    [Senate Hearing 110-384]
    [From the U.S. Government Publishing Office]

                                                            S. Hrg. 110-384

            DRUG USER FEES: ENHANCING PATIENT ACCESS AND DRUG SAFETY

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

                                    HEARING

                                     OF THE

                        COMMITTEE ON HEALTH, EDUCATION,
                              LABOR, AND PENSIONS

                              UNITED STATES SENATE

                           ONE HUNDRED TENTH CONGRESS

                                 FIRST SESSION

                                       ON

        EXAMINING ENHANCING PATIENT ACCESS AND DRUG SAFETY RELATING TO
                 PRESCRIPTION DRUG USER FEES, INCLUDING S. 484

                                   __________

                                 MARCH 14, 2007

                                   __________

     Printed for the use of the Committee on Health, Education, Labor, and
                                    Pensions

      Available via the World Wide Web: http://www.gpoaccess.gov/congress/
                                     senate

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              COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS

                   EDWARD M. KENNEDY, Massachusetts, Chairman

    CHRISTOPHER J. DODD, Connecticut     MICHAEL B. ENZI, Wyoming,
    TOM HARKIN, Iowa                     JUDD GREGG, New Hampshire
    BARBARA A. MIKULSKI, Maryland        LAMAR ALEXANDER, Tennessee
    JEFF BINGAMAN, New Mexico            RICHARD BURR, North Carolina
    PATTY MURRAY, Washington             JOHNNY ISAKSON, Georgia
    JACK REED, Rhode Island              LISA MURKOWSKI, Alaska
    HILLARY RODHAM CLINTON, New York     ORRIN G. HATCH, Utah
    BARACK OBAMA, Illinois               PAT ROBERTS, Kansas
    BERNARD SANDERS (I), Vermont         WAYNE ALLARD, Colorado
    SHERROD BROWN, Ohio                  TOM COBURN, M.D., Oklahoma

               J. Michael Myers, Staff Director and Chief Counsel

               Katherine Brunett McGuire, Minority Staff Director

                                      (ii)

                                C O N T E N T S

                                   __________

                                   STATEMENTS

                                 MARCH 14, 2007

                                                                       Page
    Kennedy, Hon. Edward M., Chairman, Committee on Health,
      Education, Labor, and Pensions, opening statement..............     1
        Prepared statement...........................................     2
    Enzi, Hon. Michael B., a U.S. Senator from the State of Wyoming,
      opening statement..............................................     4
        Prepared statement...........................................     5
    Mikulski, Hon. Barbara A., a U.S. Senator from the State of
      Maryland, statement............................................     6
    Von Eschenbach, M.D., Andrew, Commissioner of Food and Drugs.....     8
        Prepared statement...........................................    10
    Burr, Hon. Richard, a U.S. Senator from the State of North
      Carolina,......................................................    19
    Brown, Hon. Sherrod, a U.S. Senator from the State of Ohio.......    21
    Coburn, Hon. Tom, a U.S. Senator from the State of Oklahoma......    23
    Allard, Hon. Wayne, a U.S. Senator from the State of Colorado,
      statement......................................................    26
    Witczak, Kim, Founder of WoodyMatters, Minneapolis, MN...........    30
        Prepared statement...........................................    32
    McClelland, Mark, M.D., Ph.D., American Enterprise Institute.....    36
        Prepared statement...........................................    38
    Burlington, D. Bruce, M.D., Executive Vice President, Quality,
      Regulatory and Safety, Wyeth Pharmaceuticals...................    44
        Prepared statement...........................................    46
    Dorman, Diane Edquist, Vice President, Public Policy, National
      Organization for Rare Disorders................................    49
        Prepared statement...........................................    51

                              ADDITIONAL MATERIAL

    Statements, articles, publications, letters, etc.:
        Prepared statements of:
            The FDA Alliance.........................................    66
            The American Society of Health-System Pharmacists........    67
            Michael Fitzpatrick, Executive Director, National
              Alliance on Mental Illness (NAMI)......................    73
        Response to questions of Senator Kennedy by:
            Kim Witczak..............................................    75
            D. Bruce Burlington, M.D.................................    77
            Stephen R. Mason, HHS Acting Assistant Commissioner for
              Legislation............................................    79
        Response to questions of Senator Enzi by:
            Kim Witczak..............................................    76
            D. Bruce Burlington, M.D.................................    78
            Stephen R. Mason, HHS Acting Assistant Commissioner for
              Legislation............................................    83
        Response to questions of Senator Burr by Stephen R. Mason,
          HHS Acting Assistant Commissioner for Legislation..........    83
        Response to questions of Senator Hatch by Stephen R. Mason,
          HHS Acting Assistant Commissioner for Legislation..........    83

                                     (iii)

            DRUG USER FEES: ENHANCING PATIENT ACCESS AND DRUG SAFETY

                                  ----------

                           WEDNESDAY, MARCH 14, 2007

                                           U.S. Senate,
           Committee on Health, Education, Labor, and Pensions,
                                                        Washington, DC.
        The committee met, pursuant to notice, at 10:21 a.m., in
    Room SD-430, Dirksen Senate Office Building, Hon. Edward M.
    Kennedy, chairman, presiding.
        Present: Senators Kennedy, Mikulski, Brown, Enzi, Burr,
    Coburn, and Allard.

                      Opening Statement of Senator Kennedy

        The Chairman. We will come to order. I thank our witnesses
    today for their understanding and their patience. We will get
    started on our hearing.
        So I welcome our committee's members and our distinguished
    witnesses today on today's hearing on improving the drug user
    fee program and enhancing drug safety. Patients across the
    Nation look with hope to our biotechnology, our pharmaceutical
    research to develop medical breakthroughs for the illnesses
    they face. Every day that such breakthroughs are delayed is
    another day of hope denied for patients afflicted with cancer,
    Parkinson's disease, spinal cord injury, or other serious
    illnesses.
        We in Congress have a responsibility to see that the FDA
    has the expertise, the information and resources it needs to
    make the right decisions as quickly as possible for the
    patients who need such treatments. Obviously, the need for
    swift review does not mean that drugs should be rushed to the
    market regardless of proper safety precautions. A review
    conducted with inadequate regard for safety subjects patients
    to unacceptable risks of serious side effects or even death.
        The user fee program that the committee considers today is
    an attempt to strike the right balance. Its goal is to give the
    FDA the support it needs to review new drugs as swiftly as
    proper regard for safety allows. Most drugs are now approved
    first in the United States, due in part to the user fee
    program, which has reduced both review times and approval times
    for new drugs. I commend FDA and the biotechnology and
    pharmaceutical industries for having reached agreement on
    recommendations to Congress for the renewal of this essential
    program.
        All of us are committed to moving this authorization
    through Congress as quickly as possible. The user fee program,
    however, demonstrates the failure by Congress to give FDA the
    funds it needs to do the job that the American public counts on
    it to do. Congress ought to correct this failing so the FDA
    does not have to rely excessively on user fees for its basic
    budget.
        Thorough reviews are essential in assuring drug safety, but
    the commitment to safety does not stop when the initial review
    is completed. As the recent Institute of Medicine report
    emphasized, there must be a life cycle approach to drug safety
    that includes both a thorough initial review and ongoing
    reviews to oversee safety through the life cycle of the drug.
        Part of the ongoing responsibility for assuring safety is
    to take effective action to protect patients from unacceptable
    risks that are detected after drugs reach the market. The
    approach described by the IOM is at the heart of the bipartisan
    legislation that Senator Enzi and I have introduced on drug
    safety. Our legislation gives FDA clear authority to reduce
    label changes after drug approval to make certain that
    additional safety studies are conducted where needed. Our
    proposal includes a structure to oversee safety that is
    flexible enough to be tailored to the unique characteristics of
    each new drug and strong enough to protect patients from
    unacceptable risks.
        I will include the rest of my statement in the record and
    ask Senator Enzi if he would say a word.
        [The prepared statement of Senator Kennedy follows:]

                     Prepared Statement of Senator Kennedy

        I welcome our committee members and our distinguished
    witnesses to today's hearing on improving the drug user fee
    program and enhancing drug safety.
        Patients across the Nation look with hope to our
    biotechnology and pharmaceutical research to develop medical
    breakthroughs for the illnesses they face. Every day that such
    breakthroughs are delayed is another day of hope denied for
    patients afflicted with cancer, Parkinson's disease, spinal
    cord injury, or other serious conditions.
        We in Congress have a responsibility to see that FDA has
    the expertise, the information and resources it needs to make
    the right decisions as quickly as possible for the patients who
    need such treatments. Obviously, the need for swift review does
    not mean that drugs should be rushed to market, regardless of
    proper safety precautions. A review conducted with inadequate
    regard for safety subjects patients to unacceptable risks of
    serious side effects, or even death.
        The user fee program that the committee considers today is
    an attempt to strike the right balance. Its goal is to give FDA
    the support it needs to review new drugs as swiftly as proper
    regard for safety allows. Most drugs are now approved first in
    the United States, due in part to the user fee program, which
    has reduced both review times and approval times for new drugs.
    I commend FDA and the biotechnology and pharmaceutical
    industries for having reached agreement on recommendations to
    Congress for the renewal of this essential program. All of us
    are committed to moving the reauthorization through Congress as
    quickly as possible.
        The user fee program, however, demonstrates the failure by
    Congress to give FDA the funds it needs to do the job that the
    American public counts on it to do. Congress ought to correct
    this failing, so that FDA does not have to rely excessively on
    user fees for its basic budget.
        Thorough reviews are essential in assuring drug safety, but
    the commitment to safety does not stop when the initial review
    is completed. As the recent Institute of Medicine report
    emphasized, there must be a life cycle approach to drug
    safety--that includes both a thorough initial review and
    ongoing reviews to oversee safety throughout the life cycle of
    the drug. Part of the ongoing responsibility for assuring
    safety is to take effective action to protect patients from
    unacceptable risks that are detected after drugs reach the
    market.
        The approach described by the IOM is at the heart of the
    bipartisan legislation that Senator Enzi and I have introduced
    on drug safety. Our legislation gives FDA clear authority to
    require label changes after drug approval, and to make certain
    that additional safety studies are conducted where needed. Our
    proposal includes a structure to oversee safety that is
    flexible enough to be tailored to the unique characteristics of
    each new drug, and strong enough to protect patients from
    unacceptable risks.
        The same goal of improving safety and protecting patients
    also underlies the legislation that our colleague, Senator
    Dodd, has introduced with Senator Grassley on the issue.
    Senator Dodd was among the first to recognize that
    Congressional action is needed to improve drug safety, and I
    commend him for his vision and leadership in this important
    area.
        Although there are significant differences in our two
    bills, their basic goal is identical--to see that consumers
    receive the best, most effective, and safest drugs possible.
    Our bills also share the goal of giving patients and doctors
    access to the best possible information about risks and
    benefits when they choose among different drugs to treat a
    disease. I look forward to working with Senator Dodd, and all
    the members of the committee on these important issues.
        It's an honor to welcome all of our distinguished witnesses
    to today's hearing, but it is a particular pleasure to welcome
    Dr. Andrew von Eschenbach for his first hearing in which the
    word ``Acting'' has been removed from his title as Commissioner
    of FDA. The agency needs a strong, effective and confirmed
    leader, and I commend our colleagues, and particularly the
    skillful chairmanship of Senator Enzi, for enabling FDA once
    again to have a confirmed Commissioner at the helm.
        We are also graced today by the presence of one of his
    illustrious predecessors as Commissioner, Dr. Mark McClellan. I
    understand that he comes to us after attending a conference
    that IOM convened on this issue on Monday.
        I also welcome, Ms. Kim Witczak, who will describe in
    personal terms the tragic loss that can occur when we fail to
    get it right on drug safety.
        I also welcome Diane Dorman of the National Organization
    for Rare Disorders and Dr. Bruce Burlington of Wyeth
    Pharmaceuticals who will provide valuable perspective from the
    viewpoints of patients and the pharmaceutical industry on this
    important issue.
        Your recommendations will help guide our committee and
    Congress as we take up the vital work of renewing the drug user
    fee program and giving FDA the resources and authority it needs
    to do the job that American families are counting on it to do.

                       Opening Statement of Senator Enzi

        Senator Enzi. Thank you, Mr. Chairman. I appreciate your
    holding this important hearing. We are here today to talk about
    reauthorizing the prescription drug user fee program, more
    widely referred to as ``PDUFA.'' The prescription drug user fee
    program is a tried and tested program. It's a successful
    partnership between industry and the Food and Drug
    Administration. FDA must meet rigorous timeframes for the
    review of important new drug therapies for patients. Through
    fees on drug manufacturers, PDUFA has enabled the partners to
    meet these deadlines while still preserving patient safety.
        However, where we are today is not where we need to be
    tomorrow. We are not a rear view mirror country. We are a pedal
    to the metal country. We are always optimistic. We are looking
    to the future and at how to make things better.
        While the PDUFA program is a strong system the public can
    count on, it can and should be improved. In the early 1990s,
    AIDS and cancer advocates picketed in the front of the Parklawn
    Building at the FDA demanding faster access to lifesaving
    drugs. At that time new therapies were being approved in other
    countries, while there was a significant lag of time before
    they were approved in the United States. Americans were dying
    because of this drug lag.
        While the drug lag has now shifted to other countries and
    most drugs are now approved first in the United States,
    patients still want safe drugs, but don't want to suffer or die
    while waiting for them. Increasing access to lifesaving drugs
    initially drove the goals of the drug user fee program,
    resulting in even faster approvals. This has had a tremendous
    effect on the number of available new therapies, particularly
    for such conditions as AIDS and cancer.
        We are now at a point at which approvals are probably as
    fast as they can or should be and attention is turning back to
    safety issues. Of course, a drug that is never approved is
    completely safe, but this is not a tradeoff that Americans are
    willing to make. So now our challenge is getting back to basics
    and moving toward a model in which increasing access also
    includes an increased focus on activities directed toward
    identifying and managing safety issues.
        We can and should achieve these goals, increasing both
    access and safety. This improved, integrated approach entails
    rapid pre-market evaluation of innovative new therapies
    combined with tracking and evaluating safety issues in the
    postmarket setting over the entire lifespan of the product. An
    example of the drugs that should be continually monitored are
    those that have turned fatal diseases into chronic conditions.
    The safety issues associated with a drug that is taken for
    years are different than one that's taken for a week. On the
    one hand, patients with a life-threatening disease may be more
    willing to take a drug with risks, but if they may be on that
    drug for years they also want to know about side effects and
    weigh safety and access differently.
        I believe the FDA needs new authorities to acquire and
    evaluate safety information and act on it promptly. Senator
    Kennedy and I have introduced legislation to grant the agency
    those new authorities. Our proposal creates robust systems to
    collect, assess, evaluate, and respond quickly to safety
    information.
        In addition to the new authorities, I believe we need to
    examine the persistence of some of the very conditions that led
    to the enactment of PDUFA. The users fees were never intended
    to supplant appropriations. They were intended to supplement
    appropriated funds. While the industry has committed ever-
    increasing amounts of money, the agency has committed to
    meeting ever more ambitious performance goals. As part of the
    reauthorization of this program, we must ask ourselves what
    sort of commitment we, the Congress, need to make to this
    agency. We must review our financial commitment to the program
    and be open to rethinking what we have agreed to do in the
    light of evidence that funding is currently not sufficient to
    do all we require of the FDA.
        I have a number of statements from outside groups and I
    would ask unanimous consent that they be entered in the hearing
    record.
        [The prepared statement of Senator Enzi follows:]

                       Prepared Statement of Senator Enzi

        Thank you, Mr. Chairman, for holding this important
    hearing. We are here today to talk about reauthorizing the
    Prescription Drug User Fee program, or more widely referred to
    as PDUFA.
        The Prescription Drug User Fee program is a tried and
    tested program. It is a successful partnership between industry
    and the Food and Drug Administration (FDA). FDA must meet
    rigorous timeframes for the review of important new drug
    therapies for patients. Through fees on drug manufacturers,
    PDUFA has enabled the partners to meet the deadlines, while
    still preserving patient safety. However, where we are today is
    not where we need to be tomorrow.
        We are not a ``rear view mirror'' country. We are a pedal
    to the metal country--always optimistic and looking to the
    future--always looking at how to make things better. While the
    PDUFA program is a system the public can always count on, it
    can and should be improved.
        In the early 1990's, AIDS and Cancer advocates picketed in
    front of the Parklawn Building at the FDA demanding faster
    access to life saving drugs. New therapies at that time were
    being approved in other countries, and there was ``drug lag''
    of sometimes years before they were approved in the United
    States. Americans were dying because of this ``drug lag.''
        While the ``drug lag'' has now shifted to other countries
    and most drugs are now approved first in the United States,
    patients still want safe drugs but don't want to die waiting
    for them. Increasing access to life saving drugs initially
    drove the goals of the drug user fee program resulting in ever
    faster approvals. This has had a tremendous effect on the
    number of available new therapies, particularly for conditions
    such as AIDS and cancer.
        We are now at a point at which approvals are probably as
    fast as they can or should be, and attention is turning back to
    safety issues. A drug that is never approved is completely
    safe. But this is not a tradeoff that Americans are willing to
    make. So now our challenge is getting back to basics and moving
    towards a model in which access includes an increased focus on
    activities directed toward identifying and managing safety
    issues. We can and should achieve both goals--access and
    safety.
        This better approach entails rapid pre-market evaluation of
    innovative new therapies combined with tracking and evaluating
    safety issues in the postmarket setting over the entire life
    span of the product. An example is the many drugs which have
    turned fatal diseases into chronic conditions. The safety
    issues associated with a drug that is taken for years are
    different than one that is taken for a week. On the one hand,
    patients with a life threatening disease may be more willing to
    take a drug with risks, but if they may be on that drug for
    years, they also want to know more about side affects and weigh
    safety and access differently.
        I believe the FDA needs new authorities to acquire and
    evaluate safety information and act on it promptly. Senator
    Kennedy and I have introduced legislation to grant the agency
    those new authorities. Our proposal creates robust systems to
    collect, assess, evaluate, and respond quickly to safety
    information.
        In addition to the new authorities, I believe we need to
    examine the persistence of some of the very conditions that led
    to the enactment of PDUFA. The user fees were never intended to
    supplant appropriations--they were intended to supplement
    appropriated funds. The industry has committed ever-increasing
    amounts of money. The agency has committed to meet ever more
    ambitious performance goals. As part of the reauthorization of
    this important program, we must ask ourselves what sort of
    commitment we, the Congress, need to make to this agency. We
    must review our financial commitment to the program and be open
    to rethinking what we have agreed to do in light of the
    evidence that funding is currently not sufficient to do all we
    require of FDA.
        I have a number of statements from outside groups. I ask
    Unanimous Consent that they be entered into the hearing record.
        Again, I thank the Chairman for holding this hearing and
    the witnesses for agreeing to participate. I look forward to
    hearing your testimony today.

        [Information referred to may be found in Additional Material.]

        The Chairman. It will be so ordered.
        Senator Enzi. And again, I thank you for holding this
    hearing.
        The Chairman. Thank you very much.
        We always try to accommodate our members' schedules and I
    know that Senator Mikulski, who has a special interest
    obviously in the FDA, wishes to be recognized to say a word. We
    welcome her, her comment, because I know she has to----

                         Statement of Senator Mikulski

        Senator Mikulski. Senator, if you wanted to go right to the
    questions, I would be happy to come after you and Senator Enzi.
        The Chairman. Well, we were going to hear from Dr. von
    Eschenbach, so maybe----
        Senator Mikulski. Fine. I think that's well taken.
        I must go to a Defense Appropriations hearing. The Army's
    testifying and of course the issues of Army medicine from acute
    care all the way through to long-term care will be very much on
    the agenda.
        To my colleagues and also to our director of FDA, first of
    all, FDA is very important I think to the Nation and certainly
    to me as the Senator from Maryland. I think that there is among
    the constellation of Federal agencies--this is one of the most
    important agencies because it stands sentry over the safety of
    our food supply and the safety over our drug supply.
        There are those who question whether the agency can do
    both. That will not be the purpose of this hearing, but I think
    it should be the purpose of further discussion.
        The concerns that are being raised are: Does FDA have the
    right resources? I believe we have all fought for the right
    resources and we will be looking at the framework for that. But
    what I'm talking about today is the right leadership. Now, Dr.
    von Eschenbach, I supported your nomination. I believe you are
    a professional. I knew your work at the National Cancer
    Institute. But we need your help and we need your leadership.
        What I am deeply concerned about is, No. 1, the perception
    that FDA has been politicized, and where it has been
    particularly focused has been on the Office of Women's Health,
    that first of all we felt that Dr. Wood was pressured out when
    she was head of the FDA of Women's Health because she spoke out
    on Plan B. We feel that the office was downgraded when your
    predecessor's predecessor put in a veterinarian to head up the
    Office of Women's Health.
        Then No. 3, most recently you have said that you were going
    to downgrade the financing of this office. And yet we do know
    that there are gender differences or certain drugs that do
    pertain particularly to women, both for acute care and then
    long-term care, chronic management. Certainly the hormone
    replacement therapy shows what I'm talking about. So we need to
    hear from you your commitment, No. 1, to an agency that is not
    political and that, No. 2, it's not perceived as political; and
    then also to reinstitute the Office of Women's Health that has
    strong support from all the women in the Senate, and my
    colleague Senator Snowe and I have been particular leaders on
    that.
        No. 3, we are also looking for an independent way of
    reviewing the drugs, particularly in a postdrug surveillance. I
    could list from acne drugs to Vioxx to others. We need your
    help and we need your leadership. You come from an outstanding
    background of clinical practice. I know it from the research
    and being at NCI. Now help us create once again the confidence
    that we have in FDA where we work on the right resources, but
    we need the right leadership.
        I will have other questions if my time permits, and if not
    I will be willing to follow up with these with you in any way
    that you deem appropriate in the most collegial way.
        The Chairman. Thank you. Thank you very much, Senator
    Mikulski. Those are good.
        I would hope that in your comments you can include
    responses to those questions, if you would.
        We are glad to have you back here, Dr. von Eschenbach. As a
    physician, you know this is essential to have as many effective
    medicines as possible, treat patients under the care, and as a
    cancer survivor and a former patient you know it's just as
    important patients have confidence in the safety of the
    medicines they rely on to improve their health and extend their
    lives. We look forward to hearing your perspective and
    recommendations on the drug user fee and on the important drug
    safety issues and any other comments that you wish to make.
        We thank you for coming back to the committee and for all
    of your help to the committee that you continue to provide.
    Thank you.

    STATEMENT OF ANDREW VON ESCHENBACH, M.D., COMMISSIONER OF FOOD
                               AND DRUGS

        Dr. von Eschenbach. Thank you very much, Mr. Chairman,
    Senator Enzi, and other members of the subcommittee.
        Let me begin by first thanking you all for the tremendous
    support and commitment that you have made to the Food and Drug
    Administration as we continue to serve the American people by
    protecting and promoting their health. Let me say at the
    outset, in response to Senator Mikulski's comments----
        The Chairman. Is your mike on? There you go. Thank you.
        Dr. von Eschenbach. Thank you, sir.
        Let me say at the outset that as I have come to the Food
    and Drug Administration both in the role of Acting Commissioner
    and now as the confirmed Commissioner, I am adamantly committed
    to the fact that this agency will be both a science-based and a
    science-led organization with regard to its decisions in order
    to promote and protect the public health.
        I'm pleased to be here today to both propose and emphasize
    the importance of reauthorizing the Prescription Drug User Fee
    Act, commonly known as PDUFA. This is the fourth time that
    Congress will consider PDUFA reauthorization, having first
    passed the PDUFA package in 1992 and the third reauthorization
    having occurred in 2002.
        Today's proposal builds on that past experience and
    includes significant modifications that will further improve
    the program and assure the funds provided by these fees not
    only enhance the efficiency of processing of applications for
    new drugs and biologics, but more importantly contribute to the
    safety of those products. The new proposal, referred to as
    PDUFA IV, outlines the fee structure and the services supported
    by those fees and includes application fees, establishment
    fees, and product fees, and a separate provision for providing
    for reviews of direct-to-consumer advertising.
        Let me state and emphasize that these are fee for service,
    much like any fee paid to process any application. They in no
    way will or do affect the decisions regarding those
    applications. Although funds are largely used to support
    personnel costs, this is an administrative accounting function
    and reviewers typically have no direct knowledge of the source
    of those funds.
        With regard to the structure of PDUFA IV, there are a few
    key points I would like to emphasize this morning. First, I am
    also grateful for the cooperation of industry to arrive at a
    proposal that's satisfactory to industry and the FDA and, most
    importantly, a proposal that is good for the American people.
    The proposal provides a revenue stream that is much more
    aligned with the services we will be providing. For example, it
    provides for additional revenues that support drug application
    consultation meetings at all stages of drug development. These
    are labor-intensive meetings, but they are good for industry
    because they can prepare better applications. They are good for
    the FDA because they enhance our efficiencies. And they are
    good for the American people because they get products to
    patients more quickly.
        The fees also now better match the full cost of the
    personnel required, and this is important because it will
    assure the industry of our ability to meet goals. It will help
    the FDA to avoid any unexpected shortfalls, and the structure
    is good for the public because it leverages public funds with
    private funds to ensure a strong drug review system.
        PDUFA IV builds on the foundation that was established in
    PDUFA III to use these fees to directly address issues with
    regard to safety. It enhances the utilization of resources that
    are dedicated to the safety of these products throughout their
    entire life cycle. For example, in the premarket arena PDUFA IV
    will help to minimize the risk of adverse events by funding
    development of guidance documents that will assist in the
    development of clinical trial and trial designs that will
    improve our ability to define efficacy as well as safety.
        In the postmarket arena, PDUFA IV triples the PDUFA
    investment in postmarketing safety that will provide and enable
    more tools to help detect and mitigate unforeseen and
    unexpected risks after drugs are approved and are available to
    wide diverse populations.
        Every drug has benefits and risks, but effective risk
    management requires us to learn about these products long after
    their approval and utilization. Safety initiatives included in
    PDUFA IV include, among others, developing epidemiologic best
    practices to survey populations, expanding our database and
    database mining resources, developing and validating risk
    management tools, improving communication and coordination
    between the various components, and, most importantly,
    eliminating our 3-year limitation on the use of funds to
    monitor drugs in the postmarketing setting, which will enable
    us to track drugs throughout their entire life cycle.
        Mr. Chairman, as I conclude I must emphasize that PDUFA III
    expires on September 30, 2007 and in order to maintain this
    trajectory of continuous improvement and this process and
    maintaining the infrastructure that's been established it is
    critical that reauthorization occur seamlessly without any gap
    between the expiration of the old law and enactment of PDUFA
    IV. FDA is ready to work with you and other members of this
    committee to accomplish this outcome.
        We value the input from Congress, patients, and the medical
    community as we are engaged in a continuous, ongoing effort to
    develop and refine drug safety initiatives, including the
    continued effort as recently announced in our response to our
    Institute of Medicine study that we commissioned and in
    launching our drug safety commitment.
        We thank you for your support and your commitment to the
    mission of FDA as we all collectively continue to protect and
    promote the health of the American people.
        Thank you and I'm happy to entertain your questions.
        [The prepared statement of Dr. von Eschenbach follows:]
               Prepared Statement of Andrew von Eschenbach, M.D.
                                  introduction
        Mr. Chairman and members of the committee, I am Andrew von
    Eschenbach, Commissioner at the Food and Drug Administration (FDA or
    the Agency). I am pleased to be here today to discuss the Agency's
    success in implementing the Prescription Drug User Fee Act (PDUFA) and
    to emphasize the importance of reauthorizing this law well in advance
    of its September 30, 2007, expiration date. I will summarize highlights
    of our proposal for PDUFA IV and take this opportunity to share my
    vision for the future of FDA's drug safety program and to present a few
    of the initiatives and opportunities that we have embraced.
                                   background
        FDA's review of new drug applications (NDAs) and biologics license
    applications (BLAs) is central to FDA's mission to protect and promote
    the public health.
        In 1992 Congress enacted PDUFA, intending to reduce the time
    necessary for new drug application review, and subsequently has
    reauthorized it twice. The most recent reauthorization of PDUFA
    directed FDA to consult with the House Committee on Energy and
    Commerce, the Senate Committee on Health, Education, Labor, and
    Pensions, appropriate scientific and academic experts, health care
    professionals, patient representatives, consumer advocacy groups, and
    the regulated industry in developing recommendations for PDUFA
    reauthorization. We have complied with these requirements in preparing
    our PDUFA IV proposal.
                               pdufa achievements
        PDUFA has produced significant benefits for public health,
    including providing the public access to 1,220 new drugs and biologics.
    During the PDUFA era, FDA reviewers have approved:

         76 new medicines for cancer;
         178 anti-infective medications (including 56 for treatment
    of HIV or Hepatitis);
         111 medicines for metabolic and endocrine disorders;
         115 medicines for neurological and psychiatric disorders;
    and
         80 medicines for cardiovascular and renal disease.

        In addition, PDUFA implementation efforts have dramatically reduced
    product review times. While maintaining our rigorous review standards,
    we now review drugs as fast as or faster than anywhere in the world.
    The median approval time for priority new drug and biologic
    applications has dropped from 14 months in fiscal year 1993 to only 6
    months in fiscal year 2006. For standard NDAs, the median approval time
    was 22 months in fiscal year 1993. By fiscal year 2006 median approval
    times had declined to 16.2 months for standard NDAs.
                             fda goals for pdufa iv
    1. Sound Financial Footing
        User fees have provided substantial resources to FDA, but these
    resources have not kept up with the increasing costs of the program due
    to inflation or the expanding review workload. The PDUFA III provision
    for adjusting fees has not adequately accounted for actual growth in
    costs and workload. Therefore, we are proposing changes for the PDUFA
    IV financial provisions to correct for these shortcomings.
        For example, in PDUFA IV we recommend changing the calculation of
    inflation adjustment to include the actual FDA rate of increase in
    costs of salary and benefits per full-time employee (FTE) over the most
    recent 5-year period.
        Additionally, the surrogates and workload adjusters should more
    accurately reflect Agency activity. The workload adjuster contained in
    PDUFA III did not provide adequate accounting of the volume of FDA
    review activities. For example, since fiscal year 2000, meetings
    scheduled at the request of drug sponsors grew by 72 percent, up to
    2,288 meetings in fiscal year 2006--this translates to more than nine
    formal meetings per business day. PDUFA IV would include adjustments
    for the growth in the number of meetings and special protocol
    assessments for investigational new drug applications, and labeling
    supplements and annual reports for the NDA and BLA workload surrogates.
        To pay for these proposals for sound financial footing, as well as
    for enhancements to premarket and postmarket review, discussed below,
    we are recommending that PDUFA fees be increased by approximately $100
    million, to an estimated total of $393 million in fiscal year 2008.\1\
    This amount would be adjusted in later years based on measured changes
    in inflation and workload.
    ---------------------------------------------------------------------------
        \1\ The exact amount will be determined when we have the final-year
    workload data for PDUFA III. That number would be used to calculate the
    exact fee amounts for fiscal year 2008, the first year of PDUFA IV.
    ---------------------------------------------------------------------------
    2. Enhance Process for Pre-Market Review
        For PDUFA IV, FDA recommends enhancements in two areas for the pre-
    market review process: (1) expanding implementation of Good Review
    Management Practices (GRMPs) developed under PDUFA III and (2)
    additional initiatives designed to help expedite drug development. In
    the area of GRMPs, we propose to further implement the principles and
    goals outlined in the 2005 Guidance for Review Staff and Industry on
    Good Review Management Principles and Practices for Prescription Drug
    User Fee Act Products (2005 Guidance), enhancing the efficiency and
    effectiveness of our review process. One area that we will focus on is
    developing a planned timeline for the review of the application with
    attention to important work such as: (1) discussion of labeling and
    post-marketing study commitments; (2) decisionmaking; and (3)
    documentation of such decisions in the administrative record by the
    signatory authority. By providing such a timeline, applicants will
    better understand FDA's review plan and when to expect feedback from
    the Agency on important issues such as application deficiencies,
    labeling, and post-marketing study commitments.
        The PDUFA IV proposal also includes increased user fees to fund
    additional staff resources to further enhance the science base of our
    review processes, including developing guidance documents to assist in
    clinical drug development. By clarifying the Agency's expectations on
    important topics such as clinical trial design, we can allow the
    industry to focus their efforts on useful trials and decrease less
    useful experimentation. Increased resources will also free up reviewer
    time enabling greater participation in scientific training and research
    collaborations that will ultimately help clarify regulatory pathways
    for development of promising future therapies.
        Last, the PDUFA IV proposal allocates funds to further improve the
    information technology (IT) infrastructure for Human Drug Review and
    increase the efficiency of the review process.
    3. Modernize and Transform the Post-Market Drug Safety System
        FDA would use the proposed PDUFA IV funds to strengthen the drug
    safety system, particularly the Agency's efforts to address the full
    life cycle of drug products. This effort includes the initiatives
    identified as most critical by our Office of Surveillance and
    Epidemiology (OSE) and provides resources that will facilitate
    collaboration between the Office of New Drugs and OSE, as recommended
    by the Institute of Medicine (IOM).
        Our recommendations for PDUFA IV would triple the amount of user
    fee revenue available to improve the post-market drug safety system. We
    also propose to eliminate the current statutory time limit that
    restricts user fee funding of drug safety activities to the first 3
    years that a drug is on the market, so that PDUFA IV fees could fund
    drug safety activities on a marketed product at any time in the drug's
    life-cycle. Eliminating the statutory time limitation will enable
    assessments of drug products over time to adequately manage drug risks,
    regardless of approval date.
        As part of this effort, we would adopt new scientific approaches to
    improve the utility of existing tools for the detection, evaluation,
    prevention, and mitigation of adverse events associated with drugs and
    biological products. In addition, FDA would use these funds to continue
    to enhance and improve communication and coordination between pre- and
    post-market review staff, a recommendation proposed by IOM in their
    September 2006 Report.
        More specifically, PDUFA IV fees would allow FDA to procure
    external research to determine the best way to maximize the public
    health benefits associated with the collection and reporting of adverse
    events throughout a product's life cycle. Such studies would attempt to
    answer such central questions as: (1) the number and types of safety
    concerns that are discovered by various types of adverse event
    collection; (2) the age of the medical products at the time such safety
    concerns are detected; and (3) the types of actions that are
    subsequently taken and their ultimate effect on patient safety.
        The increased funds in PDUFA IV also would allow FDA to gain input
    from academia, industry, and others in the public to identify
    epidemiology best practices. This would inform our development of a
    guidance document that addresses epidemiological best practices and
    scientifically sound observational studies using quality data sources.
        Another critical part of the transformation of the drug safety
    program supported under PDUFA IV would be maximizing the usefulness of
    tools used for adverse event detection and risk assessment. PDUFA IV
    funds would be used to obtain access to additional drug safety
    information such as population-based epidemiological data and other
    types of observational databases, as well as to hire additional
    epidemiologists, safety evaluators, and programmers.
        PDUFA IV also would allow us to develop a plan to: (1) identify,
    with input from academia, industry, and others from the general public,
    risk management tools and programs for the purpose of evaluation; (2)
    conduct assessments of the effectiveness of identified Risk
    Minimization Action Plans (RiskMAPS) and current risk management and
    risk communication tools; and (3) conduct annual systematic review and
    public discussion of the effectiveness of one or two risk management
    programs and one major risk management tool.
        In addition, FDA would hold a public workshop to obtain input from
    industry and other stakeholders regarding the prioritization of the
    plans and tools to be evaluated. By making such information available
    to industry, we would promote effective and consistent risk management
    and communication.
        To ensure the best collection, evaluation, and management of the
    vast quantity of safety data received by FDA, we would use the
    additional PDUFA IV funds to improve our safety-related IT systems. We
    would improve our IT infrastructure to support a safety workflow
    tracking system, access to externally linked databases, and enhance the
    Agency's surveillance tools.
    4. Review of Direct-to-Consumer (DTC) Advertising
        We also are proposing a new program to assess fees for advisory
    reviews of DTC television advertisements. Research has shown benefits
    associated with DTC prescription drug television advertising, such as
    informing patients about the availability of new treatment options and
    encouraging patients to see a physician about an undiagnosed illness.
    However, some have expressed concerns that DTC advertisements may
    overstate benefits or fail to fairly convey risks.
        Currently, companies have the option of submitting their planned
    advertisements to FDA for advisory review before public dissemination.
    This approach provides the benefit of FDA input on whether or not the
    advertisements are accurate, balanced, and adequately supported,
    enabling advertisements to be changed, if necessary, before they are
    shown to the public.
        Companies recognize the benefits this advisory review mechanism
    offers. However, though FDA's DTC advisory review workload has been
    steadily increasing, our staffing for this activity has remained
    relatively level. As a result, it is impossible for FDA to review all
    of the DTC television advertisement advisory submissions it receives in
    a timely manner.
        Therefore, we propose creating a separate program to assess,
    collect, and use fees for the advisory review of prescription drug
    television advertisements. These user fees would not be funded by
    application, product, or establishment fees assessed under PDUFA.
    Instead, these new fees would be assessed separately and collected only
    from those companies that intend to seek FDA advisory reviews of DTC
    television advertisements. This program would provide for increased FDA
    resources to allow for the timely review of DTC television
    advertisement advisory submissions and ensure FDA input on whether or
    not the advertisements are accurate, balanced, and adequately
    supported.
        To ensure stable funding for the program in case the number of
    advisory submissions fluctuates widely from year to year, the program
    would assess a one-time participation fee to be placed in an operating
    reserve. The program would then charge fees each year for each advisory
    review requested. These new fees would provide sufficient resources for
    FDA to hire additional staff to review DTC television advertising
    submissions in a predictable, timely manner. FDA anticipates collecting
    $6.25 million in annual fees during the first year of the program (and
    a similar amount to go into an operating reserve fund) to support 27
    additional staff to review DTC television advertising. Advisory review
    fee amounts would be adjusted annually for inflation and to take into
    account increases in workload. As part of this program, FDA is
    proposing to commit to certain performance goals including review of a
    certain number of original advisory review submissions in 45 days and
    resubmissions in 30 days. The goals would be phased in over the 5 years
    of the program to allow for the recruitment and training of staff.
                   fda's commitment to the drug safety system
        New drugs, devices, and diagnostics present a significant
    opportunity to improve health care. In general, the number of lives
    saved and extended by new therapies vastly outweighs the risks that the
    treatments themselves pose. Nevertheless, ensuring the safety of drugs
    and other medical products regulated by FDA has always been a key focus
    of our commitment to protect and promote the public health. In the past
    few years, FDA has reassessed its drug safety programs because of the
    rapid advances in science and technology resulting in increasing
    complexity of medical products as well as the increased attention to
    safety-related issues by consumer advocates, health professionals,
    academic researchers, and Members of Congress.
        FDA has a proud, 100-year record of being the world's gold standard
    and we have maintained this record by our willingness to look
    internally to see what transformations are necessary to sustain this
    standard. For this reason, the Agency asked IOM to study the
    effectiveness of the U.S. drug safety system, with an emphasis on the
    postmarketing phase, and to assess what additional steps FDA could take
    to learn more about the side effects of drugs as they are actually
    used.
        On September 22, 2006, IOM released its report entitled The Future
    of Drug Safety--Promoting and Protecting the Health of the Public. The
    report recognized the progress and reform already initiated by the
    Agency. We have implemented an aggressive effort, including developing
    new tools for communicating drug safety information to patients,
    Through our Critical Path initiative, we are working to improve the
    tools we use and to more effectively evaluate products and processes,
    working with our health care partners.
        The IOM report makes substantive recommendations about additional
    steps FDA can take to improve our drug safety program. We believe the
    proposed PDUFA fees provide FDA the resources needed to improve its
    record on drug safety. We have the regulatory and statutory authority
    needed to carry out our commitment to ensure drug safety as outlined in
    January of this year and hope to work with the committee to evaluate
    any proposals to ensure that any legislation improves drug safety
    without new burdens and mandates that could drive up costs or harm
    patient access.
    1. Strengthening the Science
        First, I am committed to strengthening the science that supports
    our medical product safety system at every stage of the product life
    cycle, from pre-market testing and development through postmarket
    surveillance and risk management. We will focus our resources on three
    areas of scientific activity: (1) those relating to improving benefit
    and risk analysis and risk management; (2) surveillance methods and
    tools; and (3) incorporating new scientific approaches into FDA's
    understanding of adverse events. As discussed above, we propose that
    these activities be supported, in part, by PDUFA IV funds.
        Specifically, new scientific discoveries are generating an emerging
    science of safety that will help prevent adverse events by improving
    the methods used in the clinic to target a specific drug for use in
    patients for whom benefits relative to risks are maximized. This new
    science combines an understanding of disease and its origins at the
    molecular level (including adverse events resulting from treatment)
    with new methods of signal detection, data mining, and analysis. This
    approach enables researchers to generate hypotheses about and to
    confirm the existence and cause of safety problems, as well as explore
    the unique genetic and biologic features of individuals that will
    determine how he or she responds to treatment. This science of safety
    encompasses the entire life cycle of a product, from pre-market animal
    and human safety testing to widespread clinical use beyond original
    indications and should be used for all medical products so that safety
    signals generated at any point in the process will robustly inform
    regulatory decisionmaking.
    2. Improving Communications
        Second, I am committed to improving communication and information
    flow among all stakeholders to further strengthen the drug safety
    system. This will require a comprehensive review and evaluation of our
    risk communication tools with the benefit of Advisory Committee
    expertise, improving communication and coordination of safety issues
    within FDA.
        One example of our efforts to improve communication is establishing
    a new advisory committee to obtain input to improve the Agency's
    communication policies and practices and to advise FDA on implementing
    communication strategies consistent with the best available and
    evolving evidence. We will include patients and consumers on the
    committee as well as experts in risk and crisis communication and
    social and cognitive sciences. Although IOM's report recommends
    legislation to establish this Advisory Committee, we intend to
    implement this recommendation more expeditiously through administrative
    procedures.
    3. Improving Operations and Management
        Finally, I am committed to improving operations and management to
    ensure implementation of the review, analysis, consultation, and
    communication processes needed to strengthen the U.S. drug safety
    system. We need to improve the culture of safety at FDA, and in the
    Center for Drug Evaluation and Research (CDER). Under my direction,
    CDER has initiated a series of changes designed to effect a true
    culture change that will strengthen the drug safety system. CDER has
    moved to reinvigorate its senior management team and charged its
    members with the responsibility to lead the Center in an integrated
    manner that crosses organizational lines.
        CDER has employed process improvement teams comprising staff in
    various organizations including Office of Surveillance and Epidemiology
    (OSE) and Office of New Drugs (OND) to recommend improvements in the
    drug safety program. Their recommendations to: (1) establish an
    Associate Director for Safety and a Safety Regulatory Project Manager
    in each OND review division within CDER and (2) conduct regular safety
    meetings between OSE and all of the OND review divisions are now being
    implemented. We are committed to providing the necessary management
    attention and support to effect sustained culture change in our drug
    safety program.
        We have recently engaged external management consultants to help
    CDER develop a comprehensive strategy for improving CDER/FDA's
    organizational culture. In addition to the ongoing FDA activities to
    improve how our organization supports the individuals who work on
    safety issues in the FDA, we are enlisting the help of external experts
    in organizational improvement to help us identify additional
    opportunities for change and assist us with carrying out those needed
    changes.
                                   conclusion
        PDUFA III expires on September 30, 2007, and I re-emphasize the
    importance of achieving a timely reauthorization of this law. FDA is
    ready to work with you to accomplish this goal. If we are to sustain
    our record of accomplishment under PDUFA III, it is critical that the
    reauthorization occur seamlessly without any gap between the expiration
    of the old law and the enactment of PDUFA IV. Any hesitation or delay
    in the reauthorization of this program could trigger sudden erosion in
    our workforce, particularly among senior reviewers whose skills are in
    very high demand. The repercussions of such a loss would be with us for
    years to come.
        At FDA, providing the American public with safe and effective
    medical products is a core component of our mission. We base decisions
    to approve a drug, or to keep it on the market if new safety findings
    surface, on a careful balancing of risk and benefit to patients. This
    is a multifaceted and complex process. The recent initiatives we have
    announced will improve our current system to assess and advance drug
    safety.
        As always, we value input from Congress, patients and the medical
    community as we develop and refine these drug safety initiatives. Thank
    you for your commitment to the continued success of PDUFA and to the
    mission of FDA. I am happy to answer questions you may have.

        The Chairman. Thank you very much.
        I will be glad to recognize Senator Mikulski first and then
    Senator Enzi, if she has to go.
        Senator Mikulski. Well, Senator, thank you for the
    courtesy. And I know we have a vote at 11:15 and I'm going to
    dash to my hearing.
        Dr. von Eschenbach, do you want to respond to the points
    that I made, particularly about the Office of Women's Health?
    And then I have one other question about the after-drug
    surveillance. But most of all this perception of politicization
    and also that somehow or another the Office of Women's Health
    has become a flashpoint and therefore it at times seems
    administratively punished.
        Dr. von Eschenbach. Thank you, Senator. I first of all
    absolutely share with you your passion and your commitment to
    addressing the issues that are unique to women with regard to
    the issue of both effectiveness as well as risks associated
    with drugs and pharmaceuticals. And to that point, one of the
    important initiatives that I proposed in the 2008 budget was to
    enhance the effort that is currently under way and currently
    has been supported by the women's health initiative with regard
    to doing research in our Center for Toxicologic Research in
    Arkansas that is specifically looking at the genetic basis for
    gender differences and specifically the reason why----
        Senator Mikulski. Doctor, I don't want to interrupt. I
    really--I want to make sure that we view this as a courteous--
    but the question is, that in the budget, we were talking about
    the women, the Office of Women's Health losing 25 percent of
    its funding. And the office was meant to go across lines to
    ensure that perspective was there, just the way Senator DeWine
    made sure children were being included.
        Dr. von Eschenbach. Well, I do not understand the source of
    that perception or misperception, because in fact we have not
    finalized, and we are in the process of submitting that to
    Congress this week--our plan for the 2007 budget. I was
    referring to the proposal that I testified to with regard to
    our 2008 budget and the commitment to an initiative
    specifically addressing women's health.
        Let me state, Senator, that there is no intention
    whatsoever to minimize or reduce our commitment to addressing
    issues related to women's health, nor any effort to minimize
    the important role and the resources that are operative in the
    Office of Women's Health. This is not my intent and it is not
    what our plan is currently considering.
        Senator Mikulski. Well, I appreciate that answer. Senator
    Snowe and I would like to know specifically then what are the
    resources that are needed that should be specified in both the
    authorizing and then also as we go forth in the appropriations.
    Senator Snowe is not a member of this committee, but I told her
    that we were going to have this conversation.
        My second question--and I appreciate that. Let's go to
    postdrug surveillance. One of the things that concerned me when
    the vaccine came out to prevent cancer through sexually
    transmitted diseases and Merck was that you need to take three
    shots at about $460 a pop, and we were talking about 9-year-
    olds getting this. I was concerned that, regardless of, now you
    have approved this, what does this mean in terms of
    surveillance, postdrug surveillance, to a vaccine for not an
    infectious--an infectious disease like a parasite?
        There was a lot of concern, particularly in the pediatric
    community and adolescent health community. We all want to
    prevent cancer. You have been one of the leading researchers.
    But then here was a new concept, a vaccine to prevent cancer,
    and the vaccine was going to be given to children who might be
    sexually promiscuous with then no post anything surveillance.
    Could you tell us how this would work in this particular
    situation?
        Dr. von Eschenbach. The vaccination against the virus,
    human papilloma virus, which would then mitigate and prevent
    the risk of subsequent diseases associated with that virus,
    including cancer, FDA approved that vaccine based on the
    demonstration of its effectiveness and its safety. Now, what we
    also need to do is continue to monitor and track that vaccine
    as a process of research, because there are still unanswered
    questions.
        Senator Mikulski. But how would it work? If we do PDUFA IV,
    how then would you have the tools to do that? We are talking
    about 9-year-olds getting a vaccine against sexually
    transmitted, in case they engage in sexual promiscuity. It's
    not like a 21-year-old.
        Dr. von Eschenbach. There are research projects that would
    address a sub-population of the overall population, that would
    be able to define subsequent questions that still need to be
    answered. For example, the need for revaccination or unexpected
    adverse events.
        Senator Mikulski. Well, would PDUFA pay for this or is this
    done through other ways?
        Dr. von Eschenbach. Well, the primary responsibility rests
    with the sponsor and with the producer of the vaccine to carry
    on ongoing trials regarding subsequent----
        Senator Mikulski. Is that mandatory? Is that mandated?
        Dr. von Eschenbach. With regard to that specific vaccine, I
    would have to answer that for the----
        Senator Mikulski. I don't think it is. Now, you see, this
    then comes back to--I know my time is up and the Chairman and
    the Ranking Member have been very courteous. What then do we
    leave on the drug company? This is a nonjudgmental phase and
    what then does FDA's responsibility for ongoing monitoring or
    mandating that as subject to an ongoing post-clinical
    distribution review? Do you see what I'm saying?
        Dr. von Eschenbach. Yes.
        Senator Mikulski. So, and again, so Merck has got this
    vaccine out. Several governors are rushing to make it
    mandatory. I'm not getting into that policy debate, but if you
    have got a 9-year-old taking this type of vaccine I think we
    need to be able to follow that, and I think that needs to be a
    mandated process. And then it's the question of then who pays
    for it or what kind of partnership.
        My time is up, but you see where I'm heading here?
        Dr. von Eschenbach. Yes, ma'am.
        Senator Mikulski. And where PDUFA comes in. So I think we
    have a lot of good work to do and I really look forward to
    working with my chairman and the ranking member. This is one of
    the most important public policy issues we will be addressing.
        Thank you so much.
        Dr. von Eschenbach. Thank you, Senator.
        The Chairman. Thank you, Senator. Very important.
        Senator Enzi.
        Senator Enzi. Thank you, Mr. Chairman.
        We began this reauthorization process for PDUFA with a
    November 2005 meeting and there have been extensive
    negotiations between the agency and industry since that time,
    as well as further public participation in the process. Now, as
    you mentioned, we are facing disastrous consequences if this
    program is allowed to expire on September 30th. But so far we
    haven't received all of the PDUFA IV proposal. We got part of
    it yesterday and we are still missing the second half, which
    outlines the agency performance goals.
        I was hoping we would get to see that before this hearing
    and be able to study it to make this hearing as worthwhile as
    possible. Can you give me a timeframe as to when we are going
    to get that final problem resolved and when we will see the
    final proposal?
        Dr. von Eschenbach. Senator Enzi, we continue to work
    directly with you, your staff, the rest of the committee staff,
    continuing to move this process through the administrative
    structure to get all of the details and all of the final parts
    and pieces of this proposal before you. Clearly, there is a
    great deal of complexity that's been associated with this
    particular process and we are trying to expedite that as
    quickly as possible.
        I would expect that this will occur within a matter of
    perhaps a few weeks, to have the entire package before you.
        Senator Enzi. September 30th is coming up fast, and we
    can't do our work until you have done your work. So I hope you
    will put a lot of emphasis on getting that done.
        Dr. von Eschenbach. It's an extremely high priority for us
    at the FDA and we are working with other parts of the process
    to get this to you as rapidly as possible, while at the same
    time being certain that we have addressed all of the specific
    issues and details that are necessary in order to make certain
    that the proposal is sound.
        Senator Enzi. I will have a considerably more detailed
    question to nail that timeframe down a little bit better as a
    written question.
        I would like to hear more about how the FDA will use some
    of the large patient databases to conduct drug safety studies.
    Can you tell me how this is happening now and how that's going
    to change under PDUFA IV?
        Dr. von Eschenbach. This is an extremely important part of
    our ongoing commitment to a comprehensive approach to product
    safety, including not just drugs and biologics, but devices.
    And that's the opportunity to look at the full life cycle.
        With regard to postmarketing, there are opportunities for
    us now to access databases that are being developed, for
    example, in large health care plans, where there is significant
    information regarding the utilization of drugs and particularly
    combinations that patients may be taking, the ability to detect
    signals of adverse outcomes that might be occurring in that
    diverse population.
        What we will be doing is first of all partnering with those
    kinds of health care systems, currently United Health. We have
    signed a memorandum of understanding with the Veterans
    Administration. We will be working with the Center for Medicare
    and Medicaid Services. By accessing those databases and then
    bringing to that modern tools of information technology,
    including sophisticated data mining, things that are operative
    in other areas, like banking and finance, we will begin to have
    a system in place that will actively, not just simply passively
    but actively, early on be able to give us insights into
    unexpected adverse outcomes that are occurring in a real world
    population, if you will.
        Senator Enzi. Thank you. I have several other questions,
    but I will submit those in writing and get some more definite
    answers.
        The Chairman. Just quickly, Commissioner, when do we expect
    to get the MDUFA, you know, the device industry? A long history
    of complexity in getting that aspect approved. But are you
    somewhat hopeful that this is moving ahead? I thought we had
    that behind us.
        Dr. von Eschenbach. I have been working very directly, have
    worked very directly with the industry in an effort to continue
    to accelerate that process. Mr. Chairman, we currently have a
    proposal that has met and addressed all of the major issues.
    There appears to be one particular area that still needs
    further resolution.
        But again, as with PDUFA, it's an area in which we want
    very much to accelerate that process. I cannot give you a
    specific time line on that, but it is a high priority.
        The Chairman. If you think there's a way Senator Enzi and I
    we can be helpful, because this is a key aspect and is
    enormously important, please let unknow.
        On the issues of dividing, separating drug review and drug
    safety programs at FDA, some of us have mentioned that. Maybe
    we could get your position on that. There are some on the
    committee that feel that that's the best way to go. Others
    think that--and a patients' group, that that may slow down some
    of the potential drugs. Your view?
        Dr. von Eschenbach. I agree, Mr. Chairman, in principle
    with the need for a very distinct and very clear focus on both
    sides of the equation, the efficacy and the adverse events that
    could occur with the drug. However, I do not believe that those
    two processes should be separated. I believe that with the new
    tools that are emerging in molecular medicine we actually will
    benefit in the future from having much greater integration of
    those two aspects of understanding the drug. There are animal
    models that are being developed, for example, that will enable
    us to see both sides of that issue almost simultaneously as we
    apply a drug.
        I do believe that it's important that we create systems
    within that environment that allows for vigorous and, even if
    not necessarily aggressive, debate of both sides of that
    equation. But that should all be done within an integrated
    framework rather than silos that would actually, I think, in
    the long run perhaps do more harm than good.
        The Chairman. Just finally, that Institute of Medicine
    report on drug safety raised concerns over the culture at FDA,
    and the report described an organizational culture in crisis.
    You had indicated that you were going to try and deal with this
    issue. Could you comment about what steps you have taken to try
    and deal with this?
        Dr. von Eschenbach. Yes, sir. We have taken a number of
    steps to address the issue, beginning with the construct, Mr.
    Chairman, that I believe that the ideal opportunity for us is
    to create an environment in which we actually promote and
    stimulate diversity of thought, diversity of perspective, and
    an aggressive debate and discussion of those various aspects
    within the decisionmaking process regarding drugs.
        Structuring that in an environment that allows that to
    occur, putting processes and mechanisms in place, are what we
    are currently engaged in as we speak. We are looking at
    opportunities for conflict resolution. We have taken
    responsibility and ownership to continue to promote this within
    the Office of the Commissioner. I have recently established
    within the Deputy Commissioner for Policy an Office of
    Integrity and Accountability that will look at our internal
    issues with regard, for example, as to how we manage conflict
    of interest.
        We are developing guidances for our advisory committee
    functions so that we can bring a richness of information and
    insight and input into that decisionmaking process.
        So it is a multifactorial approach to a culture of
    diversity of thought that results in the best decision for the
    American people.
        The Chairman. Thank you. We had a very good hearing the
    other day on follow-on biologics, and if you at the agency have
    some views on that we would like to have them, but we need them
    rapidly. But we appreciate any guidance you can help us with.
        Dr. von Eschenbach. I look forward to that.
        The Chairman. Thank you.
        Senator Burr.

                                  Senator Burr

        Senator Burr. Thank you, Mr. Chairman.
        Welcome, Dr. von Eschenbach. It's my understanding that
    PDUFA IV negotiations are complete. We haven't received
    everything. Let me ask you, if the Kennedy-Enzi bill were in
    fact passed, would you have to renegotiate PDUFA IV?
        Dr. von Eschenbach. The negotiation of the package that has
    been finalized and negotiated did not include provisions that
    may be contained in the outcome of Senator Kennedy and Senator
    Enzi's bill.
        Senator Burr. So the answer is you would have to go back
    and renegotiate the entire user fee.
        Dr. von Eschenbach. We would have to find additional
    resources.
        Senator Burr. Thank you.
        Do you agree that the Kennedy-Enzi bill incorporates many
    of the drug safety tools that the FDA currently has under its
    existing RISKMAP program?
        Dr. von Eschenbach. We have been continuing to be anxious
    to provide technical support for Senator Kennedy and Senator
    Enzi's bill. I believe that there are opportunities for us with
    regard to our RISKMAP program to continue to enhance our
    ability to make certain that with certain products we have in
    place a very well-
    defined trajectory of being able to monitor and modulate drugs
    that are of concern.
        Senator Burr. Well, there are no Risk Evaluation Mitigation
    Strategies, ``REMS'' for the acronym. REMS must include a drug
    label. You currently require a drug label at the FDA?
        Dr. von Eschenbach. Yes, we do.
        Senator Burr. It requires quarterly and annual reports on
    adverse events. You currently do that through MEDWATCH, and are
    there any other?
        Dr. von Eschenbach. We have an adverse events reporting
    system which we are continuing to improve, of which MEDWATCH is
    a component as part of our passive surveillance.
        Senator Burr. They have pharmacovigilance statements and
    justifications indicating whether routine adverse events are
    adequate or whether postmarketing studies or clinical trials
    are needed. You currently have the capabilities at the FDA and
    do exercise the requirement of postmarketing studies as needed.
    Is that correct?
        Dr. von Eschenbach. Yes, sir. We are working with companies
    to develop postmarketing studies that would be necessary for
    particular drugs.
        Senator Burr. The last requirement that they have within
    REMS is a timetable for periodic assessment of REMS, which
    since there's no REMS you currently don't have that. It says
    REMS may include MEDGUIDE or patient package insert. We
    currently require a package insert, don't we, at the FDA for
    pharmaceuticals?
        Dr. von Eschenbach. Yes, sir.
        Senator Burr. Communication plan to health care providers.
    Do we currently have a communication plan to health care
    providers?
        Dr. von Eschenbach. Yes, sir, we have the means to do that.
        Senator Burr. Postapproval studies. Again, we concluded you
    do have that capability today and do utilize it.
        Dr. von Eschenbach. Yes, sir.
        Senator Burr. Post-approval clinical trials, is that a
    power that exists at the FDA today?
        Dr. von Eschenbach. We can ask for clinical trials, yes,
    sir.
        Senator Burr. Pre-clearance of direct-to-consumer ads. It's
    my understanding that that's negotiated in PDUFA IV.
        Dr. von Eschenbach. Yes, sir. We have a provision for fees
    that would enable us to enhance that opportunity to screen and
    advise.
        Senator Burr. A 2-year ban on direct-to-consumer
    advertising, that's currently not something that you have at
    the FDA and currently something that probably would reach a
    constitutional test; you would agree?
        Dr. von Eschenbach. There may be constitutional questions
    with regard to first amendment rights.
        Senator Burr. Restrictions on distribution or use. You
    currently have the ability to put restrictions on use and
    distribution. You do have some restrictions on use and
    distribution based upon certain products?
        Dr. von Eschenbach. Yes, sir.
        Senator Burr. That would also include training, wouldn't
    it?
        Dr. von Eschenbach. It could.
        Senator Burr. A system to implement, monitor, and evaluate
    the restrictions on distribution and use. So you do have a
    tracking mechanism now that tells you if people are following
    the restrictions that you put on distribution and use?
        Dr. von Eschenbach. We can access that kind of data.
        Senator Burr. Let me just say, I think you have all the
    tools that are currently in this bill. They may not be
    statutorily, but you have got regulations that cover it. I had,
    I know, with Dr. Coburn a very lengthy conversation in 1997
    when we passed FDAMA with Dr. Kessler.
        Our attempt was to try to set up a surveillance mechanism
    postapproval. We thought surveillance was the absolute key and
    at that time Dr. Kessler felt that MEDWATCH was the correct
    tool. I think over time we have seen that MEDWATCH was not as
    effective as Dr. Kessler might have thought. There's still a
    need for a surveillance program today, but I would suggest that
    the Kennedy-Enzi bill is not a surveillance program; it is
    taking FDA regulation and statutorily putting it in the law.
        Does the FDA currently have the authority to require
    postmarket studies?
        Dr. von Eschenbach. In certain circumstances.
        Senator Burr. Looking at the numbers from an FDA notice
    published in the Federal Register as of September 30, 2006,
    only 3 percent of the NDA companies delayed postmarket studies.
    Now, I found that to be extremely low. Is that a correct
    assumption on my part?
        Dr. von Eschenbach. There are a variety of reasons why
    there is the potential for delay in the institution of studies
    and one of the----
        Senator Burr. So the 3 percent should not be a great
    concern?
        Dr. von Eschenbach. I think it would depend on the
    particular study and the importance of it.
        Senator Burr. Do you think that the press coverages of the
    drug safety issue really display the facts of how well the FDA
    executes the regulations that are at your disposal?
        Dr. von Eschenbach. Well, I think when one looks at the
    entire portfolio there are extraordinary stories of
    effectiveness and efficiency with regard to the FDA's activity.
    Having said that, as with all of our issues, I am constantly
    committed to a process of improvement and looking for better
    ways to improve. So the input as to how we can do that is
    certainly welcome.
        Senator Burr. Thank you. My time has expired. Mr. Chairman.
        The Chairman. Senator Brown.

                           Statement of Senator Brown

        Senator Brown. Thank you, Mr. Chairman.
        Thank you, Dr. von Eschenbach. Nice to see you again. There
    are two reasons people give, some people give, to oppose making
    the results of clinical trials publicly available. One is that
    the individuals will be scared away from taking the drugs
    because of the warnings--one of the arguments that is made is
    individuals are not sophisticated enough to really understand
    the description and analysis of the clinical trials. I think
    that's frankly pretty insulting to the American people.
         The second reason is that clinical trials would disclose
    commercial information proprietary to the drug maker. My answer
    to that is that the drug--my understanding is that the bill
    would not require the release of the results until after the
    drugs approval, on the market.
        Could you give me your thoughts on especially what we do
    with stage 2 and stage 3 clinical trials?
        Dr. von Eschenbach. I think it's very important that we
    continue to pursue a strategy of open sharing of data and
    information regarding the utilization of these drugs. I think
    there are complexities with regard to the messaging of that so
    that people fully understand risk as well as benefit.
    Oftentimes that is something that does require management in
    the context of a doctor-patient relationship and understanding
    a particular drug in particular circumstances and the value
    equation of risk versus benefit.
        So as we do that in a broad disseminated way, I think there
    are clearly important safeguards that we have to have in place
    to make certain that the public accurately interprets the
    information by virtue of the fact we have appropriately
    communicated it. So I do not have any opposition to
    communicating data. I do want to be certain we are doing it in
    the proper and appropriate way.
        Senator Brown. That sort of leads me to the whole issue of
    direct-to-consumer advertising. My father was in general
    practice for 50 years and retired in the early 1990s. He told
    me that when drugs came to market in the old days, well until
    DTC was allowed and became so common--that a drug would come on
    the market, that it would be in a medical journal, that a few
    drug reps--there weren't nearly as many then--would come to
    their offices and doctors would talk among themselves.
        So that a new drug coming on the market, it's use would
    slowly increase, and over time, over the first year or two, the
    public would, even with the mistakes that can always happen in
    clinical trials and with little injury if there was a drug with
    a problem, the public would become aware of it, as well as the
    medical community. There would be significantly fewer people
    damaged by that drug.
        Today, obviously, a drug comes to the market with the drug
    reps, with direct-to-consumer advertising, and all that
    happens. The use just starts off with the marketing campaign at
    a very high level.
        My understanding is the Kennedy-Enzi bill, which I think
    makes major progress both on the clinical trial release of
    information and on the whole direct-to-consumer advertising by
    giving you the option of delaying for 2 years, why would we not
    just directly say that we cannot--that no drug maker can do
    direct-to-consumer advertising within the first year or the
    first 2 years, until we have had a chance to see what the
    reaction to this drug is in the general public?
        Dr. von Eschenbach. One of the things I think is occurring,
    Senator, is a really significant change in the culture of
    medicine. I think patients have become much more active
    participants in their care. They are much better informed,
    because for example of the Internet and access to information.
        So I think the earlier we get information out to patients
    in the proper and appropriate way, I think the greater
    opportunity we have for them to be even better informed
    participants.
        Senator Brown. Is direct-to-consumer advertising the proper
    way, your words, compared, contrasted to how consumers can get
    their information other ways? Is the direct-to-consumer
    advertising a little too one-sided to encourage them to push
    their doctors to prescribe this instead of letting it play out
    in the population a while longer?
        Dr. von Eschenbach. I concur that direct-to-consumer
    advertising has to be done appropriately. The information has
    to be accurate and factual. I think we have seen situations in
    which it's heightened, for example, disease awareness with
    regard to, for example, depression. It's also led patients to
    better understand the options and choices that might be
    available.
        But at the same time, I fully concur with you that it's
    only a part of the communication set.
        Senator Brown. Is the FDA equipped, are you equipped, to
    make those decisions drug by drug, that this one we should
    allow direct-to-consumer advertising the day that it's on sale,
    but these others we should delay 2 years before we allow? Is
    that a decision you can make drug by drug by drug?
        Dr. von Eschenbach. At this point we can make decisions
    regarding the accuracy of the information that's being provided
    and whether it in fact is appropriate.
        Senator Brown. My understanding is that pre-clearance
    hasn't been done particularly effectively either, though. Is
    the burden a little too great? My understanding from hearings
    in the past, if I could, Senator Kennedy, is that the FDA
    really has not been able to--just in a cursory sort of way,
    pre-approve those advertisings.
        Dr. von Eschenbach. Well, one of the things with PDUFA IV
    is to enhance our resources and our ability to specifically
    address our ability to preview and prescreen and to help make
    certain that that advertising is in fact appropriate.
        Senator Brown. But if we are not given the resources--and
    as I said, I think the Kennedy-Enzi bill has made major
    progress in this, PDUFA IV. But if you don't have the resources
    to really screen this advertising, wouldn't it be better to err
    on the side of safety and say for the first year in this huge
    marketing campaign, the first year we are not, at least we are
    not going to allow the direct TV to consumer advertising?
        Dr. von Eschenbach. I think that would have to be balanced
    by what potential down side might there be by not informing
    patients of the availability of a particular opportunity. So I
    don't know that I know that value equation at this point, but
    it's certainly something I think we need to discuss and
    address.
        Senator Brown. Thank you, Dr. von Eschenbach.
        The Chairman. Senator Coburn.
        Senator Coburn. I think Senator Allard was here before me.
        The Chairman. We still use the old-fashioned rule,
    seniority, unless there's somebody who has an appointment or
    schedule conflict and we try to recognize them. The old-
    fashioned, old-fashioned way.

                                 Senator Coburn

        Senator Coburn. Dr. von Eschenbach, thank you for your
    service. It is a tough job.
        The Kennedy-Enzi bill would give the FDA authority to
    impose restrictions on the use of a drug, including, as I read
    the language, a restriction on off-label use. Is that your
    understanding?
        Dr. von Eschenbach. We are in the process of providing
    technical assistance with regard to Senator Kennedy and Senator
    Enzi's bill----
        Senator Coburn. But as it is written now, that is what it
    would do, correct?
        Dr. von Eschenbach. I would not be able to say that
    specifically, sir.
        Senator Coburn. Well, I will say it specifically. It would.
        Dr. von Eschenbach. To me that's----
        The Chairman. I think if the Senator would yield, I don't
    think that's our understanding of the legislation. I will ask
    the staff to explain it if you want to go through that, but
    that's not what our understanding is.
        Senator Coburn. All right, thank you. I will take that
    under advisement.
        The problem I have with what I see coming is that the FDA's
    going to be interfering with the practice of medicine and that
    highly concerns me. Your background is oncology. Have there not
    been hundreds of times when you have used an off-label cancer
    therapeutic drug and achieved a great benefit?
        Dr. von Eschenbach. Yes.
        Senator Coburn. There is no question about it. And the
    reason for that is because companies can not afford to do a
    clinical trial for every significant disease. And with that
    there is an informed consent, is there not, when you are using
    a drug off-label?
        Dr. von Eschenbach. There's an opportunity within the
    context of that individual patient and that doctor, as you well
    know as a physician, to be able to make a therapeutic decision
    that utilizes what's available in an effort to serve that
    patient's individual needs.
        Senator Coburn. You bet. And I am very worried about what
    this bill will do to that. I will just tell you that.
        The Kennedy-Enzi bill also would give authority to the FDA
    to restrict which providers can prescribe drugs. Now, you
    already have that?
        Dr. von Eschenbach. I am sorry, sir?
        Senator Coburn. Which providers can prescribe drugs? You
    already have that. You did that with Symlin, much to the
    negative detriment of people in rural America and in small
    towns, because they do not have access to an endocrinologist or
    a diabetologist. So therefore a drug, even, granted, with a
    narrow therapeutic index, is made available only if you live in
    a big city, which really has a constitutional question of a
    different class of citizen because you do not have access.
        The question I would raise, as I look at Symlin and its
    therapeutic index and insulin and I also look at Coumadin and
    its therapeutic index, I would wonder why the FDA wouldn't want
    to restrict what doctors could prescribe Coumadin.
        Dr. von Eschenbach. Well, I think that there is, as you
    well appreciate, a spectrum in which we approve a drug but
    under certain circumstances want to continue to define the
    utilization of that drug to populations in whom we believe that
    the safety and efficacy relationship is appropriate and not go
    beyond or outside of that where we do have reason to believe
    there will be significant adverse events.
        On the other hand, there are drugs that are appropriate for
    large populations and in which patients can make individualized
    decisions about the utilization of that drug without any
    additional restrictions on that practice of medicine.
        Senator Coburn. What do you think would happen if aspirin
    was a new drug today and had to go through the FDA?
        Dr. von Eschenbach. In terms of whether it would be
    approved?
        Senator Coburn. First of all, it would not be approved,
    would it? Five-hundred thousand to six-hundred thousand cases
    of GI bleeding a year with deaths from aspirin; transfusion
    reactions that lead to death from aspirin; kidney damage
    significant in this country from aspirin usage. It would have a
    tough time getting approved, correct?
        Dr. von Eschenbach. I think you are making the important
    point, doctor, that there is no drug that's absolutely----
        Senator Coburn. Right.
        Dr. von Eschenbach [continuing]. Always safe, nor is there
    a drug that under every circumstance is always effective. What
    we are looking for is that appropriate balance between the
    benefit to be obtained and the circumstances in which it's
    being administered versus what potential risks there might be.
        Senator Coburn. Well, one of my concerns is, for example,
    with Accutane, I am a certified provider for Accutane, done all
    the stuff and done that. But I live in a small town. I cannot
    prescribe Symlin because I am not an endocrinologist. My
    patients do not have that. Prior to coming here, I took care of
    about 400 diabetics. I cannot give them one of the latest drugs
    because you have decided that I am not capable of making those
    decisions, which gets back to the problem is the FDA
    interfering in the practice of medicine.
        So one of the things I am worried about is carrying this
    logic on further with the Kennedy-Enzi bill and what it will do
    in terms of interfering additionally in the practice of
    medicine. I think the charge under the Federal Food, Drug, and
    Cosmetic Act is safety first and efficacy second, and I see us
    moving in the direction far beyond that.
        I will stop with that. I want to answer one other thing. I
    am not a big fan of direct-to-consumer advertising, but I am a
    big fan of the Constitution, and there is no authority in the
    Constitution for the government to say what a company can
    advertise and what it cannot. It may have to be accurate and we
    can hold them accountable. But this idea of saying that the
    Congress is going to tell who has a first amendment right and
    who does not needs to get out of our head. It will never pass
    muster with the courts. It sounds great. It is a great
    political play. But drug companies have the right to advertise
    their product just like everybody else, unless they come to a
    negotiated agreement that they will not.
        But we have no business taking away or delaying a first
    amendment right on advertising. I would just take this further,
    just for a second. The way drugs used to be marketed is very
    competent, well-trained individuals, most of them pharmacists,
    would come in and teach a doctor about the drug and about its
    side effects and about its drug-drug interactions. And drugs
    were utilized, maybe not as fast as they were, but because we
    had confidence in the people who were teaching us then we would
    utilize drugs very quickly if we had a significant need and
    they provided a new solution.
        I have a lot of confidence in you, Dr. von Eschenbach, but
    I think it is very important that we are very frank with you.
    We do not put a lot of laws on the books for things you already
    have the authority to do and take judgment out of the FDA. I
    think your scientific judgment most times is very, very good.
        Dr. von Eschenbach. Thank you, sir.
        The Chairman. Senator Allard.

                          Statement of Senator Allard

        Senator Allard. Well, thank you, Mr. Chairman.
        It's a challenging day. You just got it from a physician.
    Now you are going to have to listen to a veterinarian.
        I'm glad to hear that you stressed the fact that you use
    good science and you want to make science-based decisions. I'm
    certainly very appreciative of that fact, and I know that you
    employ a lot of veterinarians within the FDA and, unknown to
    most of the populace, I think we are very highly educated and
    have got a lot of training in pharmacology. My experience
    includes both private practice as well as a health officer,
    which surprises some people now and then.
        But I am in a profession where perhaps more, I think more
    so than in human medicine, for example, cost gets to be more of
    a consideration when you move forward. So I obviously am very
    concerned about policies and what-not in the FDA that raise the
    cost of the drugs, but also I want to make sure that they are
    properly licensed and processed.
        Some of the things that I have a hard time understanding is
    that when a drug's been out on the market for 30 or 40 years--
    and we have some of those--sometimes as a practitioner, if we
    are talking about drug resistance, for example, we have found
    out that going to a very old antibiotic that hasn't been used
    much for years, you might be better able to deal with the
    resistance problem than maybe some of the newer products. So I
    think they are still useful out there, but they have an
    extensive history of being used clinically and a lot of
    scientific articles written about it.
        I don't understand sometimes the relicensing that you are
    requiring on many of those projects, when you have such a broad
    database already out there. And it is a concern that gets
    raised to me by my profession, and I would like to have you
    address that.
        Dr. von Eschenbach. Yes, sir. Thank you, doctor. One of the
    important aspects of our addressing drugs that have been out on
    the market for a long period of time, as you point out, but are
    unapproved in that they never went through the regulatory
    process, is to really take a risk management approach to that,
    a risk mitigation approach to that. Where we identify and are
    identifying drugs that with their application do in fact raise
    serious concerns, those are the drugs that we are really
    addressing from the point of view of requiring them to go
    through the appropriate processes before we would allow that
    appropriate use.
        Senator Allard. So you are looking at some of the adverse
    reaction reporting data and then using that as a selection for
    a review on a particular drug that was approved earlier?
        Senator Coburn. Also the circumstances for which the drug
    is being currently recommended. For example, if it's being
    recommended in a pediatric use, in a pediatric formulation, we
    would look at that in terms of that presenting a unique risk to
    that population.
        Senator Allard. Well, you have a real challenge as far as
    my profession is concerned because we use off-label drugs a
    lot. I'm pleased to hear a physician talk about that, because
    we deal with such a wide variety of species. And minor use is
    important. Occasionally compounding may be important, which we
    write instructions to the pharmacist to do something. So that
    becomes very important, I think. I just hope that you remain
    sensitive to that.
        I have had reported to me that pharmacies, to sometimes
    just do a color change on the label, have to go through a whole
    relicensing process and everything. And if that's true, it
    seems rather frivolous to me. I can understand if they are
    changing print size or something like that that it might be an
    issue.
        But I would like to more fully understand what you require
    when you have a relabeling and everything, if you are actually
    requiring them to retest and go through a relicensing if they
    are just changing some of the labels, like the color for
    example, is something like that a minor change? I would like to
    have an explanation.
        Dr. von Eschenbach. I would be happy to provide for you,
    Senator, for the record the framework in which those decisions
    are made. But let me say at the outset that I concur with you
    with regard to the fact that for a practitioner--veterinarian,
    physician, or pharmacist--in the context of a particular
    patient with a prescription, that the idea of being able to
    create the right compound or the right medication for that
    patient is a perfectly appropriate part of practice.
        I think our concerns at the FDA are primarily focused on
    the other end of the spectrum, where that process is being used
    essentially as a drug manufacturing process for widespread
    utilization, and that's the area of compounding that we have
    great concerns with.
        Senator Allard. So describe for me how the post-market
    safety enhancements would work with the Enzi-Kennedy drug
    safety legislation?
        Dr. von Eschenbach. As I indicated, we are in the process
    of engaging in technical assistance with regard to addressing
    the provisions of the bill. What we are working toward, what we
    are looking forward to, as I indicated in my testimony, is to
    address the full life cycle of a drug and begin to really
    utilize the opportunities in postmarket surveillance,
    particularly with the databases that are now becoming
    available, and to do that in a way that we can pick up early
    signals of adverse events and really be able to do that in a
    risk mitigation strategy that is not simply a blanket coverage,
    but really gives us an opportunity to look at risk across the
    entire spectrum.
        Senator Allard. Can you describe the need for increases in
    user fees to more adequately cover FDA's costs and what these
    increases will be used for?
        Dr. von Eschenbach. If I understand your question, Senator,
    it's with regard to how these fees will be used?
        Senator Allard. Yes.
        Dr. von Eschenbach. They are specifically intended to be a
    fee for service that is compartmentalized to enable us to
    address the ability to have the resources to efficiently
    process applications. We have broken them down in terms of
    establishment fees, product fees, and application fees.
        Senator Allard. Do you have as part of your objectives, to
    try and reduce the rules and regulations that impact private
    practice, whatever that might be?
        Dr. von Eschenbach. Well, we are not in any stretch of the
    imagination in any way lessening our rigor, discipline, and
    precision and the rules of our regulatory process. That is not
    something that we would ever embrace in an effort to make the
    process more efficient.
        Senator Allard. But you would agree that rules and
    regulations will outdate and may not be as pertinent today as
    they were 20 years ago and you ought to look for some of the
    outdated rules and regulations? Also, you may need new rules
    and regulations. But I do think you need to have a balance on
    both ends of that. That's my point.
        Dr. von Eschenbach. Yes, I fully concur with that, Senator.
        Senator Allard. Thank you.
        Dr. von Eschenbach. Thank you.
        The Chairman. Thank you very much.
        I think that this has been a good discussion. Obviously,
    what we are interested in, Senator Enzi and I, is to be
    sensitive to the dangers that have been out there, whether the
    agency really has the authority and the power to get these
    companies to make the changes that they are supposed to. Your
    only ability to get them to change is if you are going to
    withdraw the drug and that hasn't been used. Otherwise, the
    idea that they are going to do more clinical trials or take
    these other steps, there's not been a very dramatic record of
    willingness to follow along on these safety items. At least I
    haven't seen it. Maybe it's out there.
        When you look at the dangers in Vioxx, for example, the
    delay that it took 14 months because of the tensions between
    the company and the FDA prior to your watch, we begin to
    understand the necessity of making sure we are going to have
    adequate safety. I go back a while. I still remember
    Thalidomide and what happened in that danger, and we have seen
    these problems with antidepressants and the rise of suicides
    among younger children and real kinds of dangers.
        I mean, this idea that we have got an agency that is not
    going to put a very, very high level and priority in terms of
    safety, we want to get these various products out as fast as we
    can. I'm a great believer we are in the life science century;
    we ought to get them out.
        Postmarketing surveillance can do a great deal. It's taken
    us a long time to get to this point. The Europeans have been
    after this for a long, long period of time. We have been
    reluctant. Industry's been reluctant. Now they are for it and
    we are trying to do it in such a way that's going to be
    responsive to the particular kind of item, giving that kind of
    flexibility and authority to the agency.
        But it's clearly, if we are able to get--and obviously we
    are able to get information technology with higher technology
    on there and greater kind of reporting, greater kind of breadth
    in terms of the coverage. It's enormously important.
        I just talk from a personal point of view, having a son who
    was a chronic asthmatic, went to a school in Massachusetts and
    had an asthma attack and was unable to get through that asthma
    attack, went to the Lawrence Hospital in Lawrence, a first-rate
    hospital. They weren't authorized to give the kind of drug to
    him. He finally had to go back to Children's Hospital. They
    gave the drug. He was in for 5 days in a very difficult kind of
    health condition, but survived.
        Because of the high toxicity of that particular kind of
    chemical, there were five different areas around the country
    that had the authority to use that with those kinds of
    indicators on it. But it had high, high kinds of possible
    toxicity.
        He's been able to survive. He's done very, very well. We
    are going to try and bring the best that we have in terms of
    American medicine out to make sure that it's going to be
    applicable to the sickest individuals. We want to give maximum
    flexibility, but we also want to have maximum safety for
    people. And even though there are some who might think that the
    idea that we have the Institute of Medicine's recommendations
    in terms of direct advertising, it's a good deal different.
    Some would think it would be more dramatic than actually the
    ones that we have on it.
        But we want to make sure in these that the--and I would
    think most people would feel that having an agency, that you
    would feel a lot more comfortable in getting matters out into
    the public and get them out there faster and quicker if they
    have various safety guidelines on it. If you are not going to
    be able to get those safety kinds of conditions on it you are
    going to have to do a good deal more to make sure that mistakes
    aren't made.
        That's the balance that we are trying to do and it seems to
    me that we have a pretty good balance if we take what's been
    the lessons of history with the FDA and their power and how
    their suggestions and recommendations, how they have been
    treated in the past. We want to make sure that they have the
    best in terms of science, you are going to be able to get the
    best and the newest drugs out to the people in the most timely
    way, but it's going to be done understanding the issues on
    safety.
        Senator Enzi has voted early. Doctor, we want to thank you.
    We will have others. We appreciate very, very much and look
    forward to hearing from you on the biologics. I thank you very
    much for your presence here today.
        We will introduce our next panel and represent a broad and
    important range of experience, critical issues, drug safety.
    Kim Witczak is showing courage today coming to our committee to
    tell of an irreplaceable loss, calling on us to respond by
    improving drug safety. We commend her for her courage.
        The committee is honored to be hosting not only the current
    FDA commissioner, but also a distinguished predecessor, Mark
    McClellan, whose wisdom and experience on drug safety will be
    of enormous value to our committee's consideration.
        We will hear from Dr. Bruce Burlington, who served with
    great distinction at FDA for many years. He now comes from
    Wyeth Pharmaceuticals. We look forward to his perspective on
    user fees and congratulate him on his leadership in negotiating
    agreements between FDA and industry.
        And Ms. Diane Dorman, who for many years has been a
    tireless champion of the rights of patients. Her views on this
    matter are of major importance in developing the right policy
    on safety.
        We will have a brief recess. As soon as Senator Enzi
    returns, he will start the hearing, and I will be right back.
        [Recess from 11:28 a.m. to 11:37 a.m.]
        Senator Enzi [presiding]. I will call the hearing back to
    order again so that we can have the testimony from the
    witnesses and meet the next deadline that we will have on doing
    some voting here at the same time.
        Ms. Witczak.

           STATEMENT OF KIM WITCZAK, FOUNDER OF WOODYMATTERS

        Ms. Witczak. Thank you. Thank you, Mr. Chairman, members of
    the committee. Thank you for inviting me to testify here today.
    I am here to represent the voice of thousands of families who
    live every day with the consequences of the current drug safety
    system. Behind me I have Matthie Downing. She's also a family
    member. She lost her 12-year-old daughter.
        Unfortunately, I know firsthand what it's like to lose
    someone because of unsafe drugs. On August 6, 2003, my life
    changed forever. I became a widow. My husband of almost 10
    years was found dead hanging from the rafters of our garage, of
    Zoloft-induced suicide at age 37. Woody was not depressed, nor
    did he have a history of depression or any other so-called
    mental illness.
        Woody had just started his dream job as vice president of
    sales with a start-up company 2 months prior and was having
    trouble sleeping, which is not uncommon for new entrepreneurs.
    So Woody went to his general practitioner and was given Zoloft
    for insomnia. Five weeks later, Woody took his own life.
        No cautionary warning was given to him or me about the need
    to be closely monitored when first going on this drug or dosage
    changes. In fact, I was out of the country on business for the
    first 3 weeks. When I returned from business, I found Woody
    sitting in the fetal position in our kitchen floor with his
    hands wrapped around his head like a vice crying, going ``Kim,
    help me, help me; I don't know what's happening to me; my
    head's outside my body looking in; I'm losing my mind.''
        Never once, never once, did we question the drug. Why would
    we? It was FDA-approved, heavily advertised as safe and
    effective, and it was given to him by his doctor.
        From the beginning, something didn't add up about Woody's
    death. So my brother-in-law, Eric Swan, who's here, and I
    started researching the only thing that made Woody change
    during this extremely short period of time, and it was Zoloft.
    As a result, we established WoodyMatters Web site as a place, a
    concept and a place for information for consumers.
        Our journey for the truth has led us to the FDA, HHS,
    Congress, and the courts. In fact, this is our 25th trip out
    here since Woody died. In our battle for Woody, we were able to
    get confidential internal drug company and FDA documents made
    public that the suicide risk was known since the late 1980s. In
    fact, according to a 1990 internal FDA memo, Dr. David Graham
    expressed concern that he didn't think Eli Lilly adequately
    addressed the suicide risk with Prozac.
        In 1991 the FDA held a public hearing on antidepressant-
    induced suicidality in adults on Prozac. At that time the FDA
    determined that further studies were needed to look at
    suicidality. The drug companies never conducted them and FDA
    never followed up on it.
        Meanwhile, by the end of 1991 the FDA received over 17,000
    adverse event reports through the MEDWATCH. Fast forward. More
    antidepressants enter the market with millions of adults and
    now children taking the drugs. By 2004, the mounting public
    pressure and other countries reporting the link between
    antidepressants and suicide, the FDA held another public
    hearing on antidepressants and children. It ultimately led to a
    black box warning for children under 18 and the FDA agreed to
    look at clinical trials to see if the risk existed for adults.
        Just this past December 2006, 15 years after the first
    hearing, the FDA held another hearing to share their findings
    for the adults. It's interesting to note it is literally the
    same people conducting the review and approve the drugs in the
    first place. After reviewing the original clinical trial data,
    the FDA recommended that the black box warning be extended to
    adults 25 and under. My husband still would not be under that
    warning. He was 37.
        How many unnecessary deaths happened between that time
    period of 15 years? This I am afraid is our current drug safety
    system at work.
        One thing that was particularly hard for me to discover was
    the side effect that killed my husband was known very early in
    the clinical trial. I obviously hope that you amend the bill to
    include phase 2 and even phase 1 trials. It seems to me that if
    a drug is tested on a human being and there are side effects
    that emerge, life-threatening side effects, it belongs to all
    of us. This is vital information that the doctor-patient
    decision needs to have for the risk-benefit. Woody would have
    appreciated knowing this information as he was given Zoloft for
    sleep issues.
        I would also like to see a separate and independent Office
    of Drug Safety, as Senator Dodd and Grassley have proposed. It
    is telling that the current office is called Surveillance and
    Epidemiology, not exactly a clear message to the public. A
    separate office with power to regulate and not just negotiate
    is vital. In the mean time, there should be posters hanging
    around the FDA that say ``Safety First,'' like on every
    construction site in America.
        I have offered an idea and a solution in my written
    statement that addresses the power struggle between the pre-
    and the post-market offices.
        Let's talk technology. The FDA needs to be funded into a
    21st century organization. Its Web site is in drastic need of
    updating. It's confusing and needs to be redone, making it
    consumer-friendly and searchable. A separate section needs to
    be dedicated specifically to drug safety and all the names that
    the drugs use. A lot of times I hear the FDA using the actual
    chemical name as opposed to what it is marketed to the consumer
    as.
        The MEDWATCH system needs to be updated in electronic
    reporting so that it is easy to use by doctors and consumers.
    It needs to be promoted to the public so they know it exists.
    There is a survey that was done and only 2 percent of the
    public knows that MEDWATCH, the FDA even has a MEDWATCH system.
        I believe if DTC advertising is a must or is going to be
    here to stay, that we need an 800 number or the medwatch.gov
    Web site should be required at the end of every drug
    commercial, that consumers know that they can write to the FDA
    and report, because the real clinical trial happens when
    millions of people take the drugs. Consumers need to be a part
    of the drug safety system and the FDA has to be able to use
    that and search it.
        You, in a sense, are the board of directors and we are the
    shareholders. We need you to fix this system, this agency, to
    protect us.
        In conclusion, as you guys debate FDA reform I want you to
    remember Woody, for his story represents countless of Americans
    who have personally paid the price. Your decisions have real
    life consequences. When I leave Washington and go back to
    Minneapolis, I will go back to an empty house of shattered
    dreams. I will never grow old with Woody and have children with
    him. All I have are pictures and memories of a life cut too
    short. But you have the ability and the responsibility to
    change this. Please bring the FDA back to the gold standard it
    once was.
        Thank you.
        [The prepared statement of Ms. Witczak follows:]
                       Prepared Statement of Kim Witczak
        Mr. Chairman, Senator Enzi, members of the committee, thank you for
    inviting me to testify today.
        I am here today to represent the voice of thousands of families who
    live every day with the consequences of the current drug safety system.
    Unfortunately, I know first hand what it feels like to lose someone
    because of unsafe drugs. On August 6, 2003, my life changed forever. I
    became a widow.
        My husband of almost 10 years was found dead hanging from the
    rafters of our garage of Zoloft-induced suicide at age 37. Tim Witczak,
    known to most as Woody, was not depressed nor did he have a history of
    depression or any other so-called mental illness. Woody had just
    started his dream job as Vice President of Sales with a start up energy
    efficient lighting company a couple months prior and was having
    difficulty sleeping which is not uncommon for new entrepreneurs. So
    Woody went to see his general physician and was given Zoloft for an
    insomnia diagnosis. Five weeks later, Woody took his own life. His
    doctor gave him a 3-week Pfizer-supplied sample pack that automatically
    doubled the dose after week one. No cautionary warning was given to him
    or me about the need to be closely monitored when first going on drug
    or dosage changes. In fact, I was out of the country on business for
    the first 3 weeks he was on Zoloft. When I returned, I found Woody one
    night in the fetal position on our kitchen floor with his hands wrapped
    around his head like a vise, crying, ``Help me, help me!'' ``I don't
    know what is happening to me. I am losing my mind. It's like my head is
    outside my body looking in.''
        Never once did we question the drug. Why would we? It was FDA-
    approved, heavily advertised as safe and effective, AND it was given by
    Woody's doctor that he has seen for years and trusted.
        From the beginning, something didn't add up about Woody's death. So
    my brother-in-law, Eric Swan and I started researching the only thing
    that made Woody change during this extremely short period of time--
    Zoloft.
        In our battle for Woody, we were able to get confidential internal
    drug company and FDA documents made public that showed the side effect
    that killed my husband and many others was known in the original
    clinical trials from the 1980s. In fact, according to a 1990 internal
    FDA memo, Dr. David Graham expressed concern that he didn't think Eli
    Lilly adequately addressed the suicide risk with Prozac. In 1991, the
    FDA held a public hearing on the antidepressant-induced suicidality in
    adults taking Prozac. At that time, the FDA determined that further
    studies were needed to look at suicidality. The drug companies did not
    conduct studies even though protocols were created. Subsequently in the
    years to follow, more antidepressants entered the market with millions
    of adults and now children taking the drugs. With mounting pressure and
    other countries reporting the link between antidepressants and suicide,
    the FDA held another public hearing in 2004 on children and
    antidepressant-induced suicidality. It ultimately led to a blackbox
    warning for children under 18 and the FDA agreed to review clinical
    trials to see if the risk exists for adults. In December 2006, 15 years
    after the first public hearing, the FDA held another hearing to share
    their findings on a link between antidepressants and suicide in adults.
    [It is interesting to note that it's literally the same people
    conducting the review and approved the drugs in the first place.] After
    reviewing the original clinical trial data, the FDA recommended that
    the blackbox warning further be extended to adults 25 and under. The
    FDA acknowledges that the suicide risk exists in people taking
    antidepressants--adults and children. Why would you confuse the public
    by not warning ALL people of the suicide risk? If my husband were still
    alive, the current FDA recommended blackbox warning would not cover him
    because he was 37 years old.
        Our journey for the truth has led us to the FDA, HHS, Congress and
    the courts. In fact, this is our 25th trip out here since Woody died.
    Unfortunately, Woody's story is not an isolated case (or anecdotal
    story). I have been working with many other families who have lost
    loved ones due to unsafe drugs and they could tell similar stories.
    WoodyMatters was founded to give a voice to Woody and our activism. The
    Web site also gives other families a chance to tell their stories and
    get information.
        I tell Woody's story in the hope that you will use the once-in-5-
    year opportunity of PDUFA extension to make fundamental reforms in FDA,
    so that other families will not have to suffer what I and so many
    others have endured.
        To be blunt, the draft agreement reached between the industry and
    the FDA is totally inadequate.
        First, let me say for the record that consumers, most legitimate
    patient groups, and the Institute of Medicine are deeply troubled by
    the whole user-fee program. The FDA is one of America's most vital
    public agencies, and its duty is to ensure the quality and safety of
    over a fifth of our economy. Its client is the American public, and
    therefore it ought to be funded totally out of the general Treasury. If
    user fees are needed in lieu of general appropriations, then there
    should be no conditions attached on how that money is spent. I support
    legislation that Rep. Maurice Hinchey proposed in the last Congress,
    which breaks the morale-destroying conditions that are part of the
    current PDUFA system.
        If breaking those ties is not possible, then we need increased
    resources for safety and the post-approval drug monitoring process--and
    we need specific goals for the use of those resources, just like
    industry gets on the pre-approval side.
        The Institute of Medicine report did not give one specific number
    for the cost of its various recommendations, but it appears to be
    between $100 million and $200 million. The draft industry-FDA agreement
    provides for only about $29 million for increased safety. Some of that
    $29 million is said to be earmarked (we would like to see the specific
    language of how that will be done) for some very worthy improvements.
    For example,

               The proposal would no longer limit how long user
            fees could be spent on a specific drug's post-market approval
            safety issues (it eliminates the current 2- to 3-year limit),
            since, as the FDA says, ``current data show that safety issues
            can arise after a drug has been on the market for 8 or more
            years'';
               PDUFA IV monies could be used to ``obtain access to
            additional databases and increase program staffing with
            epidemiologists, safety evaluators, and programmers who can use
            these new resources.''

        But all too much of the new ``safety money'' is spent on ``let's
    just do more of what we are doing,'' let's hold forums and symposia,
    let's develop ``papers.'' For pre-
    approval, industry gets specific, rapid deliverables. In postapproval
    safety, we get placebos. That's a strong statement, but look at the
    draft agreement: The industry gets 90 percent of new drug applications
    decided within a certain number of days, and requests for meetings
    answered within 2 weeks. What does the consumer public get? We get
    sentences like:

            ``. . . FDA would use these funds to continue to enhance and
            improve communication and coordination between pre- and post-
            market review staff.''

        We get phrases like:

            ``Potential activities in this area might include integration
            of certain proposed recommendations made by the [IOM].''

        And

            ``a public workshop to identify best practices in this emerging
            field, ultimately developing a document that addresses
            epidemiology best practices . . .''

        I urge you to amend the PDUFA agreement and/or section 107 of S.
    484, to spell out additional resources for specific safety achievements
    such as:

               Give the FDA the computer resources to detect
            dangers faster. S. 484 calls for the FDA to submit a strategic
            plan for information technology within a year. The FDA has told
            consumers that they need $20 million a year to implement their
            modernization plan, and that at the end of 2006 vendors would
            no longer serve over half their IT equipment because it is so
            outmoded. But I urge this committee to require regular progress
            reports from the FDA on how they are using this money. I just
            had an opportunity to see the heavily censored ``Breckenridge
            Institute'' analysis of the FDA's efforts to modernize the
            Adverse Event Reporting System. The report describes
            incompetence and waste that is breath-taking. It describes a
            culture that explains how antidepressants and so many other
            drugs have been on the market for so long with so little safety
            action taken. As the Breckenridge analysts say,

                      ``One of the root causes of the confusion and delay
                    surrounding the AERS II system from 2003 onward is a
                    lack of effective leadership and management on the part
                    of CDER's Office of Information Technology . . . CDER's
                    culture can be characterized as one in which managers
                    at all organizational levels fail to move from the
                    awareness of organizational problems, to the kind of
                    action that will produce positive change.''

        Please, I urge this committee--the Board of Directors of the FDA--
    to make sure that the agency starts to move to action, and stops
    wasting precious time and money.

               Within the next 5 years make sure the FDA's
            computers can use the goldmine of information available from
            Medicare part A, B and D data to detect what is dangerous and
            what works;
               Do more to ensure the timely pre-clearance not just
            of TV ads, but of all advertisements and informationals,
            including ads on the Internet and at continuing medical
            education displays. My career is in advertising, and I can tell
            you that a goal of 30 to 45 days for pre-clearance of TV ads is
            much too long and will not work for industry. I oppose direct-
            to-consumer advertising of drugs, but if you are going to do
            it, do it right, and that means doing it in a timely manner;
               The lying and falsification of data in the Ketek
            case is outrageous and you hear rumors of similar trial
            distortions (why is it that so many trials, especially Phase IV
            postapproval trials come in favorable to the people paying for
            the trial?). Spend PDUFA safety money to double the number of
            trials and investigational review board applications audited to
            ensure the ethical treatment of enrollees, and the integrity of
            the data;
               Investigate all serious adverse event reports within
            15 days; also program FDA computers so they can better detect
            patterns or clusters of adverse event reports to determine if
            REMS action should be taken. Clusters of AERs should trigger
            studies and trials to determine if there is fire where there is
            so much smoke;
               Spend some money to actively recruit non-conflicted
            advisory committee members. As others have said, with about 125
            medical schools in this Nation, we ought to be able to develop
            a ``library'' of experts who are conflict free and willing to
            serve. Without spending some money to recruit these people, it
            is too easy for the FDA to complain that they do not exist. As
            we can find more conflict-free experts, you can amend Title IV
            of S. 484 to require a gradually rising percentage of conflict-
            free advisors.
               Spend money to take action (which may include the
            levying and collection of civil monetary penalties provided by
            S. 484) against at least 50 percent of the applicants who have
            failed to complete follow-up safety studies or trials. When the
            FDA was first reviewing anti-depressants in 1991, it ordered
            follow-up safety studies that were never done--and are part of
            the tragedy of Woody's story.

        As I indicated above, I oppose direct-to-consumer advertising of
    drugs, because there are so many side effects and dangerous
    consequences that we do not know about until a drug has been on the
    market for years and even decades. To encourage overuse and the
    medicalization of every problem leads to the death and injury of many
    who may not really have needed a particular drug. Vioxx is a prime
    example. If there is advertising, then the law should require that each
    ad include a 1-800-number where consumers are advised to report adverse
    side effects. Currently, it is very difficult for consumers to use the
    FDA Web site to search for dangers in drugs. The whole Web site needs
    to be re-designed to be made easier for the public--starting with the
    use of the commonly advertised name of drugs. The public does not know
    the nearly unpronounceable, multi-syllable chemical name of drugs; the
    simple step of using the advertised name would be a huge improvement.
        One other key point: there is nothing in PDUFA or that I can see in
    S. 484 that addresses the key FDA problem: the internal culture to
    ``approve drugs quickly/consider safety slowly.''
        We all want life-saving drugs approved quickly, but the FDA is out-
    of-balance and must give more attention to postapproval safety.
        You can legislate culture and staff morale, by improving the
    transparency of the agency and of the approval process.
        First, I urge you to strengthen S. 484's Title III: report the
    results of all trials, within a year of the last trial on the specific
    drug, whether it is submitted for approval or not. In addition, trials
    of drugs that are currently on the market should gradually be included
    so that there is a public library of the scientific trials conducted in
    the last decade or so.
        Dr. Steven Nissen, President of the American College of Cardiology
    testified before this committee on November 16, 2006:

              When drugs show serious toxicity in patients, the results are
            rarely published. Accordingly, other companies subsequently
            expose patients to closely-related drugs without knowing that
            their competitors' study of a similar agent showed significant
            harm. I am aware of a class of drugs where more than a dozen
            compounds showed serious toxicity, resulting in termination of
            development, but without a single publication of results
            [emphasis added]. In my view, when a patient volunteers to
            participate in a drug or device study, there is an implicit
            moral obligation that the patient's participation will benefit
            medical science. When studies are not published, we learn
            nothing from the experiment and make the same mistakes over and
            over again.

        In other words, fellow citizens have 12 times been subject to
    danger as human guinea pigs on a chemical or biologic that was
    dangerous, had toxic effects, and was a scientific dead end. That is
    outrageous. If Phase 1 results were made public, then after the first
    failure, 11 other sets of volunteers--probably over 200 people--would
    not have been endangered, and the cause of science would have been
    advanced.
        Publishing Phase 1 results can also speed drug discovery at lower
    cost. I find it ironic--and sad--that the pharmaceutical industry
    complains about the high cost of research, yet the results of
    unsuccessful trials that waste millions and endanger volunteers are
    hidden. The FDA's PDUFA discussion published in the Federal Register of
    January 16, 2007 says:

              ``Our experience and insight, gained through years of review,
            can help the industry avoid wasting scarce research and
            development resources on clinical trials that are not likely to
            produce results because of flawed designs.''

        True! And imagine how much more would be saved if the world
    scientific community could see the results of Phase 1 trials. If there
    is a proprietary secret, the patents surrounding the whole drug process
    provide some protection. But it is immoral to continue human guinea-
    piggism in the name of proprietary secrets and without advancing the
    cause of science.
        If you have questions about making Phase 1 results public, I urge
    you to at least amend S. 484's GAO study about whether to report late
    Phase 2 trial results, and instead make it a study of whether to report
    Phase 1 results.
        I obviously hope you will amend S. 484 to report all Phase 2
    trials. That should be a given in the name of science and to facilitate
    meta-analysis studies of safety and effectiveness.
        S. 484 provides for publication of a trial result 2 years after the
    final completion of the trial. I understand that this is to allow time
    for publication in peer-reviewed medical journals. But I also
    understand that the world of medical journal reporting is changing
    rapidly to be quicker and more electronic, and that some are urging
    that the great journals concentrate on discussions of the implications
    of findings from one or more trials, and not be a slow, front-line
    source of basic trial data. Certainly in cases where the trial or study
    has raised concerns about aspects of a drug on the market, a way should
    be found to make that data public for further study by the world
    scientific community.
        Mr. Chairman, Senator Enzi, I particularly appreciate the provision
    in S. 484 that requires both a technical and a more-laypersons
    descriptions of the results of clinical trials. A relatively ``user
    friendly'' version will empower patients and patient advocates to
    understand better the drugs that are available and whether they want to
    ``dig into'' the more technical explanation.
        There is a second major transparency step that Congress should
    legislate: make the details of all FDA approval decisions public within
    a month or two of approval, so the world can see what the issues are
    and what needs more study. By legislating disclosure you can instill a
    climate of scientific openness and dissent so the staff's morale is
    restored. Those who say that having pro and con data public about a
    drug will confuse the public and cause drugs not to be used are just
    saying that we consumers and--even worse--our family physicians are too
    dumb to understand or too stupid to handle complexity. They obviously
    have never lost a loved one to a drug reaction. It is an arrogant
    argument, and it is an insensitive argument--and it certainly doesn't
    fit with all the talk I hear from Washington about patient empowerment
    and ``shopping'' for health care.
        I would like to see a separate and independent Office of Drug
    Safety, as Senator Dodd and Grassley have proposed. It is telling that
    the current office is called Surveillance and Epidemiology--not exactly
    a clear message to the general public! The public needs to hear a clear
    message about this office--a message like you see on construction
    sites: Safety First! The Commissioner and many others oppose such a
    separate office, saying it would be a duplicate bureaucracy and slow up
    approvals.
        I would like to offer a solution: Give the head of Drug Safety
    (currently the head of the Office of Surveillance and Epidemiology) the
    authority--and the responsibility--to say he believes there are enough
    safety questions about a drug, pre- or post-
    approval, that the drug should not be approved, or if approved, that
    REMS (as established by S. 484) should be adjusted, or that it should
    be pulled from the market. If the head of the Office of New Drugs
    disagrees, the two Office heads present their cases to the Commissioner
    within a date certain, say a week, and he makes a decision within a
    day. This would not slow down the process, but it would make a career
    professional physician-scientist responsible for standing up for safety
    when he thinks the facts justify it. Today, there appears to be little
    or no accountability for the woeful saga of Ketek and other
    questionable drugs. This process should, of course, be very public,
    with reports to Congress on the details of when such disagreements have
    arisen and how they were resolved. In addition, points of contention
    should be subject to Advisory Committee review and comment by national
    and international experts.
        Under my idea, there would be no separate bureaucracy. No new
    expense. The two offices would still work together. But there would be
    accountability. Doesn't that bridge the argument pro and con about a
    separate Office of Drug Safety?
        There is a great deal more I could say. But in conclusion, I think
    transparency and openness is the key to restoring the FDA as the
    world's ``gold standard'' in drug approvals and safety. Dr. David Ross,
    currently with the NIH, recently left the FDA with, I gather, a great
    deal of sadness and frustration. He has described the FDA decision-
    model as very military and one that squelches dissent. Once a decision
    is made, no more questions! And as he says, that can be necessary on a
    battlefield. But the FDA is a scientific organization, and the heart of
    any such organization is open-mindedness, willingness to look at new
    data, and flexibility. If the culture of the FDA became one of
    openness, there would be fewer future drug disasters, and I gather it
    would be a much better place for scientists to work.
        Mr. Chairman, Senators, it is said the history of the FDA is
    written in the tombstones of drug and food safety disasters.
        Stop the march of tombstones.
        Do what is right for the American public.
        Give us a strong, well-funded FDA.

        Senator Enzi. Thank you. I know that was difficult. It was
    well done.
        Dr. McClellan.

     STATEMENT OF MARK McCLELLAN, M.D., PH.D., AMERICAN ENTERPRISE
                               INSTITUTE

        Dr. McClellan. Senator Enzi, thank you for the opportunity
    to join the committee today on issues, as you just heard from
    Ms. Witczak, that are so important to our Nation. Thanks to
    your bipartisan leadership, this year holds an historic
    opportunity for strengthening the ability of the FDA to help
    Americans live longer and better lives through access to safe
    and effective medicines that keep getting better. And for the
    first time, we have the opportunity to use new 21st century
    tools to make transformational improvements in drug safety in
    the United States.
        I want to highlight two key points in making the most of
    this unique opportunity. First, the FDA will need significantly
    greater appropriations to improve postmarket safety. The FDA is
    overstretched and a lack of trained staff and technical
    capabilities to perform the oversight necessary on thousands of
    prescription drugs is an even more pressing issue than
    providing the FDA with new regulatory authorities. This need
    has broad support, for example from the Coalition for a
    Stronger FDA.
        As PDUFA and the appropriations process go forward, all of
    these stakeholders appreciate your support that you reiterated
    today to give the FDA the resources it needs to do its tough
    job.
        The tight FDA budget and the high cost of medications also
    highlight the need for finding ways to achieve needed drug
    safety improvements at a lower overall cost, and that leads to
    my second point: Building on the elements in your drug safety
    proposals, it is feasible to implement an active population-
    based surveillance system for prescription drugs, to identify
    and follow up on the drug safety problems faster and more
    effectively than in the past. The core feature of this approach
    is putting together existing population-based electronic data
    on prescriptions linked to information on complications, such
    as hospitalizations for particular diagnoses or deaths.
        The data sources include health insurance databases
    maintained by large private health insurers and by Medicare,
    some State Medicaid programs, and potentially other government
    programs. Virtually all of these data with appropriate privacy
    protections are already being used piece by piece for safety
    studies, but they have not been put together to answer drug
    safety questions as quickly and completely as possible.
        Over time this infrastructure could be augmented by
    additional clinical data, such as electronic medical records
    and computerized information from networks such as the NIH's
    emerging consortium of academic medical centers that have
    received clinical translational science awards.
        To assure focus on the most pressing public health
    questions, it could be guided by the FDA, with reliance on the
    FDA's expert advisory groups, with a process for public input.
    The analysis of the public-private electronic drug safety data
    could be performed by expert groups such as the Centers for
    Education and Research on Therapeutics, the CERTs, and academic
    medical programs that focus on drug safety and effectiveness
    issues, such as MIT's Center for Biomedical Innovation.
        This electronic drug surveillance system would require some
    limited additional resources, but it's likely to be less costly
    overall and it definitely gets us more for the money than what
    we are doing now. Data like these are increasingly being used,
    but they are being used separately, incompletely, and
    inconsistently by health plans, government agencies, and drug
    manufacturers. With legislative support, a public-private
    collaboration to use health IT for drug safety would
    significantly reduce the duplicative and rising costs of case-
    by-case efforts and one-off risk management plans by drug
    manufacturers. It could also achieve safety improvements that
    are not possible through the efforts of individual drug
    manufacturers, such as understanding whether the risks of a
    particular drug extend to other drugs in the same class.
        Senator Enzi, members of the committee, we know that no
    drug is or ever will be completely safe. Every drug will have
    side effects and, while we can do much to improve the science
    of predicting and avoiding risk, no feasible pre-market testing
    will enable us to identify and fully understand all of the
    risks in actual practice.
        With your continued leadership, we can give the American
    public much more confidence that they will not be exposed to
    preventable risks. The 21st century should be an era of
    electronic health care, to improve quality and avoid excess
    health care costs. When it comes to drug safety, we need to do
    better than just seeing the tip of the iceberg of a safety
    problem after it has already hit us. We are past the time when
    our core strategy for postmarket safety should be relying on
    the hope that overly busy health professionals will file
    individual reports on adverse events involving drugs. Health IT
    for drug safety, Senator Enzi, is an idea whose time has come.
        Thank you for your leadership.
        [The prepared statement of Dr. McClellan follows:]
               Prepared Statement of Mark McClellan, M.D., Ph.D.
                                  introduction
        Mr. Chairman, Senator Enzi, and members of the committee, thank you
    for the opportunity to testify today, as the committee takes steps to
    improve our current system for monitoring the safety of drugs. This
    year is a critical year for strengthening the ability of the Food and
    Drug Administration (FDA) to help Americans live longer and better
    lives through access to safe and effective medicines that keep getting
    better.
        As you and others have noted, there are opportunities to improve
    the pre-market process for evaluating the safety of drugs, particularly
    through new resources that would enable FDA to develop better
    information tools for evaluating the safety data it receives as well as
    better scientific tools for evaluating preclinical and clinical safety.
    But the greatest opportunities for improvement are in the postmarket
    process. Consequently, I will spend the bulk of my time outlining steps
    I believe we can use to improve the postmarket process for evaluating
    drugs after they are approved for marketing.
        With the highly-publicized drug safety incidents involving Vioxx (a
    selective anti-inflammatory drug) and newer antidepressants (selective
    serotonin re-uptake inhibitors, or SSRIs) in 2004, followed by the
    Institute of Medicine's recommendations for a range of changes to
    enhance postmarket drug safety at FDA in 2006, it is clear that our
    current system of monitoring the safety of marketed drugs can be
    significantly improved. I want to thank the Chairman and Senator Enzi,
    and the other members of this committee and the Congress, for your
    leadership to address this challenge as effectively as possible. Your
    leadership, in conjunction with hard work by the FDA and new ideas from
    patient advocacy groups, product developers, and other stakeholders,
    has created a unique and unprecedented bipartisan opportunity to
    achieve a fundamentally more effective system for monitoring drug use
    and aggressively addressing the questions about safety that inevitably
    arise in the postmarket setting.
        Legislation to improve post-market drug safety involves a
    combination of better information on drug risks, new regulatory
    authorities, organizational reforms, and additional resources to carry
    out these new steps effectively. Significant new resources for FDA to
    support drug safety programs are absolutely essential to this strategy.
    Now is also the best opportunity we have ever had to move to a 21st
    century, electronic approach to monitoring and acting on potential drug
    safety problems, one based on much more complete and timely information
    than is available to FDA today. In particular, building on the elements
    to improve safety information in the legislation proposed by Senators
    Kennedy and Enzi, it is feasible to implement much more active,
    complete population-based monitoring of adverse events associated with
    prescription drugs, to identify and follow up on drug safety problems
    much faster and more effectively than in the past. This system, which
    would draw on public and private electronic prescription and health
    information which has not yet been put together in a comprehensive
    strategy for drug safety, would directly address the delays in
    developing and addressing safety ``signals'' that have resulted in
    delays in resolving drug safety problems like Vioxx. While this public-
    private collaborative system would require limited additional
    resources, it would significantly reduce the duplicative and rising
    costs of case-by-case efforts by drug manufacturers and health plans to
    address safety issues--efforts that are also incomplete and
    inconsistent. It could also achieve safety improvements that are not
    possible through imposing more regulatory requirements on drug
    manufacturers or making organizational changes at the FDA.
       key questions and objectives for improving the drug safety system
        With this unique opportunity to make fundamental enhancements in
    drug safety, it's important to keep asking some key questions as we
    consider possible solutions.
        First, will the proposed steps have the greatest impact on reducing
    the likelihood of another Vioxx or SSRI-type event?
        In evaluating approaches to enhance drug safety, there are at least
    three main areas to consider. None of these alone are sufficient to
    achieve success, but if all are addressed together, the result can be
    fundamental improvements in our post-market monitoring system:

         Regulatory authority: Pending legislation and the IOM
    recommendations appropriately recognize the need to review and consider
    updating FDA's regulatory authority to require drug manufacturers to
    take appropriate and effective steps to mitigate risks associated with
    marketed drugs. FDA's current selective application of RiskMAP tools is
    a necessary component of postmarket monitoring, for drugs that present
    special issues that cannot be addressed through standard labeling and
    communication. Given the limited resources available to the agency to
    oversee these authorities, and the already high costs of our health
    care system, a key principle at FDA is efficient regulation: achieving
    the regulatory goal of addressing safety risks without imposing excess
    costs or unnecessary burdens. In addition, the elements described
    below--sufficient resources and better information--can help achieve
    the intended goal of a new authority more effectively and with less
    burden.
         Resources and technical capabilities: FDA needs the
    manpower, technical skills, and technical support to carry out their
    increasingly complex oversight requirements effectively. Inadequate
    resources even for existing FDA activities, let alone enhanced drug
    safety activities, is now widely regarded as a significant problem. As
    I will discuss, in addition to providing more resources to FDA--and a
    relatively small amount of additional funding, properly spent, can go a
    long way--there are significant opportunities for public-private
    collaborations with expert academic groups to augment FDA's
    capabilities on drug safety.
         Good Information: Regulatory decisions, like other policy
    decisions, can only be as good as the information on which they are
    based. Too often, we have faced important questions about drug safety
    that have major consequences--whether a drug should be on the market,
    and which patients should use it--without information that is nearly as
    good as it could be and should be. Today, as prescription drug
    information is increasingly electronic, there are growing opportunities
    to use more data more effectively for postmarket safety.

        Second, will the proposed steps achieve the maximum improvement in
    safety at the lowest cost? Of course, no one wants to put a price on
    health. But we have consistently imposed very tight budgets on the FDA,
    and many people are also concerned about the impact of regulatory
    burdens that may increase the time and cost of making lifesaving drugs
    available to the patients who need them. Consequently, in making policy
    decisions about drug safety, it's important to ask whether a particular
    safety goal is being achieved at the lowest feasible cost to taxpayers,
    and to the consumers and patients who will ultimately be using the
    drugs. By considering all the tools available to improve safety--new
    regulatory authority for the FDA, as well as new resources and better
    information--we can achieve major improvements in postmarket safety
    while minimizing additional costs and difficulties in access to
    valuable medications.
        I want to be clear that additional resources will be required to
    provide adequate support for postmarket monitoring. But if designed
    carefully, an enhanced post-market safety system can make tight budget
    dollars go much further toward achieving the goal of maximizing
    benefits from medications and avoiding inappropriate drug use, and may
    lead to significant cost savings from addressing safety questions more
    completely and efficiently.
        To be maximally effective, the improved drug safety system would:

         Recognize, based on pre-market testing and other
    biomedical knowledge, potential areas of risk for drugs, particularly
    new drugs coming on the market, to help avoid safety problems in the
    first place and focus postmarket monitoring on identifying true safety
    signals rather than random associations.
         Identify safety ``signals''--whether potential risks are
    actually observed--much more quickly and reliably.
         Permit significantly better and more timely monitoring of
    how drugs are used in practice.
         Enable post-market clinical trials and other costly,
    sophisticated clinical studies to be focused more quickly and
    effectively on instances where a safety signal is real, but whether a
    drug has caused the signal cannot be determined from monitoring drug
    use and patient outcomes alone.

        Finally, because the 21st century should be an era of electronic
    health care to improve quality and avoid excess health care costs, an
    ideal safety system should be based on and should foster effective
    health information technology (IT). We are past the time when our core
    strategy for postmarket safety should be relying on the hope that
    overly busy health professionals will file individual reports on
    adverse events involving drugs. ``Health IT for drug safety,'' and
    catalyzing the movement to electronic data systems more broadly, is an
    idea whose time has come.
        It is possible, by building on the steps in pending legislation, to
    make major progress toward this fundamentally enhanced drug safety
    system this year. In the next sections, I describe how both the current
    system and proposed administrative and legislative changes can help get
    there, and some specific, feasible ways to build on these steps to make
    sure we get the most out of the unique opportunity we face today.
              current drug safety system and proposed improvements
        While most of my testimony addresses postmarket issues, I would
    like to commend the committee for seeking to make some important
    enhancements in the pre-market setting to avoid drug safety problems
    later. In particular, while there isn't and won't be any completely
    safe drug, improving the science of pre-market evaluation of drugs can
    help reduce the risk that patients will have serious adverse events
    without delaying or reducing access to needed cures. Improving the
    science of drug safety includes such steps as supporting the
    development of better preclinical and clinical techniques for
    predicting whether a drug will cause serious risks such as liver and
    cardiac toxicity. These drug side effects often complicate and add to
    the costs of drug development programs. It also includes the
    development of new clinical trial designs such as adaptive approaches
    that can surface more information more efficiently about the safety and
    effectiveness of drugs. New technologies such as pharmacogenomics can
    also help target drugs more effectively to patients, so that they will
    be more likely to realize benefits and avoid side effects of new drugs.
    Building on its ``Critical Path'' initiative, FDA has recently reported
    on plans outlining these and other scientific improvements, and these
    steps are reinforced by the proposed legislation. However, I also want
    to emphasize that these improvements will only be realized if
    sufficient additional resources accompany the new emphasis on better
    science for developing drugs. These investments will be well worth it:
    a more robust scientific base for pre-market drug evaluation will
    provide a better understanding of potential areas of risk for drugs,
    and which patients may actually face those risks, particularly for new
    drugs coming on the market. It will help focus our postmarket
    monitoring on identifying true safety signals rather than random
    associations.
        Even with these and other proposed pre-market reforms, there will
    inevitably be unresolved questions related to the safety of every drug
    that comes on the market. This is because no feasible amount of
    premarket testing in clinical studies can evaluate all real-world
    conditions of use--patients with multiple comorbidities, varying
    practice settings, possible use in off-label clinical indications, and
    the like. These real-world circumstances may affect both the benefits
    and risks of treatment, and with the growing potential of genomics and
    other steps toward personalized medicine, there will likely be more and
    more to learn in the postmarket setting about how drugs can be used
    most effectively in particular patients. Because it is not possible to
    replicate all of these settings and surface all of these real-world
    issues in pre-market testing, it is very important to have reliable and
    effective ways of learning more about the safety and effectiveness
    after drugs start to be used in clinical practice. Creating a true
    ``life cycle'' strategy for maximizing drug benefits and minimizing
    risks is a key challenge for the Nation's public health, and deserves
    the careful and deliberate consideration of this committee.
        Right now, our postmarket surveillance is largely dependent on
    FDA's Adverse Event Reporting System (AERS) as well as limited use of
    existing electronic health databases. While these tools are important,
    it is feasible to achieve fundamentally better post-market safety
    monitoring, by building on some recent developments in electronic
    records of prescriptions, medical services, and patient outcomes.
        FDA is currently working on an improved AERS system, AERS II, which
    will make it easier to collect reports from clinicians and enable
    better tools for evaluating this information once it is received by
    FDA, so that the most important safety signals can be surfaced more
    quickly. Pending legislation could also strengthen FDA's authorities to
    compel drug manufacturers to take potentially costly further steps to
    support the collection of such data on their drugs. However, even with
    these enhancements, the potential to detect safety problems much
    earlier and more reliably will continue to be missed. AERS, with the
    required event reports from manufacturers that make up most of its
    data, is not routine and automatic. Rather, it depends on busy health
    care providers filing reports on a case-by-case basis, and then often
    requires further followup to obtain reasonably complete medical
    histories and utilization details. Only a small fraction of adverse
    events are captured with such a system, and they are not captured
    consistently.
        Consequently, with regard to preventing future incidents like Vioxx
    and the SSRIs, if we remain unable to identify most adverse events in a
    consistent and timely way, it may still take years longer than
    necessary to confirm whether potential safety ``signals'' are real.
    Further, important issues such as whether the safety concerns are
    specific to an individual drug, versus broader drug class effects
    (e.g., is the enhanced cardiovascular risk with prolonged use also
    present in other cox-2 inhibitors, or perhaps in an even broader range
    of nonsteroidal anti-inflammatory drugs?) cannot be reliably studied
    using ``one-off '' event reporting on particular drugs. To solve these
    problems, we need a more comprehensive and routine system for
    identifying adverse events, not a system primarily dependent on case-
    by-case reporting requirements for individual drug manufacturers.
        FDA has long recognized these limitations, and has taken steps to
    build a more active system for drug safety surveillance, similar to the
    systems that are in place when it comes to medical devices through
    FDA's MedSun initiative or for vaccines through the Vaccine Adverse
    Event Reporting System. In fact, FDA has purchased or obtained
    electronic data on prescription use, medical utilization, and
    complications for certain populations--health plan data, or Medicare
    Part B data linked to hospital use and other complications--to help
    evaluate certain individual drug safety questions. The recent PDUFA IV
    draft agreement provides some additional funding and staff to support
    this analysis, and pending legislation also supports the use of such
    electronic databases. Further, in its recent administrative actions,
    FDA has proposed some additional enhancements to its ability to obtain
    and analyze electronic population databases. Recently, FDA has also
    sought broad public comment and expert input to design a ``Sentinel
    Network'' that would begin to link each of these individual databases
    and authorities together--the makings of a true, systematic approach to
    identifying safety signals in a broad part of the U.S. patient
    population. However, current legislative authority and budget authority
    does not provide as much momentum as it could for achieving this
    system. Without such steps, it is unlikely that our drug safety system
    will have the data, resources, and analytic capabilities to minimize
    the risk of future post-market safety problems. At the same time,
    proposed legislation holds the potential to achieve fundamental
    improvements in post-market drug safety.
       establishing a routine electronic system for reliable post-market
                                  drug safety
        In 2007, it is feasible to achieve fundamentally better post-market
    safety monitoring, by building on existing initiatives and proposals
    combined with recent developments in electronic tracking of medication
    use and patient results. This updated system would have:

    1. Faster, More Reliable Detection of Potential Safety Problems
            (``Signal Detection'') Using Better Data and Technical Support
        The core feature of this approach is the creation of a public-
    private infrastructure to draw together relevant population-based,
    electronic data on prescriptions linked to information related to
    patient complications, such as hospitalizations for particular
    diagnoses or death. The data sources include insurance claims databases
    maintained by large private health insurers and by Medicare, some State
    Medicaid programs, and potentially other government programs including
    the VA. Virtually all of these data, with full patient privacy
    protections (e.g., full compliance with HIPAA requirements and other
    steps to assure confidentiality), are already being used for particular
    safety studies. But there is not yet an established system for reliably
    putting the power of these data sources together to answer drug safety
    questions as quickly and completely as possible. This infrastructure
    could potentially be augmented by additional clinical data sources as
    they become available, such as electronic medical records and
    computerized data from research networks such as NIH's emerging
    consortium of academic medical centers that have received Clinical
    Translational Science Awards (CTSAs).
        While public and private stakeholders have already taken many steps
    to make this network a reality, recognition of the central value of
    this approach and limited new resource support through legislation
    would create the momementum to bring this surveillance or sentinel
    network for drug safety together now. For example, legislation could
    note that safety questions could be addressed through such a network,
    where it could provide more complete and efficient answers than RiskMAP
    requirements for a drug manufacturer, who would not have the capacity
    to develop this kind of comprehensive data.
        To assure that the network's efforts focus on the most pressing
    safety questions from a public health standpoint, it could be guided by
    the FDA with reliance on the FDA's expert advisory groups. For example,
    in conjunction with a process for public input such as an advisory
    committee meeting or a public posting for comment, the FDA could
    identify the top safety questions to be answered using the data in the
    network, and outline the methods that would be used in the data
    analysis. These top questions would include adverse events that are
    suspected (but not proven) for new drugs as well as for existing drugs
    and drug classes, and severe, idiosyncratic adverse events (e.g.,
    aplastic anemia, liver failure). FDA oversight of this process is
    appropriate and necessary, because FDA is charged with using all
    available information to reach appropriate conclusions about drug
    safety and effectiveness for purposes of labeling and marketing in the
    United States.
        While FDA oversight of this process is necessary, carrying out the
    analyses of these data will require the ongoing participation of
    additional academic experts, even if additional resources enable the
    FDA to make needed enhancements in its statistical and epidemiologic
    capabilities. Interpreting observational data to identify safety
    ``signals''--whether there is a significant and meaningful association
    between use of a drug and an important adverse event--is generally not
    straightforward. Fortunately, many groups with relevant expertise are
    available and are already working on these kinds of safety questions.
    These include: the Centers for Education and Research on Therapeutics
    (CERTs) which, with funding from the Agency for Healthcare Research and
    Quality (AHRQ), already conduct analyses using these data to address
    key issues on the effects of treatments, including questions of
    interest to FDA; academic programs that focus on drug safety and
    effectiveness issues, such as MIT's Center for Biomedical Innovation,
    and on learning more about treatment effects in routine clinical
    practice, such as Duke Medical Center's community-based clinical
    networks; and many other experts in the public and private sectors.
    Expert groups like these can form the backbone of an ongoing
    infrastructure for routinely answering priority safety questions using
    electronic population data quickly and effectively.
        The reports from these analyses, using much larger population-based
    electronic data, have the potential to identify much more quickly
    whether there is a significant association between use of a drug and an
    adverse event. For example, according to calculations by Richard Platt
    (Principal Investigator of the HMO Research Network CERT), electronic
    and other data actually used to determine a significant association
    between Vioxx use and serious cardiovascular events took almost 3 years
    to detect a statistically significant association, based on the limited
    population data available for analysis at the time. If data from large
    health plans could have been pooled to provide more definitive evidence
    on this potential safety risk, as envisioned in this strategy, the
    significant association could potentially have been detected within
    just several months, enabling much faster action to address the safety
    problem. Moreover, if the safety monitoring infrastructure enables
    needed data to be put together for analysis more quickly when needed
    for priority safety questions, the ``lag time'' in obtaining the data
    needed could also be reduced compared to the situation today, when such
    data must be assembled on a ``one-off '' basis. This would provide
    additional speed in resolving possible safety questions, as well as
    lower costs compared to ``one-off '' studies by particular drug
    manufacturers or health plans that are less complete and consistent.
        It is important to note that a significant association between use
    of a drug and an adverse event does not necessarily mean that the drug
    has caused the adverse event. Such associations may occur by chance, or
    because the patients actually taking a drug differ in ways that are
    important but hard to measure, compared to other patients who are not
    taking the drug. For example, patients in poorer health may be more
    likely to be treated with a drug, and also be more likely to have
    subsequent cardiovascular problems because of their health status not
    because of the drug. Consequently, until statistical methods can be
    enhanced, the more complete data developed as part of this drug safety
    infrastructure are generally not suitable for simply ``fishing'' for
    statistically significant associations between drugs and adverse
    events. Rather, as noted above, this system will be most useful for
    monitoring rare, serious adverse events that generally should not
    occur, and following up on questions where a suspicion of a safety
    problem has already been raised but has not been resolved. Other
    sources of evidence, such as suspected signals based on pre-market
    clinical and biological data, can provide the needed guidance for this
    system. For example, pre-market and peri-market clinical evidence of a
    potential elevated risk of cardiovascular events with prolonged use of
    Vioxx suggested the possibility of a safety signal; with that clinical
    foundation, determining quickly whether a significant association does
    exist is important supportive evidence. In many cases, however, further
    clinical evaluation will be necessary to understand the implications of
    a clear ``safety signal,'' as described below.
    2. More Complete Monitoring of Patterns of Drug Use
        In addition to providing much faster and more reliable evidence on
    the association between drug use and important adverse events, this
    drug surveillance network would also provide much better insights into
    how drugs are being used and how use is changing over time. For
    example, many new drugs over time may be used in indications other than
    those for which they were initially approved by the FDA. These ``off-
    label'' uses can provide important clinical benefits for many patients;
    at the same time, the quality of the evidence on their safety and
    effectiveness may be more limited than for approved indications. The
    same data used to provide much better evidence on potential safety
    problems can also provide a more complete picture on which types of
    patients are being treated, subject to the limitations on clinical
    detail in existing electronic databases. For example, even when new
    drugs are clearly beneficial for their approved indications, patients
    who are elderly, have multiple co-
    morbid diseases, are taking other prescription medications, or are from
    racial or ethnic minority groups who are often underrepresented or
    cannot be represented in sample sizes large enough in pre-market
    clinical studies to determine if significant differences in risks or
    benefits exist for them.
        The large populations incorporated in this surveillance network
    would permit more insights into how drugs are being used in different
    types of patients, and may highlight areas where risks or benefits may
    be greater, or where significant use is occurring and risks and
    benefits are unclear. This tracking of actual prescription drug use is,
    once again, likely to involve much more population data than are
    generally available to a drug manufacturer about which patients are
    actually using the drug, and so can provide insights about how drugs
    are being used that are not possible through a manufacturer RiskMAP.
    3. Determination of Causal Relationships Through Better-Targeted
            Followup Studies
        In many cases, establishing a statistically significant
    relationship between drug use and an adverse event may not be
    sufficient to determine that the drug caused the adverse event, even in
    light of prior evidence. Clinical trials in which patients are
    randomized to different treatments, or other sophisticated clinical
    studies, may be needed to provide definitive evidence. For example, a
    drug may have a significant association with an adverse event, but it
    may be due to the characteristics of the patients using the drug not
    the drug itself. In these cases, the enhanced drug surveillance
    described here will not settle the safety issue, but it can be very
    useful in identifying the most important questions for further clinical
    study and the most effective research methods for resolving the
    questions. Quickly identifying significant rates of adverse events, and
    better characterizing which patients are actually using the drug and
    experiencing the events, can guide the further clinical-epidemiologic
    studies and post-market clinical trials needed to reach a definitive
    conclusion. Because these clinical studies will be guided by much
    better evidence on drug use and adverse events, they can be designed
    and implemented more quickly and efficiently. Such trials can be very
    costly and time-consuming, and so targeting them effectively is an
    important public health goal.
        Further, establishing the surveillance network to bring together
    FDA staff, academic investigators and other clinical experts, and much
    better postmarket data will itself lead to better post-market clinical
    studies. For example, the network could facilitate working with health
    plans to set up such studies, and could reduce the scope and cost of
    further data collection and analysis as part of the studies. It will
    also facilitate the development and validation of improved statistical
    methods for reaching conclusions using these improved data.
        Because the building blocks for all three of these key steps toward
    an ideal post-market safety system are already in place, it is feasible
    to implement this health IT-based system now. Private health plan data
    are already being used plan by plan for these purposes; some Medicaid
    programs already participate in safety studies; Medicare Part A and B
    data have also been used; and Medicare proposed using Part D data for
    such purposes last fall. Moreover, the resources required would also be
    relatively limited, and in any case it is less costly to build a post-
    market safety infrastructure that can be used routinely and quickly
    than to try to re-create it (less comprehensively) on a ``one-off ''
    basis through drug by drug RiskMAPs.
        This approach is not intended to replace current adverse event
    reporting systems or planned improvements in those systems. But the key
    question is where the new postmarket requirements and efforts in the
    pending drug safety legislation should be focused. A relatively modest
    investment in an infrastructure including available electronic
    population data related to drug use and adverse events, plus a capacity
    for routine and transparent analysis of these data, would lead to a
    much more comprehensive capacity for identifying safety signals and
    acting on them effectively than we have today. It's time to move from a
    drug by drug approach to a systematic, routine, population approach to
    promoting drug safety in the United States.
        This is also the best path for the future--a future that should
    include much more extensive use of electronic, interoperable, real-time
    clinical data systems for active safety surveillance. Indeed, not only
    is this approach a big step forward based on using electronic data
    today, but it provides a much stronger foundation into which more
    sophisticated data from electronic medical record systems can be added.
    Over time, the speed, clinical sophistication, and analytic
    sophistication of the postmarket network will continue to increase,
    with continuing benefits for the safety and effectiveness of drugs.
                                   conclusion
        Chairman Kennedy, Senator Enzi, and members of the committee, your
    leadership has created the opportunity to make fundamental progress on
    enhancing drug safety and the effective use of drugs in the United
    States. As part of this effort, it is possible to learn more about the
    risks and benefits of drugs before they come to market, and to do a
    fundamentally better job of addressing the safety issues that will
    inevitably arise when drugs are on the market. This will require some
    new investments in drug safety, but most of all, it will involve a
    shared commitment between the public and private sector to build
    systems and collaborations that can surface and resolve drug safety
    questions as quickly as possible. With all of the advances that we are
    making in the more effective use of IT in healthcare, we should aim for
    nothing less than world class data for evaluating drugs through their
    life cycle. And we should not wait, so that better information on drug
    risks and benefits can enable the FDA, health care providers, and
    patients can get the most out of prescription drugs, and so that we
    make the most of this unique opportunity to prevent or mitigate future
    drug safety problems.

        Senator Enzi. Thank you.
        Dr. Burlington.

        STATEMENT OF D. BRUCE BURLINGTON, M.D., EXECUTIVE VICE
           PRESIDENT, QUALITY, REGULATORY AND SAFETY, WYETH
                            PHARMACEUTICALS

        Dr. Burlington. Senator Enzi, thank you very much for the
    opportunity to testify at this important hearing. I am the
    Executive Vice President of Business Practices and Compliance
    at Wyeth. Before joining Wyeth I worked for 17 years at the
    Food and Drug Administration in the Centers for Biologics, the
    Center for Drugs, and then the Center for Medical Devices. Last
    year I led the team from the Pharmaceutical Research and
    Manufacturers of America as we worked with the FDA on their
    proposed recommendations for reauthorization of the
    prescription drug user fee program.
        I'm here today to urge Congress to adopt the FDA's
    recommendations and promptly reauthorize PDUFA. It's critical
    that Congress renew this PDUFA before the current law sunsets
    because by doing so it will ensure patients continue to have
    timely access to important and sometimes lifesaving new
    medicines.
        By any measure, PDUFA has been a resounding success. Before
    Congress passed the first user fee act in 1992, regulators in
    foreign countries reviewed applications for new pharmaceutical
    products far before FDA. As a result, we had what we called the
    drug lag. Great Britain led the United States in the number of
    first introductions of new medicines by a 3 to 1 margin. Worse
    yet, patients in the United States waited, sometimes for 2, up
    to 5 years, after patients in other countries were already
    being treated with valuable new medicines.
        The first three PDUFA laws helped the FDA fix this
    unacceptable state of affairs. PDUFA ensured that FDA had more
    staff and this led to substantial reductions in the time it
    took FDA to review and, when FDA decided it was appropriate, to
    approve new medicines for marketing. Perhaps the greatest
    evidence for the success of PDUFA is the increased access to
    new medicines for patients. According to FDA, between September
    1993 and October 2006 the FDA approved more than 1,200 new
    medicines. They included many important advances for the
    treatment of cancer, cardiovascular diseases, renal disease,
    metabolic and endocrine disorders.
        Congress was wise to require that PDUFA be reauthorized
    every 5 years. Each successive PDUFA agreement has allowed
    Congress and the FDA to address new needs and issues in the
    approval process. That is certainly true with respect to the
    current proposal.
        Indeed, FDA's recommendations PDUFA IV contain several
    groundbreaking innovations which will further advance patient
    interests and drug safety. First, PDUFA would increase the
    annual user fee collections by some $87 million over those for
    the current year.
        Second, $150 million over the 5 years of this new funding
    will be dedicated to further assuring the safety of medicines
    after they are on the market. This will allow FDA to hire 82
    more employees specifically to work on postmarket surveillance
    and safety. It will permit the FDA to identify risks more
    quickly and accurately using modern techniques and tools, such
    as enhanced use of epidemiology studies and review of large
    medical databases.
        Third, FDA will also be able to undertake research to
    identify which risk management and risk communication tools are
    the most effective. And FDA will run a pilot to test a major
    renovation of how they review proprietary names of medicines
    before they are used, so that we can reduce the potential for
    medication errors arising from drug name confusion.
        Fourth, the FDA has proposed a new set of user fees
    exclusively for the review of direct-to-consumer television
    ads. The agency will hire 27 additional employees to oversee
    drug promotional activities. They will review ads in a thorough
    and timely manner before they are run. This will benefit
    patients by permitting the free flow of important medical
    information that is accurate, balanced, and useful.
        Finally, the recommendations will advance the FDA's
    critical path initiative. The FDA will develop draft guidance
    in areas related to safety assessment, clinical trial design
    and the use of biomarkers. This will hopefully lead to new ways
    to develop drugs for critical diseases such as Alzheimer's, on
    which my company Wyeth is hard at work.
        The proposed recommendations for PDUFA IV will materially
    improve the agency's review processes. More importantly, they
    embody critical new approaches for ensuring the safety of
    medicines throughout their life cycle.
        We understand that the PDUFA reauthorization may become a
    vehicle for considering drug safety legislation such as S. 484,
    Enhancing Drug Safety and Innovation Act, introduced by the
    ranking member and Chairman Kennedy. Wyeth believes that S. 484
    is a thoughtful effort to maintain the important balance of
    safety and providing patients access to new therapies. The REM
    system which we have heard described would bring the FDA closer
    to the risk management approach taken by the European Union.
    This is a desirable goal.
        But risk mitigation elements in REMS may have far-reaching
    impact on the availability and use in medicines. So it is
    important that decisions on them should be approved only at the
    highest levels of the agency. Having said that, a statutory
    construct that is somewhat less prescriptive would be
    preferable. It would be better to have the law lay out
    principles and create a framework. This would guide FDA in
    developing specific criteria and processes by which they would
    apply risk mitigation tools. These should be put in place
    through rulemaking.
        Under such a system, the FDA would have flexibility to vary
    risk management for medicines with different levels of risk and
    it would let them more easily adapt to new techniques for post-
    marketing risk evaluation as our knowledge evolves.
        In conclusion, we urge Congress to reauthorize the
    Prescription Drug User Fee Act in a timely manner this year. In
    the interest of patients, the FDA, and drug safety, we can
    demand no less.
        [The prepared statement of Dr. Burlington follows:]
                Prepared Statement of D. Bruce Burlington, M.D.
        Thank you, Mr. Chairman and members of the committee. I bring to
    the hearing today a broad perspective on the Prescription Drug User Fee
    Act (PDUFA). Prior to joining Wyeth I spent more than 17 years at the
    Food and Drug Administration (FDA) where I had responsibilities in the
    Biologics and Drug Centers. I was the Acting Deputy Center Director for
    Medical Affairs when PDUFA was enacted in 1992. I finished my career at
    FDA by serving for 6 years as the Director of the Medical Device and
    Radiological Health Center during the period when Congress enacted the
    Food and Drug Modernization Act (FDAMA).
        At Wyeth, I serve as the Executive Vice President for Business
    Practices and Compliance. I have had overall responsibility for
    regulatory submissions to the FDA, including New Drug Applications
    (NDAs) and Biologic License Applications (BLAs). I also was responsible
    for manufacturing quality assurance, drug safety and FDA compliance.
        Wyeth is a member of the Pharmaceutical Research and Manufacturers
    of America (PhRMA), the trade organization which represents the
    research-based pharmaceutical and biotechnology industries. During the
    past year, I served as Chairperson of PhRMA's PDUFA reauthorization
    team, which met with FDA representatives to develop improvements to
    PDUFA. The outcome of those 9 months of intense discussions, the FDA's
    PDUFA IV proposal, will be the principle focus of my testimony today. I
    will also comment on drug safety proposals currently before Congress.
        Reauthorization of PDUFA is one of the most important legislative
    issues facing Congress this year. By virtually any measure, PDUFA has
    been a resounding success. Since its enactment in 1992, PDUFA has
    delivered tangible and important benefits to patients, the FDA, and the
    pharmaceutical industry. PDUFA provides the FDA with critical
    additional resources to conduct rigorous reviews of new drug
    applications. As a direct result of PDUFA, important new medicines are
    now available to patients much more quickly.
        In 1997, Congress built upon the early success of PDUFA when it
    adopted PDUFA II by passing FDAMA. PDUFA II further increased FDA's
    resources and provided improved interactions during the drug
    development process, which enhanced the drug approval process. In 2002,
    PDUFA III addressed FDA's need for a sound financial footing and
    provided additional resources for drug safety initiatives. PDUFA II and
    III also directed funding toward information technology so that the
    FDA, industry, and, most importantly, patients could realize the
    significant efficiencies of electronic regulatory submissions.
        Congress must continue to build on the success of PDUFA by passing
    PDUFA IV reauthorization legislation in a timely manner this year.
        Throughout the 15 years of PDUFA's existence, the exacting
    standards by which FDA evaluates New Drug Applications have not been
    compromised or diluted. Indeed, user fees provide indispensable
    additional funds to FDA so that it can be more rigorous, and yet
    expeditious, in discharging its critical function of reviewing safety
    and effectiveness of potentially life-saving medications.
        The level of evidence of safety and effectiveness needed for the
    approval of a new medication have not been reduced in any way. In fact,
    the extent of clinical studies and safety information in applications
    has increased markedly since PDUFA's inception. For instance, instead
    of assessing the general safety data base to address the chance that a
    drug might cause changes in heart rhythms, as was done in 1992, the
    drug industry now routinely submits additional studies of new drugs
    given at higher doses than therapeutic levels to specifically address
    this concern. When the FDA studies new applications, the outcome of its
    review is not affected in any way by PDUFA funding. The decision to
    approve or disapprove an application is predicated exclusively on the
    FDA's analysis of the science and the evidentiary data in the
    application.
        Each successive reauthorization of PDUFA has focused on issues
    critical to the FDA's mission. Enhancements to PDUFA have always been
    carefully structured to be responsive to the needs of both the agency
    and the public.
        The FDA's PDUFA IV proposal is carefully crafted and contains
    important new provisions and resources to:

         Enhance and modernize the FDA drug safety program;
         Add a new user-fee program to give FDA additional
    resources to review and provide advisory opinions on direct-to-consumer
    (DTC) television advertisements;
         Improve drug development; and
         Provide more stable financing for the program.

        There can be no doubt that patients will be well-served by the
    improvements contained in the PDUFA IV agreement.
        The substantial new funding provided to enhance and modernize the
    FDA drug safety system--nearly $150 million dollars plus additional
    information technology (IT) support--will continue to assure that FDA's
    pre- and post-market safety assessment system is the world's best. In
    addition, the PDUFA IV proposal incorporates many of the
    recommendations made by the Institute of Medicine in its report on the
    U.S. drug safety system which it issued last year.
        The additional resources under the PDUFA IV agreement for
    postmarketing surveillance will allow the FDA to augment its reliance
    on the spontaneous reporting of adverse events through modernized
    techniques and resources, such as epidemiology studies and large
    medical databases, to identify risks more quickly and accurately. The
    FDA will be able to use new IT systems, secure access to electronic
    health records, employ new algorithms for detecting drug safety
    signals, and use new approaches to validate drug safety signals. The
    PDUFA IV agreement provides the funding for these initiatives.
        The FDA's PDUFA proposal provides funds to develop guidance on best
    epidemiology practices that will serve as a base for agency, academia,
    and industry use. The guidance is intended to serve the public's
    interest by assuring that studies reporting drug-associated signals of
    risk do so based on defined scientific standards. It also provides
    funds necessary to identify which risk management and risk
    communication tools are effective. Moreover, the drug industry will
    benefit by having an array of risk management tools that work,
    simplifying the development of drug-specific risk management plans.
        FDA will also conduct research during PDUFA IV to determine the
    best way to maximize the public health benefit associated with
    collecting and reporting adverse events. This will lead to a better
    deployment of drug safety resources.
        A key patient safety initiative in PDUFA IV is effectively
    addressing the potential for medication errors arising from confusion
    in drug names. The FDA proposal allocates a portion of the user-fee
    funding to improving the trade name review process. Trade names are
    reviewed by the FDA to help ensure that new trade names are unlikely to
    be confused with existing trade names in an effort to reduce possible
    medication errors. FDA will now have additional resources to review
    trade names during drug development and provide industry with guidance
    on ``good naming practices.''
        The FDA's PDUFA proposal also includes a new user fee for direct-
    to-consumer (DTC) television advertisements. In 2005, PhRMA issued a
    set of voluntary guiding principles regarding DTC advertising. In those
    guiding principles, PhRMA member companies committed to submit all new
    DTC TV ads to FDA prior to public dissemination to ensure that FDA's
    suggestions could be addressed before the advertisement is seen widely
    by the public. The PhRMA principles are working but they will be
    enhanced by a strong and fully funded FDA drug advertising review
    program. The proposed new user fee will allow FDA to hire 27 additional
    employees in the Division of Drug Marketing, Advertising and
    Communications (DDMAC) and elsewhere to oversee drug promotional
    activities and to ensure that TV advertisements voluntarily submitted
    in accordance with the PhRMA principles are reviewed in a thorough and
    timely manner. This will benefit patients and the public health by
    permitting the free flow of important medical information that is
    accurate, balanced and useful.
        The PDUFA IV agreement also enables the FDA to fully implement the
    good review management principles that were developed and piloted
    during PDUFA III. FDA will communicate to sponsors a timeline for
    discussing labeling and postmarket commitments in advance of the action
    date. This will improve the predictability of the drug review process
    and lead to postmarket studies that are more meaningful and appropriate
    for the new drug.
        Under the agreement, funding is allocated for the purpose of
    advancing how FDA can expedite drug development under the agency's
    Critical Path Initiative. This will permit FDA staff to be directly
    involved in external activities such as partnerships and consortia that
    generate data and information that will be used to create new paradigms
    for drug development. FDA has also committed to developing draft
    guidance in areas related to safety assessment, clinical trial design,
    and the use of biomarkers. In addition, FDA will participate in
    workshops and other public meetings to explore new approaches to a
    structured model for benefit/risk assessment. The results of these
    interactions will be used to assess whether pilot(s) of such new
    approaches can be conducted during PDUFA IV.
        Finally, it is important that we continue to assure that FDA is
    appropriately funded through a combination of appropriations and user
    fees so that the drug review program can address America's public
    health needs with the development of new medicines. During our
    discussions with the agency, a considerable amount of time was spent
    examining the increased workload within FDA, how it is measured, and
    how an appropriate workload adjuster can be constructed. The increases
    in funding to the program from the end of PDUFA III together with the
    new approach to workload adjustment will provide the sound financial
    footing needed to continue keeping FDA's drug and biological review
    program strong throughout the PDUFA IV years.
        PDUFA is vital to ensuring that FDA has the necessary resources to
    perform its critical functions of fostering drug development and
    innovation and protecting the public health. The PDUFA IV proposal will
    provide FDA with substantial new funding and resources to enhance its
    oversight over drug safety and DTC advertising while ensuring that the
    drug review program is as robust and efficient as possible.
              s. 484, ``enhancing drug safety and innovation act''
        Wyeth believes the Kennedy-Enzi bill presents a thoughtful effort
    to maintain the important balance of providing safe drugs while not
    unduly delaying patient access to new therapies. The Risk Evaluation
    and Mitigation Strategy (REMS) system would bring FDA closer to the
    risk management approach taken by the European Union, a desirable goal.
        To this end, a statutory construct that is somewhat less
    prescriptive and instead lays out principles and creates a framework to
    guide FDA in developing specific criteria for applying risk mitigation
    tools, through regulations, would be a preferable approach. Under such
    a system, FDA would be afforded the flexibility to develop varied
    programs for medications with differing levels of risk and to adapt to
    evolving technologies for post-marketing risk evaluation. Because the
    bill envisions broad latitude in developing REMS plans that may have
    far-reaching impact, it is important that these decisions be approved
    at the highest levels of the agency.
        Additionally, the funding mechanism proposed in S. 484 conflicts
    with the PDUFA agreement so that matter would need to be reconciled
    before proceeding.

        Senator Brown [presiding]. Thank you, Dr. Burlington.
        Ms. Dorman, thank you for joining us.

       STATEMENT OF DIANE EDQUIST DORMAN, VICE PRESIDENT, PUBLIC
            POLICY, NATIONAL ORGANIZATION FOR RARE DISORDERS

        Ms. Dorman. Thank you. Senator Enzi and members of the
    committee. Thank you for this opportunity to testify today
    regarding the reauthorization of the Prescription Drug User Fee
    Act and pending legislative proposals to enhance the
    postmarketing safety of prescription drugs.
        The National Organization for Rare Disorders is a leading
    national nonprofit voluntary health agency dedicated to the
    identification, treatment, and cure of more than 6,000 known
    rare diseases that affect an estimated 25 million Americans. We
    appreciate the committee's continuing interest in our views on
    user fees, postmarket safety of prescription drugs, and the
    strength of the FDA. In addition to its own perspective, NORD
    plays a leadership role in the FDA Alliance as well as the
    Alliance for Drug Safety and Access. I will reflect some of the
    views of both during this testimony.
        We are all aware that confidence in the FDA's judgments on
    the safety of a wide range of products has been greatly shaken.
    Congress needs to provide FDA with more authority, increased
    appropriations, and more consistent agency oversight. We join
    others in recommending that Congress enact the PDUFA IV
    reauthorization in a timely manner. It is necessary and
    important, but insufficient by itself.
        NORD believes strongly that Congress should strengthen
    FDA's authority to assure postmarket drug safety, secure
    substantial additional nonuser fee appropriations, and provide
    consistent oversight to assure that the agency's leadership
    pursues independence and objectivity in its U.S. scientific and
    regulatory operations. We also believe that the FDA has secured
    several important improvements to the existing user fee
    program, but it has omitted other equally important potential
    improvements.
        Our principal concern with the recommendations is how the
    program operates in conjunction with the Orphan Drug Act, which
    has led to the development and approval of more than 300 drugs
    and biologics for treatment of rare diseases. We do not want
    small companies deterred from pursuing promising orphan drug
    opportunities because modest revenues will be further
    diminished by product and facility user fees. This is a view
    that Congress has shared from the beginning of the user fee
    program and resulted in orphan drugs being totally exempt from
    application user fees.
        We are not seeking exemption of all orphan drugs from
    product and facility user fees. Rather, we have the desire to
    assure that the purposes of both acts be maximized. We want
    your help in resolving this in a way that assures the
    continuing success of the Orphan Drug Act.
        A second principal concern is that the $37.5 million in
    user fee funds dedicated to enhancing postmarket safety is
    inadequate. A substantially greater investment in additional
    user fees and appropriations will be needed to contribute to
    important CDER programs. Furthermore, we are also concerned
    that the PDUFA IV recommendations only allocate an additional
    $4 million for strengthening informational technology
    infrastructure for drug user fees--for drug reviews. This is
    wholly inadequate given the sadly outmoded and inefficient
    computer systems now in place.
        Like many public and private stakeholders, NORD has been
    deeply concerned that the FDA does not have adequate resources.
    We urge the committee to become activists for FDA funding, not
    only through PDUFA and other user fee programs, but through
    greater sustained appropriations.
        The FDA Alliance specifically asks Congress to appropriate
    $2 billion for the FDA in fiscal year 2008, in addition to
    revenues for user fees. This is the amount needed to restore
    FDA to its fiscal year 2003 operating level, as well as fund
    the additional program responsibilities mandated by Congress in
    subsequent years.
        Congress and the FDA must also address the need for
    sustained leadership that will help the agency shed recent
    unwanted blemishes. We are encouraged by the Senate's
    confirmation of Dr. von Eschenbach. He continues to be NORD's
    friend and a friend of the rare disease community.
        Finally, NORD believes strongly that enactment of the
    Enhancing Drug Safety and Innovation Act is essential to
    improve the completeness of FDA's statutory authority, address
    clear deficiencies in agency practice and culture, and better
    secure public confidence in FDA's ability to protect the public
    health. The bill builds upon this foundation with essential
    duties, such as required pharmacovigilance, and additional
    requirements such as patient registries.
        S. 484 also endows FDA with the critically important
    authorities to require postmarket studies and to compel
    labeling changes to reflect new safety information when
    sponsors fail to act in a timely or appropriate manner. I would
    like to add that NORD does not support efforts of some to
    establish a separate Center for Drug Safety. This would only
    serve to fragment the agency further and shrink already
    inadequate financial resources.
        There are enhancements, however, that could strengthen its
    already important provisions. First, NORD believes that the
    Fair Access to Clinical Trials Act of 2007 sponsored by
    Senators Dodd and Grassley offers superior features such as
    increased civil monetary penalties.
        Second, we would like to see postmarketing studies
    conducted for off-label uses. This is important because most
    patients with rare diseases and those in the pediatric
    population are treated off-label. By necessity, orphan drugs
    and biologics are tested on relatively small numbers of rare
    disease patients and therefore postmarket surveillance and
    studies are especially critical for gaining more widespread
    patient safety information over time.
        Third, minor enhancements to the REMS paradigm are
    possible, such as omitting exceptions for current sponsor-
    controlled label changes.
        Finally most importantly, NORD believes that S. 484 can
    provide for additional mechanisms to assure patient and
    provider input in the development of REMS plans.
        In conclusion, rare disease patients are no different from
    most patients in their views and concerns about drug safety. We
    know safety can never be absolute, which is exactly why
    patients are so dependent on the thoroughness and competency of
    FDA's review process and why FDA needs additional authority to
    oversee and act during the postmarket period.
        Passage of S. 484 is a matter of urgency and one which
    benefits all stakeholders. Failure to enact it risks a repeat
    of the uneven and often disastrous safety decisions that have
    led to drug withdrawals, questionable sponsor practices, and
    apparent regulatory failures that have so badly eroded public
    confidence in the FDA.
        Thank you.
        [The prepared statement of Ms. Dorman follows:]
                   Prepared Statement of Diane Edquist Dorman
                                  introduction
        Chairman Kennedy, Senator Enzi, and members of the committee. Thank
    you for this opportunity to testify today regarding the reauthorization
    of the Prescription Drug User Fee Act (PDUFA) and pending legislative
    proposals to enhance the postmarket safety of prescription drugs.
        I am Diane Dorman, Vice President for Public Policy of the National
    Organization for Rare Disorders (NORD). We are a leading national non-
    profit voluntary health agency dedicated to the identification,
    treatment and cure of rare diseases. There are more than 6,000 of these
    disorders, cumulatively affecting an estimated 25 million Americans.
    NORD has a long successful history working with Congress on the Orphan
    Drug Act of 1983, PDUFA and other healthcare-related legislation.
        For these reasons, we appreciate the committee's continuing
    interest in our views on user fees, postmarket safety of prescription
    drugs, and the strength of FDA. In addition to its own perspective,
    NORD plays a leadership role in the FDA Alliance, as well as the
    Alliance for Drug Safety and Access (ADSA) and will reflect the views
    of both during this testimony.
        We are all aware that confidence in the FDA's judgments on the
    safety of a wide range of products--from the food on our dinner tables
    to bestselling, blockbuster drugs, and the latest, breakthrough
    biotechnology therapies and medical devices--has been greatly shaken.
    The problems are systemic, cultural and financial. Congress needs to
    provide FDA with more authority, increased appropriations, and more
    consistent agency oversight. FDA, an agency that is hardworking and
    well meaning, needs to remember that regulated industries are
    ``stakeholders,'' not customers and that it is the patients and
    consumers who may live or die and who are most at risk based on the
    quality and independence of its decisions.
        We join others in recommending that Congress enact a PDUFA IV
    reauthorization in a timely manner well before the current law expires.
    The reauthorization is necessary and important, but insufficient by
    itself. NORD believes strongly that Congress has other, equally
    important tasks to fulfill in an equally timely fashion.

         Strengthen FDA's authorities to assure post-market drug
    safety;
         Secure substantial, additional nonuser-fee appropriations
    to adequately fund FDA; and,
         Provide consistent oversight to assure the agency's
    leadership pursues independence and objectivity in its scientific and
    regulatory operations.
     comments on the pdufa iv recommendations, including impact on orphan
                              product development
        Based on our review of the summary of PDUFA IV enhancements and
    recommendations, NORD believes that the FDA has secured several
    important improvements to the existing user-fee program. It has omitted
    other, equally important potential improvements. We would also caution
    that nothing can be certain about the PDUFA IV recommendations until
    actual legislative language has been made available to the public and
    to patients for review.
        The PDUFA IV recommendations offer some clear improvements by:

         Allowing FDA to expend user-fee revenues for purposes of
    post-market risk management and scrutiny of products during the entire
    duration of their marketing, not restrained by the current limitation
    of 3 years postapproval;
         Creating dedicated user fees for the review of voluntary
    direct-to-consumer (DTC) television advertisements; and,
         Funding of guidance development and the revision of
    inflation and workload ``adjusters'' to account for actual submissions
    and the inflation-adjusted calculation of FDA's review costs.

        NORD's principal concern with the FDA's PDUFA IV recommendations is
    how the program operates in conjunction with the Orphan Drug Act (ODA),
    which has led to the development and approval of more than 300 drugs
    and biologics for treatment of rare diseases. Since so much orphan drug
    development is conducted by small, start-up companies, there is an
    ever-present risk that user fees (or the perceived burden of user fees)
    present a potential barrier to innovation, research, product
    development and market entry.
        In particular, we do not want small companies deterred from
    pursuing promising orphan drug opportunities because modest revenues
    will be further diminished by product and facility user fees. This is a
    view that Congress has shared from the beginning of the user-fee
    program and resulted in orphan drugs being totally exempt from
    application user fees.
        The current waiver program administered by FDA for product and
    facility fees has chosen to interpret gross revenues of $10 million or
    greater as evidence that an entity and its affiliates are fully capable
    of developing and marketing orphan drugs without regard to the cost of
    user fees. We know that FDA believes that a higher threshold than $10
    million in corporate gross sales will result in a significant expansion
    of waived products and a noticeable increase in the fees that would be
    charged to remaining companies. Nonetheless, this does not conform with
    any common sense view of what constitutes a small company in the bio-
    pharmaceutical industry and seems unrealistically low, especially with
    the higher fees that will be required under PDUFA IV.
        We come to this issue with a desire to assure that the purposes of
    both acts be maximized. We do not seek the exemption of all orphan
    drugs from product and facility user fees, but neither do we feel
    confident that product and facility user fees are an inconsequential
    aspect of the development of orphan drugs for small populations or for
    which there is otherwise modest revenue potential. We seek Congress'
    help in resolving this in a way that assures the continued success of
    the Orphan Drug Act without undercutting the user-fee program.
        A second principal concern is that the $37.5 million in user-fee
    funds dedicated to enhancing postmarket safety are inadequate. By
    comparison, the Institute of Medicine called for $100 million as a
    baseline investment in new funds for this purpose. This substantially
    greater investment in additional user fees and appropriations will be
    needed to permit the Center for Drug Evaluation and Research (CDER) to:

         Develop, validate, staff, deploy and utilize a wider and
    ``smarter'' range of post-market safety tools and activities;
         Increase staffing in Office of Drug Safety and Office of
    Surveillance and Epidemiology; and,
         Broaden access to data, employment of new and improved
    data-mining techniques, and additional epidemiology contracts.

        Similarly, we are concerned that the PDUFA IV recommendations only
    allocate an additional $4 million for strengthening the information
    technology infrastructure for drug reviews. This is wholly inadequate
    given the sadly outmoded and inefficient computer systems upon which
    CDER relies and the absence of resources to dedicate towards developing
    uniform standards. While improved IT related to drug safety is a
    purpose for which appropriated funds should also be requested, we are
    concerned that what FDA has in mind is a mere drop in the bucket
    towards the goals of enhancing post-market safety surveillance and
    boosting electronic pre-market submissions. As a point of reference,
    patient and consumers groups have been informed that roughly half of
    the agency's outmoded IT systems actually can no longer be serviced by
    commercial vendors. A large investment is clearly needed if IT is to
    contribute toward improved drug safety at anytime in the next few
    years.
        NORD believes that other resource-starved and otherwise
    underemphasized enforcement activities need further support. While fees
    are levied upon submissions, this does not cover the needed level of
    activity in areas such as facility inspections and FDA's Bioresearch
    Monitoring Program (BIMO) inspections. The FDA must shift from reliance
    upon incomplete, unreliable passive surveillance and the Adverse Event
    Reporting System (AERS/AERS II) to more directed surveillance and FDA-
    conducted or mandated observational studies.
    increasing fda's non-user fee appropriations is critical to protecting
                     public health and advancing innovation
        Like many public and private stakeholders, NORD has been deeply
    concerned that the FDA does not have adequate resources. We
    participated in the founding of The FDA Alliance, a broad-based, non-
    partisan coalition of consumers, patients, health care professionals,
    and industry, and I serve as a board member and the Alliance's Vice
    President. With more than 100 members, including seven former FDA
    Commissioners, the FDA Alliance is an advocate for increased
    appropriated funding for FDA to enable the agency to effectively carry
    out its dual roles as a leading guardian of consumer health and safety
    and as an active leader in advancing global scientific and medical
    innovation.
        As the Senate authorizing committee with jurisdiction over the FDA,
    we urge the committee to become activists for FDA funding--not only
    through PDUFA and other user-fee programs, but through greater,
    sustained appropriations. This is essential to the agency's proper
    functioning as a regulator of food safety, of drug and device safety,
    and of its critical oversight of the explosive innovation in fields as
    varied as nanotechnology, molecular diagnostics, pharmacogenomics, and
    material sciences.
        The FDA Alliance specifically asks Congress to appropriate $2
    billion for the FDA in fiscal year 2008, in addition to revenue from
    user fees. By our calculations, this is the amount needed to restore
    FDA to its fiscal year 2003 operating level, as well as fund the
    additional program responsibilities mandated by Congress in subsequent
    years. This would be an increase of $450 million over the fiscal year
    2007 Continuing Resolution, a large but also prudent and overdue
    investment in strengthening the FDA, protecting the public health, and
    enhancing innovation.
        As important as this user-fee reauthorization is, we cannot
    emphasize enough how dire the FDA's resource situation has become and
    how badly the agency is in need of an immediate and substantial
    infusion of additional appropriated dollars. In short, PDUFA is a
    necessary and valuable component of FDA's funding, but it is not
    sufficient in itself and is simply no substitute for increasing FDA
    appropriations.
         leadership is urgently needed to restore agency independence
                                and credibility
        Congress and the FDA must also address a third, critical unmet
    need: sustained leadership that will help the agency shed recent and
    unwanted blemishes to its ``gold standard'' reputation for scientific
    independence and regulatory rigor. NORD has consistently represented to
    Congress and to the FDA that the agency's success cannot be measured by
    the speed of its work, but rather the completeness and scientific
    soundness of its work. I will not belabor the obvious examples of the
    crises in public confidence suffered lately by the agency, but there is
    clearly much work to do.
        As the Institute of Medicine so forcefully concluded in its
    September 2006 report, ``The Future of Drug Safety'':

            ``[R]ecent highly-publicized controversies . . . have
            contributed to a public perception that the drug safety system
            is in crisis . . . [and q]uestions [have] also surfaced about
            the independence of the scientific expertise relied on by FDA .
            . . and about the possibility of undue industry influence
            related to CDER's increasing dependence on PDUFA funding . . .
              . . . Many observe signs of an organizational culture in
            crisis.''

        These are views shared widely among patients, media and regulated
    industry: that only a strong FDA can sustain--or regain--public
    confidence in the food, drugs and devices it regulates.
        We are encouraged by the Senate's confirmation of Dr. von
    Eschenbach, an accomplished clinical scientist and manager, to be
    Commissioner. We hope that he will steer the agency back towards a more
    vigorous and timely enforcement of science-based regulatory policy
    without concession to ideology or politics. We also recommend that
    Congress undertake two specific tasks to help assure this takes place:

         First, we believe that more consistent and focused
    oversight by the committee of the agency's enforcement activities and
    regulatory policies is needed. We have noted with concern that, over
    time and certainly since the last PDUFA reauthorization, the agency's
    responses to congressional requests for information may have become
    less timely. We consequently encourage the committee to undertake
    bipartisan oversight of priority FDA operations through the committee's
    investigative staff, sustained communications with agency scientific
    managers, and the appropriate use of the General Accountability Office
    and the HHS Inspector General.
         Second, we recommend that the committee enact revisions to
    the FDA's statutory mission in the Federal Food, Drug, and Cosmetic Act
    to reflect and reinforce the importance of scientific independence,
    integrity and objectivity. While this might be dismissed as a gesture,
    NORD believes that the Commissioner, political managers and career
    employees alike do or should take heed of the law and of congressional
    directives in undertaking their duties. That is why we agree with the
    IOM's recommendation that Congress change the agency's mission
    statement to further underscore the importance of science,
    independence, integrity and objectivity.
       enactment of s. 484 is needed to strengthen fda's authorities and
                         better assure postmarket drug
        Finally, NORD believes strongly that enactment of S. 484, the
    Enhancing Drug Safety and Innovation Act of 2007, is essential to
    improve the completeness of FDA's statutory authority, address clear
    deficiencies in agency practice and culture, and better secure public
    confidence in FDA's ability to protect the public health. We believe
    that the bill closely aligns with the Institute of Medicine's
    recommendations, and that Congress should do no less than what is
    proposed in the Enzi-Kennedy bill to address the many drug safety
    crises and failures that have transpired in the recent past.
    A. Key Features and Improvements to Postmarket Safety Through S. 484
        Rather than delve into the specific provisions of S. 484, we
    believe that the committee should bear certain key principles in mind
    when it considers this legislation in the near future. First, the
    concept of ``risk evaluation and management strategy'' is based upon
    well-established FDA regulations, standards and practice. Minimal
    elements of the proposed ``REMS,'' such as product labeling and adverse
    drug reaction reporting, are already in place today for all drugs. But
    the bill builds upon this foundation with essential duties such as
    required pharmacovigilance, and also provides FDA flexibility to add
    more requirements, such as patient registries, when called for by the
    risk-benefit profile of the given drug product.
        Because NORD works globally on orphan drug issues, we also believe
    the committee should be aware that Europe requires REMS for all drug
    products in Europe.
        We are aware of criticism of the scope and comprehensive reach of
    the REMS paradigm. But these critics fail or refuse to understand that
    S. 484 does not require a ``one-size-fits-all'' application of these
    safeguards. FDA has historically had great success in applying REMS
    requirements where the agency has exercised careful scientific judgment
    about balancing the risks and benefits of their application. First, it
    is the case that all drug products currently marketed are already held
    to some or all of the requirements. Second, REMS are particularly
    useful in challenging cases such as Tysabri, a novel, first-in-class
    biotechnology therapy for multiple sclerosis, a serious, life
    threatening disease. FDA's cooperative employment of appropriate
    ``REMS'' controls with the drug sponsor has led to the re-introduction
    of the therapy in the United States after its voluntary market
    withdrawal.
        It is within the REMS paradigm that S. 484 also endows FDA with the
    critically important authorities to require postmarket studies and to
    compel labeling changes to reflect new safety information when sponsors
    fail to act in a timely or appropriate manner. The legislation also
    creates a publicly accessible registry of clinical trials and clinical
    trial results. These are vital changes to FDA authority that must be
    enacted to address past failings, to close loopholes in the law, and to
    secure patient access to safe and effective drugs and the information
    needed to use them.
    B. Potential Enhancements to S. 484
        There are enhancements to S. 484 that NORD believes could
    strengthen its already important provisions. First, NORD believes that
    the Dodd-Grassley Fair Access to Clinical Trials (FACT) Act of 2007
    offers superior features in the organization and implementation of a
    clinical trial registry and disclosure database. Second, minor
    enhancements to the Kennedy-Enzi REMS paradigm are possible, such as
    omitting exceptions for current sponsor-controlled labeling changes to
    ensure FDA remains the ultimate arbiter of safety-related drug
    labeling. And finally and most importantly, NORD believes that S. 484
    can provide for additional mechanisms to assure patient and provider
    input in the development of REMS plans--and the features of future
    PDUFA reauthorizations.
                                   conclusion
        Rare disease patients are no different from most patients in their
    views and concerns about drug safety. We want innovative medicines as
    quickly as they can be tested, evaluated, proven, approved, and
    marketed. We can accept certain risks in new medications, if they are
    properly considered by FDA, accurately labeled by the sponsor, and
    correctly prescribed by health care professionals.
        Safety can never be absolute, which is exactly why patients are so
    dependent on the thoroughness and competency of FDA's review process
    and why FDA needs additional authority to oversee and act during the
    postmarket period. Patients depend on the industry's skill in
    innovation and product development, but will necessarily be cautious
    without the assurance that FDA has thoroughly evaluated the safety and
    effectiveness of new therapies.
        Although I cannot speak for industry, the credibility of FDA's
    review process should be every bit as important to them. Public
    confidence in FDA translates into patient and prescriber confidence in
    FDA-approved therapies. A strong FDA review process increases the value
    of approved products from both the patient and company perspective.
        Seen this way, passage of S. 484 is a matter of urgency and one
    which benefits all stakeholders. Conversely, failure to enact S. 484
    risks a repeat of the uneven and often disastrous safety decisions that
    have led to drug withdrawals, questionable sponsor practices, and
    apparent regulatory failures that have so badly eroded public
    confidence in FDA--and by extension in the safety and effectiveness of
    drug therapies.

        The Chairman [presiding]. Thank you all very much.
        I think all of us here on the committee believe that FDA
    ought to have greater resources. My friend Senator Hatch is not
    here. He and I for years and years have fought for additional
    resources over a long period of time. We ought to be able to
    get that help on modernizing all of that equipment at FDA,
    coordination of the various campuses. There's a wide variety of
    different things when you think about the responsibility that
    this agency has on health care, and we all bear responsibility
    that we haven't been able to give it the kind of funding it
    needs. We can imagine what that agency would be like if we
    didn't have the PDUFA and MDUFA. So this is something at least
    and a place where we can start.
        We have a short time. There's a number of areas I would
    like to cover. I wanted to thank all of you for being here.
        Dr. McClellan, just as you are a physician as well as a
    very dedicated public servant, you have looked at the
    legislation. When you were commissioner, did you feel that you
    would want some additional legal tools, that would be
    advantageous and helpful and useful to you in terms of drug
    safety?
        Dr. McClellan. Mr. Chairman, when I was commissioner I was
    faced with the same issues that you have been hearing about
    today. Without adequate resources, it's very hard to do the
    planning necessary to do appropriate postmarket monitoring. I
    think the way that this committee is approaching the issue and
    the way that you are approaching it in your bill, of taking a
    comprehensive look at all the steps that are needed--
    information, resources, which are definitely needed, additional
    statutory authorities, and organizational issues--is the right
    way to approach this.
        This is a once in 10-year opportunity and I truly commend
    you for taking this comprehensive look on getting all these
    issues on the table as you are.
        I think there's a lot that could be done at the agency with
    additional resources and information that would make its job
    easier in terms of these postmarket activities, as I discussed
    in my testimony.
        The Chairman. To Mr. Burlington, you testified that you
    thought the Enzi-Kennedy bill strikes a balance between safety
    and innovation. If you could just focus on that for just a
    moment. You have heard some of the discussion earlier today
    from the different sides. Maybe you could just elaborate on
    that point if you would, please.
        Dr. Burlington. Thank you, Mr. Chairman. I think it is
    important that we continue to make sure that when we look at
    safety tools that we ensure that there be access for products
    to patients who need them. We are always trying to get the
    right balance between safety information and the benefits. It's
    critically important that we keep benefits in view as we do so.
        The Chairman. Well, just with regards to this balance, as
    we have talked about, are you satisfied with that legislation
    that we have done that? Do you think it's particularly weighted
    as being too overly burdensome, or do we hit about the zone
    that you would think that balances safety and innovation on
    this? Do you have a comment on that?
        Dr. Burlington. I do, Mr. Chairman. The legislation as it
    is drafted provides broad discretion to the Food and Drug
    Administration, as well as a tool kit, if you will, for
    mitigation strategies. The threshold for applying any one of
    those strategies is really quite low, and as a consequence it
    is very important that these be seriously reviewed, that they
    be not imposed on drug companies in such a way as to restrict
    access easily, but in fact should be very substantive
    determinations made at the most senior levels of the agency.
        The Chairman. Kim, I regret I wasn't here for your
    testimony. I have a question--some have said that perhaps
    Congress should not take action on improving the drug safety,
    that the current system is adequate. Could you just respond to
    that? I think I saw you earlier during the course of the
    hearing when there was pretty good exchange by the other
    members on this issue, and I know you were listening carefully.
    Maybe you would comment on your own view.
        Ms. Witczak. Sure, Mr. Chairman. I personally--right now I
    appreciate the first step on safety, but I don't feel that the
    current system is adequate in monitoring safety in the
    postmarket. Obviously, with the history--and the reason I gave
    the history of the antidepressant is to really show from 1991
    and all the internal documents that have come out--I feel
    there's a lot more that could be done.
        I think the ability to give the FDA more technology or to
    be able to search for postmarket safety data is needed. I would
    love to have an investigative attitude in regards to postmarket
    safety, almost like when a plane crashes the NTSB is out there
    and they are investigating all things. I understand that a lot
    of times you will hear these are anecdotal stories. But when
    you start seeing a trend emerge, whether it is the postmarket,
    the adverse events, I think we need to go out there and
    actually actively search and find these safety issues.
        The Chairman. Senator Enzi.
        Senator Enzi. Thank you, Mr. Chairman.
        I appreciate all of your testimony. I have questions, lots
    of questions, and I hope you will answer some of them in
    writing as I'm limited on time.
        I will start with Dr. Burlington. I don't believe that user
    fees are a bad thing, but I am concerned about the ever-growing
    portion of the drug review program that is funded by user fees.
    It's been suggested that the appropriations trigger should be
    changed both to use a different base year and to use a more
    accurate inflator to change the amount from year to year. That
    would result in a significant increase in appropriated funds to
    the agency.
        I'm interested in that idea, but I'm not convinced the
    larger appropriations alone would solve FDA's problems. What do
    you think?
        Dr. Burlington. Thank you, Senator. I believe that it would
    be preferable for the Food and Drug Administration to be fully
    and adequately funded out of appropriations. But this is the
    system we have today. User fees do provide very substantial
    resources to the agency to undertake their work and augment
    appropriations.
        The concern that FDA is somehow unduly influenced by this I
    believe was commented on earlier by Commissioner McClellan.
    When I was at FDA, one didn't think about where the money was
    coming from. You understood that what your job was was to look
    at the safety and effectiveness and to try and reach the right
    balance in any determination you were making.
        In terms of the specific question you raised about whether
    adjusting the trigger would be a mechanism to ensure greater
    appropriated funds, the way that Congress decides to allocate
    the available money is something obviously that you and the
    other members are far more expert in than I could be. I do
    think it is important that we not set up a mechanism whereby we
    would back FDA into having to give pink slips to a couple of
    thousand people currently supported by user fees and that we
    would then deprive American patients of the staff who are
    necessary, not only to look at new medicines, but also to
    continue to review and monitor the safety of those drugs on the
    market today.
        Senator Enzi. Just to be clear on something, in your
    testimony you indicated that the Kennedy-Enzi bill is in
    conflict with the PDUFA agreement. I hope you meant that it
    would change the agreed upon dollar commitment, not that the
    two proposals are substantively in disagreement. Do I have that
    right? How much more do you think our bill would cost?
        Dr. Burlington. Senator, it is of concern that there is
    additional work that would undoubtedly fall to the agency under
    the Kennedy-Enzi bill. Exactly how much this would cost I'm not
    clear about. I suspect that the agency is much better able to
    develop a model for how much work that is going to be. But it
    is clear that there would be first year additional costs and
    that it is appropriate that there be a mechanism to fund those.
        If you can find the appropriated dollars to do it, that
    would be best. If you can't find the appropriated dollars to do
    it, then yes, you would need to reconcile the user fee proposal
    which is in front of you today with the extra work that would
    be required to implement Kennedy-Enzi.
        Senator Enzi. Thank you. I will have some more technical
    follow up questions on that. I appreciate that.
        Dr. McClellan, we have all been working on some health
    information technology and I think that that information
    technology will answer a lot of the questions. I hear a lot
    about the total inadequacy of the FDA's technology
    infrastructure, which seems to me to be a precondition of
    getting a drug safety system nationwide. What sort of resources
    would it take to get the FDA's information technology up to
    par, up to date?
        Dr. McClellan. Well, Senator, thank you again for your
    leadership with Senator Kennedy and others on getting to 21st
    century health IT. It's so important. With respect to the FDA's
    budget, I think there are two pieces. One is the overall IT
    support at the agency. This is everything from doing e-mail to
    tracking correspondence to everything else besides dealing with
    adverse events and drug safety issues. The FDA does need
    substantial resources to modernize their overall IT support,
    and that's why so many groups from all across the spectrum of
    perspectives are all unified behind significant increases in
    resources--$500 million over 5 years, maybe $180 million if
    possible in this current round, much of which would go to
    modernizing the overall IT infrastructure at the agency.
        With respect to postmarketing monitoring, it's a more
    contained problem. You need three things. You need adequate
    systems for the FDA to interact with the outside world in all
    these data systems that I described in my testimony. You need a
    system for bringing together all the different pieces that are
    out there now from health plans, Medicare, and other sources.
    It's all there. It's just not working together yet. And you
    need to fund keeping those pieces of data in place and usable
    for these efforts.
        We are already spending a lot of money on those efforts. We
    are just doing it separately. Medicare is doing some analysis,
    FDA is buying data sets on a one-off basis. Drug companies, as
    part of their risk management plans, are doing single one-off
    analyses. If we put that together, we may even be able to save
    money in this.
        So I think overall for that problem we are talking about
    low tens of millions of dollars, not an enormous new
    investment.
        Senator Enzi. Thank you.
        My time has expired. I will submit some additional
    questions.
        The Chairman. Senator Brown.
        Senator Brown. Thank you, Senator Kennedy.
        Ms. Witczak, thank you very much for coming. I'm sorry, we
    were on the floor and I didn't get back. But I have read your
    testimony. I, as you, am opposed to direct-to-consumer
    advertising. I think that we can do a better job regulating.
    Senator Coburn said--I'm not a lawyer, nor is he--but that
    there may be constitutional issues there.
        You have suggested in your testimony that you have thought
    this through about some things we could do if we can't ban it,
    which I think we should at least have a 2-year ban on it. I
    don't know if this committee will accept that. But there are
    some things that we can do to regulate it. One of the things
    you mentioned which I thought was pretty intriguing is any
    advertisement has to, as you say, require each ad to include a
    1-800 number where consumers are advised to report adverse side
    effects.
        Elaborate on other ideas you might have that, if we are
    going to allow direct-to-consumer advertising in these huge
    multi-million, multi-tens of millions of dollars marketing
    campaigns, how we can perhaps steer them in a little different
    direction?
        Ms. Witczak. Thank you for the question. Well, first of all
    I do think the fact--you know, I'm against DTC advertising. I
    have spent my entire career in advertising, so I kind of go
    against what is out there, because I think they should be held
    to a different standard. But I do believe that it is here to
    stay, and with that I think there are some things that we can
    do by requiring that 800 or MEDWATCH as a tag at the end. We
    have to listen to the side effects anyway, but it really allows
    the consumer to actually bring forward their perspective,
    because we are the real clinical trials. I think a lot of
    direct-to-consumer advertising actually drives people to their
    doctor, because of the messages that they are out there
    promoting, especially like on the antidepressants and even on
    some of the sleeping medications. I think we are
    overprescribing. I mean, people are going for every little
    thing.
        Because of that, I think there are some mechanisms that
    should be put into place. I do think that the idea of putting
    more moneys toward approving the advertising, I do think that
    it should be mandatory. Right now it's voluntary that they are
    going to get their messages approved. I think it should be
    mandatory.
        But I do know that last year one of the companies ran a
    sleep medication ad during back to school and the FDA just sent
    out a memo in March telling them to pull it, to pull it, and it
    ran in September. So I think there needs to be better tracking
    inside the agency for communications that might be misleading
    or you want to change.
        But I would really like to see that 800 number and bring
    the consumer into it.
        Senator Brown. Thank you for that.
        Dr. McClellan, nice to see you again. I want to talk to you
    and shift for a moment if I could, Mr. Chairman, to another
    safety issue that's not really related to this bill, although I
    would like it to be, and that is the whole issue of antibiotic
    resistance. You and I have talked about that in the past in
    your position at the FDA. I think perhaps this bill can take
    that issue more seriously and including it in this bill--if I
    could pick your brain about any ideas you have. Maybe with
    better data collection, maybe with shifting the burden of proof
    to the industry.
        If, for instance, a drug is approved for prophylactic use
    in an animal, an antibiotic, then the burden, I believe, is on
    the government to show that that could have an impact in
    creating or building antibiotic resistance in the human
    population. Talk that through with me. It's an increasingly
    serious problem with hospital infections, with what happens
    with this new XDR TB, this extremely multidrug-resistant TB
    that's beginning to kill people in pretty large numbers in the
    developing world and is as infectious as other forms of TB and
    is much, much, much more deadly. And we are not doing well
    enough with getting enough antibiotics in the pipeline. We know
    all that.
        What can we do to preserve the safety of antibiotics by
    using the FDA, with data collection, with perhaps shifting that
    burden of proof to the industry rather than to the government
    to show what it might mean on the human population?
        Dr. McClellan. A couple of things. In terms of the impact
    of animal drug use on human antibiotic resistance, which I
    think is the main point here, that is an issue that has been
    negotiated out by the FDA recently with industry, and I think
    those negotiations and the guidances that result from them are
    continuously subject to revision. So if there are better ways
    to do it, I think the FDA would be open to hearing about it,
    and I think you may not even need legislation to make sure that
    those most recent and up-to-date safety concerns are being
    addressed.
        With respect to this legislation that's pending right now,
    taking a step back to this broader problem that we have, of not
    enough new antibiotics in the pipeline to give us confidence in
    the future that we will be able to treat very resistant
    organisms, which is the main point. I think having a better
    surveillance system on how drugs are actually being used in
    people would be very helpful.
        The detection of safety problems more accurately and more
    quickly is a very important goal for using this network of
    databases that I described. But the same network can also help
    us get a better understanding of how antibiotics are actually
    being used in practice, what kinds of clinical indications are
    being treated using what specific medications. Well, if we can
    get a better handle on that, then good information puts you on
    the path to influencing how drugs are being used appropriately.
        Something else that came up earlier in this hearing as
    well. Getting the health plans and these other groups to get
    information out about appropriate use. Health plans, as you
    know, can have a big impact. Medicare, private health plans,
    can have a big impact on which drugs are used and how. Bringing
    the FDA together more closely with these other parts of our
    health care system to promote better use of medication, getting
    the most for our money in drugs, including antibiotics, I think
    would be a very important side benefit of the kind of
    legislation that's being worked on here.
        Senator Brown. Thank you.
        Thank you, Mr. Chairman.
        The Chairman. Senator Burr.
        Senator Burr. Thank you, Mr. Chairman.
        Kim, I want to thank you for excellent testimony. We are
    all saddened at your loss. Your statement that the current
    system is deficient, I agree with totally. I think that you
    raise some good issues with the 800 number, with the
    recruitment process for advisory boards, and I would tell you
    we can't stop with the 800 number. It needs to be electronic
    means to contact as well, and I hope that we can do that. But I
    do thank you for your willingness to come.
        Dr. McClellan, it's good to see you. If I can, I would like
    to shift because I have believed since 1997 when we did FDAMA,
    and when you were at the FDA I expressed this to you, that our
    real focus was that we needed a real surveillance program, one
    that looked at trends, one that did exactly what Kim said: When
    you identify something that looks like a problem, it sends you
    like a laser beam to figure out, are there more people that are
    experiencing this? Is this something that we didn't intend and
    that we didn't pick up in the original clinical trials?
        We do a poor job of doing that. We have the ability today.
    We capture 99 percent of the scripts that were written
    yesterday, we capture today. We know exactly who took them.
    That's followed up in some way, shape or form with potentially
    an insurance claim that might detect an adverse reaction to
    that, probably processed within the same company or grouping of
    companies.
        Why can't we tap into that? Why can't we process it? I
    realize that not every doctor's office is necessarily putting
    everything electronically. But the claim, the claim for
    insurance purposes, is. And it gives us a tremendous tool,
    whether it's Quintiles or any of the other companies. Is that
    feasible to do?
        Dr. McClellan. Senator, I think it is. It is important you
    brought up FDAMA in 1997 because that was the last time we took
    a close look as a nation at what needed to happen fundamentally
    at the FDA to improve the safe and effective use of
    medications, to get them to patients fast, but, as Senator
    Kennedy highlighted as well, to make sure that we are avoiding
    safety problems wherever possible.
        Back then, you couldn't do the kinds of things that you
    were just talking about now. Nice idea to have a surveillance
    mechanism in place, but we didn't have the same level of 99
    percent electronic transactions involving prescriptions and all
    of the databases that are actually being used now piece by
    piece on a one-off basis to do exactly what you are saying.
        What hasn't happened yet is putting it together in a
    national strategy for an infrastructure that on a routine and
    ongoing basis could conduct active surveillance and follow up
    on these issues. Now, I don't want to overstate this because
    just because you have got the data doesn't mean you can solve
    every safety problem. A lot of times you will see an
    association between a drug and an adverse event and it won't be
    the drug that caused the adverse event; it will be other
    factors, characteristics of the patient, other things.
        But if you combine this kind of active surveillance system
    with good information that we have about drugs going to market,
    the areas where we want to look at potential risks, the kinds
    of things that Ms. Witczak highlighted, that for a long time
    nobody was able to put together real effectively, too long of a
    time, then you have a pretty good foundation for doing a much
    better job for preventing safety problems. And on top of that,
    you have a good infrastructure for conducting any necessary
    follow up clinical trials, randomized trials, other detailed
    clinical studies, which can be quite costly and time-consuming
    in the postmarket setting. You can target those more
    effectively and quickly.
        So I do think this is the time and it's important for the
    committee to realize it's probably going to be another decade
    before we get another chance like this. And by that time, I
    sure hope we have gotten an electronic health care system.
        Senator Burr. Mark, you hit on a real key. Usually when we
    are talking about trying to implement a surveillance mechanism
    like this we are deficient on the data and we have the means to
    do it. This time we have all the data that's being accumulated
    because we track the scripts that are written, we track the
    insurance claims that are paid. The data is there. It seems
    like the easy thing is to figure out how we bring this all
    under one umbrella, where we can tap into it, not for a
    determination but for trend lines that would give individuals
    at the FDA reason to ask additional questions of a manufacturer
    to look and search a database of patients that they might reach
    out to to see if anybody else is having similar things that
    they haven't in fact communicated.
        That's why I'm a little bit standoffish on this
    legislation, because I don't see us going in the avenue of
    surveillance. I see us going in the avenue of taking the tools
    that the FDA currently has and they exercise in the ways that
    are historically influenced, and those need to shift, the
    paradigms need to shift.
        Let me point to one area. Dr. Burlington, it's good to see
    you again. You talked about principle versus process. Under the
    REMS, drug companies would have to monitor providers. Providers
    are doctors and nurses. They would have to monitor pharmacists
    and they would have to monitor patients, for compliance with
    the restrictions. Not only is monitoring I think unworkable for
    the company; the company would be liable in this legislation.
        So I go back to the innovation side that you didn't have
    concerns with and I ask you, if you present them with an
    unworkable situation and you hold them liable for the
    unworkable situation, will you have the degree of innovation
    tomorrow that you have today?
        Dr. Burlington. Senator, I share your concern that it does
    not sound very workable to ask the pharmaceutical industry to
    be policing the practice of medicine. I think that in many ways
    it is important for the pharmaceutical industry to take
    responsibility. We do look at safety as a very important issue.
    We work with the agency when issues arise in terms of putting
    in place marketing approaches or distribution approaches that
    will reduce the probability of having adverse events, serious
    adverse events. Those sometimes have included restrictions on
    the way products are used.
        But in the end, it is not appropriate to ask a company to
    try and control how a doctor works with a patient.
        Senator Burr. But that's what the legislation before us
    today actually does. It puts that requirement on doctors and
    nurses and pharmacists and patients. I'm not necessarily sure
    that at the end of the day we have any better information about
    adverse reactions. That is my big concern, and that's the
    objective that we are after.
        REMS could also require a provider to be trained. Now, I
    represent a State with a tremendous rural population, as Mark
    knows because of his other hat of CMS grand poobah. One of the
    challenges I had was transportation. I couldn't get somebody
    from their home to a place that provided a service because
    transportation stood in the way. The question is how do we take
    this rural infrastructure of America and set up a training
    mechanism per drug, per manufacturer, where we don't at some
    point risk the chance of not being able to provide a medication
    that an individual needs? It may not be a lifesaving
    medication, but it may address a real chronic illness that they
    have, that there's no provider that's trained based upon FDA
    guidelines that were prescribed to them that can actually write
    the prescription.
        Dr. Burlington. Senator, the strategy of developing
    training for the use of a particular product is undoubtedly
    derivative from previous experience in the medical device
    arena, where, particularly for many complicated surgical
    devices, there currently is a requirement for training in how
    to use them before given physicians are authorized.
        Now, of course that's not controlling what the physicians
    do. That's just setting up a requirement----
        Senator Burr. And most of those procedures are not done in
    rural America.
        Dr. Burlington. Absolutely correct. I think to the extent
    that any sort of training program ought to be envisioned it
    ought to be very rarely used. It ought to be used only in the
    most extraordinary cases. It ought to be a determination at the
    most senior level of the agency and one needs to be confident
    that that's what is necessary in order to maximize the benefit
    of the product. And then you need to develop mechanisms to make
    sure the training is available to those physicians who need to
    prescribe the product.
        Senator Burr. Well, let me say I applaud the chairman and
    the ranking member for bringing drug safety up again. It's an
    issue that I have raised since 1997 when we passed FDAMA. It's
    something that I think we have the capabilities to do in a much
    more effective way today. Even if we didn't pass this
    legislation, I believe that with the right resources within the
    FDA today we could have a surveillance program that teaches us
    a lot more and that the partnerships between the applicants,
    the drug companies, and the FDA, the regulators, would raise
    the confidence level of the American people.
        I'm not sure that we need legislation to do that. But where
    legislation can enhance, where it can provide the FDA with
    tools that possibly it doesn't explicitly have today, where it
    can be empowered to address direct-to-consumer advertising,
    which I think that the industry in total has handled in a very
    inappropriate way with some of the advertising that they
    choose--but by the same token, I also see that people
    throughout the country that never visit a doctor, saw an ad
    that talked about a medication that described their condition,
    and they went in and got blood pressure medicine and they are
    not the recipient of bypass surgery today, or they got a
    medication that saved them from an in-hospital incident.
        So there is value to it. The tricky thing is finding the
    balance, and part of that is the responsibility of the industry
    on a voluntary basis. Part of it is the enforcement at the FDA,
    Mark, and I think you and I have talked about that in the past,
    in finding what we are comfortable with the FDA having control
    of and what the courts will allow us to do, which means a
    majority of it has to be voluntary.
        Mr. Chairman, you have been very patient because I know I
    have exceeded my time. I appreciate your time on this and
    Senator Enzi's time and look forward to working with you on
    this.
        The Chairman. Good. Well, we thank you very much, Senator
    Burr, and thank all of our panel. I think that this gets into,
    as we have all been wrestling with, on the one hand permitting
    the best in terms of the medical practice, but also
    understanding the issues of medical safety. Somebody has a bad
    liver and a particular drug may do potential damage to the
    liver. The FDA issues some rule or regulation with regard to
    that; does that interfere with a doctor's practice of medicine?
    Well, it does. It does. It's based upon science. Is that
    healthy or for the good? I would expect so, and certainly with
    regards to the individual who had the liver problem it's in
    their best interest.
        So does it interfere with the practice of medicine? This is
    the balance. I don't know whether, Dr. McClellan, you want to
    make any general comments. I mean, I think all of us understand
    if discretion is taken to an excess that you can perhaps draw
    one conclusion and if not perhaps another.
        But the hope is that we are providing the tools and the
    discretion for science, so that individuals who have that
    responsibility can make a judgment. But what's your sense about
    whether we have this about right or not?
        Dr. McClellan. Senator, I appreciate you are striving for
    balance. Let me also just add that I want to give a special
    thanks to your staff, Senator Enzi's staff, and other staff on
    the committee who have been working very hard to take a complex
    and challenging issue, realizing just how important this once
    in a decade opportunity is, to get it right, to take good ideas
    and modify them so you do get that balance right.
        There are all kinds of influences on medical practice
    today. Some come from the FDA, as you said, through their
    announcements and the like. Many come through health care
    financing mechanisms, what health plans will pay for, what
    Medicare pays for, and other types of regulation.
        One thing that I hope we can continue to do--your staff has
    really been helpful in making this happen--is view these safety
    steps and the further steps to improve access to safe and
    effective medicines as part of an overall effort to improve our
    health system. We often think of issues siloed, drug safety as
    an FDA responsibility. That's not all that it is. It's the
    responsibility of the FDA, it's the responsibility of the drug
    companies, but also, as Ms. Witczak said, it's something where
    consumers can help. It's something where health plans can help.
    It's all of our responsibility.
        If we take a step back from just looking at one traditional
    way of dealing with this problem and instead use all the tools
    that are available through information from health plans and
    how they can influence, hopefully in a positive direction,
    medical practice--there's no question they do--the FDA, all of
    these different parties, I think you have a unique opportunity
    to have a huge impact on drug safety in the United States and
    improving access to medicines at the same time.
        The Chairman. Thank you.
        Ms. Dorman, do you want to make a comment whether you view
    the availability and the accessibility of those special drugs
    will be still available under this kind of a regime?
        Ms. Dorman. I think most definitely so. There are some
    people who have thought because people have rare diseases that
    their standards for how a drug reacts in their system is
    somewhat lower, and that has never ever been the case. Safety
    and efficacy is probably one of the most important things for
    people with rare diseases.
        But in some respects, our position on how the FDA works and
    how drugs work is somewhat unique because patient populations
    are so small. So we want to just make sure that whatever occurs
    within this legislation or any type of legislation, that people
    think about the orphan products, the exclusivities, because
    there are 304 products on the market now to treat rare
    diseases, but yet there are over 6,000 rare diseases. Many of
    them do not have any treatment at all. So we want to ensure
    that those protections for these patients continue to be
    strong.
        The Chairman. Well, certainly that whole orphan drug and
    the Hatch-Waxman, they made an enormous difference in a very,
    very positive way.
        Very helpful panel. Thank you very, very much. Very
    appreciative. And I think we are going to have some questions
    we might try and impose on you. So we will keep the record open
    for a period of 10 days.
        Thank you very much.
        [Additional material follows:]

                              ADDITIONAL MATERIAL

                    Prepared Statement of The FDA Alliance*
        Chairman Kennedy, Senator Enzi and members of the committee, the
    FDA Alliance is pleased to provide this statement for the record of
    your hearing on FDA resources, user fees and drug safety.
    ---------------------------------------------------------------------------
        * For more information, contact Steven Grossman, FDA Alliance, at
    info@StrengthenFDA.org.
    ---------------------------------------------------------------------------
        The FDA Alliance is a broad-based, non-partisan coalition of
    consumers, patients, health care professionals, and industry. With more
    than 100 members, including seven former Commissioners of the Food and
    Drug Administration, the FDA Alliance is an advocate for increased
    appropriated funding for FDA to enable the agency to effectively carry
    out its dual roles as the leading guardian of consumer health and
    safety and as an active leader in advancing global scientific and
    medical innovation.
        FDA is underfunded and understaffed. Its budget is woefully
    inadequate. A weakened FDA undermines consumer protection. The United
    States needs a strong FDA that is sized and modernized to carry out its
    responsibilities in the 21st century.
        FDA receives minimal new funds each year. Its ability to fulfill
    its mission is compromised by increasing costs, evolving missions,
    expanding science, and changing technologies. The American people and
    the Congress expect more from the FDA than it can deliver without
    additional money.
        User fees are an important component of the resources available to
    the FDA, but cannot substitute for a significantly increased
    appropriations and a long-term commitment by Congress to assure that
    the FDA has the resources it needs.
        The U.S. Food and Drug Administration needs $2 billion in fiscal
    year 2008 appropriated budget authority. Adding in user fee revenues,
    this would result in a total budget of at least $2.45 billion. This
    modest budget increase would merely restore FDA to the capabilities it
    had in fiscal year 2003. Since then, FDA's budget has actually lost
    buying power.
        An investment in FDA is long overdue. We need to preserve and
    sustain FDA's ability to protect Americans, advance innovation, and
    remain the regulatory ``gold standard'' worldwide.
        Analysis done by FDA suggests that the agency appropriation is
    underfunded by $300 million to $800 million, compared to what is needed
    to accommodate its existing statutory program responsibilities and
    congressional mandates. An updated version of this analysis is appended
    to this statement and demonstrates that $2 billion in budget authority
    (plus user fees) is an appropriate target for immediate reinforcement
    of FDA and its mission.
        For example, $2 billion in fiscal year 2008 appropriated funding
    (budget authority) is needed to sustain the public health and safety
    priorities given to FDA by Congress in such critical areas as:

         food safety counterterrorism/defense,
         pandemic preparedness,
         drug/patient safety,
         medical device, animal drug and generic drug reviews,
         BSE/Mad Cow Disease, and
         new technologies, such as nanotechnology.

        Other key priorities include funding for improved and more capable
    information technology systems at FDA and restoring post-9/11 funding
    levels for the field force that inspects foods, imports and regulated
    manufacturing sites.
        Much of the historic underfunding of FDA can be attributed to
    failure to fund the personnel costs required to fulfill the agency's
    mission. FDA spends more than 83 percent of its budget to support its
    workforce. The costs of maintaining and supporting staff have increased
    at a much faster rate than the agency's appropriated resources. By its
    own calculations, FDA needs inflation increases each year of at least
    5.8 percent just to maintain its current service and staff level.
    Annual appropriations to FDA never include the full cost to the agency
    of pay and benefit increases or rising non-pay costs.
        Currently, Congress appropriates just $4.94 per American per year
    (excluding user fees) to the FDA. At $2 billion in appropriated funds
    for fiscal year 2008, this would still represent only $6.67 per
    American to enable FDA to keep pace with its vital missions and
    services.
        Congress should make a long-term commitment to upgrade FDA's
    appropriated funding. As the committee of jurisdiction overseeing the
    FDA, we ask you to be advocates in the budget and appropriations
    process to assure that Congress provides needed funding to support the
    agency in carrying out its mission.
        Providing $2 billion in appropriated funding in fiscal year 2008--
    and sustaining that level of budget authority and providing budget
    growth as needed for the next 4 fiscal years--will help the FDA fulfill
    its mandate and be innovative in its approach to regulation, oversight,
    inspections, approvals, and monitoring.

    Prepared Statement of the American Society of Health-System Pharmacists
        The American Society of Health-System Pharmacists (ASHP)
    respectfully submits the following statement for the record to the
    Senate Health, Education, Labor, and Pensions (HELP) Committee hearing
    on ``User Fees: Enhancing Patient Access and Drug Safety.''
        ASHP is the 30,000-member national professional and scientific
    association that represents pharmacists who practice in hospitals,
    health maintenance organizations, long-term care facilities, and other
    components of health systems. For more than 60 years, ASHP has helped
    pharmacists who practice in hospitals and health systems improve
    medication use and enhance patient outcomes. This includes working with
    patients to help them access the medications they need and to use them
    safely and effectively.
        The Society has long-standing policies that express support for
    congressional action to provide the Food and Drug Administration (FDA)
    with increased authorities to require post-marketing studies on the
    safety of drugs that are in the public interest. ASHP policy has also
    supported broader authority for the FDA to require additional labeling
    or the withdrawal of certain products on the basis of review of such
    studies.
        While ASHP is pleased that the PDUFA program continues to support
    the FDA's mission to protect and promote public health, we believe that
    the next reauthorization must go much further in this regard. As PDUFA
    has allowed faster drug approvals, manufacturers must bear some of the
    responsibility to provide support for drug safety initiatives. We are
    pleased that the reauthorization of the Prescription Drug User Fee Act
    (PDUFA) will address this issue, targeting resources to modernize the
    post-market drug safety system.
        As we noted in our comments to the FDA early in the reauthorization
    process, critical elements of this reauthorization must include: (1)
    improved post-marketing safety regulation, (2) addressing the impact of
    direct-to-consumer advertising on medication-use safety, and (3)
    developing models of patient care that bring actual medication use into
    better alignment with medication-safety information. We believe that
    FDA's recommendations do attempt to address these key areas, however,
    some additional improvements can be made and we ask the committee to
    consider several points as it pursues a legislative strategy.
                           pre-market risk assessment
    Restricted Drug Distribution
        There are many concerns regarding the existing restricted drug
    distribution system (RDDS) framework. RDDS programs are developed for
    many reasons, most importantly to ensure that drugs with very high
    risks are prescribed, dispensed and administered safely. While these
    systems are necessary in appropriate circumstances to protect patients,
    there are many challenges associated with their administration,
    especially in the hospital setting, which compromise the quality of
    patient care.
        ASHP recently conducted a survey (see attached) of its members who
    have experience with RDDS to better understand what hospital
    pharmacists and their patients are experiencing with regard to these
    programs. ASHP received 521 responses from hospitals and health-systems
    nationwide with 49 States represented. Most significant findings
    indicate that timely access to drugs for patients and care continuity
    are frequently or occasionally a problem in the vast majority of
    hospitals and health-systems. The findings also indicate that most
    hospital and health-system pharmacists believe that some aspects of
    RDDS programs can be standardized.
        The reauthorization of PDUFA provides a unique opportunity to
    improve elements of FDA's oversight of these programs, improving
    patient care and reducing unnecessary burdens on the health care
    system. ASHP suggests that this PDUFA reauthorization provide for
    research on how well existing and new restricted drug distribution
    systems are achieving their goals. Additionally, new PDUFA
    reauthorization legislation should mandate that drug manufacturers and
    the FDA partner with professional organizations in conducting this
    research.
        The Society also recommends that this PDUFA reauthorization direct
    the FDA Drug Safety and Risk Management Advisory Committee to craft
    recommendations to improve RDDS programs. The committee should analyze
    current FDA standards and recommend new policy in several key areas
    related to RDDS including: (1) feasibility of standardizing basic
    elements of all programs, (2) ensuring timely access to drugs for
    patients, (3) eliminating continuity of care problems, and (4)
    permitting exceptions from various RDDS program registration rules for
    those practitioners that meet pre-determined agency standards and
    requirements.
                           postmarketing surveillance
        ASHP supports the elimination of statutory restrictions so that
    PDUFA fees could be used to assess safety issues postapproval,
    independent of a product's approval date and allow the agency to review
    the drug's safety in whatever timeframe risks arise using all available
    resources. The Society does ask the committee to consider the following
    as it drafts its final PDUFA proposal:
        Adverse Event Reporting and Assessment.--ASHP was pleased to see
    that the FDA's draft recommendations included an initiative to conduct
    research on maximizing the public health benefits associated with
    collecting and reporting adverse events throughout a product's life
    cycle. Additionally, we support access to population-based data to
    utilize signal detection as part of improved post marketing
    surveillance. Pharmacists are especially positioned to provide
    leadership in medication-error reporting programs and we would urge the
    committee to require FDA to include these health care professionals in
    its research efforts to improve the use of adverse events data that are
    collected and reported.
        Drug Naming and Labeling.--ASHP is pleased that the FDA's draft
    recommendations suggest the development of new guidance materials to
    improve methods for naming and labeling drugs. With respect to measures
    to reduce medication errors related to look-alike and sound-alike
    names, we support the recommended pilot program to explore a different
    paradigm for proprietary name review. The agency recommends publishing
    three guidance documents in this area including: naming, labeling, and
    packaging. We urge the committee to require the inclusion of
    pharmacists as part of the agency's consultation in developing this
    guidance.
        Effective Risk Communication Strategies.--While we are pleased that
    FDA has suggested a draft recommendation to expand the types of tools
    available for adverse event detection, this will have only limited
    impact if risk information is not made available to the public in some
    way. ASHP would suggest that the committee include in its PDUFA
    proposal a new research program which would examine methods and
    mechanisms for effective risk communication by health professionals,
    including looking at who--pharmacists, physicians, industry, etc.--and
    where--in the pharmacy, by telephone, via DTC--such communication is
    most effective.
                         direct-to-consumer advertising
        ASHP has long advocated for FDA to develop research to evaluate the
    medication-use safety implications of FDA policies and industry
    marketing practices related to direct-to-consumer (DTC) advertising of
    prescription medicines. We believe that FDA's draft recommendations for
    PDUFA IV in this area fall short. Data on the impact that DTC ads have
    on the appropriateness of medication use remains negligible. ASHP
    members have also supported policy that promotes delays in DTC
    promotion until postmarketing data are collected and assessed. ASHP
    suggests that in combination with this delay, it would be consistent
    with the FDA's public health mission for the agency to commission
    research on this topic.
                      innovations in health care practice
        In order to fully address medication safety, it is critical to
    allot dedicated research funds to study innovations in health care
    practice that may improve the safety of medication use. Insufficient
    attention is given to evidence about how to use a medication safely,
    and by ignoring this critical element of research the government
    continues to miss an opportunity to identify and solve a significant
    portion of the drug safety problem. ASHP would encourage the committee
    to expand FDA's research base through PDUFA reauthorization, dedicating
    funds to research in this important area of drug safety.
                                   conclusion
        We appreciate the opportunity to share our views on aspects of the
    PDUFA reauthorization. It is essential that the American public have
    confidence in our Nation's ability to maintain the integrity of our
    drug supply and protect patient health through appropriate drug
    approval and monitoring systems. ASHP and its members are committed to
    working with the Congress, FDA and other stakeholders to achieve this
    goal.

    Statement of Michael Fitzpatrick, Executive Director, National alliance
                            on Mental Illness (NAMI)
        Chairman Kennedy, Senator Enzi and members of the committee, on
    behalf of the 210,000 members and 1,200 affiliates of the National
    Alliance on Mental Illness (NAMI), I am pleased to submit the following
    statement reform of the Food and Drug Administration (FDA) and on the
    Prescription Drug User Fee Act IV agreement. As the Nation's largest
    organization representing people with severe mental illness and their
    families, NAMI would like to express support for PDUFA IV.
        Mr. Chairman, at the outset I would like to restate NAMI's thanks
    and strong support for the committee's moving so expeditiously to
    favorably report S. 558, the Mental Health Parity Act of 2007. This
    landmark legislation will bring about equitable insurance coverage for
    individuals living with mental illness and their families. The strong
    bipartisan action on the part of the committee is a reflection of the
    hard work that you and your staffs--working with Senator Domenici--have
    put into this effort to end insurance discrimination. This is a strong
    bill that will make an enormous difference in the lives of people
    living with mental illnesses such as schizophrenia, bipolar disorder,
    major depression, severe anxiety disorders and other mental illnesses.
    NAMI is committed to working with you and your colleagues in the Senate
    and the House to make sure that this legislation reaches the
    President's desk this year.
        NAMI has long placed the highest value on scientific advance and
    development of newer and more effective treatments for serious
    illnesses such as schizophrenia, bipolar disorder, major depression and
    severe anxiety disorders. Over the past two decades, we have seen a
    revolution in the development of new treatments for these disorders.
    While this advance has helped millions of individuals living with these
    illnesses move toward recovery, more is needed. NAMI feels strongly
    that both publicly funded research and the commercial market must move
    toward a new generation of medications that reach toward cures for
    severe mental illness.
        NAMI is hopeful that the goals of PDUFA IV will help foster an
    environment in which this new generation of medications can be rapidly
    made available to millions of Americans living with these illnesses,
    and their families. As a patient advocacy and family organization, NAMI
    has a strong interest in PDUFA IV bringing the FDA forward as a
    stronger agency that is well resourced, develops modern information
    technology systems and is able to recruit and retain talented
    scientists.
        In NAMI's view, PDUFA IV should help FDA progress toward being an
    agency that:

         Engages in effective pre-market review of products,
         Fosters expedited drug development,
         Moves toward rapid progress for fully automated drug
    reviews,
         Invests in full funding and staffing of the Critical Path
    Initiative (this agreement is a first step toward that goal), and
         Brings about a transformed post-market drug safety system
    at the agency.

        It is on this final goal that NAMI believes PDUFA IV makes
    important progress. It is clear that additional resources are needed to
    address the increasing volume of adverse event reports. In NAMI's view,
    the FDA simply cannot keep pace with this increase in volume by relying
    solely on an expectation that Congress increase appropriated funds over
    the short term. Clearly, additional resources beyond appropriated funds
    are in order for the agency to engage in effective post-market safety
    beyond the current limited 3-year window. PDUFA IV moves us toward
    making sure that the agency has the resources to engage in these
    important safety review activities.
        As this committee moves forward to enhance post-market safety
    review, NAMI urges that you not lose sight of what is the greatest risk
    for people living with severe mental illness and their families, not be
    able to access available treatments. NAMI strongly supports individuals
    living with mental illness being able to access the full array of
    available treatment options. They should be able to work with their
    physician to weigh efficacy, side effects, patient and family history
    and other factors to make an individualized treatment decision. NAMI's
    hope is that PDUFA IV will move toward an environment in which those
    treatment options are broadened.
        In commenting on this PDUFA IV agreement, NAMI would make the
    following observations:
    1. There is widespread agreement that the FDA has been hampered by a
        lack of resources, both in terms of financial resources and human
        capital. PDUFA IV is a significant step forward in terms of drug
        development, drug safety and information technology. NAMI also
        feels strongly that Congress must also step forward with additional
        appropriations for the agency.
    2. Since the early 1990s, PDUFA has succeeded in expanding the drug
        review process, what was once a 3-4 year process has been reduced
        to less than a year in many instances.
    3. People living with mental illness and their families--like other
        patients who live with significant chronic illness--understand that
        there are risks associated with any prescription medication. What
        patients and their families want most is to have a variety of
        treatment options and clear understanding of the risks and benefits
        of each treatment option and to make an informed decision in
        consultation with their doctor. PDUFA can, and should, help expand
        and illuminate these important treatment decisions.

        NAMI would also like to go on record with concerns about the
    process for enactment of legislation in Congress that is needed to make
    this agreement a reality. Reauthorizing PDUFA this year presents the
    committee with an important opportunity to make improvements in the
    performance of the FDA, especially with respect to post-marketing
    safety monitoring. NAMI supports efforts to make these improvements to
    ensure that patients that rely on medications for daily living and
    functioning are protected from unsafe products.
        At the same time, it should be recognized that the legal authority
    for the FDA to continue operating the PDUFA program and retain
    scientists and drug review staff at the agency depends on
    reauthorization of the law by October 1. Delaying action on PDUFA
    legislation would have enormous potential to derail drug reviews, hurt
    agency morale and in the long run, limit access to new medications.
    NAMI therefore urges the committee to move the reauthorization process
    forward expeditiously.
        Finally Mr. Chairman NAMI would urge the committee to take a
    balanced approach to FDA reform. NAMI is especially concerned that some
    of the Agency's harshest critics may be using perceived problems with
    safety of medications commonly prescribed to treat mental illness as a
    proxy for a separate agenda that calls into question whether or not
    these serious disorders are genuine medical conditions. I want to be
    clear, NAMI supports giving the FDA all of the legal authority and
    financial resources it needs to ensure that all approved medications
    are safe and effective and prescribed consistent with recognized
    treatment guidelines and protocols.
        At the same time, there are advocacy organizations that view the
    debate over PDUFA reauthorization and FDA reform as an opportunity to
    undermine public confidence both in the efficacy and safety of
    medications to treat mental illness--specifically anti-depressants and
    anti-psychotics and the very existence of brain disorders such as
    schizophrenia, bipolar disorder, major depression and severe anxiety
    disorders. NAMI would urge the committee to be careful with respect to
    any effort to direct the FDA to impose a separate safety standard for
    psychotropic medications or separate threshold for safety warnings
    associated with these medications. Reform of the FDA should not result
    in barriers to treatment for people living with mental illness and
    their families.
        Thank you for the opportunity to present NAMI's views on this
    important issue.
       Response to Questions of Senator Kennedy and Senator Enzi by Kim
                                    Witczak
                          questions of senator kennedy
        Question 1. Some have said that Congress should not take action to
    improve drug safety. What would it do to your hopes and hopes of others
    who have experienced intense personal loss from drug side effects if
    Congress missed this opportunity to improve drug safety?
        Answer 1. This year represents the greatest opportunity for
    Congress to help fix the broken drug safety system in our country. At
    the present time, the public has little faith in the FDA's ability to
    protect the American public. We are relying on Congress to step in and
    make meaningful change that brings back confidence to the phrase ``FDA
    approved.''
        It's not only those who have been personally affected by FDA
    failures that are concerned with drug safety. The American public is
    taking prescription drugs more than ever. We rely on the FDA to make
    sure the drugs we take are ``safe and effective.'' Every individual and
    family is potentially at risk. No one is immune from experiencing what
    our family and countless others have.
        Drug safety is an extremely important part of the risk/benefit
    equation. It is simply good medicine practice. We need this information
    to be both accurate and timely.
        While its seems like all the congressional pressure on the FDA has
    been a ``good thing'' with their recent warnings, policy changes, etc.,
    it's when Congress isn't looking that the public needs to be concerned.
    The past behavior of the FDA and industry has shown that they can NOT
    be trusted to voluntarily manage drug safety system on their own
    without sweeping changes. The ``sweep it under the rug'' approach,
    explain it with ``science'' or manipulated statistics, or wait until it
    becomes a public relations issue before anything is done is not
    beneficial for anyone, including the drug companies.
        PDUFA was originally created to help expedite the approval of
    lifesaving drugs at the FDA. While this goal has been accomplished, it
    has not been without consequences. Since the last PDUFA
    reauthorization, we have seen a plethora of drug safety scandals like
    Vioxx, antidepressants, Ketek and just last week with Pergolide and
    Zelnorm.
        I have attached a copy of an internal FDA memo dated December 24,
    1991 from Dr. Paul Leber to Dr. Robert Temple that serves as a good
    example of why we need a stronger post-market system in place at a time
    when the agency is expediting drug approvals. In the memo, Dr. Leber
    acknowledges that although several foreign national regulatory agencies
    were not willing to grant Zoloft approval due to ``lack of robustness''
    in clinical evidence, the FDA felt pressured to quickly approve Zoloft.
        In Dr. Leber's own words,

              . . . Many of these foreign regulatory initiatives have
            potential merit, but, given the perceived urgency we express as
            an institution for expediting the public's access to new,
            potentially promising, drugs, I do not believe we can
            successfully introduce similar, more demanding, requirements
            domestically, at least until there is a significant ``sea
            change'' in our society's collective attitude toward Federal
            regulation of new drug approvals.
              . . . Approval may, however, for the reasons enumerated above
            come under attack by constituencies that do not believe the
            agency is as demanding as it ought to be in regard to its
            standards for establishing the efficacy of antidepressant drug
            products.

        This is heartbreaking to read when one's husband and many others
    unnecessarily died or were put at risk because the FDA did not do
    proper post-market surveillance or follow up in the subsequent years
    when there were thousands of serious adverse event reports including
    suicide. In addition, there was mounting scientific evidence from
    around the world of severe adverse reactions from this class of drugs.
    It seemed that the agency turned a blind eye and now is reeling to
    defend itself with manipulated ``science.''
        By not adequately addressing the drug safety side of the equation,
    the FDA basically sends the message to the public that the status quo
    is good enough. How many lives will be affected if Congress does
    nothing or just includes a few token safety changes? We need meaningful
    drug safety measures put in place that will help protect the public
    against the next Vioxx.
        Things need to change and you have the ability and responsibility
    to help restore the FDA back to the gold standard it once was.
                           questions of senator enzi
        Question 1. You have indicated that you would support preemption of
    State clinical trials databases if the Federal database created by our
    legislation contains the results of clinical trials conducted prior to
    enactment of the bill. I see your point, but I also see that there are
    thousands of drugs on the market, some approved many years ago. How
    might we limit the ``look-back'' provision so that we get the most
    beneficial clinical trials information for the least burden?
        Answer 1. I would support Federal preemption of State clinical
    trial databases ONLY if S. 484 covered clinical trial data of drugs
    currently on the market. Right now, I am NOT comfortable with the
    current legislation as it only covers the Phase III and IV trials
    starting in 2008. It will be years before these drugs hit the market.
        As you may be aware, we have been working hard in Minnesota to get
    a clinical trials disclosure bill passed that would require that all
    clinical trials (dating back to 1990) of drugs covered by the State's
    Medicaid program be posted on a publicly accessible Web site. Several
    other States have introduced similar legislation as well. Under the
    current language in S. 484, these sorts of State consumer protection
    laws would be preempted by S. 484. It's going to be hard to tell your
    constituents that the State law designed to protect them from potential
    drug safety scandals would be null and void by Federal preemption.
        The plain and simple motivation behind the State-based clinical
    trial disclosure legislation is to protect the public where the Feds
    are not. As we have seen with the recent drug safety scandals, some of
    the serious side effects were first detected in the clinical trials and
    kept in drug company files, some without the FDA even knowing the
    trials existed. Ultimately, this sort of safety information does come
    out, usually through court proceedings after there has been serious
    harm or death caused by the drug.
        PhRMA, in principal, has agreed this is a good idea and voluntarily
    agreed to post their clinical study results on their Web site from 2002
    and on. Unfortunately, it is voluntary, doesn't go back far enough, and
    only provides the summary of the data. Most of the clinical trials of
    the recent drug safety scandals were conducted prior to 2002.
        One compromise that I would be willing to support would be to amend
    S. 484 to require that the clinical trial data for drugs currently on
    the market that have known safety concerns (i.e. COX-2, NSAID/Celebrex,
    Antidepressants, Antipsy-
    chotics, sleep medications, etc.) or those that are most heavily
    advertised be covered in the legislation. As we all know, the
    advertising drives millions of people to take these drugs whether they
    truly need them or not and greatly increases the potential for serious
    side effects to emerge.
        The industry will say that this is proprietary company data. The
    clinical trial results are not proprietary when public safety is at
    risk. We are not asking for formulas or other true proprietary
    information to be disclosed. Only safety and efficacy data.
        Ultimately, transparency of data is good for public health. It's
    good pharmacovigilance.

        Question 2. Are there any changes to the Enzi-Kennedy drug safety
    legislation that you would suggest in addition to those in your
    testimony?
        Answer 2. While, I am happy to see that the Enzi-Kennedy
    legislation brings much-needed attention to post-market safety, there
    are a couple of areas that could be strengthened to further enhance the
    bill.

         I would like to reiterate the need for a strong Office of
    Drug Safety that has separate but equal powers. Ideally, I support
    Grassley-Dodd's version of separate Office of Drug Safety. Barring
    that, I think there is a way to give the head of Drug Safety (currently
    the head of the Office of Surveillance and Epidemiology) the
    authority--and the responsibility--to say he believes there are enough
    safety questions about a drug, pre- or post-approval, that the drug
    should not be approved, or if approved, that REMS (as established by S.
    484) should be adjusted, or request additional safety studies, or that
    it should be pulled from the market. If the head of the Office of New
    Drugs disagrees, the two Office heads present their cases to the
    Commissioner within a date certain, say a week, and he makes a decision
    within a day. This would not slow down the process, but it would make a
    career professional physician-scientist responsible for standing up for
    safety when they think the facts justify it. This process should, of
    course, be very public, with reports to Congress on the details of when
    such disagreements have arisen and how they were resolved. In addition,
    points of contention should be subject to Advisory Committee review and
    comment by national and international experts.
         The current legislation would require clinical trial
    results to be made public starting in 2008. It could be years before
    these drugs are on the market. I would like to see the results of drugs
    on the market today made public and not buried in drug company or FDA
    files. In the previous question, I offered a couple suggestions on how
    to get clinical study results made public for drugs currently on the
    market without being too burdensome for the drug companies.
         Require that simple, consumer-friendly or layperson
    language be used to describe a drug's risks and benefits. There has
    been talk about taking this provision out. The consumers should not be
    treated as too ``dumb'' to understand what these detailed warnings
    mean. We can make a decision for ourselves. It is often said, an
    informed consumer is the best consumer, especially when it comes to the
    drugs we put in our body.
         I fully support the use of the massive Medicare database
    to conduct epidemiological studies to detect more quickly safety
    problems in the use of a drug. This should serve as an additional tool,
    NOT a substitution for other new post-market safety measures in Enzi-
    Kennedy legislation to help proactively seek out potential safety
    issues.
         Finally, Title IV on the ethics of Advisory Committees has
    been rendered nearly moot by the FDA's recent announcements. At
    minimum, I hope you codify the FDA's proposed guidance policy of no
    participation on advisory board if conflict is over $50,000 and no
    voting rights if conflict is under $50,000. However, this is a perfect
    opportunity to strengthen the Advisory Committee policy by lowering the
    $50,000 to $10,000. If the FDA thinks that an individual who has more
    than $10,000 of conflicts is an expert in a particular field, they
    could be invited to testify as a ``witness'' but not as a panel member.
    A few other ideas include:

        1. Ensure that each advisory committee has a full range of experts
    (i.e. epidemiology, pharmacovigilance, statistics, prescribing doctors,
    etc.). In the case of the recent antidepressant advisory board held in
    December 2006, the majority of members were psychiatrists discussing
    suicide blackbox issues. There were no General Practioners sitting on
    board when 70-80 percent of antidepressants are given by GPs.
        2. Make all review materials available to the public at least 7
    days ahead of advisory committee meetings so that public witnesses can
    have a chance to react to materials.
        3. Require review papers to include room for additional scientific
    views, dissents, and remaining questions from FDA review staff. The
    public deserves to know if others within the FDA have dissenting views.
    This also could trigger the need for an advisory board meeting.
        4. Impose monetary penalties for any drug company sponsor that
    withholds data or provides inaccurate or misleading information to the
    advisory committee. No more Keteks or Trasylol.
        5. Hold semi-annual general drug safety and risk management
    advisory committees for the public.
          Responses to Questions of Senator Kennedy and Senator Enzi
                          by D. Bruce Burlington, M.D.
                          questions of senator kennedy
        Question 1. Please share with the committee your views on whether
    the additional money for drug safety in the user fee agreement provides
    enough for that function. If not, should Congress consider increasing
    the amount in the user fee program for drug safety, and by what amount?
        Answer 1. Yes, the funds provided for in the user fee agreement are
    satisfactory to meet FDA's needs for the next 5 years. The funding will
    allow the FDA to enhance and modernize its drug safety operations by
    hiring additional staff for drug safety activities including experts in
    epidemiology; increasing access to and use of large medical databases
    to perform more active safety surveillance; and reducing the agency's
    reliance on spontaneous reports of adverse drug reactions. At the time
    these provisions were being developed, the Institute of Medicine (IOM)
    was completing its report on the U.S. drug safety system. The report
    was issued shortly after the PDUFA IV provisions were agreed to. Both
    FDA and industry examined the IOM recommendations to insure that those
    recommendations that could be addressed through PDUFA--recommendations
    pertaining to increased resources and the science of safety--were
    addressed. In separate analyses, both FDA and industry agreed that this
    was in fact the case.

        Question 2. As you know, the top trigger in the user fee program
    requires the total FDA appropriation to increase at the rate of
    inflation, but not at the higher rate at which FDA's costs actually
    increase. Should this trigger be changed so that the total FDA
    appropriation increases at the rate FDA's costs increase?
        Answer 2. Yes, industry believes that the trigger should be changed
    to fairly adjust the appropriated portion of the budget for the real
    increases in personnel costs. It is our observation that the drug
    review program has suffered a loss in full time employees over the past
    2 years because the current adjuster does not adequately cover these
    increases. At a minimum, appropriations should cover a fixed employee
    base within the agency. The PDUFA III agreement in 2002 assumed that
    there would be a fixed employee base of 1,277 FTEs. Unfortunately
    today, FDA is approximately 150 FTEs below this mark, a contributory
    factor to resource shortage.

        Question 3. In your opinion, what would be the consequences if
    Congress failed to take action this year to improve the drug safety
    practices at FDA?
        Answer 3. It is important to note that drug safety practices would
    be dramatically improved through several PDUFA IV provisions. As noted
    in the response to question 1, the agency would receive significant new
    funds ($150 million over 5 years) specifically allocated to the office
    that is engaged in studying post-market safety. This is in addition to
    funding that was agreed to in PDUFA III. The PDUFA IV agreement
    contains several other critical safety initiatives including:

         Modernizing the Adverse Event Reporting system (AERs) to
    enhance the collection, aggregation, and analysis of drug safety data,
         Development of a 5-year plan for the FDA to take advantage
    of new IT capabilities to conduct more active surveillance using
    electronic health records,
         Providing the FDA with the resources to examine which risk
    communication and risk management programs work and which don't, and
         Providing FDA with resources to improve trade name reviews
    so medication errors are reduced.

        In addition, the Office of New Drugs, which is responsible for new
    drug reviews, would receive additional funding so that the Good Review
    Management Practices that were developed during PDUFA III can be fully
    implemented. One of the important parts of these practices is earlier
    discussions of drug labeling and post-market studies. Too often these
    discussions take place close to the action date, resulting in labeling
    that may not optimally convey information to health care providers or
    post-market studies that don't answer the most important questions. In
    fact, Dr. Bruce Psaty, a member of the IOM panel, noted in testimony
    before the House Energy and Commerce Committee that ``many of the
    studies aren't well designed, and probably 20 percent don't deserve to
    be done.'' With the additional time coming from the PDUFA IV increases,
    studies will be designed to answer essential questions.
                           questions of senator enzi
        Question 1. You indicate in your testimony that the REMS approach
    is similar to what your company is already complying with in Europe,
    and as such is not a bad idea. Yet you also suggest that REMS be
    limited in scope. Could you tell me more about what you had in mind,
    and how your proposed scope might differ from the European approach?
        Answer 1. Harmonization of REMS with European risk management is
    desirable from our point of view. The European approach is
    comprehensive and should satisfy the goals of the REMS proposal without
    creating redundancy or conflict. We do not think that REMS should be
    limited as it relates to the EU approach but we believe that certain
    principles and elements of REMS should be limited in scope. First, this
    legislation should lay out principles and create a framework to guide
    the FDA in developing specific criteria for applying risk mitigation
    tools. Second, the controls mandated in the legislation should be
    applied when necessary (with well understood thresholds) so as to not
    unnecessarily restrict patient access to medicines and information. Any
    requirement applied in the interest of safety should impose the least
    possible burden to meet the intent of the restriction and to ensure it
    is commensurate to the risk it is aimed at addressing, including
    resulting in Medication Guides, communication plans, new studies,
    clinical trials, restrictions on advertising and promotion, or direct-
    to-consumer advertising bans. The threshold for imposing actions
    already described in current regulation or guidances should conform to
    the current standard. Third, the enforcement of these controls should
    not fall to the sponsor because, in general, it is not feasible for a
    sponsor to control the individual physician/patient interaction.

        Question 2. What is Wyeth doing regarding drug safety, beyond what
    is currently required in statute?
        Answer 2. Wyeth strives to effectively manage and communicate the
    benefits and risks of our products to regulators, investigators,
    prescribers, and users of the Company's products. To that end, Wyeth is
    starting its formalized benefit risk assessments for development
    products early in the clinical development program. Currently Wyeth
    also submits a risk management plan with each NDA submission for a new
    chemical entity.

        Question 3. In your testimony, you indicate that the potential
    costs of provisions in the Enzi-Kennedy bill (S. 484) are not included
    in the PDUFA agreement. That is true. How much more do you think our
    bill would cost?
        Answer 3. It is very difficult to estimate how much the provisions
    in S. 484 will cost. During the PDUFA IV negotiations, participants had
    the benefit of significant data from FDA related to ongoing activities
    both with respect to their number and the FTE time allocations. In many
    cases there was 8-10 years of data. This made it possible to make
    informed estimates about how much new work arose from increased
    meetings, clinical protocol reviews, and IND workload. Even with such
    data, there was significant difference of opinion between the FDA and
    industry over the reliability of the new workload adjuster proposal.
    The industry agreed to an adjuster with the proviso that it would be
    examined in detail by an outside accountant following the first year of
    PDUFA IV. The REMS proposal in this legislation represents
    substantially new work for FDA. We do not know how FDA will implement
    or account for its REMS activities, the initial extent of FDA resources
    that will be required or how to compensate FDA for this increased work.
    In short, we do not have any historical data on which to base an
    accurate estimate. It is very possible, however, that the increased
    costs will be significant, pushing the proportion of the FDA's drug
    review budget funded by user fees even higher than it stands today.
      Response to Questions of Senators Kennedy, Enzi, Burr, and Hatch by
      Stephen R. Mason, HHS Acting Assistant Commissioner for Legislation
                          questions of senator kennedy
        Question 1. The user fee program has allowed for significant
    resources to improve drug review and approval times at FDA. However,
    there are concerns that while user fees have strengthened drug reviews,
    resources for other functions such as drug safety have stagnated or
    fallen. What more, beyond money in the user fee agreement, does the
    agency need to ensure that safety can remain a top priority for the
    agency?
        Answer 1. Ensuring the safety of drugs and other medical products
    regulated by FDA has always been a key focus of our commitment to
    protect and promote the public health. In the past few years, FDA has
    reassessed its drug safety programs because of rapid advances in
    science and technology that have resulted in increasingly complex
    medical products. We take very seriously our response to safety-
    related issues from all sources, including those raised by consumer
    advocates, health professionals, academic researchers, and Members of
    Congress. Some examples of what the Agency is doing to ensure the
    safety of drugs are described below.
        Included in the fiscal year 2008 President's budget is a proposal
    for a significant additional investment in FDA to modernize the process
    for ensuring drug safety. With the funds requested, FDA expects to
    strengthen the science and tools that support the product safety system
    at all stages of the product life-cycle from pre-market testing and
    development through post-market surveillance and risk management. Also,
    FDA expects to improve communication and information flow among all
    stakeholders engaged in promoting the safe use of medical products.
    These additional appropriations, combined with PDUFA IV resources, will
    support FDA's ability to effectively detect, communicate, and act on
    important safety issues thereby improving patient safety.
        On September 22, 2006, the Institute of Medicine (lOM) released its
    report entitled, The Future of Drug Safety--Promoting and Protecting
    the Health of the Public. The report recognized the progress and reform
    already initiated by the Agency. The IOM report makes substantive
    recommendations about additional steps FDA can take to improve our drug
    safety program. The recommendations are consistent with the Agency's
    commitment to drug safety, including: (1) strengthening the science
    that supports our medical product safety system, (2) improving
    communication and information flow among key stakeholders, and (3)
    improving operations and management. Our Prescription Drug User Fee Act
    (PDUFA) proposal would, in part, support some of these initiatives.
        We are working diligently on the actions we have committed to in
    our response to the IOM Report and have already made significant
    progress on several projects. For example, in March 2007, we issued
    final guidance that describes FDA's current approach to communicating
    drug safety information, including emerging safety information, to the
    public. The guidance affirms the Agency's commitment to communicate
    important drug safety information in a timely manner, including in some
    situations when the Agency is still evaluating whether to take any
    regulatory action. FDA's communication about drug safety information is
    available through FDA's Web site.
        In addition, we are well on our way to implementing an electronic
    drug safety tracking system. This system, which replaces multiple
    office and division specific systems, is already helping the Center for
    Drug Evaluation and Research (CDER) reviewers and managers to
    prioritize their work on safety issues. In March 2007, FDA issued
    guidance designed to make the advisory committee process more rigorous
    and transparent so that the public has confidence in the integrity of
    the recommendations made by its advisory committees.
        We have implemented an aggressive effort to strengthen our drug
    safety program, including developing new tools for communicating drug
    safety information to patients. Through our Critical Path initiative,
    we are working with our health care partners to improve the tools we
    use to more effectively evaluate products and processes.

        Question 2. I think we agree Congress should increase the FDA's
    appropriation, and that it would be better for the FDA not to have to
    rely on user fees for its budget. But some have gone a step further,
    and have called on Congress to discontinue the user fee program. Can
    you describe for the committee what effect it would have on FDA and on
    medical innovation if Congress were to discontinue the user fee
    program?
        Answer 2. In fiscal year 2008, FDA expects to collect approximately
    $438 million in PDUFA fees, after the workload adjustment is made.
    These fee revenues will provide the funds that will pay for about 60
    percent of the staff that FDA will use for drug review in fiscal year
    2008.
        If PDUFA is not reauthorized, and if the $438 million anticipated
    from PDUFA fee revenue is not available in fiscal year 2008 through
    fees or made up by appropriations, then FDA could no longer employ the
    60 percent of review staff paid for through the fees. FDA also would be
    responsible for severance pay and the payment of unused annual leave.
    The loss of 60 percent of the drug review staff would have a
    devastating impact on the drug review process in the United States. FDA
    would be unable to meet the 6- and 10-month review timelines that have
    existed under PDUFA. In the initial few years after such a reduction,
    the drug review process in America would most likely revert to review
    times that average 3 or more years, as was the case prior to the
    enactment of PDUFA. The United States would cease to be the first
    market of entry for most new pharmaceutical and biotechnology products
    that enter into world commerce, and ``drug lag'' would re-emerge--
    meaning that most new pharmaceutical and therapeutic biotechnology
    products would again only be available to U.S. citizens long after they
    were first approved and available in other countries.

        Question 3. The Institute of Medicine report on drug safety raised
    concerns over the culture at the FDA. The report described the agency
    as ``an organizational culture in crisis.'' We asked you about this
    issue at your confirmation hearing and you promised to address the
    problem. Please describe in detail what you have done.
        Answer 3. Addressing the organizational culture issue is a top
    priority for FDA. Significant culture change is an evolving process
    that has already begun. As noted in FDA's written statement, FDA's
    Center for Drug Evaluation and Research (CDER or the Center) has
    initiated a series of changes designed to effect a true culture change
    that will strengthen the drug safety system. CDER has moved to
    reinvigorate its senior management team and charged its members with
    the responsibility to lead the Center in an integrated manner that
    crosses organizational lines.
        CDER has already implemented process improvements recommended by
    CDER's Office of Surveillance and Epidemiology (OSE) and Office of New
    Drugs (OND) staff including their recommendations to (1) establish an
    Associate Director for Safety and a Safety Regulatory Project Manager
    in each OND review division within CDER and (2) conduct regular safety
    meetings between OSE and all of the OND review divisions are now being
    implemented. We are committed to providing the necessary management
    attention and support to effect sustained culture change in our drug
    safety program.
        Also, as noted in FDA's written statement, we have recently engaged
    external management consultants to help CDER develop a comprehensive
    strategy for improving CDER/FDA's organizational culture. In addition
    to the ongoing FDA activities to improve how our organization supports
    the individuals who work on safety issues in FDA, we are enlisting the
    help of external experts in organizational improvement to help us
    identify additional opportunities for change and assist us with
    carrying out those needed changes.

        Question 4. I'm intrigued by the plan to review the available
    information about a drug, 18 months after approval. But this innovation
    suggests something very disturbing about the current drug safety
    system: FDA doesn't currently look pro-
    actively at the information about the safety of a drug. Instead, it
    only does so if something truly striking happens, like several liver
    failures, or the termination of a clinical trial for safety reasons. In
    the absence of something such as this, a drug simply isn't looked at
    now. Is that correct?
        Answer 4. This is not correct. Staff in OSE and OND review post-
    marketing safety continuously. FDA reviews reports of serious and
    unexpected adverse experiences that drug companies are required to
    submit within 15 days, periodic safety reports that are submitted by
    drug companies quarterly for the first 3 years following approval and
    annually thereafter, and reports of serious problems sent directly by
    health care professionals and consumers, in addition to information
    from medical literature, clinical trials, other members of a class of
    drugs, and other sources.
        With the rapidly increasing number of adverse event reports that
    the Agency receives (under 200,000 in 1996 and over 470,000 in 2006),
    we are focusing on making our post-marketing drug safety review
    processes more effective and efficient. We embarked on the New
    Molecular Entity Pilot Evaluations to examine whether we can more
    rapidly and predictably detect problems in newly approved drugs. In the
    pilot program, we are closely examining all available safety data of a
    few drugs selected for the pilot after they have been on the market for
    a period of time, such as 18 months or 2 years. We are examining the
    analyses needed, the most efficient approaches to communicating and
    discussing the data, the timeframes in which it can be accomplished,
    and how this systematic look compares to the review processes already
    in place. We will also be measuring the resources needed to conduct
    these scheduled reviews. At least four drugs will be studied initially.
    Then, FDA will assess the pilot program for possible wider
    implementation.

        Question 5. I am concerned about antibiotics used for human
    treatment and how use of these antibiotics in animals may contribute to
    the development of drug-resistance in bacteria. I have several
    questions related to the use of antibiotics in animals. Do you think
    Congress should give the FDA the authority to collect data on how much
    of an antibiotic is used for treatment of animals and on which animals
    it is used in a way that protects legitimate confidential business
    information? What programs does the FDA's Center for Veterinary
    Medicine now have in place to collect and compile information on post-
    approval antibiotic use?
        Answer 5. FDA currently requires that drug sponsors provide
    information on the distribution of each approved new animal drug
    product. Title 21, Code of Federal Regulations (CFR) 514.80(b)(4)(i).
    This requirement applies to all approved new animal drugs and does not
    include any provisions specific to antimicrobial new animal drugs. The
    required information must include the total number of distributed units
    of each size, strength, or potency. However, the current requirements
    are limited to drug distribution (sales) data. Furthermore, depending
    on whether a given product is approved for multiple animal species or
    indications, the current requirements do not necessarily provide
    information for each intended use or type of animal for which the drug
    is approved.

        Question 6. FDA Guidance Document #152 focuses on the impact of
    animal drugs on food-borne infections in people. The World Health
    Organization has issued a report examining the impact on all human
    infections. Do you think the FDA, when considering approval of
    medically important antibiotics for use in animals, should follow WHO's
    approach and consider the impact of such use on all human infections?
        Answer 6. FDA recognizes that food-borne human exposure to
    antimicrobial resistant bacteria is complex and often involves the
    contributions from other sources of exposure; for example, direct
    contact between animals and humans and the introduction of resistant
    bacteria and resistance determinants into the environment. However, FDA
    believes that evaluating antimicrobial new animal drug safety relative
    to the most significant exposure pathway, i.e., food-borne pathway, is
    the best way to qualitatively assess the risk of antimicrobial drug use
    in food-producing animals. Nonetheless, as stated in Guidance 152, non-
    food-borne bacteria may be considered when deemed necessary; for
    example, uncertainties regarding the contribution of other exposure
    pathways may be considered during the development of appropriate risk
    management strategies.
        In developing criteria for ranking antimicrobial drugs with regard
    to their importance in human medicine, FDA considered broad issues
    associated with the efficacy of drugs in human medicine and factors
    influencing the development of antimicrobial resistance. Specific
    factors include the usefulness of the drug in food-borne infections,
    the types of infections treated, the availability of alternative
    therapies, the uniqueness of the mechanism of action, and the ease with
    which resistance develops and is transferred between organisms.
        The World Health Organization (WHO) has also developed a system for
    ranking antimicrobial drugs with regard to their importance to human
    medicine. However, the WHO approach differs somewhat from the approach
    adopted by FDA. WHO determines the critical nature of an antimicrobial
    drug based on its use as the sole therapy or one of few alternatives to
    treat serious human disease and on its use to treat diseases caused by
    organisms that may be transmitted via non-human sources or diseases
    caused by organisms that may acquire resistance genes from non-human
    sources. WHO is looking broadly at diseases worldwide that may not be
    present in the United States.
        As mentioned previously, FDA believes that human consumption of
    animal-
    derived foods represents the most significant pathway for human
    exposure to antimicrobial resistant bacteria that have emerged or been
    selected as a consequence of antimicrobial drug use in animals.

        Question 7. Does the FDA have legal authority to place extra-label
    use restrictions on an animal drug prior to the drugs' being marketed
    when either a drug sponsor's own risk assessment or an internal FDA
    risk assessment finds that a potential drug approval presents a high
    risk of resistance adversely affecting human health? Does the FDA have
    the legal authority to act pro-actively to put in place an extra-label
    prohibition on an antimicrobial drug in cases where research shows that
    the drug is likely to select for resistance that would harm human
    health, but because the drug has not yet been marketed there is no
    evidence that extra-label use has caused a problem?
        Answer 7. FDA has the legal authority to prohibit the extra-label
    use of an approved new animal drug or human drug if it has evidence to
    support the conclusion that the extra-label use in question presents a
    risk to public health. Such evidence could be based on a risk
    assessment, published literature, surveillance data, or any other
    available information. FDA issued an order in May 1997 (62 FR 27944) to
    prohibit the extra-label use of fluoroquinolone and glycopeptide drugs
    in food-producing animals. At the time of issuance of that order,
    fluoroquinolone drugs were approved and marketed for use in certain
    animal species. Although certain glycopeptide drugs were approved for
    use in humans at that time, no glycopeptide drugs were approved or
    marketed for use in animals nor are any drugs in the glycopeptide class
    approved for use in animals today. To date, FDA has not issued an order
    to prohibit the extra-label use of a drug concurrently with the
    approval of that drug in animals. However, FDA believes it has the
    authority to do so if evidence supports a finding that extralabel use
    of the drug presents a risk to public health.
        FDA's extra-label use regulation defines presents a risk to public
    health to mean FDA has evidence that demonstrates that the use of the
    drug has caused or likely will cause an adverse event. (21 CFR
    530.3(e)) The most recent example of FDA exercising its authority to
    prohibit extra-label use was the order issued on March 22, 2006, to
    prohibit the extra-label use by veterinarians of anti-influenza
    adamantane and neuraminidase inhibitor drugs in chickens, turkeys, and
    ducks. Although these anti-influenza drugs are approved for use in
    humans, these drugs are not approved or marketed for use in animals.
    Nevertheless, FDA compiled sufficient evidence to meet the statutory
    standard that such extra-label use presents a risk to public health.

        Question 8. Section 17 of the Best Pharmaceuticals for Children Act
    required the Food and Drug Administration to issue within a year a
    final rule to require that FDA-approved drugs be dispensed with the
    toll-free MedWatch number, so patients can report adverse events. FDA
    issued a proposed rule on April 22, 2004, more than 2 years after the
    date of enactment of the BPCA. FDA has yet to issue the final rule,
    more than 5 years after enactment. When will FDA issue the final rule
    required by BPCA?
        Answer 8. The proposed rule on Toll-Free Number for Reporting
    Adverse Events on Labeling for Human Drug Products published on April
    22, 2004, with the comment period ending July 21, 2004. In the proposed
    rule FDA solicited comments on the wording of the proposed labeling
    statements. We received a number of comments suggesting changes to the
    specific wording of the proposed statements. We have been conducting
    studies designed to resolve issues raised by the comments and to
    optimize consumer understanding of the labeling statements. We plan to
    finalize the rule upon completion of these studies.
                           questions of senator enzi
        Question 1. Some PDUFA IV resources are focused on giving FDA more
    ability to use some of the large patient databases to conduct drug
    safety studies. How many new information sources would the PDUFA IV
    funds allow access to? How many studies of the user fees might these
    increased fees support?
        Answer 1. PDUFA IV proposes to increase funding directed to
    purchasing access to databases for post-marketing research to about
    five times the current funding level (from about $1,000,000 to
    $5,000,000). The funding will support formal epidemiologic drug safety
    studies and active surveillance. We cannot determine how many databases
    or studies we will be able to support with these funds because the cost
    depends on a number of factors such as size of the database, type of
    study, i.e., epidemiological or active surveillance research, and other
    study design elements. One study alone could cost as much as $500,000
    to $1,000,000, or even more.

        Question 2. Right now, if a safety issue arises after a drug is
    marketed, can the agency require a study or clinical trial to follow up
    on the issue? My understanding is that you can request it, but not
    require it. Is that correct?
        Answer 2. Yes, that is correct, but post-marketing studies may
    occur in the following circumstances:

         A post-marketing study might be conducted because an
    applicant and FDA agree, in writing, that one or more such study should
    be conducted. These agreements can be made at the time of approval or
    after FDA grants marketing approval.
         In addition, an applicant may be required to conduct a
    post-marketing study under certain circumstances. FDA can require an
    applicant to conduct studies to verify and describe clinical benefit
    for a drug or biological product approved in accordance with the
    accelerated approval provisions at 21 U.S.C. 356(b)(2)(A); 21 CFR
    314.510 and 601.41.
         For a drug or biological product approved on the basis of
    animal efficacy data because human efficacy studies are not ethical or
    feasible, an applicant must conduct studies when ethical and feasible
    to verify and describe clinical benefit and to assess the product's
    safety.
         The Pediatric Research Equity Act of 2003 authorized FDA
    to require pediatric studies of marketed drugs that are not adequately
    labeled for children.

        Question 3. I think there's a lot to like in the PDUFA IV proposal
    for drug safety. However, I believe FDA needs new authorities to really
    do its job. Do you agree? If not, why not?
        Answer 3. We believe it is important that FDA have appropriate
    resources and the capacity to develop better scientific tools and
    approaches to drug review and safety. We have provided technical
    assistance on drug safety bills and FDA and the Administration are
    currently evaluating whether new authorities are necessary or
    appropriate. FDA will use our current authority to the best of our
    ability.
                           questions of senator burr
        Question 1. I know that this is off-subject, but last week we held
    a hearing on follow-on biologics, I like to call them biosimilars. Do
    you think that the Clinton-Schumer bill sets up a good pathway for the
    FDA to approve biosimilars?
        Answer 1. Given the complex scientific and legal considerations
    addressed in this legislation, we are still looking at this and other
    bills in relation to our developing thoughts on this issue. We would be
    happy to speak with you or appropriate staff about this legislation.
        Please let us know if you have further questions.
                           questions of senator hatch
        Question 1. On January 11, 2007, FDA announced that ``serious
    questions remain about the validity of bioequivalence data'' of 140
    marketed generic drugs. As FDA has previously said, ``bioequivalence is
    critical for drawing the conclusion that both the original and generic
    drugs will produce similar therapeutic results.'' If FDA has ``serious
    questions'' about whether 140 generic drugs actually work like the
    brand drugs for which they are substituted, how can FDA allow those
    questionable drugs to stay on the market?
        Answer 1. FDA had serious questions about the conduct of
    bioequivalence studies done by MDS Pharma Services (MDS Pharma) that
    were submitted to the Agency in support of various abbreviated new drug
    applications (ANDAs). MDS Pharma is a contract company that performs
    bioequivalence studies for a number of pharmaceutical companies.
        FDA conducted a series of lengthy inspections of MDS Pharma
    bioequivalence studies covering laboratory analyses and analytical
    results, and found significant deficiencies with several studies that
    were conducted by MDS Pharma from 2001 to 2005. As a result of these
    deficiencies, FDA was unable to verify the results reported from these
    studies. The bioequivalence studies for these particular products in
    question were either re-analyzed or repeated by the ANDA sponsors, and
    this additional work by the sponsors confirmed the accuracy of the
    bioequivalence findings from the initial studies. It is important to
    note that FDA inspected many other MDS Pharma bioequivalence studies
    conducted during the 2001 to 2005 time period and found those studies
    acceptable.
        The Agency then focused on those remaining bioequivalence studies
    conducted by MDS Pharma during the 2001 to 2005 time period that had
    not been inspected by FDA and that were submitted in support of 140
    approved ANDAs. Although the Agency had serious concerns about the
    conduct of some of the bioequivalence studies by MDS Pharma based on
    its previous inspection findings, the Agency did not have any adverse
    inspection findings for these specific studies that would undermine the
    Agency's bioequivalence conclusions regarding these products. In
    addition, these products had satisfied the Agency's rigorous chemistry
    and manufacturing standards for approved drugs.
        Nevertheless, FDA took additional steps to assure that the
    bioequivalence data for these 140 products were reliable. To obtain
    these necessary assurances, on January 11, 2007, FDA sent written
    requests asking that the ANDA sponsors do one of the following, in
    order of FDA preference, within 6 months:

        a. Repeat the bioequivalence studies;
        b. Re-assay the samples at a different bioanalytical facility. For
    this option, the integrity of the original samples must be demonstrated
    for the frozen storage period; and
        c. Commission a scientific audit by a qualified independent expert,
    who is knowledgeable in the area of bioequivalence studies and
    bioanalytical data, selected by the manufacturer rather than by MDS, to
    verify the results obtained by MDS.

        Confirmatory data received from sponsors thus far have supported
    the bioequivalence determinations that were made. At the end of the 6-
    month period, FDA will reassess whether any additional steps will need
    to be taken.

        Question 2. Why did FDA announce it had ``serious questions'' about
    these 140 marketed drugs, but not disclose their identities to the
    American public, so they could decide for themselves whether they
    wanted to take these questionable products?
        Answer 2. FDA took these actions described in response to Question
    1 as a precautionary measure to ensure that data submitted to the
    Agency and used to support approval decisions were accurate. FDA's
    routine adverse event surveillance monitoring program has not detected
    any signals or evidence that any of the drugs involved pose a safety
    risk or that there has been any impact on efficacy. FDA does not have
    any evidence that there are problems with the quality, purity, or
    potency of the affected drug products. Moreover, the studies at issue
    were conducted by MDS Pharma, a contract research organization with
    which the ANDA holders had a contractual arrangement, and the
    information was considered to be confidential commercial information
    and not releasable to the public.

        Question 3. Absence of evidence is not evidence of absence. FDA
    says it has no evidence that the 140 drugs pose a safety risk or have
    impaired efficacy. I question how you can be sure. You stated, ``FDA's
    routine adverse event surveillance monitoring program'' has not
    detected any problems. This is the same monitoring that the recent IOM
    Report found inadequate for new drug adverse event reporting, and which
    current drug safety legislative proposals seek to improve. If FDA's
    current monitoring system is inadequate, how can you be sure none of
    the 140 drugs have problems?
        Answer 3. Approval of a generic product depends on meeting
    standards for purity and potency of the drug substance as well as
    bioequivalence. These products have all met the usual chemistry and
    manufacturing standards for approved drugs. As noted in the answer to
    Question 1, FDA has asked all sponsors of the 140 relevant products to
    follow one of the three options within 6 months to confirm that
    bioequivalence standards have been met.
        While FDA generally relies on AERS and MedWatch and post-marketing
    safety reporting as the sources for surveillance monitoring, the Office
    of Generic Drugs (OGD) also receives reports of potential
    bioequivalence problems from many other sources, and follows up on
    these reports from sources including individual patients, and problems
    reported in the literature.

        Question 4. Please explain how FDA's adverse event monitoring
    system tracks generic drugs. Do you track adverse events by
    manufacturer?
        Answer 4. The Adverse Event Reporting System (AERS) is a
    computerized information database designed to support FDA's post-
    marketing safety surveillance program for all approved drug and
    therapeutic biologic products (including both brand and generic
    products). The goal of this system is to improve the public health by
    providing the best available tools for storing and analyzing safety
    reports.
        FDA receives adverse drug reaction reports from manufacturers as
    required by regulation. Health care professionals and consumers send
    reports voluntarily through the MedWatch program. These reports become
    part of a database. The structure of this database is in compliance
    with the international safety reporting guidance (ICH E2B) issued by
    the International Conference on Harmonization.
        The reports in AERS are evaluated by clinical reviewers in the
    Office of Surveillance and Epidemiology in CDER to detect safety
    signals and to monitor drug safety. Reports about generic drugs are
    tracked in the same manner as reports about new drug products. The
    analyses of reports are usually done to assess the potential adverse
    effects of the molecule, and not the drug product of an individual
    manufacturer.

        Question 5. Does FDA have any monitoring system capable of
    detecting bioequivalence problems? If so, what data are incorporated
    into the monitoring program that would provide a signal of a
    bioequivalence problem? If not, on what scientific basis can FDA confer
    a judgment that the absence of evidence of safety and efficacy problems
    is a sufficient validation that ANDA sponsors have submitted
    information showing bioequivalence?
        Answer 5. Although bioequivalence problems are difficult to detect
    because of the large amount of variability between individuals, and
    from time to time within the same individual, regarding the therapeutic
    response to a drug, the AERS database and MedWatch post-marketing
    safety reporting are capable of detecting bioequivalence problems. It
    is acknowledged that the voluntary reporting on which the systems are
    based is a limiting factor. However, OGD also receives reports of
    potential bioequivalence problems from many other sources, and follows
    up on these reports from other sources including individual patients,
    and problems reported in the literature. See the response to Question 1
    for a description of the steps FDA has taken with respect to the 140
    products at issue in the MDS Pharma case.

        Question 6. Please provide the committee with a list of the 140
    generic drugs subject to the January 11 announcement.
        Answer 6. We are unable to provide the list of products because
    information about companies that have contractual arrangements with MDS
    Pharma is confidential commercial information.

        [Whereupon, at 12:42 p.m., the hearing was adjourned.]