[Senate Hearing 109-99]
[From the U.S. Government Publishing Office]
S. Hrg. 109-99
NOMINATION OF LESTER M. CRAWFORD
=======================================================================
HEARING
OF THE
COMMITTEE ON HEALTH, EDUCATION,
LABOR, AND PENSIONS
UNITED STATES SENATE
ONE HUNDRED NINTH CONGRESS
FIRST SESSION
ON
TO BE COMMISSIONER, FOOD AND DRUG ADMINISTRATION, U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
__________
MARCH 17, 2005
__________
Printed for the use of the Committee on Health, Education, Labor, and
Pensions
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COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS
MICHAEL B. ENZI, Wyoming, Chairman
JUDD GREGG, New Hampshire EDWARD M. KENNEDY, Massachusetts
BILL FRIST, Tennessee CHRISTOPHER J. DODD, Connecticut
LAMAR ALEXANDER, Tennessee TOM HARKIN, Iowa
RICHARD BURR, North Carolina BARBARA A. MIKULSKI, Maryland
JOHNNY ISAKSON, Georgia JAMES M. JEFFORDS (I), Vermont
MIKE DeWINE, Ohio JEFF BINGAMAN, New Mexico
JOHN ENSIGN, Nevada PATTY MURRAY, Washington
ORRIN G. HATCH, Utah JACK REED, Rhode Island
JEFF SESSIONS, Alabama HILLARY RODHAM CLINTON, New York
PAT ROBERTS, Kansas
Katherine Brunett McGuire, Staff Director
J. Michael Myers, Minority Staff Director and Chief Counsel
(ii)
C O N T E N T S
__________
STATEMENTS
MARCH 17, 2005
Page
Enzi, Hon. Michael B., Chairman, Committee on Health, Education,
Labor, and Pensions, opening statement......................... 1
Sessions, Hon. Jeff, a U.S. Senator from the State of Alabama.... 4
Crawford, Lester M., D.V.M., Ph.D., to be Commissioner, Food and
Drug Administration, U.S. Department of Health and Human
Services....................................................... 6
Prepared statement........................................... 8
Harkin, Tom, a U.S. Senator from the State of Iowa, prepared
statement...................................................... 28
ADDITIONAL MATERIAL
Statements, articles, publications, letters, etc.:
Clinton, Hon. Hillary Rodham, a U.S. Senator from the State
of New York, prepared statement............................ 37
Jeffords, Hon. James M., a U.S. Senator from the State of
Vermont, prepared statement................................ 38
Mikulski, Hon. Barbara A., a U.S. Senator from the State of
Maryland, prepared statement............................... 38
Letters of concern from various organizations................ 39
Letters of support from various organizations................ 42
Response to questions of Senator Bingaman by Dr. Crawford.... 66
Response to questions of Senator Burr by Dr. Crawford........ 73
Response to questions of Senator Clinton by Dr. Crawford..... 77
Response to questions of Senator Ensign by Dr. Crawford...... 82
Response to questions of Senator Frist by Dr. Crawford....... 84
Response to questions of Senator Jeffords by Dr. Crawford.... 90
Response to questions of Senator Roberts by Dr. Crawford..... 95
Response to questions of Senator Gregg by Dr. Crawford....... 97
Response to questions of Senator Harkin by Dr. Crawford...... 103
Response to questions of Senator Hatch by Dr. Crawford....... 107
Response to questions of Senator Isakson by Dr. Crawford..... 112
Response to questions of Senator Dodd by Dr. Crawford........ 112
Response to questions of Senators Kennedy/Mikulski by Dr.
Crawford................................................... 124
Response to questions of Senator Kennedy by Dr. Crawford..... 128
Response to questions of Senator Enzi by Dr. Crawford........ 137
(iii)
NOMINATION OF LESTER M. CRAWFORD
----------
THURSDAY, MARCH 17, 2005
U.S. Senate,
Committee on Health, Education, Labor, and Pensions,
Washington, DC.
The committee met, pursuant to notice, at 9:34 a.m., in
room 430, Dirksen Senate Office Building, Senator Enzi,
chairman of the committee, presiding.
Present: Senators Enzi, Isakson, DeWine, Ensign, Hatch,
Sessions, Roberts, Kennedy, Dodd, Harkin, Mikulski, Jeffords,
Bingaman, Murray, and Clinton.
Opening Statement of Senator Enzi
The Chairman. Good morning, and welcome to the confirmation
hearing for Dr. Lester M. Crawford to be the Commissioner of
the Food and Drug Administration.
Recently when we met, it became obvious our shared
commitment to protect and advance America's health. Clearly, we
have a lot of work to do together.
Dr. Crawford, the FDA is no stranger to you. In fact, over
the last 30 years, you have been at the FDA four times, twice
serving at the helm of the agency already. Next year will mark
the 100th anniversary of the landmark legislation that ushered
the FDA into the modern era. This is truly a historical
milestone and a dramatic time for you to take up the reins of
the agency.
Back then, 100 years ago, there was a controversy--similar
to today's drug controversy--that spurred the FDA's dramatic
growth from a chemist at the Department of Agriculture to the
full-fledged agency it is today. Back then, it was a crisis in
food safety. Today, it is a concern with drug safety. The FDA
weathered the previous storm. It will handle this one, too,
with the same kind of talent, diligence, and hard work that
solved the previous one.
You will face some tough questions today, but I want to let
you know that we will be asking these questions so that we can
be sure the man chosen by President Bush to head the FDA at
this critical juncture in its history is up to the task.
The FDA has a very broad and critical mission in protecting
the public health. You will be in charge of an agency that
regulates $1 trillion worth of products a year. The FDA ensures
the safety and effectiveness of all drugs, biological products,
such as vaccines, medical devices, and animal drugs and feed.
It also oversees the safety of a vast variety of food products,
as well as medical and consumer products, including cosmetics.
As Commissioner of the FDA, you will be responsible for
advancing the public health by helping to speed innovations in
its mission areas and by helping the public get accurate,
science-based information on medicines and foods.
The FDA has been without a confirmed Commissioner for over
a year. You have been picking up the reins during that time and
pulling it through.
Earlier this year, 17 members of this committee sent a
letter to the President urging him to nominate a Commissioner
to provide the agency with greater clarity and certainty in its
mission to protect our food and drug supplies. By having you
before us today, it is clear that the President is committed to
restoring the FDA to its fully mandated authority and we
appreciate the promptness with which your nomination followed
our letter.
One of Congress's most important responsibilities is
oversight. As Chairman, I have already held bipartisan hearings
on drug safety and drug importation and I plan to continue to
focus on these and other important areas.
Dr. Crawford, you are as committed to government
accountability and responsibility as I am, so I know you will
welcome our participation in the process.
In recent months, the FDA and its system for approving
drugs and ensuring their safety have been on the front pages of
our newspapers--quite often lately. The role of pharmaceuticals
in health care has never been as vital to our health as it is
today. That is why people need to be reassured that they can
trust the FDA. Our bipartisan hearings to review the FDA's drug
approval and postmarketing surveillance system examined the
recent controversies and reviewed some options for
strengthening our drug safety system. I trust you share our
concerns and that you will continue to work with us to evaluate
and eventually implement the necessary reforms to the system.
We also need to look at last year's flu vaccine shortage
and what steps we need to take to prevent this from happening
again. Both the FDA and the Centers for Disease Control and
Prevention have been criticized. I intend for this committee to
review what happened and to determine how we, as legislators,
should respond. One thing we must do, however, is attract
companies back into the vaccine business. Relying on one or two
companies to produce some of the most critical vaccines is a
prescription for public health disaster. I would welcome your
thoughts on how we can rebuild our domestic vaccine industry.
With respect to food safety, I represent a State that has
substantial agricultural interests. Issues of food safety and
food labeling are critically important to me and my
constituents. The FDA is responsible for the safety of a
variety of our food products and I look forward to hearing from
you what the agency plans to do to continue protecting the
American food supply from outside threats.
It will fall upon you to build on your record on behalf of
President Bush, and I am confident that the President has
chosen wisely in nominating you to be the Commissioner of the
FDA. I look forward to working with you, with Senator Kennedy,
and with the other members of the committee to protect and
promote the public health and to maintain the FDA's status as
one of the strongest regulatory agencies in the world.
We all know the FDA has a storied past that made it the
gold standard of the world. In previous hearings, we heard from
members of your staff who spoke with pride of that designation.
Recent events have called into question that standard in the
eyes of some of the people in the public. I have no doubt that
with the right leadership in place, the FDA will again be the
gold standard and our regulatory process the envy of the world.
I look forward to hearing your testimony today. I welcome
your wife, Kathy, to the hearing, and I would turn the floor
over to Senator Kennedy on this great Irish day.
Senator Kennedy. You can keep going, St. Patrick's Day--
[Laughter.]
Thank you very much, Mr. Chairman. I want to say how much
we appreciate your calling the hearing this morning on the
nomination of Lester Crawford to be the Commissioner of the
Food and Drug Administration and I welcome Dr. Crawford and I
look forward to hearing about his plans for leading the agency
in the coming years and I join Senator Enzi in welcoming Mrs.
Crawford, as well.
Effective leadership of FDA is essential to protect the
health of all Americans, and friends and colleagues speak
highly of Dr. Crawford's dedication and commitment to public
service. But our committee has a special responsibility to make
a careful evaluation of the qualifications of any nominee for
this critical position.
As Acting Commissioner, Dr. Crawford has led FDA during
troubled times. Serious side effects were belatedly discovered
for several major drugs already on the market, raising alarming
questions about the adequacy of FDA's review. And there have
been significant failures by FDA to disclose and manage
conflicts of interest on scientific advisory panels. Over half
of the Nation's flu vaccine was lost to contamination. And
disturbing allegations have been raised that FDA has prevented
open scientific discussion of important drug safety issues, has
disregarded science that conflicts with ideology, and has
retaliated against whistleblowers. And just today, the New
England Journal of Medicine published an article stating that
at FDA, there is an atmosphere that stifles debate and
discourages some employees from expressing scientific concerns
about drugs.
It is essential to address these serious issues and for Dr.
Crawford to present a clear plan to restore the Nation's trust
in the ability of FDA to do its job. FDA, as our chairman has
pointed out, oversees about a quarter of all products purchased
by American consumers. Whether FDA does its job effectively can
mean the difference between whether the infant formula you feed
your child is safe or not, or whether the prescription drug you
take does more harm than good.
Doubts have risen about the agency's effectiveness in the
wake of Merck's withdrawal of its pain-killing drug Vioxx from
the market because of estimates that tens of thousands of
patients may have suffered heart attack or stroke because of
it.
And last October, we learned that half of last year's flu
vaccine was lost because of poor manufacturing conditions at a
plant in Britain, and we were surprised to learn that FDA had
not actively inspected the plant and then compounded the
problem by doing too little after it learned that some of the
vaccine had been contaminated.
Last year, the agency declined to approve emergency
contraception for over-the-counter use after a nearly unanimous
advisory group recommended such approval, and the agency is now
2 months late in ruling on a revised request for such use.
The agency has also prohibited or discouraged some of its
medical officials from presenting their studies at advisory
committee hearings, at scientific meetings, or in respected
journals. The agency also chose not to disclose in advance
potential conflicts of interest by members of the advisory
committee who reconsidered Vioxx and related drugs a few weeks
ago and approved their continuation on the market.
As the President's nominee, Dr. Crawford owes this
committee, the Senate, and the American people his assurance
that if the committee confirms him as Commissioner, there will
not be more of the same. The stakes could not be higher. No
patient who takes a pill should have to worry whether the drug
inside is safe or whether the decisions to approve the drug
were based on politics or profits instead of science. It is a
tragedy that the FDA's recent failures have caused millions of
patients to ask those questions now. It would be far worse if
we don't insist on clear answers.
We know that Dr. Crawford is here to answer these questions
and other questions of the committee and I look forward to his
response and I thank you very much, Mr. Chairman, for holding
these hearings.
The Chairman. Thank you, Senator Kennedy.
I would mention that we are doing a little different
seating arrangement on this side. Since we allow people to ask
questions in the order in which they arrive after the gavel has
sounded, we are just moving everybody up here in that order on
this side.
This morning, we have the Senator from Alabama to do an
introduction, Senator Sessions.
STATEMENT OF HON. JEFF SESSIONS, A U.S. SENATOR FROM THE STATE
OF ALABAMA
Senator Sessions. Thank you, Mr. Chairman. It is an honor
to be before you as chairman of this committee. We came to the
Senate together and you have moved up more rapidly than most of
us to chair this august body and I couldn't be more proud of
you. You have the right instincts for public service, the
professional commitment to doing things right, and the work
ethic that is necessary to deal with the complex issues that
come before us.
Mr. Chairman, it is my honor and privilege to introduce my
fellow Alabamian, Dr. Lester Crawford, to this committee. I am
addressing the committee today not only because Dr. Crawford
hails from Demopolis, AL, which was the original vine and olive
colony founded by a group of Napoleon losers who had to flee
France and established on the river there in Alabama the vine
and olive colony. I am not sure it succeeded as a vine and
olive colony, but it has succeeded as a wonderful community
that sets a good example in that whole region of the State.
He received his Doctorate of Veterinary Medicine at Auburn
University, one of the Nation's great universities. But I am
also here because this nominee is a recognized scientist,
scholar, and academic, a public servant of unassailable
personal integrity who brings with him the perspective of
personal experience in academia, government, private practice,
and industry. Most importantly, he combines openness, good
humor, and a commitment to the common good.
Dr. Crawford brings to the agency expertise in a remarkable
range of relevant fields. We frequently forget that in addition
to authority to regulate drugs, the FDA is charged with
overseeing foods, biological products, medical devices, animal
feed and drugs, among other responsibilities. I don't know that
you could find another candidate with his degree of expertise,
not only in pharmacology and issues related to drugs and
biologics, but also food safety, and in the era of ``mad cow''
disease and avian flu, the fields of agriculture and veterinary
medicines, which are proving ever more crucial to the public
health. In fact, he has a particular expertise in mad cow
disease.
At a time when rising to the substantial challenges will
require innovation and interdisciplinary thinking, a man who
brings this quintessentially interdisciplinary training and
experience could not be more appropriate.
In addition to his substantial academic and professional
achievements, Dr. Crawford has demonstrated a tremendous
dedication to public service during more than 13 years at the
Food and Drug Administration and the United States Department
of Agriculture. Colleagues who have worked with Dr. Crawford
over the years unfailingly note his exemplary personal
qualities, as well. Integrity, dedication, and enthusiasm have
been hallmarks throughout his training and career.
Dr. Timothy Boosinger, Dean of Auburn University's
nationally recognized College of Veterinary Medicine, called
yesterday to share his own and Auburn's unreserved endorsement
of Dr. Crawford as a scientist and administrator, a leader, and
a man. He is really one of our most distinguished alumni.
Auburn is proud of the contribution he is making to all our
lives, he said.
I think that his own advice to a recent class of veterinary
graduates is telling. He noted that he has always tried to let
his own life be guided by the Latin phrase, I credo, I believe.
The point is, he explained, when you have talent, you have to
develop it and practice it. Develop your own credo and live by
it. And Dr. Crawford has throughout his career demonstrated not
only remarkable talent, but a consistent dedication to honing
and applying that talent for the public good.
In summary, I believe that Dr. Lester Crawford is a man of
great knowledge, talent, dedication, and integrity. As
Commissioner, he will be even better able to bring these
qualities to bear in the service of the safety and well-being
of the American people. I urge you to join me in working to
enable this superb nominee to get to his essential task as soon
as possible.
Thank you, Mr. Chairman. I am honored to be with Dr.
Crawford.
The Chairman. Thank you, Senator.
We welcome Dr. Crawford. I would mention that the committee
has received over 100 letters and statements of support for Dr.
Crawford's nomination from individuals and organizations around
the country. We received one letter with some concerns, that if
they are not addressed at the hearing, we will ask that you
address following the hearing. I would ask unanimous consent
that all of those letters be entered into the record, without
objection.
The Chairman. Dr. Crawford, we look forward to hearing your
testimony.
STATEMENT OF LESTER M. CRAWFORD, D.V.M., PH.D., TO BE
COMMISSIONER, FOOD AND DRUG ADMINISTRATION, U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
Dr. Crawford. Thank you very much, Mr. Chairman. First, I
would like to introduce my wife, who is seated over here. This
is my wife, Katherine, who is from Birmingham, Alabama, and is
the mother of my two daughters and the grandmother of my four
grandchildren.
The Chairman. Welcome.
Dr. Crawford. I would like to thank the committee for
inviting me here today. I am honored to be here and I
appreciate the opportunity to tell you about myself and share
ideas for how we can strengthen and advance the Nation's public
health.
FDA is the Nation's principal consumer protection agency
when it comes to food, drugs, and medical devices. The agency
impacts the lives of all Americans every day. We ensure the
safety and efficacy of the medicines they consume. We regulate
80 percent of the food Americans eat. FDA regulated products
account for approximately 20 cents out of every dollar in the
economy. American consumers rely on FDA to protect and advance
the Nation's public health while people around the world share
the view that the agency upholds the gold standard in terms of
public health protection.
I have had the opportunity over the course of my career to
serve four different tenures at FDA. This is the second time I
have served as Acting Commissioner of the agency. I previously
served as FDA Deputy Commissioner from 2002 to 2004, and as
Director of FDA's Center for Veterinary Medicine from 1982 to
1985. Prior to that, I held several different positions,
including Director in the former FDA Bureau of Veterinary
Medicine in 1970s.
My career outside of FDA has likewise been dedicated to
advancing public health. I served as Administrator of the Food
Safety and Inspection Service, or FSIS, at the U.S. Department
of Agriculture from 1987 to 1991. Prior to that, I was Chair of
the Department of Physiology-Pharmacology at the University of
Georgia and held the position of Associate Dean for several
different offices at the University of Georgia's College of
Veterinary Medicine.
More recently, from 1997 to 2002, I was Director of the
Center for Food and Nutrition Policy at Georgetown University
and at Virginia Tech, where it moved in 2001. I also served as
the Executive Director of the Association of American
Veterinary Medical Colleges.
I am a member of several professional and scientific
societies. I am a member of the National Academy of Sciences
Institute of Medicine, a Fellow of the Royal Society of
Medicine in the United Kingdom, and a Fellow of the
International Society of Food Science and Technology. In 1984,
I was inducted into the French Academy of Veterinary Medicine
and I received the Wooldridge Award, the British Veterinary
Association's highest award, in 1991. Additionally, I have been
an advisor to the World Health Organization of the United
Nations.
In terms of academic training, I received my Veterinary
degree from Auburn, my Ph.D. in Pharmacology from the
University of Georgia, and I have an Honorary Doctorate from
Budapest University.
Throughout my diverse career, I have had the unique
opportunity to contribute to a number of groundbreaking public
health initiatives. For example, I played major roles in the
development of mandatory nutrition labeling and the control of
chemical and microbiological contaminants of food. In recent
years at FDA, I have led efforts to combat the obesity
epidemic, counterterrorist threats through new food security
regulations, and revitalized the regulation of biomedical and
food industries through the development of current good
manufacturing practices. I also played a role in designing
FDA's Critical Path Initiative, a new cutting-edge approach to
advancing medical innovation that seeks to bridge the so-called
gap between bench and bedside.
Going forward, as Commissioner of the Food and Drug
Administration, if confirmed, I look forward to the opportunity
to build on these initiatives to help America reach new levels
of public health protection and innovation.
This is a critical time for the Nation's health. We face
exciting opportunities from new cross-cutting science and
biomedical innovation, but at the same time, we are confronted
with profound challenges of every shape and size--emerging
diseases, product safety concerns, the threat of bioterrorism,
and much more.
Our success and the Nation's health are continually
challenged by these emerging threats, changes in technology and
global market forces. At the same time, FDA's responsibilities
are growing in scope and complexity. To overcome these growing
challenges and to truly capitalize on the boundless
opportunities presented by modern science, we need a vision for
the future, a vision for a 21st century FDA.
I would like to tell you briefly about my vision for the
future of FDA. It is one of transformation. Internally at FDA,
we are transforming from domestic-focused, paper-based
processes employing yesterday's technologies to global,
electronic data-driven decisions that apply the latest science.
And we are transforming our culture to one of transparency,
collaboration, and cutting-edge thinking.
We are going to tap into new technologies and new ways of
thinking and build upon collaborations with a broad network of
partners, public and private, U.S. and international. By
capitalizing on 21st century innovation, information
technology, and regulatory process innovation, we can leverage
public investment in FDA to yield an even greater level of
public health protection and a more efficient and predictable
critical path to innovation. By adopting a quality systems
approach in all our operations, we will increase productivity
and promote better health outcomes.
In particular, I am committed to addressing existing
concerns regarding postmarket safety of FDA-regulated products,
both in medical products and food, respectively. I remain
focused on bioterrorism and on minimizing the threat of
terrorist attacks both through heightened food security and
through the development of new medical countermeasures.
As we confront 21st century challenges, 21st century
solutions are key. That is why innovation will be at the center
of everything FDA does in the time ahead. I look forward to
helping lead the way as we enter a new era of individualized
medicine and electronic health.
Finally, we need to continue to do more to empower our
citizens with better health information about the foods they
eat, the medicines they use, and the other health products they
consume. Under my leadership, I will see to it that FDA
continues to provide all Americans with the tools they need to
make informed choices about their health so that they can live
longer, happier, and healthy lives.
These issues affect us all and I look forward to being part
of the solution to these problems. Thank you, Mr. Chairman.
The Chairman. Thank you, Dr. Crawford.
[The prepared statement of Dr. Crawford follows:]
Prepared Statement of Lester M. Crawford, D.V.M., Ph.D.
Mr. Chairman and members of the committee, I am Dr. Lester M.
Crawford, D.V.M., Ph.D., Acting Commissioner of the Food and Drug
Administration (FDA or the Agency). I would like to thank the Committee
for inviting me here today. I am honored to be here, and I appreciate
the opportunity to tell you about myself and share ideas for how we can
strengthen and advance the Nation's public health.
FDA is the Nation's principal consumer protection agency when it
comes to food, drugs and medical devices. The Agency impacts the lives
of all Americans every day. We ensure the safety and efficacy of the
medicines they consume. We regulate 80 percent of the food Americans
eat. FDA-regulated products account for approximately 20 cents out of
every dollar in the economy. American consumers rely on FDA to protect
and advance the Nation's public health while people around the world
share the view that the Agency upholds the gold standard in terms of
public health protection.
I have had the extraordinary opportunity over the course of my
career to serve four different tenures at FDA. This is the second time
I have served as Acting Commissioner of the Agency. I previously served
as FDA Deputy Commissioner from 2002 to 2004 and as Director of FDA's
Center for Veterinary Medicine from 1982 to 1985. Prior to that, I held
several different positions --including Director--in the former FDA
Bureau of Veterinary Medicine in the 1970s.
My career outside of FDA has likewise been dedicated to advancing
the public health. I served as Administrator of the Food Safety and
Inspection Service at the U.S. Department of Agriculture from 1987 to
1991. Prior to that, I was Chair of the Department of Physiology-
Pharmacology at the University of Georgia, and held the position of
Associate Dean for several different offices at the University of
Georgia College of Veterinary Medicine.
More recently, from 1997-2002, I was Director of the Center for
Food and Nutrition Policy at Georgetown University and at Virginia
Tech, where it moved in 2001. I also served as Executive Director of
the Association of American Veterinary Medical Colleges from 1993 to
1997.
I am a member of various professional societies. I am a Member of
the National Academy of Sciences Institute of Medicine, a Fellow of the
Royal Society of Medicine (UK), and a Fellow of the International
Society of Food Science and Technology. In 1984, I was inducted into
the French Academy of Veterinary Medicine. In 1991, I received the
Wooldridge Award, the British Veterinary Associations highest award.
Additionally, I have been an advisor to the World Health Organization
of the United Nations for much of my career.
In terms of academic training, I received my Doctor of Veterinary
Medicine (D.V.M.) from Auburn University, my Ph.D. in pharmacology from
the University of Georgia, and an Honorary Doctorate (M.D.V.) from
Budapest University.
Throughout my diverse career, I have had the unique opportunity to
contribute to a number of groundbreaking public health initiatives. For
example, I played major roles in the development of mandatory nutrition
labeling and the control of chemical and microbiological contaminants
of food. In recent years at FDA, I have led efforts to combat the
obesity epidemic, counter terrorist threats through new food security
regulations, and revitalize the regulation of biomedical and food
industries through the development of current good manufacturing
practices. I also played a key role in designing FDA's ``Critical
Path'' initiative, a new cutting-edge approach to advancing medical
innovation that seeks to bridge the so-called gap between bench and
bedside.
Going forward, as Commissioner of the Food and Drug Administration,
if confirmed, I look forward to the opportunity to build on these
initiatives and help America reach new levels of public health
protection and innovation.
This is a critical time for the Nation's health. We face exciting
opportunities from new cross-cutting science and biomedical innovation,
but at the same time we are confronted with profound challenges of
every shape and size--emerging diseases, product safety concerns, the
threat of bioterrorism, and much, much more.
Our success--and the Nation's health--are continually challenged by
these emerging threats, changes in technology, and global market
forces. At the same time, FDA's responsibilities are growing in scope
and complexity. To overcome these growing challenges, and to truly
capitalize on the boundless opportunities presented by modern science,
we need a vision for the future--a vision for a 21st century FDA.
I would like to tell you briefly about my vision for FDA and my
priorities for the time ahead. The FDA of today understands, perhaps
better than ever, the need for both protecting and advancing the public
health, and we are focusing on new and better ways to perform our core
mission.
My vision for the future of FDA is one of transformation.
Internally at FDA, we're transforming from domestic-focused, paper-
based processes, employing yesterday's technologies, to global,
electronic-data driven decisions that apply the latest science. And
we're transforming our culture to one of transparency, collaboration,
and cutting-edge thinking.
We're going to tap into new technologies and new ways of thinking,
and build upon collaborations with a broad network of partners--public
and private, U.S. and international. By capitalizing on 21st century
information technology and regulatory process innovation, we can
leverage public investment in FDA to yield an even greater level of
public health protection, and a more efficient and predictable critical
path to innovation. By adopting a quality systems approach in all of
our operations, we will increase productivity and promote better health
outcomes.
In particular, I am committed to addressing existing concerns
regarding post-market safety of FDA-regulated products, both in medical
products and food, respectively. I remain focused on bioterrorism and
on minimizing the threat of terrorist attack both through heightened
food security and through the development of new medical
countermeasures. As we confront 21st century challenges, 21st century
solutions are key; that is why ``innovation'' will be at the center of
everything FDA does in the time ahead. I look forward to helping lead
the way as we enter a new era of individualized medicine and e-health.
Finally, we need to continue to do more to empower our citizens with
better health information about the foods they eat, the medicines they
use, and the other health products they consume. Under my leadership, I
will see to it that FDA continues to provide all Americans with the
tools they need to make informed choices about their health, so that
they can live longer, healthier, and happier lives.
These issues impact us all. I know that the members of this
committee are genuinely focused on doing all you can to address these
public health challenges and capitalize on our public health
opportunities. I am truly honored to have worked with you in the past
to advance FDA's public health mission, and I look forward to
continuing to work with each and every one of you to better protect and
advance the public health in the time ahead. Thank you.
The Chairman. We will now have a series of 5-minute rounds
to give everybody a chance to ask some questions. We appreciate
your being here today. We appreciate the turnout of the members
of the committee. This is the first round of the NCAA
tournament, a great Irish day, and also the hearings on the
House side on baseball steroids, which has some relationship to
this. [Laughter.]
I have heard some people argue that the Prescription Drug
User Fee Act was a bad idea because the fees co-opt the FDA and
force the agency to make a hasty or unwise decision. I assume
you disagree with this perspective, so would you please explain
to the committee the importance of PDUFA and the way you will
ensure, as Commissioner, that there will continue to be no
compromise on FDA's standards in reviewing products covered by
user fees?
Dr. Crawford. Yes. Thank you, sir. As you know, the
Prescription Drug User Fee Act was enacted in the early 1990s
and it is reenacted as it sunsets every 5 years. The two times
that it has been up for review, changes have been made and so
we anticipate that, based on experience, probably we will be
entertaining some new proposals.
Virtually every country in the world has a user fee system.
The question is how they utilize that user fee system.
We think the goal letter that we develop between the
industry that we regulate and FDA gives us an indication of
what is coming down the pike, what new kinds of drugs and drug
classes are coming and what the load will be upon FDA. And so
we are--and as you know, that goal letter is ratified by the
Congress as we finish it.
The second part is is that because of the Prescription Drug
User Fee Act, we get funding to increase our staff and to be
more efficient in the drug approval process. That has worked
well for FDA under the years of PDUFA. One particular year in
the mid-1990s, we approved more drugs than any other year in
history, and I think we are doing a better job of reviewing
them. Some drugs are not approved. Some need more work. But
what the companies pay for is the review itself, and I think on
balance that it is working well.
The Chairman. Thank you. Most of the questions today will
shift gears pretty fast so that we can cover a wide range of
things.
The GAO report released earlier this week indicates serious
breaches in the FDA's oversight of the 1997 ban on the feeding
of meat and bone meal from livestock to other livestock. This
ban is intended to guard against the spread of mad cow disease
in the United States. This report follows up on a 2002 report
that also found gaps in the FDA's enforcement of this
regulation. GAO also noted that the FDA may not even have
enough information to assess compliance rates. What are you
planning to do to improve the enforcement and compliance with
this and other food safety regulations?
Dr. Crawford. We are in the process of analyzing the GAO
report. As you know, we worked with them through the 2-year
process that they employed to come up with the report. There
are some suggestions in there that we think are very good and
we intend to implement them.
The report does say that we made improvements since the
last report, and we appreciate that. There are more
improvements to be made. We now know that there are about a
million people in the United States that feed one or more
cattle. We have to adopt a program that both educates them
about the use of the prohibited material in feed and also
encourages them to be very careful about what they mix in their
cattle feed. We now know that that is a menace FDA has to stay
on top of, so we appreciate the report and we will adopt the
recommendation.
The Chairman. Thank you. I do want to also discuss the
FDA's action on the abortion drug RU-486. I don't believe that
the FDA should spend time and resources reviewing products that
are intended solely to end life. I am also very concerned that
a number of deaths have been linked to RU-486.
In August 2002, a number of organizations sent a citizen
petition to the FDA asking that the FDA revoke its approval of
RU-486. The petition argues that FDA violated drug law and its
own regulations and standards in approving the RU-486 for
medical abortion. Now, these are pretty serious allegations,
and 18 months later, the FDA has yet to give a final response.
Can you assure me that the FDA will respond to this petition
sooner rather than later?
Dr. Crawford. As you know, the issues raised in the
petition are very complex, indeed. We are still working through
those. We are in the final stages of that. I can assure you we
will respond to the petition. I can't give an exact date, but
we are in the final stages of it.
The Chairman. Thank you. My time has almost expired.
Senator Kennedy.
Senator Kennedy. Thank you, Mr. Chairman.
As we all know, the FDA should be the gold standard for
objective science and unwavering commitment to the public
health. On Plan B, emergency contraception there are serious
concerns the FDA was guided more by ideology than by sound
science.
In your testimony on March 11, 2004, before the House
Appropriations Committee, you said that the Scientific Advisory
Committee on Plan B was all over the board, but that is not
really the case, I don't think. Isn't it the reality that the
Advisory Board voted 24 to three to approve OTC status for Plan
B?
Dr. Crawford. That is correct.
Senator Kennedy. Yet the FDA rejected the recommendation?
Dr. Crawford. Actually, what we did was we evaluated the
then-application and we could not approve it. But the company
has now submitted a second one. We also have, just in the last
few weeks, been sued on the original decision, so we are
evaluating what the impact of that is and we are also
considering the application that is before the agency at the
present time. We are continuing to evaluate both as we go
forward.
Senator Kennedy. Well, in response to the question from
Representative Farr at the March 2004 hearing, you said the
FDA's deadline for acting on the resubmitted application was
January 22 of this year. Is it usual for FDA to miss the
deadlines by months, and who is responsible for the hold-up?
Dr. Crawford. We usually don't miss the deadlines. In this
case, it is very complex. We have a kind of application that
the company is seeking which we have never approved before, and
so it is taking a little longer than it would have in the past.
Senator Kennedy. Well, do we want to leave it there? The
problems, as you indicated in your earlier answer were the
difficulty in the application and then the review of the legal
issues and the suit, and you are unable to indicate to us when
you are going to act?
Dr. Crawford. I can't give a date, but it won't be very
much longer.
Senator Kennedy. Well, are we talking days? Are we talking
weeks?
Dr. Crawford. I wouldn't want to say days, Senator. I would
say weeks.
Senator Kennedy. I want to move on. On the drug safety
issue, we have talked about this and you have commented on it,
so it is an old issue, but I want to get answers today. Last
year, Merck withdrew Vioxx from the market because the drug
doubled the risk of a heart attack or stroke, but that was more
than 5 years after the FDA approved the drug and after 20
million Americans had used it. As a result, tens of thousands
of Americans needlessly suffered heart attack or stroke and
many died. It is the single largest drug safety failure the
Nation has ever faced. It simply should not take that long, nor
should so many people use a drug before such a significant
safety risk is discovered.
If a similar disaster had happened through fire or flood or
terrorism, we would be moving heaven and earth to make sure
that such a catastrophe never happened again, yet the FDA has
so far recommended only minimal adjustments to its procedures.
In our hearings on drug safety earlier this year, the FDA
witness, Dr. Kweder, admitted that there had been lapses in how
the FDA handled this tragedy. Do you agree that there were
lapses, that mistakes were made?
Dr. Crawford. When these drugs entered the marketplace, as
you mentioned, in the late 1990s and early parts of this
decade, they held great promise. As they were used over time,
and particularly in two NIH trials at higher doses for longer
durations of therapy, some problems did show up. They could not
have been anticipated, we do not believe, until that time. We
had ordered earlier warnings and we were monitoring the drug
very carefully, but it was only the very large, very long,
high-dosage trials at NIH that revealed the problem.
Senator Kennedy. ``They can't be anticipated'' is rather an
ominous response when you have put at risk so many people on a
prescription drug. I want to know whether this is going to be
business as usual out at FDA or whether you are setting up some
kind of system that will be able to flag these issues. I mean,
we have just gone through one of the great, great, lapses for
whatever reasons. I am not sure the American people are going
to be satisfied that there are a number of situations that
can't be anticipated and, therefore, that is the way it is
going to be. That is not the answer that the American people,
or certainly I, would like to hear.
We heard Dr. Kweder indicate that there had been lapses,
and I think most of us believe there had been, and the real
issue is what the agency is going to do to deal with those
lapses. I think, first of all, there has to be a recognition
that there is a serious problem, and if there is, what are you
going to do about the problem, is what I would like to direct
your attention to.
Dr. Crawford. To make sure there aren't lapses in the
future, what we are going to do is like a multipronged
approach. We are instituting a Drug Safety Board which will,
when we get these signals, such as we did on Vioxx and some of
those other kinds of drugs, we will put it in to the board.
They will prescribe for us what we should do in order to find
out whether or not this is a false signal, that is a false
alarm, or whether it is something real. We will announce that
at that point, not wait, and the Drug Safety Board's
deliberations will be public, and we will also advise the
Nation's physicians as well as consumers, that is patients, of
what we have found at that point and what we are doing in order
to get to the bottom of the matter. Then we will establish a
drug watch so that we will list that drug so that it is
accessible on our websites and elsewhere to the American people
and we will have a progress report as we go forward.
And then the other things we have asked the National
Academy of Sciences Institute of Medicine to evaluate and
affect the FDA culture. We want to figure out a system that is
more transparent for decision making. We also want to
effectuate a system so that minority opinions are involved. It
is true that in the culture and milieu of FDA, there is a lot
of give and take on these decisions based on the science, but
we want to honor that and also to record what the minority
opinions are.
Senator Kennedy. My time is up, Mr. Chairman. I would just
ask about that recent advisory board, you know, there were
questions about the conflicts of interest. Are you committed
when you publish the members of the board to also indicate the
background of each?
Dr. Crawford. We will. We are going to change those
procedures. There is disclosure, but there should be easier
disclosure for the press and others to get access to. We are
going to change that entirely.
Senator Kennedy. My time is up. Thank you, Mr. Chairman.
The Chairman. Thank you. Senator Sessions.
Senator Sessions. Thank you, Chairman Enzi.
You have a difficult challenge. Delaying an effective drug
from coming on the market because of concerns that prove to be
insubstantial can cost hundreds, maybe thousands, of lives. And
likewise, if a drug is approved too rapidly, it turns out to
have side effects unexpected, it can also cost lives. So I know
it is a very challenging position for you. Sometimes, the only
way we can know for certain is to see a drug actually operate
over a period of years and the costs then are weighed against
the benefits and you can make the best decision insofar as
possible.
But your challenge is to identify in advance what will
work, what will not work, and make those decisions that are
best. I think your integrity, experience, and background will
lead you to make good decisions, and that is what we expect and
that is all we can ask. We can't expect perfection.
Dr. Crawford, I have an interest in generics. I asked you
about it as we talked yesterday, about let us not create a
situation in which generics are delayed too long because that
keeps the price higher for the public. A generic drug will come
in at a lower cost, normally. You provided some information on
that. I would like to get your philosophy about generics and
what we can do to bring those on at the appropriate time.
Dr. Crawford. Three years ago, when we began to address
this problem, we found that generics were taking about 19
months to be approved or disapproved, that is, to be reviewed.
We have now been able to shorten that down to 12 months, and
what that has resulted in is the approval of a new generic drug
in America every day. We are now trending toward somewhere
between 400 and 500 generic drug approvals for this coming
year.
Generic drugs cost less, and not only that, they cost less
in America than they do in other countries around the world.
The key thing, though, I think, in terms of our efforts with
generics is that now, about half of all prescriptions are for
generic drugs. Generic drugs, we are pledged to make sure are
as safe and as effective and as potent as any other drug that
is on the market, including the prescription counterparts in
cases.
So we are very pleased with this. We continue to work with
generic drugs in order to get them on the market and also to
have them be an appreciable percentage of the prescription
drugs that are used by the American people.
Senator Sessions. I think that is good progress, and I
salute you for it. I think we ought not to have unnecessary
delays in the time between an expiration of a drug
manufacturer's patent and the approval of generic products.
That just costs the purchasers of those drugs extra money, and
I salute you for the progress that you made there.
Would you share with us any thoughts you may have
concerning the problem that lawsuits, liability questions, have
with regard to establishing effective vaccines' availability in
this country? It is something that seems to me to be rather
significant and we need to deal with it or we may never get the
vaccine problem settled.
Dr. Crawford. Well, as you know, we have had a number of
hearings on the subject, starting back in 2002. The main focus
of that hearing in Congress was to expose the fact that the
vaccine industry was extremely fragile. We predicted then that
we would have only one supplier by this past flu season, this
flu season that we are in, and there was a great deal of
discussion about how to incentivize and indemnify the industry.
The result of that hearing was some extra funding in order to
develop alternative vaccine production methods which would make
for a more viable industry, but not much was done with respect
to liability.
That is not an area that I testified on, not an area that I
am expert in. It was, I believe, the report of that hearing and
also two of these hearings that we have had recently did
explore that, but I am not sure if conclusions were made.
Senator Sessions. I think it is a factor in the declining
number of suppliers, and I think it is something we are going
to have to deal with.
Thank you, Mr. Chairman.
The Chairman. Thank you. The next Senator is Senator
Clinton.
Senator Clinton. Thank you, Mr. Chairman. If I could, I
would like to submit additional questions for the record.
The Chairman. Yes. The record will be held open so that
people can submit questions.
Senator Clinton. Thank you very much, and welcome, Dr.
Crawford. There are a number of issues that are of concern to
me, ranging from the flu vaccine, which was mentioned, the
eventual decision on the COX-2 issue, and others which I will
submit, but I want to zero in on this emergency contraception
issue.
Back on July 8, I, along with six of my colleagues on this
committee, sent a letter asking that you and Dr. Galson meet
with us to discuss this matter. My staff followed up
repeatedly, but we were never able to establish a meeting time.
So my first question, very simply, is can I have your
assurance that in the future, you will make yourself available
to meet with members of this committee to discuss matters that
are of great importance to us?
Dr. Crawford. Absolutely. I think that might have turned
into a briefing, but I apologize for not meeting with you
personally and that will not happen again.
Senator Clinton. Thank you. Now, Dr. Crawford, I would like
to ask a simple, straightforward question that may help to
illuminate a great deal of the concern and confusion in the
press and elsewhere about what exactly emergency contraception
is and what it isn't.
The label for Plan B says the method is indicated, and I
quote, ``for the prevention of pregnancy after unprotected sex
if a contraceptive fails or if no contraception was used,''
unquote. Would you clarify for the committee that emergency
contraception is a method for prevention of pregnancy, not the
termination of pregnancy?
Dr. Crawford. I can certainly clarify. I may need to confer
with the experts in the FDA about exactly what the physiology
of it is, but the label will say prevention.
Senator Clinton. Well, in fact, as the FDA's own questions
and answers on Plan B released in May 2004 say, and I quote
again, ``Plan B works like other birth control pills to prevent
pregnancy. Plan B acts primarily by stopping ovulation. It may
prevent fertilization. If fertilization occurs, Plan B may
prevent a fertilized egg from attaching to the womb.''
So just to be clear, are you confirming that FDA, in its
own printed information which I have a copy of here, in
response to questions that people legitimately have from both
the public and other points of view, that it says explicitly
what is emergency contraception, and I quote, ``emergency
contraception is a method of preventing pregnancy.'' That is
the FDA position, is that correct, Dr. Crawford?
Dr. Crawford. We haven't finally finished the label, but
that is what is before us at the present time and we have not
at this present time finally decided. We have no real dispute
with the label at this point. But as you know, the product is
not approved and so I can't say how it will finally turn out.
If I may answer that for the record, I can give some of the
scientific interpretations of what happens at conceptus and
whether or not--the term of art here is called nidation,
whether or not the conceptus attaches to the wall of the
uterus. But I would like, if I may, to consult with the experts
in the Center and----
Senator Clinton. Well, in fact, though, Dr. Crawford, the
experts at FDA have made their recommendation, that emergency
contraception should be available and it should be available
over the counter and that the studies on it and the assessment
of it confirm that it is as described, emergency contraception,
a method of preventing pregnancy.
And what has disturbed many of us is what appears to be
political interference in a scientific process. For those of us
who believe that prevention is the key for decreasing the
number of abortions, it is somewhat disturbing to see the
injection of political concerns. I think it is perfectly
appropriate for citizens to petition, to send letters, to ask
questions, but there must be a scientific basis for these
decisions.
And insofar as we are aware, the experts at the FDA and the
outside experts have voted overwhelmingly in favor of making
this drug available. More than 70 organizations, including the
American Academy of Physicians, Family Physicians,
Obstetricians and Gynecologists, the American Medical
Association submitted testimony. If we are going to return the
FDA to the gold standard, then it is perfectly appropriate for
people to say, don't use this or that it is somehow
inappropriate and to be in any way involved in the public
debate over it, but not to politicize the science, and that is
what I want your assurance of, Dr. Crawford.
It is deeply disturbing to me. We rely on the FDA for
everything we take. I am hopeful that we will reverse what
appears to be a dangerous slide into political opinion as
opposed to scientific evidence.
Dr. Crawford. Well, I can assure you that this decision
will not be based on politics. It will be based on science. It
is delayed, and I think that is the way to look at it, because
it is a very complex approval process that the company has
proposed. And so we are working through the legality of that.
But I am not aware of political pressure to make the decision
one way or the other.
You are absolutely correct about the Advisory Committee, so
I think the science part is generally done. We are just now
down to how the label will look. This is going to be a very
unusual sort of approval and it is delayed and I apologize for
that, but----
Senator Clinton. When might we expect the approval to be
forthcoming?
Dr. Crawford. I can't say for sure because we--Mike could
have predicted it, but the lawsuit has complicated it a little
bit. We have to work through that. It is for the prior
approval, and what effect it has on it, I can't really say at
this time. But I don't think it is going to be a long delay.
Senator Clinton. Thank you. Thank you, Mr. Chairman.
The Chairman. Thank you. Senator DeWine.
Senator DeWine. Thank you, Mr. Chairman.
Dr. Crawford, like drugs, for too long, we assumed that
children were small adults and could just take reduced doses of
adult products. We are finding that many essential medical
devices used extensively by pediatricians are really not
designed and sized for children's special needs.
According to pediatricians, the development of cutting-edge
medical devices suitable for children's smaller and growing
bodies can lag 5 to even 10 years behind those for adults. That
is really not acceptable. Could you tell us, under your
leadership, what the Food and Drug Administration will be able
to do to ensure that devices used in children are designed and
sized for their use?
Dr. Crawford. Thank you for the question. When I came on as
acting in 2002, we had just gotten the Best Pharmaceuticals for
Children Act, as you know, and it was my privilege to implement
that and it has gone forward. After that time, we had the
codification of our regulation on labeling for pediatric uses
of existing drugs. We had a regulation that was overturned in
the courts. We pursued that. The Congress codified the
regulation, thereby making it legal.
And what has happened since that time is for those drugs
that are on patent, the ones that have exclusivity, we have
gotten a lot of activity and there have been multiple changes
in the labeling, and also as the products go on the market,
more and more, they do show pediatric indications. Not all
drugs can be used in children, but many can and many more are
as a result of these two pieces of legislation.
The other thing is those drugs that are off-patent,
however, we haven't made as much progress with because we
actually need the National Institutes of Health to do some work
on those products in order to make sure they are okay for
pediatric uses. As you may know, Secretary Thompson and the
past administration did order some funding for this particular
project and it has yielded some results, but not enough at this
point.
Senator DeWine. Doctor, my question--I appreciate that. My
question was about devices, though, which is a new area. What
can you do in that area?
Dr. Crawford. We are going to have the same people who work
in my office that have spearheaded this effort with the drugs
do it also with the devices. They have essentially the same
kind of scheme, the same authorities in order to get it done,
and I expect--you have my assurance that I am fully committed
to that project. I will make the resources available for it,
and I expect the same kind of results, and we will hold them to
that expectation.
Senator DeWine. What is your timing on that?
Dr. Crawford. The timing on setting up the office is within
this fiscal year, so it should be done within a month or two.
Senator DeWine. Setting up the office?
Dr. Crawford. The office is already set up, basically. We
have to recharge it----
Senator DeWine. What will be done within a couple months?
Dr. Crawford. The office will be fully charged to do
devices evaluation, the same as it did in drugs.
Senator DeWine. Let me go on to another question.
Currently, few programs specifically target the treatment of
children with HIV/AIDS in developing countries. A primary
reason, of course, is the lack of appropriate pharmaceuticals
for use in children. We all know that children do need special
drugs. With 2.5 million children infected with HIV/AIDS around
the world, it is essential that we have appropriate medications
to treat them.
Let me ask you, Doctor, how do you plan to ensure that HIV/
AIDS drugs, both generic and brand name, approved by the FDA
expedited process also include pediatric formulations as well
as important dosing information needed for treating the
different age groups?
Dr. Crawford. We are actually using these same authorities
that I mentioned in the drug area. As you know, the President
has made $15 billion available over a period of time for the
use of these kinds of therapies in Africa and elsewhere. We
have had to put in, with great dispatch, an FDA quick approval
process for those kinds of products that will be used in
Africa. We had many countries willing to enter that market once
the amount of funding was made available. However, we have
insisted that they be FDA approved, and the fact that they go
through an abbreviated approval process also means that the
Best Pharmaceuticals for Children Act and so forth will be
applicable. So we will try to use that mechanism to make sure
it works.
Senator DeWine. Doctor, you are looking at the--you have
been looking at the issue of salt in what is called healthy
food products. When could we expect those guidelines, or what
are you doing in that area?
Dr. Crawford. Essentially, what has happened there is that
we gave the industry, that is the food industry, a grace period
of 6 years to try to reformulate the products that they would
be drastically reducing the salt content of so that they would
be palatable and also that they would be at the same nutrition
level.
The industry has had a hard time doing that, and yet we
have some notable brands that have materially reduced the salt.
We think that is good for public health. We don't want to in
any sense invalidate those procedures, what they have done, and
the progress that has been made, so we are considering now the
finalization of a regulation which will enable them to label
correctly and also to proceed with those efforts.
That will be done sometime this summer, but there has been
some concern that we might take action against companies in the
salt area. I assure you that we are working with them. If there
is too much salt, we will also be working with them. But those
that are genuinely trying to reduce the salt and maintain the
nutrition level, we will have a place for them.
Senator DeWine. But something will happen this summer?
Dr. Crawford. Yes.
Senator DeWine. Thank you, Mr. Chairman.
The Chairman. Thank you. Senator Murray.
Senator Murray. Thank you, Mr. Chairman, and first, let me
commend Senator DeWine for his work on pediatric labeling. I
share his concern and agree with him that we need to really
make sure we are moving forward on that.
Dr. Crawford, thank you for coming before this committee at
a very troubling time for FDA, where across this country, we
are seeing allegations of safety lapses, of political
interference, conflict of interest. It is extremely important
that FDA's reputation remain sterling and that the public can
count on FDA to give us the best scientific information and
approve drugs and let consumers make decisions for themselves,
and we have heard that on this committee many times as we have
had discussions about safety over the last several weeks, on
the COX-2 drugs, for example, that patients need to know about
the drug, but they need to have the right to make decisions
about it themselves.
So within that context, I just want to follow up on a
comment that was made earlier on this committee on RU-486. RU-
486 is not about ending life, it is about protecting women's
health, and, in fact, FDA has approved this drug as safe and
effective, is that not correct?
Dr. Crawford. That is correct.
Senator Murray. Thank you. I just want that for the record.
Now, on the emergency contraceptives, Plan B and emergency
contraceptives, I heard you say that this is unusual. You have
a panel that has recommended 24 to 3 to approve this. I know
you said a court filing has been made, but what is unusual? Are
there other times that it's 24 to 3 and it is not approved?
Dr. Crawford. Yes. There have been times when we have
overturned the Advisory Committee. I think it is important for
me to state that we have a decision pending with respect to the
product you asked about and we are moving forward. What is
unusual is the kind of application that the company has filed
with us----
Senator Murray. In what way?
Dr. Crawford. I can't--I am really not supposed to discuss
what they have filed, but it is complex and it has never been
done before, so it is taking us a little longer. I am not
saying we are going to deny it, but we are moving toward a
decision. But it is a unique application.
Senator Murray. You may or may not know, but Washington
State is one of the four States that currently have an over-
the-counter agreement on emergency contraceptives. It is based
on good science. It is based on good public health policy. It
allows consumers to make their own decisions. And I, frankly,
think that is part of what we need to do to make sure that FDA
is something that all of us have confidence in, that it is not
political decisions, it is based on good health, good public
health, and good science.
So I just want to ask you, you said that a decision is
coming, a decision is coming. Will this committee know by the
time we vote on your confirmation--I believe it is April 13--
either what that decision is or an exact time line of when that
decision will be made?
Dr. Crawford. I can't commit to that.
Senator Murray. Well, I find that troubling because this is
an issue that is extremely important. I think many of us on
this committee care deeply that FDA make decisions based on
good science, good public health policy, and that troubles me
greatly that we won't have that answer.
Senator Mikulski. Would the gentlelady yield? Perhaps, I
wonder if Dr. Crawford could share--he can't say this at a
hearing. Could he say this at a briefing, perhaps with you and
I and Senator Clinton and the leadership of the committee?
Dr. Crawford. Yes. I would be happy to meet with you.
Senator Murray. Then I would request that we have that time
and that briefing before this committee votes on this
nomination, if I could ask the chairman for his approval of
that.
The Chairman. We will work on that.
Senator Murray. OK, and I think there are a number of us
who would like to----
The Chairman. We will work on having that happen. We have a
little bit of time to----
Senator Murray. I appreciate that.
The Chairman. We have a number of people to get together. I
hope we are not counting on all of them being there all at the
same time, if that is what presents the difficulty.
Senator Murray. I think we are asking for a specific
briefing from Dr. Crawford before this committee votes on his
nomination to give us the reason why he believes that the
request on the Plan B emergency contraceptives is unusual.
Senator Mikulski. And the relevant people will be Senator
Clinton, you and I, the leadership of the committee if it
wishes to participate, and, of course, your staff being
present, Senator.
The Chairman. Certainly. The point that I am making,
though, is that if we have to coordinate all of those people to
be at the same place at the same time----
Senator Mikulski. We will be there.
Senator Murray. We will be there.
The Chairman. [continuing]. As opposed to setting up a
time----
Senator Murray. You tell us the time.
The Chairman. OK.
Senator Murray. All right. We will work on that with you. I
have other questions I will submit for the record, and I thank
the chairman.
The Chairman. Thank you. Senator Hatch.
Senator Hatch. Dr. Crawford, welcome to the committee.
Congratulations on this nomination. I have been around here a
long time and watched all kinds of FDA Commissioners come
through. I have to say, you are as qualified as anybody who has
ever been nominated for this position. I know that you have
done an excellent job during the time that you have been there
as Acting Commissioner, but also in other capacities, as well.
So I am grateful for your willingness to serve and expect you
to be a great Chairman.
I look forward to working with you on a wide variety of
issues, including drug safety, Hatch-Waxman reform, DSHEA, the
White Oak facility, which, of course, I take a great interest
in, as you know, and so many other issues. And I agree with
those who have spoken for you and have mentioned your
integrity, your capacity, the background, the education, and
all the things that you have that would add, I think, a great
deal to this position.
Let me just ask you this. Would you please take just a few
minutes to talk about your plan to ensure the safety of our
food supply against bioterrorist threats?
Dr. Crawford. Thank you, Senator. We were blessed when I
came on board in 2002 with the fact that the Bioterrorism Act,
which I know you and other members worked on, was about to be
passed. The President signed it into law in June of that year
and we immediately went to the four regulations that
implemented that law. They are now, I am happy to report, are
all in place.
For the first time in its history, FDA has a thoroughly
effective legislative authority to protect the food supply. We
deployed a number of our inspectors in specific areas. At the
time of the passage of the law, we were only at 35 ports of
entry. We are now at basically half of them, which is well over
100. We are also able to order companies to tell us when they
are having food come into the United States. We are also able
to debar them, to prevent them from entering. We can condemn
the food. We have a very strong food safety net both
domestically and internally.
I think the proof of the pie is in the pudding. We have
been able to prevent these kinds of attacks and we also are
doing a better job at essential food safety, because each time
there is a major outbreak of any kind, we ask ourselves first,
could this be a terrorist attack, and because of that, our
people are in tune with looking very much more carefully at
food safety events than they were in the past.
So I think the system is working very well and a lot of it
has to do with that law.
Senator Hatch. Thank you so much. I would like to talk a
little bit about your broad view of drug safety and basically
how we should approach this issue so that consumers are better
informed. Senator Kennedy referred to serious lapses on the
FDA's part and specifically mentioned Vioxx, as you know. Dr.
Crawford, how many serious lapses do you believe have taken
place at the FDA on drug safety review and how do you feel
about the creation of an independent Board on Drug Safety? Is
that really a good solution?
Our HELP Committee hearings on drug safety heard from a lot
of people who did not think that an independent board was a
very good solution or approach. Instead, they supported keeping
the drug safety review within the FDA so that those overseeing
drug safety could directly communicate with those who reviewed
the drug application. I would just like to have your thoughts
on these areas.
Dr. Crawford. Well, the Drug Safety Board will be within
FDA. There was some interest in having it placed outside the
agency. That is not something we are considering. We want to
take advantage of the critical mass of personnel in the
scientific and medical areas that we have in FDA when these
problems come up. So the Drug Safety Board will be appointed by
the Commissioner and will report within FDA. So I think that is
the way to do it.
The other thing that we have to do in concert with that is
be more open, to inform the public what we have under
consideration, and also to have a better system of
communicating with physicians.
Senator Hatch. Thank you. My time is just about up. Let me
just ask one last question, but it is a very important one. As
you know, I take a great interest, as does Senator Mikulski and
others on this committee, in the White Oak facility that is
being built pursuant to the bill that I passed a long time ago
on this committee, the FDA Revitalization Act. I am watching
its progress closely. Could you provide us with a progress
report on the work done to date, your projected time table for
the future, and the cost estimates of the remaining work? Is
the necessary funding to complete work at White Oak
contemplated in the President's budget?
Dr. Crawford. Yes. We are now about halfway through at
White Oak and we want to thank you, Senator Mikulski, and
others for the FDA Revitalization Act. That was the stimulus
that got us where we are today. FDA is in 55 different
buildings in the Washington area. It is very difficult to
manage the agency like it is. Once White Oak is open, which
will be 2010, it will be a far more effective and efficient
FDA.
We have about half of the funding that we need. We need
just under a billion dollars total. We have already had
committed by the Congress between--slightly over $500 million,
and we do ask for the recommended amount in this upcoming
budget. We haven't had the budget hearings yet, but we have
made public the President's budget for 2006 and we do include
the increment that we need to stay on course for occupying the
building fully in 2010.
Senator Hatch. Thank you so much. I appreciate it, Mr.
Chairman.
The Chairman. Thank you. Senator Jeffords.
Senator Jeffords. Before I go on to my questions, Dr.
Crawford, I want to say that I share the same concerns as
Senators Kennedy, Murray, and Clinton about the FDA's handling
of Plan B.
Dr. Crawford, there have been concerns raised that having
both the Office of Drug Safety and the Office of New Drugs in
the same component of the FDA creates conflicts. What are your
thoughts on taking ODS out of CDER and putting it elsewhere
within the FDA?
Dr. Crawford. Well, that is one of the suggestions that has
been made. The Office of Drug Safety, we have over the past,
actually, about 5 years, we have doubled the number of people
and also doubled its budget and made it a separate unit. It
does report to the same director as the people that are in the
pre-approval process and we are still looking into that.
But the Drug Safety Board that I mentioned that will
oversee all this will not include people that are primary
reviewers, that is, those people that evaluate the drugs before
they come on the market. We have heard it said, and we believe
it could be true, that they may have an affinity with a drug
that probably doesn't look good, at the very minimum, so we are
going to make that separation of personnel. But we have not
decided to move it outside of FDA, change its location, at the
present time.
Senator Jeffords. Would you give us some ideas of the
things that you would do to increase the FDA's commitment to
drug safety?
Dr. Crawford. Yes. I think we need to continue to build up
the Office of Drug Safety. Ten years ago, it had very few
personnel and virtually no funding. It now is--I would call it
fully funded, and we are adding more funds this year in the
President's budget, also more personnel--in fact, an
appreciable increase in personnel if the budget is accepted. I
think the strength of the Office of Drug Safety is very
important and they need to be carefully monitored by me and the
other leadership in FDA to make sure that they are truly
experts in drug epidemiology, in other words, figuring out the
early signals that would make us either bring about a labeling
change or in some cases suspend marketing or take the drug off
the market. They need to have that mentality and they also need
to have the tools to do it. So that is what we are committed to
doing.
Senator Jeffords. Relative to PDUFA, in the past, the
Congress has authorized the FDA to accept user fees to augment
its ability to review drug and medical device products. Some
have urged that a portion of these fees should be directed
toward ensuring the safety of these products. Thus far, the
Congress has agreed with the industry's position that
postmarket product safety review is the responsibility of the
government and should be paid for through general revenues.
Dr. Crawford. That is correct. That has been what the
situation is now. I understand that there are people that think
that some of these funds should come out of PDUFA, and as you
know, we are reauthorizing that particular law--hopefully we
are reauthorizing it in a year and a half, I think it is. So I
suspect that will be under consideration.
Senator Jeffords. I would like to hear your thoughts on how
you plan to provide funding for postmarket product safety.
Failing the availability of appropriations, would some portion
of user fees be a reasonable source of funding?
Dr. Crawford. Right now, the law as constructed doesn't
really provide for that. However, we have always generally been
able to redirect funds, with the permission of the appropriate
Appropriations Committees on Capitol Hill, to take care of
these kinds of exigencies, and we will continue to--we will
keep it funded. The funding profile of the Office of Drug
Safety has been steadily improving.
Senator Jeffords. Dr. Crawford, clinical trials are an
important part of the drug approval and use process.
Information that comes out of clinical trials continues to be a
vital concern to doctors, patients, manufacturers, and
regulators. To that end, it seems like a good idea to expand
the amount of information about trials that is available. What
is the response to the idea of creating a mandatory clinical
trials registry?
Dr. Crawford. We have been working with the National
Institutes of Health and other entities both in the government
and outside to consider that. We have heard the unalloyed
message from the public that they want to know about those
clinical trials. They want to be able to read about them, air
them if possible, and they think there ought to be a common
source. So that is a charge to keep that we have and we will
move forward with that as best we can.
It may take some funding, but I think that funding would
probably come through NIH and not FDA because they maintain the
database. Nonetheless, I think it is a good idea and it is one
we are pursuing.
Senator Jeffords. Dr. Crawford, you will likely be the
third Commissioner of the FDA since the Congress first passed
legislation allowing for the reimportation of prescription
drugs. The FDA helped draft that bill almost 6 years ago, but
since then, the agency has opposed any efforts to allow
reimportation. I would like you to tell me that you are ready
to change that situation.
Dr. Crawford. Well, that has a history, as you know, within
FDA. When the Prescription Drug Marketing Act of 1987 was
passed, it basically made reimportation illegal. But then after
that, you are absolutely correct, another bill was passed which
called on first Secretary Shalala and then Secretary Thompson
to affirm that this process would be safe. Neither of them were
able to affirm that it would be safe, so as Acting
Commissioner, I was guided by the determination that these
products were not safe.
Our concern is safety. FDA has been into the cost debate.
That is not something that we have authority over. As far as
the drugs being safe, that worries me a lot. We have to be very
concerned about it. I am not trying to stonewall the situation,
but we are not at this time able to tell you that the
government is changing its position.
Senator Jeffords. Well, are you willing to work with us?
Dr. Crawford. I am certainly willing to work with you, and
as a matter of fact, as we have gone around prior to this
hearing, a number of Senators have said that they have bills
pending or they are thinking about it and we offered FDA's
expertise in evaluating that in terms of safety and those
responsibilities that we have. So yes, we are open to that.
Senator Jeffords. Thank you, Mr. Chairman.
The Chairman. Thank you. Senator Isakson.
Senator Isakson. Thank you, Mr. Chairman. First of all, Mr.
Chairman, I would like the record to reflect that Dr. Crawford
has his Ph.D. in Pharmacology from the University of Georgia,
and further, serves as the head of the Department of Physiology
and Pharmacology, which in and of itself should certify his
complete competence to serve in this capacity. [Laughter.]
I say that as a Senator from Georgia who is very proud of
your nomination.
Dr. Crawford. Thank you, sir.
Senator Isakson. Following up a little bit on some of the
questions, the Office of Drug Safety is a postapproval office,
is that correct?
Dr. Crawford. That is correct.
Senator Isakson. And it collects data from drugs that have
been approved from various sources to determine whether there
is a safety problem.
Dr. Crawford. That is right.
Senator Isakson. How do you collect that data?
Dr. Crawford. What we do is there are about three major
sources. There are databases. For example, the Veterans'
Administration has a very complex and very useful database
where they keep records on adverse reactions and so forth. So
do some of the HMOs, Kaiser Permanente, the National Institutes
of Health, and we tap into those databases.
The second thing is that there are scientific reports that
appear in the scientific literature around the world. We comb
through that.
And then we receive adverse event reports each and every
day of the year and we compile all of that.
So those are the three main sources of information, and
then once we get one of those signals that something may be
wrong, it is up to the Office of Drug Safety to evaluate
whether it is a false alarm or the real thing.
Senator Isakson. Is that collection system
institutionalized within the agency or does someone just have
the responsibility of going to these three sources and asking
if they have information?
Dr. Crawford. No, it is institutionalized in the agency.
There is an Office of Drug Safety. I would say that prior to 10
years ago, prior to 1995, it was not institutionalized, but it
was at that point, and gradually over the years the funding and
the number of people in that office have improved both in terms
of what they do and what their expertise is, and we are asking
this year in the President's budget for more personnel. I think
this is the biggest increase we have asked for. We are also
asking for more funding for the office. I am taking a personal
interest in it, as is the rest of FDA's leadership.
Senator Isakson. Is any of that collection electronic?
Dr. Crawford. Not as much of it as it should be. What we
are working with--I met with the Secretary of Veterans' Affairs
just recently and what we are hoping to do is get online with
their medical databases. We also want to do that with NIH. And
I think we are very close. But right now, it is a little bit of
both.
Senator Isakson. The reason I asked the question is that
life experiences are the best teachers. My sister's life was
saved through a field trial where she was a volunteer and she
had a very serious, complex case of cancer. And so I am fully
an advocate of getting drugs to the marketplace and
technologies as expeditiously as possible for the benefit of
those who suffer from terribly crippling diseases or other
effects.
I am equally committed to ensuring that we have good
safety, and it seems to me like two things. One, drug safety
ought to remain within the agency. If you get into sending it
outside, that doesn't seem to make any sense at all except to
maybe be symbolic of something that I don't think needs to be
symbolized.
But second, it would appear to me that the timely
collection from all sources of adverse effects or some
commonality of reoccurrences of those on different drugs or
taking different treatments postapproval would serve to be a
great second certification of what a field trial in itself does
from the beginning.
And I guess my comment is--I am not really asking you a
question, but after the two hearings I have attended on this
and conversations I have had and my personal experience, it
would seem like to me if the Department--and it may be doing
this--could initiate or institutionalize electronic collection
from all sources--Veterans' Administration is a great source
and you have great reliability in the information, but once you
go beyond that, like Kaiser Permanente or an HMO or maybe this
drug program or that drug program, it seems to me like it is
probably as comprehensive as you can get given what you have
but not as comprehensive as we probably ought to have.
And so I would hope you all would look toward initiating
whatever you can to expedite the collection of all that data
from its various sources, and I think then the post safety
process will be that much better and certainly that much more
timely. Spoken as one who has no degree in any chemistry or
pharmacology, but just based on what I have heard.
The Chairman. Thank you. Senator Mikulski?
Senator Mikulski. Thank you very much, Mr. Chairman, and
good morning to you, Dr. Crawford.
First, I want to associate myself with Senators Clinton and
Murray on the issues raised by Plan B and look forward to a
briefing with you and discussing it in an appropriate forum,
recognizing your legal and regulatory constraints.
I am really proud that FDA is a Maryland agency. Nine
thousand people work there, and what a great cornucopia, to
have NIH down Route 270 and you up there in FDA, and hopefully
with the move to White Oak, then to have these surrounded by
the great academic centers that do research, like Hopkins and
Maryland and Georgetown. So we are really very, very, very
proud of it.
And we worked on a nonpartisan basis here on FDA reform.
Some of the greatest advocates for making sure that the
employees who work so hard and are so diligent have the best
facilities, the move to White Oak has been jointly with myself,
Senator Hatch, and Senator Frist. So you see where we are.
Looking at where we are, though, with FDA, there is a
crisis of confidence over drug safety in the public's mind and
even with some clinicians. Looking at page three of your
testimony, you talk about transformation, which I think we
would want to support, but I was puzzled why the number one
issue wouldn't be to restore in the public's mind the integrity
of FDA. So I am going to come back to that and ask for your
elaboration about the drug safety issue so that patients,
doctors who don't want to get their advice from a drug
salesperson need to know FDA is there.
You talked about this independent agency, a separate group.
Would you give us your views on whether or not, in all candor,
you think that within the agency itself, no matter how
diligent, there can be that independent review, because it is
not a change of buildings. Your own staff, Dr. Graham, has
recommended an independent agency, a watchdog agency separate
from FDA and almost a devil's advocate approach to watching
this to ensure ongoing safety.
Could you share with us, do you think that FDA can truly be
a watchdog of itself, recognizing the professionalism of the
people who work there, but do you think we need not a watchdog
system in a different building or a different block on an
organizational chart, but a truly independent agency with its
own staff and no ties to the industry?
Dr. Crawford. Well, thank you for the question. It is up, I
think, to me to make sure that they act independently, that
they are not intimidated, that the conclusions of the Office of
Drug Safety are given the kind of emphasis that they should be.
FDA, as you mentioned, is a large organization, about 10,000
people all told, so I think it is possible, and I think it is
being done, to have the Office of Drug Safety serve in a place
in the organizational chart and also physically so that they
are not subsumed by the primary drug reviewers and the other
parts of the Center for Drugs.
I believe they are operating independently. I believe we
need to do more work, though, on what you referred to earlier,
which essentially is the culture of FDA. I think that decision
making is not understood by the public. I think it is
basically, like most scientific--when scientists get together,
they sort of shout each other down. We need to have it very
different, because we are talking about something other than
scientific debate. We are talking about the safety of the drugs
that are on the market, and so we need to work on making that
transparent. The National Academy of Sciences Institute of
Medicine is advising us on how to make that sea change in how
we do business.
Senator Mikulski. Doctor, I am going to ask you to walk me
through it. First of all, the public wants two things. No. 1,
they want those dazzling cures available as quickly as we can,
that our colleague, Senator Isakson's, sister would be able to
be cured of cancer, but anyone else facing it--my dear father
with Alzheimer's, though he has since passed away, my mother,
who had a chronic condition like diabetes, to be able to find
either a cure or even more drugs to help people not develop all
the complications of it. So the public wants it and so do the
clinicians and the practitioners, and we want them in America.
The other, though, is they want to be safe when they take
it. So there is the dual pressure. It is a dual pressure, and
FDA has served us well. That is why they are the gold standard.
Emerging democracies that could never afford to have an FDA
look to us.
So, again, how mechanically would that be? Are you going to
have a separate office? Is it going to have a separate staff?
Who is that person responsible to? How will they be held
accountable, and yet then not get entwined with the other
administrative or bureaucratic assets? How do you envision
that?
Dr. Crawford. Well, the Office of Drug Safety, as it is
being changed, will be a separate entity entirely with its own
director. We are about ready to announce the appointment of the
director----
Senator Mikulski. Is that person--will that person only be
responsible to you?
Dr. Crawford. The person will be responsible to me, but
through the Center Director for Drugs. So he will go through
that person to me.
Senator Mikulski. Can I ask you why? First of all, I know
that you are busy. I mean, an FDA Commissioner's job is really,
between food safety and drug safety, it is really three jobs.
But why not to you directly, because doesn't that again give
them one more layer of bureaucracy, one more justification when
we want intellectual rigor, scientific scrutiny, transparency?
Dr. Crawford. Well, I think it is up to me to make sure
that I am intimately involved in what they do. If the person
reported to me, which is always something that we can consider
and we are open to, I would essentially have to be the person
who did their job evaluations, take care of their budget
amendments----
Senator Mikulski. But that is the crux of it.
Dr. Crawford. Yes, I know.
Senator Mikulski. That is the crux of it.
Dr. Crawford. Well, I am not closed to that----
Senator Mikulski. Who is going to evaluate it--the chicken,
the egg, do you see?
Dr. Crawford. Mm-hmm.
Senator Mikulski. That is the point. I am not saying, let
us create a whole new independent agency. Senator, I know my
time is up, but that is the crux of it. Who evaluates them? Who
decides whether they get the promotion? Who decides whether
they keep the job?
Dr. Crawford, I know you are a professional person. You
stood in twice now as acting. We need a permanent Commissioner
of FDA. We are proud of FDA. And I am not saying that person in
between you and the drugs, the watchdog department, would not
be faithful as you intend to be. But I am telling you, I really
strongly recommend that if it is going to be independent, it
has got to be independent of the entire bureaucracy,
responsible to the Commissioner to whom we then hold
responsible.
Dr. Crawford. Maybe we could talk further about that.
Senator Mikulski. Thank you very much.
Mr. Chairman, you have been very indulgent. I appreciate
it.
The Chairman. Thank you. Senator Harkin.
Senator Harkin. Thank you very much, Mr. Chairman, and
welcome, Dr. Crawford. I would ask that my statement be made a
part of the record, Mr. Chairman.
The Chairman. Without objection.
[The prepared statement of Senator Harkin follows:]
Prepared Statement of Senator Harkin
Thank you, Mr. Chairman. And I also thank Dr. Crawford for
appearing before us today. Dr. Crawford and I have a long,
positive history of working together on issues at the Food and
Drug Administration. And I am pleased to see him here.
I'd like to take this opportunity to bring up two issues.
First, as you know, Dr. Crawford, Congress passed the
Dietary Supplement Health and Education Act (DSHEA) to ensure
the availability and safety of dietary supplements that
millions of Americans rely on. Under the leadership of Dr.
McClellan as Commissioner and you as Acting Commissioner, the
FDA has made significant progress in implementing and enforcing
DSHEA. I look forward to continuing to work with FDA to fully
implement DSHEA, and to make sure that U.S. consumers have
access to safe, effective, and affordable dietary supplements.
Second, as you know, Dr. Crawford, our Nation is
confronting a major obesity epidemic, among both adults and
children. While obesity is a complex condidtion with many
contributing factors, that fact is that we need a comprehensive
approach to combating it--with an active role by government,
parents, communities, and also the food and restaurant
industries. Last year HHS/FDA released a report titled,
``Counting Calories: Report of the Working Group on Obesity.''
It notes that food consumed away from home--mostly food from
restaurants--has increased dramatically over the last 3
decades. In 1970, this accounted for 33 percent of the average
consumer's food budget. By 2002, it accounted for 47 percent.
But while people are eating out more and more, they have little
or no information available to make informed food choices in
restaurants. I am sponsoring legislation, the Healthy
Lifestyles and Prevention Act, which would require mandatory
nutritional labeling on menues and menu boards in chain
resyaurants.
I have questions on both these issues, and several
additional questions for the record.
Senator Harkin. First of all, Dr. Crawford, I would like to
commend you on your work as Acting Commissioner in an area in
which I have a great deal of interest and have since I was one
of the authors of the Dietary Health and Supplement Education
Act, but your work on vitamins, minerals, and dietary
supplements. The FDA has made significant strides in the past
couple of years in implementing and enforcing what is known as
DSHEA and I look forward to working with you to ensure that we
continue to make this progress.
Some people have been critical of DSHEA, saying that it
does not give FDA the tools it needs to ensure the safety of
dietary supplements. Do you believe that the Dietary Supplement
and Health Education Act gives the FDA sufficient authority to
regulate dietary supplements, vitamins, and minerals?
Dr. Crawford. Yes. We need to go ahead and make solid
this--the GMP part of it. It has not been finalized, and I know
that is your next question. Until we do that, it is not really
possible to thoroughly answer that question, but it is my
belief that once we get that done, we will have the authority
we need.
Senator Harkin. Let me ask a follow-up on that question,
then. Do you believe that the Dietary Health and Supplement
Education Act gives the FDA the authority to remove harmful
items from the shelves?
Dr. Crawford. Yes. As you know, we have done that with
ephedra and also with andro and some other products, and so
obviously we do have the authority.
Senator Harkin. So looking back to the first question,
then, you said that as soon as the GMPs, the Good Manufacturing
Practices, are promulgated, you will have sufficient authority
then. Your predecessors have answered that question by saying
that they thought they had sufficient authority. But then
again, we have waited 10 years--10 years, the FDA has drug its
feet on getting the Good Manufacturing Practices out. Can you
inform the committee, or provide us with a more definitive date
as to when the final Good Manufacturing Practices regulations
will be published in the Federal Register?
Dr. Crawford. I hope to be able to do that within--to tell
you the exact date within a few days. I cannot at this point,
but if I can follow up in writing, I will do what I can do.
Senator Harkin. I would appreciate it, because your
predecessors going back to 1995, when the law was passed, and I
have sat here and asked every one of them, they have said, oh,
yes, we are going to get the GMPs out. Then they get confirmed
and that is the end of it. And so I really want to try to pin
you down as much as I can.
Dr. Crawford. Well, you can pin me down and I will agree
that 10 years is too long to wait for it.
Senator Harkin. Right.
Dr. Crawford. So I am on track to try to get it out as
quickly as I can.
Senator Harkin. I appreciate that. And you will let us
know----
Dr. Crawford. Absolutely.
Senator Harkin. [continuing]. Sometime, when, the next
couple of months? Sixty days?
Dr. Crawford. I can't really say, but it is sooner rather
than later, for sure. You have heard that before, too, Senator,
and I really can't answer that. I just don't have a publication
date.
Senator Harkin. Before the end of the year?
Dr. Crawford. Yes.
Senator Harkin. Thank you. That is great. I finally got it
before the end of the year. [Laughter.]
My second question, Dr. Crawford, last year, the FDA
released a report on obesity, and I certainly again appreciate
your work on this issue. You have been in the forefront on
this. But I am concerned by the fact that many of the
recommendations that pertain to the food industry, especially
restaurant foods, are voluntary rather than mandatory. The FDA
report notes that food consumed away from home, mostly from
restaurants, increased significantly from 33 percent of
consumers' food budget in 1970 to 47 percent in 2002. Over the
same period, total calories consumed from food purchased
outside the home increased from 18 percent to 32 percent. So we
know that consumers eat more when they are out and they are
less aware of nutritional information.
The report that came out of FDA had specific
recommendations for the industry, and specifically, the FDA
urged the restaurant industry to launch, quote, ``a nationwide
voluntary and point-of-sale nutrition information campaign for
customers,'' end quote. Can you tell me about the progress the
restaurant industry has made toward that recommendation?
Dr. Crawford. Yes. I think certain segments, and like fast
food corporations and also chain restaurants that have an
identifiable name, have made progress with it. When we unveiled
the Obesity Working Group Report, which was called ``Calories
Count,'' you recall that Secretary Thompson did say that we
were going to try the voluntary approach for a while. If it
didn't work, we were going to have to do something else.
So I think some progress has been made. It has been uneven.
Not every chain restaurant you go into and not every fast food
restaurant has the material available, and it is voluntary. As
you remember, the NLEA was silent on that subject, so we don't
have the authority to require it. I have been encouraged by
comments from restaurants, though, that seem to think that it
is working and that it is good for them.
Senator Harkin. Of course, as you know, NLEA was mandatory,
and I don't know that we want to go back and say that all of
the information that shoppers, now they go into a food store
and you look at all the nutritional--and by the way, the FDA is
doing some good work there in standardizing that, too, so that
is good. But we know that consumers are using those labels now
and they are reading them. But they don't have that kind of
information when they go to a restaurant. And now that we know
there is an obesity epidemic--there was just a new study that
was just published today again.
And if you have voluntary guidelines, I am all for
voluntary if they will do it. But then that leads to one chain
having one sort of set of guidelines and another one having
another set of guidelines and who do you know? At least with
NLEA, we have got some basic standards by which you can measure
different items in packages or cans or bottles and stuff like
that. But how do you know when you go in a restaurant? You
really don't.
So voluntary is fine, but it seems to me the FDA really has
got to step in here and design an information system that will
be helpful to consumers when they go out to eat.
Dr. Crawford. You mean try to standardize it? Yes, I think
you are right.
Senator Harkin. Something like that so that it is across
the board so they know what they are getting, something like
that. I don't know how much longer we are going to go with the
voluntary. Again, a few of the chains have done a pretty darn
good job, but then the others haven't, so what do you wind up
with here? There is kind of a mishmash of stuff out there.
And again, because of the obesity epidemic, because of the
onset of diabetes earlier and earlier, we just may have to have
the FDA come up with standardization guidelines and with some
mandatory provisions for these restaurants to all at least put
it out there in understandable form for people to read and
understand.
Thank you very much, Dr. Crawford.
The Chairman. Thank you. Senator Dodd.
Senator Dodd. Thank you very much, Mr. Chairman, and Dr.
Crawford, welcome to the committee. I appreciate your
willingness to take on this job.
Let me, before our colleague from Iowa leaves, on his last
point of questioning, the obesity issue, I think the papers
this morning indicate that we may be looking at the first
generation of Americans who will live shorter lifespans than
their parents because of this issue, and I think too often in
the past, it has been sort of ridiculed a bit.
I know when Senator Frist and I, along with Jeff Bingaman,
introduced legislation a year or so ago dealing with improved
nutrition and physical activity, really sort of a harmless
piece of legislation that passed the Senate, we weren't able to
get it out of the House, there was some sense of sort of
ridiculing, here is the Federal Government sort of telling
people whether they can go to fast food restaurants or not,
which is obviously not the case of what we were trying to do.
But I would hope the FDA would take this issue seriously.
Too often, I think there is a negative association with this
issue. There have been a lot of studies and a lot of news
reports and so forth indicating the seriousness of this issue,
and particularly when you consider some of these food producing
companies that are getting exclusive rights in schools by
offering poor schools significant money if they can put their
vending machines in those schools for use during the day. It is
dangerous and it is a serious problem. It really deserves
someone like yourself to really champion this issue and make
something of it, so I would hope you would do that. Senator
Harkin raised a very good point.
Second, I just want to raise--I know Mike DeWine was here
earlier, but he and I have worked a long time on the pediatric
testing issues, as you know, and the Better and Best
Pharmaceutical Acts for Children, which were adopted a number
of years ago. I just want to, again, I want to comment quickly
and go ahead, but we would like you to continue to work on
expanding pediatric testing. The SSRI issue certainly
highlights the importance, and I know there were tests done on
those--many of them were inconclusive with younger children and
adolescents particularly. But pediatric testing is something
that is very, very important, and I presume you agree with
that, as well.
Dr. Crawford. I do agree completely.
Senator Dodd. And we will talk about expanding the
opportunities for pediatric testing.
Dr. Crawford. We are, and we are going to make sure that
both on the exclusive side, where there is a patent, and off-
patent that we get the same kind of penetration with those
firms as they move forward with labeling.
Senator Dodd. Let me come back, I know Senator Mikulski,
and she had to leave, and I believe Senator Kennedy, certainly
Senator Jeffords in the time I was sitting here, talked about
the Office of Drug Safety issue. I am going to be a little bit
repetitive here, but I think it is an important issue, and
maybe because I am going back over some of this ground again
you get some sense of the importance of this issue.
Senator Grassley and I are planning to introduce as I think
you are aware--you and I talked on the phone about this----
Dr. Crawford. We did, yes.
Senator Dodd. Legislation to create an independent office
within FDA to deal with this issue, and you have expressed your
views on this a bit already, but I want to continue to make the
point to you here.
Let me, as a backdrop, underscore the point that I am sure
all of my colleagues have made here. There is nothing like,
when you travel around the world and you go out to buy a
product someplace in a store in some foreign country and you
see on the shelves, ``product approved by the FDA.'' It is the
gold standard, still all over the world. That Good Housekeeping
Seal of Approval, that this is a product approved by the Food
and Drug Administration of the United States, is incredibly
important. And obviously, the issues of Vioxx and the SSRI
issues and so forth have raised some serious questions.
So as a backdrop to all of this, and I know you feel this
way, as well, but I think it is important to be stated here. We
really need to make sure that the reputation of this incredible
agency that has done so much to put products in the marketplace
that have changed people's lives, extended lives, the quality
of lives, as well as protecting people from adverse effects of
those products that either are approved or those that shouldn't
be approved. So there is a tremendously important critical
moment we are at here and I am worried that if we don't get
this right in the next couple of years, we could see this gold
standard be diminished, and then I think we all suffer terribly
as a result of that.
So this Office of Drug Safety idea, the idea of making it
more independent so that you don't have to go through a 2-year
period with Vioxx where literally tens of thousands of people
have lost their lives--and I don't blame the FDA for this, but
the ability to have someone that can say, outside of the group
that has approved the product in the first instance, to make
the decision to take it off the shelf, we think is very, very
important.
I wonder if you would share just sort of your general
thoughts about this. Is there a sense, and let me just give you
an opportunity, I presume there is, but a sense of this FDA
standard approval being tarnished a bit by all of this, and
what steps do you envision, maybe going a little bit further,
to make the point that we are not going to allow this to
happen, particularly on your watch?
Dr. Crawford. We are not going to allow it to happen. I
don't think we have been tarnished. Checking with our
international colleagues and also checking with various polls
that are done, it looks like the American people have full
confidence in the FDA.
I don't want to see it happen, though, and you are
absolutely correct. That specter has been raised over the past
few months and I pledge to you that I will do everything in my
power to stem the tide by doing the right thing and I look
forward to working with you, Senator Grassley, and whoever else
has some legislation in this regard.
I am open to solutions. I don't want on my watch FDA to be
tarnished in any sense. I want us to move forward strongly and
better than ever. We have some special challenges with the 500
percent increase in food trade and now a great increase in drug
trade that is occurring. However, an independent Office of Drug
Safety is something I am certainly open to discuss and I look
forward to spending time with you on that.
Senator Dodd. Obviously, we are talking to people, and
Senator Enzi and Senator Kennedy and others are interested, as
well, on the subject matter.
There was an internal study, as you know, conducted by the
Health and Human Services Office of the Inspector General in
2002--I know you are aware of this--that revealed that
approximately one-fifth of drug reviewers had been pressured to
approve a drug despite concerns about safety, efficacy, or
quality. In addition, more than one-third said, and I am
quoting, ``they were not at all or only somewhat confident that
initial decisions of the Center for Drug Evaluation and
Research adequately assessed the safety.''
That seems to have been the case with Dr. Mosholder, if I
am pronouncing his name correctly, when he had data to suggest
that certain anti-depressants might increase the risk of
suicide in children and adolescents. And as with Dr. David
Graham when he had data to suggest that Vioxx was connected
with cardiovascular problems.
I wonder if you might just, whether or not you would agree
that mistakes were made in the handling of both of these two
cases or not.
Dr. Crawford. Well, I came on board when that report came
out that you mentioned from the Office of the Inspector General
and it was my responsibility to try to make sure that that part
was fixed and remedied, and what we did was we put more funding
in the Office of Drug Safety, gave them a bit more authority,
and we continue to do that.
I think that the key to it is my own personal involvement.
I mean, I have got--nothing is more important at FDA right now
than this drug safety issue and I will continue to monitor it
and we will also continue to enhance not only the number of
personnel and the resources in the Office of Drug Safety, but
the kinds of people. We need these epidemiologists that I
mentioned earlier and we are building them up. I am going to
monitor it very closely myself because if there is one thing
that we are vulnerable in right now in terms of our reputation
worldwide, that is it.
Senator Dodd. Yes, you have hit it on the head. The
transparency issue is related to this, obviously, and I would
love at some point to be able to talk with you about that.
Mr. Chairman, I appreciate this and we will look forward to
working with you on this, because obviously, doing it right is
going to be tremendously important. The point that Senator
Mikulski raised, and again, you are overburdened as it is, but
that transparency issue, that sense of competence is going to
be tremendously important, that whatever the entity is that we
create, that there is going to be a sense they can act and act
intelligently when these matters arise. So I look forward to
working with you.
I should mention, as well, Senator Grassley and I also
introduced legislation dealing with clinical trials, which I
know you have an interest in and we want to work with you on
that, as well.
Dr. Crawford. Absolutely.
Senator Dodd. Thank you, Mr. Chairman, very much. I
appreciate it very much.
The Chairman. Thank you, and since I allowed an average of
two-and-a-half extra minutes per person on this side for
questioning, is there one last quick question from either of
you?
Senator Hatch. I won't ask a question, because I know the
questioning is over for now, but I want to tell you how
strongly I support you for this position.
Dr. Crawford. Thank you, sir.
Senator Hatch. I know you will do a good job, but one last
thing: Congress has appropriated funds to support a national
inventory of high-quality cord blood units, an especially
important resource for ethnic minority patients. It is my
understanding the FDA has been collecting data on the
therapeutic use of cord blood for some time, yet it has not
issued regulations that would address the need for a set of
standards or licensing to assure that cord blood units
collected for therapeutic use are meeting the high quality
expected of a biological product.
So what I would like you to think about under your
leadership is to a way of assuring the quality and safety of
cord blood and issuing regulations as soon as you can. Cord
blood looks to me as though it may have remarkable stem cell
advantages over adult stem cells and maybe help us resolve some
of the conflicts and problems with regard to the whole
embryonic stem cell area, as well.
So I hope you will give some real thought to that. It is
important. I think it is important for you to make that a major
part of your work. I won't ask you any questions on it, but I
just wanted to ask you to really get into that, because what I
am studying and what I am reviewing shows some tremendous
promise.
Senator Dodd. Would my colleague yield on this point?
Senator Hatch. I am happy to.
Senator Dodd. I want to totally support Senator Hatch's
point on this. Being the father of a 2-week-old, with my first
child and second child, we took the cord blood. It is
complicated to do this. There are private operators that do it,
but a lot of them don't last very long.
Senator Hatch. That is right.
Senator Dodd. The ones that do, we used the one out in
Berkeley, California, which is a university-associated one, to
send the child's cord blood, to go through it so you are part
of the test, everything has to be done exactly right. I had to
have a person on the phone making sure the packaging was all
done properly.
But Senator Hatch is absolutely correct in this. There are
some tremendous opportunities, I think, with the cord blood
issue, much more so than people even thought a few years ago. I
would like to support you in every effort you make along those
lines.
Senator Hatch. Thank you, and I appreciate you jumping on
that, because----
Senator Dodd. It is a great point. Thanks.
Senator Hatch. Well, thanks. Thank you. We support you
strongly.
The Chairman. Senator Isakson.
Senator Isakson. I will be quick, Mr. Chairman, but I want
to go back to the obesity and the labeling thing. What
percentage of that flier that I get when I get a prescription
filled, the thing with the real small print, what percentage of
all that information is dictated by the FDA after the approval
of a drug?
Dr. Crawford. You mean what is on the----
Senator Isakson. Just as a guess.
Dr. Crawford. [continuing]. On the bottle itself?
Senator Isakson. Well, not just the bottle, but the inside
stuff.
Dr. Crawford. A hundred percent.
Senator Isakson. A hundred percent?
Dr. Crawford. Mm-hmm.
Senator Isakson. OK. My comment is this, and I mean this
very sincerely. I respect what Senator Harkin said about
labeling on prepared foods and about the issue of obesity, but
our first responsibility is to instill more personal
responsibility in people than self-satisfy ourselves that we
can label them into better health habits, particularly in
something like the food issue.
CDC in Atlanta is doing a marvelous job, I think, on the
obesity issue and you all are working in concert with them, but
before we succumb to making ourselves feel good that we get
into the mandatory labeling of menus as addressing the problem
of obesity, let us do more to inform people so they make good
decisions for themselves as advocates in the public sector, and
that is the only thing I wanted to say, Mr. Chairman.
The Chairman. Thank you very much.
I appreciate Dr. Crawford's testimony. Unless there is
objection, we will end the rounds of oral questions, but we
leave it open for written questions.
I would mention that in regard--there was a lot of emphasis
on an independent safety panel, a lot on the independence, and
we covered that in one of the FDA hearings that we held. There
was a lot of concern by a wide variety of panelists that if it
is really independent, people watch ads on television and there
are always some things that they ought to watch out for. And if
you are in an office where your only job is safety, those may
all sound like really bad things, and so you could end the drug
if you have total independence. There are a lot of people
relying on some of those drugs, even though they know the side
effects, even though they know that it has affected people in
their own family previously. For pain, they think that it is
essential even though they know they will have heart problems
from it.
So I am hoping there is some balance, as there always has
been in FDA, of realizing that some people actually rely on
these things even knowing the consequences. We even talked a
little bit about how that affects the clinical trials and at
what point ethically you can have people that were not in the
actual test group begin to get the medicine.
So I hope everybody will review the results of that hearing
and it will provide a little bit of a balance that I think you
covered well in your testimony, but we will have some follow-up
questions to do that.
Members of the committee may submit questions in writing.
Per an agreement between myself and Senator Kennedy, we will be
submitting our written requests to Dr. Crawford by Friday,
March 18. That is tomorrow. Members will be notified of this,
and we ask them to respectfully submit their written questions
by that same date. And then, accordingly, it is my
understanding that Dr. Crawford will answer the questions
before we return from recess.
We will schedule the briefing that was talked about this
morning so that to the degree that you can talk about an
application prior to action on the application, you can brief
us on what the status is and what the complications are.
I want to compliment the staff for, since this is St.
Patrick's Day, for using the green tablecloth--which we always
use--[Laughter.]
Thank you all very much for your participation and
attendance. The hearing is now adjourned.
[Additional material follows:]
ADDITIONAL MATERIAL
Prepared Statement of Senator Clinton
Thank you, Chairman Enzi and Senator Kennedy. And thank you
to Dr. Crawford for appearing before the HELP Committee this
morning.
I know that two of your colleagues--Dr. Sandra Kweder and
Dr. Janet Woodcock--have recently appeared before this
committee to testify about issues of drug safety, primarily in
response to the controversies surrounding Cox-2 drugs and
pediatric use of antidepressants. These drug safety
controversies occurred during your tenure as Acting
Commissioner of the FDA, and, quite frankly, I was disappointed
by your response to them. I think that the American public lost
a great deal of confidence in the ability of the agency to
ensure the safety of their medications.
As someone who has worked to give the FDA the authority to
increase the safety of drugs, particularly pediatric drugs, I
would like additional assurances that you will use such
authority to guarantee the safety and effectiveness of our drug
supply.
Today, I will be looking for assurances that you will seek
to strengthen the FDA's commitment to drug safety and increase
the use of already-existing enforcement tools like the
Pediatric Rule.
In addition to drug safety issues, I am concerned about the
way that the FDA is letting political considerations interfere
with scientific treatment decisions. During your tenure at FDA,
you denied an application to make emergency contraception (EC)
available for sale over the counter, despite the fact that the
FDA's own advisory committees and career professionals at the
agency had made such a recommendation.
The New York Times reported that several former FDA
officials said they had never seen the recommendations of both
staff and an advisory committee overruled in such a manner
prior to the rejection of this EC application. The notion that
politics might have entered into any decision about a drug
approval is deeply disturbing and alarming.
During your tenure, the Nation also experienced its third
influenza vaccine shortage since 2000, after the British
government's drug safety agency closed down a contaminated
vaccine manufacturing plant in Liverpool. While the FDA was
aware of the problems that existed at this plant prior to the
shutdown, it failed to alert the rest of the government about
the possibility of a shortage.
Dr. Crawford, the FDA is a demoralized agency. It needs a
strong leader with a clear vision of ways to restore its
reputation. Today, you have the opportunity to present us with
your ideas as to how to improve the FDA. More importantly, you
have the opportunity to demonstrate what you have learned from
the mistakes that have occurred during your tenure at the FDA,
and what actions you will take to keep such mistakes from
happening in the future. Our citizens look to the FDA to give
its good housekeeping seal of approval. They need to trust that
the Agency is looking out for their well being. I'm afraid that
the gold standard which FDA has held for so long is in
jeopardy. We need real leadership to ensure that our citizens
can have faith that decisions being made are in their best
interests. I look forward to hearing your testimony and answers
to the committee today.
Prepared Statement of Senator Jeffords
Mr. Chairman, I want to join you in welcoming Dr. Crawford
before the HELP Committee. I've had the opportunity to meet
with Dr. Crawford, and although there are some serious issues
that need to be raised about the agency's ability to meet it's
fundamental mission, I fully expect to support his nomination
and to vote in favor of his appointment as the new Commissioner
of the Food and Drug Administration.
Dr. Crawford, you may be the most important presidential
appointee whose nomination this committee will have the
opportunity to consider during this Congress. The members of
this committee know well of the vital role that the Food and
Drug Administration plays in the health and well being of our
citizens, and we are also well aware of the impact the agency
has on the industries you are charged to regulate.
The FDA also holds a special significance for many of us
because of our involvement with passage of the FDA
Modernization Act; a measure intended to guide the FDA in its
mission to protect the American public. That act emerged after
several years of debate over the appropriate role the FDA
should have in approving the products it regulates
Many in industry and some in the consumer community argued
that the agency was taking too long to approve new life saving
medical devices and medicines; that the agency was acting as a
roadblock to progress. More recently, new charges are emerging
that the FDA is being too lax in its oversight of industry and
that some of the products being approved are unsafe. What we
need at the agency, and what I hope you will bring with your
leadership is a better balance between these competing
interests.
I had the privilege of being chairman of this committee
when FDAMA passed and I continue to believe that that measure
made substantial improvements to the agency. But, I will say
again what I said then--I stand ready to work with FDA and my
colleagues to ensure that the agency is able to meet its
mission.
In some respects I view your, and the agency's, role to
that of a traffic cop whose job is not just to stop the bad
drivers, but is also to ensure that the good drivers get
through unimpeded. This is not an easy task but I expect to
hear you tell and convince this committee that you are up to
that challenge.
Prepared Statement of Senator Mikulski
Thank you for calling this prompt hearing on the vitally
important nomination of Dr. Lester Crawford to be the
Commissioner of the Food and Drug Administration (FDA).
The position of FDA Commissioner is critically important to
the public health of the United States but it has been vacant
for nearly 1 year. I am so pleased that Maryland is home to the
FDA. FDA makes sure that safe and effective drugs, biologics,
and devices come to the market to help save lives, help
patients live longer, and help improve the quality of their
lives.
FDA also plays a critical role in ensuring the safety and
security of our country's food supply. FDA affects the lives of
Americans everyday whether it is a pill you take or the food
you eat. FDA-regulated products account for about 25 cents of
every consumer dollar spent--a total of $1 trillion per year.
Criteria--My criteria for looking at each nomination are
competence, integrity, and commitment to the mission of the
agency.
I look forward to hearing from Dr. Crawford today about his
vision and qualifications.
Competence--As head of the agency that regulates everything
from food to the latest medication for heart disease, the FDA
Commissioner must be knowledgeable about medicine and science.
Management expertise is essential to effectively run FDA
without red tape and bureaucracy.
FDA has over 9,000 dedicated employees. FDA has a budget of
close to $1.8 billion and about 9,000 employees. Strong
management skills and leadership to ensure that FDA can
efficiently and effectively carry out its many
responsibilities.
Recruiting and retaining the best and brightest employees
at FDA is especially important as products reviewed by FDA
become increasingly more complex and advanced.
Integrity--Well respected by patient/consumer groups and
the industry so that FDA commands the respect of the public and
the industry it regulates.
Honest broker and listener who can make tough calls on
contentious issues.
Commitment to the Mission of the Agency--Decisions based on
sound science and public health, not ideology. Maintaining the
FDA gold standard of safety and efficacy. Ensuring timely
approval of new therapies to save lives, help patients live
longer, and improve their quality of life. Continual
improvement in mammography quality and ensuring access to new
screening and detection tools. Ensuring safety of our food
supply.
Closing
While Dr. Crawford may have an unusual background for
Commissioner of FDA. He could also bring a fresh perspective
with new thinking and new ideas. I will evaluate Dr. Crawford,
as I do each and every nominee, based on his competence,
integrity, and commitment to the mission of the agency. Thank
you again, Mr. Chairman, for convening this hearing on this
critically important nomination to the health of this country.
------
Letters of Concern
March 4, 2005.
Dear Senator: We write to share our serious concerns about the
President's nomination of Dr. Lester Crawford to serve as Commissioner
of the U.S. Food and Drug Administration. The continued delay on a
decision to make Plan B emergency contraception available without a
prescription undermines public confidence in the Acting Commissioner's
commitment to promoting the public's health and welfare.
Overwhelming scientific evidence shows that making emergency
contraception easier to obtain would substantially reduce the incidence
of unintended pregnancy and need for abortion. A recent study published
in the Journal of the American Medical Association provides the latest
evidence that Plan B should be made readily available by demonstrating
that using emergency contraception does not lead to more risky sexual
behavior or other health risks for women.
In December 2003, following review of hundreds of studies, the FDA
independent advisory committees voted 23-4 to approve Plan B for over-
the-counter status. Based on FDA guidelines, a decision was anticipated
in February 2004. Following a 90-day delay, on May 6, 2004 the FDA
issued a non-approvable letter to Barr Pharmaceuticals, citing the lack
of data concerning use in adolescents under age 16. The final decision
was made by Acting Center Director Dr. Steven Galson, contrary to the
recommendations of his own professional staff.
Barr Pharmaceuticals responded in good faith with a revised
application supporting the marketing of Plan B as a prescription-only
product for women 15 years of age and younger, and a non-prescription
product for women 16 years of age and older. A decision was due on
January 21, 2005, but instead the agency only gave notice of another
delay and provided no reason for delay or date for completion of
review.
Each day that this decision is delayed increases the serious health
implications for women. The agency needs a leader who will ensure FDA
decisions are based on scientific evidence and not political interests.
To restore public confidence in the agency's integrity, Dr. Crawford
must provide a full account of the decision processes that caused the
FDA to go against the recommendations of the review panel and
professional staff, share his assessment of the current situation, and
provide assurances that a decision will be made on Plan B over-the-
counter based totally on science and not politics. Until he provides
this information and assurances, we urge you not to confirm him as
Commissioner.
Sincerely,
National Partnership for Women and Families,
Reproductive Health Technologies Project.
Organizations: Advocates for Youth; American College of
Obstetricians and Gynecologists; American Society for Emergency
Contraception; Association of Reproductive Health Professionals;
Campaign for Access to Emergency Contraception (Champaign, IL); Center
for Reproductive Rights Center for Women Policy Studies; Champaign
County Health Care Consumers; Clara Bell Duvall Project, ACLU of
Pennsylvania; Family Planning Advocates of New York State; Family
Planning Council (Philadelphia, PA) Feminist Majority Foundation;
Florida NOW Young Feminist Taskforce; Gainesville Area National
Organization for Women; Gainesville Women's Liberation Gynuity Health
Projects; Ibis Reproductive Health; Institute for Reproductive Health
Access; Massachusetts Emergency Contraception Network; Morning-After
Pill Conspiracy; NARAL Pro-Choice America; NARAL Pro-Choice Colorado;
NARAL Pro-Choice Massachusetts; NARAL Pro-Choice Texas; National
Abortion Federation; National Association of Nurse Practitioners in
Women's Health; National Family Planning and Reproductive Health
Association; National Latina Institute for Reproductive Health;
National Organization for Women; National Women's Health Network;
National Women's Law Center; New York State Reproductive Rights
Taskforce; People for the American Way; Pharmacy Access
Partnership;Physicians for Reproductive Choice and Health; Planned
Parenthood Federation of America; Population Connection; Redstockings
Allies and Veterans, New York City; Religious Coalition for
Reproductive Choice; Sexuality Information and Education Council of the
United States (SIECUS); Students for Access to Emergency Contraception
(IL); University of Florida Campus NOW; Women's Health Task Force (IL).
Individuals: Philip Corfman, M.D. (Bethesda, MD); Betty Farrell,
CNM, MPH (Brooklyn, NY); Diana Romero, Ph.D. (Mailman School of Public
Health, Columbia University.
______
Consumers Union,
Consumer Federation of America,
U.S. Public Interest Research Group,
March 15, 2005.
Hon. Michael Enzi,
Committee on Health, Education, Labor, and Pensions,
U.S. Senate,
Washington, D.C. 20510.
Dear Mr. Chairman: This Thursday, the Senate Committee on Health,
Education, Labor, and Pensions will consider the nomination of Dr.
Lester Crawford to be the Commissioner of the Food and Drug
Administration.
Before voting on his nomination, we urge you to ask, and get
answers to, important questions about Dr. Crawford's record at FDA and
his plans to achieve meaningful drug safety reform as Commissioner.
Dr. Crawford has served at the helm of FDA, as either Deputy or
Acting Commissioner, for the last 3 years. During that time, the
agency's high profile missteps and failure to take timely action to
protect consumers from unreasonable drug safety risks have raised
serious questions about his leadership, his ability to manage
interagency conflicts and willingness to act in the best interest of
consumers.
Dr. Crawford and Secretary of Health and Human Services Michael
Leavitt recently announced the creation of an independent drug safety
oversight board at FDA. Unfortunately the move offers no true
substantive reform and bears little resemblance to the ``emboldened new
vision'' it is supposed to represent. The Drug Safety Board does
nothing to improve the agency's weak regulatory capacity or to address
the inherent internal conflicts of interest that prevent FDA from
identifying unreasonable safety risks and taking timely action to
protect the public from them.
The agency's recent high-profile failings on the safety of widely
used painkillers and antidepressants are symptoms of a larger problem
that can only be resolved with critically needed new laws. First, FDA
lacks authority to require drug companies to conduct safety studies
once a drug is approved and to require timely protective action when
unreasonable risks arise.
Second, the organizational structure of the FDA suffers from
inherent conflicts of interest by allowing reviewers in the Office of
New Drugs to make important determinations about the post-market safety
of drugs they approve. In 2004, these conflicts discouraged public
release of findings by reviewers in the Office of Drug Safety, who have
no authority to take action on their own, nor even the right to ensure
that FDA advisory committees, doctors and patients have access to their
findings.
And third, patients and doctors don't have access to all clinical
trial results, both good and bad, for widely prescribed medications.
Meanwhile, drug makers are free to publish the positive results in
medical journals, while downplaying less favorable findings.
In the face of widely publicized regulatory shortcomings at FDA,
Dr. Crawford has not acknowledged the need for substantive changes to
increase the FDA's ability to protect consumers.
Though he claims to have a bold vision for the FDA, the question is
whether or not Dr. Crawford is committed to achieving substantive
rather than symbolic drug safety reform. Such reforms must include full
public disclosure of all clinical trial results, greater independence
for the Office of Drug Safety, stronger authority to require additional
studies on the safety of approved drugs, and increased capacity to take
action to mitigate unreasonable risks when they arise.
Before the Senate HELP Committee reports his nomination, we urge
you to compel Dr. Crawford to enumerate steps he will take to change
the agency's culture and achieve meaningful administrative and
legislative reforms to FDA's drug safety system.
Sincerely,
Jeannine Kenney,
Senior Policy Analyst,
Consumers Union.
Travis Plunkett,
Legislative Director,
Consumer Federation of America.
Lindsey Johnson,
Consumer Advocate,
U.S. Public Interest Research Group.
______
Letters of Support
University of Georgia Alumni Association,
Athens, GA 30602-6372,
February 17, 2005.
Lester M. Crawford,
U.S. Food and Drug Administration,
Rockville, MD 20852.
Dear Dr. Crawford: Congratulations on being named Commissioner of
the Food and Drug Administration. I wish you the best as you move
forward with your appointment.
On behalf of the University of Georgia Alumni Association, I would
like to extend our appreciation for your commitment to excellence. You
bring honor to your alma mater.
If I may ever be of service, please do not hesitate to contact me.
Sincerely,
Deborah A. Dietzler,
Executive Director.
______
American Society of Health-System Pharmacists,
Bethesda, MD 20814,
February 16, 2005.
Hon. Michael B. Enzi,
Chairman,
Committee on Health, Education, Labor, and Pensions,
U.S. Senate,
Washington, D.C. 20510.
Dear Chairman Enzi: The American Society of Health-System
Pharmacists (ASHP) is writing today to applaud the President's
nomination of Lester M. Crawford to be Commissioner of the Food and
Drug Administration (FDA). For more than 60 years, ASHP has helped
pharmacists who practice in hospitals and health systems improve
medication use and enhance patient safety. The Society's 30,000 members
include pharmacists and pharmacy technicians who practice in inpatient,
outpatient, home-care, and long-term-care settings, as well as pharmacy
students.
The FDA has the enormous task of safeguarding our Nation's drug
supply, ensuring that safe and effective products reach the market in a
timely manner, monitoring products for continued safety after they are
in use, and securing accurate, science-based information about these
products for consumers. Despite extraordinary efforts on the part of
the FDA, more can and should be done. As a result, the FDA has come
under significant fire in recent times to strengthen its focus on
public health and safety.
The confirmation of a permanent FDA commissioner is an important
step in positioning the FDA to fulfill its role. Dr. Crawford has
exhibited the knowledge and leadership qualities that make him the
right person for the job. During the confirmation process, we hope that
you will request that Dr. Crawford put forward his plan for achieving
this important goal. ASHP is particularly interested in FDA plans to
enhance confidence in the integrity of the drug products reaching the
pharmacy, increase drug safety information available to health
professionals and the public, and facilitate the exchange of
information to providers in times of product shortages or public health
emergencies.
ASHP looks forward to continuing our work with Dr. Crawford in his
new position. We encourage the committee and the Senate to confirm him
quickly. PIease feel free to contact us at any time if we can be of
assistance. Kathleen Cantwell, ASHP's Director of Federal Legislative
Affairs and Government Affairs Counsel can be reached via e-mail at
[email protected] or by phone at 301-664-8710.
Sincerely,
Henri R. Manasse, Jr.,
Ph.D., Sc.D.,
Executive Vice President and
Chief Executive Officer.
______
National Restaurant Association,
March 16, 2005.
Committee on Health, Education, Labor and Pensions,
U.S. Senate.
Dear Chairman Enzi: I am writing to express the support of the
National Restaurant Association for Dr. Lester Crawford, the nominee
for Commissioner of the Food and Drug Administration. We hope the
Senate Health Committee, without hesitation, will approve Dr. Crawford.
As Administrator of the USDA's Food Safety and Inspection Service,
Dr. Crawford has an unique perspective on the important oversight role
that both the FDA and USDA provide in maintaining a safe food supply--
this is of the utmost importance to the National Restaurant
Association.
In addition, Dr. Crawford's experience in life science, coupled
with a laudable record of public service focused on those issues makes
him the ideal candidate for this position. His previous roles as Acting
FDA Commissioner, and Director for the FDA's Center for Veterinary
Medicine, give him an unprecedented familiarity with roles and
responsibilities of the FDA.
His commendable track record of successes in a variety of settings
is ample evidence of Dr. Crawford's capabilities. We hope that the
members of the Senate Health Committee, and the Senate overall, will
confirm Dr. Crawford as FDA Commissioner.
Sincerely,
Steven C. Anderson,
President & CEO.
______
Strock-Wise Animal Clinic P.A.,
Charleston, SC 29412,
February 28, 2005.
Dr. Lester Crawford,
U.S. Food and Drug Administration,
Rockville, MD 20857-0001.
Dr. Lester Crawford: Congratualtions on your appointment to
Commissioner of the FDA, I have been following your many
accomplishments in the city by the Potomac and wanted to tell you what
a great representative of the veterinary profession you have been
throughout your professional career. If you are ever in Charleston, SC,
please look me up.
I spoke with Roger Wilbur the other day; he sends his regards and
congratulations also. Keep up the good work.
Wilbur Wise.
______
The 60 Plus Association,
Arlington, VA 22209,
March 16, 2005.
Hon. Michael B. Enzi,
U.S. Senate,
Washington, D.C. 20510-5004.
Dear Senator Enzi: I am writing to express my support for Dr.
Lester Crawford as the next Commissioner of the Food and Drug
Administration. Dr. Crawford brings to the post a successful 1-year
tenure as Acting Commissioner of the FDA as well as unique credentials
and noteworthy achievements that qualify him for leadership of the
agency's many and varied responsibilities.
As you may know, Dr. Crawford previously led the FDA as Deputy
Commissioner as the agency stepped up to counter the threat of
bioterrorism. He also served the FDA two other times in the past 30
years, as director of the agency's Center for Veterinary Medicine, from
1978 to 1980 and again from 1982 to 1985. Dr. Crawford's credentials
are unmatched. He has dedicated his career to promoting safer products
for the public; his vast experience positions him well to lead the
agency going forward.
Today, the FDA's plate is full, brimming with challenges that when
successfully accomplished will help 21st century Americans live longer,
healthier and happier lives. Dr. Crawford has already demonstrated his
leadership skills and his ability to deliver on the agency's core
objectives, as measured by the FDA's unprecedented achievements toward
its comprehensive strategic action plan.
In 2004, thanks to Dr. Crawford's inspired leadership, the FDA
improved consumer protection by employing new bioterrorism
countermeasures. The agency created regulations for safer dietary
supplements. By applying innovative technologies, the agency bolstered
protections against medical errors. And the FDA gave consumers the keys
for improving their own health by educating people with better
information about the foods they eat and the medicines they take. Of
paramount importance to the 5 million senior citizens I represent, in
2004 the FDA gave citizens faster access to safe and affordable
medicines.
But there's much more to be done. The FDA estimates it has
completed about one-third of the work detailed in its strategic action
plan. The agency has committed to completing three-quarters of the
remaining work this year. A tall order, yes, but Dr. Crawford is the
right leader at the right time, one who can focus the FDA's work and
ensure that the FDA is not given burdensome responsibilities outside of
its core mission that would dilute its purpose.
For example, the FDA has worked hard to reduce the time and expense
of new drug approvals, steadily increasing the speed of its processes
since the 1990s. But more improvements are needed, as the demand for
safe, fast and affordable medication escalates, especially among
seniors. Companies today may spend as much as $800 million to bring a
new drug to market. That cost is prohibitive and discourages
innovation, a problem that must be resolved.
In its role as health educator, the FDA should teach the American
public, seniors in particular, about current discounts for prescription
drugs. Discounts are available but not yet well understood by citizens.
If the FDA were to leverage its credibility as the Nation's public
health agency and primary consumer protection agency, it could launch
an information campaign to advise citizens the best ways to avail
themselves of the best prices on prescription medicines, and
simultaneously cool down the drug reimportation issue.
Dr. Crawford's experience in regulating medical, agricultural and
food product safety will serve well the FDA and the Nation. We welcome
his vision, focus and leadership on the agency's fundamental
imperatives, and hope that you will approve his nomination as the next
Commissioner of the Food and Drug Administration.
60 Plus is an 11-year-old nonpartisan group with a less government,
less taxes approach to seniors' issues. 60 Plus has become one of the
fastest growing seniors groups in the country, doubling then tripling
its support in the past year. 60 Plus now calls on support from nearly
4.5 million citizen lobbyists to print and mail millions of letters and
petitions. 60 Plus publishes a newsletter, SENIOR VOICE, and a
SCORECARD, bestowing a GUARDIAN OF SENIORS' RIGHTS award on lawmakers
in both parties who vote ``pro-senior.'' 60 Plus has been called ``not
only an increasingly influential lobbying group for the elderly,'' but
also `` the conservative alternative to the AARP.
Sincerely,
Jim Martin,
President.
______
University of Florida,
College of Veterinary Medicine,
Gainsville, FL 32610-0136,
February 25, 2005.
Dr. Lester Crawford,
U.S. Food and Drug Administration,
Department of Health and Human Services,
Rockville, MD 20857.
Dear Dr. Crawford: Congratulations! I am excited that you were
nominated by President George Bush for the position of Commissioner of
the Food and Drug Administration. This is a tremendous accomplishment
and demonstrates your hard work and dedication to our Nation. I am sure
President Bush made a very wise choice and that you will excel in your
new role as Commissioner.
Please accept my congratulations on your nomination and my very
best wishes for your continuing success.
Sincerely,
Dr. Eleanor Green,
DVM, Dipl DACVIM, Dipl DABVP,
Professor and Chair, Chief of Staff.
______
Association of American Veterinary Medical
Colleges,
Washington, D.C. 20005-3536,
March 7, 2005.
Hon. Michael B. Enzi,
Chairman,
Committee on Health, Education, Labor, and Pensions,
U.S. Senate,
Washington, D.C. 20510.
Dear Mr. Chairman: The Association of American Veterinary Medical
Colleges strongly supports President Bush's nomination of Dr. Lester M.
Crawford to be Commissioner of the Food and Drug Administration. Dr.
Crawford's unequaled experience, including his current tenure as Acting
Commissioner and his previous positions as Deputy Commissioner and
Director of the FDA's Center for Veterinary Medicine, make him
eminently qualified for this position.
Dr. Crawford is one of the Nation's preeminent scientists and a
world renowned leader in the veterinary medical profession. His recent
election to the Institute of Medicine is evidence of his significant
contributions to the advancement of the medical sciences and public
health. In addition, Dr. Crawford's extensive experience in achieving
cooperation and communication among numerous Federal Agencies and
private organizations underscores his qualification for high public
office.
The FDA is facing unprecedented challenges in ensuring the safety
of foods, drugs and medical devices for all Americans. It is imperative
to name a Commissioner with proven leadership ability and impeccable
scientific acumen. Dr. Crawford embodies these traits and his
appointment would provide the proper scientific basis of operation and
exceptional communication skills in the position.
On behalf of the Nation's 28 colleges of veterinary medicine, the
AAVMC urges the Senate to confirm Dr. Crawford's appointment as FDA
Commissioner without delay.
Sincerely,
Lawrence E. Heider, DVM, DACVPM,
Executive Director.
______
Canadian Food Inspection Agency,
February 23, 2005.
Dr. Lester M. Crawford,
Commissioner,
Department of Health & Human Services,
Food and Drug Administration,
Rockville, MD 20857.
Dear Lester: This is just a quick note to congratulate you on your
appointment as Commissioner. The task will be a difficult one but I am
certain you will do very well.
The follow-up to our Argentina PAHO Veterinary Project continues--
next session will be in June 2005. Enclosed is a paper which Enrique
collaborated on. I am sure you will be interested in the
recommendations.
Kind Regards,
Anne MacKenzie,
Science Advisor, Science Branch,
Canadian Food Inspection Agency.
______
RetireSafe,
Oakton, VA 22124.
March 15, 2005.
Hon. Michael B. Enzi,
Chairman,
Hon. Edward M. Kennedy,
Ranking Minority Member,
Committee on Health, Education, Labor, and Pensions,
U.S. Senate,
Washington, DC 20510.
Dear Senator Enzi and Senator Kennedy: On behalf of RetireSafe's
300,000 senior citizen supporters across America, I write to express
our strong support for the nomination of Dr. Lester Crawford, Jr. to be
the next Commissioner of the U.S. Food and Drug Administration (FDA).
We believe the older Americans we represent, and the Nation as a whole,
will be extremely well served by Dr. Crawford in his new role as FDA
Commissioner. RetireSafe applauds Dr. Crawford's appointment by
President Bush, and urges your swift confirmation of his nomination to
this critical post.
Today, the FDA faces a host of challenges, as well as an expansion
of responsibilities. It is vitally important that this agency have the
benefit of a strong, experienced leader. Dr. Crawford, now serving as
Acting Commissioner of the FDA, is more than qualified to fill that
need. He is truly a champion of both food and drug safety, exactly the
kind of individual FDA needs at the helm. This is evidenced by Dr.
Crawford's work as an advisor to the World Health Organization and the
United Nations, and as a leader in mandatory nutrition labeling and the
control of chemical and microbiological contaminants of food.
Dr. Crawford's prior service at the FDA, as the Administrator of
the Food Safety and Inspection Service (USDA), as Chair of the
Physiology-Pharmacology Department at the University of Georgia, and as
Director of the Center for Food and Nutrition Policy at Georgetown
University and at Virginia Tech, all indicate that he is a person
superbly qualified to head the FDA. As a Member of the National Academy
of Science, a Fellow of the Royal Society of Medicine, and a Fellow of
the International Society of Food Science and Technology, Dr. Crawford
is very well respected in the scientific community.
With these outstanding qualifications, Dr. Lester Crawford is an
excellent choice to serve as the Commissioner of the FDA. RetireSafe
urges your strong support of Dr. Crawford, and the swiftest possible
confirmation of his nomination.
Sincerely,
Charles G. Hardin,
President.
______
LUPUS Foundation of America, Inc.,
Washington, D.C. 20036,
March 16, 2005.
Hon. Mike Enzi,
Chairman,
Committee on Health, Education, Labor, and Pensions,
U.S. Senate,
Washington, D.C. 20510.
Dear Mr. Chairman: On behalf of the Lupus Foundation of America,
which represents the more than 1.5 million Americans with the disease
lupus, their families and their health professionals, we are writing to
express our enthusiastic support for the confirmation of Dr. Lester M.
Crawford as Commissioner of the U.S. Food and Drug Administration
(FDA). As Acting Commissioner, Dr. Crawford's focused leadership has
served the Agency and the Nation well during this period of transition.
While many national nonprofit voluntary health organizations have
reason to provide input regarding this important position, the Lupus
Foundation of America has a unique interest in the individual who will
be confirmed by the Senate. As you may know, the FDA has not approved a
new lupus medication in nearly 40 years. In recent years, drug
development for lupus has entered a critical period in which an
increasing number of biotechnology and pharmaceutical companies are
developing new therapies for lupus. For individuals with lupus, the
decisions of the FDA will have a great impact on their quality of life
and survival.
Dr. Crawford has included lupus among the diseases that are part of
the FDA's Critical Path Initiative that seeks to address unmet medical
needs. Additionally, the Agency is preparing to release the first-ever
industry guidance document on lupus. Under Dr. Crawford's on-going
leadership, we believe the FDA will continue to take steps to ensure
that patients with lupus will soon have access to new life-saving
medicines aimed at bringing the disease under control. We applaud these
efforts and look forward to working with him.
We urge you to confirm Dr. Crawford as the next Commissioner of the
U.S. Food and Drug Administration. Thank you for your consideration of
our views. Please let us know if we can be of assistance on this issue
or any other matters.
Sincerely,
Sandra C. Raymond,
President & CEO.
______
WomenHeart,
Washington, D.C. 20006,
February 15, 2005.
WomenHeart Endorses Appointment of Lester Crawford as FDA Commissioner
Washington, D.C. (February 15)--WomenHeart: the National Coalition
for Women and Heart Disease applauds President Bush's selection of
Lester Crawford as the new Food and Drug Administration (FDA)
Commissioner. It also urges Congress to swiftly approve his
appointment.
``Dr. Crawford has many years of experience at FDA safeguarding the
Nation's prescription drug and medical device approval processes, as
well as our food supply,'' said Nancy Loving, WomenHeart's executive
director. ``We have worked very well with him on many important patient
safety issues, including the need to include more women in clinical
trials. He is an exceptional public servant.''
Crawford, she noted, supported the Bioshield Act that ensured rapid
FDA action for medical technologies that could improve the Nation's
defense against bioterrorism threats and also efficiently secured
sources to provide added flu vaccine in the 2004/2005 flu season.
WomenHeart is the Nation's only patient advocacy organization
serving the 8,000,000 American women living with heart disease and
provides them support, information and advocacy services. It is a
public charity headquartered in Washington, D.C. Visit online at
www.womenheart.org.
______
Pan American Health Organization,
Washington, D.C. 20037-2895,
February 18, 2005.
Lester Crawford, D.V.M., Ph.D.,
Acting Commissioner,
U.S. Food and Drug Administration (FDA),
Rockville, MD, 20857-1706.
Dear Dr. Crawford: I am writing to congratulate you on your
nomination as Commissioner of the Food and Drug Administration. Your
advice and support of the Veterinary Public Health Program in PAHO has
been greatly valued over the years, and I have also very much enjoyed
our personal discussions.
It is a pleasure to see this recognition of your abilities. Best
wishes for successful nomination hearings and subsequent work in your
new role.
Sincerely,
Stephen Corber, M.D.,
Area Manager,
Disease Prevention and Control.
______
Pan American Health Organization,
Washington, D.C. 20037-2895,
February 18, 2005.
Lester M. Crawford, D.V.M., Ph.D.,
Commissioner-Designate,
U.S. Food and Drug Administration,
Rockville, MD, 20557-1706.
Dear Dr. Crawford: I wish to congratulate you on your recent
nomination as Commissioner of the United States Food and Drug
Administration (USFDA) by President George W. Bush.
I share the opinion of the Health and Human Services Secretary, Mr.
Mike Leavitt, that you are ``an outstanding choice'' for the post. I am
highly honored to have the head of one of the most important and
prestigious U.S. health agencies as a friend who has provided steadfast
advice to the Pan American Health Organization/World Health
Organization (PAHO/WHO).
Please accept my best wishes for continued success in your new
position.
Sincerely yours,
Mirta Roses Periago,
Director.
______
Massachusetts Institute of Technology,
Bedford, MA 01730 USA,
February 26, 2005.
Lester M. Crawford, D.V.M., Ph.D.,
Office of the Commissioner,
Food and Drug Administration,
Washington, D.C. 20204.
Dear Doctor Crawford: I wish to congratulate you on your many
accomplishments and superb service to the government and society in
general over the many years since you left the ``lovliest village'' of
the plains in Auburn. Particularly significant is the most recent
appointment at the FDA, a confirmation of your commitment to the
protection and improvement of the health and well-being of all of us
citizens. In all of the many assignments you have had you have brought,
among other things, wisdom, integrity, and humor to sometimes difficult
situations. For this, I for one, and for the entire Veterinary
Profession in general thank you.
One event which affected me personally and which I've not forgotten
was a meeting you were chairing somewhere in the western United States
in the late 1970s. I presented the results on nitrate/nitrite studies
conducted at MIT under contract to the FDA. Members of the pork
producers in the audience was ready to tar and feather me for
suggesting that the food industry might do as well with a little less
nitrates and nitrites in our foods. You saved me from that rather
miserable and unfortunate event and for that I have been eternally
grateful.
I look forward to following your continuing remarkable career and
to observe how you grapple with FDA problems, especially with what
sometimes seems to be a pharmaceutical industry out of control. I've
worked with the industry all of my active career and came to recognize
many of their problems. However, if I were limited to only one
suggestion as to how to improve the current situation in that regard,
it would be to reduce the amount of direct to consumer advertising;
this probably contributes more than any other single action to problems
now under consideration by the Agency (i.e., cox-2 pain killers). As
our old Professor, Will Bailey would say ``you've done us proud.'' Keep
up the good work and my best wishes.
Sincerely,
Paul M. Newberne,
D.V.M. M.Sc., Ph.D.,
Professor Emeritus,
Nutritional Pathology.
______
Health Canada,
Ottawa, Ontario K1A 0L2,
February 17, 2005.
Dr. Lester M. Crawford, D.V.M., Ph.D.,
Acting Commissioner,
Food and Drug Administration,
Rockville, MD 20857-0001.
Dear Dr. Crawford: On behalf of the Health Products and Food Branch
of Health Canada, I would like to congratulate you on your nomination
as FDA Commissioner, a position of enormous importance in the United
States.
You come to this position with a very distinguished and outstanding
career, and the FDA is fortunate to have your leadership in this
position.We welcome your nomination and believe that you will continue
to bring to the FDA programs, the vision and energy that had made you a
success as FDA's Acting Commissioner over the past years.
Once again, I offer my sincere congratulations to you and look
forward to a continued collaboration between our two organizations on a
number of issues, and want you to know how much we have appreciated
your leadership, support and insights in the past.
Yours sincerely,
Diane C. Gorman,
Assistant Deputy Minister.
______
The Tipton Group, Inc.,
Washington, D.C. 20003,
February 23, 2005.
Dr. Lester M. Crawford,
Acting Commissioner,
Food and Drug Administration,
Rockville, MD 20857.
Dear Les: Congratulations! I am most pleased that President Bush
has nominated you to be Commissioner of the Food and Drug
Administration. In my view, you are clearly the correct choice, and you
should have been nominated to the position much sooner.
I am already telling my friends on the Hill that you are the right
person to take over leadership of FDA. If I can ever be of help to you
on any specific issues or with Members of Congress, I would like the
opportunity to try.
Again, my sincerest congratulations!
My best regards,
E. Linwood Tipton,
Chairman & CEO.
______
Food Marketing Institute,
Washington, D.C. 20005-5701,
March 16, 2005.
Senator Mike Enzi,
Chairman,
Committee on Health, Education, Labor, and Pensions,
U.S. Senate,
Washington, D.C. 20510-6300.
Chairman Enzi: The Food Marketing Institute would like to offer its
support for the nomination of Dr. Lester Crawford to be Commissioner of
the Food and Drug Administration (FDA). FMI works with FDA on issues
related to food safety, food security and nutrition on behalf of its
1,500 member companies--food retailers and wholesalers--in the United
States and around the world. FMI's U.S. members--large multi-store
chains, regional firms and independent supermarkets--operate
approximately 26,000 retail food stores with a combined annual sales
volume of $340 billion. Its international membership includes 200
companies from 50 countries.
Because of Dr. Crawford's present position as Acting Commissioner,
as well as his previous experience as FDA's deputy commissioner, he
would bring an unprecedented depth of knowledge to the job. His past
experience as the U.S. Department of Agriculture's Food Safety
Inspection Service (FSIS) Administrator and his tenure at FDA guarantee
that he understands the need for uniformity in food safety policy as
well as how vital it is for FDA's Center for Food Safety and Applied
Nutrition to work in tandem with its sister food safety department,
FSIS.
Dr. Crawford also brings a unique perspective to the job of
commissioner as he has a global view that he applies to U.S. food
policy. He has seen firsthand how the amount of food products imported
into the U.S. has increased and understands that developing food policy
that applies only within our borders is no longer viable. His
experience gives him the ability to see things with a wider lense, for
example, he was instrumental in the formation of the World Trade
Organization and has been an advisor to the World Health Organization
of the United Nations for much of his career. He is a Fellow of the
Royal Society of Medicine (UK) and a Fellow of the International
Society of Food Science and Technology.
Not only does he have a special perspective on the world's food
supply, he is also a scientist. He was Chair of the Department of
Physiology-Pharmacology at the University of Georgia and he was the
Director of the Center for Food and Nutrition Policy at Georgetown
University and at Virginia Tech (where it moved in 2001). With his
extensive knowledge regarding the control of chemical and
microbiological contaminants of foods, Dr. Crawford is able to take his
science background and use it to create practical solutions for food
safety issues. In addition, he has also been involved with many of the
major food safety initiatives in recent history; two of which were
mandatory nutrition labeling and the recent bioterrorism act.
Dr. Crawford's distinguished career has also included his induction
into the French Academy of Veterinary Medicine and he has been a
recipient of the Wooldridge Award, the British Veterinary Association's
highest award. Having a commissioner with a background in veterinary
medicine is most timely as we face such critical issues as regulating
animal feed and the rise of antimicrobial resistant stains of bacteria.
With Dr. Crawford's well-rounded career in food science and food
policy it ensures that food issues will be given proper attention at
FDA. Once confirmed, the food industry will look forward to sound,
science-based policy and regulatory decisions under Dr. Crawford's
guidance.
Sincerely,
Tim Hammonds,
President and CEO,
Food Marketing Institute.
______
Medical Device Manufacturers Association,
Washington, D.C. 20006,
March 18, 2005.
Hon. Michael Enzi,
Chairman,
Committee on Health, Education, Labor, and Pensions,
U.S. Senate,
Washington, D.C. 20510.
Dear Chairman Enzi: On behalf of the Medical Device Manufacturers
Association and the hundreds of manufacturers of medical devices,
diagnostic products and health care information systems we represent, I
wish to convey strong support for the prompt confirmation of Dr. Lester
Crawford to be the Commissioner of the Food and Drug Administration so
he can continue the important work of ensuring the public health safety
of the Nation's citizens.
As a representative of the innovative sector of the medical
technology industry, MDMA has worked closely with Dr. Crawford during
his tenure at the FDA. He has always proven an able leader and has
fought tirelessly to uphold the FDA's mission.
MDMA believes Dr. Crawford, as both a veterinarian and dedicated
public servant, is uniquely suited to lead the FDA. With rapidly
developing technologies and advancements in medicine it is imperative
that FDA is led by a Commissioner who has the ability, dedication and
integrity to lead the agency. Dr. Crawford has exhibited these
qualities and it is our sincere hope that the Senate will move quickly
to confirm him as the next FDA Commissioner.
Sincerely,
Mark Leahey,
Executive Director.
______
Consumer Healthcare Products Association,
Washington, D.C. 20006,
March 1, 2005.
Hon. Michael B. Enzi,
Chairman,
Committee on Health, Education, Labor, and Pensions,
U.S. Senate,
Washington, D.C. 20510.
Dear Senator Enzi: The Consumer Healthcare Products Association
(CHPA) sends this letter to express its support for the Senate
confirmation of Dr. Lester M. Crawford to be Commissioner of Food and
Drugs.
Dr. Crawford has devoted most of his career to public service,
including his current term as Acting FDA Commissioner. The Food and
Drug Administration has been hampered for too long by having an acting
head.
Dr. Crawford is very familiar with the public health policy issues
confronting the agency and his appointment will assure continuity in
the leadership of FDA at a critical juncture. He has demonstrated a
willingness to work cooperatively with stakeholders on important
matters, and we believe that collaboration is a key to the credibility
of the regulatory process. We urge the committee to give prompt
consideration to Dr. Crawford's nomination.
Sincerely yours,
Linda A. Suydam,
President.
______
University of California, Davis,
Davis, California 95616-8558,
February 24, 2005.
Commissioner Les Crawford,
Federal Drug Administration,
Rockville, MD 20857.
Re: Western U.S. FDA Center of Excellence
Dear Commissioner Crawford: First, let me congratulate you on your
nomination as Commissioner of the Food and Drug Administration (FDA).
Your continued interest and investment in the future of our Nation's
food supply certainly qualifies you for this critical leadership
position. I look forward to working with you in the future.
As Chancellor of the University of California, Davis, I am very
supportive of the opportunity to develop an FDA Center of Excellence on
the Davis campus. As we lend our support for an added FDA research
center of excellence, I would like to seek information from you
regarding the FDA's level of interest in and priority for such an
endeavor in the Western United States.
UC Davis established the Western Institute for Food Safety and
Security (WIFSS) in 2002 to enhance our ability to provide a secure
food supply by developing a research and training program in food
defense. Through the Department of Homeland Security (OHS) cooperative
agreement, we have been developing a region-wide training program for
individuals and groups that are invested in the safety of our food
supply, including the import of workers and food from Mexico, Canada,
and the Pacific Rim.
Could you share with me those focus areas in which FDA would have a
specific interest in a western FDA Center of Excellence?
The University of California, Davis has a long history for
supporting agriculture and the extensive food systems in California
through education, research and outreach. The University has been
essential to California maintaining its leadership as the premier
agricultural State in the Nation for over 50 years, We look forward to
an opportunity to develop a strong collaborative research program with
FDA in California.
The University recognizes its obligation to help the public,
through industry, address the extraordinary challenges of improving and
assuring food safety and food defense. For several years we have
supported the California food industries' efforts to establish a FDA
research center of excellence in the Western United States. By joining
the talents we have assembled at the Western Institute for Food Safety
and Security with those of FDA, we will be able to efficiently and
effectively address the threats to our Nation's food systems and those
that accompany the movement of food across our borders.
Again, I look forward to working with you on this endeavor and any
focus areas in which FDA would have a specific interest in a western
FDA Center of Excellence.
Sincerely,
Larry N. Vanderhoef,
Chancellor.
______
Advanced Medical Technology Association (AdvaMed),
February 15, 2005.
Appointment of Permanent FDA Commissioner Applauded
Washington, D.C.--AdvaMed welcomed the Bush Administration's
appointment today of Lester M. Crawford as commissioner of the Food and
Drug Administration. Crawford has served as Acting Commissioner since
the departure of former FDA Commissioner Mark McClellan in March 2004.
``We look forward to continuing to work with Dr. Crawford,'' said
Pamela G. Bailey, AdvaMed President. He understands the unique
characteristics of the medical technology industry.''
``Dr. Crawford's experience will be invaluable as Congress and FDA
craft legislation this year that will add predictability and stability
to the medical device user fee program and allow for the program's
continuation beyond the current fiscal year,'' Bailey said.
Crawford served as Acting FDA Commissioner before Dr. McClellan
joined the Agency in November 2002 and was involved in key negotiations
that led to the landmark ``Medical Device User Fee and Modernization
Act of 2002.''
AdvaMed is the world's largest association representing
manufacturers of medical devices, diagnostic products, and medical
information systems AdvaMed's more than 1,300 members and subsidiaries
manufacture nearly 90 percent of the $75 billion of health care
technology products purchased annually in the United States, and more
than 50 percent of the $175 billion purchased annually around the
world. AdvaMed members range from the largest to the smallest medical
technology innovators and companies. Nearly 70 percent of our members
have fewer than $30 million in sales annually.
______
Alliance for Aging Research,
Washington, D.C. 20001,
February 16, 2005.
Alliance Endorses Dr. Lester Crawford's Nomination as FDA Commissioner
Washington, D.C.: The Alliance for Aging Research, a not-for-profit
organization, supports President Bush's nomination of Dr. Lester
Crawford as the next FDA commissioner and encourages Congress to act
swiftly in approving his appointment.
``Dr. Crawford is the perfect candidate to lead the FDA at this
critical time,'' said Daniel Perry, Executive Director of the Alliance
for Aging Research. ``We are confident that Dr. Crawford will enhance
the lives of our Nation's aging population by promoting better medical
practices and guaranteeing the safety of drugs that affect our most
vulnerable population.''
``Dr. Crawford,'' continued Perry, ``will use sound judgment and
good science when dealing with drug safety. We look forward to continue
working with him at the FDA in assuring the safety and efficacy of the
next generation of therapies and treatments.''
Crawford has been acting commissioner of the FDA since March of
2004 when Dr. Mark McClellan left the post to become administrator for
the Centers for Medicare and Medicaid Services.
Founded in 1986, the Alliance for Aging Research is a nonprofit
independent organization dedicated to supporting and accelerating the
pace of medical discoveries to vastly improve the universal experience
of aging. The Alliance combines the interests of top scientists, public
officials, business executives and foundation and academic leaders to
promote a greater national investment in research and new technologies
that will prepare our Nation for the coming senior boom, and improve
the quality of life for older Americans. Visit online at
www.agingresearch.org.
______
Alliance of Specialty Medicine.
Hon. Michael Leavitt,
Secretary,
U.S. Department of Health and Human Services,
Washington, D.C. 20201.
Dear Secretary Leavitt: The Alliance of Specialty Medicine supports
the nomination of Lester M. Crawford Jr. for Commissioner of the Food
and Drug Administration and urges the Senate to confirm him. Dr.
Crawford has served the FDA with distinction since be was named to
serve as deputy commissioner in 2002 and more recently as Acting
Commissioner.
As specialty physicians, the more than 200,000 members of the
Alliance of Specialty Medicine and the millions of patients they care
for, support the critical role the FDA plays in assuring that the
Nation's food is safe and properly labeled, The FDA also assures that
pharmaceuticals, biological products and medical devices are safe,
effective and properly labeled. Dr. Crawford has devoted his career to
promoting safer products for the public. His leadership skills and
experience equip him well for this important position.
We hope the Agriculture, Nutrition and Forestry Committee and full
Senate will vote favorably on this nomination.
Sincerely.
______
American Society for Microbiology (ASM),
Washington, D.C. 20036-2594,
February 22, 2005.
Lester M. Crawford, Ph.D.
Acting Commissioner,
Food and Drug Administration,
Rockville, M.D. 20857.
Dear Dr. Crawford: We would like to thank you for the generous time
you took to make such an excellent presentation to the ASM's Public and
Scientific Affairs Board on February 11. Thank you for being so
flexible with your schedule. Your presentation of issues and
information related to the Food and Drug Administration was extremely
valuable to ASM.
We would like to congratulate you on your appointment as
Commissioner of FDA. The Society stands ready to assist you and the FDA
on issues and policy.
With best wishes,
Ruth L. Berkelman, M.D.,
Chair, Public and Scientific Affairs Board.
______
Association of American Veterinary Medical
Colleges,
Chicago, IL, 60610,
March 7, 2005.
Hon. Michael B. Enzi,
Chairman,
Committee on Health, Education, Labor, and Pensions,
U.S. Senate,
Washington, D.C. 20510.
Dear Mr. Chairman: The Association of American Veterinary Medical
Colleges strongly supports President Bush's nomination of Dr. Lester M.
Crawford to be Commissioner of the Food and Drug Administration. Dr.
Crawford's unequaled experience, including his current tenure as Acting
Commissioner and his previous positions as Deputy Commissioner and
Director of the FDA's Center for Veterinary Medicine, make him
eminently qualified for this position.
Dr. Crawford is one of the Nation's preeminent scientists and a
world renowned leader in the veterinary medical profession. His recent
election to the Institute of Medicine is evidence of his significant
contributions to the advancement of the medical sciences and public
health. In addition, Dr. Crawford's extensive experience in achieving
cooperation and communication among numerous Federal agencies and
private organizations underscores his qualification for high public
office.
The FDA is facing unprecedented challenges in ensuring the safety
of foods, drugs and medical devices for all Americans. It is imperative
to name a Commissioner with proven leadership ability and impeccable
scientific acumen. Dr. Crawford embodies these traits and his
appointment would provide the proper scientific basis of operation and
exceptional communication skills in the position.
On behalf of the Nation's 28 colleges of veterinary medicine, the
AAVMC urges the Senate to confirm Dr. Crawford's appointment as FDA
Commissioner without delay.
Sincerely,
Lawrence E. Heider, DVM, DACVPM,
Executive Director.
______
American Veterinary Medical Association,
Schaumburg, IL 60173-4350,
February 17, 2005.
Hon. Michael Enzi,
Chairman,
Committee on Health, Education, Labor, and Pensions,
Washington, D.C. 20510.
Dear Mr. Chairman: The American Veterinary Medical Association
(AVMA), on behalf of its more than 72,000 members, strongly endorses
President Bush's nomination of Dr. Lester M. Crawford to be
commissioner of the Food and Drug Administration (FDA). Dr. Crawford's
exemplary record of service and leadership in public health, food
safety, and regulatory medicine brings invaluable experience and a
myriad of accomplishments in government, academia, and industry to this
most esteemed position.
We echo Secretary Mike Leavitt's comments that Dr. Crawford is an
``outstanding choice'' for commissioner, especially as the FDA enters a
new era of medicine and rapidly developing science.
Dr. Crawford's admirable public service at the FDA as Acting
Commissioner mirrors his previous appointments as deputy commissioner
of the FDA, director of the FDA Bureau of Veterinary Medicine, and
director of the FDA Center for Veterinary Medicine. Noteworthy
experience in his distinguished and varied Federal career is his
appointment as administrator of the Food Safety and Inspection Service
at the U.S. Department of Agriculture. Dr. Crawford's breadth and depth
of experience in seeking out and facilitating cooperation and
communication between numerous agencies and organizations underscores
his qualifications for the office of commissioner.
In the academic venue, Dr. Crawford has served as the head of the
Center for Food and Nutrition Policy at Georgetown University and
Virginia Tech, chairman of the University of Georgia's Department of
Physiology-Pharmacology, and executive director of the Association of
American Veterinary Medical Colleges.
In addition, Dr. Crawford played a key role in the formation of the
World Trade Organization has been an advisor to the World Health
Organization of the United Nations for much career.
The AVMA is the recognized voice of the veterinary profession in
presenting its views on veterinary medicine, including its relationship
to public health, biological science, and agriculture, to government,
academia, agriculture, pet owners, the media, and other concerned
publics. As such, we strongly endorse Dr. Crawford and encourage the
Senate to confirm his appointment as FDA commissioner.
Sincerely,
Bonnie V. Beaver,
BS, DVM, MS, DACVB,
President.
______
American Medical Association,
Chicago, IL 60610,
March 15, 2005.
Hon. Michael B. Enzi,
Chairman,
Committee on Health, Education, Labor, and Pensions,
U.S. Senate,
Washington, D.C. 20510-6300.
Dear Senator Enzi: On behalf of the American Medical Association, I
write to strongly endorse the confirmation of Lester M. Crawford,
D.V.M., Ph.D., as Commissioner of the Food and Drug Administration
(FDA). The FDA Commissioner plays a crucial role in protecting the
public from unsafe drugs and dangers associated with the Nation's food
supply while ensuring that the United States remains a leader in
medical innovation. Today's world of quickly evolving science and an
increasing reliance on the healing power of prescription drugs calls
for effective, seasoned leadership at the helm of the FDA. Dr. Crawford
will provide that leadership.
Dr. Crawford has dedicated his career to advancing the public
health, is well known for his work in food safety, and is a first rate
scientist committed to public service. He has shown a strong commitment
to improving patient safety, something that we as physicians value most
highly. As a member of the National Academy of Sciences' Institute of
Medicine he has contributed to providing accurate, scientifically sound
information to the public. Importantly, Dr. Crawford has held several
assignments at the FDA, serving as Deputy Commissioner, and most
recently as Acting Commissioner. His expertise and experience will
serve him well as Commissioner.
During his tenure as Acting Commissioner, Dr. Crawford has pursued
initiatives to improve drug labeling standards to make it easier for
physicians to read information critical to the safe and effective use
of prescription drugs. He has continued the agency's increasing
oversight of dietary supplements, and also has focused on slowing the
growth of antibiotic resistance. Furthermore, he has worked to speed
innovations to make medicines safer and more affordable to the American
public. He has enhanced bioterrorism countermeasures to protect
consumers, and is helping to empower Americans by providing more and
better information about the medicines and food they consume every day,
We have great confidence that Dr. Crawford's vision and leadership will
continue to improve the FDA, and will benefit patients and the
physicians we represent.
Sincerely,
ABXD,
Michael D. Mayes,
Executive Vice President.
______
Additional Letters of Support
Novartiz AG,
February 24, 2005.
Lester M. Crawford, D.V. M., Ph.D.
Commissioner Designee,
U.S. Department of Health and Human Services,
Food and Drug Administration,
Parklawn--Room 1471,
3600 Fishers Lane,
Rockville, MD 20857.
Dear Dr. Crawford: It is with great pleasure that I extend sincere
congratulations on the announcement of your nomination to the post of
Commissioner of Food and Drugs. It is not only an honor to be named for
this high post, but an expression by President George W. Bush of his
confidence in your education, skills, experience and judgment. You have
clearly demonstrated an abiding commitment to the health and safety of
U.S. citizens.
I wish for you a speedy and successful confirmation process and I
look forward to continuing our cordial working relationship.
Best personal regards,
Daniel Vasella, MD.
______
U.S. Office of Government Ethics,
Washington, D.C.,
March 1, 2005.
Mr. Lester M. Crawford,
Department of Health and Human Services,
Food and Drug Administration,
5600 Fishers Lane,
Rockville, MD.
Dear Mr. Crawford: Congratulations on your nomination to the
position of Commissioner, Food and Drug Administration, Department of
Health and Human Services. I hope you will find that this position will
be both challenging and rewarding.
Enclosed for your information is a copy of the letter sent to the
U.S. Senate stating that the Office of Government Ethics has reviewed
your financial dlsclosure report and that you are in compliance with
applicable laws and regulations governing conflicts of interest. Also
enclosed is ``Ethics Starts Here: A Guide for Senior Officials'' to
provide you with an introductory guide to the government ethics rules.
We hope you will find this overview helpful.
In addition, as you may already know, all Federal Agencies have a
Designated Agency Ethics Official (DAEO). If, in the course of the
confirmation process, you have any questions about conflicts of
interest or other ethics related matters, you should contact your DAEO,
Edgar M. Swindell, who can be reached at 202-690-7258.
I wish you all the best as you proceed through the confirmation
process.
Sincerely,
Marilyn L. Glynn,
Acting Director.
______
U.S. Office of Government Ethics,
Washington, D.C.,
March 1, 2005.
Hon. Michael B. Enzi,
Committee on Health, Education, Labor, and Pensions,
U.S. Senate,
Washington, D.C.
Dear Mr. Chairman: In accordance with the Ethics in Government Act
of 1978, I enclose a copy of the financial disclosure report filed by
Lester M. Crawford, who has been nominated by President Bush for the
position of Commissloner, Food and Drug Administration, Department of
Health and Human Services.
We have reviewed the report and have also obtained advice from the
Department of Health and Human Services concerning any possible
conflict in light of its functions and the nominee's proposed duties.
Based thereon, we believe that Mr. Crawford is in compliance with
applicable laws and regulations governing conflicts of interest.
Sincerely,
Marilyn L. Glynn,
Acting Director.
______
Center for Biosecurity, Food Safety, and Public
Health,
Lakeworth, FL.
Lester M Crawford, DVM, Ph.D.,
Acting Commissioner,
Food and Drug Administration,
Rockville, MD.
Dear Lester: Congratulations and best wishes for a speedy
confirmation. You have been an outstanding professional, a dedicated
public servant, and a perfect exemplar of how members of the veterinary
profession can contribute to benefit one medicine.
You will be challenged daily in a manner that would test your inner
strength. That is the price that you will pay as you continue to serve
the needs of our Nation--it is a small price. Stay the course, but pace
yourself and avoid as much as possible the stresses linked to the job.
I wish you well. You are most deserving.
Sincerely,
Don A. Franco,
President.
______
Cystic Fibrosis Foundation,
Washington, D.C.,
February 18, 2005.
Hon. Michael O. Leavitt,
Secretary of Health and Human Services,
U.S. Department of Health and Human Services,
Washington, D.C.
Dear Sec. Leavitt: The Cystic Fibrosis Foundation supports the
nomination of Dr. Lester Crawford as Commissioner of Food and Drugs.
Representing 30,000 people with cystic fibrosis (CF) and their
families, the CF Foundation is keenly aware of the importance of a
strong leader at the FDA to ensure innovation and protect the public
health.
Cystic fibrosis is a chronic, progressive, life-threatening,
genetic disease that makes breathing difficult and impairs digestion of
food, It creates abnormally thick, sticky mucus in the lungs and
pancreas, which results in persistent coughing and chronic lung
infections, as well as poor weight gain. A bacterial or viral lung
infection that has a minimal impact on a healthy person could be life-
threatening to someone with CF. While 30,000 people in the United
States have CF, more than 10 million Americans are unknowing,
symptomless carriers of a copy of the defective CF gene; individuals
with CF have two copies of the gene.
Several new drugs for CF that have been approved in the last decade
are the result of key incentives, including the Orphan Drug Act and the
fast track approval process for life-threatening diseases. These drugs
are critical to the people with CF who desperately need more effective
medications to enjoy longer, healthier lives with this disease. Though
we believe the FDA plays a vital role to ensure the safety of all
medications, our community is well aware of the risk/benefits required
and the impact on their own health of delaying approval of new
technology. We hope that as Commissioner, Dr. Crawford will provide the
essential leadership that will enable the FDA to maintain the priority
on the timely approval of drugs to treat life-threatening diseases,
such as CF.
We look forward to working with the Commissioner in the months and
years ahead.
Sincerely yours,
Robert J. Beall, Ph.D.,
President and CEO.
______
Federation of American Hospitals,
February 16, 2004.
Federation Commends Nomination of Dr. Lester M. Crawford for FDA
Commissioner
The Federation of American Hospitals commends President Bush's
nomination of Dr. Lester M. Crawford as Commissioner of the Food and
Drug Administration (FDA).
Dr. Crawford has an exemplary record of public service, with both
the FDA and the U.S. Department of Agriculture, and has performed
admirably as acting FDA Commissioner. Furthermore, Dr. Crawford has an
extensive background in consumer health and safety issues, including
safety issues with medicine and food. We believe Dr. Crawford is an
excellent choice for FDA Commissioner and look forward to working with
him on regulatory issues of mutual interest.
Chip Kahn,
President.
______
5504 Goldsboro Road,
Bethesda, MD,
February 14, 2005.
Lester Crawford, DVM, Ph.D.,
Commissioner,
Food and Drug Administration,
5600 Fishers Lane,
Rockville, MD.
Dear Commissioner Crawford: Congratulations on your well deserved
appointment. You join a very distinguished list of individuals to hold
this position.
It appears that this appointment will mark some significant
firsts--first Deputy elevated to full Commissioner; first veterinarian
trained professional to the post.
If my accounting is correct, there will have been chemists,
physicians, a pharmacist, a zoologist and now a veterinarian.
My best wishes for success in what is one of the best and most
difficult jobs in Washington.
Sincerely,
Sherwin Gardner.
______
Girl Scouts of the USA,
March 14, 2005.
Hon. Michael Leavitt,
Secretary,
U.S. Department of Health and Human Services,
200 Independence Avenue, SW,
Washington, D.C.
Dear Mr. Secretary: On behalf of the Girl Scouts of the USA, I
enthusiastically applaud the nomination of Dr. Lester Crawford to serve
as the new Federal Drug Administration (FDA) Commissioner. Dr. Crawford
has served the FDA with distinction as Deputy Commissioner and now
Acting Commissioner, and we believe he will make an excellent
Commissioner.
Throughout our 93-year history we have offered girls innovative
programs in sports, nutrition and health. Our long-standing commitment
to the health and well-being of girls gives our organization a profound
understanding of the complex issue of obesity. From the beginning of
his tenure at the FDA, Dr. Crawford recognized the need to respond to
the increase in adolescent obesity and was instrumental in creating our
Healthy Living partnership between your agency and the GSUSA to educate
girls and their families about nutrition and the importance of physical
activity. His leadership and guidance will help to ensure that this and
other FDA initiatives regarding the health and well-being of children
and families are successful.
We look forward to his confirmation and to continuing to work with
Dr. Crawford to promote healthier lifestyles for all Americans.
Sincerely,
Kathy Cloninger,
Chief Executive Officer.
______
Generic Pharmaceutical Association,
February 14, 2005.
Hon. Lester Crawford,
FDA Commissioner.
Arlington, VA, Feb. 14 Newswire--The Generic Pharmaceutical
Association (GPhA) today welcomed the White House's nomination of Dr.
Lester M. Crawford to be Commissioner of the Food and Drug
Administration (FDA). Dr. Crawford has served as Acting Commissioner
since 2004,
``We're pleased that the White House has decided to nominate Dr.
Crawford to this key position, A permanent, fully confirmed
Commissioner will have the authority to move forward on many of the
important tasks facing the FDA.'' said GPhA President and CEO Kathleen
Jaeger. ``GPhA has been working with Dr. Crawford in his current role
and we are looking forward to continuing our conversations with him as
the permanent Commissioner, once he is confirmed by the Senate.''
Jaeger noted that because Dr. Crawford has served as Acting
Commissioner for nearly 1 year, he already is familiar with many of the
issues affecting the generic industry. Those include the development of
an abbreviated approval pathway for generic biopharmaceuticals, an end
to the practice of authorized generics, the timely approval of generic
medicines, and concerns with price controls/reimportation.
GPhA represents the manufacturers and distributors of finished
generic pharmaceuticals, manufacturers and distributors of hulk active
pharmaceutical chemicals, and suppliers of other goods and services to
the generic drug industry. Generics represent 51 percent of the total
prescriptions dispensed in the United States, but less than 8 percent
of all dollars spent on prescription drugs. For further information,
please contact GPhA at 703-647-2480, or visit our web site at http://
www.gphaonline.org/.
Sincerely,
Kathleen Jaeger,
President and CEO.
______
February 15, 2005.
The undersigned organizations are writing to express our support
for Dr. Lester Crawford as Commissioner of the Food and Drug
Administration.
Background: People with HIV/AIDS rely on the FDA for approval of a
vast array of medical treatments. It is the major source of the
prescription drugs that can forestall their illness and disability. It
is also the major source of much of the diagnostic and preventive care,
as well as treatment for those who become sick. We urge the
confirmation of Dr. Crawford and look forward to his continued
leadership.
Sincerely,
AIDS Action Project Northwest, AIDS Alliance for Children, Youth,
AIDS Foundation of Chicago, AIDS Legal Council of Chicago, AIDS Project
Los Angeles, AIDS Rochester, AIDS Services of Dallas, AIDS Survival
Project, AIDS Treatment Activists Coalition, AIDS Treatment Data
Network, 1AIDSmeds.com, Asian and Pacific Islander Wellness Center,
Boulder County AIDS Project, Care for the Homeless, Cascade AIDS
Project, Catholic Charities AIDS Services, Center for AIDS, Community
HIV/AIDS Mobilization for Power (CHAMP), Critical Path AIDS Project,
Doorways, an Interfaith AIDS Residence Program, Fenway Community Health
Center, Florida Keys HIV Community Planning Partnership, foundation for
Integrative AIDS Research (FIAR), Gay, Lesbian, Bisexual, and
Transgender Community Center of Baltimore and Central Maryland, Harm
Reduction Coalition, Health Education Resource Organization. Inc.
(HERO), Hemophilia Association of New York, Hep-C Alert, Hepatitis C
Action & Advocacy Coalition, Hepatitis C Caring Ambassadors Program,
Hepatitis C Outreach Project, HIV/AIDS Alliance for Region Two, Inc,
Housing Works, HUG-ME Program, Orlando Regional Healthcare,
International Foundation for Alternative Research in AIDS (IFARA), Iris
House, Inc. Latino Commission on AIDS, Latino Organization for Liver
Awareness (LOLA), Lifelong AIDS Alliance, Long Island Association for
AIDS Care (LIAAC), Metro St. Louis HIV Health Services Planning
Council, McAuley Health Center, Minnesota AIDS Project, Montrose
Clinic, Movable Feast, Inc., NAMES Project Foundation, Nashville CARES,
National Healthcare for the Homeless Council, New York City AIDS
Housing Network, Persons Living with HIV Action Network of Colorado,
Philadelphia FIGHT, Positive Employment Options, Project Open Hand,
Provincetown AIDS Support Group, Rochester Area Task Force on AIDS, San
Francisco AIDS Foundation, San Mateo County AIDS Program, Seattle
Treatment Education Project (STEP), Siouxland and Local Area AIDS
Project, St. Louis Effort for AIDS, T.H.E. Clinic, Tennessee AIDS
Support Services, Inc., The Health Association, Treatment Action Group,
Treatment Access Expansion Project (TAEP), Vermont People With AIDS
Coalition, Visionary Health Concepts, West Virginia HIV Care
Consortium, Williamsburg/Greenpoint/Bushwick HIV CARE Network, Wilson
Resource Center.
______
Institute of Medicine of the National Academies,
Washington, D.C.,
February 16, 2005.
Lester M. Crawford, Ph.D.,
Commissioner of Food and Drugs,
Food and Drug Administration,
5600 Fishers Lane,
Rockville, MD.
Dear Les: What great news! Congratulations, and thanks for the
continued leadership. It's terrific when good work is recognized, and
that's clearly the case here. We all look forward to working with you.
Meanwhile, warm wishes for great success.
Sincerely,
J. Michael McGinnis, M.D., M.P.P.,
Senior Scholar.
______
Interamerican College of Physicians and Surgeons,
Washington, D.C.,
February 15, 2005.
The Interamerican College of Physicians and Surgeons was founded in
1979 to promote cooperation among U.S. Hispanic physicians and to
advance their professional and educational needs. The ICPA reaches a
vast majority of the Hispanic medical community in the United States
and Puerto Rico--over 39,000 physicians--and a growing number of health
professionals in Mexico, the Caribbean, Central and South America, and
Spain. The ICPS is the largest association of Hispanic physicians in
the Nation.
Today, the ICPS is writing to express our support for the
nomination of Dr. Lester Crawford as FDA Commissioner. Dr. Crawford has
a long and distinguished record of bringing safe and effective new
treatments to all patients. His leadership and expertise will continue
to guide the FDA to ensure safe regulation of food and medical
products.
Again, ICPS urges confirmation of Dr. Crawford.
______
Kidney Cancer Association,
Evanston, IL,
February 15, 2005.
The Kidney Cancer Association is pleased to support the nomination
of Lester M. Crawford to be Commissioner of Food and Drugs at the
Department of Health and Human Services.
Dr. Crawford's track record with regard to regulation of medical
products and ensuring timely access to safe, effective new tests and
treatments is an indication of his commitment to patient safety. In
addition, his FDA service record combined with his science based
leadership in medical regulation should enable him to serve all
Americans well--especially the hundreds of thousands with life
threatening illnesses, such as kidney cancer, demand safe and
efficacious treatments.
Sincerely,
William P. Bro,
CEO.
______
National Alliance for the Mentally Ill,
Arlington, VA,
February 16, 2005.
Hon. Mike Enzi,
Hon. Edward M. Kennedy,
Committee on Health, Education, Labor, and Pensions,
U.S. Senate,
Washington, D.C.
Dear Chairman Enzi & Senator Kennedy: On behalf of the 210,000
members and 1,200 affiliates of the National Alliance for the Mentally
Ill (NAMI), I am writing to urge support for the nomination of Dr.
Lester Crawford as Commissioner of the Food and Drug Administration
(FDA). As the Nation's largest organization representing individuals
with severe mental illnesses and their families, NAMI is pleased to
support this important appointment.
In NAMI's view, Dr. Crawford brings unique qualifications to the
important position of FDA Commissioner. He has a strong track record of
working to ensure timely access to safe, effective new tests and
treatments. This includes a long record of service at the FDA in both
the Carter and Reagan administrations. He has a demonstrated record of
effectiveness in promoting a science-based approach to patient safety.
NAMI urges the HELP Committee to act swiftly on this important
nomination. It is critically important that the FDA have a strong
leader in place address challenges faced by the agency with respect to
safety and monitoring of medications.
Sincerely,
Michael J. Fitzpatrick, MSW,
Executive Director.
______
National Milk Producers Federation,
Arlington, VA,
March 9, 2005.
Senate Committee on Health, Education, Labor, and Pensions.
Dear Chairman Michael B. Enzi: I a writing to express the support
of the National Milk Producers Federation for Dr. Lester Crawford, the
nominee for Commissioner of the Food and Drug Administration. We hope
the Senate Health Committee, following the necessary hearing and
deliberations, will act quickly to approve Dr. Crawford.
Few commissioners in the history of the FDA have the depth and
breadth of Dr. Crawford's experience in life science and food safety
issues, coupled with a laudable record of public service focused on
those issues. His two recent stints as Acting FDA Commissioner, coupled
with his previous service as Director for the FDA's Center for
Veterinary Medicine, give him an unprecedented familiarity with roles
and responsibilities of the FDA.
By the same token, his past service as Administrator of the USDA's
Food Safety and Inspection Service also provides him a unique
perspective on the important oversight role that both the FDA and USDA
provide in maintaining the public health.
On a personal note, I had the privilege of serving at FDA with Dr.
Crawford early in my career and I have first hand knowledge of his
capabilities, statesmanship and leadership. His early life growing up
on a dairy farm in Alabama also serves him as a man of character,
discipline, and fortitude.
His commendable track record of successes in a variety of settings
is ample evidence of Dr. Crawford's capabilities. We hope that the
members of the Senate Health Committee, and the Senate overall, will
also acknowledge those capabilities by acting quickly to confirm Dr.
Crawford as FDA Commissioner.
Yours truly,
Jerry Kozak,
President and CEO.
______
Response to Questions of Senator Bingaman by Lester Crawford, DVM,
Ph.D.
(1) Response to Letters
Question 1. We await responses to the March 2004 anthrax vaccine
letter and the July 2004 letter sent with Senator Reed regarding drug
trials. Can we obtain answers to these letters? What is the timeframe
for such responses?
Answer 1. On June 4, 2004, the Food and Drug Administration (FDA or
the Agency) responded to your letter of March 7, 2004. Although the
response was limited due to pending litigation, additional public
information has become available since our June 2004 response.
There is only one anthrax vaccine licensed in the United States,
Anthrax Vaccine Adsorbed (AVA), also known as Biothrax, which is
manufactured by BioPort Corporation, located in Lansing, Michigan. AVA
was first licensed by NIH in November 1970. AVA is recommended for
individuals who may come in contact with animal products that may be
contaminated with Bacillus anthracis spores and for individuals engaged
in diagnostic or investigational activities that may bring them in
contact with Bacillus anthracis spores. It is also recommended for
persons at high risk, such as veterinarians and others handling
potentially infected animals.
In an October 27, 2004 court order currently on appeal, the
district court for the District of Columbia invalidated the January 5,
2004, final rule referenced in your letter. On December 29, 2004, in
deference to the court, FDA republished a proposed rule and proposed
order to provide notice and comment to give interested persons an
opportunity for input. Comments were due by March 29, 2005. The
proposed rule and order can be accessed on FDA's website: http://
www.fda.gov/cber/vaccine/anthrax.htm.
In the December 29, 2004, proposed rule and proposed order, FDA
categorized those bacterial vaccines and toxoids licensed before July
1972 according to the evidence of their safety and effectiveness, and
issued a proposed response to recommendations made in an advisory
panel's report. Pursuant to the FDA regulations Title 21, Code of
Federal Regulations 601.25, the advisory panel was convened on July
12, 1973, in an organizational meeting, followed by multiple working
meetings until February 2, 1979. The Final Report of the advisory panel
was completed in August 1979. The advisory panel's recommendations
concern conditions relating to active components, labeling, tests
required before release of product lots, product standards, or other
conditions considered by the advisory panel to be necessary or
appropriate for assuring the safety and effectiveness of the reviewed
products.
FDA will be considering all comments submitted in response to the
December 29, 2004, proposed rule and proposed order.
(2) Office of Drug Safety
Background
The Office of Drug Safety (ODS) is responsible for ensuring the
safety of drugs already approved and on the market. It is housed within
the Center for Drug Evaluation and Research (CDER). CDER is also home
to the Office of New Drugs (OND), which is responsible for reviewing
new drug applications and approving drugs for market.
There have been allegations that having both ODS and OND in the
same component of the FDA creates conflicts. These conflicts stem from
the fact that both offices are subject to the same management, which
may not want drugs it has approved for market to be the subject of too
much scrutiny, and also from the fact that OND and ODS staff are
colleagues, which may create situations in which less than complete and
impartial review of safety concerns occurs. The co-location of ODS and
OND within CDER may have a chilling effect on raising and addressing
safety concerns.
Question 2. Dr. Crawford, we have heard allegations about the
conflicts that stem from the fact that the Office of Drug Safety (ODS)
and the Office of New Drugs (OND) are co-located within the Center for
Drug Evaluation and Research. There is some concern that drug safety
concerns may not receive as much attention as they warrant given the
potentially divergent missions of ODS and OND.
What are your thoughts on taking ODS out of CDER and putting it
elsewhere within the FDA, like the Office of the Commissioner? Will
that help foster scientific debate about drug safety? Will moving the
Office of Drug Safety help ensure that drug safety concerns receive the
appropriate amount of attention?
Are there other things that you would do to increase the FDA's
commitment to drug safety? Are there other things you would suggest
Congress do?
How do you intend to balance the need to expediently approve
innovative drugs while ensuring the safety of consumers? Are you
supportive of an independent office of drug safety?
Answer 2. Recently, I joined Secretary Leavitt to announce
important efforts that we are undertaking with FDA to improve its
ability to monitor and respond to emerging drug safety information.
These steps will ensure both a better internal process of deliberation
on drug safety issues that ensures appropriate and independent
consideration of all issues, as well as a stronger ability to gather
data about drug safety issues once a drug has been approved.
Most importantly, we are moving to encourage more transparency and
to ensure that patients and physicians have the most up-to-date and
complete information necessary to inform their treatment decisions.
This new Drug Information Initiative will give patients, healthcare
professionals, and other consumers quick and easy access to the most
up-to-date and accurate information on medicines and make FDA's drug
review, approval, and monitoring programs as transparent a possible.
This is in addition to FDA's Five Point Plan to Improve Drug
Safety, a major initiative designed to improve the monitoring of drug
products recently approved for marketing. The major components of this
initiative include:
Sponsoring a major study of the Drug Safety System by the
Institute of Medicine;
Implement a Program for Adjudicating Differences of
Professional Opinion;
Conducting a nationwide search to identify a permanent
director for the Office of Drug Safety;
Conducting a series of workshops and meetings on drug
safety and risk management; and
Publishing risk management guidance.
FDA's Office of Drug Safety (ODS), in the Center for Drug
Evaluation and Research (CDER), is already an independent office
separate from the Office of New Drugs, the office that reviews new drug
applications. Both the Office of New Drugs and the Office of Drug
Safety report directly to the Director of the CDER. ODS has independent
authority to perform its own research and does so every day. To be
valuable, this independent research must conform to widely accepted
scientific standards and normal scientific procedures and peer review
should not be bypassed. And when drug safety issues are identified,
they must be factored into the risk-benefit equation so that safe and
effective drugs remain available to patients who need them.
FDA has a longstanding commitment to provide a strong resource base
for its drug safety program. The budget for fiscal year 2006 continues
this commitment. The President has proposed a 24 percent increase for
FDA's post-market safety program to help further ensure that America's
drug product supply is safe and effective, and of the highest quality.
Under this proposal, CDER's ODS would receive increased funding to
expand the Agency's ability to rapidly survey, identify and respond to
potential safety concerns for drugs on the market. ODS will hire
additional staff to manage and lead safety reviews, will increase the
number of staff with expertise in critical areas such as risk
management, risk communication and epidemiology, and will increase
access to a wide range of clinical, pharmacy and administrative
databases. Our commitment to increase resources available for post-
market safety will enhance the structural changes we are proposing to
advance drug safety.
(3) Office of Orphan Products
Background
The Director of the Office of Orphan Products Development (OOPD),
Dr. Marlene Haffner, is a respected and accomplished leader of OOPD.
She is a highly dedicated public servant, respected by the
pharmaceutical and biotechnology industry, by patient organizations,
researchers, and by national drug regulatory authorities not just in
the United States but throughout the world.
Through the office, there are 267 FDA approved orphan drugs and
several ``humanitarian'' medical devices that treat at least 13 million
Americans today--Americans who would otherwise have no treatment at
all--and millions more throughout the world. Just last year, the FDA
reported that the ``program is widely viewed as a major success in
assisting in development of treatments for rare diseases, at a very
modest investment. FDA is conducting an internal review of how the
successes of Orphan Products development research might be applied to
other kinds of critical path problems.''
It is our understanding that Dr. Haffner does not want to retire
and continues to serve in the Public Health Service (PHS). Under her
leadership, the FDA's orphan drug program has led the rest of the world
in an international cooperative effort to address these devastating
diseases. When Dr. Haffner decides to retire, the FDA should conduct a
nationwide search for an individual with medical and/or pharmacy
background and extensive knowledge of orphan products and rare diseases
to ensure the continued growth and international influence of the FDA's
Office of Orphan Products Development.
Question 3. The FDA Office of Orphan Drugs has a long successful
history. It is my understanding that you are considering management
changes in the office. If the office has been so successful, why are
such changes being considered? What are your plans for ensuring that
future management has the knowledge, subject expertise, and track-
record necessary to ensure continued office and program success,
including expertise in orphan drugs, biologics, or humanitarian use
devices?
Answer 3. All FDA offices are required to have succession plans.
The incumbent in the Office of Orphan Drugs has been in that position
for 17 years. Traditionally, FDA leaders have rotated into other
positions following lengthy periods in one position. This is the best
for the institution and for the individual. No current Director,
Associate Commissioner, or Deputy Commissioner has served for 17 years
in one position. Finally, whenever FDA conducts recruitments for
vacancies, we strive to identify individuals that have the relevant
management and subject matter expertise for the position.
(4) Labeling
The Food and Drug Administration's (FDA) Office of Nutritional
Products, Labeling and Dietary Supplements (ONPLDS) is responsible for
essential public health and consumer protection programs. ONPLDS
develops policy and regulations for nutrition labeling, food standards,
infant formula and medical foods. During hearings last year by the
House Appropriations Subcommittee on Agriculture, Rural Development and
Related Agencies, FDA stated that it would need 10-12 additional full
time equivalents (FTEs) to complete five important projects, the
majority of which are food labeling projects associated with reducing
the costly rise in obesity among Americans. In addition, the Senate
Committee on Appropriations last year recognized the important public
health responsibilities of this Office and noted that its funding for
activities other than the regulation of dietary supplements has
remained level for several years. In Senate Report 108-340, the
committee, therefore, encouraged ``FDA to determine if additional
funding is necessary for ONPLDS to more effectively carry out its
important responsibilities, and if appropriate, increase funding for
this office in its fiscal 2006 budget request.''
Questions 4. Why did FDA fail to request additional FTEs in its
2006 budget for labeling activities when it told the House that it
needed 10-12 additional FTEs and was encouraged by the Senate to
determine if it needed more funding? If these matters are not
addressed, how will FDA ensure that the market is not flooded with
deceptive claims appealing to consumer's desire to control their weight
especially in light of the cut in inspections?
Answer 4. FDA's Office of Nutritional Products, Labeling and
Dietary Supplements' (ONPLDS) responsibilities continue to grow,
including initiatives on infant formula review notifications, better-
informed consumers, obesity, and allergen labeling. In addition, the
Office has a continuing challenge to protect the safety and security of
the food supply from tampering and from counterfeit products. The
President's fiscal year 2006 budget request delineates FDA's priorities
in this regard. FDA will continue to evaluate if additional funding is
necessary for ONPLDS to more effectively carry out its important
responsibilities.
(5) Food and Drug Administration Advisory Committees
The FDA relies on advisory committees to evaluate the scientific
evidence supporting applications for new drugs, biologics, medical
devices, and foods. Advisory committees also play a key role when drug
safety issues come to the fore, as they have in the past year with the
use of antidepressants in children leading to suicide and the
cardiovascular risk from the newer arthritis pain relief medicines
known as COX-2 inhibitors. Though the Federal Advisory Committee Act
(FACA) prohibits outside scientists recruited to serve on these
advisory panels from having conflicts of interest with companies whose
products are under review, the FDA staff routinely waives such
conflicts. These waivers are allowed under the law. Moreover, the staff
usually waits until the eve of the advisory panel's meeting to release
the names of the scientists who will be serving on the panel and the
questions they will be asked, thus making it almost impossible for the
public to scrutinize their choices to determine if the agency has met
FACA's requirements for eliminating conflicts of interest and assuring
that the committee is balanced with regard to points of view. The use
of waivers reached a nadir at the recently concluded advisory panel on
COX-2 inhibitors, where at least 10 of the 32 scientists on the panel
had financial relationships with the companies involved. These
conflicts were not disclosed at the meeting. Moreover, the FDA claimed
that they didn't need to be disclosed because it was just a general
discussion of the issue and not specific to any one company even though
at the end of the 3-day meeting, specific votes were taken on three
drugs.
Questions 5. Why did the FDA say at the advisory committee meeting
that voted on specific COX-2 inhibitors that financial relationships
with the companies making those drugs did not have to be disclosed?
What efforts did the FDA make, prior to that COX-2 inhibitors meeting,
to find additional experts who did not have a financial relationship
with the manufacturers of those drugs? More generally, what do you
intend to do at the FDA to clean up the advisory committee process for
drugs, biologics, medical devices, and foods so that scientists who
serve on your panels don't have conflicts of interest with the
companies whose products are under review?
Answer 5. FDA screened the Advisory Committee members and other
invited special Government employees (SGEs) for conflicts of interest
according to the same strict ethics guidelines FDA applies to all its
advisory committees. This transparent process requires the Agency to
carefully weigh any potential financial interest with the need for
essential scientific expertise in order to protect and advance the
public health. It is very difficult to obtain qualified advisory
committee panel members who are totally free from any previous
association with manufacturers. The Nation's experts (and in some
cases, there are only a few experts on a particular topic) are sought
after for consultation by both the Agency and industry because of the
scarcity, and therefore the value, of their expertise. Utilizing less
experienced or less highly qualified scientists in order to completely
remove any potential conflict from the committee would hamper the
Agency's ability to protect and advance the public health.
The Agency's staff examines all potential financial interests. The
Agency's process is to evaluate the potential financial interests of
members and other invited special government employees. FDA makes a
determination as to whether the participation of an individual with
some financial ties outweighs the need for the agency to understand the
science on the topic before the committee. Although the Agency has
guidelines for this process (see Waiver Criteria Document 2000 on the
FDA website: http://www.fda.aov/oc/advisory/conflictofinterest/
intro.html.), this is not a black and white process. It requires
careful consideration of all facets of the issue in order to evaluate
that balance. Congress, by permitting waivers for potential conflicts
of interest, has ensured that the Agency and the public (through the
advisory committee process) have access to the most knowledgeable
individuals on the meeting topic.
Although 18 U.S.C. Section 208 provides that a copy of any waiver
determination is available to the public upon request, the Agency may
withhold from disclosure information that would be exempt under the
Freedom of Information Act, 5 U.S.C. 522(b). Under this provision,
all of the information concerning conflicts of interest may be withheld
as exempt pursuant to 5 U.S.C. 522(b)(3) because the Ethics in
Government Act prohibits release of the information. Nevertheless, in
order to provide meaningful disclosure of conflicts of interest
information, the Office of Government Ethics has concluded that, under
section 208, Federal agencies have discretion to disclose information
concerning the waived conflict of interest absent a foreseeable harm to
be caused by the disclosure. The Office of Legal Counsel, United States
Department of Justice (OLC), concluded that FDA may exercise its
discretion in making disclosure to avoid making the disclosure
requirement so intrusive or onerous as to make outside experts
unwilling to serve on advisory committees.
In January 2002, the FDA issued draft guidance on ``Disclosure of
Conflicts of Interest for Special Government Employees Participating in
FDA Product Specific Advisory Committee.'' The guidance provides
information on the type and amount of information that will be
disclosed to the public when a member is granted a conflict of interest
waiver with the topic to be discussed by the committee. The guidance
applies only to those advisory committee meetings at which a particular
matter relating to a particular product is discussed (product specific
meetings). The guidance does not apply to advisory committee meetings
that provide advice on topics of general applicability (i.e., those
meetings that could affect a class of products and their sponsors) even
if the members on the committee received general matters waivers
covering their participation on the committee.
The disclosure for particular matters identifies whether the
interest is related to the sponsor or competitor that markets a product
competing with the product at issue (without naming the competitor),
the type of interest (stock, consulting, contracts/grants, patents/
royalties/trademarks, expert witness, teaching, speaking, or writing),
and the magnitude of the interest is described as a range.
After conducting the Agency's standard thorough review of the
potential conflicts of interest for all potential members and invited
SGEs on the advisory committee discussing the class of COX-2
inhibitors, several types of conflicts of interest were found. At least
one potential participant was recused from the meeting entirely. In
other cases, FDA found the conflicts not to be of sufficient magnitude
to outweigh the need for the SGEs' specific scientific expertise for
this public meeting. Accordingly, the Agency approved waivers to allow
the participation of 19 scientists. The additional 16 participants did
not require waivers.
SGEs who serve the public interest on advisory committee panels are
world-class experts who are highly renowned and respected in their
fields. Most consider it an honor and a privilege to serve on advisory
committees. SGEs disclose all relevant personal and imputed financial
information and members of the public may request copies of the waivers
granted under 18 U.S.C. 208 through the Freedom of Information Act
process. FDA has no reason to believe that any potential conflict
affected the participant scientist's recommendations given our careful
evaluation of all potential conflicts, selection of appropriate
experts, and adherence to our standard process for granting and
disclosing waivers where the need for essential scientific information
for public discussion is so warranted.
FDA's process of evaluating potential committee members for
conflicts is very extensive and transparent. At the beginning of each
meeting, a conflict of interest statement is read into the record,
which summarizes the results of the conflicts of interest screening.
FDA has been commended by the Office of Government Ethics (1997) for
serving as ``a model for other Agencies to use in developing their own
systems and procedures.'' Nonetheless it is always prudent to regularly
assess the Agency program and determine if any improvements are
warranted. In the near future, the Agency will review the advisory
committee conflicts of interest disclosure process and consider if
further improvements are necessary to make the disclosures more easily
accessible to the public.
(6) Trans Fat in Partially Hydrogenated Vegetable Oils
Trans fat in partially hydrogenated vegetable oils is a major
public health problem because it promotes heart disease. In July 2002
the Institute of Medicine (``IOM'') of the National Academy of Sciences
concluded that the consumption of trans fat is at least as unhealthful
as the consumption of saturated fat and that consumption of trans fat
in any amount increases the risk of heart disease. In December 2003 the
IOM concluded that it is feasible to exclude from the diet trans fat
from partially hydrogenated vegetable oil. In April 2004 the Nutrition
Subcommittee of the Food and Drug Administration (``FDA'') Food
Advisory Committee concluded that trans fat is more conducive to
coronary heart disease than is saturated fat. The January 2005 Dietary
Guidelines recommended minimizing consumption of trans fat from both
partially hydrogenated oils and meat and dairy products.
Questions 6. In addition to inclusion of trans fat information on
Nutrition Fact labels by 2006, what other measures will be taken by FDA
to promote public health in regard to trans fat intake?
Answer 6. FDA is requiring the declaration of trans fat amounts
directly under the saturated fat line on the nutrition facts panel
(without a %DV). This requirement goes into effect January 1, 2006.
(The trans fat labeling rule, which was published on July 11, 2003, in
the Federal Register, can be found at http://www.cfsan.fda.gov/-
acrobat/fr03711a.pdf). We believe this information will allow consumers
to lower their intake of trans fat. We estimate that 3 years after the
January 1, 2006 effective date, trans fat labeling will result in
approximately 600 to 1,200 fewer cases of coronary heart disease and
240-480 fewer deaths each year, saving $900 million to $1.8 billion per
year in medical costs, lost productivity, and pain and suffering.
FDA understands the important public health concern associated with
the consumption of products that contain cholesterol-raising lipids
such as trans fat which, in turn, may increase the risk of coronary
heart disease. We encourage consumers to choose foods with lower
amounts of saturated fat, trans fat and cholesterol as part of a
healthy diet (see FDA's education material entitled ``Trans Fat Now
Listed with Saturated Fat and Cholesterol on the Nutrition Facts
Label'' on the web at http://www.cfsan.fda.gov/-dms/transfat.html). FDA
also recommends that saturated and trans fats be replaced with mono-
and polyunsaturated fats because mono- and polyunsaturated fats do not
raise LDL (or ``bad'') cholesterol levels and have health benefits when
eaten in moderation. The 2005 Dietary Guidelines for Americans contain
these same recommendations. The FDA has worked closely with other
offices within the Department of Health and Human Services to foster
the incorporation of these messages into consumer education materials
as it relates to nutrition labeling. To further disseminate FDA's
consumer message about trans fat and other cholesterol raising fats, we
are planning additional outreach efforts, including a Newsflash that
can be incorporated into consumer magazines and other publications.
The Agency has no regulation defining nutrient content claims or a
reference value for trans fat. In the near future, we hope that we will
be able to establish definitions for claims such as ``trans fat free''
and in response to an ANPRM that published the same day as the trans
fat labeling final rule (http://wvvw.cfsan.fda.gov/-Ird/fr03711b.html).
Soon, FDA will be conducting consumer research to determine consumer
perception of trans fat labeling including nutrient content claims and
a possible footnote statement. Currently, the label or labeling may
contain a statement about the amount of trans fat provided the
statement is not false or misleading and in no way characterizes the
level of trans fat in the food. For example, ``0 g trans fat/per
serving'' and ``2 g trans fat/per serving'' are appropriate when, in
fact, the nutrition facts panel represents these same amounts of trans
fat per serving.
FDA is also working to develop educational strategies and
partnerships to support appropriate messages and teach people,
particularly children, how to lead healthier lives through better
nutrition.
Fostering the development of healthier food products for American
consumers is an important aspect of public health. FDA is aware of the
impact labeling trans fat has on the manufacturer (e.g., by creating an
incentive to reformulate), and the alternative ingredients or
processing techniques under consideration for reducing trans fat. FDA
is monitoring industry progress in this effort.
(7) Nutrition Education Strategy
Background
In commenting on the Calories Count report of March 2004, you (FDA
Deputy Commissioner Lester M. Crawford, D.V.M., Ph.D.) said, ``Our
report concludes that there is no substitute for the simple formula
that ``calories in must equal calories out'' in order to control
weight. We're going back to basics, designing a comprehensive effort to
attack obesity through an aggressive, science-based, consumer-friendly
program with the simple message that ``Calories Count.'' Thus far, we
have seen that education campaign in the form of the updated nutrition
facts label website and the consumer brochure that accompanied the
release of the 2005 Dietary Guidelines for Americans.
Question 7. What ``aggressive, science-based, consumer friendly''
strategies do you have planned for the future?
Answer 7. FDA believes that all parties, including the packaged
food industry, restaurants, academia, and other private and public
sector organizations in addition to government agencies at all levels,
have an essential role to play in communicating the report's messages
to the public. FDA is focusing its science-based, consumer friendly
strategies in 3 areas at this time:
Developing education materials and partnerships to promote
appropriate weight management messages.
Evaluating the need for changes to the food label to make
it easier for consumers to understand the calories and portion sizes
they are consuming.
Working with a third party facilitator to begin a national
policy dialogue, seeking consensus-based solutions, on the obesity
problem and away-from-home foods.
FDA is working to develop educational strategies and partnerships
to support appropriate messages and teach people, particularly
children, how to lead healthier lives through better nutrition. We are
starting work with the Girl Scouts of the USA, under terms of a
Memorandum of Understanding signed this past fall, to provide outreach
and education in a science-based initiative to focus on improving
health, nutrition, and physical activity. In addition, FDA's field
offices are participating in local partnerships to reach and teach
children. For example, in Central Florida, FDA's SE Region is part of
the Seminole County Healthy Kids Partnership to promote positive
opportunities for school-aged children in Seminole County to learn
healthy nutrition and the value of increased daily physical activity.
These are examples of how FDA is working to leverage its ability to
convey appropriate messages on obesity to the public with the goal of
changing behavior and ultimately reversing obesity trends in the United
States.
FDA has published advance notices of proposed rulemaking (ANPRMs)
addressing prominence of calories on the label and certain provisions
of the nutrition labeling regulations related to serving size.
FDA also stresses that the regulatory scheme for claims in food
labeling, whether health claims, nutrient content claims, or other
types of claims, must be science based. We continue to consider
modifications to our regulations to keep up with recent scientific
developments. A benefit of standardized, science-based terminology
(e.g., terminology concerning fat content) is that it allows consumers
to compare across products and it encourages manufacturers to compete
based on the nutritional value of the food. FDA, however, does not
regulate television and other media marketing of food products.
In June 2004, FDA signed a contract with the Keystone Center, a
nationally recognized facilitator for policy and scientific issues, to
begin a dialogue on away-from-home foods and the pediatric obesity
(education) issue. The goal of the away-from-home foods dialogue will
be to consider what can be done, given the best available evidence to
date, to support consumers' ability to manage energy intake with
respect to preventing undue weight gain and obesity. The dialogue will
produce a report to FDA and options for a range of actions by diverse
stakeholders, including government, industry, voluntary health
agencies, consumer organizations, and others. Keystone will convene its
first plenary meeting of stakeholders, to include representatives from
the restaurant industry, academia, consumer groups and government on
April 26-27, 2005.
The final Keystone report, and comments received on the two ANPRMs,
in combination with other information, will provide FDA with
information on which to base future activities.
(8) Scientific Evidence vs. Personal or Political Ideology
Questions 8. Do you have a personal commitment to keep politics or
political ideology out of the FDA approval process? If so, how do you
plan to accomplish this?
Answer 8. The law is clear that FDA approval decisions should be
based on science, and the requirements of the law, not ideology or
opinion. Sometimes the science is not adequately developed to provide
for a clear decision, and decisions have to be deferred until adequate
information is available.
I am committed, if confirmed, to ensuring that during my tenure as
commissioner, FDA's decisions will be based on science and the
requirements of the law and that the basis for FDA's decisions are open
and transparent to the public.
My vision for the future of FDA is one of transformation. And one
aspect of that transformation will be ensuring an agency culture of
transparency, collaboration, and cutting-edge thinking.
______
Response to Questions of Senator Burr by Lester Crawford, DVM, Ph.D.
Question 1. On Monday, March 14, 2005, the NIH inadvertently posted
on its website at 2:22 p.m. the results of a large clinical trial that
showed a Genentech drug helped certain lung-cancer patients live
longer. The NIH was supposed to publish those results at 4 p.m., after
the close of trading. Due to the mistake, Genentech's stock shot up 25
percent and the NYSE halted trading in the shares just before 3:30
p.m.--but in the preceding 10 minutes, 4.7 million shares had changed
hands. There has been some discussion around the drug safety issue
about putting more clinical trial data on the web. Shouldn't we
consider examples like what happened on March 14 and think twice about
putting more and more clinical trial data on the web?
Answer 1. As you know, I recently joined Secretary Leavitt to
announce important efforts that we are undertaking with FDA to improve
its ability to monitor and respond to emerging drug safety information.
These steps will ensure both a better internal process of
deliberation on drug safety issues that ensures appropriate and
independent consideration of all issues, as well as a stronger ability
to gather data about drug safety issues once a drug has been approved.
Most importantly, we are moving to encourage more transparency and
to ensure that patients and physicians have the most up-to-date and
complete information necessary to inform their treatment decisions.
This new Drug Information Initiative will give patients, healthcare
professionals, and other consumers quick and easy access to the most
up-to-date and accurate information on medicines and make FDA's drug
review, approval, and monitoring programs as transparent as possible.
You raise an important point, and I agree that it is important that
we make this information available in a meaningful, accurate and
responsible manner, and I hope to continue to work with this committee
as we move forward.
Question 2. FDA and USDA have joint responsibility over the Food
Emergency Response Network. Who at the FDA will be in charge of working
on that Network and how directly will they report to you?
Answer 2. As you know, the Food Emergency Response Network (FERN)
is a nationwide laboratory network that integrates existing Federal and
State food testing laboratory resources by utilizing standardized
diagnostic protocols and procedures. FERN is the collaborative work of
USDA and FDA with support from the Department of Homeland Security
(DHS), Centers for Disease Control and Prevention (CDC), Department of
Defense (DOD), Federal Bureau of Investigation (FBI), Customs and
Border Protection (CBP), and the Environmental Protection Agency (EPA).
By increasing our laboratory search capacity, FERN will enhance the
Nation's ability to respond swiftly to a terrorist attack.
The FERN Steering Committee, which includes Federal and State
representation, was established in September 2003 and is jointly
chaired by Patrick C. McCaskey, Senior Executive for Laboratory
Services within the Office of Public Health Sciences in USDA's Food
Safety and Inspection Service and John R. Marzilli, Deputy Associate
Commissioner for Regulatory Affairs in FDA's Office of Regulatory
Affairs (ORA). FERN Subcommittees have also been formed which provide
guidance and expertise regarding the development and implementation of
FERN programs to Messrs. McCaskey and Marzilli specifically, and the
steering committee, in general.
Participating FERN laboratories fall within one of five
geographically based Regional Coordination Centers (RCCs), otherwise
known as regional ``hubs''. The regional hubs include the Northeast
RCC, the Southwest RCC, the Southeast RCC, the Pacific RCC and the
Central RCC. Each RCC is led by an Interdisciplinary Scientist who
receives direction from, and reports directly to, the FERN National
Program Office (NPO) located within FDA's/ORA's Division of Field
Science. Scientists within the Division of Field Science who have
oversight of FERN programs subsequently advise, inform and notify Mr.
Marzilli of all issues involving FERN laboratories. FDA's Center for
Food Safety and Applied Nutrition also assists the FERN initiative by
providing specialized scientific expertise, laboratory capabilities,
and research capabilities, as well as training, proficiency, and
logistics support.
Mr. Marzilli reports to his immediate supervisor, the Associate
Commissioner for Regulatory Affairs who, in turn, reports directly to
the Commissioner of Food and Drugs.
Question 3. The DOD and USDA use the Carver Analytical Tool to
perform threat assessments and understand where vulnerabilities are in
a particular system. Will the FDA also use the Carver Analytical Tool
on the food system? I would think that there could be better
coordination between the DOD, USDA and FDA if everyone is using the
same tool to perform threat assessments.
Answer 3. I agree with your statements. To perform threat
assessments, the Agency has been using the CARVER + Shock Analytical
Tool since April 2003. In preparing for the CARVER + Shock analysis,
FDA worked with DOD, CIA, FBI, and our colleagues at USDA/Food Safety
Inspection Service to develop a design basis threat (i.e., what a party
intent on doing damage could do based on their capability, intent, and
past history). The CARVER + Shock analyses for two food products have
now been classified as SECRET. Furthermore, seven other products under
FDA jurisdiction are currently being finalized using the CARVER + Shock
Analytical Tool. In addition to these assessments, FDA has been working
with selected higher risk commodity industry groups to initiate threat
assessment and identify preventive measure options using a CARVER +
Shock approach. Also, FDA has collaborated with USDA using the CARVER +
Shock Analytical Tool on specific commodities that are of joint
interest in relation to the school lunch program.
Question 4. The FDA's Core Mission covers a wide spectrum,
including:
Maintaining the safety of the Nation's food supply from
threats such as BSE or ``mad-cow'' disease;
Ensuring that vaccines are safe and in ready supply for
the American public;
Reviewing the safety and efficacy studies for new medical
drugs and devices; and
Monitoring approved medical drugs and devices for
unforeseen health consequences, to name a few.
Does FDA possess adequate resources and expertise to carry out
these core missions?
Do you believe there are other areas not currently within the
agency's purview that it should address?
If so, is the regulation of tobacco one of those areas?
If there are other areas, how would you expect to allocate FDA's
limited resources to address these new areas without impacting the
agency's ability to carry out its core mission?
Answer 4. FDA has a highly motivated and well-trained staff. Our
resource levels have been sufficient to meet critical needs and
requirements and have been augmented by Congress when new demands are
identified as occurred, for example, with the fiscal year 2002 Counter
Terrorism supplemental appropriations. Our mission involves the
regulation of food and medical products that are valued at more than 20
percent of every consumer dollar spent in the U.S. The Administration's
budgets are set at a level to effectively accomplish FDA's core
mission. If new needs arise, the Administration will work with Congress
to address them.
Question 5. Critics have argued that FDA cannot be trusted to
safeguard the American drug supply and that we need to set up an
independent drug safety office, separate from the FDA and the FDA
personnel who review and approve drug products, to oversee drug safety.
Do you believe that an independent drug safety is necessary? Is there,
in fact, some benefit to having the drug safety review function remain
within FDA even after approval? What is the FDA doing internally to
enhance the independence of its drug safety oversight?
Answer 5. Recently, I joined Secretary Leavitt to announce
important efforts that we are undertaking with FDA to improve its
ability to monitor and respond to emerging drug safety information.
These steps will ensure both a better internal process of
deliberation on drug safety issues that ensures appropriate and
independent consideration of all issues, as well as a stronger ability
to gather data about drug safety issues once a drug has been approved.
Most importantly, we are moving to encourage more transparency and
to ensure that patients and physicians have the most up-to-date and
complete information necessary to inform their treatment decisions.
This new Drug Information Initiative will give patients, healthcare
professionals, and other consumers quick and easy access to the most
up-to-date and accurate information on medicines and make FDA's drug
review, approval, and monitoring programs as transparent as possible.
This is in addition to a major initiative designed to improve the
monitoring of drug products recently approved for marketing. The major
components of this initiative, including the IOM study, include:
Conducting a nationwide search to identify a permanent
director for the Office of Drug Safety;
Conducting a series of workshops and meetings on drug
safety and risk management; and
Publishing risk management guidance.
FDA has a longstanding commitment to provide a strong resource base
for its drug safety program. The budget for fiscal year 2006 continues
this commitment. The President has proposed a 24 percent increase for
FDA's post-market safety program to help further ensure that America's
drug product supply is safe and effective, and of the highest quality.
Under this proposal, CDER's ODS would receive increased funding to
expand the Agency's ability to rapidly survey, identify and respond to
potential safety concerns for drugs on the market. ODS will hire
additional staff to manage and lead safety reviews, will increase the
number of staff with expertise in critical areas such as risk
management, risk communication and epidemiology, and will increase
access to a wide range of clinical, pharmacy and administrative
databases. Our commitment to increase resources available for post-
market safety will enhance the structural changes we are proposing to
advance drug safety.
With regards to an independent drug safety office, FDA's Office of
Drug Safety (ODS), in the Center for Drug Evaluation and Research
(CDER), is already an independent office separate from the Office of
New Drugs, the office that reviews new drug applications. Both the
Office of New Drugs and the Office of Drug Safety report directly to
the Director of the CDER. ODS has independent authority to perform its
own research and does so every day. To be valuable, this independent
research must conform to widely accepted scientific standards and
normal scientific procedures and peer review should not be bypassed.
And when drug safety issues are identified, they must be factored into
the risk-benefit equation so that safe and effective drugs remain
available to patients who need them.
FDA will await the views and findings of the IOM study before
making any major structural changes with regard to ODS. The benefits of
having both OND and ODS under one FDA center are many. Most
importantly, the current structure allows important risk information on
drugs to be shared rapidly between the two offices that are most
familiar with the benefits and risks of the drug. It is this close
collaboration that allows FDA to make the critical decisions with
regard to a drugs benefit-to-risk profile.
Question 6. In November 2002, the FDA disbanded its Medical Imaging
Drugs Advisory Committee (MIDAC), ending the 25 year existence of that
body. Medical imaging drugs are now the only significant class of drugs
for which FDA does not have a standing advisory committee. We
understand that FDA is currently obtaining expert medical imaging
advice by retaining medical imaging experts on an ad hoc basis and
assigning them to existing standing committees as temporary members for
particular meetings. In its notice terminating the MIDAC, FDA said this
system would be ``more effective'' than a standing MIDAC, but did not
explain why. It is difficult to understand how this ad hoc system would
be more effective than having a cohesive group of imaging experts with
appropriate continuity meeting as a standing committee at regular
intervals. Please explain how the current system of assigning experts
ad hoc to existing committees on a meeting-by-meeting basis is ``more
effective'' than having a standing committee.
Answer 6. The MIDAC met only infrequently in the preceding years.
The decision to terminate MIDAC was based on several factors. We
believe that the FDA advisory committee assessment of the risks and
benefits to patients of a new imaging procedure is enhanced through the
perspective of physicians who are providing direct care to patients,
and, as part of that direct patient care, are ordering all imaging
procedures for their patients. As part of the assessment of a patient's
care, these attending physicians must determine the risk and benefit to
their patients of all imaging procedures. As such, the current FDA
advisory committee assessment of a new imaging procedure is performed
by the advisory committee that represents the specialty of patient care
physicians that will order the new imaging procedure, in conjunction
with all other imaging procedures. We believe we can continue to obtain
the essential external advice from imaging trained specialty physicians
for the FDA advisory committees by supplementing the membership of our
patient care specialty advisory committees. For example, medical
imaging special government employees (SGEs) were part of the Pediatric
Subcommittee of the Anti-Infective Drugs Advisory Committee that
occurred in February 2004 to discuss the use of imaging drugs in
conjunction with cardiac imaging procedures in the pediatric
population. They were also part of the November 2002 meeting of the
Peripheral and Central Nervous System Drugs Advisory Committee on the
role of brain imaging as an outcome measure in Phase 3 drug trials in
Alzheimer's disease. Most recently, they were also part of the March
2005 Oncology Drugs Advisory Committee that assessed the performance of
lymph node imaging in patients with possible metastatic cancer.
Please be assured that the Agency believes it possesses the
scientific expertise required to perform thorough reviews of
applications pertaining to these drug products and make informed
decisions, and can supplement that expertise with outside input. In
addition, we are committed to resolving scientific issues regarding
medical imaging in a timely manner.
Question 7. I have always been concerned that a generic biologic
would not pass the FDA's gold standard safety test, especially without
the FDA using protected information from other companies' biologic
applications. Where does the generic or follow-on biologic process
stand at the FDA?
Answer 7. As you know, FDA is conducting a public process to
examine the many questions, including scientific and legal issues, that
must be answered regarding these products and to ensure that all
interested parties have an opportunity to comment. When this process is
complete, FDA intends to provide guidance to industry to clarify,
consistent with its legal authority, the approval pathway and
principles for review of such products, which will protect the public
health.
Question 8. Since the implementation of the Generally Recognized as
Safe (GRAS) notification process at the Center for Food Safety and
Nutrition, what has been the number of full time employees (FTEs)
involved in the review and safety evaluation of food ingredients before
and after GRAS notification, how many food ingredients have been
reviewed under GRAS notification compared to immediately prior to
implementation of GRAS and what is the average review time for GRAS
petitions submitted under GRAS notification before and after
implementation? Would implementation of GRAS notification at the Center
for Veterinary Medicine be possible? If not, please explain.
Answer 8. FDA published a proposed rule to establish a GRAS
notification program in 1997 (62 FR 18938; April 17, 1997; Substances
Generally Recognized as Safe; the GRAS proposal). Under the GRAS
proposal, FDA evaluates whether each submitted notice provides a
sufficient basis for a GRAS determination and whether information in
the notice or otherwise available to FDA raises issues that lead the
Agency to question whether use of the substance is GRAS. Following this
evaluation, FDA responds to the notifier by letter.
The Center for Food Safety and Applied Nutrition (CFSAN)
implemented a pilot GRAS notification program and received its first
notice for a food ingredient in 1998. Through the end of 2004, CFSAN
had filed 162 notices (ranging from 12 to 30 notices per year, with an
average of 23 per year) and had completed its response to 155 of them.
CFSAN has responded to 80 percent of the filed GRAS notices within 180
days (ranging from 7 to 643 days, with an average of 163 days). Over
the past 3 years, CFSAN estimates that approximately 7 to 8 FTE's were
devoted to support the review of GRAS notices.
In regard to review times of GRAS affirmation petitions submitted
before and after implementation of the GRAS notification program, CFSAN
last filed a GRAS affirmation petition in 1997 (62 FR 10285; March 6,
1997). Prior to the implementation of the GRAS notification program,
CFSAN published an average of 5 affirmations of GRAS status in the
Federal Register per year for 1995 and 1996. The time elapsed since
CFSAN filed the petition until CFSAN published the final rule ranged
from just under 3 years to more than 13 years. CFSAN estimates that
approximately 5 or fewer FTE's were devoted the GRAS affirmation
petition process prior to implementation of the GRAS notification
program (i.e., a time when CFSAN had re-allocated resources to reduce
the backlog of food and color additive petitions). The GRAS affirmation
petition process required rulemaking, and was far more resource-
intensive than the GRAS notification process, so that fewer responses
were achieved per FTE.
While it would be possible for the Center for Veterinary Medicine
(CVM) to implement GRAS notification before publication of a final
rule, CVM has not done so because an alternative process has existed
for many years through establishment of feed ingredient definitions by
the Association of American Feed Control Officials (AAFCO) and
implementation of a notification program would require significant
reallocation of resources currently allocated to high priority
programs. CVM has participated in the AAFCO process by serving in a
technical scientific review capacity ensuring that the listed
ingredients are safe and function as claimed. No comparable process
exists for human food. In addition, CVM traditionally has received only
a small number of GRAS affirmation petitions and currently does not
have resources dedicated for review of GRAS submissions. Implementation
of a GRAS notification program at CVM also would be complicated by
other issues. CVM, for example, is responsible for many animal species,
and review of GRAS notices would need to address the different
physiologies and the potential for toxicity in each species. CVM also
would need to review whether a notified substance would produce
residues that raise human food safety concerns when these substances
are fed to livestock species. Addressing complex issues such as these
would place significant additional demands on resources. Affected
resources would include both personnel and implementation technologies,
such as CVM computer systems, which would require modification and
support to implement publicly available database of GRAS notices and
their ultimate disposition. CVM has met recently with two major feed
trade associations on GRAS notification and is reviewing its options,
which may include implementing a notification program that uses longer
timeframes in consideration of its resource limitations.
______
Response to Questions of Senator Clinton by Lester Crawford, DVM, Ph.D.
Question 1. In your opinion, what are the appropriate roles of the
scientific advisory committees and the senior staff of the FDA, if not
to make recommendations about the safety and efficacy of drugs like
Plan B?
Answer 1. Advisory committees at the Food and Drug Administration
(FDA or the Agency) are designed to offer a wide range of views on
topics that are discussed in a public forum and to be advisory in
nature. FDA seeks and appreciates the recommendations made by the
committees. By law, however, the final determination on a drug
application, however, remains with the Agency. Although the Agency
frequently makes final decisions concerning a new drug application
(NDA) that are consistent with an advisory committee's recommendations,
FDA is not bound to follow their recommendations. Ultimately, a final
decision is based on FDA's evaluation of the data, taking into account
all of the views expressed.
Question 2. In your opinion, under what circumstances is it
appropriate for the FDA to overrule such a strong, united,
scientifically-based recommendation?
Answer 2. The Agency considers the recommendations made by advisory
committees very carefully and takes the suggestions made very
seriously. However, as noted above, by law, the Agency has final
decision-making authority on a drug application. Although the Agency
frequently makes final decisions about NDAs that are consistent with
advisory committee recommendations, the recommendations are not
binding, and FDA may make a different decision.
Occasionally, there are differences of opinion among staff at the
Agency on a particular issue. The scientific interchange of ideas is
widely encouraged during the review process to ensure a thorough
vetting of the issues. Decisions on drug reviews, however, cannot be
made by simple majority or with the Agency feeling obligated to rubber
stamp an advisory committee vote. None of the advisory committee
members are permanent FDA employees with the same responsibilities as
our permanent staff. Ultimately, a final decision must be made based on
the Agency's evaluation of the scientific data, taking into account all
of the views expressed. The greatest responsibility for a final
decision concerning an NDA falls on the Center Director or other FDA
staff who must put his or her signature on the final action on an NDA
and will be the primary individual with the responsibility to defend
that decision in the future.
Question 3. As you may be aware, the agency's decision on the EC
application last May was widely decried as politically influenced. In
fact, my colleague Senator Kennedy and I organized 15 of our colleagues
to initiate a GAO investigation into the process, and we are looking
forward to the results. Can we count on you to ensure that the GAO has
the FDA's full cooperation in the investigation? What steps will you
take to ensure that medical and scientific evidence, not politics, is
the basis for the agency's future decisions? Can we count on greater
transparency in the FDA's decision-making process?
Answer 3. The Agency makes every effort to fully cooperate with the
GAO, and we are doing so with regards to the study that you and Senator
Kennedy et al., initiated concerning the Barr/Plan B application.
Additionally, FDA now publishes on its Internet site full
information about the Agency's review process on an application if the
application is approved. Included in this information is the medical
and scientific evidence taken into account when reviewing the
application.
Question 4. On November 5, 2004, you pledged to fill the position
of Director at the Office of Drug Safety. Can you please update us on
the status of this search, over 4 months after you made this pledge?
Answer 4. The Agency has experienced difficulty in recruiting high
quality candidates for the position of Director, Office of Drug Safety,
through traditional mechanisms such as scientific journal
advertisements and government vacancy announcements. We are committed
to using all available resources to ensure a systematic, inclusive
recruitment process for this critically important position. To that
end, FDA has partnered with the recruitment and staffing professionals
at the Office of Personnel Management (OPM), Center for Talent
Services, to develop and manage a recruitment strategy that we are
confident will yield a sizable number of strong candidates and
ultimately, a top-notch director. We feel that the additional time and
resources invested in a thorough analysis of the leadership and
technical competencies required to successfully manage the drug safety
program, including input from internal and external subject matter
experts and stakeholders, will be time well spent.
Question 5. During your tenure as either Acting Commissioner or
Deputy Commissioner of the FDA, the agency placed a black box warning
on antidepressant medications because several studies linked this
medication to increased risk of suicidal ideation. While the FDA has
little control over the off-label use of drugs, the Pediatric Rule, if
applied to its fullest extent, could have helped prevent much of the
controversy around pediatric antidepressant safety. Could you please
tell me how you plan to increase FDA reliance upon the Pediatric Rule,
as well as the Best Pharmaceuticals for Children Act, as tools to
increase the safety of drugs for Americans?
Answer 5. As of February 2005, FDA has requested studies on 298
products under the Best Pharmaceuticals for Children Act (SPCA), has
received the results of those studies on over 117 products, and has
added new labeling to 87 products. Most importantly, about 25 percent
of the time, when these products that were being used in the pediatric
population were studied, we discovered the following: a need for a
change of dosing, a new pediatric specific safety concern, or a lack of
pediatric efficacy. In fact, most of the pediatric studies conducted to
assess the efficacy and safety of the selective serotonin reuptake
inhibitors (SSRI) antidepressants were performed utilizing the SPCA
process. The data collected for these studies allowed FDA to evaluate
the risk of suicidality (thoughts or attempts) in children who have
taken these products.
As you know, in December 2003 the Pediatric Research Equity Act
(PREA) became law and established FDA's authority to implement the
principles of the Pediatric Rule. Since PREA was enacted, the Agency
has required evaluation of the pediatric need for drug and biologic
product applications that are submitted for an adult indication.
Through this process, the Agency determines if pediatric studies are
required, may be deferred, or should be waived for each product for the
specified indication. Waivers are granted, for example, if the disease
or condition to be treated does not occur in pediatrics, such as
prostate cancer or Alzheimer's disease. Once a pediatric need
determination is made, the sponsor is informed if pediatric studies are
required, have been deferred, or are waived.
The BPCA and PREA work together as powerful FDA tools for obtaining
important safety, efficacy, and dosing information for pediatric
patients.
Question 6. Following the flu vaccine shortage that occurred in
fall 2004, which was the third shortage experienced by our Nation since
2000, several questions were raised about the FDA's oversight of
vaccine manufacturing facilities, especially after it was revealed that
the agency had been aware of contamination issues at the Chiron
facility prior to the shutdown of this facility by British drug
regulators. With the loss of this production capacity, the U.S. vaccine
supply for the 2004 flu season was effectively cut in half. If you are
confirmed as Commissioner, how will you work to ensure, from the
regulatory standpoint, that future flu shortages do not occur? What
activities will you undertake to assist manufacturers who are currently
in or who enter the flu vaccine market with producing a safe, reliable
and uncontaminated vaccine product? What other steps can the FDA take
to ensure an adequate supply of flu vaccine on an annual basis?
Answer 6. FDA is working with manufacturers and its regulatory
counterparts in anticipation of having an ample supply of influenza
vaccine for the coming season and annually thereafter.
FDA is using a dual-track strategy. FDA's first track is to
facilitate Chiron's effort to correct its manufacturing problems. FDA
and MHRA, the British regulatory agency, have an agreement with Chiron
that allows full information sharing. FDA has used that agreement to
collaboratively review Chiron's remediation plans and activities, and
the Agency is providing continuing and extensive feedback to both
Chiron and MHRA. In addition, FDA signed an information sharing
agreement with MHRA that will, among other things, permit advance
communication on important issues. The agreement was effective February
14, 2005.
FDA is actively communicating on inspection activities. Only after
passing MHRA and FDA inspections will Chiron be able to provide vaccine
to the U.S. market. In the spring when critical stages of manufacturing
are taking place, the Agency plans a comprehensive inspection to verify
whether Chiron has adequately addressed its problems. While much work
remains to be done, it appears that Chiron is making progress.
FDA's second track is to facilitate overall greater capacity and
diversification in the U.S. influenza vaccine supply. It is important
to recognize that the demand for vaccine and other economic issues are
primary factors that determine whether a manufacturer will seek and
maintain a license in this country.
CDC and FDA are working to encourage vaccination throughout the flu
season, including January and February. To increase the total doses
available, manufacturers can produce vaccine over a longer time period,
and that becomes available during these months. Because influenza cases
usually continue well after November and December when most people are
seeking immunization, later vaccination is beneficial. The Public
Health Service is working to better communicate this important public
health message.
In addition, FDA has been working to stimulate manufacturers not
licensed in the U.S. to provide or, where needed, develop the safety
and effectiveness data to obtain U.S. licensure. The Agency has
actively engaged several interested companies. FDA has informed
manufacturers that the Agency is willing to consider all approaches to
licensing, including accelerated approval based on surrogate markers,
e.g., the patients' immune response to the vaccine. In addition, Sanofi
Pasteur and MedImmune have indicated their willingness, if needed, to
do what they can to increase production.
Very importantly, FDA has challenged itself to identify other
lessons learned from this year's influenza season and is evaluating how
this experience could be used to prevent similar events in the future.
While there are some elements that FDA cannot control, the Agency is
making significant changes. For example, FDA plans to conduct
inspections of influenza vaccine manufacturers on an annual basis, and
the Agency is completing or has completed agreements that allow
information sharing with numerous foreign regulatory agencies. In
addition, FDA has recently engaged in a confidentiality agreement with
MHRA that covers exchange of information for all inspections.
Question 7. There are many clinical areas where the synthesis and
evaluation of existing research, as well as better, more definitive
research, could improve the quality of care and reduce costs. The
Agency for Healthcare Research and Quality (AHRQ) has recently begun a
program of comparative effectiveness studies, for which my colleagues
and I managed to secure $15 million dollars in funding last year. One
of the first studies to be initiated under this comparative
effectiveness program is a systematic review of the Cox-2 drugs, which
will be completed in August 2005. Could you please comment on the ways
in which such comparative effectiveness reviews can be used to enhance
the work of the Office of Drug Safety?
Answer 7. We are more than willing to use any information that may
be discovered by the comparative effectiveness studies to assist the
Office of Drug Safety. Although such studies are not necessarily
designed to identify unknown safety concerns, it is certainly possible
that valuable information may be identified. We would want to evaluate
the results and data before we can comment as to whether such studies
will enhance the work of the Office of Drug Safety.
Question 8. Several questions have been raised as to whether the
FDA has the legislative and regulatory authority it needs to carry out
its mission. What additional authority would you identify as necessary
to enable the FDA to ensure the safety and efficacy of the drugs,
medical devices and foods manufactured and sold in our Nation?
Answer 8. FDA is fully capable of carrying out its mission under
its current statutory and regulatory authority. If we identify gaps in
our authority as we move to implement our various initiatives, we will
work with the Administration and the Congress to address those. We have
worked with Congress on many legislative efforts including MDUFMA,
generic and pediatric exclusivity provisions, food allergens, minor use
and minor species for animal drugs, and bioterrorism protections--all
of which have enhanced our ability to help protect public health.
Question 9. Do you feel the FDA has adequate access to clinical and
scientific expertise in the full range of specialties and sub-
specialties? If not, what steps can the agency take to improve this
access? How can the agency better utilize the scientific and medical
resources in our Nation in a way that will not raise the conflict of
interest issues for which the FDA has been criticized in its
experiences with both the Cox-2 and silicone breast implant advisory
panels?
Answer 9. The Food and Drug Administration (FDA) has a
responsibility to regulate products that comprise approximately one
fourth of the Nation's consumer expenditures. Within the United States
there are only a limited number of experts on any given topic; these
experts usually work together through effective scientific
collaboration. Most of the Nation's scientists are honored to serve
their country by becoming members of FDA's advisory committees and,
consequently, the Agency has little trouble recruiting the foremost
experts in the field to serve on such advisory committees. Inherent in
the process of clinical product development and evaluation is the
competition for the Nation's experts. FDA staff evaluates the potential
for financial conflict of interest and weighs these facts with the need
for the Agency to use the most qualified experts to gain the necessary
scientific information upon which to evaluate decisions that impact the
public health.
Question 10. At a hearing of the House Appropriation Committee's
Subcommittee on Agriculture on March 11, 2004, you stated: ``The FDA is
overwhelmed by imports, which have increased fivefold since 1994. It's
difficult for us and we are missing the mark, but we pledge to do
better.'' The FDA's proposed budget for 2006 includes a 5 percent cut
for food-safety inspections. How do you plan to ensure the safety of
FDA-regulated food imports? What percentage of food shipments should
FDA be inspecting and on what basis do you make that determination?
Answer 10. The fiscal year 2006 Budget does not reduce field
examinations of imported food. FDA will continue to examine about
93,000 import lines in fiscal year 2006 as well as in fiscal year 2005.
To manage the ever-increasing volume of imported food shipments, FDA is
using risk management criteria to achieve the greatest food protection
with our available resources. While we cannot physically inspect every
shipment, it is important to note that every shipment containing FDA-
regulated products entered through the Bureau of Customs and Border
Protection (CBP's) automated system is electronically reviewed by FDA's
system and those FDA-regulated products requiring further investigation
are identified. FDA's Operational and Administrative System for Import
Support (OASIS) determines if the shipment meets identified criteria
for physical examination or sampling and analysis or warrants other
review by FDA personnel. This electronic screening allows FDA to
concentrate its limited enforcement resources on high-risk shipments
while allowing low-risk shipments to proceed into commerce.
The Public Health Security and Bioterrorism Preparedness and
Response Act of 2002 provided a significant new tool that enhances
FDA's ability to electronically review all FDA-regulated imported
shipments. That law requires that FDA receive prior notice before food
is imported or offered for import into the United States. Advance
notice of import shipments, called ``Prior Notice,'' allows FDA, with
the support of the CBP, to target import inspections more effectively
and help protect the Nation's food supply against terrorist acts and
other public health emergencies. With the new prior notice requirement,
specific information mandated by the Bioterrorism Act must be submitted
to FDA before the imported food arrives in the United States. This not
only allows the electronic system to review and screen the shipments
for potential serious threats to health (intentional or otherwise)
before food arrives in the United States, but it also allows for FDA
staff review of prior notices for those products flagged by the systems
as presenting the most significant risk. FDA worked very closely with
CBP in developing this screening system. FDA receives approximately
27,000 prior notice submissions about incoming food shipments every
day. The Prior Notice Interim Final Rule became effective December 12,
2003. At the time of the statement you mentioned, FDA had not yet had
much experience with the new prior notice requirement. Since then,
FDA's experience with the prior notice system has been that it permits
FDA to further refine our risk-based targeting and allocate resources
for inspections more effectively.
The fiscal year 2006 budget requests an increase of $30 million for
food defense activities. Twenty million dollars of this increase will
support a national laboratory network known as the Food Emergency
Response Network (FERN). A critical component of controlling threats
from deliberate food-borne contamination is the ability to rapidly test
large numbers of samples of potentially contaminated foods for a broad
array of biological, chemical, and radiological agents. FERN will
increase our laboratory surge capacity through a nationwide network of
Federal and State laboratories capable of testing the safety of
thousands of food samples, thereby enhancing the Nation's ability to
swiftly respond to a terrorist attack. The additional $10 million will
be used for targeted food defense research, for continued coordination
and sharing of data with the Department of Homeland Security as part of
the government-wide Bio-Surveillance Initiative, and for upgrades in
FDA's crisis management capabilities.
Question 11. Section 130 of the Food and Drug Administration
Modernization Act requires sponsors to report annually on the status of
post-marketing commitments. In what ways has such reporting improved
the FDA's ability to engage in post-approval safety monitoring? How can
the system be improved so as to avoid the confusion that arose among
patients and providers following the recent Cox-2 controversy?
Answer 11. This authority assisted FDA greatly in considering the
risk/benefit profile of marketing drugs. For example, FDA recently
convened a joint meeting of the Arthritis Advisory Committee and the
Drug Safety and Risk Management Advisory Committees to discuss overall
benefit to risk considerations for COX-2 selective non-steroidal anti-
inflammatory drugs. The Advisory Committees analyzed all available
information, much of it post marketing data obtained through this
authority, from recent studies of Vioxx, Celebrex, Bextra, naproxen,
and other data for non-selective NSAIDs and COX-2 selective products.
The Advisory Committee issued recommendations that the Agency is
promptly and carefully reviewing before taking further action.
Recently, I joined Secretary Leavitt to announce important efforts
that we are undertaking with FDA to improve its ability to monitor and
respond to emerging drug safety information.
These steps will ensure both a better internal process of
deliberation on drug safety issues that ensures appropriate and
independent consideration of all issues, as well as a stronger ability
to gather data about drug safety issues once a drug has been approved.
Most importantly, we are moving to encourage more transparency and
to ensure that patients and physicians have the most up-to-date and
complete information necessary to inform their treatment decisions.
This new Drug Information Initiative will give patients, healthcare
professionals, and other consumers quick and easy access to the most
up-to-date and accurate information on medicines and make FDA's drug
review, approval, and monitoring programs as transparent as possible.
This is in addition to FDA's Five Point Plan to Improve Drug
Safety, a major initiative designed to improve the monitoring of drug
products recently approved for marketing. The major components of this
initiative include:
Sponsoring a major study of the Drug Safety System by the
Institute of Medicine;
Implement a Program for Adjudicating Differences of
Professional Opinion;
Conducting a nationwide search to identify a permanent
director for the Office of Drug Safety;
Conducting a series of workshops and meetings on drug
safety and risk management; and
Publishing risk management guidance.
FDA's Office of Drug Safety (ODS), in the Center for Drug
Evaluation and Research (CDER), is already an independent office
separate from the Office of New Drugs, the office that reviews new drug
applications. Both the Office of New Drugs and the Office of Drug
Safety report directly to the Director of the CDER. ODS has independent
authority to perform its own research and does so every day. To be
valuable, this independent research must conform to widely accepted
scientific standards and normal scientific procedures and peer review
should not be bypassed. And when drug safety issues are identified,
they must be factored into the risk-benefit equation so that safe and
effective drugs remain available to patients who need them.
FDA has a longstanding commitment to provide a strong resource base
for its drug safety program. The budget for fiscal year 2006 continues
this commitment. The President has proposed a 24 percent increase for
FDA's post-market safety program to help further ensure that America's
drug product supply is safe and effective, and of the highest quality.
Under this proposal, CDER's ODS would receive increased funding to
expand the Agency's ability to rapidly survey, identify and respond to
potential safety concerns for drugs on the market. ODS will hire
additional staff to manage and lead safety reviews, will increase the
number of staff with expertise in critical areas such as risk
management, risk communication and epidemiology, and will increase
access to a wide range of clinical, pharmacy and administrative
databases. Our commitment to increase resources available for post-
market safety will enhance the structural changes we are proposing to
advance drug safety.
Question 12. In light of concern that FDA activities are influenced
unduly by factors other than science, what assurances can you provide
that your leadership and your leadership team will pursue a science-
based agenda, rather than an ideological-based agenda? What
qualifications are most important to you when assembling your
leadership team? Who are you considering as possible members of your
leadership team?
Answer 12. FDA has often been in the position of making decisions
that have strongly motivated interests in favor or opposed to a product
approval decision. While social factors and economic interests, for
example, may result in opposing decision preferences, FDA's statute is
clear that decisions should be based on science, and the requirements
of the law, not ideology or opinion. Sometimes the science is not
adequately developed to provide for a clear decision, and decisions
have to be deferred until the adequate information is available. I am
committed, if confirmed, to ensuring that, during my tenure as
commissioner, FDA's decisions will be based on science and the
requirements of the law and that the basis for FDA's decisions are as
open and transparent to the public as possible, consistent with the
law.
My vision for the future of FDA is one of transformation.
Internally at FDA, we're transforming from domestic-focused, paper-
based processes, employing yesterday's technologies, to global,
electronic data-driven decisions that apply the latest science. And
we're transforming our culture to one of transparency, collaboration,
and cutting-edge thinking.
As you know, I have recently appointed new Associate Commissioners
for the Office of Management and for the Office of Policy and Planning.
The qualifications that are most important to me as I assemble my
leadership team are the qualities that support transformation:
scientific and management ability, innovation and cutting-edge
thinking, ability to confer and collaborate internally and externally
and to ensure transparency of our processes, ability to manage
organizational change effectively, and vision to see leveraging
opportunities that yield public health protection.
______
Response to Question of Senator Ensign by Lester Crawford, DVM, Ph.D.
There is currently a major dispute between independent compounding
pharmacists and the Food and Drug Administration (FDA) regarding the
very legality of pharmacy compounding.
The FDA appears to be taking the position that when a pharmacist
compounds a prescription drug pursuant to a lawful order from a
physician, veterinarian or medical practitioner, that this is a new
drug that technically needs to be submitted through the new drug
approval process. This interpretation, which does not seem to be based
on existing statutes or recent court decisions, would effectively
outlaw compounding and would deny patients necessary medical care.
Recently, the FDA has been aggressive in its enforcement against
compounded medications for non-food animals, arguing that these
compounded medications are new drugs that must be submitted to an
Abbreviated New Drug Application (ANDA) process. Additionally, the FDA
has asserted that it is illegal to use bulk ingredients when
compounding for non-food animals. Since the vast majority of drugs
compounded for use by non-food animals utilize bulk ingredients, this
would result in the denial of medical care to countless animals.
Question. Can you please provide the committee with a clear
statement as to the FDA's current position on pharmacist compounding
for both human and non-food animals, including actual statutory
citations for the FDA's position?
Answer.--I. Statutory Authority: General Overview
Sections 201(p) and (v) of the Federal Food, Drug, and Cosmetic Act
(the act) respectively define the terms ``new drug'' and ``new animal
drug'' as products that are not generally recognized among qualified
experts as safe and effective for use under the conditions recommended
in their labeling. With respect to human drugs, section 505(a)
prohibits the introduction or delivery for introduction into interstate
commerce of ``new drugs'' that have not been pre-approved by FDA as
safe and effective for their intended uses. Similarly, new animal drugs
that have not been pre-approved by FDA are deemed unsafe within the
meaning of section 512(a)(1) of the act and, therefore, adulterated
under section 501(a)(5) of the act. Where the compounding is for food
or non-food animals and is from approved animal or human drugs, it is
permitted if it complies with sections 512(a)(4) and (5) of the act and
21 CFR Part 530.
Sections 301(a)-(d) and (k) of the act prohibit, among other
things, the introduction, delivery, and receipt for distribution of
unapproved, adulterated, or misbranded drugs in interstate commerce.
Because the drugs compounded in pharmacies typically are not
``generally recognized as safe and effective'' within the meaning of
sections 201(p) and 201(v), they meet the act's definition of ``new
drugs'' and ``new animal drugs.'' Accordingly, they are also
technically subject to the act's pre-approval requirements for ``new
drugs'' and ``new animal drugs.''
II. FDA's Current Approach to Human Drug Compounding
In light of the preceding statutory analysis, Congress attempted to
legalize certain aspects of traditional pharmacy compounding by
amending the act in the mid-1990s. Section 127 of the Food and Drug
Administration Modernization Act of 1997 amended the act by adding
section 503A, which specified certain conditions under which compounded
human drugs could be exempt from certain requirements of the act,
including the aforementioned requirement under section 505 that all new
drugs be pre-approved by FDA as safe and effective for their intended
uses before being introduced into interstate commerce. In April 2002,
however, the United States Supreme Court struck down as
unconstitutional the commercial speech restrictions that Congress
included in section 503A of the act. See Thompson v. Western States
Medical Center, 535 U.S. 357 (2002). The Court left in place the Ninth
Circuit's holding that the unconstitutional restrictions could not be
severed from the rest of section 503A, and that the provision
(including its exemptions) was therefore invalid in its entirety.
As a result, the agency now uses its longstanding policy of
exercising its enforcement discretion to permit certain types of
pharmacy compounding. This policy is articulated in Compliance Policy
Guide (CPG), section 460.200, issued on June 7, 2002. FDA recognizes
that pharmacists traditionally have extemporaneously compounded
reasonable quantities of drugs. This traditional practice follows the
receipt of a valid prescription for an individually identified patient
from a licensed practitioner. The compounding is performed at the
pharmacy site for nearly immediate dispensing or administration to the
patient. FDA has long expressed the view that such compounding serves
an important medical purpose, and FDA has no intention of eliminating
or frustrating this historical practice.
FDA believes, however, that some pharmacies are engaged in
practices that fall outside the bounds of traditional pharmacy
compounding. These pharmacies are engaged in manufacturing and
distributing unapproved new drugs in violation of the act. Many of
these pharmacies make large quantities of unapproved drug products in
advance of receiving a valid prescription for them, and copy
commercially available drug products when there is no medical need for
these compounded products. It is appropriate that pharmacies engaged in
activities analogous to manufacturing drugs for human or animal use be
held to the same provisions of the act as drug manufacturers.
FDA's CPG contains factors that the agency considers in deciding
whether to exercise its enforcement discretion with respect to pharmacy
compounding. One factor is whether a firm is compounding drugs for
third parties who resell them to individual patients. Another is
whether a firm is compounding drugs in anticipation of receiving
prescriptions, except in very limited quantities. Another is whether a
firm is compounding a copy, or essentially a copy, of a commercially
available FDA-approved drug product. In certain circumstances, it may
be appropriate for a pharmacist to compound a small quantity of a drug
that is only slightly different than an FDA-approved, commercially
available drug. In these circumstances, however, FDA may consider
whether there is documentation of patient-specific medical need for the
compounded product. Other factors in the CPG include whether a firm is
compounding drugs from active ingredients that are not components of
FDA approved drugs, whether a firm is compounding drugs that are like
drugs that were withdrawn or removed from the market for safety
reasons, or whether a firm is not in compliance with applicable State
law regulating the practice of pharmacy.
III. FDA's Current Approach to Animal Drug Compounding
As in the case of human drugs, FDA recognizes that some compounded
animal drugs serve an important purpose in the practice of veterinary
medicine. Accordingly, FDA continues to evaluate the appropriateness of
different animal drug compounding and to use its enforcement discretion
in applying the provisions described above. Under its policy described
in Compliance Policy Guide (CPG) 7125.40, FDA is most likely to pursue
enforcement action when the scope and nature of the compounding
activities raise the kinds of concerns normally associated with a drug
manufacturer and result in significant violations of the act. As with
human drug compounding, the CPG contains factors that the agency
considers in deciding whether to exercise its enforcement discretion
with respect to animal drug compounding. The 13 factors described in
the CPG include whether a firm is compounding drugs for third parties
who resell them; whether a firm is compounding drugs in anticipation of
receiving prescriptions, except in very limited quantities; whether a
firm is compounding a copy, or essentially a copy, of a commercially
available FDA-approved drug product; and whether a firm is compounding
from bulk active ingredients, except where the use of the bulk active
ingredient is of low regulatory concern either in general or on a case-
by-case basis.
FDA is revising the CPG to further explain its enforcement policies
with respect to the compounding of drugs for food and non-food animals.
A number of groups, including the International Academy of Compounding
Pharmacists, the American Veterinary Medical Association, the American
Association of Equine Practitioners, and other affected groups, have
met with the Agency to discuss their concerns with the current CPG and
to suggest changes to it. In revising the CPG, FDA wants to make sure
that it provides the clarity that the regulated industry believes is
lacking in the current CPG.
______
Response to Questions of Senator Frist by Lester Crawford, DVM, Ph.D.
Question 1. Americans have tremendous confidence in the United
States' prescription drug supply due to our closed regulatory system,
which includes rigorous safety and efficacy standards enforced by the
Food and Drug Administration (FDA). Following the worldwide withdrawal
of Vioxx, some have questioned the FDA's ability to maintain the
public's trust and confidence, and have argued that the FDA has not
been sufficiently concerned about the safety of Cox-2 inhibitors and
other prescription drugs. As Commissioner, what steps would you take to
strengthen the FDA's drug safety program and better protect public
health? Are there actions the FDA could take to improve its post-market
surveillance of prescription drugs?
Answer 1. I take very seriously the questions that arise concerning
safety and efficacy of drugs both before and after approval. FDA
approves a drug only when the demonstrated benefit outweighs its known
risk for an intended population. However, the Agency cannot anticipate
all possible effects of a drug during the clinical trials that precede
approval. Occasionally, FDA identifies serious adverse effects after
approval either in post-marketing clinical trials or through the
Agency's strong post-market drug safety program.
Recently, I joined Secretary Leavitt to announce important efforts
that we are undertaking with FDA to improve its ability to monitor and
respond to emerging drug safety information.
These steps will ensure both a better internal process of
deliberation on drug safety issues that ensures appropriate and
independent consideration of all issues, as well as a stronger ability
to gather data about drug safety issues once a drug has been approved.
Most importantly, we are moving to encourage more transparency and
to ensure that patients and physicians have the most up-to-date and
complete information necessary to inform their treatment decisions.
This new Drug Information Initiative will give patients, healthcare
professionals, and other consumers quick and easy access to the most
up-to-date and accurate information on medicines and make FDA's drug
review, approval, and monitoring programs as transparent as possible.
This is in addition to a major initiative designed to improve the
monitoring of drug products recently approved for marketing. The major
components of this initiative include:
Sponsoring a major study of the Drug Safety System by the
Institute of Medicine;
Conducting a nationwide search to identify a permanent
director for the Office of Drug Safety;
Conducting a series of workshops and meetings on drug
safety and risk management; and
Publishing risk management guidance.
FDA's Office of Drug Safety (ODS), in the Center for Drug
Evaluation and Research (CDER), is already an independent office
separate from the Office of New Drugs, the office that reviews new drug
applications. Both the Office of New Drugs and the Office of Drug
Safety report directly to the Director of the CDER. ODS has independent
authority to perform its own research and does so every day. To be
valuable, this independent research must conform to widely accepted
scientific standards and normal scientific procedures and peer review
should not be bypassed. And when drug safety issues are identified,
they must be factored into the risk-benefit equation so that safe and
effective drugs remain available to patients who need them.
FDA has a longstanding commitment to provide a strong resource base
for its drug safety program. The budget for fiscal year 2006 continues
this commitment. The President has proposed a 24 percent increase for
FDA's post-market safety program to help further ensure that America's
drug product supply is safe and effective, and of the highest quality.
Under this proposal, CDER's ODS would receive increased funding to
expand the Agency's ability to rapidly survey, identify and respond to
potential safety concerns for drugs on the market. ODS will hire
additional staff to manage and lead safety reviews, will increase the
number of staff with expertise in critical areas such as risk
management, risk communication and epidemiology, and will increase
access to a wide range of clinical, pharmacy and administrative
databases. Our commitment to increase resources available for post-
market safety will enhance the structural changes we are proposing to
advance drug safety.
Question 2. The National Institute for Health Care Management
(NIHCM) estimates that spending on direct-to-consumer advertising
increased to $2.5 billion on 2000, compared to $791 million in 1996.
What is the FDA's role in regulating prescription drug advertising? In
particular, has the FDA conducted recent studies or surveys of
physicians or consumers regarding the impact of direct-to-consumer
advertising on prescription drug utilization, cost, and quality of
care? And if so, what have been the results? Based on the results of
the FDA's own analysis, and the analysis of others, what is your view
regarding the impact of direct-to-consumer adverting on utilization,
costs, quality of care, and patient education?
Answer 2. Section 502(n) of the Federal Food, Drug, and Cosmetic
(FD&C) Act (or the act) provides the Agency with authority to regulate
prescription drug advertisements. Implementing regulations (Title 21,
Code of Federal Regulations [CFR] section 202.1) provide specifics
about the content of such advertisements. Nothing in the law or
regulations prohibits direct-to-consumer (DTC) promotion in any
advertising medium. Also, the advertising provisions of the act do not
address the issues of pharmaceutical coverage by insurance companies,
advertising costs, or drug product price.
FDA believes consumer-directed advertisements can play an important
role in advancing the public health by encouraging consumers to seek
treatment of diseases that may be under-treated and diseases for which
patients may not be aware of treatment options. We have conducted
research that confirms that DTC advertising, when done correctly, can
serve positive public health functions, such as increasing patient
awareness of diseases that can be treated, and prompting thoughtful
discussions with physicians that result in needed treatments being
prescribed--often, not the treatment in the DTC advertisement. Results
of our research shows that many physicians believe that DTC can play a
positive role in their interactions with patients and that many
physicians thought that DTC ads made patients more involved in their
healthcare.
At FDA, CDER's Division of Drug Marketing, Advertising, and
Communications (DDMAC) is responsible for regulating prescription drug
promotion. DDMAC's mission is to protect the public health by helping
to ensure that prescription drug information is truthful, balanced, and
accurately communicated. This is accomplished through a comprehensive
surveillance, enforcement and education program, and by fostering
optimal communication of labeling and promotional information to both
health care professionals and consumers.
In February 2004, we issued three draft guidance documents,
addressing: (1) consumer-friendly options for presenting risk
information in consumer-directed print advertisements for prescription
drugs; (2) criteria FDA uses to distinguish between disease awareness
communications and promotional materials; and, (3) a manner in which
restricted device firms can comply with the rules for disclosure of
risk information in consumer-directed broadcast advertising for their
products.
FDA adopted a comprehensive, multi-faceted, and risk-based strategy
for regulating consumer-directed advertising of medical products, which
emphasizes the use of warning letters, untitled letters, development of
guidance that facilitate voluntary compliance, frequent informal
communications with industry and advertisers, and research on the
public health effects of consumer-directed promotional materials.
While we believe the survey results discussed above confirm our
belief that DTC ads help increase patient awareness about the
availability of effective treatments for their health problems, we will
continue to ensure that our DTC policies help prevent potential
misperceptions about benefits and risks of the advertised treatment and
promote the importance of prescribing decisions being made with the
intervention of a health care professional.
Question 3a. Last year, the British Medicines and Healthcare
products Regulatory Agency (MHRA) suspended Chiron's license to
manufacture influenza vaccine, resulting in a loss to the U.S.
influenza vaccine supply. As we approach the 2005-06 influenza season,
recent events highlight the pressing need to stabilize, protect, and
strengthen our vaccine supply. What are the FDA's plans to prevent a
future potential shortage?
Answer 3a. Recent experiences, particularly those of the past 7
months, have taught us important lessons about manufacturing and
inspectional activities with respect to influenza vaccine. Although FDA
has always interacted extensively with influenza vaccine manufacturers
throughout the vaccine production cycle, the annual changes in the flu
vaccine and the increased dependence on a smaller number of
manufacturers highlight the risks of unexpected manufacturing
difficulties. For these reasons, in 2005 and the future, we plan to
conduct inspections of influenza vaccine manufacturers on an annual
basis, with additional interactions with manufacturers and, in the case
of foreign facilities, their regulatory agencies where appropriate,
based on findings or events that raise concerns.
FDA is working with manufacturers and its regulatory counterparts
in anticipation of having an ample supply of influenza vaccine for the
coming season through a dual-track strategy.
FDA's first track is to facilitate Chiron's effort to correct its
manufacturing problems. FDA and MHRA, the British regulatory agency,
have an agreement with Chiron that allows full information sharing. FDA
has used that agreement to collaboratively review Chiron's remediation
plans and activities, and the Agency is providing continuing and
extensive feedback to both Chiron and MHRA. In addition, FDA signed an
information sharing agreement with MHRA that will, among other things,
permit advance communication on important issues. The agreement was
effective February 14, 2005.
FDA is actively communicating on inspection activities. Only after
passing MHRA and FDA inspections will Chiron be able to provide vaccine
to the U.S. market. In the spring when critical stages of manufacturing
are taking place, the Agency plans a comprehensive inspection to verify
whether Chiron has adequately addressed its problems. While much work
remains to be done, it appears that Chiron is making progress.
FDA's second track is to facilitate overall greater capacity and
diversification in the U.S. influenza vaccine supply. It is important
to recognize that the demand for vaccine and other economic issues are
the primary factors that determine whether a manufacturer will seek and
maintain a license in this country.
CDC and FDA are working to encourage vaccination throughout the flu
season, including January and February. To increase the total doses
available, manufacturers can produce vaccine over a longer time period,
and that becomes available during these months. Because influenza cases
usually continue well after November and December when most people are
seeking immunization, later vaccination is beneficial. The Public
Health Service is working to better communicate this important public
health message.
In addition, FDA has been working to stimulate manufacturers not
licensed in the U.S. to provide or, where needed, develop the safety
and effectiveness data to obtain U.S. licensure. The Agency has
actively engaged several interested companies. FDA has informed
manufacturers that the Agency is willing to consider all approaches to
licensing, including accelerated approval based on surrogate markers,
e.g., the patients' immune response to the vaccine. Sanofi Pasteur and
Med Immune have indicated their willingness, if needed, to do what they
can to increase production.
FDA has challenged itself to identify other lessons learned from
this year's influenza season and is evaluating how this experience
could be used to prevent similar events in the future. For example, as
mentioned above, FDA plans to conduct inspections of influenza vaccine
manufacturers on an annual basis, and the Agency is completing or has
completed agreements that allow information sharing with numerous
foreign regulatory agencies.
Question 3b. What policy proposals are necessary to increase
domestic production capacity and advance research and development? And,
what is the status of new technologies such as animal cell culture and
reverse genetics?
Answer 3b. HHS has announced that it plans to spend $439 million
department-wide on influenza related activities in fiscal year 2006.
This amount is an increase of nearly $400 million over the fiscal year
2001 level of $41 million, and represents the Administration's
commitment to addressing this important public health concern.
The Administration is making the largest investment ever made by
the Federal Government to protect against influenza. We welcome the
continued support of Congress for this work, and view influenza
preparedness as a critical responsibility as well as an important
opportunity. The Department has announced two Requests for Proposals
designed to encourage U.S.-based influenza vaccine manufacturers to
have both the capacity and raw materials necessary to produce large
quantities of vaccine using current egg-based methods, which are
efficient and have a long and generally successful history. In November
2004, HHS awarded a contract to Sanofi Pasteur to help ensure year
round availability of an increased egg supply in case it is needed for
a pandemic or for future vaccine shortages. These contracts and other
research supported by HHS through NIAID will also help us move from
dependence solely on egg-based production technology to the development
of U.S. licensed cell-culture based and/or recombinant protein and DNA-
based vaccines. While work remains to obtain sufficient vaccine yields
and evaluate cell-based vaccines for their safety and effectiveness,
moving from an egg-based production to a cell-culture production can
potentially shorten the time needed to produce vaccine as well as
decrease the risk of contamination inherent in egg-based production.
In an important new development, HHS is supporting development of
vaccines against potential pandemic strains. Through this effort we
hope to obtain experience in the formulation and use of such a vaccine
and to prepare in the event that these strains become pandemic. As part
of HHS' efforts to support pandemic preparedness, NIAID contracted for
the production of pilot lots of potential pandemic vaccines from the
two licensed U.S. manufacturers of inactivated influenza vaccine. HHS
contracted for the production of 2 million doses of vaccine against
H5NI avian flu, the influenza type of current concern in Southeast
Asia. NIAID is preparing to initiate clinical studies of the first H5N1
vaccine under INDs that FDA oversees, and both agencies will be working
together to evaluate the results. While much work remains, these steps
to produce and evaluate pandemic influenza vaccines are a critical
component of our preparedness efforts. Reverse genetics is a method
that can lead to more rapid generation of reference strains needed to
manufacture influenza vaccines. This methodology was used to
manufacture the H5N1 investigational vaccine noted above. In addition,
studies supported by the National Institutes of Health and FDA will try
to develop vaccine strategies that could lead to longer lived immunity
and to vaccines that help protect against multiple strains of
influenza. FDA is actively engaged with sponsors and manufacturers that
are interested in developing such new technologies and has approved
cell-based and recombinant vaccines for prevention of other infectious
diseases such as chicken pox, rubella, polio, and hepatitis.
Question 4. In May 2004, the Institute of Medicine's (IOM)
Immunization Safety Review Committee examined the hypothesis that
vaccines, specifically the measles-mumps-rubella (MMR) vaccine and
thimerosal-containing vaccines, are causally associated with autism.
The committee concluded that the evidence favors a rejection of a
causal relationship between thimerosal-containing vaccines, or the MMR
vaccine, and autism.
In a joint statement in 1999, the U.S. Public Health Service, which
includes the FDA, and the American Academy of Pediatrics urged vaccine
manufacturers to reduce or eliminate thimerosal in vaccines. The U.S.
Public Health Service and the American Academy of Pediatrics noted that
they ``are working collaboratively to assure that the replacement of
thimerosal-containing vaccines takes place as expeditiously as possible
while at the same time ensuring that our high vaccination coverage
levels and their associated low disease levels throughout our entire
childhood population are remained.''
To date, what process has been made in reducing or eliminating
thimerosal in vaccines? What does scientific evidence show regarding
the affect of trace amounts of this preservative? What are the FDA's
current efforts to reduce child exposure to mercury? And, what is your
view of the current scientific evidence regarding a relationship
between vaccines and autism?
Answer 4. FDA actions have resulted in a marked reduction in
mercury exposure from thimerosal in vaccines. Since 2001, all vaccines
routinely recommended for children 6 years and under (DTa), hepatitis
B, Haemophilus b conjugate (Hib), pneumococcal conjugate, IPV, MMR, and
varicella) manufactured for the U.S. market have contained no
thimerosal or only trace amounts, with the exception of inactivated
influenza vaccine.
In 2004, the Advisory Committee on Immunization Practices
recommended routine use of influenza virus vaccine in children 6 to 23
months of age. FDA has approved preservative-free formulations (which
contain either no or only trace amounts of thimerosal) for each of the
two licensed inactivated influenza vaccines. These influenza vaccines
continue to be marketed in both the preservative-free and thimerosal-
preservative-containing formulations. Of the two licensed inactivated
influenza vaccines, Sanofi Pasteur's (Fluzone) is approved for use in
children down to 6 month's of age; Chiron's Fluvirin is approved for
individuals 4 years of age and older. The live attenuated influenza
vaccine (FluMist, manufactured by MedImmune) contains no thimerosal,
and is approved for individuals 5-49 years of age. In addition,
pediatric vaccines such as DT, which are administered only to children
for whom DTaP is not indicated, are also available in thimerosal-
preservative-free formulations, as are Td vaccines, which are indicated
for individuals 7 years of age and older.
In addition to FDA's actions outlined above, the PHS agencies have
collaborated with various investigators to initiate further studies to
better understand any possible health effects from exposure to
thimerosal in vaccines. In 2001, the Institute of Medicine (IOM), at
the request of CDC and NIH, convened the Immunization Safety Review
Committee (the committee) to review selected issues related to
immunization safety. This committee has completed two reviews of
studies addressing a potential link between thimerosal-containing
vaccines and autism. In its first review, conducted in 2001, the
committee concluded that the evidence is inadequate to either accept or
reject a causal relationship between thimerosal exposure from childhood
vaccines and the neurodevelopmental disorders of autism, attention
deficit hyperactivity disorder, and speech or language delay. The
committee believed that the effort to remove thimerosal from vaccines
was ``a prudent measure in support of the public health goal to reduce
mercury exposure of infants and children as much as possible.''
In 2004, the IOM's Committee reviewed this topic again, including
new data that had accumulated since its review in 2001. These data
included several epidemiological studies conducted in the U.S.,
Denmark, Sweden, and the United Kingdom, and studies of biologic
mechanisms related to vaccines and autism. The committee concluded that
this body of evidence favors rejection of a causal relationship between
thimerosal-containing vaccines and autism, and that hypotheses
generated to date concerning a biological mechanism for such causality
are theoretical only. Further, the committee stated that the benefits
of vaccination are proven and the hypothesis of susceptible populations
is presently speculative, and that widespread rejection of vaccines
would lead to increases in incidences of serious infectious diseases
like measles, whooping cough, and Hib bacterial meningitis.
FDA has succeeded in reducing children's exposure to mercury from
vaccines during the first 6 months of life and continues to work toward
reducing everyone's thimerosal exposure through vaccines. With the
exception of the inactivated influenza vaccine, which was recently
added to the list of routinely recommended pediatric vaccines, all
routinely recommended licensed pediatric vaccines that are currently
being manufactured for the U.S. market contain no thimerosal or only
trace amounts of thimerosal. FDA, together with our colleagues within
the other Health and Human Service agencies, will continue to study
data relating to the incidence and etiology of autism.
Question 5. This month the World Health Organization (WHO)
confirmed 10 new cases of human infection with H5N1 avian influenza
virus, as reported by the Ministry of Health in Viet Nam. Since January
2004, 69 human cases of H5N1 infection have been reported, 46 cases of
which have been fatal. Earlier this year, Senator Gregg, myself and
others unveiled S. 3, the Protecting America in the War on Terror Act
of 2005, which includes biodefense provisions to better protect and
strengthen our public health infrastructure in the event of a pandemic
outbreak. What is the FDA's role in ensuring pandemic preparedness? Are
there actions the FDA Commissioner could take to improve our
preparedness and response capabilities?
Answer 5. FDA's goal is to establish a process to produce pandemic
influenza vaccine in the shortest amount of time possible and protect
the largest number of people, using a vaccine that is safe, effective
and easy to deliver. The full details of the draft Pandemic Influenza
Preparedness and Response Plan are located on the HHS website at:
http://www.dhhs.gov/nvpo/pandemicplan/annex5.pdf. Through all these
efforts, and with enhanced global surveillance by CDC and its partners,
we have the unique opportunity to effectively intervene and potentially
blunt a global pandemic, should one occur.
FDA is actively participating in the HHS efforts for pandemic
planning as highlighted in our response to Question 3.
Question 6. Over the past 20 years, the number of people who are
obese nearly doubled in the United States. An estimated 30 percent of
U.S. adults are now classified as obese and over 60 percent are
classified as overweight. The number of obese children between the ages
of 6 and 11 has tripled over the past 3 decades. During the 108th
Congress, I introduced two pieces of legislation, the Improved
Nutrition and Physical Activities (IMPACT) Act and the Childhood
Obesity Reduction Act. Both were intended to help address this serious
and significant public health threat.
Last year, the Department of Health and Human Services (HHS)
unveiled a strategy to combat obesity. As a part of HHS' comprehensive
strategy, the FDA's Obesity Working Group released a report which
proposes a series of recommendations, including developing a national
education campaign, encouraging the availability of nutritional
information at restaurants, enhancing the calorie information on food
labels, and strengthening the coordination of obesity research. Where
does this FDA initiative stand today? What have been its results? Are
there additional steps the FDA could take in order to combat the ever-
rising tide of obesity across this Nation?
Answer 6. There is no simple solution to the problem of obesity.
Achieving success in reducing and avoiding obesity will occur only as a
result of efforts over time by individuals as well as various sectors
of our society. Most associations, agencies, and organizations believe
that diet and physical activity should be addressed together in the
fight against overweight and obesity.
Obesity is a growing and urgent public health problem in the United
States. Today, almost two-thirds of all Americans are overweight and
over 30 percent are obese. To help confront the problem of obesity in
the U.S. and to help consumers lead healthier lives through better
nutrition, in August 2003, FDA created an Obesity Working Group (OWG),
which was charged with preparing a report that outlines an action plan
to cover critical dimensions of the obesity problem from FDA's
perspective and authorities. FDA's ``Calories Count'' report was
released on March 12, 2004.
The OWG report provides a range of short and long-term
recommendations to address the obesity epidemic. For FDA's actions the
emphasis is on calories. Progress to date follows:
We have published two advance notices of proposed rulemaking
(ANPRMs), in response to the recommendations in the OWG report, seeking
comments on the following:
How to give more prominence to calories on the food label,
for example, increasing the font size for calories, including a column
in the Nutrition Facts panel of food labels for percent Daily Value for
total calories, and eliminating the listing for calories from fat. In
addition, the Agency is seeking comment on the reformulation of the
foods or redesign of packaging that may occur if any changes are made
to the food label;
Whether to amend certain provisions of the nutrition
labeling regulations concerning serving size, such as for multiple-
serving packages that may reasonably be consumed in a single eating
occasion.
We continue to encourage manufacturers to take advantage of the
flexibility in current regulations on serving sizes to label as a
single-serving those food packages where the entire contents of the
package can reasonably be consumed at a single eating occasion. We also
continue to encourage manufacturers to use appropriate comparative
labeling statements that make it easier for consumers to make healthy
substitutions. Since release of the OWG report, the Agency, in meetings
with industry, has made a point to encourage manufacturers to take
advantage of the existing flexibility in serving size regulations, and
companies are responding. For example, Kraft Foods is instituting dual
column labeling for all its packaged foods containing 2-4 servings per
package.
FDA continues to encourage restaurants voluntarily to provide
point-of-sale nutrition information to customers, including calorie
information on a nationwide basis.
FDA is also working to develop educational strategies and
partnerships to support appropriate messages and teach people,
particularly children, how to lead healthier lives through better
nutrition. We are starting work with the Girl Scouts of the USA, under
terms of a Memorandum of Understanding signed this past fall, to
provide outreach and education in a science-based initiative to focus
on improving health, nutrition, and physical activity. In addition,
FDA's field offices are participating in local partnerships to reach
and teach children. For example, in Central Florida, FDA's South East
Region is part of the Seminole County Healthy Kids Partnership to
promote positive opportunities for school-aged children in Seminole
County to learn healthy nutrition and the value of increased daily
physical activity.
Also, FDA's Center for Drug Evaluation and Research (CDER) will
continue to work with pharmaceutical sponsors to facilitate development
of effective therapies to address the important public health issue of
obesity and its attendant morbidities. An advisory committee meeting
was held on September 8, 2004 to discuss the draft guidance on Clinical
Evaluation of Weight-Control Drugs. The Agency is working to finalize
the guidance.
We believe that, when implemented, the report's recommendations
will make a worthy contribution to confronting our Nation's obesity
epidemic and helping consumers lead healthier lives through better
nutrition.
______
Response to Questions of Senator Jeffords by Lester Crawford, DVM,
Ph.D.
Emergency Contraception Questions
Dr. Crawford, while you have been the Acting Commissioner of the
FDA the agency has failed to approve Barr Laboratories' application to
make Plan B emergency contraception available over-the-counter. This is
despite the recommendations of the FDA's own advisory panels, the
support of major professional medical associations, and overwhelming
scientific evidence supporting the move. I have a series of questions I
would like to ask on this issue:
Question 1a. Please explain how the FDA failed to approve the
application when the independent medical and scientific review
performed by the FDA Advisory Committees overwhelmingly approved the
application?
Answer 1a. Advisory committees at the Food and Drug Administration
(FDA or the Agency) are designed to be only advisory in nature.
Advisory Committees offer a wide range of views on topics, usually in a
public forum. FDA seeks and appreciates the recommendations made by the
committees. The statutory responsibility for making a final decision on
a drug application, however, remains with the Agency. Although the
Agency frequently makes final decisions concerning new drug
applications (NDAs) that are consistent with advisory committee
recommendations, FDA is not bound to follow their recommendations.
Ultimately, a final decision is based on FDA's evaluation of the data,
taking into account all of the views expressed.
At the joint advisory committee meeting held December 16, 2003, to
review the Barr/Plan B OTC application, the Chairman of the Advisory
Committee on Over-the-Counter Drugs as well as other members of the
joint committee expressed concerns regarding whether the actual use
data in the application were generalizable to the overall population of
nonprescription users, chiefly because they felt the data showed
inadequate sampling of younger age groups. Their concerns were strong
enough for them to vote against approving the application, and the
Center Director felt these concerns were important enough to seek
further information from the sponsor on that issue. It is his job to
see that the data meet the standards for safe and effective OTC use
before a final decision is made.
Question 1b. To better understand how this decision on Plan B was
reached, can you provide a full account of the decision processes that
caused the FDA to go against the recommendations of the review panel
and professional staff?
Answer 1b. After completing review of the supplemental application,
FDA concluded that the application could not be approved at this time
because: (1) adequate data were not provided to support the conclusion
that young adolescent women can safely use Plan B for emergency
contraception without the professional supervision of a licensed
practitioner and (2) a proposal from the sponsor to change the
requested indication to allow for marketing of Plan B as a
prescription-only product for women under 16 years of age and a non-
prescription product for women 16 years and older was incomplete and
inadequate for a full review. The supplemental application that was
submitted proposed OTC status for both adults and children based
primarily on an actual-use study in 585 subjects. Only 29 of the 585
subjects enrolled in the study were 14-16 years of age, and none was
under 14 years of age. Therefore, FDA concluded that the application
was not approvable during that review cycle.
In its letter notifying the sponsor of this decision, the Agency
stated the following:
``Before this application can be approved, you would have to
provide data demonstrating that Plan B can be used safely by women
under 16 years of age without the professional supervision of a
practitioner licensed by law to administer the drug. Alternatively, you
could supply additional information in support of the revised
indication to allow for marketing of Plan B as a prescription-only
product for women under the age of 16 years and a non-prescription
product for women 16 years and older, including draft product labeling.
If you take the latter approach, your response to this letter would
have to include details of how you propose to implement simultaneous
prescription and non-prescription marketing of Plan B for women of
different ages in a single packaging configuration while complying with
all relevant statutory and regulatory requirements for labeling and
marketing of this product. We will have to assure ourselves that your
proposed approach is consistent with our statutory authority. If you
pursue the alternative approach, we also would request details of your
proposed program to educate consumers, pharmacists, and physicians
about the dual marketing of Plan B as both a prescription and non-
prescription product, as well as your proposed program to monitor
implementation of this novel approach.''
The issuance of the Not Approvable letter in May 2004 did not mean
that a supplemental application could not be approved in the future.
The Not Approvable letter described what the applicant would need to do
to obtain approval for its initial supplemental application. In this
case, the applicant chose to revise its application and requested to
market Plan B as prescription-only for women under the age of 16 and as
nonprescription for women 16 years of age and older. FDA is reviewing
this latest supplemental application.
Question 1c. Barr Pharmaceuticals has submitted a revised proposal
to the FDA, but even though a deadline has passed, they have not been
notified of any outstanding questions or requests for information. Can
you tell us what the reason is for the delay at this point, why the
review was not completed on time and when a decision could be expected?
Answer 1c. The Prescription Drug User Fee Act (PDUFA) goal date for
the Barr Laboratories/Plan B OTC supplemental application was January
22, 2005. Because of the complexities involved, the application is
under review at the Center.
Use of PDUFA Funding for Drug Safety
In the past, the Congress has authorized the FDA to accept user
fees to augment its ability to review drug and medical device products.
Some have urged that some of those fees should be directed to ensuring
the safety of these products. Thus far, the Congress has agreed with
the industries' position that post-market product safety review is the
responsibility, and should be paid for, through general revenues.
Question 2. I would like to hear your thoughts on how you plan to
provide funding for post market product safety. Failing the
availability of appropriations, would some portion of user fees be a
reasonable source of funding?
Answer 2. Under the current system of user fees, a portion of fees
is used for drug safety activities. Drug safety activities are a
cornerstone of the drug approval process, and PDUFA user fees support
these activities. Moreover, under PDUFA III, Congress authorized the
use of user fees for certain post-market risk management activities.
Thus, user fees already fund drug safety activities, and the Agency
supports the use of fees for this essential activity.
Clinical Trials Database
Dr. Crawford, clinical trials are an important part of the drug
approval and use process. Information that comes out of clinical trials
continues to be of vital concern to doctors, patients, manufacturers
and regulators. To that end, it seems like a good idea to expand the
amount of information about trials that is available.
Question 3. What is your response to the idea of creating a
mandatory clinical trials registry, modeled after clinicaltrials.gov,
which makes information available about all clinical trials? Would
having complete information, including results information, available
publicly help doctors and patients make better decisions about
medications?
Answer 3. I believe that patients and health professionals should
have as much information possible to inform their treatment decisions.
That is why I joined Secretary Leavitt to announce important efforts
that we are undertaking with FDA to improve its ability to monitor and
respond to emerging drug safety information.
Importantly, we are moving to encourage more transparency and to
ensure that patients and physicians have the most up-to-date and
complete information necessary to inform their treatment decisions.
This new Drug Information Initiative will give patients, healthcare
professionals, and other consumers quick and easy access to the most
up-to-date and accurate information on medicines and make FDA's drug
review, approval, and monitoring programs as transparent as possible.
Moreover, clinicaltrials.gov is the world's largest source of
information about federally- and privately-sponsored clinical trials
throughout the United States and abroad, making critically important
public health information available to patients and the healthcare
community. Working together and in collaboration with our sister
agencies in the HHS, FDA implemented section 113 with the establishment
of ClinicalTrials.gov in February 2000. Today, ClinicalTrials.gov
contains information on more than 11,000 publicly and privately funded
trials. Recent public attention to the increasing availability of
clinical trial information has made pharmaceutical companies more aware
of the responsibility to list clinical trials in ClinicalTrials.gov.
Moreover, many companies that previously listed ``pharmaceutical
company'' in the drug sponsor field are now identifying themselves by
their company name.
Moreover, the agency has been making information from drug approval
packages publicly available for some time. Drug approval packages,
which include medical, chemistry, pharmacology, statistical, and
clinical pharmacology/biopharmaceutics reviews, are posted on the FDA
website Drugs@FDA (http://www.accessdata.fda.gov/scripts/cder/
drugsatfda/) and are made available in response to requests under the
Freedom of Information Act after certain trade secret, confidential
commercial or other privileged information has been redacted in
accordance with relevant legal requirements. The Best Pharmaceuticals
for Children Act (BPCA) requires FDA to make available to the public a
summary of the medical and clinical pharmacology reviews of the
pediatric studies conducted for supplements submitted under the BPCA.
This information can be found at: http://www.fda.gov/cder/pediatric/
Summaryreview.htm. Additional information is also available from
questions and answers posted on FDA's website and can be found at:
http://www.fda.qov/cder/drugsaffda/FAQ.htm.
Protecting First Responders
In order to ensure that first responders are prepared to respond to
a chemical terrorist attack, the Congress and Department of Homeland
Security have worked hard to ensure that funding is available and that
the first responders and the public have the best possible equipment
and medical countermeasures. The military for decades has used
effective countermeasures against chemical, biological, radiological or
nuclear (CBRN) threats. There is concern about how the FDA is
transitioning use of these products from the battlefield to the
domestic sector as terrorist threats have expanded.
Question 4a.Please explain what FDA is currently doing to ensure
the chemical, biological, radiological or nuclear (CBRN) medical
countermeasures are reviewed and approved without jeopardizing the
safety of the general public.
Answer 4a. FDA is working diligently to speed the development and
availability of safe and effective medical products to protect
Americans from the harmful effects of chemical, biological,
radiological, and nuclear (CBRN) agents. The Agency is coordinating and
collaborating with the Centers for Disease Control and Prevention
(CDC), the National Institutes of Health (NIH), the Department of
Defense (DOD), academia, and industry regarding novel medical
countermeasures (MCMs) and new (counterterrorism) indications for
approved medical products for the public and the U.S. military. An
important part of this effort is FDA's participation in several
interagency working groups to address scientific and policy issues
related to medical countermeasure development.
FDA has a number of mechanisms that may be used to expedite
approval and access to MCMs. These include the familiar processes for
fast track, priority review, and accelerated approval, as well as
innovative new tools, such as the ``Animal Rule.'' Under the Animal
Rule, animal efficacy data may be used for product approval when human
efficacy studies are not ethical or practical and when safety is
established through human studies. FDA continues to play a critical
role in the design and analysis of animal models that mimic disease
progression in humans, recognizing that the lack of established animal
models for the study of CBRN agents and associated medical products is
a key impediment to future MCM development.
Though not an approval process, FDA also is implementing new
authority to allow the use of unapproved medical products and
unapproved uses of approved medical products to protect the public and
U.S military forces during a declared emergency involving a heightened
risk of exposure to a CBRN agent. FDA may issue an Emergency Use
Authorization (EUA) for a medical product only if certain statutory
criteria are met, including a requirement that the known and potential
benefits outweigh the known and potential risks. The Agency may impose
certain conditions on the EUA and may revoke the authorization if
appropriate to protect public health or safety.
FDA's current activities on specific CBRN agents and MCMs include
the following:
Ongoing development efforts associated with a new
preventative anthrax vaccine and therapies to treat anthrax infections;
a new and safer preventative smallpox vaccine and therapies to treat
active smallpox infections; a vaccine to protect against botulinum
toxin; therapies for plague; and treatments for special populations,
such as children, pregnant women, and those with weakened immune
systems, when standard therapies are not advised.
Continuing an Interagency Agreement (IAG) with CDC for
clinical trials to collect human data on plague in African countries to
label an antibiotic that would otherwise require an investigational new
drug application for product deployment.
Funding, with the National Institute for Allergies and
Infectious Disease, the development of a non-human primate model of
pneumonic plague.
Conducting workshops and meetings to discuss strategies
for developing therapeutics for certain CBRN agents.
Drafting guidance on MCMs for anthrax toxins.
Working on animal model studies for radiation-related
countermeasures.
Maintaining a database of approved and investigational
products that may be candidates for medical countermeasures against
Category A agents.
Many of the CBRN threats demand immediate medical treatment, which
creates substantial medical and first responder logistical challenges.
Question 4b. Please tell us what FDA's position is regarding the
expanded availability of existing medical countermeasures, including
the availability of these countermeasures through prescription for
individuals, before a terrorist incident occurs.
Answer 4b. The Department of Health and Human Services (HHS) has a
lead role in protecting Americans from the effects of terrorist attacks
by enhancing public health preparedness and response capabilities.
Within HHS, the CDC works with provider and first responder
organizations on terrorism prevention and preparedness efforts. FDA's
role is to speed the availability of new medical countermeasures
through responsive regulatory review of these medical products.
Within the scope of the Agency's statutory authority and mission,
FDA participates in and collaborates with HHS and other Federal
Agencies on certain public health preparedness and response activities.
These include working with CDC in the Cities Readiness Initiative
(CRI), a pilot program to aid cities in increasing the capacity to
deliver medicines and medical supplies during a large-scale
catastrophic event. CRI participants include City/State medical,
bioterrorism, and emergency responders, Health Resources and Services
Administration (HRSA), Department of Homeland Security Federal
Emergency Management Agency (DHS-FEMA), Strategic National Stockpile
(SNS), the Department of Justice (DOJ), the Federal Bureau of
Investigation (FBI), the Veteran's Administration (VA) and the United
States Postal Service (USPS).
FDA also works closely with CDC's SNS, which stockpiles large
quantities of medicine and medical supplies to protect the American
public if there is a public health emergency (terrorist attack, flu
outbreak, earthquake) severe enough to cause local supplies to run out.
Once Federal and local authorities agree that the SNS is needed,
medicines will be delivered to any State in the United States within 12
hours. Each State has plans to receive and distribute SNS medicine and
medical supplies to local communities.
Post Marketing Study Commitments Under Fast Track
When Congress passed the Food and Drug Modernization Act in 1997,
we included new authorities for FDA to provide fast-track approval for
drugs to treat serious and life threatening diseases. The law was
intended to ensure that innovative new treatments would be made
available to patients in a timely manner while at the same time
ensuring they were both safe and effective. We did that by empowering
FDA to mandate additional post approval studies on both safety and
efficacy without delaying the approval process. Instead, FDAMA provided
the agency with the authority to withdraw approval of a fast-track drug
if the drug sponsor failed to conduct a required study with due
diligence.
The law has clearly been effective in getting new life-saving
treatments on the market. But I'm concerned about reports concerning
drug maker compliance with post-approval study commitments those
studies are an important piece of the safety and efficacy picture. Now
however, questions are being raised about how many of those fast track
studies are actually completed.
Question 5a.Please provide a summary on the status of each fast
track studycommitment, including the date of the drug's approval and
the expected date of the study fulfillment. For those that have not yet
been initiated, please provide an explanation as to why.
Answer 5a. FDA has approved 38 products under fast track review.
Nineteen of the approved fast track products were approved under
accelerated approval. All fast-track products that FDA approved under
accelerated approval (based on a surrogate endpoint or on a clinical
endpoint other than survival or irreversible morbidity) must complete
post-marketing confirmatory studies (refer to 21 CFR 314.510). There
are 19 such approvals, listed in the answer to question. These products
are: Alimta (NDA 21677 only), Erbitux, Velcade, Iressa, Fabrazyme,
Fuzeon, Arimidex, Eloxatin, Zevalin, Viread, Gleevec, Campath, Kaletra
(NDAs 21226 and 21251), Agenerase (NDAs 21007 and 21039), Ziagen (NDAs
20977 and 20978), and Sustiva.
Twenty three percent (18/80) of accelerated approval confirmatory
studies are proceeding according to or ahead of the original schedule.
Twenty-six percent (21/80) of accelerated approval confirmatory studies
are considered ``pending.'' Many older postmarketing study commitments
(e.g., those established prior to FDAMA 1997) did not have study
schedules specified at the time of approval. A commitment cannot be
deemed ``delayed'' unless the progress of the study has fallen behind
the original study schedule (21 CFR 314.81(b)(2)(vii)). Because some of
these older commitments do not have an original study schedule on which
compliance may be based, they cannot be considered ``delayed.'' Studies
remain ``pending'' for a variety of reasons; typically while a study is
``pending,'' FDA and the applicant are working together to design a
study that will adequately address the objective of the commitment.
Four percent (3/80) of accelerated approval confirmatory studies
are considered ``delayed.'' Studies are considered ``delayed'' if they
are proceeding, but not meeting the original study schedule. Studies
can be considered ``delayed'' for a variety of reasons (e.g.,
enrollment problems, ongoing analysis of study results, or submission
of the final study report later than the scheduled date). The review
divisions work proactively with sponsors to design trials that will
provide the required information and to identify obstacles to
completing the trials as they are initiated and begin accrual. However,
when unexpected or unavoidable obstacles are encountered and the study
becomes ``delayed,'' FDA continues to work with the sponsor to address
and try to resolve the reasons for the delay. Sometimes when the
obstacles associated with the original study design cannot be readily
resolved, new confirmatory studies with defined study schedules are
established. One percent (1/80) of accelerated approval confirmatory
studies are considered ``terminated.'' FDA encourages sponsors to
submit final study reports for ``terminated'' studies as soon as the
reports are completed.
Final study reports have been ``submitted'' for 60 percent (48/80)
of accelerated approval confirmatory studies. Of these 48 PMCs, FDA has
reviewed 45 (94 percent) of them and determined that the terms of the
commitment have been met (i.e., ``fulfilled''); a fulfillment letter
has been issued for these PMCs. Three are currently considered
``submitted'' while the other 45 are considered ``fulfilled'' according
to 21 CFR 314.81(b)(2)(vii). All of the studies for which final study
reports were submitted were completed (i.e., none of the final study
reports were submitted for ``terminated'' studies).
Question 5b. Have you ever withdrawn a fast track drug for failure
to conduct a required study? What factors guide the FDA in making these
decisions?
Answer 5b. For drugs approved under accelerated approval or the
animal efficacy provisions, FDA may withdraw approval (described
further under 21 CFR 314.530 and 314.620) if:
A post-marketing clinical study fails to verify clinical benefit;
The applicant fails to perform the required post-marketing study
with due diligence;
Other evidence demonstrates that the drug product is not shown to
be safe or effective under its conditions of use.
If a manufacturer fails to submit a supplemental application
containing the information or request for approval of a pediatric
formulation within the time specified by FDA (i.e., deferred pediatric
studies under PREA), the drug product may be considered misbranded or
an unapproved new drug or unlicensed biologic.
To date, FDA has not undertaken an enforcement action in any of the
scenarios described above; however, FDA actively monitors the
completion of the required post-marketing commitments and works with
individual sponsors to address factors that may delay timely completion
of the required studies (e.g., slow enrollment, changes in practice or
disease patterns).
Question 5c. Can you tell us what you'll do as Commissioner to
ensure drug makers make good on fast-track study commitments in a
timely manner.
Answer 5c. In addition to the enforceable post-marketing study
commitments described above, the Food and Drug Administration
Modernization Act of 1997 (FDAMA) provided FDA with additional
authority for monitoring the progress of post-marketing studies.
Section 130(a) of Title I of FDAMA added a new provision (section 506B)
on post-marketing studies to the Federal Food, Drug, and Cosmetic Act
356b (``the act'') (21 U.S.C. 356b). This new provision required
sponsors of approved drugs and biological products to report to FDA
annually on the progress of their post-marketing study commitments. In
addition, FDA was required to do the following:
Develop and publish regulations prescribing the format of
the reports sponsors are to submit to FDA.
Report annually in the Federal Register on the performance
of post-marketing commitment studies.
Report to Congress on the studies.
After receiving and considering public comments on its proposed
rule, FDA published the final rule on October 30, 2000 (65 FR 64607)
and the regulations, promulgated under 21 CFR 314.81(b)(2)(vii), became
effective in April 30, 2001. In the preamble to the proposed and final
rules, FDA announced its intention to make basic information about the
status of each post-marketing study commitment available to the public
on the Internet. In May 2003, the Agency launched this website. The
website is updated quarterly. It includes a searchable database of
information on post-marketing studies for drugs and biological
products. The database is maintained internally and tracks the progress
of all post-marketing study commitments; including those that are
required and those that are agreed upon by applicants. FDA's Report to
Congress was delivered to Congress in March 2002, and there have since
been three annual reports (fiscal year 2002, fiscal year 2003, and
fiscal year 2004) on the performance of post-marketing commitment
studies published in the Federal Register.
Publication Bias
Among the controversies FDA has faced in recent years is the
question of antidepressants prescribed to children. In one now well-
publicized case, the drug sponsor had results of several pediatric
studies of its widely prescribed drug an off-label use--only one of
which demonstrated efficacy in treating major depressive disorder. That
single study was published and promoted to doctors, while the other
studies, including some submitted to FDA were not publicized.
While I understand the importance of ``off label'' use drugs to the
practice of medicine, I'm equally concerned about cases in which FDA
has the results of failed efficacy trials for an off-label use and
knows the drug remains widely prescribed for that use.
Question 6.What is FDA's obligation to the public and healthcare
providers to proactively inform them about information the agency has
that contradicts published studies about the safety or efficacy of off-
label uses?
Answer 6. FDA makes every effort to keep the public and healthcare
providers proactively informed about information concerning the safety
and efficacy of drugs that they use. In fact, under our new safety
initiative, we plan to release important new information about safe and
effective product use, and we intend to make information about emerging
risks regarding drug uses available earlier. This will include
information such as known and potential safety issues based on reports
of adverse events, new information that may affect prescribing of the
drug, and the approved indications and benefits of the drug. Under this
initiative, we want to make emerging safety information available to
practitioners and to patients, so they may consider the information
themselves.
______
Response to Questions of Senator Roberts by Lester Crawford, DVM, Ph.D.
Question 1. Currently, a decision is pending in the commissioner's
office regarding the use of an FDA approved antimicrobial for the
treatment of severe respiratory outbreaks in poultry. While I
understand you cannot comment on this case, many experts in poultry
science, veterinary medicine, risk assessment and medical epidemiology
have questioned the validity of FDA's evaluation which has been
challenged as not being compliant with the Information Quality Act.
Further, it appears that the potential benefits to food safety and
human health associated with the use of this product were presented to
FDA but not considered. As commissioner, will you subject such
assessments and decisions to unbiased scientific peer review to ensure
that the best science is used in making decisions that support food
safety and protect human health, yet not taking away the ability of
livestock and poultry producers to judiciously use the valuable tools
that they need?
Answer 1. FDA is committed to using the best available science in
its decision-making and has, like other HHS agencies, developed
guidelines concerning the Data Quality Act. We are also working, as are
other Federal Agencies, to implement where applicable the OMB's Peer
Review Bulletin. Moreover, as you know, the formal process for
withdrawing approval of a new animal drug gives the drug's sponsor the
opportunity to present evidence and legal arguments in support of
keeping the drug on the market. In such cases, I review the sponsor's
evidence and legal arguments before reaching my determination, and I am
not required to follow the rulings by the Administrative Law Judge.
Question 2. We appreciate your leadership last year in FDA moving
forward with the draft guidance for the Early Food Safety Assessment.
Given the importance of final guidance to assisting USDA in working
with our trading partners to keep our international grain markets open,
could you give us an indication on when we could expect to see the FDA
Early Food Safety Evaluation guidance be published in its final form?
Answer 2. We are currently analyzing over 2000 comments the Agency
received on the proposed guidance on the Early Food Safety Evaluation
of New Proteins Produced by New Plant Varieties, and we intend to
finalize the guidance by the end of the year. FDA's commitment to
finalize this document is reflected in the Center for Food Safety and
Applied Nutrition 2005 Program Priorities list, or yellow book, where
the guidance is an ``A-list'' goal slated for completion by the end of
2005.
Question 3. The Medical Device User Fee and Modernization Act of
2002 (MDUFMA) required reprocessors of certain types of previously
cleared reprocessed medical devices originally intended for single use
only to submit to FDA supplemental cleaning, sterility, and
functionality data demonstrating that the device functions ``like new''
in order for the FDA to provide continued market clearance for the
device. Approximately 1,800 models of reprocessed SUDs required
validation data under MDUFMA. The FDA announced toward the close of
2004 that it had completed its review of supplemental validation data
submitted by reprocessors and determined that a significant number of
these devices can no longer be commercially distributed. In light of
the FDA's determination that at least 33 percent of these submissions
failed to demonstrate substantial equivalence, would it not be in the
interest of patient safety to require reprocessors to submit validation
data for all reprocessed single use devices in order for them to remain
marketable?
Answer 3. In the Medical Device User Fee and Modernization Act of
2003/P.L.107-250 (MDUFMA), Congress specified a detailed process by
which FDA was to re-evaluate previously-cleared reprocessed single use
medical devices (SUDs). In accordance with the intent of Congress, FDA
has expended significant resources to accomplish the following:
Premarket Review
On April 30, 2003, FDA identified certain reprocessed SUDs for
which 510(k)s must now include ``validation data . . . regarding
cleaning and sterilization, and functional performance'' to show that
the devices remain substantially equivalent to predicate devices after
all intended reprocessing. FDA issued a guidance document on July 8,
2003 (revised June 1, 2004), describing the types of validation data
that would satisfy this MDUFMA requirement.
For devices in this category that already had cleared 510(k)s,
validation data (referred to as ``Supplemental Validation Submissions
(SVSs)'') were required to be submitted to FDA by January 30, 2004. FDA
received 44 SVSs for reprocessed SUDs for which the 510(k)s had already
been cleared. This represented approximately 1,800 previously cleared
reprocessed SUDs. Regulatory decisions on all but two of these SVSs
were issued by November 1, 2004 as outlined below.
Fifty-two percent of these devices were determined to be
substantially equivalent (SE) to a legally-marketed predicate device
and may continue to be marketed.
An additional 33 percent of the models were determined to
be Not Substantially Equivalent (NSE) to a legally marketed predicate
device based on the failure to submit supplemental data OR the
submission of inadequate supplemental data to FDA. These devices may no
longer be legally marketed since they are no longer cleared for
commercial distribution in the United States at this time. Reprocessors
of these devices may seek clearance for the subject devices anytime in
the future by submitting a new 510(k) premarket notification to FDA
that satisfies the Agency's premarket requirements including
supplemental validation data.
Approximately 15 percent of previously cleared reprocessed
SUD models were withdrawn by the reprocessor. These devices may no
longer be legally marketed at this time. Also, FDA conducted field
inspections to verify discontinuance of marketing.
In November, 2004, FDA posted, on its website, the status of
previously-cleared, reprocessed SUDs that were subject to supplemental
validation data requirements described above. This allows hospitals and
other interested parties to verify the status of reprocessed devices
for use in their facilities. The website includes lists of devices
found to be Substantially Equivalent based on a review of the
supplemental data. These devices appear under the heading of ``Legally
Available.'' In addition, the website lists those devices which may no
longer be legally marketed because supplemental data were required but
not received, subject 510(k)s were withdrawn by the sponsor, or
supplemental data were determined by FDA to be inadequate. These
devices are listed as ``No Longer Legally Marketed''.
On April 30, 2003, FDA also published a list of ``critical''
reprocessed SUDs whose exemption from premarket notification
requirements was terminated. Reprocessors of the devices on this list
were required to submit 510(k)s, including the types of validation data
described above, by July 30, 2004. No reprocessors of the critical
reprocessed SUDs provided any submissions. FDA will conduct follow-up
inspections to verify that the firms have stopped marketing these
reprocessed devices.
On April 13, 2004, FDA published a list of ``semi-critical''
reprocessed SUDs whose exemption from premarket notification
requirements was terminated. Reprocessors of the devices on that list
are required to submit 510(k)s, including validation data, by July 13,
2005.
MDUFMA created a new type of premarket submission, a ``premarket
report'' (PMR), for reprocessed SUDs that otherwise would have required
premarket approval applications. Among other items, a PMR must include
data on reprocessing procedures, such as validation data regarding
cleaning, sterilization, and functional performance.
Adverse Event Reporting
In accordance with MDUFMA, FDA revised the mandatory and voluntary
MedWatch report forms to incorporate the reporting of information on
incidents related to reprocessed SUDs. FDA posted the revised forms on
the MedWatch website in October 2003, along with revised instructions
for mandatory reports, and, in early 2004, published a Federal Register
notice announcing the availability of the revised MedWatch forms.
Inspections/Enforcement
Since MDUFMA was enacted, FDA has inspected over 150 third-party
reprocessors and hospitals engaged in reprocessing. As a result of the
information collected, CDRH's Office of Compliance has issued two
Warning Letters (to a hospital and a third-party reprocessor).
In fiscal year 2004, FDA inspected over 100 U.S. hospitals and
found none currently reprocessing single use devices. FDA has also
issued an inspection assignment in fiscal year 2005 for five firms that
reprocessed SUDs to ensure that they have discontinued marketing of the
devices that were NSE. The five inspections have just been completed
and inspection reports are being prepared.
Next Steps
FDA will continue to review submissions for reprocessed single use
devices as they are received. FDA has received comments on the lists of
critical and semi-critical reprocessed SUDs whose exemption from
premarket notification requirements was terminated, and we are
currently reviewing these comments. Finally, FDA will continue to
inspect reprocessors as appropriate and will inspect new hospital or
third-party reprocessors as they are identified.
Response to Questions of Senator Gregg by Lester Crawford, DVM, Ph.D.
Question 1. In response to controversies surrounding FDA's actions
taken with the popular pain-management drugs Vioxx and Celebrex and
other medications, FDA recently announced new initiatives to improve
drug safety monitoring. Among the initiatives is a plan to provide
emerging safety information to physicians and patients. What will be
FDA's scientific threshold for determining whether ``emerging'' safety
information should be communicated? Will FDA consider factors
surrounding the use of the drug, including risks associated with
patients avoiding the use of potentially life-saving medicines based on
the preliminary data and whether there are alternative treatments
available? Does FDA need any additional authority to ensure the safety
and efficacy of new and marketed drugs?
Answer 1. An emerging risk, or emerging safety concern, is a
possible serious new side effect, potentially related to a drug on the
market, that has been reported to FDA and that FDA is analyzing. A side
effect is considered new when, for example, the effect was not seen (or
the rate or severity of the effect was not seen) during clinical
testing, but was identified after the drug went on the market. For
example, sometimes, after a drug is approved, rare but serious side
effects may emerge as the drug is more widely used. Sometimes drugs are
prescribed for new uses (off-label uses) with unanticipated results. If
FDA receives information that a drug interacts with another drug, and
this interaction may be causing a serious side effect, this information
would be considered emerging.
FDA will consider factors surrounding the use of the drug,
including risks associated with patients avoiding the use of
potentially lifesaving medicines based on the preliminary data and
whether there are alternative treatments available.
I do not believe new statutory authority is needed. We will use all
existing regulatory authority and enforcement powers when negotiating
label changes with drug companies or when monitoring or managing drug
safety issues.
Question 2. Shortly after the Bioterrorism Act was signed into law,
the FDA and Customs entered into a Memorandum of Understanding
concerning increased coordination and communication over the prior
notice requirement for imported foods. What is the status of the
implementation of that MOU? To what extent are FDA and Customs and
Border Protection (CBP) coordinating with the increased inspections and
reinspections of food products? Can you identify what are the barriers
to establishing a mechanism for providing prior notice without a
manufacturer's facility registration number for food products that are
imported for analytical testing or research and development activities
that do not involve consumption by humans or animals?
Answer 2. FDA and Customs and Border Protection (CBP) signed the
Memorandum of Understanding on December 3, 2003. It allows FDA to
commission CBP inspectors to assist FDA in the implementation of the
Prior Notice provisions contained in Section 307 of the Public Health
Security and Bioterrorism Preparedness and Response Act of 2002 (Public
Law 107-188.) This assistance includes coordinating examination and
sampling operations with local FDA personnel. At ports that are not
staffed by FDA personnel, this assistance includes responding to
requests from FDA's Prior Notice Center to examine and sample suspect
shipments arriving at such ports. As of March 2005, FDA has
commissioned approximately 9,500 CBP inspectors who have received the
requisite training. Joint FDA and CBP prior notice activities are
coordinated by FDA's Prior Notice Center, which is co-located at CBP's
National Targeting Center. This collaboration allows both agencies to
share each others' data and targeting systems to evaluate high-risk
shipments.
With respect to food imported for quality assurance, research or
analysis purposes, FDA stated, in the November 2004 revision of the
Compliance Policy Guide for Prior Notice, that it intends to exercise
broad enforcement discretion if, after a good faith effort, the person
submitting prior notices does not know the registration number of the
facility that manufactured the food and instead provides the name and
full address of the facility that manufactured the food. FDA has had a
version of this policy in effect since August 2004. FDA is also
considering this issue, and the comments it has received on it, as it
develops the final rule on prior notice.
Question 3. The Federal Food Drug and Cosmetic Act does not include
provisions to allow for abbreviated biologics license applications
(otherwise known as generic biologics). Can you identify the steps--
including steps related to scientific knowledge--needed to proceed with
the approval of follow-on versions of biological drugs? Do you agree
that any approval requires separate Congressional authorization?
Answer 3. As you know, FDA is conducting a public process to
examine the many questions, including scientific and legal issues, that
must be answered regarding these products and to ensure that all
interested parties have an opportunity to comment. When this process is
complete, FDA intends to provide guidance to industry to clarify,
consistent with its legal authority, the approval pathway and
principles for review of such products, which will protect the public
health.
In recent years--and with increasing frequency--questions about
generic or follow-on proteins have arisen in response to scientific
advances, impending patent expirations, and the ability to better
characterize and understand biological products.
Acknowledging scientific and legal limitations in this area, yet
also recognizing the public health need to move forward to assist
industry and make more products available to the public, FDA is
conducting a public process to examine the scientific, and related
issues regarding follow-on biologics. This process will ensure that
scientific considerations and issues related to Agency authority are
fully examined and that all interested parties have an opportunity for
input.
Question 4. The media has alleged that there exists a conflict of
interest on the part of many qualified specialists who serve on FDA
advisory committees. Despite that it is beneficial for both industry
and FDA to consult with top experts concerning a drug, device or
biologic, critics allege that because they have received compensation
by industry during their professional career or because they have used
a drug, device or biologic in their professional practice, they are
assumed to have conflicts which affect their professional judgment.
Would the FDA be able to have an effective advisory committee process
without the use of experts who have worked with the drug, device or
biologic of interest? Describe the process that FDA has in place to
screen and make public potential conflicts of interests before an
expert serves on an advisory committee.
Answer 4. It would not be possible for FDA to have an effective
advisory committee process without the use of experts who are familiar
with the technology related to new proposed drugs, devices or biologics
of interest. Due to the scarcity of the specific expertise necessary to
evaluate complex scientific issues, these experts are often sought
after for consultation by both the Agency and industry. Utilizing
junior scientists who are less experienced or less highly qualified in
order to completely remove any potential conflict from the committee
would hamper the Agency's ability to protect and advance the public
health.
The Agency's process is to evaluate the potential financial
interests of members and other invited special government employees.
FDA makes a determination as to whether the participation of an
individual with some financial ties outweighs the need for the agency
to understand the science on the topic before the committee. Although
the Agency has public guidelines for this process, this is not a black
and white process. It requires careful consideration of all facets of
the issue in order to evaluate that balance. By permitting waivers for
conflicts of interest, Congress has ensured the Nation that the Agency
and the public (through the advisory committee process) has access to
the most knowledgeable individuals on the meeting topic.
FDA's process of evaluating potential committee members for
conflicts is very extensive and transparent. Our methodology is
articulated in an extensive document that is publicly available on the
agency's Web site (http://www.fda.00v/oc/advisory/conflictofinterest/
intro.html). At the beginning of each meeting, a conflict of interest
statement is read into the record, which summarizes the results of the
conflicts of interest screening. FDA has been commended by the Office
of Government Ethics (1997) which stated that it was ``impressed with
FDA's Program for protecting SGEs from COI . . .'' and that FDA is ``a
model for other Agencies to use in developing their own systems and
procedures.'' Nonetheless it is always prudent to regularly assess the
Agency program and determine if any improvements are warranted and in
the near future, the Agency will review the advisory committee
conflicts of interest disclosure process and work to make the
disclosures more easily accessible to the public.
Question 5. As you know, there are no FDA approved drugs to treat
some major conditions of companion animals and horses. Despite that
many species of animals cannot be successfully treated with currently
available FDA approved drugs, the Center for Veterinary Medicine
prohibits pharmacists from filling prescriptions for animals by
compounding the prescribed drug from bulk drugs. Their policy permits
no exceptions even for non-food animals, such as cats, dogs, and
horses. Critics of this policy say that, were this ban to be fully
implemented and enforced, many animals would suffer or die needlessly.
As Commissioner would you permit licensed veterinarians to prescribe
drug products which must be compounded and pharmacists to compound such
prescriptions for non-food animals when medically warranted from bulk?
Answer 5. FDA has had a longstanding policy of exercising its
enforcement discretion regarding certain types of pharmacy compounding.
This policy is articulated in Compliance Policy Guide (CPG), section
7125.40, issued in July 2003. FDA recognizes that pharmacists
traditionally have extemporaneously compounded reasonable quantities of
drugs. This traditional practice follows the receipt of a valid
prescription for an individually identified patient from a licensed
practitioner. The compounding is performed at the pharmacy site for
nearly immediate dispensing for administration to the animal or
animals. FDA has long expressed the view that such compounding serves
an important medical purpose, and FDA has no intention of eliminating
or frustrating this historical practice.
FDA believes, however, that some pharmacies are engaged in
practices that fall outside the bounds of traditional pharmacy
compounding. These pharmacies are engaged in manufacturing and
distributing unapproved new animal drugs in violation of the act. It is
appropriate that pharmacies engaged in activities analogous to
manufacturing drugs for animals be held to the same provisions of the
act as drug manufacturers.
FDA's CPG contains factors that the agency considers in deciding
whether to exercise its enforcement discretion with respect to animal
drug compounding. The 13 factors described in the CPG include whether a
firm is compounding drugs for third parties who resell them; whether a
firm is compounding drugs in anticipation of receiving prescriptions,
except in very limited quantities; whether a firm is compounding a
copy, or essentially a copy, of a commercially available FDA-approved
drug product; and whether a firm is compounding from bulk active
ingredients, except where the use of the bulk active ingredient is of
low regulatory concern either in general or on a case-by-case basis.
Thus, for example, where a pharmacist contemporaneously compounds
reasonable quantities of drugs from bulk active ingredients for non-
food animals in response to a valid prescription for an individually
identified patient, FDA has typically not taken enforcement action.
FDA is revising the CPG to further explain its enforcement policies
with respect to the compounding of drugs for food and non-food animals.
A number of groups, including the International Academy of Compounding
Pharmacists, the American Veterinary Medical Association, the American
Association of Equine Practitioners, and other affected groups, have
met with the Agency to discuss their concerns with the current CPG and
to suggest changes to it. In revising the CPG, FDA wants to make sure
that it provides the clarity that the regulated industry believes is
lacking in the current CPG.
Question 6. On November 16, 2004, I wrote a letter to you
recommending the establishment of descriptive claims for whole grains
on food labels. Do you agree that establishing descriptor claims such
as ``excellent source,'' ``good source,'' and ``made with'' for whole
grain content can provide information so that consumers can make better
dietary choices that could lead to the prevention of some diet-related
diseases? I understand that the FDA is currently considering a petition
requesting descriptive claims for whole grains on food labels. When
does FDA expect to act on that petition?
Answer 6. FDA is committed to the goal of making available to
consumers more and better information about the health benefits of
foods. HHS and the U.S. Department of Agriculture developed the 2000
Dietary Guidelines for Americans and the Food Guide Pyramid, which
contain guidelines for increased consumption of whole grain foods. On
May 11, 2004, FDA received a petition asking the Agency to establish
the descriptive claims ``excellent source'', ``good source'', and
``made with'' for whole grain content of foods. That petition is under
review in our Center for Food Safety and Applied Nutrition.
Question 7. Under the proposed reorganization of CDER, the
Ophthalmology Sub-Division would be completely absorbed by the Division
of Anti-Infective drugs. This proposed merger could potentially have a
harmful impact to the review of ophthalmic drugs. As ophthalmic
products are merged into anti-infectives, will staff with ophthalmic
experience maintain management and review of ophthalmology drugs and
final approval recommendations for such products? If not, how does this
represent a more efficient structure to ensure the safety and efficacy
of ophthalmic drugs?
Answer 7. We expect that individuals with expertise in
ophthalmology will continue to play a critical role in reviewing new
ophthalmology products, and the reorganization will not affect the
timely approval of treatments and drug therapies available to eye care
practitioners and their patients. All drug review processes for all
products will continue to be held to existing PDUFA goals and timelines
during and as a result of the reorganization.
Question 8. FDA has a key role to play in evaluating and approving
effective treatments for tobacco dependence, like the nicotine gum,
lozenge, and patch. However, more can be done within FDA's existing
authority to help smokers who are trying to quit. Such actions include
``fast track'' status to applications involving products to treat
tobacco dependence and considering alternative indications for nicotine
replacement therapies, including relapse prevention, relief of
cravings, and extended use for those smokers who wish to gradually wean
off of tobacco consumption. What steps is FDA taking to expand access
to these promising therapies?
Answer 8. The Food and Drug Administration (FDA or the Agency) is
committed to employing tools to facilitate the development and
marketing of products that may represent important public health
advances for smoking cessation. FDA would evaluate for fast track
designation and/or priority review status novel products that have the
potential to truly represent a significant advance in the treatment of
tobacco dependence. This accelerated development/review is a highly
specialized mechanism for speeding the therapies for serious or life-
threatening illnesses or for illness for which no therapy exists.
FDA approved Nicorette Gum (nicotine polacrilex), manufactured by
GlaxoSmithKline, on January 13, 1984, under accelerated review (6
months). This product received accelerated review because it was a new
molecular entity with a therapeutic advantage over existing therapies
for smoking cessation. FDA switched Nicorette Gum to over-the-counter
status on February 9, 1996. All other approved products underwent
standard review because they did not demonstrate a significant benefit
over Nicorette Gum.
Question 9a. The FDA approval of RU-486 has raised many concerns
regarding the safety and efficacy of the drug regimen.
(a) Please describe why RU-486 was approved under Subpart-H, which
is reserved for drugs in treating serious or life-threatening
illnesses, such as AIDS and cancer?
Answer 9a. As you know, Mifeprex (sometimes referred to as RU-486)
was approved in September 2000 under a previous Commissioner. I am
therefore unable to fully respond to this question.
FDA has received reports of serious bacterial infection, bleeding,
ectopic pregnancies that have ruptured, and death. In response, in
November 2004, FDA announced new safety changes regarding the labeling
of Mifeprex. The new warnings to health care providers and consumers
include changes to the existing black box on the product to add new
information on the risk of serious bacterial infections, sepsis, and
bleeding and death that may occur following any termination of
pregnancy, including use of Mifeprex.
We will continue to closely monitor the safety of this and all
drugs on the market.
Question 9b. Would you also describe why the FDA approved RU-486
for pediatric patients but waived the pediatric rule?
Answer 9b. As you know, RU-486 was approved in September 2000 under
a previous Commissioner. I am therefore unable to fully respond to this
question. As noted above, the FDA is carefully monitoring adverse
events related to this and all drugs on the market.
Question 9c. Please describe information that you have that the
product is being promoted by the manufacturer, or by providers on
publicly accessible websites, for ``off-label'' uses. What actions has
the agency taken in response to such information?
Answer 9c. The Agency is not aware of the manufacturer promoting
off label use of Mifeprex on publicly available websites. FDA's
authority to regulate advertising is directed at advertising by the
manufacturers, packers or distributors of regulated products.
Question 10. Aside from Mifeprex, in the past 20 years how many new
drug applications has FDA approved based solely on data from
uncontrolled clinical trials? In the past 20 years how many new drug
applications has FDA approved based solely on data from historically
controlled trials? For each answer please provide the name of any drugs
listed, the NDA number, and a brief description of the trials. With
respect to historically controlled trials, please describe the control
group used.
Answer 10. Below is a brief summary of FDA's policy regarding
control groups for clinical trials intended to support an effectiveness
claim for a new drug.
An adequate and well-controlled investigation must be designed to
distinguish the effect of a drug from other influences, such as
spontaneous change in the course of the disease, placebo effect, or
biased observation. Reports of adequate and well-controlled
investigations provide the primary basis for determining whether there
is substantial evidence to support the claims of effectiveness for new
drugs. By definition, an adequate and well-controlled study uses a
design that permits a valid comparison with a control to provide a
quantitative assessment of the drug effect. Generally, we recognize the
following types of controls (21 CFR 314.126(b)(2)):
Placebo concurrent control
Dose-comparison concurrent control
No treatment concurrent control
Active treatment concurrent control
Historical control
``No treatment concurrent control'' is defined as trials where
objective measurements of effectiveness are available and placebo
effect is negligible. In such trials, the test drug is compared with no
treatment. Such trials usually include randomization. In ``historically
controlled trials,'' the results of treatment with the test drug are
compared with experience historically derived from the adequately
documented natural history of the disease or condition, or from the
results of active treatment, in comparable patients or populations.
Examples include studies of diseases with high and predictable
mortality (for example, certain malignancies) and studies in which the
effect of the drug is self-evident (general anesthetics, drug
metabolism).
In contrast, uncontrolled studies or partially controlled studies
are not acceptable as the sole basis for the approval of claims of
effectiveness. However, such studies, if carefully conducted and
documented may provide corroborative support of well-controlled studies
regarding efficacy and may yield valuable data regarding safety of the
test drug. (21 CFR 314.126(e))
As noted above, uncontrolled studies are not an acceptable basis
for establishment of a claim of effectiveness, therefore, we cannot
cite any examples of drugs approved solely based on uncontrolled
trials. With regard to historical controls, FDA does not capture
information on the type of control used in clinical investigations to
support a demonstration of effectiveness in our databases. Therefore,
we are not able to provide a comprehensive list of applications
approved based on historical controls in response to your question.
However, the following are examples to illustrate experience (NOTE:
This is not intended to be a comprehensive listing of all such
approvals.):
Example of a product approved using ``no treatment concurrent
control'':
NDA 50-747 Synercid (quinupristin/dalforpristin) for the treatment
of vancomycin resistant Enterococcus faecium bacteremia. Four non-
comparative studies were conducted. Three of the trials were
prospective; the fourth consisted of a collection of individual
emergency-use requests.
Examples of products approved using historical controls:
NDA 20-645 Ammunol (sodium benzoate/sodium phenylacetate)
for the treatment of urea cycle disorders. Efficacy was compared to
historical data from published literature to evaluate percent survival
with therapy compared to how these patients fared in other cohorts
before such therapy was available on an investigational basis.
NDA 21-227 Cancidas (caspofungin acetate) for the
treatment of invasive aspergillosis in patients who are refractory to
or intolerant of other therapies, on the basis of a historically
controlled trial with the control developed from hospital records by
the sponsor. The approval was supported by information on safety from
trials in candida infections.
BLA STN 103737 Rituxan (rituxumab) and BLA STN 125011.0
Bexxar (tositumomab plus13'I-labeled tositumomab) for the treatment of
non-Hodgkin's lymphoma. Approvals for both products were based on
multicenter, single-arm studies. The historical control is based on
knowledge of the natural history of untreated non-Hodgkin's lymphoma, a
disease that does not have spontaneous remissions.
Question 11. Aside from Mifeprex, how many drugs has FDA approved
in which an off-label, unapproved use for a second drug is mandated as
part of an approved regimen? If there are any others, please provide
the name of the drugs, the NDA numbers in which such use was mandated,
and any documents from FDA requiring such use.
Answer 11. We do not track information about references to the use
of other drugs as part of the approved labeling for drug products.
Therefore, we are not able to provide a comprehensive response to your
question. The following examples illustrate FDA's experience: (NOTE:
This is not intended to be a comprehensive listing of all such
products.)
Examples of products approved in combination with another drug for
a use that was not sought by the sponsor of the second product and for
which a change in labeling of the second product was not required
include:
NDA 20-954 Busulfex (busulfan), in combination with
cyclophosphamide, for hematopoietic stem cell transplant.
NDA 20-509 Gemzar (gemcitabine hydrochloride), in
combination with cisplantin, for treatment of non-small cell lung
cancer.
NDA 20-388 Navelbine (vinorelbine tartrate), in
combination with cisplantin, for treatment of non-small cell lung
cancer.
NDA 20-262 Taxol (paclitaxel), in combination with
cisplantin, for treatment of ovarian cancer and non-small cell lung
cancer, and for use with Adriamycin (doxorubicin) plus Cytoxan
(cyclophosphamide) in adjuvant breast cancer.
NDA 20-638 Vistide (cidofovir), for the treatment of CMV
retinitis in patients with AIDS, has a boxed warning which states that
it must be administered with probenecid to reduce nephrotoxicity.
BLA STN 103792.0 Herceptin (traxtuzumab), in combination
with paclitaxel, for first-line treatment of metastatic breast cancer.
NDA 21-462 Alimta (pemetrexed disodium), in combination
with cisplantin, for the treatment of mesothelioma.
NDA 21-663 Menopur (menotropins), for use in female
infertility in which pituitary suppression is required. Dosage
instructions are given for patients who have received a GnRH agonists;
however, GnRH agonists are not approved for this use.
______
Response to Questions of Senator Harkin by Lester Crawford, DVM, Ph.D.
Post Market Surveillance
Question 1. On February 15th, the Food and Drug Administration
announced the formation of the Independent Drug Safety Oversight Board.
The purpose of the Board is to get information to doctors and consumers
about safety concerns with drugs that have already been approved.
However, the board has no regulatory authority and is only advisory in
nature. In addition, the Board is not truly separate from the Office of
New Drugs, the entity responsible for action if a problem is found with
a drug after market approval. Shouldn't there be a separate entity
charged with post-market surveillance and evaluation of approved drugs?
Should this entity have the authority to make label changes or take
other actions designed to protect the consumer? What actions could FDA
take to inform physicians and consumers about the risks associated with
specific drugs after drug approval? What resources would be necessary
to maintain this advisory role for FDA?
Answer 1. The make up of the Drug Safety Oversight Board (Board)
and the vesting of decision-making authority in the Center Director
ensure that the Board's deliberations will be independent of the drug
approval process. Representatives of the Office of New Drugs comprise
only three of the Board's 15 voting members. To the extent possible, we
will ensure that none of the three voting members has been involved in
the actual decision-making concerning a particular drug coming to the
Board. If they have been involved in the actual decision-making
process, they will not be allowed to vote. The Board will make
recommendations to the Center Director who will make the final
decisions on drug safety issues. The Center Director and the Deputy
Center Director are not normally involved in the approval of new drugs.
Decisions made by the Center Director, based on recommendations made by
the Board, will be implemented through the appropriate program office.
The Center Director retains final authority for Center decisions. A
dissenting Office Director may appeal the Board's recommendations to
the Center Director before the Center Director makes a final decision.
The Office of Drug Safety (ODS) is charged with post-marketing
surveillance of approved drugs. ODS is already an independent office
separate from the Office of New Drugs, the office that reviews new drug
applications. Both offices report directly to the Acting Director of
CDER. ODS has strong support within both CDER and the Agency and has
been a vital part of FDA's efforts to ensure drug safety. In addition,
ODS has independent authority to perform its own research and does so
every day.
Regarding the issue of informing physicians and consumers about the
risks associated with specific drugs after approval, FDA will share
drug safety information sooner and more broadly, including information
on potential safety problems even before the Agency has reached
conclusions that would prompt a regulatory action. The new
communications include:
The Proposed Drug Watch ``Web'' Page
At the direction of the new Drug Safety Oversight Board, this Web
page will include emerging information about possible serious side
effects or other safety risks.
Healthcare Professional Information Sheets
We have also started developing and making these sheets available
to better communicate emerging risk information to the medical
community. We will continue to develop these information sheets, or
will update existing ones, as we become aware of possible serious new
side effects for a drug. The sheets will contain an FDA Alert
describing emerging information.
Patient Information Sheets
We have already begun to develop and make available on CDER's
Website user-friendly information for patients and consumers on drugs
about which we have identified emerging issues. We will continue to
develop these sheets, or update existing ones, as we become aware of
possible serious new side effects for a drug. The sheets will contain
an FDA Alert describing emerging information.
Mercury Exposure
Question 2a. Many of my constituents are concerned about the
apparent rise in the rate of Autism, or Autism spectrum disorders, in
children. One hypothesis offered to explain the rise is that increased
exposure to mercury causes autism. Scientists have demonstrated that
mercury levels are rising in fish common in human consumption. In
addition, some childhood vaccines contained mercury as a preservative.
It is my understanding that only some flu vaccine currently uses
mercury based preservative. Is this correct?
Answer 2a. Yes, this is correct. The mercury-containing
preservative referred to above is thimerosal. At this time, there are
three U.S. licensed influenza vaccine manufacturers, Sanofi Pasteur,
Chiron and Medlmmune. Both Sanofi Pasteur and Chiron manufacture
inactivated influenza vaccines, which are available in a thimerosal-
preservative containing formulation and a preservative-free formulation
that contains no thimerosal or only trace amounts ( 1 microgram
mercury per 0.5 ml dose; 0.5 micrograms mercury per 0.25 ml dose).
Medlmmune manufactures a live, intranasally administered influenza
vaccine that contains no thimerosal. Only Sanofi Pasteur's Fluzone is
indicated for children as young as 6 months of age (no influenza
vaccine are approved for children less than 6 months of age). Chiron's
Fluvirin is indicated for persons 4 years of age and older, and
Medlmmune's Flumist (a live intranasal vaccine) is indicated for
persons 5-49 years of age.
In 2004, the Institute of Medicine considered this topic, including
new data that had accumulated since its previous review in 2001. These
data included several epidemiological studies conducted in the United
States, Denmark, Sweden, and the United Kingdom, and studies of
biologic mechanisms related to vaccines and autism. The committee
concluded that this body of evidence favors rejection of a causal
relationship between thimerosal-containing vaccines and autism, and
that hypotheses generated to date concerning a biological mechanism for
such causality are theoretical only. Further, the committee stated that
the benefits of vaccination are proven and the hypothesis of
susceptible populations is presently speculative, and that widespread
rejection of vaccines would lead to increases in incidences of serious
infectious diseases like measles, whooping cough, and Hib bacterial
meningitis.
Question 2b. In existing childhood vaccines are there problems with
mercury contamination even in trace amounts? If so, in FDA's opinion is
there a health hazard or does more research need to be conducted?
Answer 2b. Childhood vaccines, are not contaminated with mercury.
Thimerosal, an organic mercury compound, has been added as a
preservative to some vaccines, including pediatric vaccines. The need
for a preservative can be eliminated to the extent that it is feasible
to manufacture vaccines in single dose vials or syringes. In those
instances where thimerosal has been used in earlier stages of
manufacture to prevent contamination, it can be removed to the extent
possible before final formulation of vaccines, but trace (0.1 microgram
mercury per 0.5 ml dose) remains.
Under the FDA Modernization Act (FDAMA) of 1997, the FDA conducted
a comprehensive review of the use of thimerosal in childhood vaccines.
Conducted in 1999, this review found no evidence of harm from the use
of thimerosal as a vaccine preservative, other than local
hypersensitivity reactions. However, as a precautionary measure, and
because the elimination or reduction of mercury in vaccines was a
feasible means of reducing an infant's total exposure to mercury in a
world where other environmental sources are challenging to eliminate,
the Public Health Service (including the FDA, National Institutes of
Health (NIH), Center for Disease Control and Prevention (CDC) and
Health Resources and Services Administration (HRSA)) established the
goal of removing thimerosal as a preservative from vaccines routinely
administered to infants as soon as possible. The PHS and the American
Academy of Pediatrics issued two Joint Statements, urging vaccine
manufacturers to reduce or eliminate thimerosal in vaccines as soon as
possible (CDC 1999) and (CDC 2000).
FDA has worked with and continues to work with vaccine
manufacturers to reduce or eliminate thimerosal from vaccines, and
significant progress has been made. Since 2001, all vaccines routinely
recommended for children 6 years of age and under (DTa), hepatitis B,
Haemophilus b conjugate (Hib), pneumococcal conjugate, IPV, MMR, and
varicella) manufactured for the U.S. market have contained no
thimerosal or only trace amounts, with the exception of inactivated
influenza vaccine. FDA has approved preservative-free formulations
(which contain no thimerosal or only trace amounts of thimerosal) for
each of the two licensed inactivated influenza vaccines. FDA is in
discussions with manufacturers of influenza vaccine regarding their
capacity to increase the supply of preservative-free vaccine.
The U.S. Public Health Service agencies have collaborated with
various investigators to initiate further studies to better understand
any possible health effects from exposure to thimerosal when used as a
preservative in vaccines. Available data has been reviewed in several
public forums including the Workshop on Thimerosal sponsored by the
National Vaccine Advisory Committee, held in August 1999, two meetings
of the Advisory Committee on Immunization Practices of the CDC, held in
October 1999 and June 2000, and the Institute of Medicine's
Immunization Safety Review Committee in July 2001 and February 2004.
Through its Vaccine Safety Datalink, the CDC has examined the incidence
of autism as a function of the amount of thimerosal a child received
from vaccines. In this study, no significant association was found
between autism and exposure to thimerosal-preservative-containing
vaccines. Additional studies are planned in these areas.
In 2001, the Institute of Medicine (IOM), at the request of CDC and
NIH, convened the Immunization Safety Review Committee (the committee)
to review selected issues related to immunization safety. This
committee has completed two reviews of studies addressing a potential
link between thimerosal-containing vaccines and autism. In its first
review, conducted in 2001, the committee concluded that the evidence is
inadequate to either accept or reject a causal relationship between
thimerosal exposure from childhood vaccines and the neurodevelopmental
disorders of autism, attention deficit hyperactivity disorder, and
speech or language delay. The committee believed that the effort to
remove thimerosal from vaccines was ``a prudent measure in support of
the public health goal to reduce mercury exposure of infants and
children as much as possible.''
In 2004, the IOM's Committee reviewed this topic again, including
new data that had accumulated since its review in 2001. These data
included several epidemiological studies conducted in the United
States, Denmark, Sweden, and the United Kingdom, and studies of
biological mechanisms related to vaccines and autism. The committee
concluded that this body of evidence favors rejection of a causal
relationship between thimerosal containing vaccines and autism, and
that hypotheses generated to date concerning a biological mechanism for
such causality are theoretical only. Further, the committee stated that
the benefits of vaccination are proven and the hypothesis of
susceptible populations is presently speculative, and that widespread
rejection of vaccines would lead to increases in incidences of serious
infectious diseases like measles, whooping cough, and Hib bacterial
meningitis.
Question 2c. Is mercury used at any other stage in the
manufacturing process? Is FDA conducting or has the FDA conducted any
research into mercury exposure and its potential linkage to Autism or
related disorders?
Answer 2c. FDA has taken seriously reports to the Vaccine Adverse
Event Reporting System (VAERS) of developmental delay following
vaccination. CBER conducted a follow-up study of VAERS reports of
autism. As part of the study, CBER, in conjunction with outside autism
experts, reviewed available medical records and surveyed parents and
others who have reported autism after vaccinations. The goal of the
interviews was to gather information about demographics, clinical
features, potential risk factors, family history, vaccines
administered, time interval from vaccination to autism onset, rapidity
of symptom onset, and interval from diagnosis to submission of reports.
Another goal was to determine how a parent makes the association
between a child's autism and vaccination. Because of the limitations of
VAERS, this study could not be designed to determine whether vaccines
cause autism. However, the study demonstrated a secular trend in the
perception that autism might be associated with vaccines. The study
specifically recommended that when providing guidance about
immunizations and vaccine-preventable diseases, the risks of
immunization should be discussed in the context of the risks of
infection [Woo J., AJPH 94(6):990-995, 2004].
As noted in the response to the previous question, CDC did conduct
a study using the Vaccine Safety Datalink that did not show an
association between thimerosal preservative-containing vaccines and
autism (Vertraeten T etal, Pediatrics 112:1039-1048, 2003). In
addition, the IOM was asked by the PHS to do an independent assessment
of this issue, and their reports (published in 2001 and 2004) are noted
above as well.
Old Drugs
Question 3. There are many old drugs on the market that have never
been approved directly by the Food and Drug Administration. Many are
very common. However, several drugs have been removed from the market
after specific manufacturers pursue a New Drug Application on the old
drug. This process has, in some cases, removed some competitors from
the market.
Last year, you testified before the House Agriculture
Appropriations Committee that a Prescription Drug Monograph System that
could govern these drugs would be too expensive to implement. But you
also said that you had another way to bring these drugs under
regulation without disrupting the market. Have you determined another
solution?
Answer 3. FDA believes that the Agency's draft Compliance Policy
Guide (CPG) on marketed, unapproved drugs, when finalized, will provide
a means of protecting the public health without imposing undue burdens
on consumers or disrupting the market unnecessarily. The Compliance
Policy Guide (CPG) describes how we intend to exercise our enforcement
discretion with regard to drugs marketed in the United States that do
not have required FDA approval for marketing. By targeting drugs based
on health risk, efficacy, and health fraud factors, the CPG will enable
the Agency to: (1) devote its limited resources to those actions most
likely to improve public health; (2) proceed against an individual
product or an entire class of products, as appropriate; (3) preserve
resources for review and approval of new, innovative drugs; and (4)
remove potentially unsafe or ineffective products from the market
without awaiting the resolution of lengthy rulemaking processes. The
CPG also will create an incentive for manufacturers of marketed,
unapproved drugs to seek approval of their products, which further
addresses safety and efficacy concerns while preserving Agency
resources. We received a number of comments on the draft CPG and we are
revising the draft in response to the comments.
Emergency Contraception
Question 4. Last spring, the FDA refused to allow over the counter
sale of emergency contraception, which prevents pregnancy in almost all
cases when taken within 48 hours and has been found to be safe and
effective. In January, the FDA failed to act by its own internal
deadline on a new request to sell emergency contraception from behind
the counter. Can you provide assurances that a decision will be made
within the next 3 months?
I understand that part of the delay is concern by the FDA about the
precedent of requiring Plan B be held behind a pharmacy counter as they
do many places in Europe. However, in Iowa and many other States we are
going to start requiring that all pseudoephedrine products be held
behind the pharmacy counter. Do you agree that keeping emergency
contraception behind the counter is a perfectly workable option?
The denial of the Plan B application for over the counter status
despite the vote of the Advisory Board and the internal staff
recommendation has created the appearance that the Agency caved to
political pressure. What plans do you have to prevent that sort of
problem in the future once you are confirmed?
Answer 4. The Prescription Drug User Fee Act (PDUFA) goal date for
the Barr Laboratories/Plan B OTC supplemental application was January
22, 2005. The application is still under review.
This current cycle review is in response to resubmission of the
application by the sponsor in July 2004. The resubmission proposes a
revised indication to allow for marketing Plan B as prescription-only
for women under the age of 16 and as nonprescription for women 16 years
of age and older. In addition, they propose an educational program for
healthcare providers, pharmacists, and patients.
The issuance of the Not Approvable letter in May 2004 did not mean
that a supplemental application could not be approved in the future.
The Not Approvable letter described what the applicant would need to do
to obtain approval for its initial supplemental application. In this
case, the applicant chose to revise its application and requested to
market Plan B as prescription-only for women under the age of 16 and as
nonprescription for women 16 years of age and older. FDA is currently
reviewing this application.
Advisory committees at FDA were established to be only advisory in
nature. When selecting participants for membership in advisory
committees, we seek experts with a broad range of experience in their
field. Such committee meetings offer a wide range of views that are
discussed in a public forum. FDA seeks and appreciates the
recommendations made by the committees. The final determination on a
drug application, however, remains with the Agency. Although the Agency
frequently makes final decisions concerning a new drug application
(NDA) that are in accord with an advisory committee's recommendations,
FDA is not bound to follow their recommendations. It is not unusual for
there to be occasional differences of opinion among staff at the Agency
on a particular issue. The scientific interchange of ideas is widely
encouraged during the review process to ensure a thorough vetting of
the issues. Decisions on drug reviews, however, cannot be made by
simple majority vote or with the Agency feeling obligated to rubber
stamp an advisory committee vote. Ultimately, a final decision is made
based on FDA's evaluation of the data, taking into account all of the
views expressed.
Decisions on this review are being made within FDA's Center for
Drug Evaluation and Research where the supplemental application is
still under review.
Restaurant Labeling
Question 5. Dr. Crawford, in your remarks, you stated some members
of the chain restaurant industry had adopted some measures to provide
nutritional information to consumers. Could you provide specific
information on which chains are meeting the recommendations found in
``Counting Calories: Report of the Working Group on Obesity.'' What are
they doing to meet those recommendations? Given the rise in eating
outside the home, Dr. Crawford, in your opinion do consumers need more
information, rather than less, to make rational, responsible, and
personal decisions about their own health? How can this information be
standardized across restaurants?
Answer 5. The FDA Report on Obesity, ``Calories Count,'' recommends
several steps be taken concerning ``away-from-home'' foods.
Specifically the Agency urged the restaurant industry to launch a
nationwide, voluntary, and point-of-sale nutrition information campaign
for consumers, to include information on calories. As a companion to
that, and in response to input from the restaurant industry that they
do respond to consumer demands, the report also calls on consumers to
routinely request calorie and other nutrition information when they eat
away from home. FDA has been doing this in speeches and meetings since
release of the report. Further, the report calls on FDA to work with a
third party facilitator to begin a national policy dialogue to seek
consensus-based solutions to specific aspects of the obesity problem
involving food consumed away from home. In June of 2004, FDA signed a
contract with the Keystone Center, a nationally recognized facilitator
for policy and scientific issues, to begin the dialogue process on this
and the pediatric obesity (education) issue. The goal of the away-from-
home foods dialogue will be to consider what can be done, given the
best available evidence to date, to support consumers' ability to
manage energy intake with respect to preventing undue weight gain and
obesity. The dialogue is intended to produce options for a range of
actions by a diverse range of stakeholders. Keystone will convene its
first plenary meeting of stakeholders, to include representatives from
the restaurant industry, academia, consumer groups and government, on
April 26-27, 2005.
You are correct that a number of chain restaurants have put in
place initiatives to address obesity. Some quick service restaurants
have made nutrition information available to consumers for years, on an
in-store poster, on tray liners, via the internet, or on request by
phone or mail. Specific examples of some of the current initiatives we
are aware of are as follows:
Over a year ago, the Ruby Tuesday restaurant chain
introduced menus with full calorie (and other nutrient) information for
each item offered. We are unaware of how many of their restaurants use
this menu at the present time.
Many of the familiar quick service restaurants, including
McDonald's, Burger King, Wendy's and Yum! Brand Foods chains such as
Taco Bell, Kentucky Fried Chicken and A&W, continue to introduce
alternative menu items focused on fruits and vegetables as alternatives
to the traditional items. Many of these same restaurants have also
focused on the need to balance calories with physical activity with
online programs combining nutrition information on their products with
recommendations for increasing physical activity.
Subway restaurants have supplied nutrition information,
including fat and calories with their menu items for some time.
FDA continues to encourage restaurants voluntarily to provide
point-of-sale nutrition information to customers, including calorie
information on a nationwide basis. For those consumers that want
calorie and other nutrition information at the point of sale, we
believe the industry should continue to strive for more innovative and
helpful solutions nationwide. This will be part of FDA's focus in the
upcoming Keystone dialogue.
______
Response to Questions of Senator Hatch by Lester Crawford, DVM, Ph.D.
Question 1. Much has been made about a recent Institute of Medicine
report, Complementary and Alternative Medicine in the United States,
which recommended amendment of the Dietary Supplement Health and
Education Act (DSHEA). In its report, the IOM recommended amendment of
DSHEA and FDAOs current regulatory scheme to address six issue areas:
(1) seed to shelf quality control; (2) accuracy and comprehensiveness
in labeling; (3) enforcement efforts against false and misleading
claims; (4) research into how consumers use supplements; (5) incentives
for privately funding research into efficacies; and (6) consumer
protection against all potential hazards.
Although I do quarrel a bit with terming supplement use
``alternative medicine,'' I do appreciate the IOM's interest in this
issue and its identification of areas for discussion. That being said,
could you comment on whether you believe either the law or FDA
regulation would need to be amended in order to address the IOM's
recommendations?
Answer 1. In November 2004, FDA published a regulatory strategy
that clearly lays out, for the industry and consumers, the Agencys
direction in implementing all the provisions of the Dietary Supplement
Health and Education Act of 1994 (DSHEA). The strategy is designed to
give consumers a higher level of assurance about the safety of dietary
supplement products and the reliability of their labeling, as well as
to improve the transparency, predictability, and consistency of the
Agencys scientific evaluations and regulatory actions to protect
consumers against unsafe dietary supplements and dietary supplements
making unauthorized, false, or misleading claims. Last year, FDA took
action on dietary supplements containing ephedrine alkaloids because
they present an unreasonable risk of illness or injury. The Agency will
continue its ongoing efforts of monitoring and evaluating product
safety, ingredient safety, and product labeling, as well as ensuring
product quality.
Question 2. Dr. Crawford, there is apparently growing concern among
many dietary supplement consumers that the CODEX Alimentarius
guidelines on vitamins and minerals, said to be adopted this July, will
supersede U.S. law and DSHEA specifically, resulting in limits on the
potency of vitamins and minerals now available in the United States.
Could you give us your understanding of whether CODEX guidelines
supersede U.S. law?
Answer 2. The Codex Alimentarius Commission was created in 1963 by
the Food and Agriculture Organization of the United Nations (FAO) and
the World Health Organization (WHO) to develop food standards,
guidelines and related texts such as codes of practice under the Joint
FAO/WHO Food Standards Program. The main purposes of this program are
protecting health of the consumers and ensuring fair trade practices in
the food trade, and promoting coordination of all food standards work
undertaken by international governmental and non-governmental
organizations. The CODEX guidelines will not supersede U.S. law--in
part because of the statutory provisions of FDAMA that direct FDA to
try to harmonize its regulatory requirements with those of other
governments specifically exclude dietary supplements. See section
410(b) of the Food and Drug Administration Modernization Act of 1997.--
(FDAMA) (Pub. L. 105-115, codified at 21 USC 383(c)).
Question 3. Doctor, 10 years ago, the Dietary Supplement Health and
Education Act authorized the Food and Drug Administration to develop
good manufacturing practice standards (GMPs) specific to dietary
supplements. I recognize that the law did not require you to do so, but
it did allow this process to begin. We were greatly heartened that FDA
did undertake to develop dietary supplement GMPs. That's the good news.
The bad news is that 10 years ago the Dietary Supplement Health and
Education Act authorized the FDA to develop GMPs for dietary
supplements, and we have not yet seen them published. It is my
understanding that the HHS-approved GMP regs were forwarded to OMB for
final clearance during the Clinton administration. Shortly after
President Bush was elected, my office received a call from a senior HHS
official stating that HHS was going to make certain the GMP regs were
exempted from the general freeze on pending regulations (so that the
new administration could review them) and allow them to proceed
forward. Over the past 4 years, we have had numerous reports that the
regs were going forward, but they still have not been published.
Accordingly, I would like to know the following things about the status
of these regulations:
Have they been cleared in final by FDA?
Have they been cleared in final by HHS?
What specific issues remain outstanding so that these
regulations may be finalized?
Please tell the committee when the regulations will be
published, that is, on what date certain can we be assured the
regulations will have been finalized?
Answer 3. I am as disappointed as you are that we have not been
able to finalize the dietary supplement GMP rule. In the past 4 years,
I assure you that there has been significant work done on the dietary
supplement GMPs. The proposed rule was published March 13, 2003, and
included responses to numerous comments received after publication of
the ANPRM in 1997. The comment period for the proposed rule was
extended until August 2003. We held public stakeholder meetings on
April 29, 2003 in College Park, MD, and on May 6, 2003 in Oakland, CA.
We also held a public meeting, via satellite downlink, on May 9, 2003,
with viewing sites at our district and regional offices throughout the
country. After the comment period closed, we began the process of
analyzing the comments submitted to the proposed rule. The issues
raised by the comments are complex, legally and substantively, and in
some cases, novel. We have expended significant internal resources on
reviewing and preparing responses to the comments received. In
addition, we have worked hard to ensure that the goals of DSHEA are
carried out with careful consideration of the impact on the dietary
supplement industry.
Since we are in the rulemaking process, I can only assure you that
we continue to work hard on the final rule and as I stated during the
hearing, I believe that the final rule should be published by the end
of the year. I recognize this has taken longer than it should have and
longer than anyone likes. But, we have come so far on the rule and
currently are in the final stages of review--I would hate to see this
critical work on the final rule lost because of problems introduced in
a last minute rush to completion. I assure you full attention is being
given to completing the rule.
Question 4. We are hopeful that the GMP regulation will include
dietary supplement, and ingredient manufacturers worldwide. How will
FDA address the issue of GMP compliance by foreign manufacturers?
Answer 4. Since we are in the rulemaking process, I can only assure
you that we continue to work hard on the final rule and as I stated
during the hearing, I believe that the final rule should be published
by the end of the year. I cannot however, comment on what will be in
the final rule. I will note that in the proposed rule, FDA proposed
applying the final rule equally to both domestic and foreign
manufacturers of dietary supplements. Also, FDA proposed addressing
cGMP compliance by dietary supplement manufacturers in the same fashion
as the Agency handles compliance for foreign and domestic manufacturers
of conventional food.
Question 5. Section 9 of DSHEA is explicit that a GMP may not
impose standards for which there are no current, generally available
analytical methods. We are aware that a number of organizations are
working very hard to develop analytical methods. What is FDA doing to
collaborate with the Office of Dietary Supplements at NIH and industry
to assure that analytical methods are available for the most important
dietary ingredients?
DSHEA is now 10 years old, and yet it is not fully implemented
although I recognize the substantial work that has been conducted under
your tenure at FDA to move us toward better implementation. Now that
the President has sworn in Secretary Leavitt, and your confirmation is
imminent, would you consider meeting with key industry leaders and the
Secretary to lay out a plan to fully implement DSHEA as soon as
possible?
Answer 5. Since 2001, FDA has had an IAG with ODS/NIH that funds a
significant portion of a multimillion dollar 5-year contract with AOAC
International to develop/identify, evaluate and validate analytical
methods for dietary supplements. Industry also contributes funds and
participates in the validation studies. Prioritization of the targeted
dietary ingredients is determined by an Ingredient Ranking Subcommittee
convened by AOAC stakeholders; the composition of this subcommittee is
balanced between members from the Federal Government (esp. FDA and
NIH), the industry, and academia. As such, prioritized dietary
ingredients for which the validation process is completed include
several that pose public health concerns (e.g., ephedra alkaloids, St.
Johns wort, and aristolochic acid). Other dietary supplements of
concern include aconotine, pennyroyal, sour orange, blue cohosh,
chapparal, comfrey, germander, mayapple, tansy and wormwood for which
laboratory studies in CFSAN continue. Twenty-two additional methods of
particular interest to the dietary supplement industry are in the
process of validation.
Because AOAC as changed the way collaborative studies are
conducted, they are able to validate more methods than originally
projected for the 5-year contract (20 methods). We are currently in the
third year of the contract.
FDA would be glad to meet with industry leaders on DSHEA
implementation.
Question 6. Dr. Crawford, I have a general and a specific question
for you on the issue of ``follow-on'' or ``generic'' biologics,
something you and I have discussed before.
First, could you outline for the committee the FDA's current
activities to develop a policy or pathway so that consumers at some
point will have available lower cost alternatives to costly biologic
products? When might FDA's activities in this area conclude:
Second, in March 2001 the FDA announced that it was working on two
generic biologic guidances for human growth hormone and insulin, and
the trade press reported in April 2002 that one guidance had been
drafted and the other was in process. In May of last year you testified
that FDA was preparing to release guidance for certain biological
products. HgG was specifically mentioned but presumably insulin was the
other product you were referring to.
Apparently you have blocked the guidances pending the FDADs larger
consideration of the generic biologics issue. Dr. Crawford, the country
is spending billions of dollars on products such as insulin and human
growth hormone. Yet, 4 years after it announced it would issue these
guidances, FDA still has not done so. When do you plan to release any
hold on the guidances that have been prepared and allow them to proceed
through clearance so companies may know what is required to develop
generic versions of Human Growth Hormone and Insulin?
Answer 6. As you know, FDA is conducting a public process to
examine the many questions, including scientific and legal issues, that
must be answered regarding these products and to ensure that all
interested parties have an opportunity to comment. When this process is
complete, FDA intends to provide guidance to industry to clarify,
consistent with its legal authority, the approval pathway and
principles for review of such products, which will protect the public
health.
In recent years--and with increasing frequency--questions about
generic or follow-on proteins have arisen in response to scientific
advances, impending patent expirations, and the ability to better
characterize and understand biological products.
Acknowledging scientific and legal limitations in this area, yet
also recognizing the public health need to move forward to assist
industry and make more products available to the public, FDA is
conducting a public process to examine the scientific, and related
issues regarding follow-on biologics. This process will ensure that
scientific considerations and issues related to Agency authority are
fully examined and that all interested parties have an opportunity for
input.
The Agency understands the importance of human growth hormone and
insulin. We are currently re-evaluating guidance documents to assure
that they are scientifically in-line with current efforts to ensure the
efficacy of follow-on biologic products.
Question 7. As you know, I take a great interest in the White Oak
Facility and am watching its progress closely. Could you provide me
with a progress report on work done to date, your projected timetable
for the future, and the cost estimates for remaining work? Is the
necessary funding to complete work at White Oak contemplated in the
President's Budget?
Answer 7. We appreciate your interest and support in the FDA White
Oak Consolidation Project. The White Oak Consolidation Project
continues its coordinated efforts to execute the 2000 Master Plan
design to provide a new state-of-the-art facility for the FDA at White
Oak.
On December 11, 2003, a dedication ceremony was held for the Life
Sciences Laboratory, a state-of-the-art chemistry, bioscience and
animal research facility. As the first new building to open on the
site, the laboratory provides approximately 124,000 gross square feet,
for 120 employees from the Center for Drug Evaluation and Research
(CDER) and the Center for Devices and Radiological Health (CDRH).
Construction for the CDER Office Building I began on November 15,
2002, and has progressed on schedule for occupancy in summer 2005. This
building provides 560,000 gross square feet of modem office space to
accommodate the Office of New Drugs, comprised of approximately 1,700
scientists and support staff. The facility also includes a 60,000
square foot, efficient document storage center, mail room and support
space.
Construction of the Central Shared Use Building began in October
2004. When complete this facility will provide employees and visitors
with a cafeteria, conference and training center, credit union, fitness
center, health unit, central library and R&W store, along with housing
the Agency security command center, central data center and NTEU
offices. The first phase of this building, including the cafeteria,
fitness center and security command center, is scheduled for completion
in spring 2006.
The construction contract for the CDRH Engineering/Physics
Laboratory was awarded in January 2005. This building will provide
approximately 128,000 square feet of high tech laboratories engaged in
evaluating electromagnetic and medical devices, radiological
instruments and consumer appliances generating radiological signals.
The facility consists of numerous vibration isolation slabs,
electromagnet shielding, an anechoic chamber and laser devices
especially dedicated to the program science. This facility is scheduled
for occupancy in early 2007.
With design to be complete in spring 2005, the approximately
291,000 gross square foot CDER Office Building II will accommodate the
Center Director's office and the balance of the CDER scientific and
support staffs. This is a uniquely designed office building in that the
entire building will be equipped with an under-floor ventilation
system. This design change provides for more offices benefiting from
indirect outside daylight, taller windows, more efficient distribution
of air and electrical wiring along with IT/Telecom and security wiring.
Finally, the design for the first phase of the site's parking
garages is complete with the finish of construction planned for 2005.
This concrete parking structure will contribute approximately 800
spaces to the overall parking for the campus.
The design and construction of the new buildings at White Oak are
funded through General Services Administration (GSA) appropriations
along with the site infrastructure, internal support services and move
costs that are covered by the FDA. These costs include: internal
communication needs, including equipment, cabling and audiovisual;
security, including infrastructure and equipment; information
technology and telecommunications cabling; modular furniture and other
equipment to furnish the building for occupancy; and, relocation costs,
including records management consolidation, relocation coordination and
moving.
FDA and GSA are working to update the estimated cost to complete
this project given that the schedule for some projects has been
delayed. Estimates developed a year ago suggest that approximately an
additional $550 million would be needed after fiscal year 2006 to
complete the headquarters project. Of this, roughly 4/5ths would be GSA
construction funding, and 1/5th would be FDA move and fit-out funding.
Question 8. We in Utah have been very concerned with the progress
of MDUFA. In the first instance our growing small medical device
companies were very worried that the PDUFA model used for pharma would
not work for medical devices. There was a great concern that this
program to advance approvals at a large cost to our small companies
would not achieve its goals. In fact it seems that our concerns are
coming true. By our reckoning the costs are going up, the approval
times are not coming down, and the Federal Government is not fulfilling
its commitments, both programatic and financial. Do you have any
assurance for us that this situation with MDUFA can be turned around in
the near future?
Answer 8. Many aspects of the Medical Device User Fee and
Modernization Act (MDUFMA) are working quite well. Chief among them is
the fact that the agency is meeting the performance goals agreed to in
conjunction with MDUFMA. Medical device application review has been
substantially improved by both the additional resources that MDUFMA
makes available for reviewing applications and by a number of new
guidance documents issued in response to MDUFMA, which tend to improve
communication about expectations in the device review process and to
standardize aspects of the review process. I have high expectations for
the continuation of these improvements in device review through fiscal
year 2007, assuming that the MDUFMA program continues.
Some of the financial aspects of MDUFMA have been disappointing for
both FDA and the device industry. First, in spite of agency urging,
financial aspects of MDUFMA were not patterned after PDUFA, which has
both annual product fees and annual establishment fees to assure fee
stability and to reduce the size of the application fee. The device
industry was adamantly opposed to such annual fees, and demanded that
all revenue come from application fees alone, which can fluctuate
widely from year to year. FDA initially opposed having only application
fees, but relented when the device industry assured revenue stability
for FDA by proposing an annual compensating adjustment in years when
revenue collected was less than statutory revenue targets. Also,
industry wanted to phase in its funding target of $35 million over 5
years. The result of that phase in, and annual inflation increases,
should have caused fees to increase at the rate of about 13 to 14
percent each year. Revenue has been less than statutory revenue targets
in each year. However, fewer application fees and the compensating
adjustment proposed by industry have caused fees to increase at rates
higher than the agreed-to 13 to 14 percent.
Unlike PDUFA, MDUFMA also specified higher annual appropriation
levels for FDA's device program. These higher levels did not occur in
fiscal year 2003 and 2004, and if they are not made up by October 1,
2005, the MDUFMA program will end. In light of this, the Director of
the Office of Management and Budget assured the Speaker of the House in
October 2003 that Administration budget requests for fiscal year 2005,
2006, and 2007 would be sufficient to meet the higher appropriation
levels specified in MDUFMA, and he asked Congress to waive the MDUFMA
requirement for make-up appropriations in fiscal year 2003 and 2004. I
look forward to working with Congress on this proposal in order keep
the MDUFMA program functional through fiscal year 2007.
(Second set of questions)
Question 1. Do you believe that mercury is a toxin that needs
careful oversight? On other uses of mercury, the FDA has taken a strong
stance.
Answer 1. Mercury, and specifically methyl mercury, is known to be
toxic to a variety of systems in the human body when exposure occurs at
a high dose and as such is a toxin that requires careful oversight. FDA
continues to monitor the science around the issues of mercury exposure
in order to react appropriately to new evidence of the impact of
mercury on human health. Lower doses of methyl mercury, such as may
occur through the consumption of certain types of fish, have been
associated with a variety of developmental delays in young children.
The mission of the FDA is to protect public health and, in the
context of methyl mercury exposure through the consumption of fish,
this requires one to consider both the health risks from exposure to
methyl mercury as well as the health benefits from consuming fish. The
FDA believes that it is important for women who may become pregnant,
pregnant women, nursing mothers and young children to avoid certain
types of fish (shark, swordfish, tilefish and king mackerel) that
contain high levels of methyl mercury. FDA recommends that this same
group eat up to 12 ounces a week of a variety of fish that are lower in
mercury. This advice was published jointly with EPA in March 2004.
Currently, the FDA is in the middle of an education campaign designed
to get this message out to the specific populations noted above.
Question 2. Why hasn't the FDA issued warnings to pregnant women
and children under 6 about mercury exposure from dental amalgam? Isn't
it true that Health Canada has issued warnings to pregnant women and
children under the age of 6 since 1996? Why hasn't the FDA taken
similar action?
Answer 2. FDA has not issued warnings to pregnant women and
children under 6 about mercury exposure from dental amalgam, as has
Canada, because while FDA and other agencies of the U.S. Public Health
Service (USPHS) continue to investigate the safety of dental amalgam,
no valid scientific evidence has shown that amalgams cause harm to
patients with dental restorations, except in the rare cases of allergy.
______
Response to Questions of Senator Isakson by Lester Crawford, DVM, Ph.D.
With respect to FDA's recent decision to reorganize the Office of
New Drugs--Ophthalmologists are particularly concerned about the
likelihood that final decisions including clinical sign-off for all
(ophthalmic) products in the Division will no longer be made by the
Ophthalmology Deputy Director, but instead will be made by the Division
Director. With respect to ophthalmic drugs, many feel that keeping the
risk decision closer to the specialty of ophthalmology as part of the
overall clinical sign-off is the most efficient and fair approach.
Question 1. If confirmed as commissioner, what steps will you take
to ensure current and future patients that the advancement of new
ophthalmic treatments/therapies into the realm of the eye care
practitioner will continue to take place as expeditiously as possible?
Answer 1. Individuals with expertise in ophthalmology will continue
to play a critical role in reviewing new ophthalmology products, and
the reorganization will not affect the timely approval of treatments
and drug therapies available to eye care practitioners and their
patients. All drug review processes for all products will continue to
be held to existing PDUFA goals and timelines during and as a result of
the reorganization.
Question 2. Given the enormous amount of drug research and
development presently going on in ophthalmology, what steps will you
take to ensure that new drug approval will not be unnecessarily delayed
as a result of the pending reorganization?
Answer 2. As noted above, the reorganization will not affect the
timely approval of treatments and drug therapies available to eye care
practitioners and their patients. All drug review processes for all
products will continue to be held to existing PDUFA goals and timelines
during and as a result of the reorganization.
______
Response to Questions of Senator Dodd by Lester Crawford, DVM, Ph.D.
Drug Safety
Question 1. Transparency
There have been disturbing reports that suggest that the FDA does
not place enough emphasis on drug safety, and that concerns raised by
those in the Office of Drug Safety (ODS) are sometimes ignored and even
suppressed.
An internal study conducted by the HHS Office of the Inspector
General in 2002 revealed that approximately one-fifth of drug reviewers
had been pressured to approve a drug despite concerns about safety,
efficacy, or quality. In addition, more than one-third said they were
``not at all'' or only ``somewhat'' confident that final decisions of
the Center for Drug Evaluation and Research adequately assessed safety.
This seems to have been the case with Dr. Andrew Mosholder when he
had data to suggest that certain antidepressants might increase the
risk of suicide in children and adolescents; as with Dr. David Graham
when he had data to suggest that Vioxx is connected with cardiovascular
problems.
Dr. Crawford, do you believe that mistakes were made in the
handling of Dr. Mosholder and Dr. Graham? As Commissioner of the FDA,
what would you do to ensure transparency, so that dissenting opinions
are seriously considered and never suppressed, especially when they
have to do with issues so critical to the health and well-being of the
public?
Answer 1. Good scientific decisions depend on robust discussion and
various layers of peer review. In encouraging such discussion, FDA will
work to ensure that FDA scientists involved in the decision making
process do not feel pressured or ignored.
The rigorous scientific review process is critical to sound
regulatory decision-making. In both Dr. Mosholder and Dr. Graham's
cases, the Agency sought the best available data upon which to make a
regulatory decision. For instance, with the SSRIs, FDA initiated the
Columbia Reclassification Project, which provided sound data upon which
to make a decision. These data confirmed Dr. Mosholder's findings,
which were based on weaker data. With the COX-2 inhibitors, FDA again
insisted on scientific peer-review of Dr. Graham's work, which he
submitted for publication prior to the standard Agency peer-review. The
Agency recently held a joint meeting of the Arthritis and Drug Safety
and Risk Management Advisory Committees to evaluate all available data,
including the work of Dr. Graham.
Pursuant to Federal law, the Agency does not retaliate against
whistleblowers or interfere with their rights to freely express their
views in public forums, such as investigations of the Congress.
FDA constantly strives to improve our drug safety process and
methods, thereby better serving the public health. Recent developments,
including the work of Dr. Mosholder and Dr. Graham, have prompted us to
refocus our drug safety efforts and take additional steps to identify
drugs that may have unacceptable risk profiles.
Recently, I joined Secretary Leavitt to announce important efforts
that we are undertaking at FDA to improve the ability to monitor and
respond to emerging drug safety information.
These steps will ensure both a better internal process of
deliberation on drug safety issues that ensures appropriate and
independent consideration of all issues, as well as a stronger ability
to gather data about drug safety issues once a drug has been approved.
Most importantly, we are moving to encourage more transparency and
to ensure that patients and physicians have the most up-to-date and
complete information necessary to inform their treatment decisions.
This new Drug Information Initiative will give patients, healthcare
professionals, and other consumers quick and easy access to the most
up-to-date and accurate information on medicines and make FDA's drug
review, approval, and monitoring programs as transparent as possible.
This is in addition to FDA's Five Point Plan to Improve Drug
Safety, a major initiative designed to improve the monitoring of drug
products recently approved for marketing. The major components of this
initiative include:
Sponsoring a major study of the Drug Safety System by the
Institute of Medicine;
Implement a Program for Adjudicating Differences of
Professional Opinion;
Conducting a nationwide search to identify a permanent
director for the Office of Drug Safety;
Conducting a series of workshops and meetings on drug
safety and risk management; and
Publishing risk management guidance.
FDA's Office of Drug Safety (ODS), in the Center for Drug
Evaluation and Research (CDER), is already an independent office
separate from the Office of New Drugs, the office that reviews new drug
applications. Both the Office of New Drugs and the Office of Drug
Safety report directly to the Director of the CDER. ODS has independent
authority to perform its own research and does so every day. To be
valuable, this independent research must conform to widely accepted
scientific standards and normal scientific procedures and peer review
should not be bypassed. And when drug safety issues are identified,
they must be factored into the risk-benefit equation so that safe and
effective drugs remain available to patients who need them.
FDA has a longstanding commitment to provide a strong resource base
for its drug safety program. The budget for fiscal year 2006 continues
this commitment. The President has proposed a 24-percent increase for
FDA's post-market safety program to help further ensure that America's
drug product supply is safe and effective, and of the highest quality.
Under this proposal, CDER's ODS would receive increased funding to
expand the Agency's ability to rapidly survey, identify and respond to
potential safety concerns for drugs on the market. ODS will hire
additional staff to manage and lead safety reviews, will increase the
number of staff with expertise in critical areas such as risk
management, risk communication and epidemiology, and will increase
access to a wide range of clinical, pharmacy and administrative
databases. Our commitment to increase resources available for post-
market safety will enhance the structural changes we are proposing to
advance drug safety.
In an effort to improve the current process immediately, CDER has
instituted a program to formally address the opinions of dissenting
scientific reviewers to ensure that the decision-making process is
transparent. For more information on this plan, please visit: http://
www.fda.povIbbs/toDics/news/2004INEW01131.html.
FDA Authority
Question 2. Dr. Crawford, during testimony before this committee
earlier this month, an FDA witness, Dr. Sandra Kweder, seemed to
suggest that additional authority to require companies to conduct post-
market studies and to make changes to the drug label would be
``helpful'' to FDA. Two days later another FDA witness, Dr. Janet
Woodcock, backed off of those statements.
According to the latest figures, companies have not even initiated
approximately 70 percent of the post-market studies that they had
previously committed to.
How does the FDA plan to address this problem?
Does the FDA need additional authority and enforcement
power to require companies to do post-market studies?
It took 2 years for the Vioxx label to change to reflect the data
suggesting an increased cardiovascular risk. Much of the delay resulted
from months of negotiation with the manufacturer.
Dr. Crawford, does this seem like an unacceptable delay
given the huge public health implications?
Does the FDA need additional authority and enforcement
power to require companies to change the drug label if a safety concern
arises?
What other authorities does the FDA need in order to
effectively respond when a safety issue is identified?
Answer 2. I do not believe new statutory authority is needed. We
will use all existing regulatory authority and enforcement powers when
negotiating label changes with drug companies or when monitoring or
managing drug safety issues. As Dr. Janet Woodcock testified, a key
factor in labeling changes is that once a label change is made, old
labels in paper form are still in distribution and it takes time to get
newer labels in circulation. Dr. Woodcock testified that the new
strategy of posting drug safety information sooner using the Drug Watch
mechanism will help alleviate that factor because it will enable the
FDA to get information directly to the people who need it in a timely
manner.
Office of Drug Safety
The Administration's fiscal year 2006 budget includes an additional
$6.5 million for the Office of Drug Safety (ODS).
Question 3a. With this budget increase, how many scientists will
the ODS employ?
Answer 3a. With the additional funds, we expect to be able to hire
eight additional FTEs in the Office of Drug Safety to establish
policies and processes regarding safety reviews and risk management, to
manage communications with the Office of New Drugs and to support
patient safety initiatives and external partnerships with CMS, AHRQ,
and other HHS Agencies.
We also plan to hire an additional 14 FTEs in the three operating
divisions of ODS. These employees will handle the increased workload of
monitoring biologic therapeutics; promote increased communication and
coordination of safety review activities within the divisions; increase
focus on medical error signal detection, address the current backlog of
unaddressed potential safety signals; increase epidemiological
expertise to explore safety risks and signals in various population
databases; and manage the increasing workload in ODS for new drug
consultations and designing post-approval studies for new drug use in
specific populations.
Finally, we plan to hire six FTEs to increase staff dedicated to
evaluating and communicating drug safety risks to the health care
community and the American public.
Question 3b. How does the ODS budget and staff compare to that of
the Office of New Drugs?
Answer 3b. The table below presents a 3-year budget and staff
comparison between the Office of New Drugs and the Office of Drug
Safety. Please note that a side-by-side comparison of the budgets of
these offices is not meaningful without considering the significant
pre-approval responsibilities performed by the Office of New Drugs.
Question 3c. Given that the ODS is charged with tracking every
single drug that is on the market, does the balance of resources seem
appropriate?
Answer 3c. We believe that the balance of resources has
appropriately reflected ODS's responsibility within the overall post-
marketing safety function. The Office of Drug Safety is not singularly
responsible for tracking post marketing safety issues of marketed drug
products. ODS works with the Office of New Drugs to evaluate safety
issues once drugs are on the market.
Question 3d. When do you plan to fill the vacant Director position
within the ODS?
Answer 3d. The agency has experienced difficulty recruiting high
quality candidates for the position of Director, Office of Drug Safety
through traditional mechanisms such as scientific journal
advertisements and government vacancy announcements. We are committed
to using all available resources to ensure a systematic, inclusive
recruitment process for this critically important position. To that
end, FDA has partnered with the recruitment and staffing professionals
at the Office of Personnel Management (OPM), Center for Talent Services
to develop and manage a recruitment strategy that we are confident will
yield a sizable number of strong candidates and ultimately, a top-notch
director. We feel that the additional time and resources invested in a
thorough analysis of the leadership and technical competencies required
to successfully manage the drug safety program, including input from
internal and external subject matter experts and stakeholders, will be
time well spent. The Office of Personnel Management is targeting the
end of May for the position to be posted on USAJOBS.
Question 3e. Why has the ODS been without a director for so long?
Answer 3e. It is very difficult to hire the appropriately skilled
individual for this position. The Director should be credentialed in
medicine and have experience and working knowledge of controlled
clinical trials, epidemiology, research, medicinal products, and drug
regulations. Any individual who has these qualifications may be
reluctant to take this position for the salary we can offer. Further,
we have tried to promote individuals with these qualifications from
within the Agency. However, we often find that these individuals
subsequently are recruited heavily by industry.
Drug Safety Oversight Board
Dr. Crawford, the centerpiece of the Administration's plan to
address the drug safety crisis is the creation of a drug safety
oversight board. While I applaud the Administration for taking action,
I am concerned that this change is not nearly significant enough to
address the problem.
Question 4. Will the new board have any decision making or
regulatory authority of its own? If not, how can patients be sure that
the FDA will act on problems that it identifies? The FDA has said that
the Deputy Director of CDER will chair the board. If this is the case,
in what way is the board independent?
Answer 4. The new board will have the authority to make
recommendations to the Center Director on drug safety questions. The
Center Director oversees all of the offices in CDER, including those
that review new drug applications as well as the Office of Drug Safety.
The DSB will include members from the FDA outside of CDER and medical
experts from other HHS agencies and government departments (e.g.,
Department of Veterans Affairs) who will be appointed by the FDA
Commissioner. The Board also will consult with other medical experts
and representatives of patient and consumer groups. The wealth of
expertise envisioned in the DSB will create an independent voice to
make recommendations to the Center Director on drug safety issues. The
Deputy Center Director is also independent of the Office of New Drugs
and the Office of Drug Safety and can be expected to manage the Board
in a fair and evenhanded manner, making sure all opinions are heard.
The Agency looks forward to receiving recommendations from the
Institute of Medicine (IOM) study that will be evaluating the current
drug safety system, and will make appropriate adjustments to its
programs after reviewing those recommendations. FDA would like to
emphasize our commitment to a culture of transparency and rigorous
scientific peer review.
Direct to Consumer (DTC) Advertising
Some have suggested that DTC advertising has increased the
magnitude of drug safety problems by drastically increasing the
population that uses a drug, even if it might not be appropriate for
some patients.
Question 5. As Commissioner, would you increase FDA regulation of
DTC advertising? What authority does the FDA have to limit or ban
advertising, or require disclosures, when a safety problem is
discovered? Does the FDA require additional authority in this area?
Answer 5. We have conducted research that confirms that DTC
advertising, when done correctly, can serve positive public health
functions, such as increasing patient awareness of diseases that can be
treated, and prompting thoughtful discussions with physicians that
result in needed treatments being prescribed often, not the treatment
in the DTC advertisement. Results of our research show that many
physicians believe that DTC can play a positive role in their
interactions with patients and that many physicians thought that DTC
ads made their patients more involved in their healthcare.
In a survey we conducted, only 8 percent of physicians felt very
pressured to prescribe the specific drug advertised. Physicians agreed
that the main effect of DTC ads was to help educate patients about
their health problems, causing them to seek needed care.
At FDA, CDER's Division of Drug Marketing, Advertising, and
Communications (DDMAC) is responsible for regulating prescription drug
promotion. DDMAC's mission is to protect the public health by helping
to ensure that prescription drug information is truthful, balanced, and
accurately communicated. This is accomplished through a comprehensive
surveillance, enforcement and education program, and by fostering
optimal communication of labeling and promotional information to both
health care professionals and consumers.
While we believe the survey results discussed above confirm our
belief that DTC ads help increase patient awareness about the
availability of effective treatments for their health problems, we will
continue to ensure that our DTC policies help prevent potential
misperceptions about benefits and risks of the advertised treatment and
promote the importance of prescribing decisions being made with the
intervention of a health care professional.
As you know, FDA has extensive authority over drug promotion. To
summarize the FD&C Act and regulations do not distinguish between
promotion to professional and consumer audiences. Section 502(n) of the
FD&C Act specifies that prescription drug advertisements must contain
``a true statement of . . . information in brief summary relating to
side effects, contraindications, and effectiveness'' of the advertised
product. The implementing regulations specify that prescription drug
advertisements cannot be false or misleading, cannot omit material
facts, and must present a fair balance between effectiveness and risk
information. Further, for print advertisements, the regulations specify
that every risk addressed in the product's approved labeling must also
be disclosed in the advertisements.
For broadcast advertisements, however, the regulations require ads
to disclose the most significant risks that appear in the labeling. The
regulations further require that the advertisement either contain a
summary of ``all necessary information related to side effects and
contraindications'' or provide convenient access to the product's FDA-
approved labeling and the risk information it contains. Finally, the
FD&C Act specifically prohibits FDA from requiring prior approval of
prescription drug advertisements, except under extraordinary
circumstances.
To encourage more effective regulation of DTC promotion, FDA plans
to develop additional guidance documents, including one addressing the
presentation of risk information in print advertisements and one
addressing outdoor advertising. FDA also will conduct a series of
studies to examine the format and content of brief summaries in direct-
to-consumer print advertisements. This will assist the agency to
finalize the draft guidance on consumer-directed print advertisements
for prescription drugs. FDA also plans to finalize the guidance on
criteria FDA uses to distinguish between disease awareness
communications and promotional materials, to encourage manufacturers to
disseminate educational messages to the public, and the guidance on the
manner in which restricted device firms can comply with the rules for
disclosure of risk information in consumer-directed broadcast
advertising for their products.
Obesity
Dr. Crawford, the FDA a year ago announced its plan to combat
obesity. The plan included modernizing guidances for developers of
drugs to treat obesity, as well as a national education campaign,
``Calories Count'', enhancing the calorie information on food labels,
urging the Nation's restaurants to disclose caloric content, and
expanding research on obesity.
Question 6. Where does this FDA initiative stand today and what do
you see as its results? If confirmed as Commissioner, what additional
steps would you like to see to combat the ever-rising tide of obesity
across this nation?
Answer 6. Obesity is a growing and urgent public health problem in
the United States. Today, almost two-thirds of all Americans are
overweight and over 30 percent are obese. To help confront the problem
of obesity in the U.S. and to help consumers lead healthier lives
through better nutrition, in August 2003, FDA created an Obesity
Working Group (OWG), which was charged with preparing a report that
outlines an action plan to cover critical dimensions of the obesity
problem from FDA's perspective and authorities. FDA's ``Calories
Count'' report was released on March 12, 2004.
The OWG report provides a range of short and long-term
recommendations to address the obesity epidemic. For FDA's actions the
emphasis is on calories. Progress to date follows:
We have published two advance notices of proposed
rulemaking (ANPRMs), in response to the recommendations in the OWG
report, seeking comments on the following:
How to give more prominence to calories on the food label,
for example, increasing the font size for calories, including a column
in the Nutrition Facts panel of food labels for percent Daily Value for
total calories, and eliminating the listing for calories from fat. In
addition, the Agency is seeking comment on the reformulation of the
foods or redesign of packaging that may occur if any changes are made
to the food label;
Whether to amend certain provisions of the nutrition
labeling regulations concerning serving size, such as for multiple-
serving packages that may reasonably be consumed in a single eating
occasion.
We continue to encourage manufacturers to take advantage
of the flexibility in current regulations on serving sizes to label as
a single-serving those food packages where the entire contents of the
package can reasonably be consumed at a single eating occasion. We also
continue to encourage manufacturers to use appropriate comparative
labeling statements that make it easier for consumers to make healthy
substitutions. Since release of the OWG report, the Agency, in meetings
with industry, has made a point to encourage manufacturers to take
advantage of the existing flexibility in serving size regulations, and
companies are responding. For example, Kraft Foods is instituting dual
column labeling for all its packaged foods containing 2-4 servings per
package.
FDA continues to encourage restaurants voluntarily to
provide point-of-sale nutrition information to customers, including
calorie information on a nationwide basis.
FDA is also working to develop educational strategies and
partnerships to support appropriate messages and teach people,
particularly children, how to lead healthier lives through better
nutrition. We are starting work with the Girl Scouts of the USA, under
terms of a Memorandum of Understanding signed this past fall, to
provide outreach and education in a science-based initiative to focus
on improving health, nutrition, and physical activity. In addition,
FDA's field offices are participating in local partnerships to reach
and teach children. For example, in Central Florida, FDA's South East
Region is part of the Seminole County Healthy Kids Partnership to
promote positive opportunities for school-aged children in Seminole
County to learn healthy nutrition and the value of increased daily
physical activity.
Regarding your question on what FDA is doing to modernize
``guidances for developers of drugs to treat obesity,'' FDA's Center
for Drug Evaluation and Research (CDER) will continue to work with
pharmaceutical sponsors to facilitate development of effective
therapies to address the important public health issue of obesity and
its attendant morbidities. An advisory committee meeting was held on
September 8, 2004 to discuss the draft guidance on Clinical Evaluation
of Weight-Control Drugs. The Agency is working to finalize the
guidance.
Pediatric Drug Testing
I have long been committed to ensuring that medicines are studied
in children so that pediatricians have information about which drugs
are most effective for their patients. The steps that we have taken in
this area--the Best Pharmaceuticals for Children Act (BPCA) and the
Pediatric Research Equity Act (PREA)--have led to enormous improvements
in our knowledge about the appropriate use of drugs for children.
Dr. Crawford, pediatric testing in children is particularly
relevant in light of the recent questions about drug safety, and
especially the possible adverse effects of antidepressants (SSRI's)
when used to treat youth. Several SSRI's had been studied in children,
but the results of those studies were inconclusive.
Question 7a. If confirmed as Commissioner, would you continue to
support efforts to expand pediatric testing?
Answer 7a. I strongly support efforts to continue pediatric
therapeutics testing. In response to the need for pediatric use
information for prescription medications in the United States, Congress
passed several important legislative initiatives. FDA has found both
the BPCA and the PREA to be useful regulatory tools to promote
development of information and studies on therapies that are or will be
utilized in the pediatric population.
As a result, the Agency has labeled almost 100 products with new
pediatric use information and has disseminated this valuable product
information to the public. In addition, the number of pediatric
clinical trials has increased dramatically. As of March 31, 2005, under
BPCA, FDA has issued 298 written requests for pediatric studies,
granted exclusivity to 110 drugs of the 120 that have been evaluated,
and approved pediatric labeling changes for 87 products. Over a third
of these products had new dosing or pediatric specific safety
information identified and efficacy was not demonstrated in 8 of these
products.
Question 7b. What steps could the agency take to improve in this
area, and to ensure that pediatric studies are answering the right
questions and providing useful results?
Answer 7b. The Agency will continue to advance its pediatric
initiatives throughout FDA Centers. FDA has found both the BPCA and the
PREA to be useful regulatory tools to promote development of
information and studies on therapies that are being utilized in the
pediatric population.
At present, the FDA is working with the American Academy of
Pediatrics, academic institutions, sponsors and the Center for Devices
and Radiological Health to assess the needs for better information on
use of devices in the pediatric population and to explore mechanisms to
promote the development of devices specifically for the pediatric
population.
Question 7c. Is there additional authority that Congress can
provide in this area that would be helpful to the FDA?
Answer 7c. FDA has not identified the need for additional authority
at this time. Congress has granted FDA significant, new pediatric legal
authority in recent years and we are aggressively working to implement
these authorities.
Global HIV/AIDS Affordable Pharmaceuticals
The President's Emergency Plan for AIDS Relief includes the goal of
treating 2 million people by 2008. While estimates vary, I understand
that we can treat at least two to three people with non-branded anti-
retrovirals (ARV) for the same price of treating one individual with
brand name drugs. While safety and efficacy must remain paramount, the
success of the President's treatment goals depends on the government's
ability to procure high quality drugs (both brand name and non-brand
name) at the most affordable price.
I was very happy to learn of the recent tentative approval of an
HIV anti-retroviral product manufactured by Aspen Pharmacare of South
Africa. I applaud the FDA and Aspen Pharmacare for working together to
secure the first tentative approval of a non-brand, first-line HIV drug
regimen. Additionally, it is very positive that the Office of the
Global AIDS Coordinator has confirmed that these products will be
available for purchase under the President's Emergency Plan. For large
numbers of people in Africa and beyond, this could be a true turning
point for providing low-cost, safe and effective AIDS drugs to those
who would otherwise face certain death.
However, while the Administration formalized an expedited process
for the FDA to review and tentatively approve non-brand drugs to ensure
their safety and efficacy in May 2004, there are still very few non-
branded drugs, and no triple-drug fixed dose combinations, that have
been tentatively approved by this process.
Question 8a. What specific steps is the Administration, and
specifically the FDA, taking to ensure that safe and effective non-
brand drugs can be purchased with U.S. government dollars for use in
the President's Emergency Plan?
Answer 8a. In May 2004, in direct support of the President's
Emergency Plan for AIDS Relief, the Department of Health and Human
Services (HHS) Secretary Tommy Thompson announced that FDA would
implement a new, expedited review program to help ensure that the
products purchased under the President's Emergency Plan would be safe,
effective, and manufactured in a quality manner. The central ethical
premise of this review program is to ensure that we are not asking
these governments to give their people medicinal products we would not
give our own people.
This new program directly supports Ambassador Tobias'
responsibility to ensure the quality of HIV/AIDS drugs purchased by the
U.S. under the auspice of the President's Emergency Plan. Subsequent to
Secretary Thompson's announcement, FDA published guidance for the
Pharmaceutical Industry encouraging sponsors (manufacturers) to submit
marketing authorization applications to FDA for approval of fixed dose
combination (FDC) and co-packaged versions of previously approved
individual component antiretroviral therapies for the treatment of
human immunodeficiency virus (HIV).
On January 25, 2005, FDA granted tentative approval to a generic
AIDS drug regimen for potential purchase under the President's
Emergency Plan for AIDS Relief. This is a co-packaged antiretroviral
drug regimen manufactured by Aspen Pharmacare of South Africa for the
treatment of HIV-1 infection in adults. The Agency's tentative approval
means that although existing patents and/or exclusivity prevent U.S.
marketing of Aspen's product, it meets FDA's quality, safety and
efficacy standards for U.S. marketing. This action makes this product
available for potential procurement by President Bush's Emergency Plan
for AIDS Relief. This action is the first tentative approval of an HIV
drug regimen manufactured by a non-U.S.-based generic pharmaceutical
company.
The guidance outlines four scenarios for review of different FDC
and co-packaged products. Some of the scenarios could permit review and
approval in as little as 2 to 6 weeks after submission of a complete,
high-quality application. For companies making products where another
firm owns the U.S. patent rights, FDA issues a ``tentative'' approval
when it finds the product meets the Agency's normal safety, efficacy,
and quality standards. A tentative approval does not allow marketing in
the U.S. because of the market protection that the patent or
exclusivity provides. However, the administrators of the President's
Emergency Plan have said they will allow manufacturers of products
``tentatively'' approved by the FDA to submit tenders for consideration
as suppliers of these products in countries where the product has the
approval of the local drug regulatory authority and where such
provision doesn't violate other laws.
Question 8b. When do you expect additional non-brand drugs,
including fixed-dose combinations, to be available for purchase as part
of the President's Emergency Plan?
Answer 8b. It is difficult to provide exact dates as to the
submission of these products, because the companies make the decision
on when/if they will submit. Moreover, we do not know in advance of our
review whether or not companies will have the data requisite to
demonstrate the products do indeed meet the standards of products we
would give our own people. However, FDA has been involved in a very
vigorous outreach effort to try to engage potential manufacturers in
this process. Vigorous discussions and other outreach efforts, both
within the U.S. and outside the U.S., have occurred and are still
underway.
Question 8c. Can you confirm that all non-brand drugs; including
fixed-dose combinations, could be purchased with U.S. government
dollars as soon as they are tentatively-approved under the FDA
expedited process?
Answer 8c. It is our understanding that once a product is either
fully approved or tentatively approved, the manufacturer is then
eligible to be considered as a provider of those products under the
President's Emergency Plan, provided the local drug regulatory
authority has approved the use of the product in the country where it
is to be ultimately provided to patients. Please note that FDA does not
administer the procurement process for this program, and therefore we
do not have details about procurement activities for the program.
Question 8d. What are you doing to encourage drug companies, both
brand and non-brand, to apply to the new expedited approval process?
Answer 8d. FDA is very proactively working with manufacturers from
around the world that have come to us with questions about this review
process as outlined in our guidance. We have met with them here in
Washington and in several of the countries identified in the
President's Emergency Plan. We are devoting much time to answering
questions about the application process and requirements for submission
to assist especially non-brand companies in submitting a quality
application for our review. We are committed to investing such time and
effort ``up front'' to help increase the probability of a quality
application and to expediting their review when the completed
application is submitted. We continue to provide requested information
from interested companies and have several outreach programs for
industry and drug regulatory authorities that are presently underway.
We plan to conduct targeted communication of FDA's Expedited review
guidance to companies in South Africa and India. We conducted a similar
program in Ethiopia in early December 2004.
Global HIV/AIDS--Pediatric Therapeutics
As we now start to treat larger numbers of people in resource-poor
countries, we must focus our attention on the unique medical needs of
children. With almost 700,000 new pediatric HIV infections last year
alone, no global agenda for HIV/AIDS care and treatment is complete
without attention to the unique treatment needs of children.
Currently, few programs specifically target the treatment of
children with HIV/AIDS in resource-poor countries. One of the reasons
for this is the lack of appropriate pharmaceuticals for their use.
Children are not small adults and treating them that way jeopardizes
their lives. Children's growing bodies respond differently to drugs
than adults, and require dosing guidelines specific to certain age
groups. For many HIV/AIDS medicines, dosing guidelines are completely
missing for younger age groups, requiring health workers to estimate
the correct dose by breaking or crushing pills made for adults.
Effective treatment of HIV requires appropriate and precise levels of
medicine to inhibit the virus and prevent the development of viral
resistance.
With 2.2 million children infected with HIV around the world, it is
essential that we have appropriate medications to treat them.
Question 9. How is the Administration ensuring that the HIV/AIDS
drugs (both generic and brand) being approved by the FDA expedited
process also include pediatric formulations as well as important dosing
information needed for treating different age groups?
Answer 9. On May 17, 2004, FDA published guidance for the
pharmaceutical industry encouraging manufacturers to submit marketing
applications for fixed dose combination (FDC) and co-packaged versions
of previously approved single entity anti-retroviral therapies. The
guidance encourages the development of pediatric formulations for fixed
dose and co-packaged antiretroviral combination products. Also,
subsequent to the publication of the draft guidance, the expedited
review program was expanded to include single product generic
applications. Most of the first line antiretroviral agents are
currently available in pediatric dosage forms, so these pediatric
formulations can be made available through the generic drug approval
process.
Regarding fixed dose and co-packaged combination products, only one
company thus far has expressed interest to FDA in developing a
pediatric combination product. This could be explained in part by the
challenges associated with dosing pediatric patients with fixed dose
combination products. Such combination products generally do not
provide the dosing flexibility needed for pediatric HIV therapy. Also,
many of the pediatric formulations are in the form of oral solutions
that are not amenable to combination product development. Combination
therapy in younger pediatric patients might best be accomplished
through the use of individually formulated antiretroviral products that
can be made available through the generic approval process. Generally,
adult combination products can be used in the older pediatric
population.
Pediatric Medical Devices
Like drugs, where for too long we assumed that children were small
adults and could just take reduced doses of adult products, we're
finding that many essential medical devices used extensively by
pediatricians are not designed and sized for children's special needs.
According to pediatricians, the development of cutting-edge medical
devices suitable for children's smaller and growing bodies can lag 5 or
10 years behind those for adults. This is simply unacceptable. As
technology for prolonging and saving lives continues to advance at a
rapid pace, children are at risk of being left further and further
behind.
Question 10. What is the FDA doing to ensure that devices used in
children are designed and sized for their use? What can Congress, and
others, do to ensure that kids have access to appropriately sized
devices?
Answer 10. Pediatric medical devices treat or diagnose diseases and
conditions from birth through age 21. Some products are designed
specifically for children, while others are borrowed from adult
applications or produced for more general use.
Bringing pediatric medical devices to market can be challenging for
a number of reasons: children are often smaller and more active than
adults, body structures and functions change throughout childhood, and
children may be long-term device users bringing new concerns about
device longevity and long-term exposure to implanted materials. In
addition, modifying an adult device for pediatric use may require
significant re-designing of the device and re-tooling of the
manufacturing process. Conducting clinical trials in children can also
be more difficult due to the small patient population and the variation
within the population.
FDA is committed to supporting the development and availability of
safe and effective pediatric medical devices. Current initiatives
include:
Obtaining pediatric expertise for FDA advisory panels
whenever there is a reasonable likelihood that the device under
discussion will be used for children.
Issuing guidance describing the protections that clinical
trial sponsors should consider when enrolling children in device
trials.
Collaborating with the Institute of Medicine on their
study of the effectiveness of post-market surveillance of pediatric
medical devices.
Collecting data on the unmet needs for pediatric medical
devices and the barriers to the development of new pediatric devices.
In May 2004, FDA finalized a guidance document to facilitate the
development of pediatric medical devices. Entitled ``Premarket
Assessment of Pediatric Medical Devices,'' this guidance defines the
pediatric population and pediatric use for medical devices, identifies
the types of information needed to provide reasonable assurance of the
safety and effectiveness of medical devices intended for use in the
pediatric population, and defines the guiding principles and
protections sponsors should consider for pediatric subjects in device
clinical trials.
In June 2004, FDA opened a docket requesting comments identifying
the unmet device needs in the pediatric population, possible barriers
to the availability of medical devices intended to treat or diagnose
diseases and conditions that affect children, and potential incentives
to facilitating the development of such devices. These comments
assisted the agency in preparing its recent ``Report to Congress:
Bafflers to the Availability of Medical Devices Intended for the
Treatment or Diagnosis of Diseases and Conditions that Affect
Children.''
In addition to preparing this report, the agency has been working
with several pediatric professional organizations to better understand
this important issue. A series of meetings were held this past fall
that included representatives from academia, medical specialty
organizations, the device industry, and several government agencies.
The group determined that further study is warranted to evaluate the
scope of the unmet needs and the most promising solutions to addressing
these needs. HHS believes that this is a critical first step and is
working with interested stakeholders to ensure that a systematic needs
assessment to promote a better understanding of the unmet needs and the
barriers to the development of pediatric device development is
conducted.
Finally, to help raise awareness of the challenging issues
surrounding pediatric device development, the Center for Devices and
Radiological Health has developed a new web page on pediatric medical
devices at http://www.fda.aov/cdrh/pediatricdevices/. In addition,
FDA's Office of Pediatric Therapeutics web page can be accessed at
http://www.fda.gov/oc/opt/default.htm. One of this Office's goals is to
coordinate and facilitate all activities effecting the pediatric
population or practice of pediatrics or involving pediatric issues. Our
Center for Drug Evaluation and Research also has a pediatric web page
at http://www.fda.aov/cder/pediatric/.
Flu Vaccine
In 2004, a Liverpool, England plant responsible for providing our
country with over 100 million doses of the flu vaccine was shut down.
As a result, we received less than half the expected doses, resulting
in a crisis for millions of Americans who depend on the flu vaccine
each year.
You have said that the FDA had no idea of escalating concerns at
the plant before British authorities suspended the plant's license in
October 2004. However, British authorities dispute this and state that
the FDA had been notified of ongoing problems as early as mid-
September. The FDA inspected this plant in June 2003 and raised
concerns then about possible contamination problems, and inspectors
returned again in August. A full inspection was still not conducted.
The FDA has been accused of inadequate follow up after major problems
were identified. You stated that the FDA followed standard procedures,
and you would not change anything the FDA did. You said: ``This is the
way we've always done it, and it's worked very well in the past.''
Question 11a. Do you stand by this statement?
Answer 11a. FDA inspects U.S. licensed vaccine manufacturing
facilities every 2 years. Based on this schedule, FDA inspected the
Liverpool, U.K. facility where the Chiron vaccine is produced in 1999,
2001, and 2003. It should be noted that Chiron acquired the facility in
July 2003 after FDA conducted the biennial inspection. During the 1999
inspection, FDA identified various concerns and, as a result, issued a
warning letter regarding the Liverpool facility. The most significant
issues identified in 1999 inspection were the lack of validation for
its manufacturing processes, including establishing proper limits for
bioburden (including bacteria) and issues related to assuring sterility
in the manufacturing process. During the 2001 and 2003 inspections, FDA
found that the company had made improvements but we also made
observations related to current Good Manufacturing Practices (cGMPs).
In each case, FDA reviewed the corrective measures and plans in
response to these deficiencies. If fully implemented, the company's
plans appeared adequate to correct deficiencies identified at the
facility.
On August 25, 2004, FDA inspectors were on site conducting a
preapproval inspection and were informed of the contamination of the
vaccine. FDA inspectors met with Chiron's staff and reviewed the
preliminary findings and the approach that Chiron was taking to its
investigation and retesting at multiple points in its process. FDA
inspectors in Liverpool faxed to CBER preliminary data and information
regarding the scope and plans for the sterility failure investigation
being conducted by Chiron. The results of these evaluations were needed
and essential for any regulatory assessment. Chiron's investigation was
in the earliest stage and, therefore, only preliminary information was
available. Chiron informed FDA that all results from the retesting were
negative for all other finished product and that its final
investigative report, including all product testing data, would be
submitted to FDA during the week of October 4-8, 2004. FDA would then
complete an in depth assessment of the report findings, which would
indicate appropriate next steps for the agency. However, on October 5,
the week the report was expected by FDA and just hours before FDA
expected to receive an update from Chiron during a previously scheduled
morning teleconference, the U.K. Medicines and Healthcare Products
Regulatory Agency (MHRA) announced their suspension of Chiron's
license. MHRA's Chief Executive, Professor Kent Woods, indicated that
MHRA did not have the legal authority to notify FDA about the
suspension announced on October 5 until after MHRA instituted its
administrative action. Dr. Woods has also stated that, ``Contrary to
some reported statements, MHRA, as the responsible regulatory authority
in the United Kingdom, made the decision to suspend Chiron's license
after an internal meeting on October 4 and first informed the company
and the FDA of this decision on October 5. At the same time, we
informed other drug regulatory authorities via an intergovernmental
rapid information alert.''
Upon learning of the MHRA's suspension on October 5, 2004, FDA
communicated with both Chiron and the MHRA. While Chiron indicated to
FDA that it believed it had satisfactorily addressed MHRA's
inspectional findings and provided to FDA a copy of those findings and
the company's response, MHRA expressed serious concerns about Chiron's
vaccine stocks and the company's ability to assure the safety of the
vaccine.
FDA performed a comprehensive review of the retesting data during
its October 10-15, 2004, inspection of the Liverpool facility. The
retesting results were indeed negative; however, FDA's inspection found
issues related to the adequacy of the statistical sampling plan used
for the retesting. These findings, coupled with the other issues
uncovered during the inspection, led FDA to conclude that it could not
assure the safety of the vaccine.
Question 11b. How would you prevent this type of incident from
happening in the future?
Answer 11b. Recent experiences, particularly those of the past 7
months, have taught us important lessons about manufacturing and
inspectional activities with respect to influenza vaccine. Although FDA
has always interacted extensively with influenza vaccine manufacturers
throughout the vaccine production cycle, the annual changes in the flu
vaccine and the increased dependence on a smaller number of
manufacturers highlight the risks of unexpected manufacturing
difficulties. For these reasons, in 2005 and the future, we plan to
conduct inspections of influenza vaccine manufacturers on an annual
basis, with additional interactions with manufacturers and, in the case
of foreign facilities, their regulatory agencies where appropriate,
based on findings or events that raise concerns.
FDA is working with manufacturers and its regulatory counterparts
in anticipation of having an ample supply of influenza vaccine for the
coming season through a dual-track strategy.
FDA's first track is to facilitate Chiron's effort to correct its
manufacturing problems. FDA and MHRA, the British regulatory agency,
have an agreement with Chiron that allows full information sharing. FDA
has used that agreement to collaboratively review Chiron's remediation
plans and activities, and the Agency is providing continuing and
extensive feedback to both Chiron and MHRA. In addition, FDA signed an
information sharing agreement with MHRA that will, among other things,
permit advance communication on important issues. The agreement was
effective February 14, 2005.
FDA is actively communicating on inspection activities. Only after
passing MHRA and FDA inspections will Chiron be able to provide vaccine
to the U.S. market. In the spring when critical stages of manufacturing
are taking place, the Agency plans a comprehensive inspection to verify
whether Chiron has adequately addressed its problems. While much work
remains to be done, it appears that Chiron is making progress.
FDA's second track is to facilitate overall greater capacity and
diversification in the U.S. influenza vaccine supply. It is important
to recognize that the demand for vaccine and other economic issues are
the primary factors that determine whether a manufacturer will seek and
maintain a license in this country.
CDC and FDA are working to encourage vaccination throughout the flu
season, including January and February. To increase the total doses
available, manufacturers can produce vaccine over a longer time period,
and that becomes available during these months. Because influenza cases
usually continue well after November and December when most people are
seeking immunization, later vaccination is beneficial. The Public
Health Service is working to better communicate this important public
health message.
In addition, FDA has been working to stimulate manufacturers not
licensed in the U.S. to provide or, where needed, develop the safety
and effectiveness data to obtain U.S. licensure. The Agency has
actively engaged several interested companies. FDA has informed
manufacturers that the Agency is willing to consider all approaches to
licensing, including accelerated approval based on surrogate markers,
e.g., the patients' immune response to the vaccine. Sanofi Pasteur and
Medlmmune have indicated their willingness, if needed, to do what they
can to increase production.
FDA has challenged itself to identify other lessons learned from
this year's influenza season and is evaluating how this experience
could be used to prevent similar events in the future. While there are
some elements that FDA cannot control, the Agency is making significant
changes. For example, as mentioned above, FDA plans to conduct
inspections of influenza vaccine manufacturers on an annual basis, and
the Agency is completing or has completed agreements that allow
information sharing with numerous foreign regulatory agencies.
Ophthalmology
Dr. Crawford, the FDA's Ophthalmology Group represents a unique
specialty distinct from other clinical areas. Given the unique nature
of drug therapies and treatments related to eye care, the work of this
important group is critical to millions of Americans at risk for
serious eye disease or blindness. Currently under the Division of Anti-
inflammatory, Analgesic and Ophthalmic Drug Products, it is my
understanding that the FDA is considering integrating the Ophthalmology
Group into the Division of Anti-Infective Products. Clearly, research
of new treatments for potentially blinding diseases is extremely
important.
Question 12. If confirmed as Commissioner, how would you address
concerns that ophthalmics may receive diminished attention and
resources if combined within antiinfectives?
Answer 12. We expect that individuals with expertise in
ophthalmology will continue to play a critical role in reviewing new
ophthalmology products, and the reorganization will not affect the
timely approval of treatments and drug therapies available to eye care
practitioners and their patients. All drug review processes for all
products will continue to be held to existing PDUFA goals and timelines
during and as a result of the reorganization.
______
Response to Questions of Senators Kennedy/Mikulski by Lester Crawford,
DVM, Ph.D.
(First Set of Questions)
Question 1. When Tommy Thompson resigned in December 2004 he
expressed ``grave concern'' about the risks of a terrorist attack on
the U.S. food supply.
As Commissioner, what steps would you take to protect America's
food supply as Secretary Thompson warned?
Answer 1. Ensuring the safety of the food supply is a top priority
for me and for the Administration. A great deal has been done in the
past few years to improve food safety and security. FDA has worked with
food safety agencies at the Federal, State, and local levels to
significantly strengthen the Nation's food safety system across the
entire distribution chain (i.e., from farm to table) to better protect
our food supply against deliberate and accidental threats. This
cooperation has resulted in greater awareness of such vulnerabilities,
the creation of more effective prevention programs, new surveillance
systems, and faster foodborne illness outbreak response capabilities.
An effective food defense system is built on a strong food safety
system.
The fiscal year 2006 budget requests an increase of $30 million for
food defense activities. Twenty million dollars of this increase will
support a national laboratory network known as the Food Emergency
Response Network (FERN). A critical component of controlling threats
from deliberate food-borne contamination is the ability to rapidly test
large numbers of samples of potentially contaminated foods for a broad
array of biological, chemical, and radiological agents. FERN will
increase our laboratory surge capacity through a nationwide network of
Federal and State laboratories capable of testing the safety of
thousands of food samples, thereby enhancing the Nation's ability to
swiftly respond to a terrorist attack. The additional $10 million will
be used for targeted food defense research, for continued coordination
and sharing of data with the Department of Homeland Security as part of
the governmentwide Bio-Surveillance Initiative, and for upgrades in
FDA's crisis management capabilities.
Significant new tools to enhance the safety of the food supply were
provided by the Public Health Security and Bioterrorism Preparedness
and Response Act (Bioterrorism Act), which the President signed in
2002. This landmark legislation represents the most fundamental
enhancement to FDA's food safety authorities in many years, and FDA has
been working hard to implement it. In response to the provisions
included in the Bioterrorism Act, FDA:
Published a final rule to implement recordkeeping
requirement on 12/9/04;
Published a final rule to implement the administrative
detention provision on 6/4/04;
Signed a Memorandum of Understanding with Customs and
Border Protection on 12/3/03 to allow FDA to commission CBP officers in
ports and other locations to conduct investigations and examinations of
imported foods; and
Published Interim Final Rules to implement the requirement
for domestic and foreign facilities to register with FDA and the
requirement for prior notice of imported food on 10/10/03.
In addition to implementing the Bioterrorism Act, FDA has many
other ongoing counterterrorism activities. For example, since September
11, 2001, FDA has increased its emergency response capability by
realigning resources to counterterrorism and by reassessing and
strengthening its emergency response plans. FDA has also conducted
numerous emergency response and preparedness exercises to further
strengthen our response to a terrorist event involving our Nation's
food supply. These exercises have included Federal, State, and industry
partners.
FDA has completed vulnerability assessments focused on specific
foods, suspect agents, and processing steps where an agent could be
intentionally introduced. These vulnerability assessments have assisted
the agency in focusing on those commodities considered to be most at
risk for intentional contamination. Government and industry have worked
together on specific and targeted mitigation steps to address the
vulnerabilities identified in our assessments. These assessments have
also assisted the agency in focusing intramural and extramural research
on four major areas: new methods for detection of agents, prevention
technologies, agent characteristics, and dose response.
FDA has also issued food security guidance documents to different
segments of the food industry on the preventive measures they can take
to minimize the risk that food or cosmetics under their control will be
subject to tampering or other malicious, criminal, or terrorist
actions.
Other Counterterrorism Activities over past 3 years include:
Increasing laboratory surge capacity by expanding
participation in the Food Emergency Response Network, constructing BSL-
3 laboratories in the field and supporting the construction and
deployment of two mobile laboratories;
Enhancing an early-warning system to identify hazardous
foods by expanding the number of Federal, State, and local laboratories
providing data through our Electronic Laboratory Exchange Network
(eLEXNET).
Conducting numerous research projects to improve our
ability to detect contamination, focusing on rapid test methods for use
in the field;
Carrying out food defense activities under Homeland
Security Presidential Directives; the Interagency Security Plan; the
Secretary's Bioterrorism Strategic Plan; and FDA's Strategic Action
Plan;
Enhancing FDA's ability to plan, manage, and respond to
food emergencies through the Emergency Operations Network (EON), an
electronic incident management system; and
Enhancing law enforcement and intelligence gathering/
analysis by, for example, participating in select Joint Terrorism Task
Forces and establishing a dedicated Counterterrorism Section in FDA's
Office of Criminal Investigations.
Question 2. FDA headquarters is currently located in 40 buildings
at 18 locations--this will change when FDA headquarters moves to White
Oak. FDA's consolidation of White Oak has been going on for over 10
years to give FDA state-of-the-art facilities. Each phase of the
project costs about $200 million; each year of delay costs millions of
dollars.
The President's fiscal year 2006 budget requests $128 million for
continued consolidation at White Oak less than half the level requested
by FDA and GSA to construct the next phase of the project (about $280
million). FDA needs these facilities for many reasons; including to
attract the best and brightest employees to FDA.
Would consolidation of FDA be a priority for you as FDA
commissioner? As FDA commissioner would you advocate for the completion
of the consolidation project at White Oak? If so, do you have a
projected time line that you would like to implement for completion of
the project? What steps would you take to make sure that the
Administration understands the importance of this project, and the need
for a strong Federal funding commitment to complete the consolidation
project?
Answer 2. The consolidation of FDA Headquarters is a priority for
the FDA, which upon completion will house over 7,700 staff in 2.3
million square feet of space. By the end of fiscal year 2005, the
campus will have almost 700,000 square feet completed with 1,850 staff
on site. The new buildings will eventually replace all 40 of the
existing facilities in 18 locations that support the Office of the
Commissioner, and all of our Centers and Field headquarters, except the
Center for Food Safety and Applied Nutrition in College Park and the
National Center for Toxicological Research in Jefferson, Arkansas. This
project will allow FDA to work towards many of the President's
Management Agenda goals by standardizing and modernizing document
handling, providing shared use facilities such as libraries and
conference areas, further reducing redundancies in administrative tasks
and allowing conversion to a single computer network. This will help
create a stronger FDA by reducing operating costs, reducing travel time
between organizations, increasing collaboration between centers and
increasing the convenience of access to FDA by the public.
This Administration has and continues to strongly support the White
Oak project. Currently, the Project is on track for GSA funding of the
Office of the Commissioner and ORA buildings in fiscal year 2008. With
funding on schedule, the move in date for these buildings would be in
fiscal year 2010. The anticipated move in schedule is provided below:
FDA Move in Timeline for the White Oak Consolidation Project
----------------------------------------------------------------------------------------------------------------
Total Employees at
Phase Completion Employees In Phase White Oak
----------------------------------------------------------------------------------------------------------------
Life Sciences Laboratory(includes COMPLETED December 2003 125.................... 125
CDER Labs & CDRH Chemistry &
Biological Sciences).
CDER Office Building I............... 2005................... 1,725.................. 1,850
Central Shared Use I................. 2006................... 150.................... 2,000
Engineering Physics Laboratory....... 2007................... 160.................... 2,160
CDER Office Building II.............. 2007................... 1,076.................. 3,236
CDRH Offices......................... 2008................... 1,298.................. 4,534
Central Shared Use II................ 2008................... 140.................... 4,674
CBER Labs............................ 2008................... 300.................... 4,974
CBER Offices......................... 2009................... 900.................... 5,874
CVM Offices.......................... 2009................... 426.................... 6,300
OC & ORA HQ Offices.................. 2010................... 1,420.................. 7,720
----------------------------------------------------------------------------------------------------------------
Question 3a. While mammograms are imperfect, they are the best tool
we have today to screen for breast cancer. However, mammography should
not be the only tool. There must be better tools. In 2001, a report
from the Institute of Medicine on developing technologies for the early
detection of breast cancer made some recommendations for FDA such as:
FDA developing and using consistent criteria for approval
of screening and diagnostic devices and tools.
FDA approval for new screening technologies should depend
on evidence of improved clinical outcome.
Has FDA implemented any recommendations from this report? If so,
what is the status? If not, why not?
Answer 3a. New screening and diagnostic processes often are new
technology, and each technology presents unique questions. The agency
has tried to reduce inconsistency in the review process wherever
possible. Note the following examples.
The agency developed a guidance document for Digital
Mammographic submissions.
CDRH is currently working on a guidance for Computer
Assisted Detection (and Diagnosis) (CAD and CADx).
A policy is in place to meet with sponsors early in the
product development cycle to allow them and us to understand the new
product and its path to market.
We are developing a guidance on the performance assessment
of imaging products. We are also training staff on these techniques.
There is a process for determining whether a new product
will follow a 510(k) or PMA marketing approval route.
CDRH follows a least-burdensome process in reviewing
device submissions.
There is strong collaboration amongst multiple CDRH
offices in the review of submissions for new devices, especially PMAs.
Review of submissions for new novel devices is expedited
according to Center policy.
A recent example of a new device approval in this area is the Kodak
Mammography CAD (computer-aided design) ENGINE. The Kodak Mammography
CAD ENGINE uses software that helps radiologists who read mammograms to
highlight areas that might be suspicious for breast cancer and might
otherwise have been missed.
Question 3b. Since its creation in 1994, the FDA Office of Women's
Health has sponsored research, conducted public education campaigns,
encouraged the participation of women in clinical trials, and served as
an advocate for women's health in agency decisions. Senator Olympia
Snowe and I recently introduced the Women's Health Office Act of 2005.
This bill would statutorily authorize the Office of Women's Health at
FDA. As Commissioner, will you support legislative efforts to authorize
this Office? When appropriate, will you seek the advice and
recommendations of the Office of Women's Health?
Answer 3b. I strongly support the FDA Office of Women's Health
(OWH). The OWH has proven to be a valuable source of information both
inside and outside of the Agency. Its leadership has served the agency
well on issues of sex and gender differences regarding therapeutic
interventions. In addition, its national award-winning public
information campaigns have made it an essential part of FDA. I have
routinely sought their advice on issues of importance to women and will
continue to do so during my tenure.
Question 4. On February 25, 2005, an article in the New York Times
revealed that 10 of the 32 government drug advisers who voted in favor
of keeping Vioxx and Bextra on the market had consulted in recent years
for the drugs' makers. If those who had consulted for the applicants
had not voted for the companies' products, they would have been
rejected by the panel.
Back in 2003, 6 of the 15 voting panel members on the general and
plastic surgery devices panel were plastic surgeons. All voted in favor
of approving silicone breast implants for general use and could profit
from allowing silicone breast implants.
A majority of the scientists on the panel voted against approval,
based on failure of the manufacturers to produce long-term data on the
safety of the product. But, because all the plastic surgeons voted in
favor, the advisory panel voted to approve silicone implants.
Following that October 2003 panel, Dr. Thomas Whalen, chair of the
advisory panel, took the highly unusual step of writing a public letter
to the FDA commissioner which stated that ``it serves the reputation of
the FDA in general, and the standing of the panel process in
particular, exceedingly poorly to have had all of the plastic surgeons
vote the PMA as approvable on such a close vote. Even in academic
settings, plastic surgeons may stand to increase their own income with
the use of these devices.''
FDA needs to restore public confidence and show its ability to
protect the public health and safety of the American people.
What is the FDA's justification for its failure to publicly
disclose the financial conflicts of interest of the panel participants?
Answer 4. Although 18 U.S.C. Section 208 provides that a copy of
any waiver determination is available to the public upon request, the
Agency may withhold from disclosure information that would be exempt
under the Freedom of Information Act, 5 U.S.C. Section 522(b). Under
this provision, all of the information concerning conflicts of interest
may be withheld as exempt pursuant to 5 U.S.C. Section 522(b)(3)
because the Ethics in Government Act prohibits release of the
information. Nevertheless, in order to provide meaningful disclosure of
conflicts of interest information, the Office of Government Ethics has
concluded that, under section 208, Federal Agencies have discretion to
disclose information concerning the waived conflict of interest absent
a foreseeable harm to be caused by the disclosure. The Office of Legal
Counsel, United States Department of Justice (OLC), concluded that FDA
may exercise its discretion in making disclosure to avoid making the
disclosure requirement so intrusive or onerous as to make outside
experts unwilling to serve on advisory committees.
In January 2002, the FDA issued draft guidance on ``Disclosure of
Conflicts of Interest for Special Government Employees Participating in
FDA Product Specific Advisory Committee.'' The guidance provides
information on the type and amount of information that will be
disclosed to the public when a member is granted a conflict of interest
waiver with the topic to be discussed by the committee. The guidance
applies only to those advisory committee meetings at which a particular
matter relating to a particular product is discussed (product specific
meetings). The guidance does not apply to advisory committee meetings
that provide advice on topics of general applicability (i.e., those
meetings that could affect a class of products and their sponsors) even
if the members on the committee received general matters waivers
covering their participation on the committee.
The disclosure for particular matters identifies whether the
interest is related to the sponsor or competitor that markets a product
competing with the product at issue (without naming the competitor),
the type of interest (stock, consulting, contracts/grants, patents/
royalties/trademarks, expert witness, teaching, speaking, or writing),
and the magnitude of the interest is described as a range.
Question 5. What conflict of interest screening measures does the
FDA currently have in place for advisory panels?
Answer 5. Because it is imperative to obtain the best scientific
information available, it is very difficult to obtain qualified
advisory committee members who are also totally free from all potential
financial conflicts of interest. The Nation's experts (and in some
cases, there are only a few experts on a particular topic) are sought
after for consultation by both the Agency and industry because of the
scarcity, and therefore the value, of their expertise. Utilizing
scientists who are less experienced or less highly qualified in order
to completely remove any potential financial conflict from the
committee would hamper the Agency's ability to protect and advance the
public health.
The Agency's staff examines all potential financial interests. The
Agency's process is to evaluate the potential financial interests of
members and other invited special government employees. FDA makes a
determination as to whether the participation of an individual with
some financial ties outweighs the need for the agency to understand the
science on the topic before the committee. Although the Agency has
guidelines for this process (see Waiver Criteria Document 2000 on the
FDA web page), this is not a black and white process. It requires
careful consideration of all facets of the issue in order to evaluate
that balance. Congress, by permitting waivers for potential conflicts
of interest, has ensured that the Agency and the public (through the
advisory committee process) have access to the most knowledgeable
individuals on the meeting topic.
Question 6. What steps as FDA Administrator you would take to limit
conflicts-of-interest in future drug advisory panels?
Answer 6. FDA's process of evaluating potential committee members
for conflicts is very extensive and transparent. Our methodology is
articulated in a comprehensive document on the agency's website (http:/
/www.fda.uov/oc/advisory/conflictofinterest/intro.html). At the
beginning of each meeting, a conflict of interest statement is read
into the record, which summarizes the results of the conflicts of
interest screening. Nonetheless it is always prudent to regularly
assess the Agency program and determine if any improvements are
warranted. In the near future, the Agency will review the advisory
committee conflicts of interest disclosure process and consider if
further improvements are necessary to make the disclosures more easily
accessible to the public.
Question 7. Given that plastic surgeons stand to befit financially
from the approval of silicone breast implants, do you think that it's
appropriate for plastic surgeons to serve on the Advisory panel, let
alone make up its plurality?
Answer 7. FDA expects this panel to include a number of plastic
surgeons, as did the October 2003 panel. Please note that plastic
surgeons comprised only four of the 16 voting panel members for that
meeting. We believe it is appropriate that the medical specialty most
likely to implant silicone breast implants be represented during
deliberations on the device. Their experience with the product and
insights into issues that impact its safety and effectiveness are
critical to the agency's evaluation.
Question 8. What do you intend to do about these conflicts before
the upcoming April advisory panel to reintroduce silicone breast
implants for general use?
Answer 8. The individuals that comprise the General and Plastic
Surgery panel for the upcoming April meeting will have been screened
according to the Agency's existing conflict of interest rules. All
panel members, new and standing, must be cleared through a formal
process prior to serving as a panel member for a specific PMA. The
final roster will be posted on FDA's website a week or two prior to the
meeting when all panel members are cleared to serve on this panel for
these PMAs.
Response to Questions of Senator Kennedy by Lester Crawford, DVM, Ph.D
(Second Set of Questions)
I understand that just 9 days before he was scheduled to testify
before the Senate Finance Committee, you offered Dr. David Graham a
newly created job in your office to lead the agency's effort to enhance
its monitoring and surveillance of approved drugs. Dr. Graham declined
the offer, and went on to testify.
Following that testimony, one senior FDA official called Dr.
Graham's work ``junk science'' and accused him of scientific misconduct
to The Lancet. Managers in the center for drugs called Dr. Graham's
lawyer posing as whistleblowers and tried to discredit Dr. Graham.
Question 1a. Why did you offer Dr. Graham a prestigious job, then
only days later allow an FDA official to label his work ``junk
science''? If his science was junk, why did you offer him the job?
Answer 1a. Your question relates to a statement made by an FDA
employee. Dr. Graham and all other FDA employees enjoy freedom of
expression as guaranteed under the Constitution. That said, it is my
understanding that this quote comes from a conversation with a
Washington Post reporter that was taken out of context. The FDA
official interviewed was asked to respond to the reporter's question
about whether it was accurate to state that a certain number of
individuals in particular Congressional districts could be said to have
died of cardiovascular events because of Vioxx. It is not possible to
derive from risk estimates the cause of a particular individual's
death. This concept is complicated to explain, and the FDA official
reacted to it by characterizing the particular statement regarding
deaths of individuals in a Congressional district as ``junk science.''
The characterization was not made with regard to all of Dr. Graham's
work. I am not aware of any FDA official accusing Dr. Graham of
scientific misconduct.
Question 1b. Some might question whether you were simply kicking
Dr. Graham upstairs to keep him quiet. Did you look for a different
candidate when Dr. Graham declined the job? Did you contact any of the
people whom Dr. Graham recommended for the job? When did you create the
new position? When did you find out that Dr. Graham was testifying
before the Senate Finance Committee? Who holds the position now, and
when was that person hired?
Answer 1b. My discussion with Dr. Graham focused on the IOM review
of drug safety and not Congressional hearings. Dr. Janet Woodcock,
Acting Deputy Commissioner for Operations, was eventually assigned the
task of designing FDA's drug safety program, including liaison with the
IOM on the study.
Question 1c. FDA managers called Dr. Graham's attorney, made
misleading statements about their own identities, and tried to
discredit him. What have you done to try to find out who made these
calls, and what disciplinary action have you taken?
Answer 1c. There is an Inspector General (IG) investigation of this
issue underway, therefore, the Agency cannot comment further on this
matter at this time.
Question 1d. An FDA manager called Dr. Graham's work ``junk
science'' and accused Dr. Graham of scientific misconduct. What have
you done to reprimand this individual, and to clarify to all agency
employees that this behavior is not appropriate?
Answer 1d. As noted above, the ``junk science'' quote comes from a
conversation with a Washington Post reporter that was taken out of
context and I am not aware of any FDA official accusing Dr. Graham of
scientific misconduct.
[NOTE.--There was no ``Q2'' in--original document]
[NOTE.--As revised by Kennedy staff 3/24] In January 2004, FDA
rejected an application for approval of silicone breast implants and
issued guidance about the information needed to win approval. Two
applications for approval of these products have now been submitted,
less than a year later. I understand FDA did not follow the
recommendation of its own reviewers who recommended that the
information in the applications was not sufficient to change the
decision from last year. Instead, the agency has convened an advisory
committee to review the applications, and is reportedly hand-picking
its members to see that they grant the implants swift approval.
Reportedly there's even an email on which you were copied from your
special science advisor, Susan Bond, to Dan Schultz, the head of the
center for devices, specifying in advance the conclusion the review
should reach.
Question 3a. On breast implants, why has FDA not accepted the
conclusion of its own scientific review that the data in these
submissions are not sufficient?
Answer 3a. FDA continues to evaluate the science with regard to
breast implants. No final conclusion has been reached.
Question 3b. Is it true that you were copied on an e-mail to the
head of the center for devices specifying in advance the conclusions he
was to reach regarding the safety of breast implants? How did you
respond?
Answer 3b. No, I was copied on an e-mail transmitting a preprint of
the views of an individual regarding breast implants. The document
contains a bibliography of recent scientific papers on the subject.
These papers are all publicly available and therefore already known to
CDRH. The bibliography was incomplete. In evaluating the safety of
breast implants, CDRH will consider the entirety of the scientific
literature.
Question 3c. Please provide me all the e-mails or other
correspondence, with all attachments, you received, were copied on, or
sent that have had to do with breast implants.
Answer 3c. Enclosed are e-mails that respond to your question.
Question 4a. On August 26, 2004, the public learned that Chiron,
one of two manufacturers of the Nation's flu vaccine, had produced
contaminated lots of vaccine at a plant in Liverpool, England.
Between that date and October 5, 2005, when the British regulatory
agency, the MHRA, suspended Chiron's license, the FDA did not inspect
the Liverpool plant. By contrast, the British carried out two full
inspections during September 2004, once on September 13th and 14th, and
again from September 29th to October 1st. British inspectors were
physically present at the plant and they required Chiron to respond to
their inspectors' report. FDA never inspected the plant before the
license was suspended.
In your testimony to the House Government Reform Committee in
November 2004, you said that after MHRA suspended Chiron's license, you
contacted Chiron and the British, but that ``Chiron indicated that it
believed it had satisfactorily addressed MHRA's inspectional
findings.'' Why did FDA trust Chiron's assurances rather than verifying
the safety of half of our vaccine supply the way the British regulators
did?
Answer 4a. In our interactions with Chiron, FDA consistently worked
to verify the safety of their vaccine product. On August 25, 2004, FDA
inspectors were onsite conducting a preapproval inspection and were
informed of the contamination of the vaccine. FDA inspectors met with
Chiron's staff and reviewed the preliminary findings and the approach
that Chiron was taking to its investigation and retesting at multiple
points in its process. FDA inspectors in Liverpool faxed to FDA's
Center for Biologics Evaluation and Research (CBER) preliminary data
and information regarding the scope and plans for the sterility failure
investigation being conducted by Chiron. The results of these
evaluations were needed and essential for any regulatory assessment.
Chiron's investigation was in the earliest stage and, therefore, only
preliminary information was available. Chiron informed FDA that all
results from the retesting were negative for all other finished product
and that its final investigative report, including all product testing
data, would be submitted to FDA during the week of October 4-8, 2004.
FDA would then complete an indepth assessment of the report findings,
which would indicate appropriate next steps for the agency. However, on
October 5, the week the report was expected by FDA and just hours
before FDA expected to receive an update from Chiron during a
previously scheduled morning teleconference, the U.K. Medicines and
Healthcare Products Regulatory Agency (MHRA) announced to Chiron, the
FDA and the world their suspension of Chiron's license.
FDA performed a comprehensive review of the retesting data during
its October 10-15, 2004, inspection of the Liverpool facility. The
retesting results were indeed negative; however, FDA's inspection found
issues related to the adequacy of the statistical sampling plan used
for the retesting. These findings, coupled with the other issues
uncovered during the inspection, led FDA to conclude that it could not
assure the safety of the vaccine.
Question 4b. Once the Chiron vaccine was unavailable, the
Administration began to identify manufacturers of vaccine for other
countries that it might be able to acquire and make available to the
public, and it reprioritized who should receive vaccine. Please assess
the difference beginning these endeavors in late August 2004 would have
made?
Answer 4b. The loss of Chiron's planned contribution to the U.S.
influenza vaccine supply posed serious challenges. FDA worked with
urgency, aggressiveness and in close coordination with CDC and other
components of HHS and the private sector to explore all viable options
to secure additional doses of influenza vaccine. FDA worked with Sanofi
Pasteur and Medlmmune to secure approximately 5 million additional
doses of U.S. licensed vaccine. Sanofi Pasteur increased production to
58 million doses of Fluzone, and Medlmmune scaled up to produce 3
million doses of FluMist. FluMist is currently recommended for healthy
individuals 5 to 49 years of age, and therefore provides an option for
those who would not receive vaccine under CDC's priority guidelines,
such as the U.S. military. Therefore, to expand further the supply of
vaccine to those with the greatest need, Secretary Thompson, in
cooperation with the Department of Defense, announced that the military
would maximize its use of FluMist as a substitute to the inactivated
vaccine, making an additional 200,000 doses of injectable vaccine
available to HHS for high-risk civilian populations. Because Sanofi
Pasteur produces pediatric dosage forms of vaccine for the U.S. market,
the supply of vaccine available for high-risk children was,
fortunately, not reduced. Through these collaborative efforts,
manufacturers increased the available supply of licensed influenza
vaccine for the U.S. population to 61 million doses for this influenza
season, compared with approximately 83 million doses distributed in
2003-04 and in 2002-03, 77 million doses in 2001-02 and 70 million
doses in 2000-01.
Because there was a concern that the need and demand could still
outstrip supply, particularly if we face a severe influenza season, we
sought additional doses of vaccine that could be safely used in an
emergency. Thus, in addition to enhancing the supplies of vaccine
approved for use in the U.S., we were able to rapidly identify
suppliers of approximately 5 million doses of additional vaccine,
licensed in other countries, that could potentially be made available
under an FDA investigational new drug (IND) application. With
remarkable cooperation from several companies and from other regulatory
agencies (including the Paul Ehrlich Institute, Germany; Therapeutic
Goods Administration, Australia; Swiss Medic and Health Canada) FDA
immediately sent inspectors and scientists to the manufacturing
facilities of potential IND sponsors to evaluate their manufacturing
processes. Coupled with these efforts, we also reviewed a large volume
of manufacturing and clinical data, all within in a few weeks. These
efforts resulted in FDA approving INDs that permitted the potential use
of approximately 4 million doses from GlaxoSmithKline (GSK) and 1
million doses from Berna Biotech, if needed. Of the 5 million doses
potentially available under an IND, FDA understands that CDC has
purchased approximately 1.5 million doses. HHS and FDA's coordinated
interactions with these and other influenza vaccine manufacturers and
regulatory agencies also provided valuable information and strengthened
relationships that we hope will help stimulate interest by additional
influenza vaccine manufacturers and potentially lead to successful U.S.
licensure.
Question 5. Last year Merck withdrew Vioxx from the market, because
the drug doubled the risk of heart attack or stroke but that was more
than 5 years after the FDA approved the drug, and after 20 million
Americans had used it. As a result, tens of thousands of Americans
needlessly suffered heart attack or stroke, and many died. This is the
single largest drug safety failure the Nation has ever faced. It simply
should not take that long, nor should so many people use a drug, before
such a significant safety risk is discovered. Dr. Sandra Kweder
testified earlier this month that authority to order both drug labeling
and drug safety studies after approval would be helpful. Do you agree?
Answer 5a. I do not believe new statutory authority is needed. We
will use all existing regulatory authority and enforcement powers when
negotiating label changes with drug companies or when monitoring or
managing drug safety issues. As Dr. Janet Woodcock testified, a key
factor in labeling changes is that once a label change is made, old
labels in paper form are still in distribution and it takes time to get
newer labels in circulation. Dr. Woodcock testified that the new
strategy of posting drug safety information sooner using the Drug Watch
mechanism will help alleviate that factor because it will enable the
FDA to get information directly to the people who need it in a timely
manner.
Question 5b. At our second hearing, Dr. Janet Woodcock testified
that the practices of the drug companies promoting their drugs to
doctors caused the overuse of new drugs. Do you see any drug company
promotional activities as a problem? Do you think that patients are
ever prescribed pills that aren't right for them because of advertising
or high-pressure sales tactics to doctors? Isn't that a particular
concern for newly approved drugs that may have safety concerns not
detected in the initial trials?
Answer 5b. We have conducted research that confirms that DTC
advertising, when done correctly, can serve positive public health
functions, such as increasing patient awareness of diseases that can be
treated, and prompting thoughtful discussions with physicians that
result in needed treatments being prescribed often, not the treatment
in the DTC advertisement. Results of our research show that many
physicians believe DTC can play a positive role in their interactions
with patients and that many physicians thought DTC ads made patients
more involved in their healthcare.
In a survey we conducted, while 75 percent of physicians believed
that DTC advertising causes patients to think the drug works better
than it actually does and many physicians felt some pressure to
prescribe something when patients mentioned DTC ads, only 8 percent
felt very pressured to prescribe the specific drug advertised.
Physicians agreed that the main effect of DTC ads was to help educate
patients about their health problems, causing them to seek needed care.
While I believe these results confirm our belief that DTC ads help
increase patient awareness about the availability of effective
treatments for their health problems, I will continue to ensure that
our DTC policies help prevent potential misperceptions about benefits
and risks of advertised treatments and promote the importance of
prescribing decisions being made with the intervention of a health care
professional.
Question 6. In Antibiotic Resistance: Federal Agencies Need to
Better Focus Efforts to Address Risk to Humans from Antibiotic Use in
Animals, the GAO lists ``the use of antibiotics in animals raised for
human consumption as contributing to antibiotic resistance in humans.''
They explain that FDA's Guidance No. 152 ``outlines a framework for
determining the likelihood that an antibiotic used to treat an animal
would cause an antibiotic resistance problem in humans,'' but note that
implementation of the Guidance for antibiotics already on the market
``may take years.'' As Commissioner, what actions would you take to
reduce, in a timely fashion, agricultural overuse of antibiotics,
particularly those that are ranked as ``important,'' ``highly
important,'' or ``critically important'' in Guidance No. 152? How long
has it taken, and how much FDA staff time and resources have been
spent, to withdraw Baytril from the market? Has the process been
efficient and effective? What will you do to make the process of
limiting the veterinary uses of important drugs more efficient?
Answer 6. FDA is concerned about antimicrobial resistance and the
use of antimicrobial drugs in food-producing animals causing an
unintentional adverse health impact on humans. FDA agrees with the
Government Accountability Office's recommendation that it is important
to review the currently approved animal drugs that are critical to
human health and to collect antibiotic use data. Guidance for Industry
No. 152, ``Evaluating the Safety of Antimicrobial New Drugs with Regard
to their Microbiological Effects on Bacteria of Human Health Concern,''
sets out the agency's recommendations for the pre-approval safety
assessment for new antimicrobial drugs intended for use in food-
producing animals. This guidance also is used for re-evaluating
currently approved veterinary antimicrobial drugs. FDA's Center for
Veterinary Medicine (CVM) has finished the assessment for the growth-
promoting uses of penicillin-containing antimicrobial drugs. CVM is
currently in the process of re-assessing the growth-promotion uses of
tetracycline-containing antimicrobial drugs.
In addition, CVM has re-evaluated the use of virginiamycin, a
streptogramin used in five species of food-producing animals, for its
potential to cause Synercid-resistant Enterococcus faecium in humans.
Synercid is a streptogramin recently approved to treat vancomycin-
resistant Enterococcus infections, a serious disease in humans. FDA has
posted the draft risk assessment on its CVM website. In addition, FDA
published an announcement in the Federal Register on November 23, 2004,
that the risk assessment was available and that FDA would accept
comments for 60 days. FDA subsequently extended the comment period an
additional 30 days to February 23, 2005. The draft risk assessment is
available at:
http.//www.fda.gov/cvm/antimicrobial/SREF RA FinalDraft.pdf. FDA
intends to evaluate all comments received, revise the risk assessment
accordingly, and then determine appropriate steps that need to be taken
to address any identified risks to humans.
FDA intends to continue to review the currently approved
antimicrobials for food-producing animals for microbial safety using
GFI 152. FDA intends to begin with antimicrobials considered as
critically important for human medical therapy. This process is slow
because it is resource intensive to review each approved new animal
drug. CVM's experience in connection with its proposal to withdraw the
approval for Baytril was that the process was expensive and resource
intensive, with an estimate in excess of 10.0 FTEs for approximately 3
years and about one-quarter that for an additional 2 years plus
approximately $500,000 in expert witness fees and travel expenses. CVM
initially published the Notice of Opportunity for a Hearing (NOOH) on
its proposal to withdrawal approval of the fluoroquinolones for use in
poultry on October 31, 2000. This NOOH procedure is required to ensure
due process for the respondent. The matter is currently under review by
the FDA Commissioner's team. Additional FDA staff members are now
expending resources on the review. The agency handles these withdrawal
proceedings as expeditiously as possible in light of other matters that
also require the Agency's resources.
After the initial assessment of the currently approved
antimicrobials with respect to microbial safety, if safety issues are
identified, CVM is hopeful that the relevant animal pharmaceutical
companies will cooperate with the agency in addressing those issues.
Question 7. That same GAO report strongly recommended that the FDA
collect, compile and publish data on antibiotic use in agriculture, so
that researchers might better ``study the linkages between antibiotic
use in animals and the human risk from antibiotic resistance and to
develop and evaluate strategies for mitigating resistance.'' I
understand that the FDA has drafted a rule on data collection that has
been stalled for some reason. What is the status of the FDA's draft
rule? Will you move forward with it this year? If not, do you have
other plans to implement the GAO recommendation?
Answer 7. The FDA Center for Veterinary Medicine recognizes the
importance of the monitoring of drug use data as a component of an
effective surveillance system. The Center currently collects certain
animal drug sales information under 21 CFR 514. However, as mentioned
in the GAO Report, more detailed data would assist us in interpreting
results from the National Antimicrobial Resistance Monitoring System
(NARMS) on changing resistance levels. Data on the amounts of drugs
used would be helpful on many levels, for example:
in analyzing associations between resistance levels in
animals and humans,
in risk assessments designed to quantify the human health
impact attributable to antimicrobial drug use in food-producing
animals,
in identifying where mitigation strategies may be
beneficial, and
in assessing the success of prudent drug use initiatives.
Also, the WHO Global Strategy for Containment of Antimicrobial
Resistance recommends the creation of national systems to monitor
antimicrobial usage in food animals and several countries have
developed drug use monitoring systems or are in the process of doing
so. In order to change the way the current drug marketing information
is reported, FDA has determined that it must promulgate a proposed
regulation with a notice and comment process, including an economic
impact assessment of the regulation. The Agency is considering how to
best meet these data needs, taking into account the burden on industry
and the Agency's data collection authority.
Question 8. I am concerned that you intend to replace Dr. Marlene
Haffner, who now leads the Office of Orphan Products Development.
Please explain why you intend to replace her and how you intend to
search for a successor with comparable expertise in human orphan
diseases. The work of this office is extremely important to me and to
the tens of thousands of patients with rare diseases. What is your
vision for the office?
Answer 8. All FDA offices are required to have succession plans.
The incumbent in the Office of Orphan Drugs has been in that position
for 17 years. Traditionally, FDA leaders have rotated into other
positions following lengthy periods in one position. This is the best
for the institution and for the individual. No current Center Director,
Associate Commissioner, or Deputy Commissioner has served for 17 years
in one position. Finally, whenever FDA conducts recruitments for
vacancies, we strive to identify individuals that have the relevant
management and subject matter expertise for the position.
Question 9. In 1996, after 2 years of assessment and consultation
with scientists and governments both within Canada and abroad, Health
Canada released a position statement on dental amalgam ``The Safety of
Dental Amalgam'' to all Canadian dentists and doctors. (http://www.hc-
sc.gc.ca/enqlish/media/releases/1996/96 63e.htm)
Health Canada stated that current evidence does not indicate that
dental amalgam is causing illness in the general population. It also
stated that a ban is not justified, and neither is the removal of
existing sound amalgam fillings.
Health Canada recommended that dental amalgam not be used in people
allergic to mercury, those with impaired kidney function, or in contact
with existing metal devices, such as braces. Health Canada also
recommended that, whenever possible, amalgam fillings should not be
placed in or removed from the teeth of pregnant women and that
alternatives should be considered for use in the primary teeth of
children. Health Canada also made a number of recommendations to
dentists about technique and handling of dental amalgam. Health Canada
emphasized that dentists should be providing their patients with
sufficient information to make an informed choice regarding the
material used to fill their teeth.
Do you agree with the Health Canada statement? Do you agree with
the recommendations from Health Canada? Please explain.
Answer 9. FDA agrees with Health Canada's statement that current
evidence does not indicate that dental amalgam is causing illness in
the general population and that neither a ban nor removal of existing
sound amalgam fillings is justified. The agency also agrees with Health
Canada's recommendation that dental amalgam should not be used in
people allergic to mercury.
FDA has not issued warnings to pregnant women and children under 6
about mercury exposure from dental amalgam, as has Canada, because
while FDA and other agencies of the U.S. Public Health Service (USPHS)
continue to investigate the safety of dental amalgam, no valid
scientific evidence has shown that amalgams cause harm to patients with
dental restorations, except in the rare cases of allergy.
FDA, together with the Centers for Disease Control and Prevention
and the National Institute for Dental and Cranio-facial Reseach,
periodically has reassessed available information on the safety of
dental amalgam in order to evaluate potential risk and potential
action. In 1993 and 1997, the United States Public Health Service
(USPHS) issued comprehensive scientific reports about the safety and
use of dental amalgam and other materials used to fill dental caries/
lesions.
The most recent review was completed in 2004 by an independent
panel of experts under the auspices of the Life Sciences Research
Office (LSRO), an independent non-profit organization, under contract
to the National Institutes of Health (NIH). LSRO undertook a
comprehensive review of the scientific literature published since the
1997 USPHS report. To help ensure an independent review, LSRO selected
experts from outside the dental research community, including experts
in immunotoxicology, neurodevelopment, reproductive toxicology,
epidemiology and pediatrics. LSRO posted an Executive Summary of its
report on its website in December 2004 and the report is also available
for purchase by the public.
The LSRO report concludes that ``there is little evidence to
support a causal relationship between mercury fillings and human health
problems.'' The authors noted, however, that there were research gaps,
which, if addressed, might settle the dental amalgam controversy once
and for all. FDA is currently reviewing the full report.
Dental mercury is currently classified as class I (21 CFR 872.3700)
and the amalgam alloy is class II (21 CFR 872.3050). An additional
encapsulated form of mercury, titrated by dentists in the office, was
never classified. In February 2002, FDA proposed a rule to bring all
amalgam products into Class II and increase the Agency's regulatory
oversight by requiring ingredient labeling and proposing conformance to
international standards. FDA has reviewed more than 750 comments
submitted to the docket. Continued work is on hold pending the
evaluation of the LSRO report.
In conjunction with the proposed rule, in February 2002, FDA
published a draft special control guidance addressing labeling for
restorative materials. The proposed labeling has the potential to
reduce allergic reactions to restorative materials. Final guidance
would recommend that the product's labeling list the ingredients in
descending order of weight by percentage and include lot numbers,
appropriate warnings and precautions, handling instructions, and
expiration dating. The guidance is also on hold (along with the related
classification rule) until the LSRO report can be evaluated.
FDA will continue its review of the LSRO report and its
consultation with its sister agencies in the Public Health Service on
this issue. FDA will then determine how to proceed on the proposed rule
for classification and reclassification of the amalgam products and the
associated guidance.
Question 10. Do you support legislation amending the Federal Food,
Drug, and Cosmetic Act to give FDA the authority to review and approve
genetically engineered crops before they are marketed to the public?
Answer 10. Bioengineered foods and food ingredients must adhere to
the same standards of safety under the Federal Food, Drug, and Cosmetic
(FD&C) Act that apply to their conventionally bred counterparts. This
means that these products must be as safe as the traditional foods on
the market. FDA has broad authority to initiate regulatory action if a
product fails to meet the requirements of the FD&C Act.
FDA established a consultative process to help companies comply
with the FD&C Act's requirements for bioengineered foods prior to
marketing. The Agency has reviewed the data on more than 60
bioengineered food products under its jurisdiction, ranging from
herbicide resistant soybeans to modified canola oil. To date, the
evidence shows that these foods are as safe as their conventional
counterparts. A list of submissions that have been reviewed by the
Agency is posted on our website at: www.cfsan.fda.gov/-Ird/biocon.htm/.
To our knowledge, all developers intending to market a bioengineered
plant food subject to FDA's jurisdiction have first participated in
FDA's current consultation process.
FDA believes that the current voluntary premarket consultation
process is working well and fully protects public health.
Question 11. I have been concerned by reports that the FDA is not
considering genetically engineered animals to be regulated as new
animal drugs, despite the fact that Congress clearly intended them to
be regulated as new animal drugs that may not be reviewed under the
special review provisions in the Minor Use and Minor Species Animal
Health Act of 2003. Please explain.
Answer 11. The Agency has been evaluating its legal and regulatory
options for regulating transgenic animals to determine the best
approach possible. As part of its review of its regulatory approach,
the agency has:
participated in executive branch deliberations to evaluate
the role of genetically engineered animals in the Coordinated Framework
for the Regulation of Biotechnology;
prepared case studies on animal biotechnology products to
serve as a basis for legal and policy deliberations; and,
participated in listening sessions sponsored by the Office
of Science and Technology Policy with stakeholders from industry, the
research community, and non-government organizations.
These deliberations are still underway.
In addition, the Agency has previously issued some guidances and
Points to Consider Documents for products from transgenic animals:
Points to Consider in the Manufacture and Testing of
Therapeutic Products for Human Use Derived from Transgenic Animals
(1995);
Public Health Issues Posed by the Use of Non-Human Primate
Xenografts in Humans (1999); and
Source Animal Product, Preclinical, and Clinical Issues
Concerning the Use of Xenotransplantation Products in Humans (2003)
working with the Center for Biologics Evaluation and Research.
Question 12. Do you believe that it would promote the public health
if partially hydrogenated vegetable oils were eliminated from packaged
and restaurant foods? If so, what steps will you take as Commissioner
to eliminate partially hydrogenated vegetable oils from these foods?
Answer 12. FDA is requiring the declaration of trans fat amounts
directly under the saturated fat line on the nutrition facts panel
(without a %DV). This requirement goes into effect January 1, 2006.
(The trans fat labeling rule that was issued on July 11, 2003 in the
Federal Register can be found here http://www.cfsan.fda.gov/-acrobat/
fr03711a.pdf).
FDA is very proud of this regulation because we believe that this
information will allow consumers to lower their intake of trans fat. We
estimate that 3 years after the January 1, 2006 effective date, trans
fat labeling will lower the risk of approximately 600 to 1,200 cases of
coronary heart disease and 240-480 deaths each year, saving $900
million to $1.8 billion per year in medical costs, lost productivity,
and pain and suffering.
FDA understands the important public health concern associated with
the consumption of products that contain trans fat. We encourage
consumers to choose alternative fats by replacing saturated and trans
fats with mono- and polyunsaturated fats. These latter fats do not
raise LDL (or ``bad'') cholesterol levels and have health benefits when
eaten in moderation.
Fostering the development of healthier food products for American
consumers is an important aspect of public health. FDA is aware of the
impact labeling trans fat has on the manufacturer (i.e., potential
reformulation, consumer demand, etc.) and the alternative ingredients
or processing techniques under consideration for reducing trans fat.
FDA is monitoring industry progress in this effort.
Question 13. How do you intend to implement the 2004
recommendations of the Institute of Medicine with respect to sugars and
added sugars in foods?
Answer 13. The 2005 Dietary Guidelines for Americans recommends
that consumers limit consumption of added sugars in foods and
beverages. The Guidelines present the concept of ``discretionary
calories'' as a way for consumers to understand the amount of added
sugars that could be incorporated into a healthful diet, and also the
concept of nutrient dense foods as a way to choose products that are
good sources of nutrients compared to their calorie content. The
Nutrition Facts panel of food labels provides consumers with
information on the total sugars in a product, and the ingredient list
provides information on what is in a product, including ingredients
that are sources of added sugars. FDA can help consumers respond to the
recommendations in the IOM report as well as the Dietary Guidelines by
educating consumers on how to use the Nutrition Facts panel and
ingredient list to determine which foods are high in added sugars.
We are in the early stages of issuing an Advanced Notice of
Proposed Rulemaking to solicit comments on revising the Daily Values
used on the nutrition label. This effort is a top priority for the
Center for Food Safety and Applied Nutrition. This process will
consider the recommendations from the IOM (Daily Reference Intakes) and
other scientific reports (e.g., 2005 Dietary Guidelines). It will be a
comprehensive effort that will include a review of the Reference Daily
Intakes (RDIs), which include vitamins and minerals as well as the
Daily Reference Values (DRVs), which include macronutrients (such as
sugar).
Question 14a. I understand that the FDA announced that its consumer
research on qualified health claims was completed nearly a year ago,
and that the International Food Information Council has completed a
similar study. Please provide me with the raw data from each of these
studies.
Answer 14a. FDA has a copy of slides from an International Food
Information Council's (IFIC) presentation, but not a copy of the study
or the raw data. We can make a copy of the slides available, but a
complete discussion of the study, with slides, can be found on IFIC's
website: www.ific.org/researchlqualhealthclaimsres.cfm.
Question 14b. Please summarize the results of these studies.
Answer 14b. IFCA has summarized its research and this summary
appears on the web site listed above. FDA is working to finalize our
study. Therefore, we do not have definitive information to summarize at
this time.
Question 14c. I understand that the studies suggest that consumers
do not understand qualified health claims. Please explain why the
agency continues to allow foods with qualified health claims to be
distributed in interstate commerce, in violation of the Federal Food,
Drug, and Cosmetic Act.
Answer 14c. FDA issued the Consumer Health Information for Better
Nutrition Task Force Report on July 10, 2003. The report contained
interim procedures to implement this initiative to make available more
and better information about foods and dietary supplements, to help
Americans improve their health and decrease the risk of certain
diseases by making sound dietary decisions. One of the goals of the
Consumer Health Information for Better Nutrition Initiative is to
encourage makers of conventional foods and dietary supplements to make
truthful and non-misleading, up-to-date, science-based claims about the
health benefits of their products. Two guidance documents pertaining to
procedures to evaluate petitions for qualified health claims were
issued in the Task Force's Report: (1) Interim Procedures for Qualified
Health Claims in the Labeling of Conventional Human Food and Human
Dietary Supplements; and (2) Interim Evidence-based Ranking System for
Scientific Data.
In addition, FDA published an Advance Notice of Proposed Rulemaking
(ANPRM) in November 2003, soliciting public comment on the issues
identified in the Task Force Report, including alternatives for
regulating qualified health claims in the labeling of conventional
human foods and dietary supplements. The consumer research conducted by
FDA is currently being analyzed. Using the consumer research and other
available information, including comments to the ANPRM, FDA will decide
how to proceed with regard to qualified health claims in food labeling.
Question 15a. I understand that the Administration's proposed
budget for 2006 cuts inspections of imported food by 5 percent. The FDA
already inspects a very small percentage of imported foods. Given the
risk of a bioterrorist attack using food identified by Secretary
Thompson, please explain why a reduction in imported food inspections
is prudent.
Answer 15a. The fiscal year 2006 Budget does not reduce field
examinations of imported food. FDA will continue to examine about
93,000 import lines in fiscal year 2006 as well as in fiscal year 2005.
To manage the ever-increasing volume of imported food shipments, FDA is
using risk management criteria to achieve the greatest food protection
with our available resources. While we cannot physically inspect every
shipment, it is important to note that every shipment containing FDA-
regulated products entered through the Bureau of Customs and Border
Protection (CBP's) automated system is electronically reviewed by FDA's
system and those FDA-regulated products requiring further investigation
are identified. FDA's Operational and Administrative System for Import
Support (OASIS) determines if the shipment meets identified criteria
for physical examination or sampling and analysis or warrants other
review by FDA personnel. This electronic screening allows FDA to
concentrate its limited enforcement resources on high-risk shipments
while allowing low-risk shipments to proceed into commerce.
The Public Health Security and Bioterrorism Preparedness and
Response Act of 2002 provided a significant new tool that enhances
FDA's ability to electronically review all FDA-regulated imported
shipments. That law requires that FDA receive prior notice before food
is imported or offered for import into the United States. Advance
notice of import shipments, called ``Prior Notice,'' allows FDA, with
the support of the CBP, to target import inspections more effectively
and help protect the Nation's food supply against terrorist acts and
other public health emergencies. With the new prior notice requirement,
specific information mandated by the Bioterrorism Act must be submitted
to FDA before the imported food arrives in the United States. This not
only allows the electronic system to review and screen the shipments
for potential serious threats to health (intentional or otherwise)
before food arrives in the United States, but it also allows for FDA
staff review of prior notices for those products flagged by the systems
as presenting the most significant risk. FDA worked very closely with
CBP in developing this screening system. FDA receives approximately
27,000 prior notice submissions about incoming food shipments every
day. The Prior Notice Interim Final Rule became effective December 12,
2003. FDA's experience with the prior notice system has been that it
permits FDA to further refine our risk-based targeting and allocate
resources for inspections more effectively.
The fiscal year 2006 Budget requests an increase of $30 million for
food defense activities. Twenty million dollars of this increase will
support a national laboratory network known as the Food Emergency
Response Network (FERN). A critical component of controlling threats
from deliberate food-borne contamination is the ability to rapidly test
large numbers of samples of potentially contaminated foods for a broad
array of biological, chemical, and radiological agents. FERN will
increase our laboratory surge capacity through a nationwide network of
Federal and State laboratories capable of testing the safety of
thousands of food samples, thereby enhancing the Nation's ability to
swiftly respond to a terrorist attack. The additional $10 million will
be used for targeted food defense research, for continued coordination
and sharing of data with the Department of Homeland Security as part of
the governmentwide Bio-Surveillance Initiative, and for upgrades in
FDA's crisis management capabilities.
Question 15b. How do you intend to ensure the safety of the
American public from both intended and unintended contamination of the
food supply?
Answer 15b. Ensuring the safety of the food supply is a top
priority for me and for the Administration. Please see our response to
one of your previous questions about the steps we are taking to protect
the food supply. That response describes some of FDA's many food safety
and defense activities to protect the food supply against intended and
unintended contamination.
______
Response to Questions of Senator Enzi by Lester Crawford, DVM, Ph.D.
Question 1. Dr. Crawford, several months ago, you announced several
changes at the FDA to improve the agency's ability to identify drug
safety concerns. Among the things you announced last year was a study
by the Institute of Medicine of FDA drug safety activities. Would you
please discuss this in more detail? I'd like to know how far along the
study is, how the IOM is involving all the stakeholders, and when you
expect to receive the report.
Answer 1. At our request, an IOM committee will be convened to
examine the current U.S. system for evaluating and ensuring drug safety
post-marketing and to make recommendations to improve risk assessment,
surveillance, and the safe use of drugs. In their proposal to us, IOM
characterized the scope of their study as including the following:
An examination of FDA's current role and the role of other
actors (e.g., health professionals, hospitals, patients, other public
agencies) in ensuring drug safety as part of the U.S. health care
delivery system;
An examination of current efforts for the ongoing safety
evaluation of marketed drug products at the FDA and by the
pharmaceutical industry, the medical community, and the public health
authorities;
An evaluation of the analytical and methodological tools
employed by FDA to identify and manage drug safety problems and make
recommendations for enhancements; An evaluation of FDA's internal
organizational structure and operations around drug safety (including
continuing post-market assessment of risk vs. benefit);
A consideration of FDA's legal authorities for identifying
and responding to drug safety issues and current resources (financial
and human) dedicated to post-marketing safety activities;
An identification of strengths, weaknesses, and
limitations of the current system; and
Recommendations in the areas of organization, legislation,
regulation, and resources to improve risk assessment, surveillance, and
the safe use of drugs.
According to their proposal, IOM will assemble a study committee of
15 experts to develop a consensus report that examines the current U.S.
drug safety system. The lead study committee will draw upon a broader
pool of experts/volunteers through the establishment of two
subcommittees. Subcommittees will conduct data gathering activities to
support the activities of the lead committee. The committee chair and
the IOM staff will determine the focus of expertise of the
subcommittees.
The IOM expects to announce the committee members very soon and is
targeting the first meeting of the committee for April 2005. After the
first meeting, there will be six subsequent meetings of the committee
at 2-month intervals. The IOM has targeted production and release of
their report as 19-20 months from inception of the effort.
Question 2. Dr. Crawford, some have expressed concern about the
authority of FDA to require drug product labeling to include important
information. One of the concerns is that FDA is not able to convince
manufacturers to change their labels in a timely manner. But my
understanding is that if FDA believes a label is false or misleading,
and a company isn't willing to make the necessary changes, FDA can
remove the product from the market. That seems to me to be a
considerable amount of authority. Is it sufficient, and if not, what
additional authority would be needed?
Answer 2. FDA has authority to determine that a drug is misbranded
if its labeling is false or misleading and can seek judicial relief to
mandate changes to the label or take action to remove the product from
the market. The process would normally begin with a warning letter to
the company expressing FDA's position, and the company would have a
chance to respond. Unless the company voluntarily made the changes, FDA
would then pursue judicial relief. Alternatively, for FDA to remove the
product from the market over a sponsor's objections, FDA would consider
whether the risks of marketing the product with false or misleading
labeling outweighed the benefits for the population of patients that
use the product. The risks may not outweigh the benefits for many
drugs. The procedures for removing a drug from the market if the
sponsor does not agree to stop marketing require publication of a
notice and of an opportunity for hearing in the Federal Register, and a
possible administrative hearing if the sponsor demonstrates that there
is a genuine issue of material fact to be decided in a hearing.
Question 3. Dr. Crawford, would you highlight in the President's
Budget the areas where additional resources will be dedicated to drug
safety activities? Specifically what will the additional funds be used
for, in terms of personnel as well as other activities?
Answer 3. In fiscal year 2006, FDA has requested an increase of
$6,500,000 and 28 full time employees (FTE) for the Office of Drug
Safety (ODS). $5,000,000 and 20 FTE of the proposed increase is in
budget authority, and $1,500,000 and eight FTE is in user fees. With
the proposed $6,500,000 increase, FDA will (1) hire eight FTE to
establish policies and processes regarding safety reviews and risk
management; manage communications with the Office of New Drugs; and;
support patient safety initiatives and external partnerships with CMS,
AHRQ, and other HHS Agencies; (2) hire 14 FTE in the 3 operating
divisions of ODS to handle the increased workload of monitoring
biologic therapeutics; increase communication and coordination of
safety review activities within the divisions; and, increase focus on
medical error signal detection and address current backlog of
unaddressed potential signals; (3) hire six FTE to increase staff
dedicated to evaluating and communicating drug safety risks to the
healthcare community and the American Public; and (4) apply funding to
increase access to a wide range of clinical, pharmacy and
administrative databases. As each drug has its own indication(s) that
may result in its differential use in different populations, it is
essential that the CDER have access to a wide range of databases to
assess adequately drug safety. FDA will also increase transparency by
sharing drug safety information sooner and more broadly to enhance
public knowledge and understanding of drug safety issues.
Question 4. Obesity has increased dramatically in this country.
Nearly two-thirds of Americans are overweight, and one-third are obese.
FDA is responsible for regulating the labeling of most packaged foods.
Could you discuss FDA's plans and actions to use that authority to
fight obesity, particularly in children?
Answer 4. There is no simple solution to the problem of obesity.
Achieving success in reducing and avoiding obesity will occur only as a
result of efforts over time by individuals as well as various sectors
of our society. Most associations, agencies, and organizations believe
that diet and physical activity should be addressed together in the
fight against overweight and obesity.
Obesity is a growing and urgent public health problem in the United
States. Today, almost two-thirds of all Americans are overweight and
over 30 percent are obese. To help confront the problem of obesity in
the U.S. and to help consumers lead healthier lives through better
nutrition, in August 2003, FDA created an Obesity Working Group (OWG),
which was charged with preparing a report that outlines an action plan
to cover critical dimensions of the obesity problem from FDA's
perspective and authorities. FDA's ``Calories Count'' report was
released on March 12, 2004.
The OWG report provides a range of short and long-term
recommendations to address the obesity epidemic. For FDA's actions the
emphasis is on calories. Progress to date follows:
We have published two advance notices of proposed
rulemaking (ANPRMs), in response to the recommendations in the OWG
report, seeking comments on the following:
How to give more prominence to calories on the food label,
for example, increasing the font size for calories, including a column
in the Nutrition Facts panel of food labels for percent Daily Value for
total calories, and eliminating the listing for calories from fat. In
addition, the Agency is seeking comment on the reformulation of the
foods or redesign of packaging that may occur if any changes are made
to the food label;
Whether to amend certain provisions of the nutrition
labeling regulations concerning serving size, such as for multiple-
serving packages that may reasonably be consumed in a single eating
occasion.
We continue to encourage manufacturers to take advantage
of the flexibility in current regulations on serving sizes to label as
a single-serving those food packages where the entire contents of the
package can reasonably be consumed at a single eating occasion. We also
continue to encourage manufacturers to use appropriate comparative
labeling statements that make it easier for consumers to make healthy
substitutions. Since release of the OWG report, the Agency, in meetings
with industry, has made a point to encourage manufacturers to take
advantage of the existing flexibility in serving size regulations, and
companies are responding. For example, Kraft Foods is instituting dual
column labeling for all its packaged foods containing 2-4 servings per
package.
FDA continues to encourage restaurants voluntarily to
provide point-of-sale nutrition information to customers, including
calorie information on a nationwide basis.
FDA is also working to develop educational strategies and
partnerships to support appropriate messages and teach people,
particularly children, how to lead healthier lives through better
nutrition. We are starting work with the Girl Scouts of the USA, under
terms of a Memorandum of Understanding signed this past fall, to
provide outreach and education in a science-based initiative to focus
on improving health, nutrition, and physical activity. In addition,
FDA's field offices are participating in local partnerships to reach
and teach children. For example, in Central Florida, FDA's South East
Region is part of the Seminole County Healthy Kids Partnership to
promote positive opportunities for school-aged children in Seminole
County to learn healthy nutrition and the value of increased daily
physical activity.
Also, FDA's Center for Drug Evaluation and Research (CDER) will
continue to work with pharmaceutical sponsors to facilitate development
of effective therapies to address the important public health issue of
obesity and its attendant morbidities. An advisory committee meeting
was held on September 8, 2004 to discuss the draft guidance on Clinical
Evaluation of Weight-Control Drugs. The Agency is working to finalize
the guidance.
We believe that, when implemented, the report's recommendations
will make a worthy contribution to confronting our Nation's obesity
epidemic and helping consumers lead healthier lives through better
nutrition.
Question 5. The Critical Path Initiative is a framework for
bringing together academia, patient groups, industry and government
agencies to create a new generation of performance standards and
predictive tools that will provide faster and more certain answers
about the safety and effectiveness of products in development. In the
FDA Critical Path report issued 1 year ago, it was noted that the
mission of the FDA is not only to protect the public health, but also
to advance the public health by helping to speed innovations that make
medicines more effective, safer, and more affordable.
As Acting FDA Commissioner, Dr. Crawford, you strongly endorsed
this initiative and publicly confirmed FDA's commitment to moving the
initiative forward. What role do you see for the Critical Path
Initiative in successfully addressing the safety issues FDA is
currently facing? Do you have sufficient resources available to
aggressively pursue this initiative?
Answer 5. As you suggest, there is significant synergy between our
efforts to improve drug safety and the Critical Path Initiative. While
it is important that we increase our post-market surveillance of
adverse events, the real goal is to prevent adverse events from
occurring. Safety should be built into medical products from the ground
up. This requires two things. First; we need better predictive science
and tools for product development, so we can identify compounds likely
to be too risky very early in development. Second, we need better tools
for predicting a patient's likely response to a product, so we can
select for treatment only those patients for whom the risks of the
product are likely to be outweighed by its benefits. These are
precisely the kinds of applied science tools that the Critical Path
sciences produce.
For example, new biomarkers that predict toxicity could guide
product sponsors in making better decisions about which potential
products, and which doses, to test in humans. The same biomarkers could
also improve treatment choices after the drug is approved, by helping
identify patients likely to respond adversely to the drug. In short,
many FDA investments in Critical Path efforts will also be investments
in improving drug safety.
Question 6. The reuse of medical devices intended for single use
has grown in frequency over the last decade as hospitals and doctors
attempt to cut costs. I'm concerned that FDA isn't receiving the
critical data necessary to establish whether reprocessed single-use
devices are still safe and effective for further use. What steps do you
plan to take to assure that the FDA collects the necessary scientific
information and enforces the law fully when it comes to reviewing
marketing applications from device reprocessing companies?
Answer 6. In the Medical Device User Fee and Modernization Act of
2003/P.L.107-250 (MDUFMA), Congress specified a detailed process by
which FDA was to re-evaluate previously-cleared reprocessed single use
medical devices (SUDs). In accordance with the intent of Congress, FDA
has expended significant resources to accomplish the following:
Premarket Review
On April 30, 2003, FDA identified certain reprocessed SUDs for
which 510(k)s must now include ``validation data . . . regarding
cleaning and sterilization, and functional performance'' to show that
the devices remain substantially equivalent to predicate devices after
all intended reprocessing. FDA issued a guidance document on July 8,
2003 (revised June 1, 2004), describing the types of validation data
that would satisfy this MDUFMA requirement.
For devices in this category that already had cleared 510(k)s,
validation data (referred to as ``Supplemental Validation Submissions
(SVSs)'') were required to be submitted to FDA by January 30, 2004. FDA
received 44 SVSs for reprocessed SUDs for which the 510(k)s had already
been cleared. This represented approximately 1,800 previously cleared
reprocessed SUDs. Regulatory decisions on all but two of these SVSs
were issued by November 1, 2004 as outlined below.
Fifty-two percent of these devices were determined to be
substantially equivalent (SE) to a legally-marketed predicate device
and may continue to be marketed.
An additional 33 percent of the models were determined to
be Not Substantially Equivalent (NSE) to a legally marketed predicate
device based on the failure to submit supplemental data OR the
submission of inadequate supplemental data to FDA. These devices may no
longer be legally marketed since they are no longer cleared for
commercial distribution in the United States at this time. Reprocessors
of these devices may seek clearance for the subject devices anytime in
the future by submitting a new 510(k) premarket notification to FDA
that satisfies the Agency's premarket requirements including
supplemental validation data.
Approximately 15 percent of previously cleared reprocessed
SUD models were withdrawn by the reprocessor. These devices may no
longer be legally marketed at this time. Also, FDA conducted field
inspections to verify discontinuance of marketing.
In November, 2004, FDA posted, on its website, the status of
previously-cleared, reprocessed SUDs that were subject to supplemental
validation data requirements described above. This allows hospitals and
other interested parties to verify the status of reprocessed devices
for use in their facilities. The website includes lists of devices
found to be Substantially Equivalent based on a review of the
supplemental data. These devices appear under the heading of ``Legally
Available.'' In addition, the website lists those devices which may no
longer be legally marketed because supplemental data were required but
not received, subject 510(k)s were withdrawn by the sponsor, or
supplemental data were determined by FDA to be inadequate. These
devices are listed as ``No Longer Legally Marketed.''
On April 30, 2003, FDA also published a list of ``critical''
reprocessed SUDs whose exemption from premarket notification
requirements was terminated. Reprocessors of the devices on this list
were required to submit 510(k)s, including the types of validation data
described above, by July 30, 2004. No reprocessors of the critical
reprocessed SUDs provided any submissions. FDA will conduct follow-up
inspections to verify that the firms have stopped marketing these
reprocessed devices.
On April 13, 2004, FDA published a list of ``semi-critical''
reprocessed SUDs whose exemption from premarket notification
requirements was terminated. Reprocessors of the devices on that list
are required to submit 510(k)s, including validation data, by July 13,
2005.
MDUFMA created a new type of premarket submission, a ``premarket
report'' (PMR), for reprocessed SUDs that otherwise would have required
premarket approval applications. Among other items, a PMR must include
data on reprocessing procedures, such as validation data regarding
cleaning, sterilization, and functional performance.
Adverse Event Reporting
In accordance with MDUFMA, FDA revised the mandatory and voluntary
MedWatch report forms to incorporate the reporting of information on
incidents related to reprocessed SUDs. FDA posted the revised forms on
the MedWatch website in October 2003, along with revised instructions
for mandatory reports, and, in early 2004, published a Federal Register
notice announcing the availability of the revised MedWatch forms.
Inspections/Enforcement
Since MDUFMA was enacted, FDA has inspected over 150 third-party
reprocessors and hospitals engaged in reprocessing. As a result of the
information collected, CDRH's Office of Compliance has issued two
Warning Letters (to a hospital and a third-party reprocessor).
In fiscal year 2004, FDA inspected over 100 U.S. hospitals and
found none currently reprocessing single use devices. FDA has also
issued an inspection assignment in fiscal year 2005 for five firms that
reprocessed SUDs to ensure that they have discontinued marketing of the
devices that were NSE. The five inspections have just been completed
and inspection reports are being prepared.
Next Steps
FDA will continue to review submissions for reprocessed single use
devices as they are received. FDA has received comments on the lists of
critical and semi-critical reprocessed SUDs whose exemption from
premarket notification requirements was terminated, and we are
currently reviewing these comments. Finally, FDA will continue to
inspect reprocessors as appropriate and will inspect new hospital or
third-party reprocessors as they are identified.
Question 7a. Please update us on the steps FDA has taken to improve
the situation with regard to vaccine supply, especially in light of
last year's flu vaccine shortage. Specifically, what changes are you
making in terms of inspections of foreign facilities, communication
with foreign regulatory authorities, etc.?
Answer 7a. Recent experiences, particularly those of the past 7
months, have taught us important lessons about manufacturing and
inspectional activities with respect to influenza vaccine. Although FDA
has always interacted extensively with influenza vaccine manufacturers
throughout the vaccine production cycle, the annual changes in the flu
vaccine and the increased dependence on a smaller number of
manufacturers highlight the risks of unexpected manufacturing
difficulties. For these reasons, in 2005 and the future, we plan to
conduct inspections of influenza vaccine manufacturers on an annual
basis, with additional interactions with manufacturers and, in the case
of foreign facilities, their regulatory agencies where appropriate,
based on findings or events that raise concerns.
FDA is working with manufacturers and its regulatory counterparts
in anticipation of having an ample supply of influenza vaccine for the
coming season through a dual-track strategy.
FDA's first track is to facilitate Chiron's effort to correct its
manufacturing problems. FDA and MHRA, the British regulatory agency,
have an agreement with Chiron that allows full information sharing. FDA
has used that agreement to collaboratively review Chiron's remediation
plans and activities, and the Agency is providing continuing and
extensive feedback to both Chiron and MHRA. In addition, FDA signed an
information sharing agreement with MHRA that will, among other things,
permit advance communication on important issues. The agreement was
effective February 14, 2005.
FDA is actively communicating on inspection activities. Only after
passing MHRA and FDA inspections will Chiron be able to provide vaccine
to the U.S. market. In the spring when critical stages of manufacturing
are taking place, the Agency plans a comprehensive inspection to verify
whether Chiron has adequately addressed its problems. While much work
remains to be done, it appears that Chiron is making progress.
FDA's second track is to facilitate overall greater capacity and
diversification in the U.S. influenza vaccine supply. It is important
to recognize that the demand for vaccine and other economic issues are
the primary factors that determine whether a manufacturer will seek and
maintain a license in this country.
CDC and FDA are working to encourage vaccination throughout the flu
season, including January and February. To increase the total doses
available, manufacturers can produce vaccine over a longer time period,
and that becomes available during these months. Because influenza cases
usually continue well after November and December when most people are
seeking immunization, later vaccination is beneficial. The Public
Health Service is working to better communicate this important public
health message.
In addition, FDA has been working to stimulate manufacturers not
licensed in the U.S. to provide or, where needed, develop the safety
and effectiveness data to obtain U.S. licensure. The Agency has
actively engaged several interested companies. FDA has informed
manufacturers that the Agency is willing to consider all approaches to
licensing, including accelerated approval based on surrogate markers,
e.g., the patients' immune response to the vaccine. Sanofi Pasteur and
Medlmmune have indicated their willingness, if needed, to do what they
can to increase production.
FDA has challenged itself to identify other lessons learned from
this year's influenza season and is evaluating how this experience
could be used to prevent similar events in the future. While there are
some elements that FDA cannot control, the Agency is making significant
changes. For example, as mentioned above, FDA plans to conduct
inspections of influenza vaccine manufacturers on an annual basis, and
the Agency is completing or has completed agreements that allow
information sharing with numerous foreign regulatory agencies.
Question 7b. Please describe what you are doing to ensure that we
won't have a major shortage situation on an important vaccine again
this year.
Answer 7b. FDA is working with manufacturers and our regulatory
counterparts in anticipation of having an ample supply of influenza
vaccine for the coming season. Details on FDA's approach to assuring
adequate supply are in the response above.
Question 8. I understand that the FDA relies on advisory panels in
making important decisions about new drugs and medical devices.
Although the panels' recommendations are not binding, FDA typically
follows advisory panels' recommendations an extremely high percentage
of the time.
What is the standard FDA uses to determine whether to accept or
reject the recommendations of advisory committees? Does the failure by
the agency to follow a recommendation undermine the advisory committee
process?
Answer 8. Advisory committees at the Food and Drug Administration
(FDA or the Agency) are designed to offer a wide range of views on
topics that are discussed in a public forum and to be advisory in
nature. FDA seeks and appreciates the recommendations made by the
committees. The final determination on a drug application, however,
remains by law with the Agency. Although the Agency frequently makes
final decisions concerning a new drug application (NDA) that are
consistent with an advisory committee's recommendations, FDA is not
bound to follow their recommendations. Ultimately, a final decision is
based on FDA's evaluation of the data, taking into account all of the
views expressed.
The agency poses questions to its advisory committee members to
obtain expert scientific advice. Often, the committee is used to obtain
highly technical information that is not available in-house. At other
times, the committee is asked to consider a scientific question that
has opposing views in the scientific world. The committee discusses the
issue in a public forum. Based on the data and/or advice presented, the
Agency scientists evaluate the advice in the context of the rest of the
product application (some aspects of which may not be publicly
disclosed due to confidentiality requirements). Non-acceptance of an
advisory committee recommendation does not undermine the agency
process, but rather supports it. The value of the advisory committee
process is not limited to the final recommendation of the panel. The
process itself, in which the Agency obtains additional scientific
information and comment by the Nation's experts and the public in a
open forum provides the Agency with invaluable scientific information
and increases credibility in the Agency's decision making process.
Question 9. I am sure you would agree with me that it is essential
that the Agency's advisory panels be free of conflicts of interest and
that any potential conflicts of interest be disclosed. What does FDA do
now to ensure against conflicts of interest on its advisory committees?
And, in light of recent criticism about potential conflicts of
interest, what will you do as Commissioner to further ensure that
decisions made by advisory committees are not influenced by committee
members' outside activities?
Answer 9. It is very difficult to obtain qualified advisory
committee panel members who are totally free from all potential
financial conflicts of interest. The Nation's experts (and in some
cases, there are only a few experts on a particular topic) are sought
after for consultation by both the Agency and industry because of the
scarcity, and therefore the value, of their expertise. Utilizing less
experienced or less highly qualified scientists in order to completely
remove any potential conflict from the committee would hamper the
Agency's ability to protect and advance the public health.
The Agency's staff examines all potential financial interests. The
Agency's process is to evaluate the potential financial interests of
members and other invited special government employees. FDA makes a
determination as to whether the participation of an individual with
some financial ties outweighs the need for the agency to understand the
science on the topic before the committee. Although the Agency has
guidelines for this process (see Waiver Criteria Document 2000 on the
FDA web page), this is not a black and white process. It requires
careful consideration of all facets of the issue in order to evaluate
that balance. Congress, by permitting waivers for potential conflicts
of interest, has ensured that the Agency and the public (through the
advisory committee process) have access to the most knowledgeable
individuals on the meeting topic.
FDA's process of evaluating potential committee members for
conflicts is very extensive and transparent. Our methodology is
articulated in an extensive document on the agency's website (http://
www.fda.gov/oc/advisory/conflictofinterest/intro.html). At the
beginning of each meeting, a conflict of interest statement is read
into the record, which summarizes the results of the conflicts of
interest screening. FDA has been commended by the Office of Government
Ethics (1997) for serving as ``a model for other Agencies to use in
developing their own systems and procedures.'' Nonetheless it is always
prudent to regularly assess the Agency program and determine if any
improvements are warranted. In the near future, the Agency will review
the advisory committee conflicts of interest disclosure process and
consider if further improvements are necessary to make the disclosures
more easily accessible to the public.
Question 10. Dr. Crawford, I understand that FDA has recently begun
a review of its citizen petition process. The FDA proposed changes in
1999 to make the process more efficient and responsive, partly in
response to an HHS Inspector General audit. However, FDA withdrew the
proposed changes in 2003, saying that FDA had improved its handling of
citizen petitions over the past several years and that the 1999
proposed rule was no longer necessary. I am concerned that FDA still
frequently fails to meet the requirement to respond to citizen
petitions within 180 days. What is FDA doing to be more responsive to
citizen petitions?
Would you provide the committee with an assessment of how many
petitions were pending at FDA as of September 30, 2004; how many of
these petitions had been pending for more than 180 days without a
tentative response; how many of these petitions had been pending for
more than 180 days without a final response; and how these figures
compare to those from the 5 previous years?
Answer 10. FDA receives several different types of citizen
petitions. Some statutory/regulatory mechanisms contemplate the
submission of citizen petitions to initiate an action by the Agency. As
a consequence, petitions may be tracked and handled by the Agency
through different mechanisms. For example, FDA's Center for Drug
Evaluation and Research (CDER) receives petitions relating to over-the-
counter drugs or ``suitability'' petitions in which a person wants to
submit an abbreviated new drug application (ANDA) for a drug product
that will differ from the reference listed drug in route of
administration, dosage form, or strength, or to substitute an active
ingredient (see 21 CFR 314.93). As of September 30, 2004, excluding
these two categories of petitions, CDER had 126 pending citizen
petitions. Thirty-nine of these 126 petitions raised regulatory or
scientific issues related to approval of a generic drug. Of the 126
pending petitions, 93 were pending for longer than 180 days. Of the 39
petitions related to a generic drug approval, 21 were pending for more
than 180 days. We believe virtually all of the petitions that were
pending more than 180 days received an interim response. Many of the
petitions pending for more than 180 days involved complex scientific
questions. Petition responses almost always require review and input
from scientists in at least one program division; these scientists are
also responsible for reviewing new drug applications.
Citizen petition submissions to some of our Centers have increased
in recent years. For example, CDER has experienced approximately a 50
percent increase in the number of citizen petitions received in CY 2004
over CY 2003. For fiscal year 2004 CDER received a total of 62 citizen
petitions (of which 27 raised issues related to generic drug
approvals). Although we issued final response letters for 55 citizen
petitions (of which 19 concerned issues raised about generic drug
approvals) in fiscal year 2004, we did not keep up with the increasing
number of citizen petitions filed. As a result, our backlog of pending
petitions increased. We are currently examining ways to improve the
citizen petition process and to reduce the backlog.
In an effort to provide as responsive a reply as possible given the
exigencies of time, we have focused our answer on citizen petitions
relating to drugs. If you are interested in additional data regarding
citizen petitions more generally or a specific type of citizen
petition, we would be happy to provide additional information. Our
records on petitions are not kept in a manner that allows for rapid
generation of comparisons over a 5-year period; but we will work with
your staff to provide responsive data by the end of the month.
Question 11. In the past, the Food and Drug Administration has
expressed concern about the importation of prescription drugs from
foreign countries. Agency officials have also reported that many drugs
obtained from other countries that appear to be U.S. approved are of
unknown quality. Could you describe some of the activities FDA would
need to conduct to ensure the safety of the drug supply and the kinds
of resources and personnel it would need if importation is legalized?
What amount of additional funding and/or personnel would the FDA need
to insure the safe commercial importation of drugs, and would personal
importation require more or fewer resources?
Answer 11. Reimported and imported foreign medications are
currently outside the regulatory system overseen by FDA and State
Pharmacy Boards. Therefore, it is very difficult for a consumer to tell
if they are getting a medication that meets FDA's strength, quality and
purity standards. We have confiscated a significant amount of
suspicious packages from foreign sources, many which have contained
drugs that don't meet FDA standards. As the government agency
responsible for the safety and efficacy of medications, we are greatly
alarmed that these drugs are bypassing established safeguards and
finding their way into the system.
The drug distribution network for legal prescription drugs in the
U.S. is a ``closed'' system that involves several entities (e.g.,
manufacturers, wholesalers, pharmacies) that move drug products from
the point of manufacture to the end user, and helps safeguard against
receiving unsafe, ineffective, or poor quality medications. All of
these entities are known and subject to Federal and State regulatory
and legislative oversight. This system evolved as a result of
legislative requirements that drugs be treated as potentially dangerous
consumer goods that require professional oversight to protect the
public health. The result has been a level of safety and efficacy for
drug products that is widely recognized as the world's ``gold
standard.''
In February 2004, HHS announced the creation of a Task Force to
study the importation of drugs. In December 2004, HHS released the
results of this study and the Task Force's findings that concluded:
It would be extraordinarily difficult and costly to ensure
that personally imported drugs are safe and effective;
Commercial importation could be feasible, but would
require, among other things, additional safety protections and
substantial resources;
National savings from a legalized commercial importation
program will likely be a small percentage of total drug spending;
Importation would reduce the development of new medicines.
The forgone benefits to consumers from not having access to new
medicines could significantly offset the savings from legalized
commercial importation.
To maintain current levels of safety, the standards that currently
exist in the United States (or some equivalent) would need to apply to
all foreign drug suppliers under a commercial importation program.
Legalized importation of drugs in such a way that creates an opening in
the ``closed'' system will likely result in some increase in risk, as
the evidence shows that weaknesses in the oversight of drug regulation
and the distribution system have been exploited. Furthermore, the
volume of packages entering the United States today has been increasing
at a steady rate. Under a personal importation program, it would be
very difficult to distinguish which of these millions of packages are
from ``permitted'' internet pharmacies and which are from rogue
websites, increasing the potential safety risks associated with
imported drugs.
It would take significant resources and new authority to enhance
current FDA procedures to ensure that imported and reimported drugs are
both safe and effective. The amount of resources needed would vary
greatly depending on the specifics of the authorizing legislation.
Question 12a. We have been talking a lot about how to ensure drug
safety over the last few months, but some of the people affected by FDA
decisions tell us there is a real and perhaps even more lethal danger
if we over-react in ways that slow the development, approval and
availability of new treatments for diseases like cancer, Parkinson's
Disease, Alzheimer's, Multiple Sclerosis and a host of more rare, very
serious and often terminal diseases. The COX-2 inhibitor drugs, for
example, are primarily approved for pain relief and to reduce
inflammation, conditions that can be life-limiting but that are not
usually life threatening. There also are treatment alternatives to COX-
2 inhibitors, so they should be held to a rigorous safety standard for
marketing, have accurate and up to date labeling, and be prescribed
only to those who need them based on consideration of a reaasonable
evaluation of risk versus benefit. However, it seems obvious that
patients with advanced lung cancer, colon cancer or Parkinson's Disease
face much more serious and certain risks from disease than does, for
example, a middle-aged golfer dealing with arthitis who is trying to
get in a pain-free round of weekend golf?
Could you share with us your thoughts on how we can best weigh
risks and benefits to serve these very different patients--one who
seeks medical care to relieve the limiting but comparatively minor
symptoms of a non-life-threatening condition like arthritis or
tendonitis, and another who is trapped in a life and death struggle
against a disease that has failed to adequately respond to approved
therapies?
Answer 12a. Benefit-risk considerations always take into account
the severity of the disease involved, the alternative treatment
available, and the nature and magnitude of the benefit of the new drug
compared to alternatives. Historically, cytotoxis drugs for cancer
treatment, for example, have been uniformly more toxic than would be
tolerated in other theraputic areas, with toxicity to bone marrow,
neurologic toxicities, candiac toxicities, ability to promote life-
threatening infection, and a wide range of other serious toxicities
that are at best debilitaing and at worst lethal. These are acceptable
if the drug provides benefit to patients with cancer because there are
in many cases no alternative and the disease being treated is lethal.
Other areas where significant toxicity is accepted include, but are not
limited to, treatment for AIDS, serious fungal infections, organ
rejection, sepsis, acute respiratory distress syndrome, and other
severe, chronic degenerative diseases.
On the other hand, with many well tolerated drugs to lower
cholesterol or blood pressure, a new drug for these purposes that was
more toxic than the available drugs would ordinarily not be approved
(or could be withdrawn) unless it could treat a resistant population
(whose risk of death would make the extra risk of the drug acceptable).
Some years ago, a new drug for Alzheimer's Disease that was no more
effective than available drugs but caused a high rate of severe
vomiting was rejected because on risk-benefit considerations it was
clearly worse than available alternatives. Had a study shown that it
was effective in people who could not respond to alternatives, a
different conclusion might have been reached. Newly available drugs can
make a previously acceptable drug unacceptable. The hepatotoxicity of
troglitizone was considered (by FDA and an advisory committee)
acceptable for certain diabetic patients until two pharmacologically
similar drugs (rosiglitizone and pioglitizone) without this toxicity
became available. Troglitizone was then withdrawn.
FDA reviewers are very conscious of the need for treatments for
conditions with no therapy and for disease that fails to respond to
available treatments and regularly weigh the benefits of treatment
against even significant toxicity. These considerations are in some
ways easiest if the diseases are lethal, but they are also critical if
diseases are life-damaging in other ways--crippling arthritis,
neurologic diseases, or mental illness, for example. Reviewers
recognize that patients with such diseases may be willing to accept
significant risks. It is critical to be sure the risks have been well
studied and described, and that drug labeling describes the risks and
benefits candidly. Even in these cases, however, there is a judgment to
be made, deciding whether the desirability of more safety data
outweighs the need for a new effective treatment. It is cases like
these that are regularly brought before outside advisory committees,
especially where the acceptability of the risk is a close judgment.
Question 12b. Among your priorities last year was writing and
issuing a draft regulation clarifying the Agency's policies on the
conditions that apply when a drug company wants to make its promising
investigational drugs available to dying and seriously ill patients.
You identified it as a priority in several of your speeches. These
programs are sometimes called compassionate use or expanded access, and
in this new regulation they are going to be called ``Treatment Use''
programs. Patients dying from terminal diseases think this regulation
should be among the FDA's highest priorities. What is the status of the
Treatment Use regulation and when will the draft regulation be
published in the Federal Register?
Answer 12b. The draft regulation is currently in the Agency
clearance process. Once it has received Department and OMB clearance,
we will publish it in the Federal Register.
Question 13. What are your thoughts on the potential for
cooperation between the FDA, NIH, CDC and CMS in moving the entire drug
development, approval and delivery of new therapies to patients
forward? For example, should there be some kind of a joint chiefs of
staff in the war on cancer and coordination at other levels between
those organizations? How can FDA, for example, participate and
contribute to NCI Director Dr. Andrew Eschenbach's goal of eliminating
suffering and death from cancer by 2015. What can we do right now to
make that coordination happen?
Answer 13. FDA and NIH recently announced the first major program
stemming from our two Agencies' collaboration in the Interagency
Oncology Task Force (IOTF). Staff from both Agencies continue to work
jointly in other major areas under the IOTF umbrella that will be
crucial to fostering the new age of medical products to conquer cancer,
including nanotechnology, surrogate markers of clinical benefit, and
chemoprevention.
Though FDA and the National Cancer Institute (NCI) have distinctly
separate missions, they share a common goal in the fight against
cancer. NCI's mission is one of basic and clinical research to foster
discovery and development of new medical products and FDA's mission is
to assure the safety, efficacy, and quality of manufacturing of new
medical products prior to marketing. Part of FDA's responsibility is to
ensure that basic discoveries turn into new and better medical
treatments. Our close collaboration with NCI through the IOTF is an
important step in joining the mission of the two agencies to produce a
seamless process for speeding new technologies to cancer patients. FDA
and NCI are implementing a Research and Regulatory Review Fellowship
Program as a critical first step in developing a knowledge base that is
built not just on ideas from biomedical research but on reliable
insights into the pathway to marketed products for use in patients.
There is no better way of learning about the problems inherent in
developing innovative products than to participate actively in the
regulatory review process. Clinicians and scientists who are selected
for these fellowships have a unique opportunity to spend from 1-3 years
at the FDA to work with, and be mentored by, experienced FDA reviewers
and researchers. They will be able to watch product development
programs succeed and fail and, in the process, to learn to recognize
the characteristics of successful product development. They will then
be able to take this knowledge of regulatory requirements back to their
home institutions and incorporate it into their research on new cancer
treatments from the earliest stages thus enhancing the likelihood of
success.
FDA looks forward to our close collaboration with NCI in this
important training initiative, and believes that this investment will
benefit the fellows, the partnered agencies, and the American public
through more efficient use of public resources.
Question 14. In March 2004, the FDA issued a major report
``Innovation or Stagnation? Challenge and Opportunity on the Critical
Path to New Products.'' This report led to the Critical Path
Initiative, which has been embraced by patients, industry and doctors.
Identification of biomarkers and creation of new surrogate endpoints
offer the promise of increasing the sensitivity of clinical trials both
for efficacy and occurrence of adverse events. Could you describe the
FDA's efforts to work with industry to identify relevant biomarkers and
validate surrogate endpoints? Could you describe collaborations that
you anticipate the FDA will participate in with other government
agencies and academia to identify biomarkers and surrogate markers?
Answer 14. A key step in FDA's efforts to facilitate development of
a robust biomarker infrastructure for product development will be
publication this spring of the 2005 National Critical Path Challenges
List. The list will include a description of the science needed to
speed biomarker identification and validation, as identified by our
stakeholders (industry, patient groups, academic researchers, and
others) through our outreach efforts over the past 12 months.
FDA's role in the work called for in this National List will vary.
In some cases, no FDA involvement will be needed. In other cases, FDA's
most important role will be to clarify regulatory expectations for the
new science. For example, FDA clarification of the level of scientific
evidence necessary to qualify biomarkers for a particular purpose could
free innovators to undertake the science needed to validate biomarkers
in their product areas. In other cases, FDA will need to be a partner
in undertaking the necessary science. Modernizing the Critical Path is
a national challenge. It will take the combined efforts of industry,
government, patients, and academia to create the robust biomarker
infrastructure we need for efficient development of safe medical
products.
We are exploring potential collaborations with several government
agencies (where our missions converge) and academic institutions to
work on modernizing the Critical Path sciences. Some of these may
involve biomarker development, but to date specific projects have not
been identified. It is not yet clear which potential partnerships will
come to fruition.
Some work in this area is already underway. For example, we are
already working with the National Institutes of Health on developing
new imaging techniques for identifying, validating, and measuring
biomarkers for certain cancers.
Question 15. Manufacturers that commercialize diagnostic laboratory
tests must comply with FDA regulations, including those on
manufacturing practices, quality systems regulations, and adverse event
reporting. However, diagnostic tests developed in-house by laboratories
(``homebrew'' tests) have not been required to comply with FDA
regulations. There has been a proliferation of homebrew tests
(particularly in the area of genetic tests) that have little regulatory
oversight. How will you address the potential public health concerns
raised by this growing number of non-FDA regulated tests?
Answer 15. Most genetic tests are currently offered commercially as
laboratory testing services (so-called ``in-house'' or ``home brew''
tests). FDA does not directly regulate these testing services. The
laboratories that conduct the tests are subject to oversight under the
Clinical Laboratory Improvement Amendments of 1998 (CLIA). Commercially
marketed reagents used by laboratories to create in-house tests are
subject to FDA regulation as analyte specific reagents (ASRs) to ensure
that they are made consistently over time according to the quality
system regulations and to ensure proper labeling.
In 1997, FDA published a rule setting forth its approach to
regulating ASRs. This rule provided incremental regulation of ``in
house'' tests by placing requirements on the building blocks (the
analyte specific reagents) used to make these tests. These include
requirements to register and list with FDA, make reagents following the
quality system regulation, report adverse events, and restrict use of
reagents to labs holding certificates that permit them to perform high-
complexity tests under CLIA.
Although the ASR rule has provided a level of complementary
oversight to that provided by CLIA, FDA has become aware of increased
instances in which manufacturers appear to circumvent the ASR rule by
marketing ASR kits that are really complete tests rather than building
blocks to be validated in laboratory developed tests.
CDRH's Office of In Vitro Diagnostics (OIVD) continues to foster
new genetic technology through development of collaborative guidance
with CDER and CBER, and to work with the Clinical and Laboratory
Standards Institute on developing standards for these tests. OIVD is
actively encouraging companies and laboratories that are developing
genetic tests to consult with the Agency about appropriate FDA
oversight for those that will be marketed to health care providers and
lay users.
On December 23, 2004, FDA cleared the AmpliChip Cytochrome P450 for
marketing. This new laboratory test system is the first to use the
patient's own genetic information to help physicians better determine
which drugs and doses to prescribe for the patient for a wide variety
of common conditions such as cardiac disease, psychiatric disease, and
cancer. This test is the first DNA microarray test to be cleared by the
FDA, and its clearance paves the way for similar microarray-based
diagnostic tests to be developed in the future. FDA cleared the test
and the scanner based on results of a study conducted by the
manufacturers of hundreds of DNA samples as well as on a broad range of
supporting peer-reviewed literature. FDA's review of this test provides
independent evaluation of its clinical validity, which is the goal of
many proposals seeking greater oversight of genetic testing.
Question 16. The scientific and medical community, as well as
regulatory authorities, acknowledges there are many scientific and
legal issues impacting the regulation of follow-on or ``generic''
biologics. Some say the science is not yet ready to allow for a safe
approval process for generic biologics, and others are concerned about
what such a policy would mean for the intellectual property interests
of innovator companies. In light of these concerns, what are your views
on the legal and scientific appropriateness of approving follow-on
biologics? What would be a suitable level of evidence required for
establishing safety and effectiveness? Do you think FDA has the legal
authority to regulate follow-on biologics, either under 505(b)(2) of
the Food Drug & Cosmetic Act or under the Public Health Service (PHS)
Act?
Answer 16. As you know, FDA is conducting a public process to
examine the many questions, including scientific and legal issues, that
must be answered regarding these products and to ensure that all
interested parties have an opportunity to comment. When this process is
complete, FDA intends to provide guidance to industry to clarify,
consistent with its legal authority, the approval pathway and
principles for review of such products, which will protect the public
health.
In recent years--and with increasing frequency--questions about
generic or follow-on proteins have arisen in response to scientific
advances, impending patent expirations, and the ability to better
characterize and understand biological products.
Acknowledging scientific and legal limitations in this area, yet
also recognizing the public health need to move forward to assist
industry and make more products available to the public, FDA is
conducting a public process to examine the scientific, and related
issues regarding follow-on biologics. This process will ensure that
scientific considerations and issues related to Agency authority are
fully examined and that all interested parties have an opportunity for
input.
Question 17. Dr. Crawford, some have suggested a kind of
``isolation'' of drug safety evaluations from medical review and drug
approval activities. We heard from Dr. Woodcock in testimony a couple
of weeks ago that complete isolation of the two functions is not a good
idea, because the people who know the most about a product are the
medical reviewers who recommended its approval. As you establish a new
drug safety board outside of the drug review function, how are you
going to ensure that there is appropriate consultation with the medical
reviewers who are experts about a product when this board is looking at
safety questions about that product?
Answer 17. The Drug Safety Oversight Board is being established to
provide independent oversight and advice to the Center Director on the
management of important drug safety issues and to manage the
dissemination of certain safety information through FDA's Website to
healthcare professionals and patients. Individuals on the Board who
have been involved in the primary review of the data for a particular
drug or who were the signatory for a regulatory action under
consideration will be recused from the Board's evaluation and decision-
making for that drug. This does not mean that they will be excluded
from participation in Board meetings. The medical reviewers most
familiar with the issues will routinely present information to the
Board because they are most knowledgeable about the specific drugs.
Question 18. Dr. Crawford, as you are aware there has been
tremendous growth in broadcast Direct-to-Consumer advertising of
prescription drugs since 1997. This growth is due in large measure to
the FDA having issued draft guidance in 1997 clarifying its regulation
regarding the way in which risk information could be communicated to
consumers. The guidance issued described an approach whereby consumers
could have the benefit of television and radio prescription drug
advertising while also ensuring consumer access to the advertised
product's approved labeling through a toll-free telephone number, a
website address, a concurrently running print advertisement, and health
care professionals. Despite my concern about the usefulness of some of
the DTC ads I have seen of late; on balance, I believe the guidance
issued was appropriate.
I am concerned, however, that all too often, product sponsors do
not use DTC advertising to help raise disease awareness, facilitate
more informed and more meaningful discussions between physicians and
patients, and/or to educate patients about various treatment options
and the risks associated with those options. Rather, consumers are all
too often bombarded with ads that make light of a disease and/or
minimize the therapy risks. Responsible direct to consumer advertising,
I believe, should inform and educate patients about treatable
conditions and available therapies.
Do you generally believe in the merits of DTC advertising and in
its role in educating and empowering patients? And if so, the question
then becomes how to ensure consumers get the best of DTC advertising?
Answer 18. FDA believes consumer-directed advertisements can play
an important role in advancing the public health by encouraging
consumers to seek treatment of diseases that may be under-treated and
diseases for which patients may not be aware of treatment options. We
have conducted research that confirms that DTC advertising, when done
correctly, can serve positive public health functions, such as
increasing patient awareness of diseases that can be treated, and
prompting thoughtful discussions with physicians that result in needed
treatments being prescribed often, not the treatment in the DTC
advertisement. Results of our research shows that many physicians
believe that DTC can play a positive role in their interactions with
patients and that many physicians thought that DTC ads made patients
more involved in their healthcare.
In February 2004, we issued three draft guidance documents,
addressing: (1) consumer-friendly options for presenting risk
information in consumer-directed print advertisements for prescription
drugs; (2) criteria FDA uses to distinguish between disease awareness
communications and promotional materials; and, (3) a manner in which
restricted device firms can comply with the rules for disclosure of
risk information in consumer-directed broadcast advertising for their
products.
FDA adopted a comprehensive, multi-faceted, and risk-based strategy
for regulating consumer-directed advertising of medical products, which
emphasizes the use of warning letters, untitled letters, development of
guidance that facilitate voluntary compliance, frequent informal
communications with industry and advertisers, and research on the
public health effects of consumer-directed promotional materials.
At FDA, CDER's Division of Drug Marketing, Advertising, and
Communications (DDMAC) is responsible for regulating prescription drug
promotion. DDMAC's mission is to protect the public health by helping
to ensure that prescription drug information is truthful, balanced, and
accurately communicated. This is accomplished through a comprehensive
surveillance, enforcement and education program, and by fostering
optimal communication of labeling and promotional information to both
health care professionals and consumers.
While we believe the survey results discussed above confirm our
belief that DTC ads help increase patient awareness about the
availability of effective treatments for their health problems, we will
continue to ensure that, consistent with the law, our DTC policies help
prevent potential misperceptions about benefits and risks of the
advertised treatment and promote the importance of prescribing
decisions being made with the intervention of a health care
professional.
Question 19. The label (or package insert) is an important part of
the FDA regulatory process. It is used to provide important information
to patients and providers about drug action, indications for use,
contraindications and side effects and drug dosing. Physicians have
expressed concern that the label does not perform its intended function
very well and have advocated for new guidance. Is the current package
insert format adequate to convey risks and benefits to patients and
providers? Is the information contained in the package insert the most
useful to patients or providers? When will FDA issue new guidance on
the package insert?
Answer 19. FDA agrees that the current package insert format is
inadequate and has embarked on a major initiative to improve it. In
recent years, there has been an increase in the length, detail and
complexity of prescription drug labeling, making it harder for health
care practitioners to find specific information and to discern the most
critical information in product labeling. In the Federal Register of
December 22, 2000 (65 FR 81082), FDA issued a proposed rule to revise
its regulations governing the content and format of labeling for human
prescription drug products. Prior to issuing the proposal, the Agency
evaluated the usefulness of prescription drug labeling for its
principal audience to determine whether, and how, its content and
format could be improved. The Agency used focus groups, a national
physician survey, a public meeting and written comments to develop
multiple prototypes and to ascertain how prescription drug labeling is
used by health care practitioners, what labeling information
practitioners consider most important, and how practitioners believed
labeling could be improved. The Agency developed a prototype based on
this accumulated information as the model for the proposed rule. FDA
received many comments on the proposed rule and is working to finalize
it. Publication of this rule will be accompanied by publication of four
implementing guidance documents.
Question 20a. The FDA currently has a two-part warning system to
identify adverse drug events resulting from the use of drugs already
approved for marketing: post-market studies; and the AERS system of
voluntary reporting. Some feel that this system is too expensive,
cumbersome and slow to protect the public health.
Answer 20a. The warning system actually has three parts. First,
there is the AERS system that is excellent at picking up rare adverse
events rapidly. The principal burden and costs of collecting and
reporting data included in this system are assumed by drug companies,
but the considerable cost of maintaining the system, receipt and triage
of reports, coding, data entry, quality control, and distribution of
information is borne by FDA. Second, there is the current Office of
Drug Safety cooperative agreement program of population-based resources
for conducting observational epidemiology studies. These are generally
used to validate and quantify safety signals found in AERS or to
examine the impact of regulatory efforts to improve safety; they have
hardly any application in detecting safety problems de novo. Population
based studies can inform suspected drug safety problems, but only if
the product has had extensive use. Third, there are post-marketing
studies done by manufacturers, either as a condition of approval for
products approved under 21 CFR 314 Subpart H, or under 21 CFR 601
Subpart E, or voluntarily at the request of FDA or by the company's
choice. In general, if FDA suspects that there may be a significant
safety problem with a drug product, FDA will take immediate action
rather than wait for a post-marketing study to be designed and
completed. In the case of Vioxx, Celebrex, and Bextra, FDA guided the
companies' pursuit of new efficacy indications in a way to clarify
safety concerns that were either in product labeling or uncharacterized
for other members of the product class.
Question 20b. Is there any evidence that drug manufacturers have
been less than forthcoming in informing FDA in a timely fashion of
adverse drug events?
Answer 20b. The vast majority of pharmaceutical firms comply with
the regulations at 21 CFR sections 310.305, 314.80, 314.98, and
314.540, which require reporting of serious and unexpected adverse
events within 15 days of initial receipt of the information and the
submission of periodic adverse (drug) experience reports quarterly for
the first 3 years after the application is approved or the license is
granted and annually thereafter. Compliance with these regulations is
assessed during field inspections conducted by the Office of Regulatory
Affairs.
Question 20c. Do you believe new types of post-marketing studies,
Phase IV randomized, controlled clinical trial, are indicated to
identify adverse events and improve safety?
Answer 20c. What you describe are not technically ``new types'' of
post-marketing studies, but the third category described at the
beginning of our response. As part of its approval of an initial
NDAIBIA application or supplement under 21 CFR 314 Subpart H or 21 CFR
601 Subpart E, FDA can require pharmaceutical firms to conduct
additional studies during Phase IV. FDA can otherwise encourage
companies to conduct additional studies on a case-by-case basis, but
these requests are infrequent and again, not the primary mechanism by
which FDA addresses safety problems. These requests reflect the need
for additional information post approval as well as the current state
of clinical trial science. These studies might be requested to clarify
the product's stability under specialized conditions, its metabolism by
special populations, and other topics. If there is a significant or
likely safety concern at the time of an approval decision that FDA
thinks is incompletely characterized, FDA ordinarily will not approve
the product until that study is done.
Question 20d. Would we be better off with a mandatory, active
reporting system? If so, what are the barriers to the implementation of
such a system?
Answer 20d. If by an active reporting system, you are referring to
what is called active surveillance systems, there are some limited
applications for such systems. Active surveillance systems collect data
in a deliberate and systematic fashion to see if there are health or
safety problems. Active surveillance is done for example by CDC for
influenza and is very useful for tracking influenza patterns across the
Nation. The downside or barrier to implementing active surveillance
systems is that they are much more expensive in terms of the cost of
the data, and they are very inefficient unless you are looking for a
specific problem, as is the case with flu. They have limited detection
power and will likely result in many false leads. The United Kingdom's
Drug Safety Research Unit does active surveillance of the first 10,000
users of a new drug, where they ask but do not require the prescribers
to report on all the side effects that their patients have after taking
the new drug. Most of the side effects they find are the common ones
that were known prior to marketing authorization, e.g., headache, upset
stomach, etc.
Besides high cost, inefficiency, and poor detection power for novel
adverse events, there are other barriers to mandatory, active systems
of reporting. Experience with mandatory reporting requirements for
vaccines and medical devices shows that these do not improve either the
quality or number of reports and may even discourage reporting. FDA
does not have the authority to require physician or pharmacist
reporting, though the Joint Commission on the Accreditation of
Healthcare Organizations, State, and professional licensing authorities
do have some role in encouraging adverse event reporting.
In the area of active surveillance, FDA has worked with CDC to
expand the National Electronic Injury Surveillance System in emergency
departments to detect adverse drug events that show up in emergency
rooms. This system appears to have value in picking up easily-
recognized and already known adverse drug events, like allergic
reactions to drugs and low blood sugar from taking too much insulin. It
adds to but does not replace the spontaneous adverse event reporting
system, which is the workhorse of the FDA post-marketing safety program
and the most common source of information used by FDA in deciding
whether withdrawal or marketing restriction of a product is necessary.
There are numerous barriers to the implementation of active and
mandatory reporting systems. These include, but are not limited to, (1)
the decentralized nature of primary health care in the United States
(patients are seen by multiple physicians/health care providers who may
not communicate with one another and thus may not be aware of all
factors that have the potential to affect their patient's overall
health); (2) the lack of a centralized, computerized health information
system in the United States; and (3) the lack of FDA jurisdiction over
patients and physicians, two key potential sources of adverse event
reports. Existing disease and injury surveillance systems are all
state-based.
Question 21. I believe that modern health information technology is
key to improving the FDA regulatory process. Certainly, there is
strong, bipartisan support on the committee for introducing this
technology into the healthcare arena, where it will afford many of the
same advantages as it does to the business community. Dr. Crawford,
what is your vision for information technology at the FDA? How can
information technology improve drug safety? What additional resources
would it take to modernize FDA's information technology systems?
Answer 21. My vision for the future of FDA is one of
transformation. Information technology will play a crucial role in
helping us realize our vision for advancing the public health and
improving FDA operations in the 215 Century. We are working to
transform the way FDA accomplishes its vital public health mission,
moving away from paper-based processes, toward electronic information
systems that provide the right information to the right people at the
right time to support rigorous analysis and well-informed decisions
that meet the highest standards of scientific excellence and
professional practice. We are actively engaged in developing and
adopting international consensus standards for clinical data and e-
health records, structured product labeling, remote automated
monitoring of regulated product manufacturing and distribution
processes, and other technologies that will help usher in a new
``golden age'' of food and medical product safety, security, quality,
and innovation. Information technology will enable business process
improvements that yield marked jumps in productivity, allowing us to
keep pace with rising demand for services in an era of limited public
resources. With modern information technology, FDA can continue setting
the gold standard for food and drug regulation throughout the world.
FDA is currently working on an agency-wide long-term plan that
communicates our vision and some important interim milestones, and we
hope to share with you the results of this effort this summer. We are
also developing an FDA information technology strategic plan that will
provide more detailed planning tools and criteria for making resource
allocation and investment decisions in the coming years, as we move
toward our vision. As we progress through this modernization planning
process, we will work collaboratively with our public health partners
in HHS and other agencies to ensure that our plans are coordinated and
efficient. Our future requests for information technology investments
will be driven by these long-term strategic plans.
In the near term, our fiscal year 2006 budget request identifies
several important information technology investments. As part of our
requested $5 million increase for the Office of Drug Safety, we hope to
provide increased access to a wider range of clinical, pharmacy, and
administrative databases that will improve our post-market surveillance
capabilities. This strategic investment would continue to strengthen
the FDA review staff's ability to examine more effectively safety data
that historically have been stored in separate program level
information silos. They would then gain a more integrated perspective
into emerging and existing regulated products that cross traditional
and organizational boundaries. Another strategic investment is the
consolidated data center at FDA's White Oak campus. This shared-use
facility will serve as a catalyst to modernize our aging information
technology systems and thereby give FDA scientists and reviewers better
access to information that was previously stored on paper or in
different systems.
With the previously stated vision and our planned investments in
information technology, FDA is focusing our current resource requests
on the highest priorities in the near term, and we are working
diligently on long-term plans that will provide a more comprehensive
view of our information technology resource needs over the coming
years.
[Whereupon, at 11:23 a.m., the committee was adjourned.]