[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


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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 
[email protected].
---------------------------------------------------------------------------
    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.]

                                    

      
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