[Senate Hearing 110-384]
[From the U.S. Government Publishing Office]
S. Hrg. 110-384
DRUG USER FEES: ENHANCING PATIENT ACCESS AND DRUG SAFETY
COMMITTEE ON HEALTH, EDUCATION,
LABOR, AND PENSIONS
UNITED STATES SENATE
ONE HUNDRED TENTH CONGRESS
EXAMINING ENHANCING PATIENT ACCESS AND DRUG SAFETY RELATING TO
PRESCRIPTION DRUG USER FEES, INCLUDING S. 484
MARCH 14, 2007
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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
C O N T E N T S
MARCH 14, 2007
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
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,
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
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
Response to questions of Senator Enzi by:
Kim Witczak.............................................. 76
D. Bruce Burlington, M.D................................. 78
Stephen R. Mason, HHS Acting Assistant Commissioner for
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
DRUG USER FEES: ENHANCING PATIENT ACCESS AND DRUG SAFETY
WEDNESDAY, MARCH 14, 2007
Committee on Health, Education, Labor, and Pensions,
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
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
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
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
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
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
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
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
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
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
[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
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
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
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
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
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
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.
STATEMENT OF ANDREW VON ESCHENBACH, M.D., COMMISSIONER OF FOOD
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.
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.
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 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;
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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. 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
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
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
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
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
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
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
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. 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
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
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
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
Dr. von Eschenbach. Yes, sir.
Senator Burr. Communication plan to health care providers.
Do we currently have a communication plan to health care
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,
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
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
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
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
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
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
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
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
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. 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
Dr. von Eschenbach. We are in the process of providing
technical assistance with regard to Senator Kennedy and Senator
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
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
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
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
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
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
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
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
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
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
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
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
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
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.
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
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
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
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
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
[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--
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
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.
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
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
``. . . 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].''
``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
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
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
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-
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
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
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
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
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
STATEMENT OF MARK McCLELLAN, M.D., PH.D., AMERICAN ENTERPRISE
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
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
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.
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
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
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
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
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
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
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
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
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.
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.
STATEMENT OF D. BRUCE BURLINGTON, M.D., EXECUTIVE VICE
PRESIDENT, QUALITY, REGULATORY AND SAFETY, WYETH
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
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
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
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
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
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
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
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
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.
[The prepared statement of Ms. Dorman follows:]
Prepared Statement of Diane Edquist Dorman
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
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
comments on the pdufa iv recommendations, including impact on orphan
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
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
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
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
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
leadership is urgently needed to restore agency independence
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
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
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
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
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
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
I'm interested in that idea, but I'm not convinced the
larger appropriations alone would solve FDA's problems. What do
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
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
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
Senator Enzi. Thank you.
My time has expired. I will submit some additional
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
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
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
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
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
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
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
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
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
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
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
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:]
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
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
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
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
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,
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
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
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
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
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
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
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
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
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.
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
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
In NAMI's view, PDUFA IV should help FDA progress toward being an
Engages in effective pre-market review of products,
Fosters expedited drug development,
Moves toward rapid progress for fully automated drug
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
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
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
Thank you for the opportunity to present NAMI's views on this
Response to Questions of Senator Kennedy and Senator Enzi by Kim
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
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
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
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,
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
Question 2. Are there any changes to the Enzi-Kennedy drug safety
legislation that you would suggest in addition to those in your
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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.]