of what one might expect to see in
    various animal food facilities. We are also working on the development
    of several guidance documents to support the final rule and will be
    engaging with industry during the process to seek their input as the
    documents are intended to help them achieve compliance with the rule.
    FDA is committed to making implementation of the animal food preventive
    control rule a success, and we recognize it will take continued
    collaboration with our State and local regulatory partners and industry
    to achieve that goal.

        Question 2. I understand the FDA is spending much of its food
    safety resources on training and education, in addition to utilizing
    State partnerships. It is also important that inspectors interact with
    those they are inspecting in a consistent manner, while also
    considering the diversity of the food industry. While some changes and
    improvements were made when the rules were finalized, the agency did
    not go nearly far enough in simplifying, ensuring consistency, and
    reducing unnecessary paperwork burdens. Now that five of the seven FSMA
    rules are final, will you commit to ensuring that the implementation
    and enforcement of the rules is consistent and as simple as possible if
    confirmed?
        Answer 2. Yes. FDA is committed to implementing FSMA efficiently
    and effectively, in collaboration with our State and local regulatory
    partners and industry. As part of this effort, we have developed a new
    inspection paradigm and enforcement strategies that reflect the
    flexible, systems-based approach of the new FSMA rules. This new
    paradigm involves a major re-orientation and retraining of more than
    2,000 FDA inspectors, compliance officers, and other staff involved in
    food safety activities, as well as thousands of State, local, and
    tribal inspectors. The training emphasizes that inspections under the
    FSMA regulations must be performed consistently from one region to
    another, and by both Federal and State officials.
        We are also working on the development of several guidance
    documents to support the final rules and will be engaging with industry
    during the process to seek their input as the documents are intended to
    help them achieve compliance with the rule. Through guidance and
    technical assistance, we will continue to work together to ensure that
    firms can tailor their food safety systems to meet their particular
    needs and exercise a myriad of flexible options under the new FSMA
    rules.
        In addition, FDA has funded and is working with three private-
    public, university-based alliances, which are responsible for providing
    standardized curricula and establishing mechanisms to train industry
    and regulators on the requirements of the produce safety and preventive
    controls rules.

        Question 3. What are the existing tools the agency has, and if
    confirmed, how do you plan to use these existing hiring authorities to
    fill the 1,800 vacancies within the agency?
        Answer 3. Addressing FDA's hiring needs is one of my top priorities
    during my time at FDA. I have already begun working with FDA's human
    resources staff to help ensure that our internal processes are working
    as efficiently as possible.
        FDA primarily uses title 5 and title 42 hiring authorities to fill
    positions. These authorities include various flexibilities facilitating
    the inclusion of veterans, disabled persons, students, minorities, and
    others, as applicable. To ensure that the 1,800 vacancies are filled in
    the Agency, we are working to implement a corporate recruitment
    strategy to identify and recruit for mission-critical scientific and
    professional positions in an expedited manner. This includes targeted
    outreach to professional and scientific organizations/communities,
    academia, and industry, to further support FDA's goals and objectives.
    Outreach efforts involve announcing vacant positions through various
    sources such as USAJOBS, social media, paid advertisements,
    professional and scientific organizations, among others. In addition,
    FDA is working to utilize all available hiring and compensation
    authorities to assist with recruiting and retaining hard-to-fill
    scientific and medical staff.
        FDA and industry agree on the importance of the Agency having
    highly qualified experts who can efficiently and expeditiously review
    cutting-edge products, and conduct post-market surveillance activities.
    We appreciate that Congress and industry have recognized the necessity
    of having a highly skilled FDA workforce, and I look forward to working
    with you to address the challenges that FDA faces in recruiting and
    retaining the talented individuals the Agency needs.

        Question 4. Over the past 2 years, four studies, including two
    published in the New England Journal of Medicine and one from the
    Institute of Medicine (IOM), have found that diets too low in sodium (<
    2,300 mg/day) result in negative health outcomes. As a cardiologist,
    why do you believe the government continues to push for population wide
    reduction in sodium intake knowing that it might be associated with an
    increase in cardiovascular disease risks? And if confirmed, would you
    continue to support this position?
        Answer 4. U.S. Government efforts focus on reducing the average
    sodium intake in the United States for those aged 2 years and older
    from the current 3,400 mg/day closer to 2,300 mg/day. The 2013 IOM
    report entitled ``Sodium Intake in Populations, an Assessment of the
    Evidence'' reaffirmed that sodium intake levels are too high and should
    be reduced to 2,300 mg/day. This recommendation is also supported by
    the Scientific Report of the 2015 Dietary Guidelines Advisory
    Committee, which thoroughly considered the 2013 IOM Sodium Report and
    other evidence in their review. The 2010 DGAs recommended a reduction
    in sodium intake to less than 2,300 mg/day and a further reduction to
    1,500 mg/day among African Americans, individuals with hypertension,
    diabetes, or chronic kidney disease, and individuals ages 51 years or
    older. Again, the focus of FDA is on the general population
    recommendation with gradual reductions in intake levels for the general
    population toward the 2,300 mg/day mark.
        A large body of evidence indicates that as sodium intake increases,
    so does blood pressure (Aburto, et al., 2013; Sacks, et al., 2001; He,
    et al., 2013; Mozzaffarian, et al., 2014). High blood pressure is a
    leading risk factor for heart disease and stroke (Stamler, et al.,
    1993; Kannel, et al., 1996; van den Hoogen, et al., 2000; O'Donnell, et
    al., 1997, Prospective Studies Collaboration, 2002). It is estimated
    that about 41-45 percent of deaths due to heart disease and stroke are
    attributed to high blood pressure (Yang, et al. 2012; Danai, et al,
    2009). Heart disease is the No. 1 killer of men and women in the United
    States and stroke is No. 5 (CDC, 2015). One in three adults in the
    United States have high blood pressure, with only half having it under
    control (Nwankwo, et al., 2013; Egan, et al., 2010). Reducing average
    sodium intake in the U.S. population can reduce blood pressure and is
    projected to save tens of thousands of deaths and billions of health
    care dollars each year (Coxson, et al., 2013; Bibbins and Domingo,
    2010), including among people whose blood pressure is above 120/80
    (Huang, et al., 2014a). Average dietary sodium intake in the U.S.
    population, aged 2 years and older, is about 3,400 mg/day before salt
    is added at the table, compared to a recommended intake of less than
    2,300 mg/day 2015 DGAC Report.) Because about 75 percent of sodium in
    the diet of the U.S. population is estimated to be added during the
    manufacturing of foods and preparation of restaurant foods, it is
    challenging for consumers to reduce their sodium intake (Anderson, et
    al., 2010; Mattes and Donnelly, 1991).
        Some recent observational studies (Stolarz-Skrzypek, et al., 2011;
    O'Donnell, et al., 2011; O'Donnell, et al., 2014; Graudal, et al.,
    2014) are inconsistent with a large body of evidence that consistently
    shows a dose-response relationship between sodium intake and blood
    pressure (Aburto, et al., 2013; Sacks, et al., 2001; He, et al., 2013;
    Mozaffarian, et al., 2014; Eckel, et al., 2014). Results of these
    recent observational studies suggest low- and high-sodium intakes are
    associated with cardiovascular disease (CVD) events or deaths, and are
    inconsistent with other observational studies showing lower sodium
    intake is associated with lower risk of CVD (Cook, et al., 2014;
    Poggio, et al., 2015). Expert review of these studies by FDA and CDC
    scientific experts indicate that they do not shift the weight of
    evidence.
        Like other studies reviewed by IOM in 2013 and an American Heart
    Association Scientific Advisory Committee in 2014 (Cobb, et al., 2014),
    these studies have major limitations in the selection of participants
    and/or measurement of sodium intake. For example, a problem with some
    of these studies is the possibility for reverse causation. Reverse
    causation could occur if participants who have a major risk factor for
    CVD, such as chronic kidney disease, have lowered their sodium intake
    because of medical advice or because their illness reduces the amount
    of food consumed. Another major weakness is use of a measure of short-
    term sodium intake, like a single 24-hour urine collection or a spot
    urine specimen that does not accurately reflect an individual's long-
    term exposure. Many studies show a spot urine specimen can over or
    under-estimate individual daily sodium intake by as much as 3,000 mg or
    more (Mente, et al., 2013 and Cogswell, et al., 2015). This means
    people with high sodium intake are mis-classified as having low-
    estimated sodium intake and vice versa. This could result in people
    with low-estimated sodium intake falsely appearing to have an increased
    risk of CVD.

        Question 5. I support encouraging industry to gradually lower
    sodium in the foods that are available to consumers, so that they will
    have more options if they choose to consume less sodium. The 2015
    Dietary Guidelines Advisory Committee (DGAC) recommended that the FDA
    should modify the generally recognized as safe (GRAS) status of salt in
    processed foods to reduce the salt content of the food supply. Given
    the Dietary Guidelines Advisory Committee's stated research gaps, and
    the science that increasing finds adverse health outcomes at low-sodium
    intake levels, would you suspend any action in this regard until
    further research is conducted and a comprehensive review of all related
    science is concluded?
        Answer 5. The Scientific Report of the 2015 Dietary Guidelines
    Advisory Committee referenced the 2010 IOM report on Strategies to
    Reduce Sodium Intake in the United States in their report. It was this
    2010 IOM report that recommended the FDA should set mandatory national
    standards for the sodium content in foods by modifying the generally
    recognized as safe (GRAS) status of salt added to processed foods to
    reduce the salt content of the food supply.
        Americans are consuming excess sodium, and this excess contributes
    to increased risk of hypertension, a primary contributor to stroke and
    heart disease. Encouraging industry to voluntarily reduce sodium in
    products so that consumers have more options does not require bringing
    consumers into an excessively low sodium intake range such as 1,500 mg/
    day. In fact, with average sodium intake at 3,400 mg/day there is
    considerable work to do to phase-down intake to the recommended level
    of 2,300 mg of sodium per day, which is consistent with the current
    State of the science.
        We are in support of conducting well-designed research to add to
    the knowledge base on sodium intake in different population groups.

        Question 6a. The 2015 Dietary Guidelines for Americans provides the
    basis of nutritional information for numerous Federal programs,
    including the Food and Drug Administration's Nutrition Facts label. The
    Dietary Guidelines are published jointly by the Department of Health
    and Human Services and the Department of Agriculture and are informed
    in part by an Advisory Committee, but most importantly are a source of
    nutritional and dietary information and guidelines. The 2015 Dietary
    Guidelines have not been finalized, yet the FDA is proposing to
    establish a new percent daily value (DV) for added sugars on the
    Nutrition Facts labels of packaged foods.
        Is it appropriate for FDA to propose a policy change that is based
    on an unofficial Advisory Committee recommendation before the
    Departments of HHS and Agriculture finalize the 2015 Dietary Guidelines
    for Americans? And how will you ensure FDA upholds its use of
    scientific consensus standards when proposing a policy change, such as
    proposing a change to the Daily Recommended Value for added sugars?
        Answer 6a. In July 2015, FDA released a supplemental proposal to
    establish a Daily Reference Value (DRV) of 10 percent of total calorie
    intake from added sugars. The comment period for the proposal closed on
    October 23, 2015. The Agency is reviewing and considering the comments.
        In developing the proposal, FDA did consider the scientific
    evidence underpinning the recommendations provided in the Dietary
    Guidelines Advisory Committee's report to set a DRV for added sugars.
    In considering any final proposal, I can assure you that FDA will
    continue to use the best available science and evidence.

        Question 6b. Will you commit to ensuring that the agency's proposal
    to require the disclosure of added sugars per serving on the Nutrition
    Facts label is adequately understood by consumers and provide
    scientific evidence that supports such consumer comprehension before
    finalizing any new labeling requirement?
        Answer 6b. FDA released the results of its consumer studies on
    added sugars in the Agency's supplemental rulemaking in July 2015. We
    initiated this research to explore consumers' potential interpretations
    of Nutrition Facts labels that include added sugars declarations. The
    Agency is considering and reviewing the comments on this consumer
    research. This research would inform any consumer education if added
    sugars are declared on the label. FDA believes that a multi-component,
    coordinated consumer education campaign should be implemented to make
    any new food label a successful tool in continuing to help consumers
    understand and use the label to assist them in making healthy food and
    beverage choices.
                                senator cassidy
        Question 1. Back in September I chaired a hearing where Dr.
    Woodcock spoke to the committee about implementation of the biosimilars
    pathway. She was, as always, very responsive and detailed in answering
    the many questions about the science and promise of biosimilars.
    However, she was repeatedly questioned about the timing of outstanding
    guidances, including those on labeling and interchangeability of
    biosimilars. She told the committee that those additional guidances are
    expected in 2015. Can you assure the committee that the outstanding
    biosimilars guidances will be published by the end of this year?
        Answer 1. FDA has published the following final guidances related
    to biosimilars: Scientific Considerations in Demonstrating
    Biosimilarity to a Reference Product; Quality Considerations in
    Demonstrating Biosimilarity of a Therapeutic Protein Product to a
    Reference Product; and Biosimilars: Questions and Answers Regarding
    Implementation of the Biologics Price Competition and Innovation Act of
    2009; and Formal Meetings Between the FDA and Biosimilar Biological
    Product Sponsors or Applicants.
        FDA has also published the following draft guidances since 2012:
    Clinical Pharmacology Data to Support a Demonstration of Biosimilarity
    to a Reference Product; Reference Product Exclusivity for Biological
    Products Filed Under Section 351 (a) of the PHS Act; Biosimilars:
    Additional Questions and Answers Regarding Implementation of the BPCI
    Act of 2009; and Nonproprietary Naming for Biological Products.
        The Agency is committed to carefully reviewing the comments
    received as we move forward in finalizing the draft guidances noted
    above. Upcoming guidances are expected to include: Considerations in
    Demonstrating Interchangeability to a Reference Product; Statistical
    Approaches to Evaluation of Analytical Similarity Data to Support a
    Demonstration of Biosimilarity; and Labeling for Biosimilar Biological
    Products.
        FDA is diligently working to issue guidance on issues that have
    been identified by FDA and key stakeholders as key topics of interest.
    While the Agency cannot provide a specific timeline for the release of
    any guidance, we continue to provide information to assist biological
    product developers--sponsors/companies--with bringing biosimilar and
    interchangeable products to market. FDA is continuing to clarify its
    approach to implementation of the BPCI Act to further facilitate
    sponsors' development of biosimilars and interchangeable biological
    products.

        Question 2. Despite FDA reporting a decline in shortages in the
    last few years, we are still hearing that shortages are a substantial
    concern for providers. How do you reconcile the decline in shortages
    FDA is tracking with the continued struggles providers are reporting?
    What do you see as the key things that the agency still needs to do to
    better position itself to address shortages?
        Answer 2. The Drug Shortage Staff in FDA's CDER is tracking numbers
    of new shortages annually, and this has greatly decreased since 2011.
    There were 44 new shortages in both 2014 and 2013 compared to 117 new
    shortages in 2012. These numbers are significantly lower than the 251
    new shortages recorded in 2011.
        FDA is well-positioned to work with manufacturers to find ways to
    prevent or reduce a shortage's impact on patients, provided we are
    aware that there is a potential for a shortage. Early and timely
    notification by manufacturers has been aided importantly by Executive
    Order 13588 and by passage of FDASIA, and has enabled FDA and
    manufacturers to prevent 195 drug shortages in 2011; 282 drug shortages
    in 2012; 170 drug shortages in 2013; and 101 shortages in 2014. FDA has
    also used other tools to prevent or mitigate shortages, including
    expediting the review of shortage-related ANDAs. Since the enactment of
    FDASIA on July 9, 2012, through December 31, 2014, CDER's Office of
    Generic Drugs expedited the review of 298 applications, including 182
    abbreviated new drug applications and 116 supplemental ANDAs, to
    prevent or mitigate drug shortages.
        FDA also continues to improve its system for data tracking and
    analysis for drug shortages, with the Drug Shortage Data System (DSDS),
    which was put into place in 2014 and enhances the efficiency and
    consistency of drug shortage data entry. FDA is continuing to integrate
    DSDS with other CDER data systems to improve its drug shortage tracking
    and reporting capabilities. FDA works to find ways to mitigate drugs
    shortages; however, there are still shortages that persist for longer
    periods of time. There are a number of factors that can cause or
    contribute to drug shortages that are outside of the control of FDA.
    These factors include:

         Production delays at the manufacturer and delays companies
    have experienced receiving raw materials and components from suppliers;
         Discontinuations--for example, older drugs that are
    discontinued by companies in favor of newer, more profitable drugs;
         In the case of older sterile injectable drugs, limited
    production line capacity, which, combined with long lead times and
    complexity of the manufacturing process, results in vulnerability to
    shortage.

        Drug shortages remain a top priority for FDA. Although FDA cannot
    directly affect many of the business and economic decisions that
    contribute to drug shortages, FDA is well-positioned to play a
    significant role as manufacturers work to restore lost production of
    lifesaving medications. While important progress has been made in
    preventing drug shortages from occurring, and decreases have been seen
    in the total numbers of new shortages, FDA continues to work to ensure
    that patients in the United States will have access to the medicines
    they need.

        Question 3. Congress has made every effort to support the
    advancement of science, most notably giving FDA explicit flexibilities
    in FDASIA to review new drug applications under accelerated approval or
    via ``breakthrough'' status. What we intended--and in some cases FDA
    has embraced--is for the Agency to maintain the highest safety
    standards but to think creatively about what data can be provided where
    the traditional large, placebo-controlled clinical trial is simply
    infeasible or unethical due to the rarity and severity of a disease or
    the small patient population. We intended for FDA to re-evaluate the
    risk-benefit model and allow patients a voice in the process, where
    higher risk and greater uncertainty may be ok with them given the
    severity of their disease. For serious and life threatening diseases,
    particularly for children, we intended for some new drugs to move
    through the approval process more quickly, allowing a drug sponsor to
    submit post market data to confirm initial safety and efficacy data.
    And we intended for FDA to take a team approach on drug applications
    where the drug could be a ``game changer,'' by allowing for additional
    communication between the Agency and the sponsor, including access to
    the senior management team.
        Yet, despite our best intentions and FDA's best intentions in
    embracing FDASIA, I continue to hear from patients and innovators that
    there are significant inconsistencies across the review divisions. I
    understand the Oncology Division has a long track record of utilizing
    the accelerated approval pathway and as a result there are fewer death
    sentences from cancer. And I have been told recently the Metabolism and
    Endocrinology division has applied regulatory flexibility by allowing
    natural history data to serve as historical controls in support of at
    least 2 approvals in 2015 of rare disease treatments. Congress
    explicitly expanded the tools adapted in the battle against cancer and
    HIV/AIDS to other diseases and I applaud FDA for these examples of
    using them to the benefit of patients.
        On the other hand, I have also been told that the Neurology
    Division continues to question that flexibility, seemingly resistant to
    approaches that are not traditional, placebo-controlled large scale
    trials that may be both infeasible and unethical for very sick
    patients, including children. This committee questioned Dr. Hamburg at
    a hearing about this very division in March 2014. And yet I am
    compelled to raise the same essential question with you again today.
        This is not about whether you approve or deny drug applications.
    The question is about embracing the science, technology and approval
    pathways that allow new treatments to get to patients under the same
    high safety standards. It is about FDA adapting across the board to
    patient needs by allowing more and consistent regulatory flexibility,
    so all patients can benefit as they have in the case of cancer and HIV.
        If confirmed, could you please share with me your ideas for
    improving the adoption of FDASIA's flexibilities across review
    divisions? How will you make flexibility the rule for rare diseases?
        Answer 3. I share your interest in improving flexibilities across
    review divisions, including for rare diseases, building on FDA's
    efforts to date. We've improved the efficiency and predictability of
    clinical drug development by developing tools such as biomarkers and
    surrogate endpoints--markers of drug effect that do not directly
    represent an improvement in how a patient feels or functions, but are
    reasonably likely to predict a clinical benefit. In the early 1990s,
    only 5 percent of FDA's new drug approvals were for targeted therapies
    using biomarkers and in 2013, 45 percent of FDA's approvals were for
    targeted therapies using biomarkers. FDA has approved hundreds of drugs
    on the basis of validated surrogate endpoints using traditional
    approval. FDA has also frequently relied upon surrogate endpoints for
    accelerated approval. When a biomarker or surrogate endpoint is already
    validated, accelerated approval is not needed, because confirmatory
    post-approval studies generally are not necessary in this context to
    verify and describe the drug's clinical benefit. Whether accelerated
    approval can be utilized rests on the availability of biomarkers and
    surrogate endpoints applicable in a given disease. In some areas, like
    oncology, robust research has focused heavily on development of these,
    but that is not necessarily the case in other disease areas.
        FDA published guidance in 2014 on our various programs to expedite
    the development and review of new drugs to address unmet medical need
    in the treatment of serious or life-threatening conditions. FDA expects
    this guidance to help sponsors consider a range of possible endpoints
    that might support accelerated approval, and we are committed to
    working closely with them to facilitate the use of accelerated approval
    where appropriate to help bring needed drugs to patients. We know this
    cuts across many therapeutic areas and rare diseases offer some of the
    biggest challenges. In fact, CDER and OND have established a Rare
    Diseases Program to facilitate OND's review divisions strategic
    engagement in best utilizing tools like accelerated approval to make
    most efficient use of clinical trials and ensure the most creative
    approaches to product development.
        For example, FDA used the accelerated approval pathway to approve
    Tysabri (natalizumab), a treatment for multiple sclerosis, based on a
    large therapeutic effect on relapse rate through approximately 13
    months of treatment, despite uncertainty about the durability of the
    observed effect. As a condition of its accelerated approval, the
    sponsor was required to continue the existing trials into the post-
    marketing period to confirm durability of the observed effect at 2
    years.
        These are exciting times as we experience simultaneous revolutions
    in the biological and information sciences. We expect that the
    astounding increase in knowledge of biological systems enabled by whole
    genome sequencing, cloud computing, social media, and wearable devices
    to monitor physiology will create challenges to traditional thinking.
    And we are confident that this increased knowledge will continue to
    expand the pipeline of new therapies. We are prepared to deal with the
    product of this scientific investment by using regulatory paradigms
    that match the State of the science and by supporting dissemination of
    the latest knowledge applied to drug development.
        In this paradigm that takes advantage of the depth of this new
    biomedical information, it will be critical to continue to support
    ongoing clinical trials and observational studies to ensure sufficient
    knowledge of the benefit-risk profile of therapies as they evolve into
    broad use. Even the best of the current surrogates such as systolic
    blood pressure cannot substitute for the entire cumulative effects of a
    drug on the intended biological target and for off-target effects.
        FDA has in place standard operating procedures and guidance on good
    review practices for management of the review of marketing applications
    that are followed by all CDER review divisions. In addition, reviewers
    undergo rigorous training to ensure consistency in application of
    guidance, regulations, and best practices. However, like drug
    development strategies, review times can differ depending on the
    condition being treated and what is known about an individual product.
    Review times can be shorter for certain conditions, such as some
    cancers, since many cancer drugs qualify for one or more of our
    expedited review programs and may present a very favorable benefit-risk
    profile and a more limited amount of data that must be reviewed prior
    to making an approval decision. It is a misconception that speedy
    reviews only occur in oncology, however. For example, approval of the
    first drug for cystic fibrosis was accomplished well ahead of the PDUFA
    goal date.
        FDA's drug approval process--the final stage of drug development--
    is the fastest in the world, which means that Americans typically have
    first access to new drugs when they are demonstrated to be safe and
    effective. But even as our Agency has transformed the approval
    process--approving 51 new molecular entities and biological products
    last year alone, including more new orphan drugs for rare diseases than
    in any previous year--drug discovery and development is not keeping
    pace for many diseases (see 2014 Novel New Drugs Summary (January
    2015), at http://www.fda.gov/downloads/drugs/
    developmentapprovalprocess/druginnovation/ucm430299.pdf).
        Speeding the availability of safe and effective drugs that treat
    serious diseases is in everyone's interest, especially when the drugs
    are the first available treatment or if the drug has advantages over
    existing treatments. To encourage innovation, we will continue to work
    with other government agencies and the health care community, including
    members of patient groups, academia, and industry. It will take a
    collaborative effort to improve our Nation's understanding of certain
    diseases and to translate any resulting scientific discoveries into
    cures.
                                 senator murray
        Question 1a. As we've discussed, FDA has jurisdiction over critical
    public health issues beyond the regulation of drugs and medical
    devices. The agency is also charged with protecting kids from the
    dangers posed by tobacco, giving Americans the nutrition information
    they need to make decisions about the foods they choose for themselves
    and their families, and ensuring the safety and nutritional soundness
    of our food supply, to name a few.
        I'm particularly eager to see full implementation of two long-
    awaited FDA rules--the first to ensure menu labeling in restaurants and
    similar establishments, and the second expanding FDA regulation of
    tobacco products to include e-cigarettes and other products--a rule
    that urgently needs to be finalized.
        Can you tell me more about what your priorities will be when it
    comes to these kinds of public health protections?
        Answer 1a. Finalizing the tobacco deeming rule is of the highest
    priority for the Agency and the Administration. We share your sense of
    urgency on this important matter. We are working diligently to finalize
    the rule as soon as possible. The rule has undergone extensive internal
    review within FDA and HHS and is now under review at the Office of
    Management and Budget.
        Once the proposed rule is finalized, some provisions (e.g.,
    establishment registration, product listing, ingredient listing, and
    the adulteration and misbranding provisions of the statute) in the FD&C
    Act would automatically apply to all deemed tobacco products. In
    addition, other provisions of the proposed rule would apply to covered,
    newly deemed tobacco products--if included in the final rule--such as:
    minimum age and identification restrictions to prevent sales to
    underage youth; requirements to include health warnings; and a
    prohibition of vending machine sales, unless in a facility that never
    admits youth.
        When the rule is final, FDA will prioritize implementation,
    including educating industry on how to comply with the requirements in
    the rule. In addition, FDA considers the deeming rule to be a
    foundational regulation, which, once finalized, will allow the Agency
    to take further actions regarding critical public health issues.
        With respect to menu labeling, on September 11, 2015, FDA issued
    the draft guidance document titled ``A Labeling Guide for Restaurants
    and Retail Establishments Selling Away-From-Home Foods--Part II (Menu
    Labeling Requirements in Accordance with 21 CFR 101.11.'' We currently
    anticipate issuing the final guidance in late spring 2016.
        FDA will be focusing the first year of implementation on providing
    educational and technical assistance for persons and covered
    establishments, and for our State, local, and tribal regulatory
    partners to support consistent compliance nationwide. Since publication
    of the final rule, FDA has been very active in attending conferences as
    invited presenters, participating in industry-sponsored webinars and
    conference calls, and meeting with industry representatives to help
    them understand the provisions of the rule and how to implement the
    provisions. We will continue to be available for these types of
    activities. In addition, we have established a special mailbox for
    covered establishments (CalorieLabeling@fda.hhs.gov) to contact us with
    their questions.

        Question 1b. Once FDA finally asserts their jurisdiction over
    additional tobacco products, what steps will you take to make sure the
    agency moves swiftly to fully use its new authority and ensure that
    Americans--and especially kids--are protected from the full range of
    tobacco products?
        Answer 1b. FDA has vigorously enforced the youth access and
    marketing restrictions for currently regulated tobacco products. This
    includes conducting more than 522,000 retail compliance checks
    nationwide to ensure retailers are complying with the law, initiating
    enforcement action when violations are observed, and providing
    compliance training and education to retailers so they understand the
    requirements under the law. These efforts will continue for newly
    deemed products, once the proposed rule is finalized.
        As stated above, when the rule is final, FDA will prioritize
    implementation of all aspects of the rule and take further actions,
    when warranted, to protect the public health.

        Question 1c. I know that limiting the amount of the sodium in the
    food supply is something the agency has been thinking about for a long
    time--and I'm guessing, as a cardiologist, as issue of personal
    interest to you. When do you think we might finally see action on this
    issue?
        Answer 1c. I do have a strong interest in this issue and I can
    assure you that FDA is continuing to work diligently in this area, but
    we do not have a specified timeframe for issuing a proposal.

        Question 2. In April 2015, Senator Isakson and I led a letter from
    a bipartisan group of 29 Senators to Acting Commissioner Stephen
    Ostroff stating,

              ``Ensuring that women have the best advice that reflects the
            latest nutrition science about what to eat during pregnancy,
            for their health and the health of their children, is of the
            utmost importance.''

        If confirmed, will you ensure that pregnant women receive final
    nutrition advice that is clearly presented and consistent with the
    latest science?
        Answer 2. FDA shares your interest in ensuring that pregnant women
    have access to sound, science-driven, and clearly understandable
    recommendations that enable them to make informed decisions about their
    diets. The final seafood consumption advice for pregnant women is
    undergoing interagency review. We will continue to take steps to ensure
    that it is reflective of the latest nutrition science. Completing the
    updated advice remains a priority for the Agency.

        Question 3. One of the many responsibilities of the Food and Drug
    Administration is to consider aspects of food and nutrition labeling
    for Americans. As you are aware, the Dietary Guidelines for Americans
    are a set of recommendations that encourage Americans to eat healthy
    foods like fruits, vegetables, whole grains, lean meats, eggs, and
    nuts. Current FDA labeling regulations, however, do not allow some of
    these foods to be labeled as ``healthy.'' Can you explain steps you
    would take to ensure FDA's approach to nutrient content claims--
    specifically the use of the term ``healthy'' to make a nutrient content
    claim--reflect current Federal dietary guidance and scientific
    evidence?
        Answer 3. The Dietary Guidelines for Americans provide information
    and advice for choosing a healthy eating pattern. Included in this
    advice are food choices that are emphasized and encouraged to help
    Americans move toward healthful eating patterns. Healthful eating
    patterns can be achieved through a wide variety of foods, not just
    foods that are considered ``healthy'' individually. The recommendations
    include a wide variety of food choices which may not, individually,
    have nutrient profiles consistent with the definition of a ``healthy''
    claim.
        FDA's regulations provide a set of minimum nutrient content
    standards for individual foods to be considered ``healthy'' and bear a
    ``healthy'' claim. A ``healthy'' claim can generally be used if a food
    contains less than 3 grams of fat, 1 gram of saturated fat, 60 mg of
    cholesterol and 420 mg of sodium per reference amount customarily
    consumed.
        It is possible that a food may not meet these minimum standards,
    yet may be able to contribute to an overall healthful eating pattern.
    To illustrate, a food can contribute an essential nutrient, such as
    calcium, to an overall healthful eating pattern, yet also contain
    nutrients that are recommended to be limited in the diet, such as
    saturated fat. This individual food could contribute to an overall
    healthful eating pattern, yet not be considered an overall ``healthy''
    food by itself.
        While we try to ensure that all regulations related to nutrition
    labeling are consistent with the Dietary Guidelines for Americans, it
    is important to understand that the focus of the Guidelines is
    healthful eating patterns. FDA will continue to monitor and assess the
    most recent science to update our nutrition and nutrition-related
    regulations as needed.
        For example, we are currently working to update our requirements
    for the Nutrition Facts label.

        Question 4. As you know, an increasing amount of manufacturing of
    both active pharmaceutical ingredients and finished pharmaceutical
    products, as well as testing for new drug applications, is occurring in
    foreign countries. How can we better ensure that drugs, devices, food,
    and other products regulated by the FDA--that are developed and made
    outside our borders--meet the quality and safety standards we require
    in this country to protect the public?
        Answer 4. All drugs delivered to patients in the United States are
    subject to the same high standards, regardless of country of origin.
    Registered drug manufacturing facilities in foreign countries are
    subject to FDA inspection, with inspection frequency determined on the
    basis of risk to patients. FDA employs a highly trained global
    inspectorate, which is skilled in evaluating processes and uncovering
    manufacturing problems during inspections. Whenever FDA investigators
    find product quality issues that potentially implicate drug safety and
    efficacy, the Agency takes appropriate action, which could include
    issuing a Warning Letter or import alert, or taking other enforcement
    action. Because of resources made available under the Generic Drug User
    Fee Amendments of 2012 (GDUFA), FDA has been able to significantly
    increase the number of inspections (both surveillance and pre-approval)
    it conducts in foreign countries (e.g., India). Having in-country
    investigators allows FDA to be more responsive to high-priority public
    health and safety issues. FDA utilizes risk-based strategies and local
    intelligence in order to maximize its resources to conduct timely and
    high quality inspections. Such strategies may include the
    establishment's compliance, records, and recalls-related history, as
    well as the inherent risks of the drug produced at the facility.

        Question 5. Please provide a description of the work that you
    performed in creating and leading the Duke Clinical Research Institute
    including what you believe is some of the most significant work you
    conducted or oversaw at DCRI.
        Answer 5. The Duke Clinical Research Institute (DCRI) was
    established in 1996 by Duke University Medical Center (Duke) as an
    institutional resource for Duke faculty members conducting clinical
    research; including clinical trials, health services research and
    health policy research (www.dcri.org). I was appointed as the founding
    director of the DCRI in 1996 and served in this capacity until 2006.
    The DCRI operates as a multidisciplinary research unit within the Duke
    University School of Medicine. The mission of the DCRI is to ``develop
    and share knowledge that improves the care of patients through
    innovative clinical research.''
        As part of their academic endeavors, Duke faculty members pursue
    grants and contracts for research studies based on their individual
    clinical and research interests. DCRI staff provide assistance to the
    faculty in preparing grant applications and proposals for potential
    studies sponsored by government agencies, non-profit organizations, and
    foundations and commercial entities.
        When grants or contracts are awarded, the faculty member serves as
    the principal investigator of a study and a team of DCRI staff members
    and faculty (including statisticians, project managers, data managers,
    regulatory associates, etc.) is assigned to perform operational and
    regulatory activities required for the conduct of the study. Following
    completion of the study, the faculty member is responsible for
    conducting an independent analysis and interpretation of the study
    results, and disseminating the results through the peer-reviewed
    literature and presentations at scientific meetings.
        In my role as director, my responsibilities included the following:

         Providing institutional leadership and a vision for
    directing the faculty toward the future of clinical research while
    meeting societal needs.
         Overseeing the work of faculty members and staff involved
    in research studies awarded to the DCRI.
         Overseeing the clinical, operational and financial
    performance and ensuring regulatory compliance of all research studies
    conducted at the DCRI.
         Ensuring the publication and dissemination of the results
    of studies conducted at the DCRI.
         Ensuring that DCRI operational capabilities are aligned
    with the research interests of the faculty.
         Developing a cadre of faculty members and staff who are
    experts in clinical research methods.
         Educating and training junior faculty, fellows, and
    students in clinical research.
         Ensuring a balanced portfolio of research studies by
    funding source to achieve financial self-sustainability and being a
    prudent steward of institutional resources.

        Significant accomplishments:

         Developed a model for academic coordination of large scale
    research, including direct involvement in national policies on CMS
    reimbursement for clinical trials, conflict of interest reporting, and
    management and policies for sustaining independent voice for academics
    and clinicians in design and interpretation of clinical research.
         Expanded from a cardiology-focused research unit to
    include almost 20 therapeutic areas, ranging from pediatrics to
    obstetrics and gynecology, anesthesiology, infectious diseases, mental
    health, drug abuse prevention and treatment, and others. To date, DCRI
    has conducted studies at 37,000 research sites in 65 countries and
    enrolled over 1.2 million patients.

         Served as a major hub of clinical trial networks, with
    Federal funding from over 15 NIH Centers and Institutes.
         Established a nexus of patient registries in partnership
    with medical professional societies to improve healthcare quality and
    prevent medical errors. The registries in acute cardiac care and
    cardiac surgery have become national models with adoption of
    performance measures by CMS.
         Participated in multiple efforts on transparency of
    results of clinical research including major role in the development of
    ClinicalTrials.gov as a member of the Lister Hill Center (National
    Library of Medicine) Board and a contributor to the development of data
    fields and analytical efforts with the database.
         Developed one of the country's largest training programs
    for clinical research and expanded the program to an international
    reach.
         DCRI published over 800 manuscripts per year in the peer-
    reviewed literature.

        Question 6. Please provide a description of the work that you
    performed in creating and leading the Duke Translational Medicine
    Institute including what you believe are some of the most significant
    work you conducted or oversaw at DTMI.

        Answer 6. The Duke Translational Medicine Institute (DTMI) was
    established in 2006 to serve as an academic home for Duke's clinical
    and translational research community. I was appointed as the founding
    director of the DTMI in 2006 and served in this capacity until joining
    the FDA in February 2015. DTMI was created to expand the DCRI model to
    faculty across the entire translational research spectrum in concert
    with Duke's first Clinical and Translational Science Award from the NIH
    (the major translational research grant offered by the NIH at the
    institutional level). The mission of DTMI is to,

            ``improve individual and population health by catalyzing
            translation across the continuum of scientific discovery,
            clinical research care delivery, and global health.''

        The DTMI serves as an umbrella organization including the
    Translational Research Institute (bench to bedside research), the
    Clinical Research Institute (described above) and the Duke Center for
    Community and Population Health Improvement. It functions as integrated
    support structure to facilitate the efforts of faculty members to
    accelerate the translation of basic science discoveries into new
    medical therapies to advance patient care and to develop methods of
    improving population health through community engaged research and the
    use of electronic records and analytics to improve access and effective
    implementation of health services. DTMI provides a continuum of
    resources and training, such as statistical expertise, degree-granting
    programs, regulatory affairs, project management, and biobanking.
        In my role as DTMI director, my responsibilities mirrored those of
    my prior role as DCRI director, with the inclusion of a much broader
    scope of research ranging from pre-clinical translation to population
    health and community engaged research.
        Significant accomplishments:

         Established the Duke Center for Community and Population
    Health Improvement to foster collaborations among community partners,
    researchers, and health system leaders with the goal of decreasing
    health inequities in the Southeast and across the country through
    studies designed to intervene at both the individual and community
    levels. This includes a CMS-funded project that uses geospatial mapping
    technology to identify residents in four counties in West Virginia,
    Mississippi, and North Carolina at greatest risk of poor health
    outcomes and implement interventions to achieve the ``triple aim'' of
    improved outcomes, better care and lower cost.
         Launched a major effort to develop innovative approaches
    for conducting pragmatic, patient-centered clinical trials. Served as
    the coordinating center for the NIH-funded Health Care Systems Research
    Collaboratory to increase the efficiency of clinical trials by using
    data from electronic health records; and the PCORI-funded National
    Patient-Centered Clinical Research Network to establish national
    networks of health systems, researchers, health care providers, and
    patients conducting clinical trials that answer ``real-world''
    questions most important to patients and their families.
         Created a regulatory affairs group to provide academic
    investigators with access to the regulatory expertise typically found
    in industry and assist them in navigating the regulatory process
    required to develop new diagnostic and therapeutic technologies. This
    group improved institutional compliance by creating a central database
    of regulatory submissions by Duke investigators and providing extensive
    training in regulatory requirements. This group is considered a model
    among other academic centers.
         Launched ``The MURDOCK Study,'' a longitudinal health
    study involving the populations of Kannapolis/Cabarrus County, NC. The
    study aims to collect genetic and behavioral health profiles from
    50,000 participants using participatory research methods to involve the
    entire community in the design and interpretation of the study. This
    has been described as a modern Framingham Study (a landmark study
    cardiovascular health). Over 11,000 participants have been enrolled to
    date.
         Developed a mechanism for all Duke investigators to access
    statistical expertise to improve research quality. The increased
    accessibility of these resources helped to facilitate a change in
    institutional culture regarding the value and importance of formal
    quantitative expertise, which is increasingly critical to ensure that
    research results are reproducible.

        Question 7. In your hearing you testified that you were unable to
    undertake as much as 70 percent of the clinical trial work that was
    proposed because industry companies were not willing to agree to DCRI's
    requirements that all data from the trials be housed at DCRI. Why is it
    important that academic research centers maintain control of study data
    and why are some industry companies unwilling to agree to this
    requirement?
        Answer 7. Under my leadership, the DCRI never and would never
    participate in coordinating a multi-site clinical trial without a
    contractual agreement that specifies the right to full access to the
    study data and to conduct its own analysis and interpretation of the
    data.
        The independent role of the academic in the analysis and
    interpretation of the study data is an important element of the
    research enterprise. I have been a strong and consistent advocate for
    transparency through both www.ClinicalTrials.gov and the creation of
    access through independent coordinating centers. As discussed below,
    when industry controls the questions asked by the study, the data
    collection, and the analysis, there is significant bias because of the
    direct financial interest involved. Although academic investigators may
    have other biases, when they are conducting research in the context of
    their role as a faculty member in a university, there is a contract
    between the university and the industry sponsor, which includes the
    independent right to publish. This provides a balancing factor that I
    believe is important to ensure that the questions addressed by clinical
    trials are in the interest of patients, the data collected are not
    biased and the analyses have a perspective independent of the sponsor.
    The important role of patients and their advocates is discussed in the
    response to question 15.
        Unfortunately, the majority of multi-site, industry-sponsored
    clinical trials do not have an academic coordinating center. Individual
    research sites that do not have coordinating center functionality do
    not have copies of the entire database, and if they did, they typically
    do not have the expertise to conduct the analyses. Thus, I believe that
    the role of academically based, not-for-profit coordinating centers is
    important to the clinical trials process.
        While most major academic medical centers have some coordinating
    center function, there are only a limited number who are capable of
    conducting large multinational trials like the DCRI. The majority of
    multi-site, industry-sponsored clinical trials are coordinated in-house
    by the sponsor or outsourced by the sponsor to a for-profit contract
    research organization (CRO). In the early years of the DCRI's
    existence, it was common for industry sponsors to be highly resistant
    or even unwilling to allow full access to the study data because of
    their view that, in the event of a negative trial result, it would not
    be in their financial interest for findings to be made public.
        It is now customary for medical journals to require that the
    authors of a manuscript attest that they had full access to the data
    and ability to analyze the data independent of the industry sponsor.
    The recommendations of the International Committee of Medical Journal
    Editors (ICMJE) now state that,

            ``we will not review or publish articles based on studies that
            are conducted under conditions that allow the sponsor to have
            sole control of the data or to withhold publication.'' \8\
    ---------------------------------------------------------------------------
        \8\ International Committee of Medical Journal Editors.
    Sponsorship, Authorship, and Accountability (2007). Available at http:/
    /www.icmje.org/news-and-editorials/update_spon_sep2001
    .html.

        I have been a strong and consistent advocate for transparency
    through both\9\ and the creation of access through independent
    coordinating centers.\10\ The composite of all of these efforts has
    changed the landscape, and industry sponsors are now much more willing
    to agree to independent analysis.
    ---------------------------------------------------------------------------
        \9\ Characteristics of clinical trials registered in
    ClinicalTrials.gov, 2007-10. Califf RM, Zarin DA, Kramer JM, Sherman
    RE, Aberle LH, Tasneem A. JAMA. 2012 May 2;307(17):1838-47. doi:
    10.1001/Jama.2012.3424. PMID:22550198. Compliance with results
    reporting at Clinical
    Trials.gov. Anderson ML, Chiswell K, Peterson ED, Tasneem A, Topping J,
    Califf RM. N Engl J Med. 2015 Mar 12; 372(11):1031-9. doi: 10.1056/
    NEJMsa1409364. PMID:25760355.
        \10\ Eur Heart J. 2010 Apr;31(8):911-7. doi: 10.1093/eurheartj/
    ehp550. Epub 2010 Feb 3. Toward a new order in cardiovascular medicine:
    re-engineering through global collaboration.
        Califf RM, Armstrong PW, Granger CB, Harrington RA, Lee K, Simes
    RJ, Van de Werf F, Wallentin L, White HD; Virtual Coordinating Centre
    for Global Collaborative Cardiovascular Research Organization.

        Question 8. The 2011-14 conflict of interest statements filed by
    you that list the names of all private companies from whom you received
    consulting fees or other funds are publicly available on the Duke
    Clinical Research Institute website. Please explain the policy of DCRI
    regarding submission and posting of these conflict of interest
    disclosures, why that policy exists, and how long it has been in place.
        Answer 8. The DCRI, as part of Duke University, abided by
    University policies. Like most major universities, Duke faculty members
    have the right to participate in private consulting 1 day per work
    week. All consulting must be reported to the University conflict-of-
    interest committee, and these consulting engagements are screened for
    the potential of conflict of interest and conflict of commitment by
    relevant committee members and institutional leaders. All of this
    information is kept within an institutional database to ensure
    followup.
        I decided to begin publicly posting my interactions with industry
    to set an example for transparency, and DCRI created the venue for
    posting. Many DCRI faculty followed suit, but it was not a requirement
    of DCRI policy.

        Question 9. Along with a number of other researchers at Duke
    University you receive consulting payments from industry companies
    through Faculty Connection, LLC. Please describe the purpose of Faculty
    Connection and the services that it performs for its consultant
    partners. Please include a description of the administrative fees and
    how excess administrative fees are used.
        Answer 9. Faculty Connection, LLC was established by a group of
    Duke faculty members to provide administrative support for the faculty
    when they participate in consulting activities involving private
    industry. It has expanded over time to include faculty from several
    other institutions with similar needs.
        It is designed to ease and consolidate the administrative burdens
    on individual faculty as they participate in consultation activities
    with industry on personal time and create greater efficiency for their
    work. Among the support it provides is:

         filing administrative paperwork required by the
    University, including summaries to facilitate accurate reporting to
    university conflict-of-interest oversight committees,
         ensuring compliance with legal and ethical requirements,
         negotiating contracts and ensuring that the contracts are
    in compliance with university policy and protect the rights of academic
    faculty to remain independent, and
         billing and accounting.

        Payments for consulting activity are made directly to Faculty
    Connection, which retains 20 percent of the fees for administrative
    overhead (primarily to cover staff salaries), and the faculty member
    receives the remaining 80 percent. Since its inception, Faculty
    Connection has donated the proceeds not consumed by administrative
    costs to Duke University (and Stanford University beginning in 2013) to
    fund research and education activities for trainees.
        In 2014, the following contributions were made by Faculty
    Connection to Duke University and Stanford University:

         $15,000 to the Stanford University Department of Medicine
    Residency Program for house staff research;
         $30,000 to the Duke Clinical Research Institute (DCRI)
    fellowship fund to support current and future fellows including the
    adult cardiology fellows;
         $24,000 to the Duke Department of Medicine for research
    and pilot projects performed by residents and/or house-staff. The main
    purpose of the donation is to help the department encourage and support
    residents as they start their research careers;
         $15,000 to the Duke Department of Pediatrics for research
    and pilot projects performed by residents, house-staff, and trainees to
    support research careers; and
         $4,000 to the Duke Cancer Institute to train and provide
    research opportunities for the residents and or house-staff.

        2013  Contributions to Duke and Stanford Universities totaled
    $115,000.
        2012 Contributions to Duke University totaled $154,000.
        2011 Contributions to Duke University totaled $100,000.
        2010 Contributions to Duke University totaled $ 75,000.

        Question 10. At your hearing you stated that you have a personal
    policy of donating all consulting fees received from industry to
    charitable organizations of your choosing. Is it correct that, not
    including funds paid toward clinical trial work conducted at Duke, all
    consulting fees you have received from industry have been paid to you
    through Faculty Connections and subsequently donated according to your
    long-standing practice?
        Answer 10. Yes, this is correct.

        Question 11. Please list any additional measures that you have
    taken to ensure that the scientific integrity of the clinical trial
    work you have undertaken in your career it is not compromised as a
    result of industry sponsorship and funding.
        Answer 11. In addition to publishing the results of all clinical
    trials I have conducted throughout my career, I have publicly posted my
    Duke conflict-of-interest information since 2006, and donated all
    consulting fees to charity. I have been intimately involved in the
    development of structural and policy changes in the global research
    enterprise to increase transparency and reduce bias in the conduct,
    analysis, and reporting of clinical trials.
        For the past three decades, I have worked with global colleagues
    who are experts in medicine, clinical research methodology, and medical
    ethics to develop new mechanisms to ensure that the data obtained from
    individuals who consent to participate in a human experiment (i.e., a
    clinical trial) are evaluated by parties who do not have a financial
    interest in the success or failure of the treatment under study, and
    who, by virtue of their employment as a faculty member in a university,
    are guaranteed the right to academic freedom. I do not use the term
    ``human experiment'' lightly, because asking someone to volunteer for a
    study carries with it a responsibility to do the best job possible to
    ensure that the trial is conducted properly and that the result of the
    trial will contribute to generalizable knowledge to help future
    patients.
        One such mechanism is the establishment of steering committees for
    an individual clinical trial, comprised of academic investigators from
    multiple institutions and countries, to serve as a collective body to
    interact with the industry sponsor in developing the protocol and
    overseeing the operational conduct of the trial. This approach
    minimizes the influence of any given individual, ensures inclusion of a
    wide range of perspectives and opinions, and provides a formal
    structure for decisionmaking. The steering committee does not include
    representation from the sponsor but may have one or two sponsor
    representatives to ensure effective communication.
        Another mechanism is the use of an independent academically based
    analytical center which is responsible for receiving data collected
    during a trial, ensuring the accuracy of the data, and analyzing the
    data following the conclusion of the trial. These are often referred to
    as Data and Statistical Coordinating Centers. This structure allows the
    database to be maintained by a party external to the industry sponsor
    and for the data to be fully analyzed before the results are shared
    with the industry sponsor.
        A third mechanism is the formation of data monitoring committees,
    comprised of independent experts who oversee the conduct of the trial
    and have access to the data to protect the safety and interests of the
    research participants. I have published significant papers with
    colleagues to improve the function and scientific basis for data
    monitoring committees.\11\
    ---------------------------------------------------------------------------
        \11\ Independent data monitoring committees: preparing a path for
    the future. Hess CN, Roe MT, Gibson CM, Temple RJ, Pencina MJ, Zarin
    DA, Anstrom KJ, Alexander JH, Sherman RE, Fiedorek FT, Mahaffey KW, Lee
    KL, Chow SC, Armstrong PW, Califf RM. Am Heart J. 2014 Aug;168(2):135-
    41.e1. doi: 10.1016/j.ahj.2014.05.003.
        Data and safety monitoring boards: academic credit where credit is
    due? Armstrong PW, Califf RM. JAMA. 2013 Oct 16;310(15):1563-4. doi:
    10.1001/jama.2013.280383. No abstract available. PMID: 24129461
        Issues in regulatory guidelines for data monitoring committees.
    DeMets D, Califf R, Dixon D, Ellenberg S, Fleming T, Held P, Julian D,
    Kaplan R, Levine R, Neaton J, Packer M, Pocock S, Rockhold F, Seto B,
    Siegel J, Snapinn S, Stump D, Temple R, Whitley R. Clin Trials.
    2004;1(2):162-9. Review.
        Liability issues for data monitoring committee members. DeMets DL,
    Fleming TR, Rockhold F, Massie B, Merchant T, Meisel A, Mishkin B,
    Wittes J, Stump D, Califf R. Clin Trials. 2004;1(6):525-31.
    PMID:16279293.
        Monitoring and ensuring safety during clinical research. Morse MA,
    Califf RM, Sugarman J. JAMA. 2001 Mar 7;285(9):1201-5. PMID:11231751.
    ---------------------------------------------------------------------------
        Finally, the formation of a publication committee, which is now
    standard practice at the DCRI and other academic coordinating centers,
    serves as another extremely valuable mechanism for ensuring independent
    decisionmaking in the interpretation and publication of trial results.
    As is the case with steering committees, publication committees provide
    a formal organizing structure for decisions regarding both primary and
    secondary manuscripts, as well as a transparent and inclusive process
    for any investigator to propose an idea for a manuscript and to access
    the data in order to perform the proposed analysis. A representative of
    the industry sponsor is allowed to serve as a member of the committee,
    however, the majority of members must be academic investigators and
    decisions require a majority vote.

        Question 12. Earlier this year, after joining the FDA you removed
    your name from three journal articles published in the Journal of
    Clinical trials that discussed pragmatic cluster randomized trials
    (PCRT). You have previously advocated for using more pragmatic cluster
    randomized trials or pragmatic clinical trials in research. Have you
    previously expressed the theme and ideas contained in these articles in
    published articles and speeches?
        Answer 12. The depiction of my actions with regard to these issues
    was inaccurate. The articles in question were part of a major joint
    project between the NIH Health Care Systems Research Collaboratory
    (``the Collaboratory'') and PCORnet, PCORI's large national network for
    clinical research. I was Principal Investigator (PI) of the
    Collaboratory and co-PI of PCORnet. Together with Professor Jeremy
    Sugarman, distinguished Chair of Medical Ethics at Johns Hopkins
    University, we organized 10 writing teams from the two projects, in
    addition to some outside experts to address ethics and regulatory
    issues that need to be better understood as the United States moves
    toward a ``learning health system'' model. Each team was assigned to
    work on a specific manuscript, all 11 of which (plus one capstone
    summary article) were to appear together in a special issue of Clinical
    Trials (published by the Society of Clinical Trials).
        At the time of my transition to FDA in February 2015, the 11
    manuscripts were moving along nicely, but they were not substantially
    complete. For three of the 11, I had done enough work personally to be
    on the author list. However, upon moving to FDA, it was clear that I
    could no longer devote the effort needed to be acknowledged as an
    author. The rules governing criteria for authorship, which include
    substantive participation throughout the process of revision as well as
    final approval of the manuscript prior to submission, are clearly
    delineated in guidelines published by the ICMJE, to which most peer-
    reviewed medical journals (including Clinical Trials) conform. (Please
    see http://www.icmje.org/recommendations/browse/roles-and-
    responsibilities/defining-the-role-of-authors-and-contributors.html#two
    for details).
        Realizing that I was unable to devote the time needed to represent
    responsibility for the full content of the articles, I worked with the
    co-authors to acknowledge my contribution in writing in each of the
    three articles up until the time I joined FDA--these acknowledgements
    are contained within the respective manuscripts. My commitment to the
    project and the general direction of the body of work is clearly stated
    in the introduction to the series, which I authored along with Dr.
    Sugarman.\12\
    ---------------------------------------------------------------------------
        \12\ Califf RM, Sugarman J. Exploring the ethical and regulatory
    issues in pragmatic clinical trials. Clin Trials 2015;12(5):436-41.
    ---------------------------------------------------------------------------
        In summary, my contributions to the articles are clearly stated in
    the articles themselves, and I am deeply committed to the development
    of appropriate methods for pragmatic clinical trials and fully support
    the body of work represented by the articles. The details of the final
    recommendations are the work of the authors of the manuscripts, and as
    editor of the series it was not my role to agree or disagree with all
    detailed recommendations.

        Question 13. It has been reported that in 2014 you gave a speech to
    healthcare and pharmaceutical stakeholders in which you characterized
    some regulations as a ``barrier'' to innovation in medicine. Please
    provide additional details regarding the speech and explain what you
    meant by this statement.
        Answer 13. I think you are referring to a slide I have used in
    multiple lectures that characterizes regulation as a barrier to
    disruptive innovation.
        This issue is a very important one for people proposing to develop
    new medical therapies. Throughout my career, I have benefited from a
    close relationship with the Fuqua School of Business at Duke and the
    many contacts it brings in the field of health economics and health
    management. Among the many brilliant people I have met is Clayton
    Christensen (``The Innovators Dilemma''), who developed the concept of
    ``disruptive innovation.'' This concept is derived from the study of
    the transformation of industries with the base case being the
    conversion of radios from the vacuum tube to the transistor. The
    concept is that the new product or method initially is inferior but
    lower priced so there is a market for it. This enables innovators to
    iteratively improve their product until it becomes better and supplants
    the old product or method. My purpose in showing this slide in multiple
    lectures is to explain to audiences that often include students,
    trainees in fellowship, and scientists who are not involved in
    development of medical products, why the risk and investment in
    biotechnology is higher than most other industries, i.e., because it is
    a highly regulated industry, which is in fact a necessary barrier to
    protect public health, as discussed below. The amount of capital needed
    is lower and the time to return on investment is shorter in many other
    industries.
        I have never stated, implied, or argued that the barrier should be
    lowered or removed. In fact I do not believe that we should be putting
    inferior medical products on the market, nor do the American people
    want inferior products to be used in medical practice. The belief that
    we should have evidence of benefits and risks before marketing in
    health care has been a driving force in my career and a motivation to
    develop more effective, efficient and unbiased ways of conducting
    generalizable clinical trials and implementing quality systems for
    learning in health care as a focus of my academic and practical work.
        In summary, the purpose of the slide is to point out an issue that
    is motivational for people who want to develop medical products that
    prevent death and reduce disability: there is a requirement to
    demonstrate that your product is safe and effective before you market
    it and that it does not put people at risk compared to the clinical
    care that is currently accessible. This is a good thing and forms the
    basis for the benefit of a strong FDA to make these determinations, and
    it places a special responsibility on innovators to develop the
    evidence base that can ensure the FDA (on behalf of the American
    public) that the product is safe and effective.

        Question 14. Are there particular FDA regulations you believe
    should be modified so that clinical trials can be run more efficiently
    and effectively?
        Answer 14. I do not believe that new FDA regulations are needed,
    but there is a major need for the U.S. system to organize around some
    key principles that can be enunciated through multiple venues,
    including FDA guidances. We are already making substantial progress in
    developing a more efficient and effective approach for the United
    States built on the solid foundation of, among others: FDA's Sentinel
    Initiative and the existing specifications, developed in consultation
    with industry and other stakeholders, for submission of drug and
    biologic applications using common data standards and terminology;
    NIH's HealthCare Systems Research Collaboratory and multiple clinical
    trial networks; the VA's networks and million veteran cohort; DOD's
    commitment to research in its vast health system; and ONC's progress on
    interoperability.
        The Precision Medicine Initiative is playing a key role as a use-
    case to develop appropriate approaches to patient volunteers, provider
    participation, data standards, interoperability and ethics. My overall
    views on these issues are described in publications #1204,\13\
    #1162\14\ and #1133\15\ on my CV. Much of this work is proceeding
    through the work of the NIH-FDA Leadership Council.
    ---------------------------------------------------------------------------
        \13\ Anderson ML, Califf RM, Sugarman J, participants in the NIH
    Health Care Systems Research Collaboratory Cluster Randomized Trial
    Workshop. Ethical and regulatory issues of pragmatic cluster randomized
    trials in contemporary health systems. Clin Trials. 2015 Jun;12(3):276-
    86. PMCID: PMC4498459.
        \14\ Sugarman J, Califf RM. Ethics and regulatory complexities for
    pragmatic clinical trials. JAMA. 2014 Jun 18;311(23):2381-82. PMID:
    24810723.
        \15\ Califf RM, Platt R. Embedding cardiovascular research into
    practice. JAMA. 2013 Nov 20;310(19):2037-38. PMID: 24240926.

        Question 15. What are your ideas about how we can improve the
    design of clinical trials to ensure we understand the effect of new
    drugs and devices on subpopulations of patients, including women,
    children, and racial and ethnic minorities?
        Answer 15. A rational approach to medical product development would
    be to include the relevant populations for whom the product is intended
    to be used. This would include women, children, minorities and
    populations identified by biological, social, or preference
    characteristics.
        Unfortunately, it is well-documented that clinical trial
    populations typically are not representative of the population intended
    to be treated, with particular deficits in the categories mentioned
    above. The solutions include consideration of the following approaches,
    and this issue is a high priority:

         The issue of designing, conducting, and analyzing clinical
    trials to produce results to give patients, caregivers, providers, and
    policymakers adequate information about benefits and risks of
    therapeutic interventions in specific individual patients and
    populations with similar characteristics is a major challenge.
    Improving the situation will require a comprehensive, multifaceted
    approach using a concept known as ``quality by design.'' \16\ The
    general tools consist of small focused trials in people with common
    characteristics using clinical and molecular markers and, on the other
    extreme, very large trials using electronic health records and quality
    registries to provide a low-cost data system. Each circumstance is
    somewhat different and carefully planned trials to most efficiently
    answer the important questions are needed. All of this needs to occur
    in the context of more efficient networks of research sites with
    standard procedures and common data standards and terminology.
    ---------------------------------------------------------------------------
        \16\ Please see http://www.ctti-clinicaltrials.org/what-we-do/
    investigational-plan/qbd-qrm for further details about this approach.
    ---------------------------------------------------------------------------
         A major new advance is the direct involvement of patients,
    their caregivers, and advocates in every aspect of the clinical trials,
    including prioritization of questions, protocol design, quality
    oversight and analysis and dissemination. FDA is already committed to
    more inclusion of patients in the effort, and as it evolves, it is
    already clear that trials are improving as result. The rapid advance of
    social media is enabling inclusion of patients in a direct and
    interactive manner, which has the potential for enormous improvement in
    generalizable enrollment into studies.
         The use of biomarkers and other patient characteristics
    can enable small, focused trials to evaluate particular populations.
    When viewed in the overall context of product development this approach
    will be a critical tool, and the Precision Medicine Initiative will
    accelerate the potential.
         On the other hand, the use of integrated health systems,
    community clinics, and community engaged research in combination with
    electronic health records and registries built on informed consent and
    developed to improve quality offer the realistic opportunity to do much
    larger trials with more generalizability at a dramatically lower cost.
    Considerable work on this approach is already underway at FDA and it
    will accelerate in the upcoming year. Before joining FDA, I was the PI
    of the NIH-funded Healthcare Systems Research Collaboratory and Co-PI
    of the (PCORnet), both of which are developing the concepts and
    operations for this transformation of the clinical trials system (see
    https://www.nihcollaboratory.org/about-us/Pages/default.aspx).
         In conjunction with industry for drugs and biologics,
    there is an agreement to submit data using common data standard over
    the next several years. This will enable FDA to look at inclusion of
    relevant populations much more effectively. Similar approaches are
    underway for devices.
         Two special populations merit consideration: pregnant
    women and the elderly.

              We know little about the proper dosing of drugs in
            pregnant women, and the success of the treatment of congenital
            disorders, serious genetically determined diseases and chronic
            diseases of childhood has dramatically increased the number of
            pregnant women who must be treated during pregnancy.
              The elderly are the most rapidly growing segment of
            our population but little is known about medical products in
            people over age 80, for example. FDA can help by calling
            attention to these efforts and working with industry sponsors,
            investigators and NIH to improve their inclusion in trials.

        Question 16. With respect to pediatric research, what else can be
    done to ensure that providers and parents have the information they
    need to help them better understand how a child will respond to a
    particular treatment? Do you have specific ideas about how new products
    can be developed to meet the unique needs of children?
        Answer 16. The Best Pharmaceuticals for Children Act (BPCA) and the
    Pediatric Research Equity Act (PREA) were passed by Congress to
    encourage the study of drugs and biological products in pediatric
    patients in order to provide adequate pediatric use information in drug
    and biological product labeling. FDASIA made permanent BPCA and PREA.
        Prior to the passage of the laws, almost 80 percent of products
    contained no pediatric-specific information. Since the passage of these
    important laws, FDA has approved almost 600 labeling changes to
    incorporate pediatric information. In addition, under PREA, sponsors
    submit pediatric study plans early enough in development to minimize
    the time from approval of a drug in adults to the addition of pediatric
    information.
        It should be noted that some products intended for treatment of
    rare disorders, including rare disorders in children, can receive
    designation under the Orphan Drug Act, and as such, not be required to
    comply with requirements under PREA. However, the Orphan Drug Act is
    also an important and successful law that provides separate incentives
    for the development of products used to treat rare diseases, including
    rare pediatric cancers.
        Additionally, under BPCA, the Pediatric Subcommittee of the
    Oncologic Drugs Advisory Committee (ODAC) was directed to evaluate, and
    to the extent practicable, prioritize new and emerging therapeutic
    alternatives to treat pediatric cancer. Products under development for
    use in adult cancers are brought forward for discussion by the
    Pediatric Subcommittee of the ODAC after consideration by pediatric
    experts within FDA; advice and recommendation of outside pediatric
    oncology experts; and pediatric oncology advocacy groups.
        If you or your HELP Committee colleagues have particular ideas in
    mind to further advance therapies for pediatric populations, we would
    be happy to discuss them.

        Question 17a. There have been media reports discussing concerns
    with the Rocket-AF trial you led while at Duke and that ultimately
    resulted in FDA approval of the anti-coagulent drug Xarelto in 2011.
        Please describe the design process for the study, and the role of
    the Steering Committee in determining the once-a-day dosage of Xarelto
    for purposes of the Rocket-AF trial.
        Answer 17a. Like other large, international Phase 3 trials in this
    field, the international Steering Committee and Executive Committee
    consisted of dozens of experts in cardiology, thrombosis,
    anticoagulation, and primary care. A large number of studies already
    had been conducted with rivaroxaban (Xarelto) when the design of the
    Phase 3 trial came into focus.

        Question 17b. The Rocket-AF trial sought to determine if Xarelto
    (Rivaroxaban) once a day was non-inferior to Coumadin (Warfarin), a
    drug that has been on the market for many years. When the results of
    the trial are examined on a country-by-country basis is there any
    country where Xarelto was found to be inferior to Coumadin?
        Answer 17b. There was no significant heterogeneity of treatment
    effect for the comparison of rivaroxaban and warfarin across countries
    included in the trial. This is assessed routinely in large
    international trials using standard methods and closely evaluated by
    FDA. The results for regions of the world are displayed in the Appendix
    to the primary publication in the NEJM (please see reference #1039\17\
    in the enclosed CV; the relevant data can be found in the figures on
    pages 21-23 of the appendix, available at http://www.nejm.org/doi/
    suppl/10.1056/NEJMoa1009638/suppl_file/nejmoa1009638_appendix.pdf).
    ---------------------------------------------------------------------------
        \17\ Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W,
    Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC,
    Paolini JF, Berkowitz SD, Fox KAA, Califf RM, ROCKET AF Investigators.
    Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl
    J Med. 2011 Sep 8;365(10):883-91. PMID: 21830957.

        Question 17c. Is data from the Rocket-AF trial publicly available?
        Answer 17c. FDA review and sponsor submissions are available, and
    27 publications are already available with another 12 in press or other
    stages of review/development, and several dozen more in the planning
    stage. The trial results are also reported in www.ClinicalTrials.gov
    (NCT # NCT00403767; https://clinicaltrials.gov/ct2/show/
    NCT00403767?term=NCT00403767&rank=1). These have extensive tables of
    baseline characteristics, outcomes, and adverse events. Study sponsor
    Johnson & Johnson is working with Yale University through an open-
    science project called YODA (http://yoda.yale.edu/) that will make the
    raw data available upon request in the future.

        Question 17d. In the 4-years since Xarelto has been on the market
    have post-market surveillance studies been conducted, and what have
    they shown regarding the safety and efficacy of Xarelto?
        Answer 17d. Over 190 clinical trials are now registered in
    www.ClinicalTrials.gov involving rivaroxaban. In addition, numerous
    registries and observational studies have been undertaken. Finally, FDA
    uses post-marketing surveillance, including its Sentinel Initiative, to
    monitor the safety of marketed drugs, but as noted in the article by
    Dr. Ellis Unger (``Atrial fibrillation, oral anticoagulant drugs, and
    their reversal agents'' http://www.fda.gov/Drugs/NewsEvents/
    ucm467203.htm), the safety of rivaroxaban has been a special area of
    interest. No signals have been announced by FDA, and the article offers
    reassurance.
                                senator sanders
        Question 1. I believe that when 35 million Americans are unable to
    afford to fill their prescriptions, as is the case now in this country,
    that constitutes a public health crisis. And FDA is a public health
    agency; as you noted in your testimony, ``a successful FDA is a
    critical factor for better public health.'' In order to address a
    public health crisis of this magnitude, we need to do far more to make
    sure medications are affordable for all Americans. The best drug in the
    world won't save someone if they cannot afford to take it.
        In your testimony you said that the United States does have the
    capability to import prescription drugs but that it would add
    additional costs and systems would have to be put in place to make it
    work. Please elaborate on what you will do, as Commissioner, to work
    with President Obama and Secretary Burwell to implement current law and
    begin importing prescription drugs from Canada. In case you are not
    aware, President Obama said in 2011,

              ``Canada and Mexico are bulk purchasers of--drugs, so they
            negotiate much cheaper drug prices with the drug companies. We
            still don't do that, and I actually think it's something we
            should do--it would save us money.''

        He added, ``It may be that importation is still something we should
    look at in terms of further lowering the price of drugs.''
        If you will not commit to importing prescription drugs from Canada
    at this time, please explain how it is possible that FDA can safely
    oversee the importation of millions of food and cosmetic products
    including vegetables, seafood, and infant formula that Americans ingest
    every day from dozens of countries--and yet FDA cannot take steps to
    import any prescription drugs from Canada.
        Answer 1. FDA oversees the products it regulates including food,
    drugs, and medical devices through the provisions in the FD&C Act,
    which includes a number of more recent congressional authorities,
    including FSMA, FDASIA, and DQSA. These authorities establish differing
    systems of oversight to monitor manufacturers, producers, and growers
    of FDA-regulated goods, depending on the FDA-regulated product. For
    example, prescription pharmaceuticals receive a facility inspection
    prior to marketing to ensure the product was manufactured in compliance
    with FDA's good manufacturing practice standards. Drugs from foreign
    sources that are not FDA-approved nor have such an inspection do not
    have the assurance of safety, effectiveness, and quality as drugs
    subject to FDA oversight.
        Drugs that are not FDA-approved nor manufactured in a facility
    inspected by FDA do not have the assurance of safety, effectiveness,
    and quality as do drugs subject to FDA oversight. There have been
    documented incidences of non-FDA-approved imported drugs found to be
    contaminated, counterfeit, containing varying amounts of active
    ingredients or none at all, or containing different ingredients than
    the FDA-approved product. Moreover, FDA would not be able to make
    safety and quality determinations for prescription drugs offered for
    import into the United States that have not gone through the U.S.
    regulatory process. In fact, FDA evaluation of non-FDA-approved
    imported drugs revealed that while nearly half of imported drugs
    claimed to be Canadian or from Canadian pharmacies, 85 percent of such
    drugs were actually from different countries. Typically, these products
    are smuggled into the United States after being transshipped to third-
    party countries in an effort to avoid detection and create an
    appearance of coming through countries that consumers may find
    trustworthy. Through FDASIA Title VII and the Drug Supply Chain
    Security Act, Congress has recognized the need to bolster this closed
    drug distribution system. Authorizing importation would compromise the
    closed drug distribution system in the United States and undermine
    these laws, thus making it easier for unapproved drugs, which may
    include counterfeit or other substandard drugs, to reach American
    patients putting their treatment at risk. FDA is concerned that the
    risks of unapproved products from foreign sources outweigh any
    potential cost savings. We are also concerned that adverse events
    flowing from importation of such unapproved products could lead to
    diminished confidence in FDA-approved products.

        Question 2. According to a 2013 CDC study, about five million
    Americans import medication for personal use in order to reduce their
    drug costs. Will you continue FDA's current personal importation
    policy?
        Answer 2. The policy referred to in the question is not based on
    considerations of whether the importation of drugs for personal use is
    to reduce drug costs. Congress charges FDA with ensuring the safety and
    effectiveness of drugs sold in the United States. The FD&C Act
    prohibits the interstate shipment (which includes importation) of
    unapproved new drugs. Unapproved new drugs are any drugs, including
    foreign-made versions of U.S.-approved drugs, which have not been
    approved by FDA for marketing in the United States. Certain Internet
    websites have stated that personal importation of up to a 90-day supply
    of prescription medications is legal. This statement is not true.
        FDA drug approvals are manufacturer-specific, product-specific, and
    they include many requirements relating to the product, such as
    manufacturing location, formulation, source and specifications of
    active ingredients, processing methods, manufacturing controls, and
    container/closure system. The drugs must be produced in FDA-inspected
    facilities. These facilities, and the drugs produced in them, are
    currently covered by the U.S. regulatory system. When individuals
    import unapproved drugs directly from foreign sources, they bypass the
    protections provided by FDA's drug approval process.
        We must emphasize that from a public health standpoint, importing
    unapproved prescription drugs for personal use is a potentially
    dangerous practice. Neither FDA nor the American public have any
    assurance that unapproved products from foreign sources are effective,
    safe, or produced under current Good Manufacturing Practices (cGMP).
    Unapproved products may not have been stored under proper conditions,
    or may not be the real product. Foreign unapproved drugs may be
    contaminated, sub-potent, super-potent or counterfeit. In addition,
    some foreign drug outlets offer to dispense prescription drugs without
    a physical examination, bypassing the traditional doctor/patient
    relationship. As a result, patients may receive inappropriate
    medications because of misdiagnoses, fail to receive appropriate
    medications or other medical care, or take a product that could be
    harmful or fatal if taken in combination with other medicines. The
    personal importation policy is explained in full on FDA's website at
    http://www.fda.gov/downloads/drugs/guidancecompliance
    regulatoryinformation/importsandexportscompliance/ucm297909.pdf.

        Question 3. If a drug company has evidence that a drug is more or
    less safe than what is indicated on the label, then that company should
    submit this new information to FDA and, if warranted, request a change
    in their label. However, FDA proposed a guidance last year on the
    distribution of medical publications that lets sales representatives
    for drug companies talk to doctors and hand out articles saying their
    drugs are less dangerous than FDA labeling says they are. Do you agree
    or disagree with this?
        Under no circumstances should the pharmaceutical industry's
    financial interests come before patient safety. It is my hope that you
    believe--and will commit--to working with FDA to revise this draft
    guidance and reiterate that companies should not be able to promote
    drugs using different risk information than what they provided to the
    agency. When new scientific information about a drug's risk is
    determined, the company should inform FDA and, if appropriate, pursue a
    label change.
        Answer 3. Under FDA's regulations, drug companies are responsible
    for updating their approved labeling, when new information becomes
    available that causes the labeling to become inaccurate, false, or
    misleading. Nothing in FDA's draft guidance, ``Distributing Scientific
    and Medical Publications on Risk Information for Approved Prescription
    Drugs and Biological Products--Recommended Practices,'' is intended to
    change companies' existing obligations to update their labeling to
    accurately reflect what is known about the safety profile of the drug,
    to ensure that the labeling is not false or misleading, or for other
    reasons.
        As stated in the draft guidance, FDA recognizes that the safety
    profile of a drug evolves throughout its life cycle as the extent of
    exposure to the product increases, and that it can be helpful for
    health care practitioners to receive significant new information about
    a risk identified in the labeling of an approved product in a timely
    manner. Accordingly, FDA issued the draft guidance to provide
    recommendations for drug companies that choose to distribute new risk
    information in the form of a reprint or digital copy of a published
    study. FDA's proposed recommendations are intended to help ensure that
    new risk information meets appropriate standards for reliability and is
    presented with appropriate disclosure of its limitations and with the
    approved labeling.
        The guidance was issued in draft to enable public comment on the
    proposed recommendations. FDA reviews the comments it receives on draft
    guidances to inform preparation of final versions of guidance
    documents. I will work with FDA on these efforts, including efforts to
    revise the guidance as appropriate.

        Question 4. On October 6, 2013, the Washington Post published an
    article, ``Pharmaceutical firms paid to attend meetings of panel that
    advises FDA, e-mails show,'' documenting FDA's convening a panel
    (IMMPACT), on the clinical testing of painkillers, a multibillion
    market in the United States, and charging pharmaceutical companies
    $25,000 to participate (``pay-to-play''). Despite NIH's warning that
    these payments would give the appearance that the panel was ``paid for
    by a few large pharmaceutical firms who are assumed to be influencing
    the outcomes,'' FDA proceeded with the private meeting. The opioid
    epidemic has only worsened since these meetings; according to CDC, the
    death rate from drug overdose in the United States has more than
    doubled since 1999. In light of FDA's history blurring conflict of
    interest lines, especially when it comes to relationships with the
    industries it regulates, and even in cases with significant public
    health ramifications such as a panel on opioids where transparency
    should have been maximal, will you commit to prohibiting any FDA
    participation in ``pay-to-play'' meetings in the future? If you decline
    to make this commitment, please explain why and provide examples of
    meetings FDA may convene where private, pay-to-play meetings are both
    necessary and justified.
        Answer 4. Your question refers to FDA involvement in the Analgesic,
    Anesthetic, and Addiction Clinical Trial Translations, Innovations,
    Opportunities, and Networks (ACTTION), a partnership between the
    University of Rochester, academia, FDA and other government agencies,
    industry, professional organizations, patient advocacy groups,
    foundations, and philanthropic organizations. Its goal is to streamline
    the development process for new analgesic drug products for the benefit
    of public health.
        ACTTION is one example of the numerous public-private partnerships
    in which FDA participates. These partnerships bring together expertise
    from all areas of drug development, including academia, government
    agencies and pharmaceutical companies, for constructive dialog and
    information sharing. Collaborations such as these, including those
    falling under the Agency's Critical Path initiative, play important
    roles in identifying and addressing knowledge gaps, public health
    questions, and unmet medical needs that plague many therapeutic areas.
        They provide a forum in which FDA representatives and external
    stakeholders can collaborate to share their considerable expertise and
    respective views, which can play an important role in streamlining and
    fostering innovation in drug development. Both the IOM and the
    President's Council of Advisors on Science and Technology have called
    for the development of additional consortia to address areas of unmet
    medical need.
        FDA takes the concerns raised about IMMPACT and ACTTION and other
    public-private partnerships very seriously. The Agency has conducted
    in-depth reviews of those specific collaborations, and has not found
    evidence that FDA officials engaged in any inappropriate behavior.
    Although FDA's PPPs produce many scientific and public health benefits,
    the credibility of FDA's public health decisions related to PPP efforts
    depends on public confidence that those decisions are impartial and
    science-based. To maintain that credibility, FDA PPPs should not create
    an opportunity for unfair access to FDA, undue influence on the
    Agency's decisions, or their appearance. FDA is currently drafting
    procedures to ensure that such collaborations are not influenced by
    conflicts of interest or the appearance of such conflicts.

        Question 5. Since your arrival at FDA in January\18\ 2015, the
    transparency of FDA deliberations regarding approvals for cardiac
    drugs, your area of expertise, appears to have deteriorated. This year,
    FDA approved two new drugs for heart failure, Entresto and Corlanor
    (Entresto approval letter) (Corlanor approval letter) without exposing
    them to public scrutiny at advisory committee meetings despite both
    drugs having publicized suspicions of safety problems, e.g.,
    Alzheimer's disease for Entresto (Wall Street Journal) and higher
    mortality for Corlanor (Corlanor label). While FDAAA requires the
    action packages for new drugs to be posted on the FDA website within 30
    days, FDA did not post the action package for Corlanor--approved on
    April 15--until November 20, more than 6 months later. FDA did post the
    action package for another recently approved cardiac drug, Savaysa, but
    then the medical reviews disappeared from the action package several
    months later and are still missing. For each of these cases, please
    explain why FDA did not comply with the laws under which it is supposed
    to operate and please describe your knowledge of or involvement with
    these cases.
    ---------------------------------------------------------------------------
        \18\ Original question stated ``January,'' however, Dr. Califf
    actually arrived at FDA in February 2015.
    ---------------------------------------------------------------------------
                              advisory committees
        Answer 5. Advisory Committee meetings are not required for all
    applications. By long-standing practice, FDA convenes Advisory
    Committees as warranted. For reasons explained below, FDA chose not to
    convene advisory committee meetings to consider these two new drug
    applications (NDAs).
        Entresto is a combination of two drugs: sacubitril and valsartan.
    Sacubitril is a new molecular entity, whereas valsartan has been
    marketed for many years. The company provided a conventionally designed
    study with typical cardiovascular endpoints. The study was well-
    executed, and the clinical benefit was clear, with 20 percent
    reductions in both hospitalizations for heart failure and
    cardiovascular mortality, and a 16 percent reduction in all-cause
    mortality.
        Sacubitril poses a theoretical risk for central nervous system
    toxicity, based on its mechanism of action. The drug was found to
    affect beta-amyloid protein levels in the spinal fluid of animals and
    humans. Beta-amyloid is the protein that builds up in the brains of
    patients with Alzheimer's disease, so the finding is noteworthy;
    however, the drug did not affect beta-amyloid in the brains of animals,
    and it is not known whether there would be any effect in humans over
    the long term. No toxicity was observed in the principal study
    supporting approval (8,442 subjects studied over more than 3 years).
    But given the theoretical concerns, the company was given a post-
    marketing requirement to assess the issue further. In light of the
    clear benefits of the drug and what is only a theoretical risk, the
    reviewing division and office deemed approval to be appropriate,
    without the need of convening an advisory committee for discussion.
        The rationale for not convening an advisory committee to discuss
    Corlanor (ivabradine) was similar. In a 6,500-patient trial, Corlanor
    was shown to reduce the combination of hospitalization for heart
    failure and cardiovascular death by 18 percent. There was a trend in
    favor of a lower rate of cardiovascular death on Corlanor, although the
    difference was not statistically significant. As with Entresto, there
    were no controversial issues, and a decision was made not to delay
    approval in order to take the application before an advisory committee.
                              savaysa and corlanor
        Savaysa was approved on January 8, 2015, and the action package for
    the NDA was posted on the web on February 13, 2015. In May 2015, we
    removed the medical officer review section of the action package from
    the web because we received a complaint related to the amount of
    information redacted from this review and needed to reassess the
    redactions. The medical review section of the action package included a
    review that had not been considered by the approving official when the
    approval action was taken. This review had not been considered because
    it was unexpected (filed to the application outside the normal review
    process). It had been written by a medical officer who had not been
    assigned to the Savaysa NDA and who had not collaborated with the
    review team. This unsolicited review was also included as an attachment
    to a review document that was part of the action package for Corlanor,
    which was approved on April 15, 2015. The posting of the Corlanor
    action package was held until the issues related to this unsolicited
    review could be resolved. Now that this unsolicited review has been
    considered and addressed by issuance of a supervisory review memo and
    the disclosure staff has confirmed that any information being withheld
    from these reviews is justified under the Freedom of Information Act,
    we have begun posting this information.

        Question 6. You testified that it is not FDA's role to set the
    prices of drugs. However, FDA's actions can assist drug companies in
    securing high prices for their new drugs. One way that FDA's decisions
    can have an impact: if care in the control arms of trials is
    compromised, as may have occurred, for example, in the following five
    trials: ROCKET AF, CHAMPION PCI, CHAMPION PLATFORM, CHAMPION PHOENIX,
    and PLATO, (such as by delaying clopidogrel administration in the
    control arms of the PLATFORM and PHOENIX trials or POGO's finding that
    the device used in the control arm of the ROCKET AF trial was faulty),
    then the new drug will appear ``superior'' to the old drugs, although
    artificially so. For additional background, see the concerns raised by
    the FDA Medical Team Leader's review at: http://www.fda.gov/downloads/
    AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/
    CardiovascularandRenalDrugsAdvisoryCommittee/UCM385234.pdf.
        A new drug that is ``superior'' to the old drugs may command a
    higher price, while the same drug that is ``non-inferior'' (or not much
    worse than) the old drugs may not. Please explain whether you believe
    this mechanism was active for the five trials and please provide the
    relevant data.
        Answer 6. The labeling for the affected drugs--rivaroxaban
    (ROCKET), cangrelor (CHAMPION studies), and ticagrelor (PLATO)--
    appropriately describes the results of the five trials. These decisions
    and relevant data reviewed are documented in memos available on line at
    Drugs@FDA, a searchable website that contains official information
    about FDA-approved innovator and generic drugs and therapeutic
    biological products..
        It is not clear or established what the relationship is between
    drug prices and efficacy or clinical impact. For example, for patients
    with atrial fibrillation, anticoagulants reduce the risk of stroke by
    some 60 percent. For patients with life-threatening infections,
    antibiotics can be lifesaving. Yet other types of new drugs, such as
    certain cancer treatments, may have relatively small effect sizes but
    be higher priced.
                                 senator casey
        Question 1. I appreciate your answers during the hearing to
    questions about your ability to remain impartial as FDA Commissioner.
    In law, we say that lawyers must not only refrain from impropriety, but
    refrain from any appearance of impropriety. Similarly, as FDA
    Commissioner, how would you, both with respect to your own actions and
    with respect to the rest of the Agency's employees, ensure independence
    and also avoid the appearance of a lack of independence?
        Answer 1. At Duke, I was honored to lead a team of researchers who
    were pioneers and advocates for the expansion of measures to enhance
    the transparency, disclosure, and public discussion of funding sources.
        Prior to joining FDA, I went through a comprehensive screening
    process for conflicts of interest, working closely with HHS staff. I
    hold my FDA colleagues to the same standards to which I hold myself.
    The United States--indeed the entire world--depends on a strong,
    unbiased FDA that can work with industry to advance critical
    technologies, but still make independent determinations to ensure safe
    and effective products. But this activity must adhere to societal
    guidelines and expectations for governing conflict of interest.
    Developing new technologies that revolutionize patient care calls for a
    community of dedicated people across the health care ecosystem. I have
    first-hand experience appropriately collaborating across industry,
    academia, the patient community, and government, which is a critical
    skill in today's science-based regulatory environment.
        Following my appointment as Deputy Commissioner for Medical
    Products and Tobacco, the Office of the Commissioner established a
    process for screening invitations that I receive for speaking
    engagements and other requests for my participation to identify
    potential situations which would require my recusal. A team of
    individuals was convened, including a representative of the Office of
    the Commissioner and the Office of Chief Counsel. These individuals
    have extensive knowledge of my ethics agreement and recusal
    obligations. This team meets on a regular basis (often as frequently as
    weekly) and on an ad hoc basis, as needed. A member of my staff submits
    detailed information regarding specific invitations/requests for my
    participation, and the team determines whether I should be recused. If
    the team has any questions as to whether something is covered by the
    recusal, the HHS Designated Agency Ethics Official's office is
    consulted. The team has a standing teleconference with a representative
    of this office in order to facilitate consultations and determinations.
        If my nomination is confirmed, I understand that I will be subject
    to more extensive recusal obligations under the President's 2009
    Executive order, and accordingly, that additional monitoring procedures
    may be needed.

        Question 2. Fitting combination products, such as products with
    both drug and device components, into the current regulatory framework
    can sometimes be challenging. However, we do not want to miss
    opportunities to innovate with combination products that would advance
    the public health because of regulatory challenges. Dr. Califf, you
    mentioned that FDA would be able to develop a proposal within a year to
    address these challenges. What does FDA envision?
        Answer 2. FDA has found that sponsors face the challenges you
    identify under the existing pathways for device-led combination
    products. Device-led combination products range from simple products
    that pose little risk and address relatively simple treatment needs
    (such as a drug-coated bandage for minor wounds) to complex, riskier
    products intended to address more significant medical needs (such as
    drug-eluting stents). The device program as currently structured,
    however, is sharply divided between 510(k) and PMA pathways. The PMA
    pathway is more akin to the innovator drug and biologic pathways (NDA
    and BLA), generally requiring an independent showing of safety and
    effectiveness. Under the 510(k) pathway, on the other hand, FDA has
    faced challenges in obtaining information critical to evaluating a drug
    or biologic component, and also on ensuring reasonable use of the
    510(k) predicate system.
        FDA believes a new premarket pathway for device-led combination
    products could significantly improve certainty and predictability for
    these products while enabling both protection and promotion of the
    public health. A pathway to achieve these goals would:

         ensure FDA has the tools necessary to assess the risks and
    benefits of device-led combination products,
         direct FDA to base data requirements on the potential
    risks and benefits of the product and what is already known regarding
    the safety and effectiveness of its constituent parts, and
         grandfather combination products that have been cleared
    under 510(k) to date and allow combination products that include the
    same drugs and substantially equivalent devices to rely on these
    grandfathered products as predicates, unless FDA finds that review
    under the new pathway is needed to establish reasonable assurance of
    safety and effectiveness for the product.

        Question 3a. Following up on my question during the hearing, I
    wanted to continue with a question about drug labeling for neonates.
    According to reports from the FDA, up to 90 percent of the drugs used
    in NICUs are used off-label. Independent research estimates that the
    percentage is even higher. As such, the labels for these drugs do not
    include information on dosing, safety or efficacy for neonates. This
    represents a serious gap in effective regulation.
        What are the most commonly used drugs in the NICU and do they have
    FDA-approved pediatric labeling?
        Answer 3a. The top 10 most commonly used drugs in the neonatal
    intensive care units (NICUs), based on a recent study by Hsieh, et al.,
    from Duke University, published in the American Journal of Perinatology
    in 2014, include the following: ampicillin, gentamicin, caffeine
    citrate, vancomycin, beractant, furosemide, fentanyl, dopamine,
    midazolam, and calfactant.
        Of these top 10 commonly used drugs in NICUs, gentamicin, caffeine
    citrate, vancomycin, beractant, calfactant, furosemide, and midazolam
    included dosing information for neonates. Gentamicin and vancomycin are
    antibiotics, beractant and calfactant are surfactant products used to
    treat respiratory distress syndrome, caffeine citrate is used to treat
    apnea of prematurity, midazolam is used for pre-operative/pre-
    procedural sedation, and furosemide is to treat edema, secondary to
    edema-forming states and acute pulmonary edema.
        Pediatric dosing, but not neonatal dosing, is present for
    ampicillin, an antibiotic, and fetanyl, a short-acting analgesic used
    during anesthesia. Dopamine does not have specific pediatric or
    neonatal dosing information.
        Of the most commonly reported medications identified in this study,
    only 35 percent are FDA-approved in the newborn (for more information,
    see the attached publication by Hsieh, et al.). Many of these drugs
    were approved years ago and without the same data to support approval,
    as are required today. For example, furosemide was approved in 1966. Of
    the 409 drugs with pediatric-specific labeling changes between 1997 and
    2010, only 28 included information for use in neonates (7 percent).
    Even more recently, of the 156 drugs with pediatric-specific labeling
    changes since 2012, only nine products were approved for use in
    neonates (6 percent).

        Question 3b. What percentage of drugs used in the NICU are off-
    patent versus on-patent? How has FDA worked with NIH through the BPCA
    NIH program to approve pediatric labeling for off-patent drugs used in
    neonates and what have we learned about the safety and efficacy of
    these drugs?
        Answer 3b. FDA does not formally track the percentage of drugs used
    in the NICU and their current patent status. However, as stated above,
    many of the drugs most commonly used in NICUs were approved many years
    ago and would not be expected to have remaining patent protection.
    Implementation and coordination of the BPCA NIH activities is conducted
    by NICHD's Obstetric and Pediatric Pharmacology and Therapeutics Branch
    (OPPTB). FDA has worked closely with colleagues in NICHD through the
    BPCA NIH program to increase the information to support pediatric
    labeling for off-patent drugs in all appropriate pediatric populations.
    For example, recent pediatric-specific labeling changes, including
    dosing information in neonates, were approved for sodium nitroprusside,
    used to treat hypertensive crisis, and meropenem, an antibiotic,
    included dosing information in neonates. Additionally, FDA meets with
    the NICHD monthly to review progress made toward increasing pediatric
    labeling for off-patent drugs.

        Question 3c. If confirmed, what actions will you consider to ensure
    that therapeutics for neonates are studied in that population so they
    can be used with appropriate safety and effectiveness?
        Answer 3c. FDA has clearly recognized the need to increase efforts
    to develop therapeutics for neonates. In October 2014, FDA convened the
    first Neonatal Scientific Workshop. This workshop was co-sponsored by
    the Critical Path Institute, Burroughs Wellcome, and FDA. The workshop,
    entitled ``Roadmap for Applying Regulatory Science to Neonates,''
    considered the feasibility of the development of a global neonatal
    research consortium, including discussions of the governance structure.
    In May 2015, as a result of discussions initiated at the FDA workshop,
    the International Neonatal Consortium (INC) was launched by Critical
    Path Institute. The INC includes global collaboration including FDA,
    EMA, NIH, neonatal advocacy groups, pharmaceutical companies, academic
    researchers and neonatal nurses. The mission of the INC is to
    accelerate the development of safe and effective therapies for
    neonates. The creation of a global neonatal consortium, dedicated to
    advancing the development of safe and effective therapies for neonates
    is a major achievement and FDA will continue to support this global
    effort.
        In addition, FDA will continue to support increasing the
    availability of safe and effective therapies for neonates through
    efficient, effective implementation of BPCA and PREA.

        Question 4. As you are aware, there has been increasing scrutiny
    over the last 2 years on the safety of certain medical devices. I
    understand from communications with your predecessor that one of the
    challenges FDA can face when the safety of a medical device is called
    into question include a fractured and still quite limited system for
    medical device surveillance. Following up on Senator Murray's question
    at the hearing, from your perspective, what would a robust, proactive
    surveillance system for devices look like to ensure that new safety
    indicators are quickly identified and addressed?
        Answer 4. Medical device post-market surveillance presents unique
    challenges due to the greater diversity and complexity of medical
    devices, the iterative nature of medical product development, the
    learning curve associated with technology adoption, and the relatively
    short product life cycle.
        Although the United States has a robust medical device post-market
    surveillance system, we believe it can be strengthened by developing a
    more integrated national system, now being referred to as the National
    Medical Device Evaluation System (NMDES). This system would not be
    owned or run by FDA; rather, it would be operated through an
    independent public-private partnership and governed by a board with
    representation from the primary medical device ecosystem communities,
    e.g., patients, providers, payers, industry, and government. The system
    would ensure the security and privacy of the information used but would
    not own the data. Data ownership would be retained by the original data
    holder, such as health care systems.
        The FDA's plan to develop NMDES provides a pathway to realizing a
    national system that harnesses novel data sources, modern analytical
    techniques and the participation of all stakeholders to optimize
    patient care. The system is envisioned to be able to develop and
    communicate an evolving understanding of devices' benefits and risks
    throughout their marketed life using high-quality, linked electronic
    health information, identify potential safety signals in near real-time
    from a variety of privacy-protected data sources serving as a safety
    net, reduce burdens and costs of medical device post-market
    surveillance, and facilitate clearance and approval of new devices or
    new uses of existing devices.
        The NMDES evolved out of a vision for a medical device post-market
    surveillance system described in two FDA white papers. The initial
    report, ``Strengthening Our National System for Medical Device Post-
    Market Surveillance,'' was issued in 2012 and provides an overview of
    FDA's medical device post-market authorities and the current U.S.
    medical device post-market surveillance system. The update to the
    report, issued in 2013, details the concrete steps that will promote
    more efficient collection of better and more timely data, helping to
    identify issues more quickly. A multi-stakeholder planning board to
    promote this vision was convened by the Engelberg Center for Health
    Care Reform of the Brookings Institution. In February 2015 the planning
    board issued a report titled ``Strengthening Patient Care: Building a
    National Post-Market Medical Device Surveillance System,'' which sets
    out the key steps to take toward development of a national system for
    development, regulation, and effective use of medical devices, while
    supporting improvements in patient safety and health outcomes. The
    system, which will support the needs of the entire community of
    stakeholders, was renamed an ``evaluation system'' with the release of
    the report ``Recommendations for a National Medical Device Evaluation
    System: Strategically Coordinated Registry Networks to Bridge the
    Clinical Care and Research'' in August 2015. MDEpiNet, a public-private
    partnership, produced this report and is working to build
    infrastructure for the national system and development.

        Question 5. There is mounting evidence documenting the value of
    immunization to protect pregnant women and their newborns from
    infectious diseases, such as influenza and pertussis. In the coming
    years, new maternal vaccines are expected to be developed at a faster
    rate, and to present FDA with a range of new considerations to take
    into account. If confirmed, what will you do to encourage maternal
    vaccine development and ensure timely approval of safe and effective
    maternal vaccines?
        Answer 5. FDA shares the goal of having vaccines available to
    protect pregnant women and their newborns from infectious diseases. To
    help facilitate more optimal development of such vaccines, on November
    13, 2015, we sought advice from our Vaccines and Related Biological
    Products Advisory Committee on appropriate clinical study designs to
    support the safety and effectiveness of investigational vaccines, as
    well as study designs of licensed vaccines that are recommended for use
    during pregnancy to protect newborns in addition to their mothers. FDA
    received helpful advice from the Advisory Committee members on ways to
    advance the development of these vaccines, and is committed to working
    closely with sponsors in this important area.

        Question 6. Specialized nutrition and medical foods are critically
    important to patients with conditions such as phenylketonuria (PKU) as
    well as many other conditions. In this rapidly changing and evolving
    field, what are your goals and priorities for specialized nutrition and
    medical foods? Additionally, while there has been growing level of
    interest and innovation, coverage and reimbursement for these products
    often lag behind new developments. To what extent can FDA work more
    closely with agencies such as CMS to help patients gain better access
    to specialized nutritional solutions?
        Answer 6. FDA recognizes the critical role of medical foods in the
    lives of patients with inherited metabolic disorders such as
    phenylketonuria (PKU). The Agency's goals for medical foods include
    staying abreast of the science in this rapidly evolving field; working
    to ensure the availability of safe and appropriately labeled products
    for patients with inherited metabolic disorders; and providing sound
    guidance to patients, health care providers, and industry.
        For example, a current FDA medical food priority is to address
    stakeholder requests for updated medical foods guidance. FDA
    incorporated the most recent available science in its updated Draft
    Medical Foods Guidance, published in August 2013. We are currently
    considering the comments we received on the draft guidance, along with
    the latest science, as we work to finalize the Medical Foods Guidance.
        FDA also prioritizes communication and collaboration with medical
    food stakeholders on scientific issues. For example, a recent NIH study
    revealed that a medical food intended for a single specific metabolic
    disorder was being inappropriately used to treat patients with a
    combination metabolic disorder, resulting in adverse effects. FDA, NIH,
    and a manufacturer of one such product collaborated on the matter,
    which led to the manufacturer changing their labeling to warn health
    care practitioners against its use for the specific combination
    disorder at issue. The manufacturer and NIH have agreed to continue
    working in partnership to further study the disorder (and other related
    metabolic disorders), with FDA providing any needed regulatory
    knowledge and guidance.
        The advances in medical food research that are critical to patients
    with inborn errors of metabolism are also an important part of FDA's
    Office of Orphan Products Development (OOPD) goals and priorities to
    advance promising products for rare disease patients. OOPD provides
    funding support for clinical studies that advance the development of
    promising medical products for rare diseases, including medical foods
    to manage rare diseases such as PKU. For example, OOPD is currently
    funding a 4-year, Phase 2 PKU medical food study conducted by the
    University of Wisconsin. The $1.5 million dollar study evaluates the
    glycomacropeptide diet with the amino acid diet for PKU patients.
    OOPD's priority on funding the best studies that can further the
    development of medical product for rare disease will advance medical
    food options for patients with inborn errors of metabolism.
        Coverage and reimbursement of specialized nutrition and medical
    foods is outside the scope of FDA's authority, but the Agency is
    committed to work collaboratively with our Federal agency partners and
    with Congress, as appropriate, to help patients with specialized
    nutritional issues.

        Question 7. As you may know, the issue of teens abusing the over-
    the-counter cough suppressant, dextromethorphan (DXM) or ``dex,'' is an
    issue I have been working to address for several years now. Years ago,
    as many as 6 percent of teens aged 13-17 abused dex by drinking cough
    syrup, sometimes as much as a full bottle or more. Since then, many
    stakeholders in the retail, pharmacy and OTC pharmaceutical sectors
    have worked together to establish voluntary restrictions on the sale of
    dex to minors, and to educate parents, educators and medical
    professionals about this problem. These efforts have led to a
    significant decrease in dex abuse, to the current rate of 3.3 percent
    for teens aged 13-17. We know that FDA has long been concerned with
    this effort and held an advisory committee hearing in 2010 on the abuse
    of dex, at which time the Agency suggested the benefit of a statutory,
    nationwide minimum age of 18 for dex purchases. I would ask that you
    continue to work with me on this issue as I continue to pursue a
    legislative solution.
        Answer 7. The Agency has been working with you and your staff, as
    well as your colleagues in the House, on this very important issue. We
    have recently provided updated technical assistance and will continue
    to work with you and your staff moving forward.
                                 senator bennet
        Question 1. Dr. Califf, in the last few years, there have been
    numerous reports on the public health threat of antibiotic resistance.
    Experts warn that unless we take action, we could find ourselves in a
    post-antibiotic era. In such an era, the risk of infection would make
    many elective surgeries too dangerous to justify, where a simple wound
    could turn deadly, or where patients with compromised immune systems--
    those being treated for cancer for example--would not have medicines to
    combat the infections to which they are highly susceptible. Senator
    Hatch and I have introduced the PATH Act, which would create a new
    regulatory pathway for antibiotics to treat potentially fatal
    infections for which there are few or no other options--in essence, the
    drugs we need the most. We have been working closely with the FDA and
    the HELP Committee as we finish our work on the legislation. Can you
    talk about how the PATH Act would work to help encourage the
    development of new, life-saving antibiotics?
        Answer 1. Thank you for your leadership combating the public health
    threat of antibiotic resistance and on the ``Promise for Antibiotics
    and Therapeutics for Health (PATH) Act''. The PATH Act would establish
    in statute an approval pathway for ``limited population'' antibacterial
    drugs.
        We understand that the objective of this pathway is to help
    expedite the development and approval of antibacterial drugs intended
    to treat a serious or life-threatening infection and meet unmet medical
    needs in limited subpopulations of patients. Drugs eligible for this
    proposed pathway could be approved based on streamlined clinical
    development programs showing that the risk-benefit profiles of those
    drugs are appropriate for limited subpopulations of patients with unmet
    medical need, such as patients with serious infections caused by multi-
    drug-resistant organisms, even if the risk-benefit profile would not
    support approval for a broader population.
        A statutory ``limited population'' pathway as proposed would
    provide FDA tools (e.g., a ``limited population'' designation on the
    label, pre-review of promotional materials) to ensure appropriate post-
    approval use of these antibacterial drugs in the indicated sub-
    population and focus on establishing a consistent and predictable
    program for drug sponsors.
        However, it is critical that any legislation be carefully crafted
    so as not to undermine FDA's ability to approve drugs under our
    existing authorities. FDA is focused on balancing the need to encourage
    the development of critically needed antibacterial drugs while ensuring
    that the current FDA drug approval standard is maintained.

        Question 2. What will you do as head of the FDA to ensure that
    medical device implants do not wear out prematurely and that patients
    are given verifiably accurate information on the life of their implant?
        Answer 2. As a complement to its premarket review process, FDA's
    plan to develop a National Medical Device Evaluation System (NMDES)
    provides a pathway to realizing a national system that harnesses novel
    data sources, modern analytical techniques, and the participation of
    all stakeholders to optimize patient care. The system is envisioned to
    be able to develop and communicate an evolving understanding of
    devices' benefits and risks throughout their marketed life using high-
    quality, linked electronic health information, identify potential
    safety signals in near real-time from a variety of privacy-protected
    data sources serving as a safety net, reduce burdens and costs of
    medical device post-market surveillance, and facilitate clearance and
    approval of new devices or new uses of existing devices. A strong NMDES
    will facilitate the ready availability of accurate information about
    implant lifespan and also support the rapid identification of
    problematic implants early in the market life of the device.

        Question 3. As the FDA continues to issue draft guidance for
    comments, can you discuss your process of consulting with health care
    scientific experts? If commenters disagree with the science behind
    draft guidance after sending in a set of comments, are there any other
    opportunities to: (1) address these concerns with FDA directly; and (2)
    better understand why FDA disagrees with their position?
        Answer 3. FDA's Good Guidance Practices (GGPs) regulations (21 CFR
    10.115) lay out the ways in which affected parties may participate in
    the guidance development process and how the Agency goes about
    soliciting input from affected parties.
        FDA has many ways to solicit and receive comments from outside
    stakeholders before, during, and after issuance of guidances. Before
    issuance of a draft guidance document, FDA can seek or accept early
    input from individuals or groups outside the Agency. When a draft
    guidance document is issued, FDA will publish a notice in the Federal
    Register and invite comments. FDA can also hold public meetings or
    workshops during this time and FDA can also present the draft guidance
    to an advisory committee for review at this time. FDA will then review
    any comments received and, when appropriate, incorporate the suggested
    changes into the final guidance document. FDA also can decide to issue
    a revised draft of the guidance document after reviewing comments on
    the draft guidance document. Even after a guidance is finalized, the
    docket remains open and comments can be submitted at any time.
        If affected parties disagree with the science behind a draft or
    final guidance, they are able to suggest that FDA revise the guidance
    or withdraw an already existing guidance by submitting comments to the
    docket.

        Question 4. Under the Biologics Price Competition and Innovation
    Act (BPCIA) of 2009, the FDA was given authority to review and approve
    biosimilars. While the FDA has approved the first biosimilar, many are
    still awaiting final guidance from the FDA on what biosimilars should
    be named, the makeup of their label, and interchangeability with the
    original biologic. When do you expect for this guidance to be released?
        Answer 4. FDA has published the following final guidances related
    to biosimilars: Scientific Considerations in Demonstrating
    Biosimilarity to a Reference Product; Quality Considerations in
    Demonstrating Biosimilarity of a Therapeutic Protein Product to a
    Reference Product; Biosimilars: Questions and Answers Regarding
    Implementation of the Biologics Price Competition and Innovation Act of
    2009; and Formal Meetings Between the FDA and Biosimilar Biological
    Product Sponsors or Applicants.
        FDA has also published the following draft guidances since 2012:
    Clinical Pharmacology Data to Support a Demonstration of Biosimilarity
    to a Reference Product; Reference Product Exclusivity for Biological
    Products Filed Under Section 351 (a) of the PHS Act; Biosimilars:
    Additional Questions and Answers Regarding Implementation of the BPCI
    Act of 2009; and Nonproprietary Naming for Biological Products.
        The Agency is committed to carefully reviewing the comments
    received as we move forward in finalizing the draft guidances noted
    above. Upcoming draft guidances are expected to include: Considerations
    in Demonstrating Interchangeability to a Reference Product; Statistical
    Approaches to Evaluation of Analytical Similarity Data to Support a
    Demonstration of Biosimilarity; and Labeling for Biosimilar Biological
    Products.
        FDA is diligently working to issue guidance on issues that have
    been identified by the FDA and key stakeholders as key topics of
    interest. While the Agency cannot provide a specific timeline for the
    release of any guidance, we continue to provide information to assist
    biological product developers--sponsors/companies--with bringing
    biosimilar and interchangeable products to market. The FDA is
    continuing to clarify its approach to implementation of the BPCI Act to
    further facilitate sponsors' development of biosimilar and
    interchangeable biological products.

        Question 5. Dr. Califf, as you know, there has been an ongoing
    concern about the rising cost of medicines. The Generic Drug User Fee
    Agreement enacted in 2012, gave FDA new resources to ensure the timely
    access to quality generic drugs. Unfortunately, there are estimated to
    be 4,000 generic drug applications still pending approval by the FDA.
    Can you please explain how the Agency is addressing and prioritizing
    these applications?
        Answer 5. Pursuant to the Generic Drug User Fee Amendments of 2012
    (GDUFA), ``backlog'' is a defined term. It means all Abbreviated New
    Drug Applications (ANDAs), ANDA amendments and ANDA supplements pending
    as of October 1, 2012 (the date of enactment). GDUFA was negotiated by
    FDA and Industry and passed by Congress as part of the Food and Drug
    Administration Safety and Innovation Act of 2012 (FDASIA).
        Pursuant to GDUFA, Industry pays FDA certain agreed-upon fees, and
    in exchange FDA agrees to certain quantitative review performance
    goals. FDA's GDUFA goal for the backlog (as defined above) is for the
    Agency to take action on 90 percent of the legacy, pre-GDUFA
    ``backlog'' submissions by the end of fiscal year 2017. We have already
    taken action on 82 percent of the pre-GDUFA ``backlog,'' well ahead of
    schedule to fulfill our negotiated commitment. There were approximately
    2,866 ANDAs in the pre-GDUFA backlog. Many of these submissions were
    long pending when GDUFA started, providing one of the key reasons that
    Industry entered into GDUFA in the first place.
        GDUFA explicitly assumed that Industry would send FDA approximately
    750 new ANDAs each year of the program, an assumption upon which the
    Agency budgeted and planned accordingly. In fiscal years 2012, 2013 and
    2014, Industry submitted 1,103; 968; and 1,473 ANDAs, respectively.
    Given that GDUFA assumed, and industry users fees reflect, a much
    smaller workload, the Agency is striving to take action on all of these
    submissions before the end of fiscal year 2017.
        The status of our pre-fiscal year 2015 workload is detailed below.
    Of the 5,720 total ANDAs that the Agency has received:

         1,316 ANDAs have been approved.
         The Agency ``refused to receive'' (RTR) 226 ANDAs--meaning
    we did not accept them for review because they were not ``sufficiently
    complete to permit a substantive review.''
         422 ANDAs were withdrawn.
           Note: ANDAs that have been approved, RTR'd or withdrawn are no
    longer part of our review workload.
         1,113 ANDAs are ``pending industry.'' This includes:

              846 submissions where FDA issued a Complete Response
            (CR) Letter. A CR Letter lists deficiencies an applicant must
            fix to obtain approval. FDA cannot take further action on these
            846 submissions until the applicant responds to the issues
            raised in the CR Letters.
              It also includes 267 Tentative Approvals (TA). TAs
            reflect the fact that the patent or exclusivity on the new drug
            product hasn't expired, and thus the Agency is barred from
            issuing a final approval, the ANDA is otherwise approvable from
            a regulatory perspective.\19\
    ---------------------------------------------------------------------------
        \19\ Pursuant to the Drug Price Competition and Patent Term
    Restoration Act, often referred to as the ``Hatch-Waxman'' Amendments,
    FDA generally cannot approve a generic until any relevant patents and
    statutory exclusivity on the new drug product expire. For many
    potential first generic ANDAs in our workload, expiry occurs at a
    future date and we cannot lawfully approve them at the time our review
    is complete, though some may be issued a Tentative Approval, as noted
    above.

    ---------------------------------------------------------------------------
         2,643 ANDAs are pending an FDA action.

              7 are pending a filing review to determine whether or
            not they will be accepted or RTR'd.
              498 have been successfully filed, but we have not
            communicated review deficiencies to the applicant concerning
            these ANDAs yet.
              For the remaining 2,138 ANDAs, we have issued at
            least one review communication to applicants. In fiscal year
            2015, we issued over 4,700 communications concerning ANDA
            review deficiencies to industry.

        In summary, out of 5,720 submissions, over 90 percent have been
    approved, RTR'd, withdrawn, are pending industry, or are under active
    review. Applicants are still waiting to hear from FDA on less than 10
    percent of our overall pre-fiscal year 2015 ANDA workload.
        As for prioritization, in August 2014 the Agency's Center for Drug
    Evaluation and Research (CDER) updated its Manual of Policies and
    Procedures (MAPP) entitled Prioritization of the Review of Original
    ANDAs, Amendments, and Supplements. This MAPP, which is publicly
    available, describes how the review of ANDAs, ANDA amendments, and ANDA
    supplements are prioritized.
        FDA considers certain types of ANDAs to be public health
    priorities, and expedites their review accordingly. Specifically, FDA
    considers potential ``first generic'' ANDAs to be public health
    priorities. First generics are the first generic to enter the market
    for a given branded product. Potential first generics are about 15
    percent of our workload. All of them have been tagged as priorities,
    and their review has been expedited. This is true regardless of when
    the ANDA was submitted. In the past 3 years, we have approved hundreds
    of first generics for more than 200 new drug products. FDA also
    considers shortage-related drugs a priority, and expedites their
    review.

        Question 6a. Dr. Califf, we appreciate the FDA's efforts to
    diligently implement Title II of the Drug Supply Chain Security Act and
    are encourage that thus far, implementation of the law appears to be
    progressing across the supply chain. As this implementation moves
    forward, we have the following questions.
        Currently, there are several guidances that are in development such
    as grandfathering, and licensures for 3pls and wholesale distributors.
    What is the status of these items and do you expect FDA will meet the
    statutory deadlines? If not, will FDA provide alternative deadline for
    supply chain stakeholders?
        Answer 6a. As you know, FDA is tasked with developing many
    guidances and regulations to implement the Drug Supply Chain Security
    Act. We are focused on accomplishing these tasks as quickly as possible
    while simultaneously addressing the myriad, complicated issues raised
    by stakeholders and providing guidance to the industry as needed.
    Unfortunately, we have not been able to promulgate the required
    national standards and licensing rules as quickly as we would like
    owing to the complexity and magnitude of the drug supply chain business
    models, the procedural requirements associated with rulemaking, and the
    Agency's limited resources. However, the national standards and
    licensing rules are a priority and we continue to work on them and the
    guidances required by the Act, including the grandfathering guidance.

        Question 6b. Regarding licensure of 3pls and wholesale
    distributors, does FDA have a plan in place for outreach and direction
    to States about: (1) how they should adopt the pending standards and
    (2) how their authority may change due to Federal preemption in this
    area under the Drug Supply Chain Security Act?
        Answer 6b. FDA's outreach includes engagement of State officials,
    and FDA has presented at various meetings hosted by the National
    Associations of Boards of Pharmacy, a group that brings together the
    State Boards of Pharmacy and others responsible for States' licensure
    of wholesale distributors and third-party logistics provider (3PLs).
    Additionally, on November 18, 2015, FDA held an inter-governmental
    working meeting on the Drug Quality and Security Act. At this meeting,
    FDA hosted representatives from the State Boards of Pharmacy and other
    State Officials responsible for licensure of wholesale distributors and
    3PLs. The following issues were discussed: timing and implementation
    issues for States related to the licensing of wholesale distributors
    and 3PLs, what issues State Officials felt clarification would be
    helpful, and how FDA and States can improve collaboration. FDA will
    continue to work with the States as it implements the licensing
    standards under the DSCSA.

        Question 6c. Colorado and many other States run nonprofit drug
    donation programs across the United States, helping get donated drugs
    to uninsured or under-insured patients. In Colorado alone, a nonprofit
    organization called the Supporting Initiatives to Redistribute Unused
    Medicine (SIRUM) has already provided 8,900 prescriptions to needy
    patients. These nonprofits never take ownership or possession of the
    drug. However, current FDA guidance threatens the ability of nonprofit
    drug donation programs and organizations transfer donated medicines to
    affiliates. The Drug Supply Chain Security Act contemplates the idea of
    a nonprofit organization distributing donated medications to
    affiliates. In that case, the transfer of medicines is not considered a
    ``transaction''. Because these nonprofits have a unique structure that
    does not take ownership or possession of the drug product, would the
    FDA be willing to provide technical assistance to these programs to
    ensure that nonprofit drug donation programs around the country can
    continue to provide the thousands of medicines a year to the uninsured
    and the underinsured?
        Answer 6c. FDA continues to conduct outreach and education to many
    stakeholders, in additional to hearing about specific issues related to
    different and complicated business models that present unique
    challenges in implementing the DSCSA. Congress enacted DSCSA to allow
    FDA to implement a robust system to better protect the quality of drugs
    throughout the pharmaceutical distribution supply chain. DSCSA exempts
    from the definition of ``transaction'' (section 581(24)(viii))

            ``the sale, purchase, or trade of a drug or an offer to sell,
            purchase, or trade a drug by a charitable organization
            described in section 501(c)(3) of the Internal Revenue Code of
            1986 to a nonprofit affiliate of the organization to the extent
            otherwise permitted by law.''

        DSCSA also exempts from the definition of ``wholesale
    distribution,''--

              ``the distribution of a drug or an offer to distribute a drug
            by a charitable organization to a nonprofit affiliate of the
            organization to the extent otherwise permitted by law''

    (section 503(3)(4)(F) of the FD&C Act). FDA is examining these issues
    and intends to provide information to stakeholders, as necessary, to
    clarify how charitable donations are treated under DSCSA.
                                senator baldwin
        Question 1a. It is imperative that consumers get the most up-to-
    date, accurate information about medical products to make the best
    health decisions and that the medicines they take are safe. I believe
    that more must be done to improve both transparency and the oversight
    of drug products after they reach the market to ensure safety. For
    example, in 2012, Ranbaxy Pharmaceuticals Inc. issued a voluntary
    recall of lots of their generic version of Lipitor because small glass
    particles were found in certain batches of the product. The company had
    already been under investigation--and later pleaded guilty--for failing
    to conduct proper safety and quality tests of several of its
    manufacturing plants in India since 2008. Further, once Ranbaxy
    announced the recall, the FDA initially issued conflicting public
    statements about the safety of these drug products, confusing patients
    and doctors.
        This raises a number of important issues that I hope the next FDA
    Commissioner will address to fulfill the agency's mission of protecting
    the public health. Specifically:
        Do you believe that FDA needs mandatory recall authority for drugs
    to guarantee that dangerous products are swiftly taken off the market?
        Answer 1a. Yes, FDA needs mandatory recall authority and the Agency
    has repeatedly sought this authority. While it is true that drug
    companies typically issue a recall voluntarily when FDA determines it
    is necessary, absent clear authority for the Agency to require a
    company to issue a recall we often lose critical time negotiating the
    terms of the recall, during which patients continue to be exposed to
    dangerous or ineffective products. Under the current system, a company
    may disagree with FDA as to the need for a recall or the scope of a
    recall. While we work out those matters collaboratively, patients are
    left vulnerable to potentially dangerous products.

        Question 1b. What steps has FDA taken, including with respect to
    internal protocols, to improve its communication to consumers and other
    stakeholders about voluntary drug recalls since 2012?
        Answer 1b. As a matter of policy, FDA will promptly post or issue
    public notification in situations that present an imminent health risk
    to consumers.
        Firms often also issue a public warning, typically in the form of a
    press release. Firms are requested to provide a draft of the press
    release for FDA to review and comment. FDA has developed recall press
    release templates for firms to follow which are posted on FDA's website
    under industry recall guidance: http://www.fda.gov/Safety/Recalls/
    IndustryGuidance/default.htm. FDA may issue its own public warning in
    instances where a firm declines to issue public warning, where a firm's
    public warning is inadequate, or where FDA believes that additional
    warning is needed to inform the public.
        In 2012, the enforcement report, where FDA publishes recall
    information, was automated thereby enhancing availability of recalls to
    the public. Further improvements to this automated process are expected
    in the near future to provide more timely and accurate data to the
    trade and public.
        FDA constantly evaluates its processes to self-identify where
    improvements are needed that serve better the health of the public. As
    part of this process and FDA transparency, FDA created the FDA Track
    Web page where the Agency provides performance metrics on different
    programs the Agency administers.\20\ One of the metrics available at
    the Web page is recall classification timeframes. This is the time it
    takes the Agency to classify a recall once a firm provides the Agency
    with a recall notification and all the pertinent information to
    evaluate the recall.
    ---------------------------------------------------------------------------
        \20\ See http://www.accessdata.fda.gov/scripts/fdatrack/view/
    track.cfm?program=cder&status
    =public&id=CDER-DQC-Percentage-of-recall-classification-meeting-
    timeframe&fy=All.
    ---------------------------------------------------------------------------
        Data reported on the Web page shows how steps taken such as
    increasing the automation of recall classification process and hiring
    of employees, has helped decrease the classification timeframes and
    help maintain a consistent high level of performance. This consistent
    high level of performance allows the Agency to publish recall
    information soon after the recall is classified.
        FDA is conducting a pilot program seeking to expedite notifications
    of human drug product recalls to the public. In addition to the
    information about classified recalls found in the weekly Enforcement
    Report, the Agency will include actions that have been determined to be
    recalls, but that remain in the process of being classified as a Class
    I, II, or III recall.

        Question 1c. Can you please provide an update on how many
    inspections FDA has conducted of domestic and foreign establishments
    and how many adverse findings that resulted in corrective actions,
    since the risk-based inspection schedule for drug facilities was
    enacted in the FDA Safety and Innovation Act of 2012?
        Answer 1c. Following FDASIA passage in 2012, our fiscal year 2013
    and 2014 domestic and foreign human drug inspectional data (GMP-
    related) is as follows.

                      Number of Inspections by Fiscal Year
    ------------------------------------------------------------------------
                                                               2013    2014
    ------------------------------------------------------------------------
    Domestic................................................    1851    1869
    Foreign.................................................     827     993
                                                             ---------------
        Total...............................................    2678    2862
    ------------------------------------------------------------------------
    Fiscal year 2015 data is not yet finalized.

        FDA issues FDA-Form 483s to companies, and an overwhelming number
    of companies undertake satisfactory corrections to the cited
    objectionable conditions. An FDA-Form 483 is issued to firm management
    at the conclusion of an inspection when an investigator(s) has observed
    any conditions that in their judgment may constitute violations of the
    FD&C Act and related acts.\21\ These are confirmed during the next
    scheduled inspection, or in an accelerated re-inspection. While
    corrections to specific citations are routinely corrected, FDA at times
    finds that problems recur, and additional interventions are necessary.
    These firms are reflected in our Import Alert, Injunction, and Seizure
    data from fiscal year 2013, 2014, and 2015, which is as follows.
    ---------------------------------------------------------------------------
        \21\ http://www.fda.gov/ICECI/Inspections/ucm256377.htm.

                               Data by Fiscal Year
    ------------------------------------------------------------------------
                                                  2013    2014       2015
    ------------------------------------------------------------------------
    Injunction.................................       5       1            3
    Seizure....................................       1       2            1
    Import Alerts..............................     146     101          144
    Warning Letters............................      86      94     Data not
                                                                         yet
                                                                   available
    ------------------------------------------------------------------------
    In addition, Warning Letter Closeout data is available at: http://
      www.accessdata.fda.gov/scripts/warningletters/
      wlPSearchResult.cfm?qryStr=&sortColumn=12+desc&Go=Go&_1_issueDt=&_2_is
      sueDt=&company=&subject=&Poffice=&hasResponseLetter=Both&hasCloseoutLe
      tter=Yes&recsPerPageDef=500.

        Question 2. Medical foods play an important role in meeting the
    distinct nutritional requirements for patients with certain diseases
    and conditions. For example, medical foods are medically necessary for
    children and adults living with phenylketonuria (PKU), an inherited
    metabolic disorder that is characterized by the inability of the body
    to process the essential amino acid phenylalanine. I am encouraged by
    the FDA's past work in recognizing medical foods and their role in
    managing disorders such as PKU, and it is critical that patients and
    providers continue to have access to the latest safe treatments.
        What more can the FDA do to apply the most recent advances in
    nutrition science to improve health outcomes for patients with PKU and
    other diseases?
        Answer 2. FDA recognizes the critical role of medical foods in the
    lives of patients with inherited metabolic disorders such as
    phenylketonuria (PKU). FDA continues to work to ensure medical food
    products are safe and appropriately labeled so that medical
    practitioners are able to make informed decisions about the best care
    of their patients, leading to overall improved health outcomes. We are
    committed to staying abreast of new science that emerges concerning
    these disorders and working with other stakeholders to improve health
    outcomes for affected patients.
        As an example, a recent NIH study revealed that a medical food
    intended for a single specific metabolic disorder was being
    inappropriately used to treat patients with a combination metabolic
    disorder, resulting in adverse effects. FDA, NIH, and a manufacturer of
    one such product collaborated on the matter, which led to the
    manufacturer changing their labeling to warn healthcare practitioners
    against its use for the specific combination disorder at issue. The
    manufacturer and NIH have agreed to continue working in partnership to
    further study the disorder (and other related metabolic disorders),
    with FDA providing any needed regulatory knowledge and guidance.
        FDA has also incorporated the most recent available science in its
    updated Draft Medical Foods Guidance published in August 2013. We are
    considering the comments we received on the draft guidance, along with
    the latest science as we work to finalize the Medical Foods Guidance.
        Advances in medical food research are critical to patients with
    inborn errors of metabolism and an important part of FDA's Office of
    Orphan Products Development (OOPD) rare disease mission. OOPD provides
    funding support for clinical studies that advance the development of
    promising medical products for rare diseases, including medical foods
    to manage rare diseases such as phenylketonuria (PKU). For example,
    OOPD is currently funding a 4-year Phase 2 PKU medical food study
    conducted by the University of Wisconsin. The $1.5-million study
    evaluates the glycomacropeptide diet with the amino acid diet for PKU
    patients. We welcome competitive grant applications that will further
    the evaluation of recent medical food research to provide better
    medical food options for patients with inborn errors of metabolism.

        Question 3. Routine screening for social and emotional distress, or
    ``distress screening'', is a key recommendation of the 2008 Institute
    of Medicine report, Cancer Care for the Whole Patient: Meeting
    Psychosocial Health Needs.\22\ According to the report, up to 43
    percent of cancer patients experiences psychosocial distress, which
    negatively impacts both quality of life and long-term survivorship
    rates. Distress and lack of social support services also contributes to
    low clinical trial participation rates among eligible patients, as well
    as decreased retention once the trials begin.
    ---------------------------------------------------------------------------
        \22\ Institute of Medicine (US) Committee on Psychosocial Services
    to Cancer Patients/Families in a Community Setting; Cancer Care for the
    Whole Patient: Meeting Psychosocial Health Needs, National Academies
    Press (US); 2008; http://www.ncbi.nlm.nih.gov/books/NBK4015/.
    ---------------------------------------------------------------------------
        What role can distress screening play in improving the efficiency
    of the clinical trials through recruitment and retention? In what ways
    can the FDA incentivize increased use of distress screening and support
    services for clinical trial participants, especially in oncology
    trials?
        Answer 3. We support excellence in patient-centered clinical care,
    in standard practice as well as clinical trials. FDA agrees that
    psychosocial distress can be an important issue for cancer patients and
    that identifying and providing services for cancer patients with
    increased levels of psychosocial distress can be a valuable component
    of routine clinical practice.
        If sponsors wish to pursue these services within the context of a
    clinical trial, these are issues relevant to an institutional review
    board's review of the informed consent process and we would be willing
    to work with stakeholders as appropriate.
                                 senator murphy
        Question 1. The passage of the Food Safety Modernization Act (FSMA)
    shifted the focus of food safety regulations from a crisis-management
    approach to a preventative model that seeks to identify risks and put
    policies and procedures in place to mitigate those risks.
        Following FSMA's passage, the FDA was required to release and
    subsequently implement a total of seven new food safety regulations.
    Two of these regulations are particularly important for Connecticut
    farmers--the preventive control for human food and the produce rule.
        I commend the FDA for taking a collaborative, thoughtful, and
    thorough approach to finalizing regulations under FSMA. As we move
    forward, it is critical Congress fully fund the FDA's budget request,
    particularly the $109.5 million increase in dedicated funding this year
    to implement FSMA. Fully funding FSMA is not only important to ensure a
    reliable and safe food supply, it is critical for ensuring farmers,
    producers, processers, and stakeholders can depend on an engaged and
    responsive regulator.
        Connecticut is not a big agricultural State, but since 1982 there
    has been a 60 percent increase in the number of farms in the State.
    Connecticut is now home to nearly 6,000 farms. Although the number of
    farms has increased dramatically, the acreage of farm land has not
    grown at nearly the same rate. As such, most of Connecticut farms are
    small and sell directly to consumers at farmers markets or through
    Community Supported Agriculture.
        Dr. Califf, under your leadership, what type of education,
    training, and technical assistance can small farmers, State agencies,
    and other stakeholders, particularly those that will be subject to
    FSMA, expect from the FDA to support a transition to FSMA compliance?
        Answer 1. Please be assured that I understand the importance in
    providing assistance to affected stakeholders, especially small
    farmers, to help them comply with the new requirements. As you may
    know, in October 2015, the Agency released a FSMA training strategy,
    which outlines training options and delivery formats as well as
    introduces the partners in government, industry, and academia who are
    working with FDA on the development and delivery of training to the
    global community of food suppliers.\23\
    ---------------------------------------------------------------------------
        \23\ http://www.fda.gov/Food/GuidanceRegulation/FSMA/ucm461513.htm.
    ---------------------------------------------------------------------------
        Industry training will be an important component of successful
    implementation of FSMA. The Agency recognizes that one-size-doesn't-
    fit-all, and that the most important goal that FDA expects of any
    training program is the outcome--that it advances knowledge among the
    food industry to meet FSMA requirements. The needs of small- and mid-
    sized farms and facilities are at the center of FSMA training
    development and will be met through multiple efforts.
        The vision of FSMA training began in 2010 through 2012 with the
    creation of public-private alliances, funded in part by FDA, as a
    resource for industry and to facilitate widespread compliance with the
    new standards. The Produce Safety Alliance, Food Safety Preventive
    Controls Alliance, and Sprout Safety Alliance (Alliances) are
    developing training to help domestic and foreign food producers--
    including small and very small farms and facilities--meet the
    requirements of the preventive controls and produce safety rules. The
    curricula developed through the Alliances are designed to be standard
    curricula with training modules that can be added to meet unique needs.
        In addition to working with the Alliances, FDA is collaborating
    with the U.S. Department of Agriculture's National Institute of Food
    and Agriculture (NIFA) to administer and manage the National Food
    Safety Training, Education, Extension, Outreach, and Technical
    Assistance Program, as mandated in Section 209 of FSMA. This
    competitive grant program will provide food safety training, education,
    extension, outreach, and technical assistance to owners and operators
    of farms, small food processors, and small fruit and vegetable merchant
    wholesalers.
        Grants issued through this program will fund a National
    Coordination Center (NCC) and four Regional Centers (RCs), which will
    be involved in both key components of training--primarily facilitating
    training delivery but also, in certain situations, facilitating
    curricula development targeted to specific audiences. FDA has awarded
    the International Food Protection Training Institute a grant of up to
    $600,000 over 3 years to establish the NCC, which will lead
    coordination of curriculum development and delivery to those food
    businesses covered by the FSMA Section 209 mandate for implementation
    of FSMA. The NCC will coordinate and support the delivery of
    standardized and/or alternate training curricula through the RCs.
        The RCs will be charged with understanding and communicating the
    landscape of training opportunities available to target businesses in
    their region. They will identify any need to develop or tailor
    curricula to meet specific unmet regional needs and/or to target a
    specific audience. Training programs may differ to meet those needs.
    The NCC will facilitate communication between the RCs, the Alliances,
    and other partnering groups about the development of such region- and/
    or audience-specific materials.
        The RCs will be established in the Southern, Western, North
    Central, and Northeast regions of the country. These centers will work
    with representatives from non-governmental and community-based
    organizations, as well as representatives from cooperative extension
    services, food hubs, local farm cooperatives, and other entities that
    can address specific needs of the communities they serve.
        As these efforts indicate, we fully recognize and respect the
    importance of small farms and processors in our economy and our food
    safety system. We look forward to continuing to work with these
    communities throughout implementation of FSMA to facilitate the
    successful transition to the new preventive food safety framework.

        Question 2. Biologics have provided major advances in the treatment
    of cancer, rheumatologic disease, and other conditions but they also
    come at great cost to our health care system due to the expense of
    developing and manufacturing a drug. For example, even though they
    account for less than 1 percent of all prescriptions dispensed in the
    United States, expenditures on biologics amount to 28 percent of
    prescription drug spending, and both their use and their cost are
    forecast to grow sharply. This increased cost is borne by our health
    care system as a whole but more specifically by patients as more and
    more insurance companies place higher cost-sharing burdens on
    biologics.
        While we may never get close to the price reductions that are seen
    in the generic market, biosimilars will likely be 15-30 percent cheaper
    than the reference biologic. These reductions will result in
    significant savings to the health care system and patients as the
    biosimilar market matures. However, FDA still has not released draft
    guidance on such key issues as labeling and interchangeability.
        Dr. Califf, do you expect draft guidance on biosimilar labeling and
    interchangeability to be issued before the end of the year as the
    Center for Drug Evaluation and Research 2015 Guidance Agenda suggests?
        Answer 2. FDA has published the following final guidances with
    respect to biosimilars: Scientific Considerations in Demonstrating
    Biosimilarity to a Reference Product; Quality Considerations in
    Demonstrating Biosimilarity of a Therapeutic Protein Product to a
    Reference Product; and Biosimilars: Questions and Answers Regarding
    Implementation of the Biologics Price Competition and Innovation Act of
    2009; and Formal Meetings Between the FDA and Biosimilar Biological
    Product Sponsors or Applicants.
        FDA has also published the following draft guidances since 2012:
    Clinical Pharmacology Data to Support a Demonstration of Biosimilarity
    to a Reference Product; Reference Product Exclusivity for Biological
    Products Filed Under Section 351 (a) of the PHS Act; Biosimilars:
    Additional Questions and Answers Regarding Implementation of the BPCI
    Act of 2009; and Nonproprietary Naming for Biological Products.
        The Agency is committed to carefully reviewing the comments
    received as we move forward in finalizing the draft guidances noted
    above. Upcoming guidances are expected to include: Considerations in
    Demonstrating Interchangeability to a Reference Product; Statistical
    Approaches to Evaluation of Analytical Similarity Data to Support a
    Demonstration of Biosimilarity; and Labeling for Biosimilar Biological
    Products.
        FDA is diligently working to issue guidance on issues that have
    been identified by the FDA and key stakeholders as key topics of
    interest. While the Agency cannot provide a specific timeline for the
    release of any guidance, we continue to provide information to assist
    biological product developers--sponsors/companies--with bringing
    biosimilar and interchangeable products to market. The FDA is
    continuing to clarify its approach to implementation of the BPCI Act to
    further facilitate sponsors' development of biosimilars and
    interchangeable biological products.

        Question 3. As FDA Commissioner, you will be charged with
    regulating a number of prominent industries that you have interacted
    with in the past. Can you inform the committee on the steps that you
    have taken thus far to steer clear of any potential conflicts of
    interest and the ongoing monitoring that is planned as new matters
    arise before the FDA?
        Answer 3. Following my appointment as Deputy Commissioner for
    Medical Products and Tobacco, the Office of the Commissioner
    established a process for screening invitations that I receive for
    speaking engagements and other requests for my participation to
    identify potential situations which would require my recusal. A team of
    individuals was convened including a representative of the Office of
    the Commissioner and the Office of Chief Counsel. These individuals
    have extensive knowledge of my ethics agreement and recusal
    obligations. This team meets on a regular basis (often as frequently as
    weekly) and on an ad hoc basis as needed. A member of my staff submits
    detailed information regarding specific invitations/requests for my
    participation and the team determines whether I should be recused. If
    the team has any questions as to whether something is covered by the
    recusal, the HHS Designated Agency Ethics Official's office is
    consulted. The team has a standing teleconference with a representative
    of this office in order to facilitate consultations and determinations.
        I am recused from all particular government matters that would
    affect Duke's financial interests, any matter in which Duke is a party
    or which would have a special or distinct effect on Duke, or that
    potentially could include particular matters involving Duke-affiliated
    research. If a particular matter potentially implicates Duke-affiliated
    research, before participating, I will consult with HHS and FDA ethics
    officials to determine whether my recusal allows for participation.
        If my nomination is confirmed, I understand that I will be subject
    to more extensive recusal obligations under the President's 2009
    Executive order, and accordingly that additional monitoring procedures
    may be needed.
                                 senator warren
    Input of Pharmaceutical Industry Sponsors on Clinical Trials Conducted
            at Duke Clinical Research Institute
        Question 1a. For the clinical trials you conducted or oversaw while
    at the Duke University School of Medicine and the Duke University
    Medical Center, can you detail for us exactly what input pharmaceutical
    sponsors did and did not have in the:

         design of the trials?

        Answer 1a. Pharmaceutical (and device) sponsors provided input into
    the design of trials including the intervention, control measures,
    eligibility criteria, randomization, study endpoints, blinding methods,
    and sample size. In order for Duke to conduct the trial as the
    coordinating center, agreement must be reached by the academic leaders
    and the industry sponsor. All aspects of the design are included in the
    protocol, which is subject to review and approval by FDA, and for
    international trials, by regulatory authorities from each involved
    country and the European Medicines Agency. Finally, any participating
    research site has a Principal Investigator and an Institutional Review
    Board (IRB) that must review and approve the protocol in order to
    proceed with enrollment.

         analysis of trial data?

        Answer. Pharmaceutical sponsors provided input into the development
    of the statistical analysis plan. The plan is included in the protocol,
    which is subject to review and approval by FDA, by regulatory
    authorities in other countries, and the data monitoring committee (a
    committee of non-conflicted experts in the relevant medical specialty,
    clinical trial methodology, and ethics of human studies) Finally, as
    noted above, any participating research site has a Principal
    Investigator and an Institutional Review Board (IRB) that must review
    and approve the protocol with its included analysis plan in order to
    proceed with enrollment. The details of how the analyses are actually
    conducted are provided below.

         publication of trial results?

        Answer. After a publication was written by the academic
    investigators (including Duke investigators and other participating
    academic leaders), the pharmaceutical sponsor was given the opportunity
    to review and comment on the publication within a period of time that
    is specified in the contract. Final decisions about publication are
    made by the trial executive committee (which is comprised of the
    academic leaders). The industry sponsor has the right to review and
    comment, but no right to censor or dictate content or verbiage.

        Question 1b. For each of the activities listed above:

         Which group had the final decisionmaking authority if
    differences arose between Duke academics and industry sponsors?
        Answer 1b. In situations in which the Duke academics were not in
    agreement with an industry sponsor regarding the design of a trial, the
    Duke academics did not participate in the trial. With regard to
    analysis of trial data and publication of trial results, the Duke
    academics always had the final decisionmaking authority per the terms
    in the contract regarding access to data and the right to publish. For
    example, the right to a copy of the database is what allows the
    academic group to perform an independent analysis and interpretation of
    the trial results.

         Did industry sponsors have veto authority over decisions
    related to data analysis and the publication or presentation of trial
    results?
        Answer. In trials coordinated by the DCRI, or in which I
    participated as a lead investigator, industry sponsors never had veto
    authority over decisions related to data analysis and the publication
    or presentation of trial results. As noted above, the majority of
    industry-sponsored multi-site clinical trials do not have an
    independent academic coordinating center, so I believe the approach we
    developed at DCRI is best practice because it provides the independent
    voice in analysis and publication of results.

        Question 1c. Referring to the input of pharmaceutical sponsors on
    the analysis of clinical trial data you said at the Senate HELP
    Committee hearing on November 17:

              ``Typically we'll have an analysis done by the company and an
            analysis done by our statisticians, then we compare the results
            to see if they match up, and resolve any discrepancies. But in
            no case did we allow the company to do the analysis and we just
            were recipients of what they said the answer was.''

        Answer 1c. As a prelude to this series of questions, it is
    important to have some key background about industry-sponsored clinical
    trials:

         The majority of multi-site, industry-sponsored clinical
    trials do not have an academic coordinating center. They are
    coordinated by industry and for-profit contract research organizations.
    In cardiovascular medicine and many other highly evidence-driven
    specialties, the independent role of the academic is an important
    element to ensure that the results are not biased, given the industry-
    sponsor's direct financial interest in the outcome. While most major
    academic medical centers have some coordinating center function, a
    limited number can conduct multi-national large trials, like the DCRI.
         The role of coordinating center is distinctly different
    from the role of a research site. The coordinating center assures that
    the trial is being conducted as designed by participating sites,
    collects the data from the sites, monitors the conduct of the trial,
    and does the analyses. The research site enrolls the patients, conducts
    the study protocol, and submits the data to the coordinating center.
    The research sites do not have a copy of the aggregate trial data and
    for the most part are not capable of doing the overall trial analysis.

              Why might discrepancies between statistical analyses
            arise?

              Answer. Data bases from large, international clinical trials
            are complex with hundreds of thousands of pages of data and
            millions of data items. The analytical code to actually perform
            the analysis takes hundreds of hours to write and it is checked
            multiple times. There is also an audit trail to assure that
            analytical steps are not altered after unblinding. Because of
            this enormous complexity, there is great value in redundant
            checking both within the academic coordinating center and on
            the industry side and in checking between the two entities. All
            of this is done before unblinding the trial.
             Academically coordinated trials that are not intended for
            regulatory review often do not have this level of rigor, which
            has led to concern about reproducibility. At the DCRI the
            procedures of checking and redundancy are standard for both
            industry-funded and government-funded trials.

              How often did these discrepancies arise?
              Answer. Because of the careful and extensive nature of this
            pre-unblinding work, it is very rare to have discrepancies that
            are significant, and, in fact, I'm not aware of any such
            instances. But small differences in coding and interpretation
            do occur, and it's critical to resolve these. Importantly,
            during this checking phase on the primary analysis, the
            statisticians are unblinded, but the clinical investigators and
            clinical development experts for the sponsor remain blinded.

              Can you describe the process for ``resolving
            discrepancies? ''
              Answer. When discrepancies arise in primary analyses, as
            described above, they are resolved prior to unblinding to
            eliminate bias. For secondary analyses and subsequent
            manuscripts, the academic coordinating center performs the
            analyses used for the study. These analyses typically are
            planned out in less detail prior to unblinding, but statistical
            analysis plans are constructed. Industry is welcome to provide
            a perspective from their own analyses, but control of the
            interpretation and message resides with the academic authors of
            the manuscript.

              What factors are involved in making a final
            determination related to the analysis?
              Answer. As stated above, the types of discrepancies
            encountered in the primary analysis are small and I have not
            encountered a situation in which a difference has occurred that
            would affect the interpretation of the trial.

              Did Duke academics or the industry sponsor have the
            final decision over what analysis was submitted to the FDA?
              Answer. Sponsors have the responsibility for regulatory
            submissions, which involve not only FDA, but the European
            Medicines Agency and dozens of national authorities for
            countries in which the product will be marketed. Accordingly,
            the sponsor has primary responsibility for the FDA submission,
            but the key analyses are duplicated by the academic
            coordinating center.

                Was the analysis published by Duke academics?
              Answer. Duke academics published in the context of the
            purview of the executive committee and the steering committee.
            The final decision was made by the executive committee of the
            trial. The sponsors, such as Johnson and Johnson and Bayer, had
            input into the primary manuscript, but no right to alter the
            decision of the executive committee.

               Was results published by the industry sponsor?
              Answer. The industry sponsor is not charged with publishing
            key results of the trial independently of the academic
            coordinating center and steering committee. After the steering
            committee has published its primary manuscripts, the industry
            sponsor may make its data available for others to do analyses
            and publish the results.

        Question 1d. How many publications have you authored or co-authored
    that report results from an industry-sponsored study regarding the
    safety or efficacy of that sponsor's product?
        Answer 1d. Please see question E below.

        Question 1e. Please list publications you have authored or co-
    authored that report a negative result from an industry-sponsored study
    regarding the safety or efficacy of that sponsor's product.
        Answer 1e. The enclosed ``Table A\24\, Clinical Trials and
    Outcomes'' contains a list of clinical trials in which I played a major
    role in the design, conduct, or oversight. The first column gives the
    acronym by which the trial was known.
    ---------------------------------------------------------------------------
        \24\ The Table referred to may be found at the end of Senator
    Warren's Questions and Responses. Due to the high cost of printing, the
    listing of Peer-Reviewed Journal Publications of Mr. Califf are being
    retained in the committee files.
    ---------------------------------------------------------------------------
        The second column gives the publication reference. In cases in
    which I was an author, the manuscript is denoted by the number on my CV
    that was submitted to the committee. Some trials are listed in which I
    played a major role, but was acknowledged in the list of committees or
    in subsequent articles. In these cases the reference is given.
        The third column gives the trial outcome:

         Positive means that the trial finding and interpretation
    favored benefit for the sponsor's product.
         Negative means that the trial finding was not beneficial
    for the sponsor's product.
         Mixed means that the finding was equivocal for the
    sponsor's product or more than one product was evaluated with mixed
    results.
         Non-inferior means that the sponsor's product was found to
    be non-inferior to the comparator, and the trial was designed for this
    purpose. So, a non-inferior trial should be considered a positive
    finding from the sponsor's perspective.
         Neutral means that trial did not reach a conclusion about
    the product.

        Of the 55 trials in total, 28 (51 percent) were negative; 15 (27
    percent) were positive; six (11 percent) were non-inferior; and six (11
    percent) were either neutral (two) or mixed (four).
        The fourth column identifies the medical product that was evaluated
    and the final column gives a brief summary of the finding.
        As expected, the majority of trials did not show a positive outcome
    for the sponsor's product. From the perspective of an academic
    researcher, the desired outcome of a trial is that it answers an
    important clinical question (regardless of whether that finding was
    positive or negative). A review of all trials done by DCRI would have a
    similar distribution, reflecting the tremendous need for more trials to
    guide clinical practice. (See Table A. Clinical Trials and Outcomes).

        Question 1f. How does the conduct of privately funded clinical
    trials (wholly or in part) at Duke Clinical Research Institute differ
    from the conduct of clinical trials at other major medical centers in
    the United States?
        Answer 1f. To fully understand the response to this question, it is
    critical to know that clinical trials have 2 major organizational
    functions: the research site and the coordinating function. Most major
    academic medical centers and integrated health systems participate in
    hundreds of industry-sponsored clinical trials as one of many research
    sites in each trial. As a research site, after agreeing that the study
    is meritorious and after independent review by the Institutional Review
    Board, the site conducts the trial and submits its data to a
    coordinating center. The individual research site is not equipped to
    analyze the trial data and does not have a copy of the aggregate data,
    nor should it, since the multi-site trials are needed to provide
    adequate sample sizes representative of the population likely to be
    treated with the therapy under evaluation, so that a single site
    analysis would not provide a valid scientific conclusion for the trial
    as a whole.
        The coordinating center oversees the overall study organization,
    distributes and collects regulatory and operational documents and takes
    responsibility for overseeing the quality of the trial through a
    combination of auditing and monitoring the conduct of the trial and
    quality of the data. The coordinating center then does the analyses and
    manages the Steering Committee functions and interactions with the Data
    Monitoring Committee.
        The Duke Clinical Research Institute (DCRI) is one of a small
    number of major academic medical centers in the United States with the
    capability of coordinating large global clinical trials. Most major
    medical centers participate in clinical trials in the role of a
    research site (i.e., enrolling patients at their institution in multi-
    site trials). So, DCRI performs many ``coordinating center'' functions
    which are not performed by most academic centers (such as clinical
    monitoring and safety surveillance). Coordinating center functions are
    also performed by commercial contract research organizations (CROs)
    which conduct this activity on a fee-for-service basis. Unlike
    academically based coordinating centers, however, CROs do not have
    requirements for independent access to data and publication rights. A
    growing number of institutions have developed coordinating functions
    similar to DCRI for the same reasons, but few have the global reach or
    capacity of the DCRI.

        Question 1g. Are the standards for preserving academic independence
    in sponsored research at Duke more stringent, less stringent or similar
    to standards at other peer institutions?
        Answer 1g. As noted above, an academic center may serve in the role
    of a coordinating center for a multi-site clinical trial or an
    individual research site responsible for enrolling patients at its
    institution in a multi-site trial.
        The standards (i.e., contractual requirements) for preserving
    academic independence are different based on the institution's role in
    the study. For example, since a specified sample size is required to
    discern whether a treatment is more or less safe and effective compared
    to another treatment (or to a placebo), the analysis of data from an
    individual research site is not scientifically valid. An individual
    research site would not typically require the right to publish the
    results of its own data, but rather would require that the aggregated
    data from all sites be subject to an independent analysis,
    interpretation and publication by the academic leadership of the trial.
        Accordingly, an assessment of the stringency of the standards for
    preserving academic independence in the setting of a coordinating
    center requires comparison with those of other academic coordinating
    centers, rather than with those of individual research sites. Because
    Duke's standards for independent access to data and publication rights
    as a coordinating center are absolute, there is no situation in which
    its standards for preserving academic independence in sponsored
    research are less stringent than those of any peer institution.

    Post-market Surveillance of Medical Devices
        Question 2a. In response to a question from Senator Murray
    regarding post-market surveillance of medical devices during the Senate
    HELP Committee hearing on November 17, you stated:

              ``The Sentinel System . . . is a model in drugs; we have 170
            million Americans' claims data so when there is a problem with
            a drug we can look almost in real time. We need the same system
            on the device side.''

        Unique Device Identifiers (UDI) will make post-market surveillance
    of devices possible, but only if they are captured in electronic health
    information.
        What steps need to occur before the FDA can integrate UDIs and
    medical device information into the Sentinel System, as mandated by
    Congress in the 2012 Food and Drug Administration Safety and Innovation
    Act?
        Answer 2a. FDA, the Office of the National Coordinator for Health
    IT (ONC), and the Centers for Medicare & Medicaid Services (CMS) are
    working closely on the shared goal of incorporating UDIs into
    electronic health records (EHRs), starting with implantable devices.
    The recently finalized rules on the 2015 HIT Certification Criteria
    (ONC) and Medicare and Medicaid Electronic Health Record Incentive
    Programs--Stage 3 and Modifications to Meaningful Use in 2015 Through
    2017 are important steps in this process as both support the addition
    of UDIs for implantable medical devices to the Common Clinical Data Set
    which would be able to be exchanged and available to providers who care
    for the patient.
        In addition, FDA and CMS look forward to continuing to explore
    options that would improve surveillance in a timely and effective
    manner. These agencies are committed to capturing appropriate data and
    sharing information transparently to improve the quality and safety of
    care delivered to people across the Nation. FDA and CMS also support
    the recommendation by the National Committee on Vital and Health
    Statistics to consider conducting voluntary pilot tests of the
    benefits, costs, and feasibility of UDIs in claims reporting between
    providers and commercial payers.
        Voluntary pilots should address key challenges to adding UDIs to
    claims, including significant technological hurdles and costs (for
    providers, payers and others), as well as difficulties in validating
    UDIs reported on claims.

        Question 2b. As a cardiologist and clinical trials expert who has
    experience with real-world data sources, how do you understand that UDI
    information in medical claims could support the evaluation of medical
    devices after approval--such as through enhancements to registries like
    those operated by the American College of Cardiology and to expand the
    Sentinel system?
        Answer 2b. The current Sentinel data model focuses on querying
    administrative and claims data maintained by partner organizations who
    share aggregated results with FDA. FDA does not receive or hold
    personally identifiable information, but can query privacy-protected
    data and receive aggregated data from local environments that together
    cover approximately 126 million patients.
        These records generally lack manufacturer or brand-specific device
    identifiers and therefore cannot be leveraged to perform meaningful
    medical device post-market surveillance. While CDRH is actively engaged
    in promoting the integration of UDI into electronic health information,
    we are also undertaking complementary efforts to develop a more
    comprehensive evaluation system for medical devices. FDA is exploring
    the means to expand Sentinel by linking national device registries to
    these claims data. We are currently linking clinical registries to
    claims data to enable the evaluation of longitudinal data. Clinical
    registries collect information that uniquely identifies and provides
    curated clinical data in selected medical device areas. These
    activities, along with establishing linkages to electronic health
    records, are envisioned to be the building blocks of a broader National
    System for Medical Device Post-market Surveillance [http://www.fda.gov/
    AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDRH/
    CDRHReports/ucm301912.htm] that would use evidence from clinical
    experience in a network of existing electronic data systems to improve
    patient safety, enhance our understanding of device performance, and
    facilitate device innovation.

        Question 2c. If UDI information is not included in claims data,
    what negative repercussions would that have for the Sentinel system to
    evaluate specific medical devices?
        Answer 2c. The current Sentinel data model focuses on querying
    administrative and claims data maintained by partner organizations, who
    share aggregated results with the FDA. FDA does not receive or hold
    personally identifiable information, but can query privacy-protected
    data and receive aggregated data from local environments that together
    cover approximately 126 million patients. These records generally lack
    manufacturer or brand-specific device identifiers.

        Question 2d. What are the benefits of the integration of UDIs into
    electronic health records?
        Answer 2d. UDIs incorporated into electronic health information,
    especially electronic health records and medical device registries, can
    help create additional, more robust, and cost-effective post-market
    monitoring and surveillance data sources and support additional device
    research by leveraging real world clinical data. UDIs allow us to more
    easily link the use of a device with a patient's experience with that
    device.
        UDIs incorporated into electronic health information will also help
    the FDA, the health care community, and industry to:

         More accurately report and analyze device-related adverse
    events by ensuring that devices associated with these events are
    correctly identified.
         More rapidly develop solutions to reported problems.
         More efficiently resolve device recalls, including the
    removal of potentially harmful devices from the market.
         Reduce medical errors by enabling health care
    professionals and others to rapidly and precisely identify a device,
    obtain important information concerning the device's characteristics,
    and improve the identification of the device through the distribution
    chain to the point of patient use.

        The Unique Device Identifier (UDI) system is essential to
    transforming postmarket surveillance of medical devices; a critical
    cornerstone of FDA's strategy is the incorporation of UDIs into
    electronic health information, particularly electronic health records
    (EHRs) and device registries. In the 2012 Food and Drug Administration
    Safety and Improvement Act, Congress required FDA to expand Sentinel to
    include medical devices.

        Question 2e. How do you plan to work with the Centers for Medicare
    and Medicaid Services, the Office of the National Health Coordinator
    for Health Information Technology, private payers, and the medical
    device industry to facilitate the integration of UDIs into multiple
    sources of electronic health information?
        Answer 2e. FDA, the Office of the National Coordinator for Health
    IT (ONC), and the Centers for Medicare & Medicaid Services (CMS) are
    working closely on the shared goal of incorporating UDIs into EHRs,
    starting with implantable devices. The recently finalized rules on the
    HIT Certification Criteria (ONC) and Medicare and Medicaid Electronic
    Health Record Incentive Programs--Stage 3 and Modifications to
    Meaningful Use in 2015 Through 2017 are important steps in this process
    as both support the addition of UDIs for implantable medical devices to
    the Common Clinical Data Set which would be able to be exchanged and
    available to providers who care for the patient.

    Antibiotic Resistance--Antibiotic Use in Animal Agriculture
        Question 3a. While FDA policies (Guidance for Industry (GFI)#209
    and #213 and the Veterinary Feed Directive Final Rule) make the use of
    antibiotics to promote animal growth illegal and subject all remaining
    uses of antibiotics to veterinary oversight, I remain very concerned
    that these policies leave the door open for dangerous antibiotic
    regimens to continue. FDA officials have previously communicated to me
    that they plan to monitor the removal of growth promotion from
    labels.\25\ However, measuring how many companies make promised changes
    in their drug labels is not an adequate measure of whether the policies
    have been successful at ending the misuse and over-use of antibiotics
    in animal agriculture.
    ---------------------------------------------------------------------------
        \25\ Secretaries Burwell, Carter, and Vilsack to Senator Warren,
    Aug. 17, 2015.
    ---------------------------------------------------------------------------
        Additionally, FDA's policies will work only if veterinarians follow
    appropriate prescribing guidelines that take into account not only the
    health of the animals in front of them, but also consider the public
    health. GFI #213 describes principles that veterinarians should
    consider when determining the appropriateness of antibiotic use for
    disease prevention. FDA has stated that the agency ``intends to work
    with veterinary and animal producer organizations to reinforce the
    importance of these principles.'' \26\ However, representatives from
    many animal producer organizations have publically voiced doubts about
    the need to reduce antibiotic use and the impact that the FDA's
    policies will have on the amount of drugs used.\27\
    ---------------------------------------------------------------------------
        \26\ Kraus, Thomas A., Associate Commissioner for Legislation, FDA
    to Senators Warren, Feinstein and Gillibrand, Sept. 8, 2014; FDA,
    Guidance for Industry #213: New Animal Drugs and New Animal Drug
    Combination Products Administered in or on Medicated Feed or Drinking
    Water of Food Producing Animals: Recommendations for Drug Sponsors for
    Voluntarily Aligning Product Use Conditions with GFI #209. December,
    2013. (pg.7)
        \27\ Christine Hoang, American Veterinary Medical Association
    (AVMA), on ``The Trouble with Antibiotics,'' PBS Frontline, October
    2014; AVMA Antimicrobial Use and Antimicrobial Resistance FAQ; Ron
    Philips, Animal Health Institute, in Flynn, Dan (27 May 2011) ``Ag
    Coalition Says Antibiotic Facts are on Its Side.'' Food Safety News;
    Coalition letter to David Hoffman, PBS Frontline Producer, August 2014;
    Juan Ramon Alaix, Zoetis in Loftus, Peter. (2013 Nov. 19). Zoetis Chief
    Leads Animal-Health Firm Following Split from Pfizer. The Wall Street
    Journal.
    ---------------------------------------------------------------------------
        Given documented disagreements among stakeholders, and given that
    veterinary adherence to appropriate antibiotic prescribing guidelines
    is a critical part of FDA's policies, how will you, as Commissioner,
    monitor, evaluate, and take necessary actions with regard to compliance
    with GFI #213's appropriate antibiotic prescribing guidelines?
        Answer 3a. The Food and Drug Administration (FDA or the Agency) is
    confident that the changes under its judicious use policy, as outlined
    in Guidance for Industry (GFI) #209 and GFI #213, will be effectively
    implemented. FDA has received written commitments from all affected
    pharmaceutical companies to align their products with the GFI #213
    recommendations. There has been positive engagement of key
    stakeholders, including the animal pharmaceutical industry, the animal
    feed industry, and veterinary and animal producer organizations.
    Furthermore, once the affected products are aligned, it will be illegal
    to use these medically important antibiotics for production purposes or
    to use these products for the remaining therapeutic purposes without
    the authorization of a licensed veterinarian. Veterinarians play a
    critical role in the diagnosis of disease and in the decisionmaking
    process related to instituting measures to treat, control, and prevent
    disease.
        The President's National Action Plan calls on FDA to collaborate
    with veterinary organizations, animal producer organizations, the
    animal feed industry, and others to develop and implement educational
    outreach efforts to ensure that veterinarians and animal producers
    receive the necessary information and training to support
    implementation of GFI #213. As part of these efforts, FDA is working
    with the U.S. Department of Agriculture (USDA) to ensure that
    veterinarians have access to timely, updated information and training
    for the appropriate use of medically important antibiotics in the feed
    and water of food-producing animals. For example, FDA is developing
    guidance on the Veterinary Feed Directive (VFD) form, which
    veterinarians will use, as well as supporting changes to veterinary
    curricula, and leveraging many opportunities to provide necessary
    education via our partnerships with various stakeholders.
        As part of its compliance efforts, FDA will utilize its authority
    to conduct inspections that will provide important information for
    determining compliance with GFI #213. For example, VFD records will be
    examined as part of inspections conducted at feed manufacturing
    facilities. Examination of such records is an important tool for
    determining whether these drugs are being appropriately authorized. In
    addition, as part of the recent revisions to the VFD regulation, FDA
    updated requirements for the establishment (by veterinarians) of a
    veterinary-client-patient relationship (VCPR) when a veterinarian
    authorizes the use of a VFD drug. Since veterinarians are licensed at
    the State level, FDA is working closely with the State boards of
    veterinary medicine on this issue.
        Ongoing surveillance of antibiotic use and resistance is also a
    critical element of FDA's strategy for assessing the impact of FDA's
    GFI #213. FDA's data collection efforts include enhancements to the
    collection and reporting of data collected under the National
    Antimicrobial Resistance Monitoring System (NARMS), enhancements to the
    collection and reporting of Antimicrobial sales and distribution data,
    as well as ongoing collaboration with USDA to collect additional on-
    farm data on antibiotic use and resistance. FDA co-sponsored a public
    meeting with USDA and the Centers for Disease Control and Prevention
    (CDC) on September 30, 2015, to obtain input from the public on
    approaches for enhancing collection of data on antibiotic use and
    resistance in animal agricultural settings. These efforts will allow
    FDA to better assess the effects of antibiotic stewardship policies and
    analyze the association between antibiotic use and resistance.
        The efforts that are currently underway represent a significant
    step forward in addressing antimicrobial resistance. We acknowledge
    that this is an ongoing effort and additional measures may be needed.
    In addition to effectively eliminating growth promotion use and
    instituting veterinary oversight, we recognize the importance of
    ensuring that meaningful stewardship principles are applied in
    conjunction with the use of medically important antimicrobial drugs for
    therapeutic purposes, including for disease prevention. FDA is
    committed to working in collaboration with USDA, CDC, veterinarians,
    animal producers, and other stakeholders on this important effort.

        Questions 3b and c. As Commissioner, what currently available data
    sources will you use to measure the success of FDA's current antibiotic
    use in animal agriculture policies at addressing the overall public
    health threat?
        How will you work with USDA to prioritize the development of
    additional data sources, including measures of how antibiotics are used
    on farms?
        Answers 3b and c. Gathering information on the way medically
    important antibiotics are used is essential to assessing the impact of
    FDA's judicious use strategy. FDA has several data sources currently
    available to measure antibiotic use in animal agriculture.
        Under section 105 of the 2008 Animal Drug User Fee Amendments
    (ADUFA 105), drug sponsors must report to FDA annually on all
    antimicrobials sold or distributed for use in food-producing animals.
    FDA collects, summarizes and reports this information annually in its
    ADUFA 105 report. In 2014, FDA enhanced the format of its annual
    summary report so that it now includes information on the importance of
    the drug in human medicine and provides aggregate data on the approved
    route of administration of antimicrobial drugs sold or distributed for
    use in food-producing animals, whether such drugs are available over-
    the-counter or require veterinary oversight, and whether they are
    approved for therapeutic indications, or both therapeutic and
    production indications.
        FDA also reanalyzed previous years' reports in the same manner. In
    May 2015, FDA proposed revisions to the ADUFA 105 reporting
    requirements in order to obtain estimates of sales by major food-
    producing species (cattle, swine, chickens, and turkeys). The
    additional data would help FDA further target its efforts to ensure
    judicious use of medically important antimicrobials. The public comment
    period closed on August 18, 2015, with varying reactions from
    stakeholder groups. The final rule is an FDA priority, and we hope to
    publish it next May.
        In addition, FDA collaborates with USDA and CDC to collect data on
    antimicrobial resistance among foodborne pathogens as part of NARMS.
    Recent enhancements to the NARMS program make the data more useful for
    measuring the effects of GFI #213, particularly a new USDA Food Safety
    Inspection Service slaughter-sampling program, launched in March 2013,
    which increases national representativeness of the animal samples. FDA
    is also working with State partners to perform whole-genome sequencing
    on NARMS samples, which will provide unprecedented details on the
    traits of resistant strains of foodborne bacteria from animals and
    animal-derived foods. In August 2015, FDA released its 2012-13 NARMS
    Integrated Report, which overall reveals mostly encouraging findings,
    with some areas of concern.
        On September 30, 2015, FDA, in collaboration with USDA and CDC,
    held a jointly sponsored public meeting to obtain public input on
    possible approaches for collecting additional on-farm antimicrobial
    drug use and resistance data. Information from the public meeting will
    help FDA determine the most efficient way to collect the additional on-
    farm use data needed to assess GFI #213's impact on antimicrobial
    resistance. Combined with existing sales data on antibiotic drugs sold
    for use in food-producing animals and the data from NARMS, the new on-
    farm data will provide a more comprehensive and science-based picture
    of antibiotic drug use and resistance in animal agriculture. This data
    collection plan is intended to provide the data needed to: (a) assess
    the rate of adoption of changes outlined in the FDA's GFI #213, (b)
    help gauge the success of antibiotic stewardship efforts and guide
    their continued evolution and optimization, and (c) assess associations
    between antibiotic use practices and resistance trends over time.
        In addition, FDA and USDA are collaborating with a Cornell
    University researcher through the National Institute of Mathematical
    and Biological Synthesis (NIMBioS) to develop a new mathematical
    modeling methodology that would inform the approach to monitoring and
    assessing the impacts of GFI #213. The work of this group is still
    ongoing. The working group has so far met in September 2014 and
    February 2015 (meeting summaries are available at http://
    www.nimbios.org/workinggroups/WG_amr).

        Question 3d. What result or results--based on those data sources--
    would indicate to you that the policies have been successful or
    unsuccessful?
        Answer 3d. FDA believes it is important to assess progress in the
    context of five key components or phases of the overall effort. First,
    FDA focused on engaging the animal pharmaceutical industry and the
    animal agriculture community more broadly to work cooperatively with
    FDA to implement the changes outlined in FDA's judicious use strategy.
    FDA has been able to successfully gain commitments from all affected
    drug companies.
        Second, FDA is focused on working with these affected drug
    companies to complete the transition from old labeling to new labeling,
    to remove all growth promotion indications, and bring the remaining
    therapeutic indications for these products under veterinary oversight.
    FDA is currently in the middle of the 3-year implementation period for
    implementing these label changes by the target date (end of December
    2016). FDA expects all affected products to be aligned by this target
    date.
        Third, FDA continues to engage consumer advocacy groups to ensure
    transparency of our efforts and that the appropriate public health
    risks related to antimicrobial use in food producing animals are
    identified and addressed.
        Fourth, FDA is currently working with USDA and CDC to develop
    approaches for collecting additional on-farm data on antibiotic use.
    Having better data on actual antibiotic use practices at the farm level
    will enhance our ability to assess whether our policies are having the
    desired effect to align such antibiotic use practices with good
    stewardship/judicious use principles.
        Finally, FDA is also working with USDA and CDC to develop
    approaches for collecting additional on-farm data on antibiotic
    resistance. This additional information, along with other sources of
    resistance information such as that provided by NARMS, will better
    enable us to assess whether our policies are having the desired effect
    to reduce resistance.
        The additional data collection efforts described above will all
    play an important role in assessing the impact of current as well as
    future measures that are implemented to address this important public
    health issue.
    MSM
        Question 4a. Earlier this year, the FDA released the ``Revised
    Recommendations for Reducing the Risk of Human Immunodeficiency Virus
    Transmission by Blood and Blood Products: Draft Guidance for Industry''
    which, if finalized, would change the blood donation policy for men who
    have sex with men (MSM) from a lifetime deferral to a 1-year deferral
    from last sexual contact with another man. I am pleased that the FDA
    has finally taken this first step toward lifting the lifetime deferral.
    However, the 1-year deferral policy is still not based on science, not
    based on an individual donor's risk of carrying a transfusion
    transmissible infection, still prevents many low-risk individuals from
    donating blood, continues to let higher risk individuals donate, and
    gives no signal from the FDA that the agency is committed to achieving
    a fully risk-based system for all donors. If you are confirmed
    Commissioner, are you committed to ending the lifetime deferral policy
    for MSM?
        Answer 4a. The Food and Drug Administration (FDA) takes its
    responsibility to regulate the blood supply and to ensure its continued
    safety for patients who receive potentially lifesaving blood products
    very seriously, and also understands the need to update these policies
    to reflect current science. In collaboration with other government
    agencies, and considering input from advisory committees, the FDA has
    carefully examined the available scientific evidence relevant to the
    blood donor deferral policy for men who have sex with men (MSM) and
    recommended a change in the blood donor deferral period for MSM from
    indefinite deferral to 12 months since the last sexual contact with
    another man. We intend to issue final guidance in the near future. In
    addition, FDA is committed to continuing to work with stakeholders to
    develop the most optimal deferral strategies, including investigating
    individual risk assessment.

        Question 4b. When the draft guidance is finalized, how do you plan
    to reach out to the MSM community to explain the change in the lifetime
    deferral policy and encourage these individuals to donate?
        Answer 4b. FDA intends to reach out to stakeholders, including the
    LGBT community as part of the rollout for the final guidance, when it
    publishes. We will explain the changes to the policy and answer any
    questions regarding blood donation.

        Question 4c. What is your plan to ensure that the 1-year deferral
    policy is only a first step toward implementing a risk-based blood
    donation policy for all blood donors, including MSM?
        Answer 4c. FDA has examined the available scientific evidence
    relevant to the blood donor deferral policy for men who have sex with
    men (MSM) and recommended a change in the blood donor deferral period
    for MSM from indefinite deferral to 12 months since the last sexual
    contact with another man. We intend to issue final guidance in the near
    future. In addition, FDA is committed to continuing to work with
    stakeholders to develop the most optimal deferral strategies, including
    investigating individual risk assessment.
        FDA has already taken steps to implement a national blood
    surveillance system that will help the agency monitor the effect of a
    policy change and further help ensure the continued safety of the blood
    supply and to develop scientific evidence potentially relevant to
    making further changes to the blood donor deferral policy in the
    future.
        Implementation of the surveillance system is not contingent upon
    changing FDA's blood donor deferral policy for men who have sex with
    men. The system will monitor a majority of the blood collected in the
    United States for a number of different transfusion-transmitted viral
    infections, including HIV. We anticipate that the system will provide
    important information that will be helpful as we continue our efforts
    to further enhance the high level of safety of the U.S. blood supply
    and potentially support further revisions to our blood donor deferral
    policies.

    Clinical Trial Data Sharing
        Question 5a. A study entitled ``Clinical trial registration,
    reporting, publication and FDAAA compliance: a cross-sectional analysis
    and ranking of new drugs approved by the FDA in 2012,'' published last
    week in the British Medical Journal, found that several major drug
    companies have not met the standards for clinical trial results
    reporting under the Food and Drug Administration Amendments Act (FDAAA)
    of 2007. FDAAA established civil monetary penalties of up to $10,000
    per day for non-compliance, and yet the FDA has never been imposed.
        What do you do you believe the impact of greater transparency of
    clinical trial data and results would be on: (a) Clinical trial
    efficiency; (b) The cost of drug development; (c) Drug safety; and (d)
    Biomedical innovation.
        Answer 5a. FDA supports the view that transparency of clinical
    trial data and results is in the public interest. FDA is committed to
    increasing the transparency of information available regarding clinical
    trials and supports the principle of providing increased access to
    registration information and clinical trial data and results. The
    requirements in Title VIII of FDAAA have resulted in greater access to
    information for significant numbers of clinical trials. The public, and
    particularly clinical trial participants, benefit from access to these
    results. An additional benefit of the transparency provided by
    ClinicalTrials.gov is that it may provide FDA reviewers with a fuller
    picture of the trials under way in a particular area. Such information
    could contribute to current efforts to improve the design and quality
    of clinical trials and provide additional analytical tools and
    methodologies for analyzing clinical trial data and results.
        FDA's role in protecting and helping to ensure the safety and
    efficacy of medical products, however, does not depend on data reported
    to the ClinicalTrials.gov data bank. FDA's regulatory and surveillance
    mechanisms for identifying potential medical product problems and
    alerting patients and health care professionals are broad and continue
    to improve through programs such as the Sentinel Initiative.
    Dissemination of research results is a fundamental and long-standing
    principle of science and affords clinical trial participants the
    opportunity to know the value of their participation. Such access
    informs future research and can improve study design as well as prevent
    duplication of unsafe trials. Ultimately, greater transparency of
    clinical trials results will enhance public trust in clinical research.
    The additional impacts on safety as a result of this transparency and
    any effects such transparency may have on the costs of drug
    development.

        Question 5b. If you are confirmed Commissioner:

        (1) How do you plan to work with the NIH to finalize the Proposed
    Rule issued this spring to fully implement and clarify the FDAAA
    policy?
        (2) How will you ensure compliance to the disclosure policy
    implemented by FDAAA? and
        (3) Will you enforce the law using civil monetary penalties or by
    other means?

        Answer 5b. FDA worked with NIH to issue the Proposed Rule
    (published in November 2014) and continues to work with NIH to develop
    a final rule to implement the FDAAA requirements. The comments made to
    the Proposed Rule were complex and raised a number of issues that FDA
    is reviewing carefully and cooperatively with NIH. Although NIH is the
    lead for developing and finalizing the regulations and for implementing
    the ClinicalTrials.gov data bank, FDA has the responsibility for
    enforcing the FDAAA ClinicalTrials.gov requirements. However,
    enforcement actions are not the only tools used by FDA to ensure
    compliance with the statutory requirements. FDA has undertaken
    significant compliance efforts with regard to the ClinicalTrials.gov
    requirements, even in the absence of a final rulemaking, and will
    continue to do so even after a final rule is effective. However,
    without a final rule explaining the statute's requirements, thus
    putting all affected parties on a level playing field, a full
    enforcement program cannot be implemented. When NIH finalizes the rule,
    FDA will be in a better position to increase its compliance/
    enforcement actions. The use of civil money penalties will depend on
    each case and the applicability and appropriateness of seeking such
    penalties. It will be part of the enforcement ``tool set.''

    Patient Medication Information
        Question 6. While the FDA strictly regulates the prescribing
    information meant for doctors and requires the Drug Facts on over the
    counter medications, patient information about a medication and its
    potential risks is largely unregulated. The FDA has been working in
    collaboration with the Brookings Engelberg Center for Health Care
    Reform since May 2010 to engage in research and facilitate discussions
    among stakeholders regarding the design, implementation, and evaluation
    of a PMI document. Janet Woodcock testified before the Senate Aging
    Committee in December 2013 to discuss the FDAs ongoing work to develop
    consumer-friendly patient medication information (PMI) documents. I
    sent a letter asking about the FDAs timeline for implementation with
    Senators Gillibrand, Nelson, and Blumenthal in March 2014, but received
    no information in the agency's response. As Commissioner, are you
    committed to issuing regulations that will require consumer-friendly
    patient medication information to be provided with prescription
    medications before the end of this administration?
        Answer 6. FDA is in the process of developing proposed rulemaking
    for PMI and regulations of this type require significant public input,
    consumer research, and economic analysis. In order to obtain
    information to determine the best path forward for patient medication
    information, FDA has conducted research and continues to engage with
    interested stakeholders including patients, industry, and others, on
    how to improve the content and availability of PMI. These meetings have
    included an open public hearing on PMI in September 2010, as well as
    four public workshops with the Engelberg Center for Health Care Reform
    at the Brookings Institution since 2010 that discussed optimizing,
    implementing, and evaluating the adoption of PMI, the last of which was
    held on July 1, 2014. In addition, RTI published the results from the
    qualitative portion of FDA's PMI study (75 FR 78252) on October 14,
    2014, in an article entitled, ``Preferences for Patient Medication
    Information: What Do Patients Want? ''
        FDA is in the process of developing proposed standards for PMI
    format and content, a central repository to serve as a source for PMI,
    and methods of distribution to patients and pharmacies.
        FDA continues to be committed to the development of a PMI framework
    where the focus is on patient comprehension and issuing regulations in
    a timely manner.
    Biosimilars
        Question 7a. The Affordable Care Act established a pathway for the
    approval of biosimilar drugs that will create competition in the
    biologic drug market. Over 5 years since this pathway became law, FDA
    has still not established clear rules of the road for drugmakers, and
    many key guidance's, including those on naming, labeling, and
    interchangeability have not been finalized. If you are confirmed
    Commissioner, what timeline will you implement for finalizing the
    outstanding guidances?
        Answer 7a. FDA has published the following final guidances related
    to biosimilars: Scientific Considerations in Demonstrating
    Biosimilarity to a Reference Product; Quality Considerations in
    Demonstrating Biosimilarity of a Therapeutic Protein Product to a
    Reference Product; and Biosimilars: Questions and Answers Regarding
    Implementation of the Biologics Price Competition and Innovation Act of
    2009; and Formal Meetings Between the FDA and Biosimilar Biological
    Product Sponsors or Applicants.
        FDA has also published the following draft guidances since 2012:
    Clinical Pharmacology Data to Support a Demonstration of Biosimilarity
    to a Reference Product; Reference Product Exclusivity for Biological
    Products Filed Under Section 351 (a) of the PHS Act; Biosimilars:
    Additional Questions and Answers Regarding Implementation of the BPCI
    Act of 2009; and Nonproprietary Naming for Biological Products.
        The Agency is committed to carefully reviewing the comments
    received as we move forward in finalizing the draft guidances noted
    above. Upcoming guidances are expected to include: considerations in
    demonstrating interchangeability to a reference product; statistical
    approaches to evaluation of analytical similarity data to support a
    demonstration of biosimilarity; and labeling for biosimilar biological
    products.
        FDA is diligently working to issue guidance on issues that have
    been identified by the FDA and key stakeholders as key topics of
    interest. While the Agency cannot provide a specific timeline for the
    release of any guidance, we continue to provide information to assist
    biological product developers--sponsors/companies--with bringing
    biosimilar and interchangeable products to market. The FDA is
    continuing to clarify its approach to implementation of the BPCI Act to
    further facilitate sponsors' development of biosimilars and
    interchangeable biological products.

        Question 7b. How do you plan to work with the medical and patient
    community to educate them about biosimilars to avoid inaccurate
    perceptions--like those that are still prevalent about generic drugs
    over 30 years since Hatch-Waxman?
        Answer 7b. FDA has a multi-phase plan for communicating with
    stakeholders about biosimilars. The first phase of communication is to
    lay a solid foundation with basic definitions and descriptions about
    biosimilars that health care professionals and consumers can easily
    understand and adopt. Concurrent with the approval of Zarxio, the first
    biosimilar licensed in the United States, FDA used a number of tools to
    help reach the medical and patient community, including working with
    stakeholder groups, including professional associations, to share the
    details on the new approval and encouraging them to disseminate to
    their memberships; updating the consumer tools on our website,
    including development of a user-friendly consumer update, and providing
    Web content that includes background information such as definitions of
    biosimilar products and interchangeable products, information on how
    these products are prescribed, and the differences between biosimilar
    products and generic drugs. FDA plans to communicate information in
    various formats to consumers as more biosimilar products are licensed
    and enter the marketplace, and as FDA issues additional guidance on
    topics such as labeling, naming, and interchangeability. In addition to
    developing communication materials, as part of its multi-phase plan,
    FDA is conducting research on prescriber's knowledge and perceptions of
    biosimilars. This research will help inform future outreach and
    education efforts to both health care professionals and consumers.
    Moving forward, FDA will continue to implement other phases of its
    biosimilars communication plan to increase health care provider and
    consumer confidence in this new category of products.

        Question 7c. How do you plan to work with CMS and private insurers
    to help inform their biosimilar policies to be sure that they are
    consistent with science, encourage market competition, and encourage
    innovation?
        Answer 7c. While the FDA does not have a role in coverage and
    payment decisions by CMS or other insurers, however, FDA and CMS
    regularly communicate about pharmacovigilance.
        FDA recognizes that healthcare providers have consistently
    indicated the importance of assurance that biosimilars will not have
    clinically meaningful differences from the originator, or reference
    product. FDA applies a scientifically rigorous review process and
    approval standard to earn and sustain confidence in biosimilar products
    and interchangeable products. We are committed to providing this
    assurance and recognize its importance to the acceptance of these
    products, and the future success of the biosimilars program.
    Opioids
        Question 8a. America is in the midst of an opioid epidemic.
    According to the Substance Abuse and Mental Health Services
    Administration, 4.3 million Americans reported use of prescription
    painkillers for non-medical reasons in the last month, and according to
    the Centers for Disease Control, 16 million Americans died of an opioid
    overdose in 2013. Congress has signaled an especially vested interest
    in reducing the impact opioids have on pregnant women by passing the
    Protecting Our Infants Act of 2015, championed by my colleague from
    Massachusetts, Representative Katherine Clark.
        What role do you believe the FDA has in combating this epidemic?
        Answer. 8a. Misuse, abuse, addiction, and overdose of opioid
    medications have become a public health crisis in this country. FDA
    plays an important role in helping to address this issue. Our work
    supporting the development of non-opioid pain medications, the
    development of abuse-deterrent formulations of opioid drugs (including
    generics), and improving prescriber education are Agency priorities.
        I am committed to doing what we can to curb the abuse of these
    drugs. We also understand the need to balance efforts to address the
    abuse and misuse of prescription opioid medications with legitimate and
    safe use of pain medicines by patients who need them.
        Our hope is that there will be alternative treatment options for
    pain management using non-opioid pain medications. We are actively
    encouraging and supporting the development of such products.
        At the same time, FDA will continue to work to reduce the risks of
    opioid abuse and misuse, but we cannot solve this complex problem
    alone. A comprehensive and coordinated approach is needed; one that
    includes Federal, State and local governments, public health experts,
    health care professionals, addiction experts, researchers, industry,
    and patient organizations.

        Question 8b. If you are confirmed as Commissioner, what FDA
    authorities could you use to help address the opioid crisis?
        Answer 8b. FDA will act within its authorities, based on science,
    to address the opioid crisis. When appropriate, the Agency is using its
    expedited programs to speed the development of products like non-opioid
    pain medications, abuse-deterrent formulations and formulations of
    naloxone that are easier to use.
        Also, FDA can require a risk evaluation and mitigation strategy
    (REMS) when necessary to ensure that the benefits of a drug outweigh
    the risks. In 2012, using this authority, FDA required manufacturers to
    make available continuing education programs on opioid prescribing
    practices for prescribers. Under the REMS for extended-release/long-
    acting (ER/LA) opioid analgesics, manufacturers have also developed a
    patient-friendly counseling tool for prescribers to give to every
    patient, when they write a prescription for an ER/LA opioid. The REMS
    also includes a product-specific Medication Guide to be provided to the
    patient when they pick up their prescriptions. Included in these
    materials is information on how to safely store medications, while
    still in use, and what to do with the leftover supply, when it is no
    longer needed. We are in the process of evaluating the effectiveness of
    the ER/LA opioid analgesics REMS and whether any changes are
    appropriate.
        Additionally, FDA held a public meeting and opened a public docket
    in February 2013 to hear from researchers, patients, health providers
    about issues concerning opioids, including the approved labeling for
    opioid medications and how it is used in clinical practice.
        We listened and reviewed the science. As a result, FDA required
    important changes to the labeling of all ER/LA opioid analgesics. In
    April 2014, we finalized these required changes to the labeling for
    these drugs, changing their indication to inform prescribers that these
    drugs should only be used for pain severe enough to require daily,
    around-the-clock, long-term opioid treatment for which alternative
    treatment options are inadequate to provide sufficient pain relief. At
    the same time FDA significantly strengthened the safety warnings for
    these opioids. We want prescribers to use these medicines with care,
    and today the labeling for ER/LA opioid medicines have some of the most
    serious warning language that can be found in drug labeling, including
    a boxed warning about their potential for abuse, and clear language
    that calls attention to their potentially life-threatening risks.
        There are additional existing post-marketing requirements for all
    of the ER/LA opioid analgesics that include a requirement to conduct
    one or more studies to provide quantitative estimates of the serious
    risks of misuse, abuse, addiction, overdose, and death associated with
    long-term use of opioid analgesics for management of chronic pain,
    among patients prescribed ER/LA opioid products.\28\ We are working
    with sponsors to develop this information and these studies are
    currently underway.
    ---------------------------------------------------------------------------
        \28\ http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/
    ucm367726.htm.

        Question 8c. How do you plan to expand our knowledge base about the
    safety of all drugs in pregnant and lactating women?
        Answer 8c. Understanding that adequate information on the use of
    medications in pregnant and lactating women is extremely sparse, the
    Agency supports efforts to spur greater research and development in
    these patient populations. Such efforts must focus on building a
    greater foundation for both the quality and quantity of research, such
    as basic pharmacokinetic data, as well as addressing key policy issues
    that hinder additional research on the use of drugs in pregnant and
    lactating women.
        Of note, the Agency intends to publish two revised guidances to
    reflect the Agency's current thinking regarding expert/scientific
    opinions and to ethical issues surrounding clinical evaluation of drugs
    used in pregnancy and lactation. These revised policy documents, DRAFT
    Guidance for Industry: Clinical Lactation Studies--Study Design, Data
    Analysis & Recommendations for Labeling, and DRAFT Guidance for
    Industry: Pharmacokinetics in Pregnancy--Study Design, Data Analysis,
    and Impact on Dosing and Labeling are in the final stages of the
    drafting process. In addition, following the May 2014 Pregnancy
    Registry Public workshop, the Agency has been engaged in revision of
    the Guidance for Industry: Establishing Pregnancy Exposure Registries
    to reflect key conclusions from this public meeting.
        The Agency is also focused on improving communication of known
    information on the use of prescription drug and biological products in
    pregnant and lactating women in the labeling of these products. On
    December 4, 2014, the ``Content and Format of Labeling for Human
    Prescription Drug and Biological Products: Requirements for Pregnancy
    and Lactation Labeling'' rule, also known as the Pregnancy and
    Lactation Labeling Rule (PLLR), was published in the Federal
    Register.\29\ The rule went into effect on June 30, 2015. The rule
    amends the Physician Labeling Rule\30\ requirements for how information
    is presented in the pregnancy and lactation subsections of labeling for
    prescription drugs and biological products. The rule replaces the
    product letter categories--A, B, C, D and X--used to classify the risks
    of using prescription drugs during pregnancy with a description of
    risks within the real-world context of caring for pregnant women who
    may need prescription drug and/or biological products. These changes in
    product labeling will help ensure labels more effectively communicate
    important health information where prescribing decisions during
    pregnancy and lactation are generally individualized and involve
    complex maternal, fetal and infant risk-benefit considerations. The
    PLLR content and formatting requirements provide a more consistent way
    to include relevant information about the risks and benefits of
    prescription drugs and biological products used during pregnancy and
    lactation based on available information.
    ---------------------------------------------------------------------------
        \29\ Content and Format of Labeling for Human Prescription Drug and
    Biological Products, Requirements for Pregnancy and Lactation Labeling
    (79 FR 72063, December 4, 2014).
        \30\ Requirements on Content and Format of Labeling for Human
    Prescription Drug and Biological Products, published in the Federal
    Register (71 FR 3922; January 24, 2006).
    ---------------------------------------------------------------------------
        There is a major need to invest in clinical research in pregnant
    women. The success of treatment of congenital and childhood diseases
    has dramatically increased the need for pharmacologic treatment of
    chronic diseases during pregnancy. Yet, we have only a fraction of the
    information that we have obtained in children, because very few studies
    have been done. Recent FDA rules have improved the labeling of drugs
    for pregnant women because the old pregnancy letter category system was
    overly simplistic and often misleading. The new format is structured to
    more clearly describe available data that can be used to aid in complex
    risk/benefit discussions between prescribers and their patients.
    However, in many cases there is still a lack of high-quality data to
    inform about the risks of a drug when used during pregnancy. In such
    cases, the new labeling format also includes required statements to
    communicate that data are lacking.

                         Comprehensive Clinical Trials
    [GRAPHICS NOT AVAILABLE IN TIFF FORMAT]

        [Whereupon, at 12 p.m., the hearing was adjourned.]