[House Hearing, 110 Congress]
[From the U.S. Government Publishing Office]
FDA FOREIGN DRUG INSPECTION PROGRAM: A SYSTEM AT RISK
=======================================================================
HEARING
BEFORE THE
SUBCOMMITTEE ON OVERSIGHT AND INVESTIGATIONS
OF THE
COMMITTEE ON ENERGY AND COMMERCE
HOUSE OF REPRESENTATIVES
ONE HUNDRED TENTH CONGRESS
FIRST SESSION
__________
NOVEMBER 1, 2007
__________
Serial No. 110-74
Printed for the use of the Committee on Energy and Commerce
energycommerce.house.gov
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45-057 PDF WASHINGTON : 2008
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COMMITTEE ON ENERGY AND COMMERCE
JOHN D. DINGELL, Michigan, Chairman
HENRY A. WAXMAN, California JOE BARTON, Texas
EDWARD J. MARKEY, Massachusetts Ranking Member
RICK BOUCHER, Virginia RALPH M. HALL, Texas
EDOLPHUS TOWNS, New York J. DENNIS HASTERT, Illinois
FRANK PALLONE, Jr., New Jersey FRED UPTON, Michigan
BART GORDON, Tennessee CLIFF STEARNS, Florida
BOBBY L. RUSH, Illinois NATHAN DEAL, Georgia
ANNA G. ESHOO, California ED WHITFIELD, Kentucky
BART STUPAK, Michigan BARBARA CUBIN, Wyoming
ELIOT L. ENGEL, New York JOHN SHIMKUS, Illinois
ALBERT R. WYNN, Maryland HEATHER WILSON, New Mexico
GENE GREEN, Texas JOHN B. SHADEGG, Arizona
DIANA DeGETTE, Colorado CHARLES W. ``CHIP'' PICKERING,
Vice Chairman Mississippi
LOIS CAPPS, California VITO FOSSELLA, New York
MICHAEL F. DOYLE, Pennsylvania STEVE BUYER, Indiana
JANE HARMAN, California GEORGE RADANOVICH, California
TOM ALLEN, Maine JOSEPH R. PITTS, Pennsylvania
JAN SCHAKOWSKY, Illinois MARY BONO, California
HILDA L. SOLIS, California GREG WALDEN, Oregon
CHARLES A. GONZALEZ, Texas LEE TERRY, Nebraska
JAY INSLEE, Washington MIKE FERGUSON, New Jersey
TAMMY BALDWIN, Wisconsin MIKE ROGERS, Michigan
MIKE ROSS, Arkansas SUE WILKINS MYRICK, North Carolina
DARLENE HOOLEY, Oregon JOHN SULLIVAN, Oklahoma
ANTHONY D. WEINER, New York TIM MURPHY, Pennsylvania
JIM MATHESON, Utah MICHAEL C. BURGESS, Texas
G.K. BUTTERFIELD, North Carolina MARSHA BLACKBURN, Tennessee
CHARLIE MELANCON, Louisiana
JOHN BARROW, Georgia
BARON P. HILL, Indiana
------
Professional Staff
Dennis B. Fitzgibbons, Chief of Staff
Gregg A. Rothschild, Chief Counsel
Sharon E. Davis, Chief Clerk
David L. Cavicke, Minority Staff Director
------
Subcommittee on Oversight and Investigations
BART STUPAK, Michigan, Chairman
DIANA DeGETTE, Colorado ED WHITFIELD, Kentucky
CHARLIE MELANCON, Louisiana Ranking Member
Vice Chairman GREG WALDEN, Oregon
HENRY A. WAXMAN, California MIKE FERGUSON, New Jersey
GENE GREEN, Texas TIM MURPHY, Pennsylvania
MIKE DOYLE, Pennsylvania MICHAEL C. BURGESS, Texas
JAN SCHAKOWSKY, Illinois MARSHA BLACKBURN, Tennessee
JAY INSLEE, Washington JOE BARTON, Texas (ex officio)
JOHN D. DINGELL, Michigan (ex
officio)
C O N T E N T S
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Page
Hon. Bart Stupak, a Representative in Congress from the State of
Michigan, opening statement.................................... 1
Hon. Ed Whitfield, a Representative in Congress from the
Commonwealth of Kentucky, opening statement.................... 4
Hon. Michael C. Burgess, a Representative in Congress from the
State of Texas, opening statement.............................. 6
Hon. Diana DeGette, a Representative in Congress from the State
of Colorado, prepared statement................................ 8
Hon. Tim Murphy, a Representative in Congress from the State of
Pennsylvania, opening statement................................ 10
Hon. Mike Ferguson, a Representative in Congress from the State
of New Jersey, opening statement............................... 10
Hon. Marsha Blackburn, a Representative in Congress from the
State of Tennessee, opening statement.......................... 12
Hon. John D. Dingell, a Representative in Congress from the State
of Michigan, prepared statement................................ 14
Hon. Joe Barton, a Representative in Congress from the State of
Texas, prepared statement...................................... 18
Witnesses
Marcia Crosse, Director, Public Health and Military Health Care
Issues, U.S. Government Accountability Office.................. 22
Prepared statement........................................... 25
Carl R. Nielsen, Director (retired), Division of Import
Operations, Office of Regulatory Affairs, Food and Drug
Administration................................................. 60
Prepared statement........................................... 62
William K. Hubbard, senior advisor, Coalition for a Stronger FDA,
Chapel Hill, NC................................................ 77
Prepared statement........................................... 78
Benjamin L. England, special counsel, Jones, Walker, Waechter,
Poitevent, Carrere & Denegre, LLP, Washington, DC.............. 90
Prepared statement........................................... 93
John B. Dubeck, partner, Keller and Heckman, LLP, Washington, DC. 134
Prepared statement........................................... 138
Bruce Downey, chairman and chief executive officer, Barr
Pharmaceuticals, Inc........................................... 156
Prepared statement........................................... 159
Guido Villax, immediate past president, Pharmaceuticals Business
Committee, member, board of directors, European Fine Chemicals
Group, Brussels, Belgium....................................... 178
Prepared statement........................................... 180
Andrew C. von Eschenbach, M.D., Commissioner, Food and Drug
Administration, U.S. Department of Health and Human Services... 199
Prepared statement........................................... 207
Answers to submitted questions............................... 240
Submitted Material
Drug Imports Graph presentation, submitted by Mr. Stupak.........
``Chinese Chemicals Flow Unchecked Onto World Drug Market,'' Walt
Bogdanich, the New York Times, October 31, 2007................ 224
``Ensuring the Safety of Imported Products, Q&A with Deborah
Ralston''...................................................... 231
Subcommittee exhibit binder...................................... 255
FDA FOREIGN DRUG INSPECTION PROGRAM: A SYSTEM AT RISK
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THURSDAY, NOVEMBER 1, 2007
House of Representatives,
Subcommittee on Oversight and Investigations,
Committee on Energy and Commerce,
Washington, DC.
The subcommittee met, pursuant to call, at 10:00 a.m., in
room 2123 of the Rayburn House Office Building, Hon. Bart
Stupak [chairman of the subcommittee] presiding.
Members present: Representatives DeGette, Inslee, Dingell,
Whitfield, Walden, Ferguson, Murphy, Burgess, and Blackburn.
Staff present: John Sopko, Chris Knauer, Scott Schloegel,
Paul Jung, Joanne Royce, Kyle Chapman, Peter Spencer, and Alan
Slobodin.
OPENING STATEMENT OF HON. BART STUPAK, A REPRESENTATIVE IN
CONGRESS FROM THE STATE OF MICHIGAN
Mr. Stupak. This meeting will come to order. Today we have
a hearing on the ``FDA Food and Drug Inspection Program, a
System at Risk.'' Each member will be recognized for 5 minutes
for an opening statement. I will begin.
This hearing is a continuation of this subcommittee's
investigations into the safety of imported products. Today we
explore the question of whether the FDA is adequately
regulating the manufacturing of pharmaceutical products and
active pharmaceutical ingredients, or APIs, as they are called,
for export into the United States. Most Americans do not
realize that many of the drug products in their medicine
cabinets come from overseas. In fact, more than 80 percent of
the active pharmaceutical ingredients that go into drugs come
from abroad. India and China account for almost half of these
imports. India's pharmaceutical imports into this country have
increased 2,400 percent from 1996 to 2006, making it the
fastest-growing drug importer, and China has doubled its
pharmaceutical imports to the United States over the last 5
years.
The Food and Drug Administration is responsible for
regulating foreign-made medicines and ensuring the American
public is supplied with safe medications. Despite a 2000
oversight hearing and a critical GAO audit in 1998, which
pointed out many of the FDA's weaknesses regarding importation
of drugs, the FDA continues to use 20th-century tools and
resources to address 21st-century regulatory challenges.
Today's hearing is intended to determine the effectiveness
of FDA in overseeing foreign drug production and explore what
resources the agency realistically needs to do the job. Unlike
food products, FDA cannot rely on any testing to determine if
the drug products are safe. Instead, FDA's main tool for
ensuring that a drug is manufactured safely is to conduct
actual onsite inspections of drug-making facilities. The FDA is
required to conduct a formal, pre-approval inspection before a
form, domestic or foreign, can begin producing drugs for the
U.S. market. After a pre-approval inspection, the agency is
required to conduct follow-up surveillance inspections of
domestic facilities to ensure they are continuing to meet U.S.
manufacturing regulations. For U.S. drug manufacturers, Federal
Law requires that follow-up inspections be done every 2 years.
Remarkably, there is no Law dictating how often the FDA must
inspect foreign drug manufacturers, even though foreign firms
pose just as great, if not greater, risk to the public health
than domestic firms.
In a petition to the FDA, the Synthetic Organic Chemical
Manufacturers Association, who will testify today, noted,
``Foreign facilities in general pose a greater risk to public
safety because when a facility is inspected infrequently, as is
the case for foreign manufacturers, there is a natural tendency
for management to become complacent that what was adequate at
the last inspection is still adequate. Maintaining regulatory
compliance requires constant effort and vigilance. Minor
deviations may not cause any apparent lack of quality, but it
is well-paved road from one minor deviation to serious quality
failures.''
Twenty years ago, the drugs Americans consumed were made in
the United States. Because few firms were overseas, the FDA was
reasonably positioned to closely monitor drug production
facilities. However, as more foreign drug producers entered the
U.S. market, FDA's ability to keep pace with inspections and
monitoring has become severely limited. This was particularly
true when the committee last examined this matter in 2000.
Through the course of that investigation, the committee found
significant shortcomings in the FDA's ability to conduct
foreign inspections. Back then, FDA was under-funded, over-
stretched, and poorly coordinated. Among the committee's
principal findings at our 2000 hearing were, FDA officials
could not determine how often foreign manufacturers were being
inspected. Drug makers in India and in China were inspected on
an average about every 4 to 5 years, which was more than twice
FDA's 2-year inspection requirement for domestic pharmaceutical
manufacturers. FDA had only enough resources to inspect foreign
pharmaceutical manufacturers on an average of once every 11
years. Finally, the agency's IT systems were in disarray,
relying on separate 15 data systems to identify foreign
pharmaceutical manufacturers, plan foreign inspection travel,
track inspection results, and monitor enforcement actions.
Nearly 8 years have passed since our last hearing, and
surprisingly most of the same problems plague the FDA today.
For example, resources dedicated to foreign inspection have
actually declined since the GAO report of 1998, while the
number of foreign drug manufacturers and imports have
dramatically increased. Despite more than a decade of warnings
from FDA's own internal reviews, the Congress, and Government
Accountability Office, FDA's IT system is still based on
multiple databases which lack integration and contain
unreliable information. Due to its poor IT systems, the FDA
cannot obtain reliable data to run their risk models so they
can effectively allocate what limited resources it does have
for inspections. FDA's IT system has made it nearly impossible
to provide the GAO, this committee, or even its own FDA
managers, with key data to measure ongoing resource needs.
Let me give you one example. For almost 3 months, our
committee and GAO have repeatedly asked the FDA for the number
of foreign firms the agency is supposed to be inspecting
overseas and where they are located. For 3 months the FDA has,
on 10 different occasions, provided numbers ranging from 2,100
foreign firms to 13,800 foreign firms. The database that we
believe is probably the most accurate shows that about 3,000
firms are registered to ship drug products to the United
States, yet the FDA's own foreign inspection risk model uses
data from about 3,300 foreign firms. Another FDA database,
called OASIS, which captures actual drug shipments to the U.S.,
now shows an even higher figure of 6,800 foreign firms. That
number was revised down from 13,800 firms just last week.
Frankly, it has been nearly impossible for the committee
staff to calculate what resources FDA needs, because its
internal data is simply in shambles. FDA may testify today that
they know with some certainty the approximate number and
location of every firm that is importing drug product in the
United States, but I am not convinced the FDA can accurately
calculate the number of foreign firms they should be
inspecting. How can we have any confidence if the FDA is truly
managing the risk that may come from foreign-made drug products
if the FDA does not know the exact number or location of
foreign drug manufacturers? This most basic information should
be available within an hour, not 3 months. I don't believe an
auto dealership could survive if it was run on the IT system
that said there is between 2,000 and 13,000 cars on its lot.
But apparently this passes muster at the FDA, even though it
involves safeguarding the U.S. drug supply.
From the limited data we have gleaned from the agency,
FDA's foreign drug inspection program has serious shortcomings.
For example, FDA is capable of conducting only 200 to 300
foreign follow-up inspections each year. These are inspections
that, by Law, FDA attempts to do every 2 years for foreign
firms. But if one assumes that at the rough estimate of 400
firms is likely around 3,000, a simple mathematic calculation
would suggest the FDA can only inspect each foreign drug firm
about every 13 years. One must also question whether FDA's
limited resources are being properly targeted. For example, we
know that China now represents the largest source of production
facilities, now shipping product to the United States with more
than 700 drug firms. Yet China represents a mere four percent
of where FDA is spending its foreign inspection resources.
The administration believes one of the best ways to solve
the FDA's lack of inspection resources is to negotiate
memorandums of agreement with foreign governments, but such
efforts will not overcome the lack of FDA funding for on-the-
ground foreign inspections. Mutual recognition agreements of
each other's inspection reports would save considerable money,
but neither China nor India, two very large producers of
pharmaceutical goods, are anywhere near being ready for such
agreements. Perhaps the FDA should open offices in these parts
of the world, such as India and China, where many
pharmaceutical firms are now located or moving their
manufacturing. Astra Zeneca, to use just one example, is one of
the world's largest pharmaceutical companies, and it plans on
obtaining 90 percent of its pharmaceutical ingredients from
China in the very near future.
The FDA does spend considerable resources in India, about
22 percent, which is a good thing. Yet it begs the question of
why the administration has not engaged in open discussions with
that country, as they have been attempting to do with China.
This is particularly strange given that the committee staff
recently visited India and met with senior officials and
industry officials, who strongly encouraged the FDA to open a
permanent office in India, to reduce the backlog of needed
inspections.
Every year, consumers see more and more counterfeits and
poorly-made drugs floating around the world. We dodged the
bullet this year on tainted toothpaste, which could have made
many people sick. But dozens of Panamanians weren't so lucky
last year when they died from taking poisoned medicine that
purportedly came from China. That can happen here, and it
surely will, if we do not get a better handle on ensuring that
foreign-made drugs are safe, and their plants are inspected
regularly. This will require resources and significant
restructuring of the program.
Chairman Dingell and I have already had legislation
designed to give the FDA more resources to do its job.
Moreover, we have already sent you, members, bipartisan
correspondence delineating certain changes to the program that
could be enacted almost immediately. We truly hope it will be
sufficient to address what are truly the root causes plaguing
the FDA's foreign drug inspection program and not mere window
dressing. We have been here before, in 1998, and we were told
by the FDA that these problems would be fixed. Unfortunately,
the problems were not fixed, and we are here again. To that
end, I believe we have an opportunity to fix FDA's foreign drug
program before Americans are sickened or killed by contaminated
imported drugs.
That concludes my opening statement, and now I would like
to turn to ranking member of the committee, Mr. Whitfield, for
his opening statement.
OPENING STATEMENT OF HON. ED WHITFIELD, A REPRESENTATIVE IN
CONGRESS FROM THE COMMONWEALTH OF KENTUCKY
Mr. Whitfield. Chairman Stupak, thank you very much. As we
all know, this subcommittee and the Energy and Commerce
Committee as a whole has had many hearings on this important
issue, and today we will examine the agency's oversight of
drugs and bulk drug ingredients imported into the United
States.
It is quite obvious that FDA falls short in ensuring that
foreign firms exporting to the U.S. market meet good
manufacturing practices. In fact, the agency devotes less than
one quarter of its inspection resources and one tenth of actual
inspections to these foreign operations. When you consider that
80 percent of active pharmaceutical ingredients originate from
abroad, and the volume of drug imports is expected only to
grow, this is especially the case with countries such as China
and India. According to reported estimates, as much as 20
percent of the finished generic and over-the-counter drugs and
more than 40 percent of bulk drugs come from China and India.
Some predict these two countries will double their share of
U.S.-imported drug supply within 15 years. And just consider
that last year, among the 714 firms in China and 410 firms in
India registered with the FDA, the agency conducted only 13 and
65 inspections respectively.
As we noted with food imports, FDA remains mired in an era
when most drugs were synthesized and produced in the United
States, and that is simply not the case today. Lack of good
quality manufacturing is a recipe for harm. A bulk drug
ingredient shipment of just 50 kilograms can result in millions
of tablets or capsules produced for consumption. A bulk product
that contains an impurity or was synthesized improperly,
something spot testing may not detect, can cause injury or
death to numerous people. And I might say that, while we have
concern about the manufacturing process and the active
pharmaceutical ingredients coming into the country, we
certainly be concerned, and should continue to be concerned,
greatly so, about drug re-importation issues as well.
We have learned on this subcommittee at past hearings that
FDA linked and unapproved and impure drug ingredients imported
from one Chinese firm to toxic reactions that occurred in over
150 patients across America in 1998 and 1999. One must wonder
how often poorly made or intentional adulterated product causes
harm, but it is undetected. Past criminal investigations have
identified many bad actors, such as agents for foreign firms
working to bring in cut-rate drug products, and we know without
adequate oversight, people and firms can take shortcuts to save
money without concern of harm to others.
It is striking that FDA has made little progress in this
area to reform its system, despite repeated findings by the
committee and others over the years. Even when thoughtful and
comprehensive plans for reform have been developed internally
at FDA, somehow it does not seem to be implemented.
Mr. Chairman, there are many issues to explore this
morning. We all want to know how FDA can work to build the
capacity for quality in countries and firms overseas so that we
can be more confident in the manufacture of foreign drugs. We
all want to know what improvements are needed for FDA's
information collection and risk assessment systems so that
public health is protected effectively. And most importantly I
know that we all want to work with Dr. von Eschenbach to make
overhauling FDA's foreign inspection program and FDA's import
operations a top priority. We want to provide the money, if
that is what we need. If we need legislation, we want to do
that. If we can help in regulations, we want to do that. And so
we would just say to him, I know he is going to be testifying
later, that we want to support, we want to rally behind him and
his leadership to fix this problem.
Thank you, Mr. Chairman.
Mr. Stupak. Mr. Burgess, for opening statement, please.
OPENING STATEMENT OF HON. MICHAEL C. BURGESS, A REPRESENTATIVE
IN CONGRESS FROM THE STATE OF TEXAS
Mr. Burgess. Thank you, Mr. Chairman. I appreciate you
holding this series of hearings because we are finding
ourselves yet on the brink of one more problem, dealing with
imports to our country. This time, the focus is a little bit
different, but the story line is exactly the same as it has
been over and over again all summer. This committee has spent a
great deal of time over the past months discussing the safety
and security of imported products, and we have learned our
Federal agencies that are tasked with keeping America safe from
harmful food or products are often using 20th-century tools or
possibly even 19th-century tools when dealing with a 21st-
century problem. The Food and Drug Administration does not
shoulder all of the blame in this situation. As I continue to
study the problem, as the committee continues to study the
problem, it becomes more and more convincing that a lot of
people, including people in the United States Congress,
actually could not have anticipated the exploding number of
imports that we have seen over the past 10 years.
Quite frankly, our Laws and regulations were never meant to
handle the ever increasing number of foreign products entering
into our ports. This doesn't absolve us from guilt. It just
means that, as the former Speaker of the House, Mr. Newt
Gingrich, so often says, real change requires real change. Now,
as a doctor, I think it is important that we spend some time
today discussing medicine and medicines. Medicine is supposed
to heal patients, not harm them. Before I took the oath of
office to become a member of the United States Congress, I
first swore an oath to my profession to first do no harm. Yet
how can we do no harm if we don't know what is in the medicines
that are coming from what is supposedly a safe and regulated
country?
It has been estimated that more than 80 percent of the
active ingredients in medicines come from overseas, and about
half of that comes from India and China. China, Mr. Chairman,
this is the same country that manufactured over 60 percent of
all the Consumer Product Safety recalls, including 90 percent
of the recalled toys. Like many other Americans, I am now
regarding the label, made in China, as warning, consume at your
own risk. While the 20- to 40-percent number is disturbing,
analysts predict that 80 percent of the active ingredients will
come from China and India within the next 15 years. If this is
true, then our action here today and in subsequent hearings is
critical.
We must help to move the Food and Drug Administration into
a 21st-century agency that can handle these 21st-century
problems. And it is not just money alone that will solve the
problems. We do need real reform. In fact, you can argue we
need to go beyond reform. It is not just changes at the margin.
It is time for real transformation. Now, at the last Oversight
and Investigations hearing on food safety, I discussed the
quality control with the witness from Tyson's Chicken. You may
remember. He informed the committee that, yeah, they did find
problems with things that were coming into their plants from
suppliers in the country where they were operating, within
China. And when they found those problems they dealt with them
internally, but they didn't tell anybody else. They are under
no obligation to self-report any problems that they encounter
with shippers, with other manufacturers, with other shippers,
or even the Federal agency charged with protecting the health
and safety of American citizens.
Today I hope that the witnesses will speak to this issue.
Mr. Chairman, before I yield back, I would be remiss if I
didn't make a couple of observations about the witnesses before
us today. Certainly I want to thank Mr. William Hubbard for
appearing before us today. Dr. Hubbard has appeared before us
in the past and has inspired at least me to introduce
legislation based on testimony that he has given to our
committee, so I thank you for being with us today, and I hope
you can continue to shed some light upon the solutions that are
needed to fulfill the organization's own mission of building a
stronger Food and Drug Administration.
And, of course, Dr. von Eschenbach is with us again today,
and we are grateful that he has given his time. Honestly, Mr.
Chairman, Dr. von Eschenbach is the head of a major Federal
agency. His time is extremely valuable, and I know you would
like to keep him in the audience so he can listen to your
penetrating and probing questions, but at the same time he does
have other duties to perform.
We have tasked the FDA with transformation. We have tasked
the FDA with keeping us safe, and yet as I sit here this is the
third Food and Drug administrator that we have had since I came
to Congress a very short time ago. He has an agency to get up
to speed, to get up to 21st-century functioning. Yet he can
scarcely perform that arduous task that we have set before him
if he spends day after day after day listening to us
pontificate from the dais. He could watch us on C-Span in
between the activities that he needs to do at his agency. I
hope in the future when Dr. von Eschenbach is called to testify
we will afford the courtesy of allowing him to go early in the
day as opposed to late in the day. I do realize that we do all
ask very entertaining and probing questions, but I know Dr. von
Eschenbach has a lot of other things he could be doing. I for
one certainly appreciate the time that he has given, the
courtesy he has shown this committee. He has never complained
about this issue, but I find it undignified that the committee
would behave in such a way.
I do know that the FDA does require additional resources.
At the same time, just this past year, when we reauthorized the
Food and Drug Administration, it wasn't just the
reauthorization of PDUFA and MDUFA, we made some basic changes
as to how data is handled at the FDA. This is going to take us
to the cusp of the 21-century type of transformation that we
all need. I hope we are not a hindrance in that process, and I
will yield back the balance of my time.
Mr. Stupak. Ms. DeGette, for opening statement.
Ms. DeGette. Chairman, I have a brilliant opening statement
that I would like to submit for the record and in the interest
of having extra time for questioning.
[The prepared statement of Ms. DeGette follows:]
[GRAPHIC] [TIFF OMITTED] 45057.001
[GRAPHIC] [TIFF OMITTED] 45057.002
Mr. Stupak. Very good. Mr. Murphy, I believe, is next.
OPENING STATEMENT OF HON. TIM MURPHY, A REPRESENTATIVE IN
CONGRESS FROM THE STATE OF PENNSYLVANIA
Mr. Murphy. Thank you, Mr. Chairman, and thank you for
holding this hearing, which is a critically important issue we
are dealing with. The American public's confidence in any
products made in some foreign countries, particularly in China,
is probably at rock bottom, and even this morning as I have
been watching ABC Good Morning, America, they tested 100
popular children's toys. Although they found 90 of them had no
lead levels of problems, still, 10 of them did and got by
Federal inspectors. Yet when it comes to children's toys and
when it comes to drugs, I think the American people should have
zero tolerance for any kind of weakening of inspections or
standards.
Although plants in the United States must be inspected
regularly every 2 years, we are not yet there for some other
pharmaceutical manufacturers around the world. And, as China is
among them, we must be concerned and want to hear everything
that our government is doing to help make sure that such plants
are inspected and are meeting top standards, particularly
because as we also see many factories around the world,
unfortunately in China, India, and others in other small
countries are involved with a great deal of counterfeiting
drugs, where not only are drugs being marketed as having active
ingredients when they have absolutely no active ingredients in
them or may actually have poisons in them or lead paint, et
cetera. This is an intolerable situation, and we, of course,
all share our concern that would any of these ever be marketed
or sent out through Internet sites and other marketing
mechanisms as if they are legitimate drugs, with all of the
stamps and other procedures on them to make them look like they
are real. The FDA is in a critically important position here,
and with this committee's oversight of looking at that, we are
hoping to hear about the significant steps being taken to
protect the American public. We want any breaches in this
exposed. We want anybody who is involved in cutting any corners
disciplined for that. It is something that this committee or
Congress simply cannot tolerate when it comes to medications
that are supposed to make things better. We cannot tolerate any
system that is using counterfeiting or cutting corners that
makes people sicker.
So I applaud the actions of this committee in moving
forward in this. I look forward to hearing the testimony about
what is being done to make sure this area is made safe. And I
yield back.
Mr. Stupak. Thank you, Mr. Murphy. Mr. Ferguson, for
opening statement.
OPENING STATEMENT OF HON. MIKE FERGUSON, A REPRESENTATIVE IN
CONGRESS FROM THE STATE OF NEW JERSEY
Mr. Ferguson. Thank you, Mr. Chairman. Thank you, Mr.
Whitfield and the members of the subcommittee and our
witnesses, for being here to discuss what many of us know is a
very important issue, the safety and the security of our
nation's drug supply. I am pleased that we are again addressing
this critical issue in this subcommittee. We have had several
hearings in recent months on all aspects of drug safety. My
biggest concern, and I think that of others on this
subcommittee, is ensuring that the safety of the drug supply
for our constituents and for all Americans. It is my hope that
our witnesses today will be able to provide us with insights
into why there seem to be gaps in the security of imported
drugs into America.
Most of you have probably the New York Times article from
yesterday, and if you have I am sure you are as alarmed as I am
about what was contained in that. It is paramount that the
citizens of this country have faith in the Federal Government's
ability to monitor and ensure the safety of all of our drugs,
and we know from recent investigations that they don't have
good reason to have faith in that process, and perhaps not as
much faith as they used to have. Many facilities have not been
inspected. Other companies are using loopholes to get
adulterated ingredients into the supply chain. However, the
majority of ingredients used in the production of drugs are
coming from outside of the U.S.
This globalization of the drug manufacturing industry is
putting a strain on the FDA and their efforts to ensure the
safety and the security of our drug supply. There are thousands
of facilities producing finished drugs and/or ingredients
around the world today creating products that will end up being
ingested by Americans across our country. The GAO has been
tasked with finding the deficiency in the safety and security
of the drug manufacturing pipeline. Their investigations
revealed that the FDA isn't completely certain as to how many
foreign manufacturing facilities are even subject to
inspection.
Using a risk-based assessment of the number of facilities
subject to inspection, the FDA comes up with the number 3,249.
However, this risk-based assessment is processed off an
unverified database. At the agency's current rate of
inspections it would take 13 years to inspect all of these
facilities. This is with the stipulation that no new facilities
be added to the list in the meantime. Even more alarming is the
fact that the Federal Government doesn't have one interoperable
database of manufacturing facilities, both foreign and
domestic, which are willing to register and be inspected. We
have three different databases for three different purposes,
the drug registration and listing system for registration
purposes, the field accomplishments and compliance tracking
system for completed inspection information, and the
operational and administrative system for import support for
information on drugs and other regulated substances being
imported.
If our government doesn't have a handle on the good actors,
the responsible actors, how can DHS and FDA and Customs work to
prevent adulterated or counterfeit drugs from entering our
supply chain from the bad actors? I am pleased to say that I am
going to be an original co-sponsor of Mr. Boullier's
legislation when he introduces it. I want to commend Mr.
Boullier. He has done an enormous amount of work on this issue.
He has been a leader on the counterfeit drug issue. He has
invested a lot of time and effort in the issue, and I think he
has come up with a very good product.
But it really drives home the point, if we can't regulate
the good actors that are playing by the rules in this industry,
how are we ever going to ensure the safety of the drug supply
of other drugs coming into America? The GAO's information is
very alarming, and I really think it drives home the point that
preventing the importation of drugs into our supply chain,
which can create safety and security problems, we have some on
this committee and in this Congress who want to kick open the
doors, kick open the flood gates of any drugs coming into this
country, and they say, well, it is only from Canada or a
country that we know of. We know for a fact that Canada and
other so-called safe countries with safe drug supplies are
really acting as a post office for drugs coming into this
country from any place in the world. It is irresponsible, and
it is wrong. We know the struggles we are having with just
ensuring the drug supply of the responsible actors of products
coming into this country. How in the name of God can we make
sure the drug supply is safe if we are going to kick open the
flood gates to any and all actors? It is the wrong way to go.
I hope we will be able to address these and other issues in
the coming weeks. I look forward to hearing the testimony of
our witnesses, and I thank you again, Mr. Chairman, for having
this hearing.
Mr. Stupak. Thank you, Mr. Ferguson. Mrs. Blackburn,
opening statement.
OPENING STATEMENT OF HON. MARSHA BLACKBURN, A REPRESENTATIVE IN
CONGRESS FROM THE STATE OF TENNESSEE
Mrs. Blackburn. Thank you, Mr. Chairman. I thank you for
calling the hearing to examine this foreign drug inspection
program. The inadequacies of our food and drug import system
have been widely reported during the past year, and you have
had the New York Times article referenced several times already
today. There is a serious problem. We all recognize that. Given
that the U.S. imports 80 percent of the active drug
ingredients, it is critical that the Federal Government improve
its drug monitoring safety system to ensure that the U.S. drug
supply remains the safest in the world.
The volume of FDA-regulated pharmaceutical imports doubles
every 5 years and will continue to increase. How much weight
can American consumers give to the label, FDA regulated, when
the FDA cannot perform timely safety inspections? When the
agency fails to enforce action against foreign manufacturers
and lacks the tools to monitor foreign drug manufacturers, how
can Americans feel safe? If American drug manufacturers are
required to follow the letter of the Law regarding FDA drug
safety inspections, Congress should expect nothing less from
foreign manufacturers. Foreign manufacturers must play by the
same rules that our domestic manufacturers follow.
If consumer safety is priority number one, and it should
be, then we have a lot of work to do to ensure that this goal
is going to be met. It is worth noting, however, that many of
the voices calling for an overhaul of the U.S. drug safety
inspection system concurrently called for legislation that
would import prescription drugs from other nations. Drug re-
importation fails to ensure the high safety standards that
Americans have come to expect. Americans clearly do not need a
flood of unsafe prescription drugs finding their way into the
medicine cabinets across this country, especially since there
is no guarantee of quality or that imported medication is
indeed safe for us.
When someone gets that imported drug, and it turns out to
be unsafe, we have another public health threat on our hands.
This subcommittee has examined drug import safety in numerous
hearings during the 110th Congress, and the record shows that
it is unrealistic for the FDA to inspect all imports coming
into the United States. However, Americans demand greater
accountability in the nation's drug supply through considerable
and expedient improvement of the FDA's current drug safety
review system.
I look forward to the testimony today from our witnesses,
and I yield back the balance of my time.
Mr. Stupak. Thank the gentlelady. Seeing no other members,
we will call our first panel to come forward. Dr. Marcia
Crosse, the Director of the Public Health and Military Health
Care Issues at the United States Accountability Office; Mr.
William Hubbard, former senior FDA employee and current Senior
Advisor to the Coalition for a Stronger FDA; Mr. Ben England,
former senior FDA employee and current Special Counsel at
Jones, Walker, et al. law firm; and Mr. Carl Nielsen, retired
Director of the Division of Import Operations within the Office
of Regulatory Affairs at the FDA.
It is the policy of this subcommittee to take all testimony
under oath. Please be advised that witnesses have a right under
the rules of the House to be advised by counsel during their
testimony. Do any of you wish to be represented by counsel?
Seeing none of you wish to, then I am going to swear you in,
but then I am going to have Mr. Dingell give an opening
statement if he so wishes. So please raise your right hand.
[Witnesses sworn]
Mr. Stupak. Let the record reflect that each witness
answered in the affirmative, and they are now all under oath.
Mr. Chairman, would you like to make an opening statement at
this time?
Mr. Dingell. Mr. Chairman, you are most gracious. This is
deja vu all over again. I have a fine opening statement. I am
sure everybody is familiar with it. It is something very much
identical to what has been given for years, and I don't want to
deter you in your good work. I commend you for what you are
doing. I thank you for your gracious kindness to me. I urge you
to continue your vigorous effort in this matter, and we are
going to try and make the American people safe from some of
these imported pharmaceuticals and imported foods that are
putting their lives at risk.
Thank you, Mr. Chairman.
[The prepared statements of Messrs. Dingell and Barton
follow:]
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Mr. Stupak. Thank you, Mr. Dingell. Dr. Crosse, if you
would, we would start with you for an opening statement,
please. A longer version will be submitted for the record, so
please try to limit your testimony to five minutes. Dr. Crosse.
TESTIMONY OF MARCIA G. CROSSE, DIRECTOR, PUBLIC HEALTH AND
MILITARY HEALTH CARE ISSUES, U.S. GOVERNMENT ACCOUNTABILITY
OFFICE
Ms. Crosse. Thank you, Mr. Chairman, and members of the
subcommittee. I am pleased to be here today as you examine
FDA's inspections of foreign drug manufacturers. As you know,
the United States increasingly relies on drugs manufactured in
other countries. Slide, please.
[Slide]
As you can see in this figure, there are firms in more than
50 countries that are registered to manufacture drugs for the
U.S. market, with the heaviest concentration in China and
India, as we have heard. The FDA is responsible for overseeing
the safety and quality of human drugs sold in the United
States, whether they are manufactured in foreign or domestic
establishments. As part of its efforts to ensure the safety and
quality of imported drugs, FDA is responsible for inspecting
foreign establishments to ensure that they meet the same
quality standards required of domestic establishments. For
domestic establishments, FDA's usual approach is to conduct
surveillance inspections of good manufacturing practices to
ensure that marketed drugs continue to be manufactured in
compliance with standards. FDA is required to conduct such
inspections every 2 years for domestic establishments, but
there is no comparable requirement for inspecting foreign
establishments.
We reported in 1998 that FDA needed to improve its foreign
drug inspection programs. Today, almost a decade later,
questions remain about FDA's ability to oversee foreign drug
establishments and whether FDA has improved its management of
the foreign drug inspection program. My remarks provide
preliminary information on the review we are conducting at your
request. Today I will discuss the extent to which FDA has
accurate data to manage the foreign drug inspection program,
the frequency of foreign inspections, and factors influencing
the selection of establishments to inspect, and certain issues
that are unique to conducting foreign inspections.
We are finding that FDA's effectiveness in managing the
foreign drug inspection program continues to be hindered by
substantial weaknesses in its databases. FDA does not know how
many foreign establishments are subject to inspection. Because
of this, FDA does not have adequate information on the full
scope of their responsibilities, which limits their ability to
appropriately manage. Instead, FDA relies on databases that
were designed for other purposes and contain inaccuracies that
FDA cannot easily reconcile. Slide, please.
[Slide]
For example, one of the databases indicates there are about
3,000 establishments registered to import drugs into the United
States, while another indicates that about 6,800 foreign
establishments actually imported drugs in the past year.
However, despite the more than two-fold different in the
estimates of foreign establishments, FDA does not verify the
information within each database. For example, the agency does
not confirm that a registered establishment actually
manufactures a drug for the U.S. market. Similarly, FDA has not
generated an accurate listing of the establishments whose drugs
have actually been imported into the United States. Slide,
please.
[Slide]
At a time when manufacturing of drugs for the U.S. market
is increasing in foreign countries, FDA's inspections have not
kept pace. FDA inspects relatively few foreign establishments.
Data used by FDA to prioritize foreign establishments for
inspection suggests that the agency may inspect about seven
percent of foreign establishments in a given year. At this
rate, it would take FDA more than 13 years to inspect each
foreign establishment once, assuming that the rate of
inspections remains constant and that no additional
establishments require inspection. Slide, please.
[Slide]
The mismatch between the number of inspections performed
and the number of establishments subject to inspection appears
to be the largest in China. Further, FDA cannot provide an
exact number of foreign establishments that have never been
inspected. But, according to FDA's data, it may be more than
2,000, and the largest number of such establishments are also
likely to be in China. Slide, please.
[Slide]
FDA's foreign inspection process is driven by the current
statutory and regulatory requirements for timely review of
applications to market new drugs. Among the limited number of
foreign inspections, most are pre-approval inspections
conducted as part of the processing of a drug application to
allow a manufacturer to begin marketing a particular drug in
the United States. In the last 6 years, 88 percent of FDA's
inspections of foreign inspections involved such pre-approval
inspections. Although FDA uses a risk model to develop a
prioritized list of foreign establishments for surveillance
inspections, to ensure continued compliance, few such
inspections are completed in a given year. This prioritized
list was used to select about 30 foreign establishments for
inspection in fiscal year 2007, and 50 are targeted for
inspection in fiscal year 2008. Further, FDA coordinates these
relatively few surveillance inspections with travel to
locations for pre-approval inspections to make efficient use of
travel funds. The need to coordinate travel is a bigger factor
in the selection of foreign establishments than FDA's risk
model. Slide, please.
[Slide]
This is in marked contrast to the pattern of domestic
inspections. About 78 percent of FDA's inspections of domestic
establishments were specifically for the purpose of a
surveillance inspection, to ensure that manufacturers continue
to comply with good manufacturing requirements. The comparable
figure for foreign establishments is 12 percent. Further, in
the last 6 years, FDA has conducted almost seven times as many
inspections domestically as abroad. And this is for about an
equal or smaller number of establishments. Slide, please.
[Slide]
Finally, the foreign inspection process also involves
unique circumstances that are not encountered domestically. For
example, FDA relies on staff that inspect domestic
establishments to volunteer for foreign inspections. Unlike
domestic inspections, FDA does not arrive unannounced at a
foreign establishment. It also lacks the flexibility to easily
extend foreign inspections if problems are encountered because
of the need to adhere to an itinerary that typically involves
multiple inspections in the same country. In addition, language
barriers can make foreign inspections more difficult than
domestic ones. FDA does not generally provide translators to
its inspection teams. Instead, they may have to rely on an
English-speaking representative of the foreign establishment
being inspected rather than an independent translator. Slide,
please.
[Slide]
In conclusion, our preliminary work indicates that
fundamental flaws that we identified in the management of this
program in 1998 continue to exist. FDA still does not have a
reliable list of foreign establishments that are subject to
inspection. As more imported drugs enter the United States, it
becomes increasingly important that foreign establishments
receive appropriate scrutiny. However, until FDA responds to
systemic weaknesses in the management of this important
program, it cannot provide the needed assurance that the drug
supply reaching our citizens is appropriately scrutinized and
safe.
Mr. Chairman, this concludes my prepared remarks. I would
be happy to answer any questions that you or other members of
the subcommittee may have.
[The prepared statement of Dr. Crosse follows:]
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Mr. Stupak. Thank you, Dr. Crosse. And, Mr. Nielsen, for an
opening statement, please, sir. Pull your mike up there a
little closer and the green light should be on, hopefully.
Thank you.
TESTIMONY OF CARL R. NIELSEN, DIRECTOR (RETIRED), DIVISION OF
IMPORT OPERATIONS, OFFICE OF REGULATORY AFFAIRS, FOOD AND DRUG
ADMINISTRATION
Mr. Nielsen. Mr. Chairman, members of the subcommittee. We
are to provide information to enable you to better assess the
adequacy of the current FDA foreign inspection program and to
help you formulate practical, effective solutions for
improvement. It is unavoidable for us to also discuss FDA's
import operations, since obviously foreign-made goods gained
entry into the U.S. market through FDA's import procedures.
FDA manages the importation of drugs using the same entry
reviewers, the same organizational structure, and the same
information technology infrastructure as those used to oversee
the importation of foods, medical devices, biologics, and all
other regulated commodities. I recall an interview with the
Journal of Commerce not long after that fateful 9/11 day. I was
Director of FDA's ORA Division of Import Operations and Policy
at the time. During the interview I was asked whether there
were significant vulnerabilities in the current FDA import
operation. I say to you today what I said then. Do the math.
The import system was broken then, and it is even more so now.
The volume of lines of entry have more than tripled since 1999,
while resources have remained essentially static or have been
reduced.
So, is FDA's foreign drug inspection program adequate to
prevent entry of unsafe drug products? Let us do a quick review
of some relevant information. Maybe some simple arithmetic can
help us come to a logical conclusion. First, FDA is expected to
handle approximately 18 million lines of entry for all
regulated commodities this year. Drugs and biologics comprise
approximately 10 percent, or 1.8 million lines, foods and
cosmetics comprise approximately 60 percent, and medical
devices comprise approximately 30 percent, or 5.4 million lines
of entry. Number two, entries of FDA-regulated goods enter
through 250 or more U.S. Customs Ports of Entry. Nationwide,
there is approximately 200 field investigators and inspectors
who spend most, but not all, of their time reviewing entries,
collecting samples, examining cargo, and conducting
investigations and inspections for all imported commodities.
That is less than one person per port on average, and 90,000
entries per person on average.
There is an estimated 300,000 plus foreign manufacturers of
FDA-regulated commodities. FDA conducts 500 to 900 foreign
inspections per year for all industries. That is an inspection
cycle of 333 to 600 years on average for all commodities. The
foreign-made products are received from 200 plus countries, not
just a handful of concern. FDA inspects an average 200 to 300
foreign inspectors of Rx drugs per year. Inspection of foreign
manufacturers of OTC drugs are virtually non-existent. There is
an estimated 3,000 to 6,800 foreign manufacturers of Rx drugs,
on top of which there are thousands of OTC manufacturers. The
estimated foreign inspection cycle for the Rx industry ranges
from 10 to 30 years or more, while the cycle for OTC drugs
could be 50 years or more, or almost never.
Conclusion--FDA knows very little about the actual
conditions of manufacture of most imported drugs, and that
should be found totally unacceptable in a professed risk-based
approach. Many potential risks are mitigated when good
manufacturing practices are used, and many potential risks are
increased when good manufacturing practices are not used. In
order to ensure a safe drug supply, FDA needs to verify
compliance by the foreign drug industry with current good
manufacturing practice requirements. FDA needs to revamp its
entire organizational structure and approach to managing
products from the international market. There is no cheap fix.
That is part of the price of a global economy. Agency oversight
must follow the regulated industry to be effective.
The current, domestic-oriented organization has had decades
to get this right. It has not, and I don't think it can. We are
sitting here talking about the very same issues from more than
a decade ago. Unless there is significant investment in the IT
systems and establishment of a new organization that can
implement an effective risk-management system for all imported
regulated products, not just for foods and drugs, then I
suspect folks will gather here in another 10 years wondering
why something wasn't done this time around that could have
avoided many injuries and deaths from unsafe, imported drug
products.
I appreciate the opportunity to appear before you all, and
I will do everything I can to avoid coming back in another 10
years on the same topic. I look forward to participating in
this hearing.
[The prepared statement of Mr. Nielsen follows:]
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Mr. Stupak. Thank you, Mr. Nielsen. Mr. Hubbard, please,
for your opening.
TESTIMONY OF WILLIAM HUBBARD, SENIOR ADVISOR, COALITION FOR A
STRONGER FDA
Mr. Hubbard. Thank you, Mr. Chairman. I have a written
statement, which is remarkably similar to yours, so I won't
repeat what you said, but I will say it is frustrating to be
back here over and over again, as Mr. Nielsen said. I remember
being here in 1986 with these issues, in the 1990s, and your
hearings in 2004, and now we are back again. And it does seem
to be a continuing concern. It doesn't get fixed.
But bottom line, though, is how can we live with a process
in which you have this pervasive regulatory system over U.S.-
produced drugs, with inspections and rigorous adherence to
quality controls, but yet the majority of our drugs are coming
from foreign countries and often developing countries, which
rarely get inspected. I think that is an indefensible
contradiction, and clearly the examples you have all given are
real. Drug ingredients coming from countries like China and
India that have weak process controls. Counterfeiting of drugs
is endemic around the world. In some countries, you are more
likely to get a counterfeit than a real drug. And, of course,
Americans are going to the Internet and buying drugs that they
think are coming from Canada, and in fact they are coming from
some of the darkest corners of the world.
So I must say this does need to be addressed. I worked at
FDA almost 30 years, with 14 acting and permanent
commissioners, and all of them were forced to play this public
health version of the kids' game, whack-a-mole, in which they
were forced to shift resources to wherever the squeakiest wheel
was of the day and try to fix that. That was all it was, and
nothing ever seemed to get fixed. And so you see now,
inadequate food inspections, you know, inspections of clinical
trials, inspections of human tissues, and of course the drug
inspections for foreign firms lags the worst in many ways.
So the safety of drug imports just keeps coming back over
and again every few years, but we just don't seem to fix it. So
I hope this time the committee will make a tenable effort to
make this a point of concern and move to fix it. This committee
has done tremendous things for the FDA over the years, and I
hope that this is one that you will stay with and tackle. Thank
you very much.
[The prepared statement of Mr. Hubbard follows:]
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Mr. Stupak. Thank you, Mr. Hubbard. Mr. England, please,
your opening statement.
TESTIMONY OF BEN ENGLAND, SPECIAL COUNSEL, JONES, WALKER,
WAECHTER, POITEVENT, CARRERE, & DENEGRE, LLP
Mr. England. Mr. Chairman and members of the committee, I
am Benjamin England. I am an attorney in the Washington, DC,
offices of the law firm of Jones, Walker, 17-year veteran of
the U.S. Food and Drug Administration. My bio is more fully
explained in my written statement, which I would ask to be made
part of the record.
Relevant to today's topic, I will only note that during my
career Carl Nielsen and I participated in a series of imported
counterfeit bulk drug investigations with Customs Enforcement
in Newark, New Jersey, prior to the creation of FDA's office of
criminal investigations. Some of those cases became of the
topic of that hearing in June of 2000 before this committee. I
am now an attorney in private practice. I represent domestic
and foreign companies before and against various Federal
agencies related to the manufacture, distribution, importation,
and exportation of FDA and USDA-regulated commodities. I spent
much of time assisting foreign companies and importers in
complying with the myriad of Federal and State regulatory
requirements prior to the process of importation to the United
States. I do represent myself as a former FDA official
interested in the matters before the committee.
At the outset, I will say I am very pleased that the
committee has taken this issue up again and to focus
specifically on the FDA's foreign drug inspection program, but
as the Chair will know, this is not a new discussion. It has
obviously been mentioned a number of times about the number of
hearings that have been had on this particular issue. And I
would also note that during the prior hearings we also
discussed these imported counterfeit bulk drug cases. That New
York Times article that published yesterday reported this
rampant counterfeit active pharmaceutical ingredient, or API,
industry in China, manufacturing not so fine chemicals and
passing them off in Europe, South America, and Canada, and even
the United States as legitimate product for drug manufacturing.
These chemicals are manufactured in an uncontrolled and
unregulated environment, as reportedly admitted by the industry
participants and the Chinese government. True to the pattern,
though, that Mr. Nielsen and I discovered in the early 1990s,
these counterfeit and unapproved APIs make their way to the
U.S. through third countries just as the Chinese manufacturer
of the counterfeit gentamycin sulfate sent its bulk drugs to
the United States through Europe. The stories of the Haitian
children that were killed by DEG-tainted over-the-counter cough
syrup, and now the more recent Panamanian incident, is all
being reported as news. I daresay it is not news to the
committee. It is not news to me, and it is not news to the FDA.
FDA's drug import program, its foreign drug inspection
program, and its information technology systems, which are
tasked with managing both and trying to integrate data, are
broken. They were broken 8 years ago, and they remain broken
today. FDA's current import program is simply not capable of
adequately assessing risks that may be associated with imported
drugs, particularly given the ever-increasing volume, variety,
and complexity of those drugs. One of the effects of free trade
is the migration of manufacturing and processing to lower-cost
markets. For FDA, that meant the answers to FDA's safety and
quality questions about drugs, the real questions, which relate
to how that drug is designed and how it is manufactured, and
the environment in which it is made, cannot be found by border
examinations in this country. You can't use a finished-product
testing regime in order to assess that risk. Only boots-on-the-
ground inspectors inside facilities can identify that.
Given the numbers of foreign manufacturers, processors,
growers, storage facilities, exporters that send products to
the United States, it is a foregone conclusion that FDA will
never cross those firms' thresholds in any meaningful number or
in any significant frequency. The question is, how can FDA get
there more often to conduct these critical GMP inspections? And
secondly, how can FDA obtain sufficient verifiable information
about what is happening inside the manufacturing plant in China
or in India or in Malaysia when FDA can't get there?
This foreign inspection problem and the import risks, the
import program are conjoined problems. To be clear, one of the
most important challenges I think FDA faces is lack of any
efficient, real-time, risk-based, intelligent operational data
screening system and its persistent siloing of agency data
systems. Without correcting that problem, FDA could not even
use the data that might emerge from more and more frequent
foreign inspections. OASIS is only screening against preset
data. It is not monitoring products that are imported. It is
not evaluating those shipments for compliance with FDA
requirements or for safety.
I think we all agree FDA needs a significant influx of
resources. I don't want to discuss many numbers. I will simply
note that the weakness of FDA's foreign drug inspection program
is not really limited just to this 3,000 to 6,800 number.
First, if you include the over-the-counter products, which is
where we actually have had these reports of the safety risks,
that number would be far, far greater. Then if we include foods
and devices and biologics, the numbers skyrocket, and what we
are left with to manage that risk is the import program, and
the numbers that are involved in that program are even worse.
Relying on that program leaves us with a more entrenched
finished-product regime. It is critical that FDA get into more
foreign firms that conduct good manufacturing practice
inspections. Without more inspections, you can't even identify
the risk baseline for drug imports, so you can't figure out
where the baseline, as it dynamically shifts, where FDA should
be focusing its resources in both the foreign inspection
program and the import program. Both of these need to be
repaired. The agency cannot use really any of the data it
receives if it cannot integrate it and assess it, and that IT
problem, if not fixed, will have us back here in 5 years with
the same problem, except much more exaggerated.
Shortly after September 11, 2001, FDA's leadership council
established an import strategic plan steering committee. By
spring of 2003, that import strategic plan was virtually
complete. FDA developed the ISP from contributions of more than
100 agency experts and all product centers, field and
headquarters components, laboratories, international program
staff, general counsel's office, and the Office of Policy,
Planning, and Legislation. I believe those ISP principles and
many of those proposed solutions are critical to establishing a
functional FDA program to integrate these foreign import and
domestic operations, and then you have something to fund. Then
you can target your resources, and you can identify and target
new authorities. I also refer you to my proposals at the end of
my written statement and look forward to a vigorous discussion
on the important topic. Thank you.
[The prepared statement of Mr. England follows:]
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Mr. Stupak. Thank you, Mr. England. That concludes the
opening statements of our witnesses. We will begin with
questioning. We will go for five-minute rounds on questioning.
Dr. Crosse, on page 13 of your testimony, you note, and I
quote, ``The FDA's data indicate that some foreign drug
manufacturers have not received an inspection, but the exact
number of establishments not inspected was unclear.'' In fact,
you note that there are more than 2,000 foreign establishments
for which the agency could not identify previous inspections.
Where are these firms? Who are these firms? What are they
shipping? What risks do they pose, and what does it mean that
there is no record they have ever been inspected?
Ms. Crosse. Well, as to who are these firms, where are
they, and what are they shipping, we don't know, and I am not
certain that FDA knows.
Mr. Stupak. Have you asked for the information?
Ms. Crosse. We are still continuing our work for the
committee to try to understand in greater depth the nature of
some of these problems and what kind of enforcement actions FDA
has been taking. The data about the number of establishments
that may never have been inspected are coming from one of the
many data systems that they have. This is from their risk-based
model, where they had between 3,200 and 3,300 establishments
that they assessed, to prioritize those for their routine
surveillance inspections. Those records, as part of the risk
assessment, examine whether or not there has been a recent GMP
inspection at a facility. Over 2,000 of those establishments
had no inspection indicated in that system.
Mr. Stupak. Did they have a pre-approval inspection?
Ms. Crosse. Not clear from these data, but because some of
the establishments included in this risk-based prioritization
system are those that have registered and may never have
imported a product into the United States--so their risk model
is not necessarily built on the base of firms that are sending
product here.
Mr. Stupak. Well, we all talked about that in a lot of the
discussion about prescription drugs or active pharmaceutical
ingredients, but that also includes, does it not, over-the-
counter drugs that you don't need a prescription for? You just
go in the drug store and buy it? Like the toothpaste with the
DEG that was found?
Ms. Crosse. Yes. In their----
Mr. Stupak. FDA has responsibility to inspect those
facilities where they are manufactured?
Ms. Crosse. That is correct. FDA is responsible for
inspecting all of those facilities. In their risk-based model,
they consider over-the-counter manufacturers to be of lower
risk than those producing certain types of prescription drugs.
Mr. Stupak. Well, let me just ask this panel or anyone who
cares to answer it, there has been a movement, and I know it
has nothing related to this hearing directly, but indirectly it
does, there has been a movement to put a third class of drug.
You have prescription drugs, you have your over-the-counter
drugs, now there is this movement to make the BTC or behind-
the-counter drugs. If we do that, a third class, is that just
opening up to more drugs with less inspections, or more drugs
with, we have no idea what they are?
Ms. Crosse. No, sir, I don't believe that is the case. My
understanding of the third class of drugs is that some current
drugs that are marketed, either over-the-counter or primarily
those that are prescription drugs, would simply move to a
behind-the-counter status, where you would have to have some
interaction with the pharmacist in order to obtain the drug.
Not that it would add a whole new category of drugs that don't
currently exist into the marketplace, would just regulate some
of them differently.
Mr. Stupak. OK, thanks. Mr. England, I was really intrigued
with your import strategy plan when 2003 recommendations were
made to the FDA on what should be done, and this was, I think,
Mr. Nielsen, were you involved in that also, the import
strategic plan?
Mr. Nielsen. Yes, I was.
Mr. Stupak. That was right after 9/11. That was what you
were referring to? How do we--What ever happened to that?
Either one, Mr. England or Mr. Nielsen, or Mr. Hubbard, if you
know, if you were a part of--were you a part of that group,
too, the ISP?
Mr. Hubbard. Yes, I was.
Mr. Stupak. What ever happened to it? 2003 was
recommendations made to finalize their plan. What happened to
it?
Mr. Hubbard. Well, the commissioner at the time was faced
with, as I said, he was faced with tremendous priorities
elsewhere and felt that to do that plan, while it was a
reasonable plan, there was simply no funding for it, and he
didn't believe that a request for funding would be welcome at
that point.
Mr. Stupak. Would be welcome by the administration or by
the Congress?
Mr. Hubbard. Well, whomever. The FDA had so many other
priorities at the time that he basically said, look, I think
you guys are on the right track here, but I would have no way
to fund this, and we can't do it without funding. But I do
understand the agency has been trying to do pieces of it----
Mr. Stupak. Well, that is what I was just going to ask Mr.
England, since you brought it up in your testimony. There were
pieces of this ISP, Import Strategic Plan of 2003, that could
be really implemented with little or no cost, right?
Mr. England. That is true.
Mr. Stupak. Give us an example.
Mr. England. Well, I will give you an example. When FDA
conducts a foreign inspection and goes in the country, you
know, FDA receives registration data from foreign facilities.
They may be food facilities, or they may be cosmetic facilities
on a voluntary basis, they might be medical device or drug
facilities. The discussion ensued during the development of the
ISP that one of our weaknesses in the agency was that there was
no real gatekeeper on the registration process. No one knows
who these people are, and so during foreign visits, would it
not be possible for a foreign inspector to perhaps stay an
extra day, take the addresses, and at least identify the
facilities that are listed in the addresses for the
registrations actually exist, or that there is not an apartment
complex there? I mean, just some basic verification of data
while inspectors are in the country. They are already there to
do a foreign inspection anyway. But those would be the kinds of
examples. The other examples might be to rely upon data that
other U.S. government agencies have from foreign inspections
they conduct. You know, there are inspections that are
conducted by other agencies of foreign seafood processors, of
bottled water manufacturers, of, you know, where there are
contracts that are let by another government agency. Another
government agency may sub-contract an inspection process prior
to procurement. That data is actually out there and could be
used for integration into the FDA import process. I think the
biggest problem we ran into, though, was, how do you integrate
the data, because the IT systems were so broken.
Mr. Stupak. Right. It is in shambles. Mr. Hubbard, my time
is up, but I want to ask you this. You have been at the FDA,
you said 30 years. You talked about the 1986 hearing. You
talked about the 1998 GAO report, the 2000 hearing. Now we are
here in 2007. What happens internally? I mean, we have these
hearings. You were in one of the key positions in the FDA,
especially 2000. I remember that one clearly because I was
here, the 1998 report. What happens? We hear these promises.
Things will be different. We will fix the IT system. It goes
back to the FDA, and all this testimony and all this just goes
in the circular file, or what?
Mr. Hubbard. Well, I share your frustration, Mr. Chairman.
I think it comes down to resources. The program has always been
a poor little sister there at FDA. It has never gotten
resources. Even now, they only devote a little over 100 FTEs a
year to these folks' market issues, so to me it is resources. I
think there needs to be some funding provided if it will fix
the problem. To me that is the big missing piece, is the
funding.
Mr. Stupak. But, again, going back to your experience, but
what happens on the resources? I mean, I don't ever remember
the FDA coming up pounding on the table before the
appropriators, saying, we need this, just from a safety point
of view, to protect America. We need these resources. Is the
gatekeeper of the resources request the administration? And if
the administration doesn't make it a priority, it doesn't put
the resource request in?
Mr. Hubbard. If you look at the last 10 or 15 years, the
president's budget usually gets funded, but if it doesn't get
in the president's budget, Congress never adds more. And the
president's budget has been very strict on FDA in recent years.
Mr. Stupak. Mr. Whitfield, questions, please. Thank you. We
are probably going to go more than one round here.
Mr. Whitfield. Well, we appreciate all of you being here
today, and certainly all of you all are experts at the FDA.
Three of you worked there for many years, and you have attended
enough of these hearings and expressed the frustration in your
own testimony, and obviously lack of dollars is one of the big
issues. And, would you all agree with that? OK. And in addition
to that, would you elaborate on some other obstacles, just from
your experiences. I mean, is there a culture over there that
has something to do with it? I know that one of you mentioned
that the most serious issue was a lack of a risk-based data
screening system that really works. But if each one of you
would just. You have all been involved in coming up with new
plans. As you say, every 2 to 3 years we are back here talking
about the same problem. So, lack of money is one big issue, and
would each one of you maybe elaborate on a couple of other
things? Dr. Crosse.
Ms. Crosse. Well, I haven't been in FDA, but it is
certainly true that resources is a major constraint here. It
also seems to me, though, that because of the resource
constraint the approach has been, OK, we can't do it all. Let
us work backwards at this. Given the regulatory requirements,
the statutory requirements for inspections, we have only got
this many resources. How many can we do, and then do some
figuring on where you can go within that, rather----
Mr. Whitfield. We can't do everything, and----
Ms. Crosse. We can't do everything, but rather than trying
to make an assessment, it appears there has been no attempt to
try to make an assessment of what the universe is and to try to
integrate the information and start from that end to assess the
risks that are the largest and to try to manage from that side.
Mr. Whitfield. OK. What about you, Mr. Nielsen?
Mr. Nielsen. I think the biggest obstacle is the current
organization is the original organization, totally organized
not for the international market. Even the location of the
facilities, or because of the location in a judicial district,
not because of incoming products. Then, on top of that, because
of the existing system largely being oriented to overseeing the
domestic industry, the work planning process is not designed to
deal with the international difficulties, either. And so it is
also my contention that the organization stove-piping is what
causes our IT stove-piping, and that is why I believe part of
the real solution is it really is an organization designed for
all of these problems we have been talking about for over a
decade. And then the requirements and the solutions can be
realized and I believe can be implemented with the appropriate
funding.
Mr. Whitfield. OK. Mr. Hubbard.
Mr. Hubbard. Well, someone suggested the way to solve this
would be some forms of memorandum of agreements with other
countries in which they step up and do a better job, and
conceptually I think that is a good idea, but take China as an
example. The Chinese are suffering 200,000 to 300,000 deaths a
year from sub-standard and counterfeit drugs, among their own
people.
Mr. Whitfield. 200,000 to 300,000?
Mr. Hubbard. Yes, that is an estimate that is out there,
and my point is, if they can't protect their own people, I
don't think we can depend on them or any other country to
protect us. I think we need to protect ourselves.
Mr. England. Yeah, I would, if I could, just build quickly
on what Mr. Nielsen and what Mr. Hubbard both said. This idea
of culture is a persistent issue in the agency, and I can
recall when I left the lab in Baltimore and went into
investigations, and I went into the import operations group,
the supervisor I worked for in the lab asked me if I was nuts.
He said he realized it is a dead-end job to go work in imports.
And then, a couple years later, NAFTA was passed, and then we
began to see these increases in imports became more
significant, and the foreign market became more significant. So
timing was good on my side. I don't propose to have any gift of
prophecy, but it has worked out. But I think that that
persists. I mean, imports and the foreign program largely is
still essentially this red-headed stepchild. A very small
percentage of the dollars that FDA expends are expended on the
foreign source market. In 2003 the number was about $7 out of
every $100 was based on imports or foreign, so it is a very
small number. I don't know what it is now, but that was the
number that I received then. I think that, in order to try to
address it, though, organizationally, this framework problem
does call for the need for an organization within the agency
that does have the responsibility. They have got the line-item
budget authority. They have got the ability to manage the field
assets. Some things that report into the commissioner level,
that it is the import foreign program, and from that can come
information sharing, but they also have to have this IT system
that is also integrated, and it can't be just about drugs. It
has to be about drugs and foods and devices and biologics. So
you really are talking about a rather substantial
reorganization in the agency in order to create the line of
authority and the budgeting in order to actually drive the
process.
Mr. Whitfield. Just one quick question. You mentioned this
Haiti, the children in Haiti. How many children died in that
incident?
Mr. England. I don't recall. There was a couple hundred. I
don't recall.
Mr. Hubbard. Well, in Haiti, I believe it was 86, and
Panama I believe it was in the 40s, but it was a lot of kids
with clearly a substitute of antifreeze, that we put in our
automobiles, for a legitimate drug.
Mr. England. And in my understanding, that product was
found here eventually and had to be recalled. And so it is
almost as if we are waiting for these deaths to occur in other
countries, and then we go looking for it. Whereas, as Carl
points out, I think in his written testimony, that GMPs would
have addressed that issue. That is a GMP--that is an incipient
ingredient processing issue that happens to be in an OTC
manufacturer, so whether there is oversight there is a
different question, but----
Mr. Stupak. Right. We used this chart before on this, and I
know Mr. Whitfield is familiar with it, the DEG that they put
into the toothpaste in both Panama and Haiti but also found in
our toothpaste here in this country.
Mr. England. That is correct, so----
Mr. Stupak. Mr. Dingell, for questions, please.
Mr. Dingell. Mr. Chairman, I would like to commend the
panel. This is one of the best panels we have had in this
committee, and I want to thank you for your quality and
vigorous testimony and for your help to us. I have a limited
amount of time, so we have to deal with this very quickly. Mr.
Nielsen, you are the former director of imports in FDA, with 28
years of experience. Isn't it true that FDA can provide a
meaningful figure on the number of firms shipping drug products
to the United States because of outdated databases?
Mr. Nielsen. Yes.
Mr. Dingell. Mr. Nielsen, FDA doesn't have a good handle on
this inventory, do they?
Mr. Nielsen. That is correct.
Mr. Dingell. Mr. Nielsen, since FDA can't calculate the
total number of foreign firms that are shipping drug products
to the United States with any precision, how can we have
confidence that the agency is truly managing risk?
Mr. Nielsen. You can't.
Mr. Dingell. Now, Mr. Nielsen, some insiders have told us
that FDA's IT or their information technology system should be
scrapped and rebuilt from scratch, simply because it doesn't
work. Do you agree with that?
Mr. Nielsen. No.
Mr. Dingell. You don't agree?
Mr. Nielsen. No. I think there are steps. It has to be
replaced, but you can't just scrap it.
Mr. Dingell. OK. We have to have a system, but we have one
that doesn't work.
Mr. Nielsen. That is right.
Mr. Dingell. And it has got to have major rebuild, does it
not?
Mr. Nielsen. That is correct.
Mr. Dingell. Now, Mr. England, isn't it true that domestic
firms are inspected properly every 2 years because Law requires
it? Isn't that so?
Mr. England. That is true.
Mr. Dingell. Mr. England, isn't it true that there is no
Law defining frequency of GMP inspections for foreign firms?
Mr. England. That is true.
Mr. Dingell. Shouldn't foreign firms be inspected at least
as frequently as U.S. firms?
Mr. England. I believe so.
Mr. Dingell. Isn't it true that foreign drug manufacturers'
facilities subject to FDA inspection rarely receive a follow-up
GMP inspection?
Mr. England. That is true.
Mr. Dingell. So that means that they are not being
adequately inspected, even the small number that are, in fact,
being inspected. Is that right?
Mr. England. I believe that is true, that there is not----
Mr. Dingell. Isn't it true that since the year 2000,
imported drug volume has nearly doubled but foreign drug
program resources have actually declined?
Mr. England. That, I believe, is true.
Mr. Dingell. Now, Mr. Hubbard, isn't it true that today
about 2/3 of the drugs consumed in the United States today
contain foreign drug components?
Mr. Hubbard. That apparently is true, yes.
Mr. Dingell. Of the millions of drug shipments arriving
from foreign countries each year, isn't it true that there is
almost no chance of an imported drug being sampled, tested at
entry into this country?
Mr. Hubbard. That is correct, Mr. Chairman.
Mr. Dingell. And if they are sent back out, they can simply
be brought in through another port?
Mr. Hubbard. Unfortunately, that does happen.
Mr. Dingell. And that happens also with regard to food,
although that is not the subject of this hearing?
Mr. Hubbard. Yes.
Mr. Dingell. Aren't we buying even larger percentages of
our drug ingredients from producers in developing countries
overseas with virtually no or no FDA inspection?
Mr. Hubbard. That is correct.
Mr. Dingell. Mr. Hubbard, can the FDA ensure the safety of
imported drug products at its current rate of foreign
inspections?
Mr. Hubbard. I am sorry, Mr. Chairman. I missed that.
Mr. Dingell. Can the FDA, and I apologize for that. I had a
very serious dental visit this morning. Aren't we buying even--
or, I am sorry. Can the Food and Drug assure that the safety of
imported drug products is real at its current rate of foreign
inspections?
Mr. Hubbard. Oh, no.
Mr. Dingell. Given the volume of foreign drug products
imported in the United States, isn't the only real way to
ensure drug safety and safe drug supply to significantly
increase the resources to conduct on-site inspections overseas?
Mr. Hubbard. I certainly believe that that is the biggest
need, yes.
Mr. Dingell. Now, gentlemen, this panel has over 80 years
of FDA experience. Are things worse now than they have been
before, or are they better?
Mr. England. I think that you would have to say that they
are worse now.
Mr. Hubbard. I think I would have to agree, simply because
the globalization has caused us an enormous shift of suppliers
from here to developing countries----
Mr. Dingell. What you are saying is that the risk is higher
and the resources are lower? Is that a fair statement?
Mr. Hubbard. That is correct. And then you have got the
concomitant concerns of people buying drugs over the Internet
and things like that, so, yes, there are great risks out there.
Mr. Dingell. Now, why, gentlemen and ladies, are things
worse now than they have been before? Starting with Dr. Crosse.
Ms. Crosse. I think, as we have heard, the globalization of
the market and the decrease in the resources that have been
available to try to handle that.
Mr. Dingell. Sir?
Mr. Nielsen. Also, besides the funding, also the failure to
redirect the resources to the global economy condition.
Mr. Hubbard. The drugs knocking on our door are less safe,
so therefore we need more protection, and we have been cutting
the FDA, so that, to me, is a simple equation.
Mr. England. Yeah, I believe the combination of all those
is true. I think there is also a continuing culture that it is
just easier for the FDA to think in terms of domestic
regulation, because they are used to it, the Statute was built
that way, and this NAFTA, the conversions that happened in
NAFTA and the economy, just have not carried over into the FDA.
They persist, I think, really, on a pre-NAFTA platform rather
than a post-NAFTA platform.
Mr. Dingell. Would this observation be correct? FDA said it
has a risk management plan. That risk management plan, being as
deficient as it is in personnel, money, and in the way that it
works, is actually of no value at all. Is that right?
Mr. England. I wouldn't say it is of no value. I would say
it has----
Mr. Dingell. Limited value.
Mr. England. --limited value.
Mr. Dingell. Now, would I be fair in saying that simply
assures that perhaps a lesser number of people are going to be
killed, defrauded, or hurt by imported pharmaceuticals? Is that
a fair statement?
Mr. England. I think that would always be true, that if you
have less resources assessing risk you always then would have a
lower number of people protected by those programs.
Mr. Dingell. Does the rest of the panel agree? There is no
nod button on the recorder's machine here.
Mr. Nielsen. Absolutely agree.
Mr. Dingell. Mr. Chairman, I have used more time than I am
entitled to. Thank you for your courtesy.
Mr. Stupak. Thank you, Mr. Dingell. We have three votes on
the floor. I think we are going to recess until twelve o'clock.
Let us try to get back at twelve o'clock so we can continue.
I am looking down this row. None of you guys can do it in
five minutes, I can tell you that right now. Go ahead, Mr.
Burgess. I think you were next in the--I was going by your list
of attendance, and I think Mr. Burgess--OK, Mr. Walden. I know
he will stay at five, and I know Mr. Burgess won't, so why
don't you go ahead?
Mr. Walden. All right, thank you. Thank you, Mr. Chairman.
My colleague from Pennsylvania, Mr. Murphy, suggested this
question, and I think it is a really good one, and I would like
a yes or no answer out of each of the panel members. If your
child were prescribed a drug that you knew was manufactured in
a facility in China that is not inspected, would you let your
child take your drug? Dr. Crosse? Yes or no?
Ms. Crosse. Yes, because if they were ill enough to require
a prescribed drug, I would be concerned that they take
something.
Mr. Walden. Mr. Nielsen?
Mr. Nielsen. Yes, because I don't feel there is an option.
Mr. Walden. Mr. Hubbard?
Mr. Hubbard. I think we are doing it every day, so there is
no choice.
Mr. England. I would agree. It is what you are left with,
that you have nothing else to go to.
Mr. Walden. That is a pretty sad commentary, isn't it? That
we are putting our kids' health at risk to take drugs that a
physician prescribes that we all now know are coming from
factories that we don't have the resources to inspect. That is
a scary proposition when we know our toothpaste is poisoned. We
know our dog food got poisoned. We know--and we have no
options? Then we had better change how FDA operates. Mr.
England, I want to ask you a couple of questions here. Please
refer to the document from the FDA's Web site called ``Consumer
Update: Ensuring the Safety of Imported Products--Q&A with
Deborah Ralston, Director, FDA's Office of Regional
Operations''. According to the FDA questioner, the number of
imported goods that FDA regulates has more than doubled in the
last 5 years. Ms. Ralston states on the Web site that the FDA
has a team of more than 2,000 scientifically-trained
specialists who conduct inspections, analyze samples, and
monitor the entry of regulated products at our nation's
borders. Is this number of 2,000 FDA people working on imports
a credible number?
Mr. England. I have no idea who they could be. I would
think that roughly 200, maybe between 200 and 250, in the
inspection side, perhaps another 100 in the lab side, that
spend more than 50 percent of their time, probably is a more
reasonable number.
Mr. Walden. Ms. Ralston states that the FDA analyzes about
30,000 import product samples annually. That sounds like a big
number, doesn't it?
Mr. England. Sure does.
Mr. Walden. 30,000 import samples.
Mr. England. It does sound like a big number.
Mr. Walden. This 30,000 samples is out of how many lines of
entry?
Mr. England. 18 million, probably, this year.
Mr. Walden. So 30,000 out of 18 million. Do you think that
is an acceptable number when our nation's health relies on
these drugs?
Mr. England. It is a remarkably small percentage.
Mr. Walden. Do we know what kind of product samples she is
talking about? Do you think a lot of these samples are drug
products?
Mr. England. The majority would be food, I would expect.
Mr. Walden. So the majority of the 30,000 of the 18 million
would be food samples.
Mr. England. I would expect that, yes.
Mr. Hubbard. Yes, they sample about 20,000 foods each year,
so the majority are food.
Mr. Walden. So we are down to 10,000? I was a journalism
major, not a math major, but that only leaves about 10,000,
then, that you estimate would be drug samples, out of 18
million?
Mr. England. It could be cosmetics, and then it could be
some pharmaceuticals.
Mr. Walden. Do these analyses tell the FDA how many of the
samples analyzed were safe?
Mr. England. Well, the FDA would have. They would make a
determination on the given shipments that they are analyzing,
but it doesn't tell them anything about the next shipment.
Mr. Walden. Do these analyses of these product samples
generate an FDA report of any kind?
Mr. England. My understanding is that there may be some
information inside the system, but it is probably very
difficult, if not impossible, to retrieve it from the system,
so I would guess probably no.
Mr. Walden. Would you expect that the committee would be
able to obtain from the FDA the results of these sample
analyses, what the FDA learned, and what action the FDA took?
Mr. England. I would expect that they should be able to do
that through its fax system and the OASIS system, the
combination of those two systems. Mr. Nielsen actually may know
better.
Mr. Walden. Mr. Nielsen?
Mr. Nielsen. Yes, I think they should be able to provide
that.
Mr. Walden. So you could provide it to us, but it sounds
like no report is generated internally at the FDA for the FDA's
own use, do you think?
Mr. Nielsen. It is usually case by case.
Mr. Walden. All right. Ms. Ralston states the FDA conducted
approximately 30 inspections of manufacturing processing sites
in China for FDA-regulated products. How many establishments
are there in China involved with FDA-regulated products?
Mr. England. Wow----
Mr. Walden. Wow?
Mr. England. It is a very large number. I don't know the
answer. I know that Dr. Lumpkin testified, I think a couple
weeks ago, that there were 3,000 medical device manufacturers
alone in China. That is just that industry, which probably is a
fraction of the entire----
Mr. Walden. Does 30 inspections a year sound like an
adequate number to ensure the safety of products from China?
Mr. England. Not overall of products from China, no.
Mr. Walden. All right. My time has expired. I thank Mr.
Chairman.
Mr. Hubbard. Mr. Chairman, may I make one comment to Mr.
Walden's earlier question?
Mr. Stupak. Yes, sir.
Mr. Hubbard. I don't think we should leave people with the
impression, though, that our drug supply is unsafe.
Mr. Walden. It is just vulnerable.
Mr. Hubbard. It is vulnerable, exactly. I mean, I think,
you know, the manufacturers here that receive these foreign
components do a good job, under FDA supervision, to screen
them. So we are not, like, taking dangerous drugs every day.
But, as you said, we are vulnerable.
Mr. Stupak. But 80 percent of the active pharmaceutical
ingredients found in over-the-counter and prescription drugs
are from offshore.
Mr. Hubbard. Right. And so clearly there is a risk, but
personally I don't think the drug supply in the United States--
I think it is actually the best in the world.
Mr. Stupak. Right, and in their--I don't mean to argue or
take any more time, but we inspect 97 percent of the plants
here in the United States every 2 years. They do a good job
domestically, but offshore is where the problem is occurring.
If 80 percent of your product is coming from offshore, we have
to devote the resources to offshore.
Mr. Hubbard. OK. The manufacturers here are required, under
FDA supervision, to do lots of screening before that pill
actually goes to the drug store, so----
Mr. Walden. My concern is it is only a matter of time if we
don't fix the inspection process.
Mr. Stupak. Absolutely.
Mr. Hubbard. No, I don't disagree with you at all.
Mr. Walden. Mr. Chairman, could we put that document in the
record? I ask unanimous consent.
Mr. Stupak. Yes. Without objection, the U.S. Food and Drug
Administration interview, Question and Answer with Deborah
Ralston, will be entered as part of the record.
With that, we have 3\1/2\ before we have a vote time
expires. We will be in recess. Let us still shoot for 12
o'clock, shortly after twelve o'clock. We will continue. We
still have many members that would like to ask questions of
this panel. Thank you.
[Recess.]
Mr. Stupak. If am I may ask Mr. Nielsen, Mr. Hubbard, and
England, Mr. Dingell and myself, Mr. Pallone has put in
legislation which would generate about $300 million for drug
safety, drug inspections. Have any of you had a chance to
review that legislation, Mr. Nielsen, Mr. Hubbard, or Mr.
England?
Mr. Hubbard. Is that the user fee?
Mr. Stupak. Right. The user fee with the Food and Drug bill
we put in.
Mr. England. I have reviewed it.
Mr. Nielsen. Yes.
Mr. Hubbard. Yes.
Mr. Stupak. Any comments on it?
Mr. Nielsen. I fundamentally have difficulty with a user
fee for that purpose. I just don't see--I use a parallel of
perhaps if I had to pay a user fee for IRS to process my income
tax form, they came to audit me, and I had to pay them to
audit, and then they put me in jail and I have to pay for that,
too. And, on the other hand----
Mr. Stupak. That is not the way it goes, though.
Mr. Nielsen. What is that?
Mr. Stupak. Nothing.
Mr. Nielsen. Yes. But I do think it needs to be
considered----
Mr. Stupak. But where else would you go to look for the
resources? I mean, you need a significant amount of resources.
Obviously, the FDA has been reluctant to ask for it. We
generate $300 million. That is $1000 a line. That is all it is,
a line. A line will give you a boat-load of goods, or it can be
one box of goods. But----
Mr. Nielsen. Well, the problem I see with that is, FDA can
ramp up the foreign inspections. If everything is done as it is
done now, you are still not going to deliver that information
into the import process. You must have the IT, and I believe a
user fee, a nominal, like 50 cents or $1.50 per line user fee
could be justified in providing service and the infrastructure
to do what needs to be done.
Mr. Stupak. So, in other words, if we did leave it at that
$1000, let us say, we have got to dedicate at least part of
that for IT, because without a data system we are done.
Mr. England. That is right.
Mr. Hubbard. If I----
Mr. Stupak. Go ahead. Mr. Hubbard?
Mr. Hubbard. The problem I have seen with user fees, Mr.
Chairman, is that the budgeters of the world see new money come
in the FDA, so they cut the budget in the non-user-fee areas,
and that clearly happened with the PDUFA program, so the food
program and the import programs have actually gotten weaker.
FDA has lost about 1,000 people in the last decade from
appropriated dollars, even though the agency's total budget has
gone up, due to these user fees. But the user fee money is
dedicated only to the review of new drug and device
applications.
Mr. Stupak. Correct.
Mr. Hubbard. So you have actually had a shift where some
programs are getting richer, and others are getting poorer. And
so I think you have to find a way to make sure that the budget
folks don't essentially take that money away from
appropriations----
Mr. Stupak. And then substitute it for annual----
Mr. Hubbard. Exactly. That is what happened with user fee,
and that is what happened with the earlier user fees, and so
you have to build some sort of firewall.
Mr. Stupak. OK. Mr. England?
Mr. England. I would say that the way I read the user-fee
legislation is that those monies would be used to essentially
help pay for border examinations and samplings of imported
product. I am afraid that it reinforces a finished product
testing regime. I also----
Mr. Stupak. Would you say it does not work, or is not the
preferred method of protection, finished product hitting the--
--
Mr. England. That is correct. And the end result----
Mr. Stupak. Do you want to explain this?
Mr. England. The end result is you are paying for a program
that is not really useful if you don't know the GMP status of
the manufacturer. I mean, if you were to test within the same
batch of drug, that batch, depending upon its size, could be
different at the front end of the process from the back end of
the process if GMPs are not in place. So if you happen to
sample from one portion of that, you may not even be able to
detect a problem within the same batch. So I think finished
product testing of drugs in particular is troublesome, but, and
I agree with Mr. Nielsen's idea of funding the IT program
perhaps through user fees at the border level. I think another
aspect about it is that if you take that money and then put it
into GMP inspections in the foreign facilities, now you have
the U.S. importer paying for essentially inspections by the FDA
in the foreign market and getting free quality assurance advice
from FDA, and who knows how many times they have to go back
before they get it right? So I think perhaps you could do it on
the registration end of it, and that way you have some gate,
and people wouldn't be inclined to go on and just register
their facilities if they knew that there was money that was
involved in it, a. And b., that that money could be used to
fund the FDA conducting an inspection in their facility.
Mr. Stupak. Good point. Ms. DeGette, for questions? I
believe you have eight minutes, since you waived your opening.
Ms. DeGette. Thank you. Thank you, Mr. Chairman. Well, all
of you testified that the FDA needs increased resources to
inspect these foreign facilities, and I certainly agree with
that, but I don't think it is just an issue of resources
because you also testified that the current computer--I think
Dr. Crosse in particular testified that the current computer
systems are inadequate for cross-referencing and determining
the various facilities abroad, so I am wondering if you can
comment, how much of the problem is more resources, and how
much of it is an inadequate computer system, and what can we do
to get the FDA to update their computers?
Ms. Crosse. Well, I think it is both. I think part of the
resource issue is resources to update their information
technology systems and that the resources have not been devoted
to that, and there was some testimony about plans that they had
had that were scrapped, largely because of the lack of
resources.
Ms. DeGette. But do you think there is a commitment on the
FDA's part to--a recognition that their IT systems are
inadequate and a commitment to improving those systems?
Ms. Crosse. I believe that there is a recognition that
their systems are inadequate. I think that the question is
better asked of others, whether there is a commitment.
Ms. DeGette. All right. Let us hear from Mr. Hubbard.
Mr. Hubbard. I would say that I saw the import folks and
the regional affairs folks ask for funding over and over again
through the budget process for these systems, going all the way
back to your hearings of the 1980's, and that money was always
denied. And even the current administration, they had this
theory that too many IT resources were being wasted, and FDA
was being constantly squeezed on IT, when IT actually saves you
money in the end.
Ms. DeGette. Right.
Mr. Hubbard. I hope that Dr. von Eschenbach will describe
how he is committed to fixing that system now, but money is
clearly the reason that they don't have it now, in my view.
Ms. DeGette. Well, another thing that we could do with
money, aside from improving the IT systems, is improve the
system of inspection that we have. Dr. Crosse testified, and
she briefed us yesterday on this pathetic system that they have
for actually inspecting the overseas facilities, where they
take a volunteer, and the volunteer goes into this factory, and
then the volunteer doesn't even have a translator. I can't
imagine how you could get any adequate information inspecting a
facility when you didn't even have someone to translate for
you, especially if it is a foreign facility that has a vested
interest in not providing and willfully withholding
information. I am wondering if you can comment a little further
on that, Dr. Crosse.
Ms. Crosse. Well, we certainly think that is a concern.
When they have a need for translation services, they are, in
general, relying upon a representative of that establishment to
do the translation for them. I have talked with some of the
folks from FDA's Office of Regulatory Affairs, and they
indicated that they believe there are many items they can look
at. They can still physically inspect the plant and see if
whether there are, you know, leaking pipes and other sorts of
problems, that some of the data they need to review is numeric,
but some of the data they need to review is not numeric, and
some of what they need to obtain has to be gathered through
interviews and discussions with officials there in the
facility. And so----
Ms. DeGette. And then they are relying on----
Ms. Crosse. I have a concern.
Ms. DeGette. And they are relying on translation by
representatives of the officials at the facility.
Ms. Crosse. That is right, and they are relying on that
facility having an understanding of what is expected out of our
regulatory system.
Ms. DeGette. And counsel just told me he was in a factory
in China, and they wanted to talk to some of the employees, and
the State Department representative who was with them said, you
know what, what the translator is saying these people are
saying, they are not saying. And you would have no way to know
that if you were just some FDA inspector standing there, right?
Ms. Crosse. Correct.
Ms. DeGette. And that is a place where resources might
help. Does the FDA, in your opinion, acknowledge this problem
as well?
Ms. Crosse. They have been reluctant to acknowledge this as
a problem to us.
Ms. DeGette. Does anyone else have a comment on the whole
inspection process and how it can be improved, Mr. England?
Mr. England. I would just note, and actually a number of
days ago I was on the phone with somebody in the FDA, and that
happens to be one of the foreign inspection cadre participants
who has done inspections quite a number of years for FDA as a
foreign inspector, and recounting, you know, they have a short
period of time to get in-country and maybe a long trip. They
are tired when they get there. They have a couple of days to do
an announced inspection, maybe 2 or 3 days, which, that same
inspection, if there are problems identified, which there
probably will be, in a foreign inspection, would probably have
been stretched out to 10 to maybe 14 days, and then they have
to get on the train or plane, get the next one. By the end of
several weeks, now they are going back to their notes and
trying to remember and rebuild the inspection and do their
inspection reports. I mean, I think all of those kinds of
things, those add to the complexity of just even the current
system at FDA. Add translation, add the fact that the
volunteers are doing it, that it is announced. Many times the
inspector is relying on the inspected firm for transportation
between locations.
Ms. DeGette. Great. Now, when the FDA inspects domestic
facilities, it can arrive unannounced, it has more enforcement
ability over domestic than foreign countries, and it doesn't
have to have things translated, and I am wondering if we need
to beef up our foreign inspections, realizing that these are
all impediments. Dr. Crosse? Or, Mr. Nielsen?
Mr. Nielsen. I think that is very--I mean, there has to be
a credible presence in the industry to give the incentive to
comply, for those provisions that do result in safe products.
There has to be a credible presence.
Ms. DeGette. And one last question, to Dr. Crosse's point,
the GAO findings are that the current U.S. firms are inspected
every 2 years by the FDA, correct?
Ms. Crosse. The data that they provided to us show that
they actually get there about every 2.7 years.
Ms. DeGette. And there is no Law defining the time between
inspections for foreign firms and, in fact, at the foreign firm
inspection, because of FDA's reliance on volunteers and so on,
it is much more sporadic than domestic. Is that right?
Ms. Crosse. That is correct.
Ms. DeGette. So I would think it would make sense to
require that foreign firms shipping drugs to the U.S. be
inspected at least as frequently as U.S. firms. Would you not
agree with that, Dr. Crosse?
Ms. Crosse. I think there is certainly every reason to
believe that the risks abroad are the same or greater than the
risks in domestic establishments.
Ms. DeGette. Would the rest of you agree that we should
have at least the same type of inspection system we have for
domestic firms, Mr. Hubbard?
Mr. Hubbard. Well, I think it would be meaningless without
the resources. They can't do the current statutory requirement
of every 2 years. If you impose that on them for foreign, they
would simply fail, so you would have to have some sort of
provision to make sure that they have the resources.
Ms. DeGette. Well, obviously, you can't do the inspections
without the resources, but don't you think that we need to have
some kind of a standard for the foreign inspections, especially
in light of the recent revelations that we have had from China
and other countries? I mean, we are not even talking here about
drug counterfeiting. We are not talking about drug re-
importation from the Internet. We are talking about legitimate
drug ingredients that are used for FDA-approved drugs, and we
are not even able to inspect them because we don't have the
resources to inspect them like we do domestically. That seems
like a backwards system, that we should really be focusing on
the foreign producers and obviously domestic, too, but it seems
like we shouldn't say, well, we are not going to inspect
foreign because we don't have the resources.
Mr. Hubbard. Well, you are absolutely right. It is
indefensible that we would be doing the domestic firms so
frequently and the foreign firms so infrequently, but again,
FDA has got to be given the wherewithal to actually do that.
Ms. DeGette. And do you think they have the will to do it
if we gave them the wherewithal?
Mr. Hubbard. I would certainly hope so.
Ms. DeGette. Mr. England?
Mr. England. I would note that in the worst-case scenario,
the equivalency is made between the domestic and the foreign
industry as far as the frequency of inspection, without
resources. What that would at least force is a shifting of
existing resources towards risk. It really should force a risk
assessment with regard to foreign versus domestic, because in
these foreign manufacturers, many times these countries are
developing countries. They don't have a regulatory regime, like
we have in the United States. They may not have potable water,
at least in the community. Hygiene could be deficient. So I
think the risks, if you were to actually lay them side by side,
the risks would be greater in the foreign market. I think it
would at least force that shift into the foreign market.
Ms. DeGette. Thank you. The Chairman was right. This was a
wonderful panel, one of the best I have seen in my years in
Congress. Thank you for your testimony.
Mr. Stupak. Mr. Burgess, for questions.
Mr. Burgess. Thank you, Mr. Chairman. Dr. Crosse, in your
testimony, and forgive me for being out of the room. So if this
has been asked, I apologize. On the use of translators, how big
a deal is that?
Ms. Crosse. I think in some countries it has got to be an
enormous deal.
Mr. Burgess. Is there a risk that, since we are depending
upon the company, the manufacturer, to provide the translator,
that it could be an inside job or an inside plant?
Ms. Crosse. There certainly is that risk. That is a concern
that we would have.
Mr. Burgess. Are those interviews or exchanges that are
taking place between the FDA and the manufacturer through a
manufacturer's supplied intermediary, are those taped or
transcribed? Is there any way to quality check the quality of
the information that has been given back and forth? Because
even with someone's best of intentions, just in the
translation, as we all know, things can get lost.
Ms. Crosse. Not to my knowledge. No, I don't believe so.
Mr. Burgess. On the whole issue of the database, I guess,
Mr. England, this morning downtown former FDA Commissioner Mark
McClellan was addressing this issue, more from the standpoint
of how it interacts with, do we get the most efficient
technology, do we deliver the most value for the patient, and
the previous lack of a reliable database at the FDA, in this
country, for those types of activities, made that a real
problem. I think it was referred to as stove-piping. I had a
younger staffer who didn't know what a stove pipe was, so maybe
we had better use silo. I guess they know what a silo is, maybe
not from farm country. But Dr. McClellan was talking about the
coverage side low, the technology side low, and how we needed
to be able to bridge that gap, and it sounds like we are kind
of talking about the same phenomenon here. Is that correct?
Mr. England. I think it is true that the IT systems FDA has
are siloed, and they are really wrapped around the agency's
internal siloing.
Mr. Burgess. And yet in the private sector, because we also
heard testimony from--or, not testimony, but it was a symposium
downtown with Health Affairs for their 25th anniversary, I
think it was Mr. Williams from Aetna Insurance Company. It
seems like I heard 10 years ago that they reinvested about 10
percent of their capital into health information technology or
information technology, and this morning he gave a figure of 15
percent of his work force of 34,000 people across the country.
Most of them aren't out there selling insurance and doing
customer service. 15 percent are actually involved with
development of software, maintaining their infrastructure, and
I think he made the statement, I may be misquoting, but I think
I heard him say that if Aetna's information technology
department were a stand-alone company it would be one of the
largest software development companies in the United States. So
it just goes to underscore how much private industry in this
country has recognized that they must invest in this, and it
sounds like, even though we did make some big steps in the FDA
reauthorization bill as far as monitoring the treatment
database, we have got to do a lot more as far as certainly this
aspect of it, in monitoring foreign manufacturers. Is that a
fair assessment?
Mr. England. I do think it is fair. I would even add that I
think because of those kinds of investments in the private
sector, and particularly in the areas where FDA has
jurisdiction, and the risks maybe even perceived with some
relevance between what FDA is trying to do and what maybe, for
instance, Aetna might be trying to do, there are more off-the-
shelf technology that you can take and you can modify rather
than developing systems from scratch. I mean, the OASIS system
essentially is a from-scratch software development program.
There are some off-the-shelf elements to it, but that ends up
costing a fair amount of money, to try to develop it and then
maintain it. Then you become married to a contractor as well,
which is problematic.
Mr. Burgess. And what would be some examples of that, in
the private sector currently?
Mr. England. Examples of off-the-shelf technology? Well, I
mean----
Mr. Burgess. What companies are, say, doing that in the
private sector that are doing it well, that have maybe a
similar problem that the FDA has?
Mr. England. You would probably see most of it in the
Customs international transactional environment, and you would
see it in--that is why I don't want to misidentify any specific
companies----
Mr. Burgess. Right.
Mr. England. But you also would see it in the defense area,
where you have just got many, many transactions, risk that is
built into those transactions someplace, and the ability to
process a high volume, high, fast stream of data, in order to
think about that data, in order to assess and mitigate risk.
Because we will never be able to eliminate that risk, but
we ought to be able to manage it a little bit better than we
are doing. Now, I get the impression from talking to the panel
that this--I think, Mr. Hubbard, you said 1986 was the earliest
figure I heard, but 1998, the year 2000, I mean, this has been
something that we have all been aware of, and I am a recent
arrival, but people have been aware of for some time, so
through several administrations, both Republican and
Democratic, through several Congresses, both Republican and
Democratic, so this obviously doesn't become a partisan issue
or an issue that is isolated to one administration, but I would
just ask, since there is so much familiarity with it over time,
what--we have a relatively new FDA Commissioner, Dr. Crosse,
have you spent time talking to Dr. von Eschenbach about this?
Ms. Crosse. I have not.
Mr. Burgess. OK. Mr. Nielsen, what sort of interplay have
you and Dr. von Eschenbach had on this issue? Have you brought
this to his attention and some of the previous suggestions that
were out there, from 2000?
Mr. Nielsen. No, I have not.
Mr. Burgess. OK. And, Mr. Hubbard?
Mr. Hubbard. I was trying to describe how the Commissioner
is juggling so many priorities, and when there is not funding
to deal with them effectively, some things fall away, and I
think imports has been one, historically, that has not been
able to rise to the top for funding. Perhaps, as a result of
some of your work this year, that will change.
Mr. Burgess. And, Mr. England, have you talked with Dr. von
Eschenbach about this?
Mr. England. I had the pleasure of meeting him for the
first time today.
Mr. Burgess. Well, he is right behind you, so I urge you to
get his card and do talk to him about this, because it is
clearly important, and clearly, legislation is going to be
developed, not from this subcommittee, but out of our full
committee, and it is important that we get it right on just so
many levels, the safety level now and how we monitor and
maintain the system decades into the future. So I yield back,
Mr. Chairman.
Mr. Stupak. Well, thanks, Mr. Burgess. Now you see why it
is so important to have Dr. von Eschenbach for all these panels
that they can direct----
Mr. Burgess. But I was trying to make sure we make good use
of his time----
Mr. Stupak. As you were saying earlier this morning----
Mr. Burgess. This morning, and I wanted to draw that in.
Mr. Stupak. Mr. Whitfield, questions? I am going to ask a
few more, and if you want to go back to the mike, we will go
back for a couple more questions. If I may, Mr. England, you
talked about, I think it was page 19 of your testimony, about
the Bioterrorism Act that we passed, I think it was in about
2002, and it came out of this committee, I know that, and you
mentioned food, but we don't have drug imports in there? And
that should be amended?
Mr. England. The provision that I was speaking about is a
provision that requires the agency to design and implement
information technology systems related to imported food that
will assist the agency in allocating its resources where the
greatest risk of, in that case, intentional adulteration of
food. But one of the elements there, also, was to facilitate
the importation of food that is in compliance with the Act, and
I perceive that as being really the opposite side of the risk
coin. There is a tremendous amount of product that is out there
that is safe. The difficulty is knowing which is which. I mean,
to go to the issue of the fact that the domestic manufacturers
do screening, that is true, but that is different than saying
that therefore we are safe. And so the opposite side of the
risk coin is that where industry can demonstrate that they are
in compliance with GMPs in the case of the drug industry, that
product should be facilitated. That provision, though, is
restricted to imported foods. It doesn't cover drugs, devices,
or any other commodities regulated by FDA.
Mr. Stupak. In questions of Mr. Walden, based on this
newsletter from U.S. Food and Drug Administration, FDA, on
Ensuring the Safety of Imported Products, we were kicking
around the numbers. It was 30,000 out of 18 million that they
look at each other, and I think you said it was about 10
percent related to drugs, so even if you gave the figure of
30,000 to use, FDA analyzes about 30,000 import product samples
annually. Even at 10 percent, or 1.8 million, that is only like
two percent, if my math is correct, 30,000 into 1.8 million.
That is only, like, about two percent, then, correct?
Mr. England. Well, 20,000 of that 30,000 would be foods, so
you are really talking about 10,000 out of 1.8 million.
Mr. Stupak. So it is probably----
Mr. England. We are assuming the balance are all drugs,
which I don't think they would be. They would be biologics and
other products.
Mr. Nielsen. And, Mr. Chairman, I would expect the majority
of those drug samples to be from activities at the
international mail facilities.
Mr. Stupak. So the figure might be closer to 20 percent of
one percent of drugs.
Mr. England. You are beyond me in your math.
Mr. Stupak. I am beyond myself, too. That is why I am
asking you.
Mr. England. I think to Mr. Nielsen's point, though, there
also is that, let us say for the sake of discussion that it is
5,000 to 7,000 of the--30,000. Probably a large percentage of
those are inspections conducted by folks at FedEx or UPS or an
international----
Mr. Stupak. For Customs, or whatever it may be.
Mr. England. Looking at very, very small packages that
Customs happens to kick out. In other words, not 30 metric tons
of product coming in. Probably a good percentage of even the
drug inspections would be related to that.
Mr. Stupak. But then it gets to the point I was trying to
make. If it is only one percent of the food that we are
inspecting, drugs are far less than that one percent, then, of
the drugs coming in here, so it is a problem, not just against
drugs from foreign countries, but also food, drugs. I mean, we
got a serious problem here. And it seems to lie with the
databases, at least that is where we should start. Mr. Nielsen,
there is a new program. Can you explain a little bit? I think
it is called Predict, that is used for seafood? And that got
funded through an earmark, correct?
Mr. Nielsen. Yes.
Mr. Stupak. A congressional earmark that everyone is
against right now but this was an earmark that was actually put
in. That is how it got funded at the FDA. Can you explain this
a little bit more to me? How would it relate here to drugs?
Mr. Nielsen. Yes, and it actually also falls into some of
the low-hanging fruit of the ISP that was implemented. But the
Predict model is being piloted or at least was being piloted, I
believe in Los Angeles, for the seafood industry. I was program
manager for the development while I was Director of Import Ops,
which is why I know about it. But what it really does is it
starts to integrate information from both external and internal
sources. It actually learns the risk posed for imports based on
a variety of data points and will assist the entry reviewer in
deciding which of the riskier shipments to do the examinations.
Mr. Stupak. Thank you. Mr. Burgess, do you have any further
questions before we let this panel go?
Mr. Burgess. Yes, I do, Mr. Chairman. Thank you for coming
back to me. Just to follow up on my last thought before we got
cut off, I mean, we have all been fairly intense in our
criticism of the FDA, which is fair. The Commissioner of the
FDA has been in his position since December of last year, so
not quite a year. Mr. Hubbard has already correctly alluded to
the fact that there is lots of things going on at the FDA, lots
of different things to juggle, so it is fair to criticize the
FDA, but at the same time if we have got constructive
solutions, and it sounds like we have had those, at least been
thinking about those for at least 20 years, so, I mean, again,
I just concur it was a great panel, but I encourage you to
follow up with Dr. von Eschenbach, and let us talk about these
and explore them. Don't, you know, don't leave it to us to
write the Law by, you know, a vacuum, because I don't think we
will do a very good job. So we count on your input, and we
count on that input being delivered to Dr. von Eschenbach, so
in turn the agency can help us help the agency. Now, on the
issue, Mr. Hubbard, you mentioned human tissue at one point, I
think, in your discussions. Is that correct?
Mr. Hubbard. Right. Well, that is just one of many, many
things that have popped up in recent years that needed
attention, got some, but then drifted away.
Mr. Burgess. Well, it got my attention when you said it,
because obviously there have been some fairly disturbing, even
macabre, stories in the news in this country about some
practices with dealing with human tissue that I found very
disturbing. Are we importing human tissue products from
overseas?
Mr. Hubbard. When I was in it, there was some. We did a
sting in which a Romanian gentleman was selling us the body of
a Russian gentleman who had apparently died in the street, and
he died of AIDS, and he was selling his whole body to us and
shipping it via the airlines flight that day. So, I mean, it
was that kind of example that caused the Commission at that
time to put in place some rulemaking and beef up regulation.
The problem is, the funding was never there, in my opinion, to
really have a permanent program to inspect tissue banks to make
sure they were following proper procedures.
Mr. Burgess. Is that likely to still be continuing today,
as we have seen this advance in globalization and all the other
pressure put on the drugs, the toys, the food imports? Is it
likely to be additional pressure put on----
Mr. Hubbard. I don't know exactly what is going on out
there now, but I can't imagine the FDA has sufficient resources
to adequately inspect all of that industry.
Mr. Burgess. Well, Mr. Chairman, I know that is beyond the
scope of this hearing, but I would encourage this committee to
very seriously consider--for some time I have thought that we
ought to look at the use of human tissue that originates in
this country. I had no idea, no idea that there was the
possibility that there is human tissue coming from outside. And
Mr. Hubbard correctly alluded to some of the problems there,
and if there is lack of quality in the active ingredients in a
Lipitor pill, goodness knows, we want that quality assurance
for people who are going to have human tissue grafted or
implanted. One last thing, Mr. Nielsen, on the good
manufacturing practice, it seems like that would affect the
whole debate of re-importation. That is, if we want good
manufacturing process, and we are crying out for more
inspections and more funding for the FDA to do more inspections
and move that chart graph that we saw, so that that blue area
becomes as a greater and greater footprint, but then we have
people in Congress today who are arguing for, hey, we can get
cheaper drugs if we just allow re-importation from Canada, and
of course the supply chain then comes from who knows where, so
it almost seems as cross purposes to argue for improvement of
good manufacturing processes and at the same time argue for re-
importation Laws. Am I missing something?
Mr. Nielsen. If the two are not connected, absolutely.
Mr. Burgess. Well, just by definition, or at least the
legislation I have seen offered for re-importation, it doesn't
really seem to have a lot of control. It just says, from
Canada, and we have all seen the reports that what looks like a
maple leaf might in fact be an insignia of some other country
and, as someone said, from the darkest corners of the world. So
if we embrace re-importation wholeheartedly, again, as some
people have suggested, and that is a bipartisan issue. I am not
putting that in anyone's theme in particular, but we know who
has been arguing for that pretty forcefully for some time,
basically that ends all product testing, does it not?
Mr. Nielsen. Yes, and I have to say, on the GMP, the
principle of the GMP is it is going to prevent the entry--it is
really going to contribute, but it is the whole process, from
the application process for the prescription drugs, to the
post-surveillance process, including adherence to the GMPs. If
you don't have the whole picture, you are just adding risk to
it, and I have to give an example. This is not just a finished
drug issue. The industry that is overseas are also finished
product manufacturers. There is even less oversight of the
ingredients going into the finished products overseas. At least
here, when the APIs or the ingredients come in, it is not going
to a black hole. We know where it is going. It can be checked.
There is a warehouse. There is a facility to go to, and there
is a process for checking potency, identity, and certificates
of analysis, and it is not an issue of waiting for more bodies
to show up. The med watch, the adverse events are not
necessarily going to say everything is going to be OK unless
there is an adverse report here. The carbamazepine scenario
experience that I painted in my written testimony is a good
example where the products going into the formulation have a
potential adverse effect if it is not in compliance with both
the application and the GMPs governing that manufacturing
process. The good thing about the carbamazepine is if it didn't
work, carbamazepine is an anti-convulsant drug. If it didn't
work, the epileptics were seizing. You could see it.
Mr. Burgess. So the bio-assay was positive.
Mr. Nielsen. On the other hand, if a drug, like gentamycin,
is knocking your kidneys out, you are not necessarily going to
see it. And you are not necessarily going to know that it is
not doing what it is supposed to do. I believe generally the
public, all of us, have kind of been trained, if something
doesn't work, something is wrong in my metabolism that caused
that drug not to work. Well, maybe yes, maybe no. And what we
are trying to do is say that there is a way to minimize the
risk from that drug that is supposed to help you.
Mr. Burgess. I thank you for that. It was very
illuminating. Mr. Chairman, I do just need to mention, I think
I mentioned a drug by brand name, and I was using that only for
the purposes of illustration. I have no knowledge that that
drug of that brand name even is manufactured in China. So I
apologize for that oversight. I was simply trying to make a
point, and I yield back.
Mr. Stupak. You have an 80 percent chance of being correct.
Dr. Crosse, thank you, and thank you to your staff for pulling
everything together quickly. I know you are going to continue
your work, and this committee and subcommittee appreciate it.
To our panel, thank you very much. Both sides, everyone has
been saying what a great panel. We could go round and round on
questions, but we do have two other panels. But thank you for
your time. Your 80 years of experience with the FDA certainly
helped us out here today. Thank you very much. I will dismiss
this panel, and we will move to our second panel of witnesses.
Mr. John Dubeck, the partner in the law firm of Keller and
Heckman, as well as counsel to the Bulk Pharmaceutical
Taskforce at the Synthetic Organic Chemical Manufacturers
Association; Mr. Bruce Downey, chairman and CEO of Barr
Pharmaceuticals and chairman of the Generic Pharmaceutical
Association; and Mr. Guido Villax, the immediate past chairman
of the Pharmaceuticals Business Committee and member of the
Board of Directors of the European Fine Chemicals Group.
Gentlemen, would you all come forward? It is the policy of this
subcommittee to take all testimony under oath. Please be
advised that the witnesses have the right under rules of the
House to be advised by counsel during their testimony. Do any
of you wish to be accompanied by counsel? All witnesses
indicate no, so I ask you, raise your right hand, take the
oath, please.
[Witnesses sworn.]
Mr. Stupak. Let the record reflect the witnesses answered
in the affirmative. They are now under oath.
Mr. Dubeck, we will begin with you, with your 5-minute
opening statement, please, sir.
TESTIMONY OF JOHN DUBECK, PARTNER, KELLER AND HECKMAN, LLP, AND
COUNSEL, BULK PHARMACEUTICAL TASKFORCE, SYNTHETIC ORGANIC
CHEMICAL MANUFACTURERS ASSOCIATION
Mr. Dubeck. Mr. Chairman, and members of the subcommittee,
on behalf of the Bulk Pharmaceutical Taskforce and the
Synthetic Organic Chemical Manufacturers Association, SOCMA, I
thank you for this opportunity to testify on two key points.
First, the current system for regulating imported drugs is
putting American consumers' health and safety at risk. Second,
there is a solution; more frequent and in-depth inspection of
the foreign facilities making these drugs.
The Bulk Pharmaceutical Taskforce submitted a citizens'
petition to FDA in January of last year, outlining the risks
associated with imported drugs and providing suggested
solutions. These risks have been well highlighted already, and
I will not repeat them. We are disappointed that we have
received no substantive response from the agency.
The drug manufacturing industry today is structured vastly
different than it was 30, 20, or even 10 years ago. No longer
are drugs primarily manufactured in-house by the major
pharmaceutical companies. Rather, these companies have
increasingly turned to outsourcing their ingredients and
sometimes even the finished product. The suppliers of these
outsourced products are overwhelmingly foreign manufacturers.
FDA is required to inspect domestic drug establishments every 2
years. These inspections are unannounced, and a single
inspection can extend over many weeks and may involve many
separate visits. And I might add that on subsequent visits at a
given inspection an inspector may call in other experts in
specialties to assist in observing something that is seen
during the first part of an inspection.
This is no comparable obligation on FDA to inspect foreign
facilities. Since FDA must be invited to perform its official
duties on foreign soil, a foreign facility always receives
several weeks' notice of an impending inspection, and the
length of the inspection is typically driven by travel
schedules, rather than the compliance status of the facility,
and it is impossible to bring additional expert investigations
to review specific issues. As a practical matter, a foreign
manufacturer is unlikely to be inspected for cGMP compliance,
except in the context of a pre-approval inspection. If you
wish, I can explain later the difference between pre-approval
inspections and cGMP inspections and why the former is of
little value in assuring the ongoing quality and purity of
imported drugs.
If routine cGMP inspections are unlikely to occur, it is
very tempting for management to put a low priority on
maintaining cGMP compliance. Statistics presented at a cGMP
conference in 2005 indicate that cGMP inspections of foreign
firms result in significantly more violations than seen in
domestic firms. When comparing data solely from pre-approval
inspections, the same discrepancy is seen. Deviations from cGMP
were more serious in foreign facilities than in U.S.
facilities. These numbers cry out for FDA to conduct more
frequent inspections of foreign facilities. They also
underscore that the frequency of foreign cGMP inspections is so
low that managers of foreign facilities have apparently made
the business decision to spend less time, attention, and money
on ensuring that their drug manufacturing operations comply
with cGMP than is necessary to assure compliance.
A dramatic and drastic overhaul of FDA's approach to the
risk posed by foreign manufactured drugs is long overdue. The
manufacturing side of the pharmaceutical industry has changed
substantially, and yet FDA's allocation of inspection resources
remains unchanged from an earlier era. In order for FDA to give
cGMP inspections of foreign facilities the priority it
deserves, the Bulk Pharmaceutical Taskforce proposed that FDA
do three things. FDA should abandon its policy of prioritizing
domestic and foreign facilities separately for inspection. FDA
should rank domestic and foreign facilities together, based on
the risks that the products from each facility pose to the
American consumer. If there are 100 foreign facilities with
higher risk profiles than the highest-ranked domestic firm, the
American consumer is ill-served unless those 100 foreign
facilities are inspected before the domestic firm.
Foreign sites, particularly those owned by U.S. companies,
would welcome more inspections of all foreign sites. This will
only happen if FDA is required to have comparable inspection
frequency for domestic and foreign facilities.
The U.S. market for pharmaceuticals is large and lucrative.
FDA's recent action to restrict imported vegetable protein
unless and until it could be shown to be free of melamine is
evidence of its broad authority to prohibit the importation of
products that appear to be adulterated. Furthermore, this is
where FDA has an enforcement advantage with regard to foreign
facilities versus domestic. It has no need to prove in an
enforcement action that a product is adulterated. Imported
products can be refused admission if they merely appear to be
adulterated.
A second proposal is that FDA should consider a facility's
foreign status per se as a risk factor in its risk-based
inspection program. As I noted earlier and explain in greater
detail in attachments to my written presentation, all
statistics indicate that drugs sourced from foreign facilities
pose greater risks to America's public safety. When a facility
is inspected infrequently there is a natural tendency for
management to become complacent. Maintaining cGMP compliance
requires constant effort and vigilance, and it is a well-
traveled road from minor deviations to serious quality
failures.
Importantly, even if FDA conducts more frequent inspections
of foreign facilities, we believe an additional risk factor
should still be assigned for foreign facilities. As a practical
matter, any inspection that provides prior notice, is
constrained by travel arrangements, and suffers from the
communications problems inherent when dealing with
documentation that is in a foreign language while using a
translator provided by the facility, is bound to be less
effective than an unannounced inspection of indeterminate
duration, conducted in the investigator's native tongue.
The Bulk Pharmaceutical Taskforce's third request is a
stopgap measure that FDA could implement before it has the
resources to conduct adequate foreign inspections. It could
actively test and monitor the impurity profiles of active
pharmaceutical ingredients produced in facilities that FDA has
never inspected.
Allow me to elaborate here. New drugs require prior
approval. Pre-approval inspections are part of that prior
approval process, but not all drugs are new drugs. Drugs that
are not new drugs do not require prior approval and do not
require a pre-approval inspection. These are the facilities
that are likely to never have any inspection, not a GMP
inspection, not a pre-approval inspection. Further, there have
been many prescription-to-over-the-counter switches in the past
few years. One of the earliest of those switches was ibuprofen.
In August 2002, FDA proposed to move ibuprofen from new-drug to
not-new-drug status. In response to the Chairman's question
about behind-the-counter drugs, and are we just moving more
drugs into a non-approved status, the issue is really not
whether it is Rx, OTC, or behind-the-counter, the issue is
whether it is a new drug that at least has a prior approval
inspection, or a not-new drug. And FDA's proposal would move
more drugs into this uninspected, not-new-drug category.
To be sure, testing and monitoring would be a poor
substitute for onsite inspections, but given budget and
staffing considerations it would be a great improvement
compared to doing nothing. Just as a stopped clock is correct
twice a day, a non-GMP-compliant facility will periodically
produce drugs that meet specifications. It is reasonable to
assume that foreign manufacturers with sub-standard cGMPs will
cherry pick production lots and ship to the U.S. only
ingredients that meet specifications. When different batches of
products coming from the same facility have significantly
different impurity profiles, it is reasonable to conclude that
they did not come from a process that is in control.
Mr. Stupak. Mr. Dubeck, I am going to have to ask you to
wrap it up here, please.
Mr. Dubeck. Just that if FDA observes through monitoring of
variable impurity profile, it could refuse admission on the
basis that the products appear to be adulterated. We sympathize
with FDA's resource limitations, but it is imperative that
foreign manufacturing facilities be inspected at the same rate.
In closing, I note that although there are many economic
factors that have resulted in nearly half of all drugs marketed
in the U.S. being produced in foreign facilities, the fact that
such production attracts less aggressive FDA oversight surely
contributes to the trend. On behalf of SOCMA and the Bulk
Pharmaceutical Taskforce, I thank you for your time and
attention to this serious matter. I will be happy to answer
questions.
[The prepared statement of Mr. Dubeck follows:]
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Mr. Stupak. Thank you, Mr. Dubeck. Mr. Downey, please, for
opening statement. Your full statement is in the record, so if
you could summarize and keep it to five minutes, we would
appreciate it.
TESTIMONY OF BRUCE DOWNEY, CHAIRMAN AND CEO, BARR
PHARMACEUTICALS, INC., AND CHAIRMAN, GENERIC PHARMACEUTICAL
ASSOCIATION
Mr. Downey. Yes, thank you, Mr. Chairman. I am Bruce
Downey. I am Chairman and CEO of Barr Pharmaceuticals. Barr
produces hundreds of prescription drugs here in the United
States and Europe, both brand and generic, both finished goods
and APIs, so I think we have a broad range of experience that
is relevant to the committee's consideration today. In fact, in
the U.S., we market nearly 5 to 6 billion tablets a year, so we
have quite a bit of experience. I am also chairman of the GPhA,
which is a generic trade association which represents companies
that produce over 95 percent of the generic pharmaceuticals
sold in the United States.
And I would like to comment on one part of the testimony
earlier this morning. I think it is not correct to say that you
can't buy products that aren't made in China. I mean, if you
look at the largest members of our association, Barr, Watson,
Teva, Mylan, Sandoz, none of those companies make finished
goods in China, and the overwhelming majority are made either
in the United States or Europe or Israel. So I think that part
of the testimony wasn't correct.
But it is important to testify today on the committee's
issue of FDA foreign inspections, and I think one thing is
clear to me, and I think it was clear to the panels before me,
that there is no justification for having fewer inspections of
foreign facilities than we have of domestic facilities. And I
say that as someone who is responsible for both. They pose
equal risks. There just simply is no justification for that.
The question I think is most important is what is the
appropriate level of oversight, and what are the different
kinds of risks we are trying to manage? And I think there was
some confusion this morning in testimony about two very
different kinds of risks that require two very different kinds
of responses. One risk is, in terms of number of incidents, is
quite small. That is the risk of counterfeit. Compared to
lawfully produced drugs, it is a quite small amount, but it is
also the group that proposes the greatest risk. And inspection
is not the answer to counterfeit drugs. People who make
counterfeit products don't register their facilities in the
database at FDA, the 6,000 or 3,000-firm database. They try to
avoid detection, so the response for counterfeiting is to
discover the counterfeiter and put them out of business. I
mean, inspection is really not the issue. And the second issue
is how do you review the compliance of lawful manufacturers,
who have registered with the FDA, who have gone through the FDA
approval process, and what is the appropriate role of
inspection in monitoring their compliance with their overall
commitments?
I think that, first and foremost, we have to allocate the
amount of resources necessary to ferret out and put
counterfeiters out of business. They pose the greatest risk,
and that isn't necessarily foreign inspectors so much as
investigators, the criminal investigation group at FDA,
international law enforcement authorities, and I think there we
need to provide whatever resources are necessary to make sure
that risk is completely covered.
If you look at the second risk, the risk posed by FDA-
regulated companies, I think today Mr. Hubbard mentioned, and I
think he is right, we have an incredibly safe system. We have a
system because testing and inspection is only one very small
component of the overall FDA-regulated process. Now I would
just like to go through it for you so you get a sense of how
comprehensive it is.
In the development area, for example, we inspect all of our
raw material suppliers' active ingredients before we even take
in samples. Once we receive the samples, we work with the raw
material manufacturers developing appropriate specifications
for that compound, which are incorporated into our section of
either the NDA or the ANDA file at FDA, and our raw material
supplier incorporates that in the DMF, which is filed with the
FDA. Those specifications and all the other components of the
application are reviewed and approved by the FDA, and our
commitment is to manufacture our products in conformity with
those specifications and the processes that are part of our
application.
Once the application is approved, and we continue to market
the product, we routinely inspect our raw material suppliers,
on average about every 3 years. We have a staff of 12
inspectors, covering the globe, inspecting our raw material
suppliers, and they are supported by support staff and the
like. So we do that self-policing, and FDA expects us to do
that self-policing. I think it is different in the toy industry
or other kinds of industries. That is the requirement of part
of our obligation to be in FDA compliance, and we take that
very seriously.
And once we are in production, as we receive lots of raw
material, we receive a certificate of analysis from our
producer, and we retest that lot so that we confirm the test
results obtained by the raw material supplier, and then as that
raw material is incorporated into finished goods, it is tested
in process, and it is tested as finished good release and
ultimately tested on stability to ensure that it remains potent
through its shelf life. So there is an enormous amount of
testing in the Rx system that ensures that products that we
sell and present to consumers meet the requirements that we
have in our applications.
And then once we get into post-marketing, we have to
monitor adverse events, we have to investigate complaints we
receive from pharmacists, physicians, patients. We conduct
annual reviews on all of our products which analyze the test
results of all the batches from the previous year, compare them
with batches from years before that. We look at any complaints
we have received and the adverse events. So we have a
comprehensive review on each, individual product to satisfy
ourselves that the product is being made safely and
appropriately.
So I think in terms of inspections in the United States, we
have five production facilities, and we have had seven
inspections, GMP inspections, in the last 18 months. If you
look abroad, I think you heard the testimony today, it is far
less frequent, and I think the key element that I would like to
leave you with is there is just simply no justification for
that. I think that we have a very safe system because of all
the safeguards built in. Inspections are one component, but not
even the most important component of that system. It is
important, but it should be spread evenly across the globe.
I would say that, if I were in charge of the overall
inspection program and I heard the testimony today, I would
tomorrow morning reallocate resources that were being used to
inspect domestically to foreign inspections, because there is
no justification for that disparity, and I would then try and
work to get the additional resources to have all the facilities
inspected at the frequency that we thought would be
appropriate. And I think there are different ways to raise
those resources. One is the direct appropriations. Second is
through a user fee program that could be expanded to generic
products and to raw material suppliers. And then third is your
legislation, Mr. Stupak. I would think that is a way to raise
the funds. I don't think it is probably the preferred way, and
I would suggest that the focus not be on further testing of the
material but in developing the infrastructure that was
described this morning, the computer systems to monitor
products as they move through the system, and ultimately to
have enough inspectors to conduct the frequency of inspections
you would like to have both here and abroad.
Just one last point, I think there is no justification
either for having a different standard for OTC products and Rx
products. We are generally in the Rx business, but people take
products either way, and I think they pose similar risks and
should be similarly treated.
[The prepared statement of Mr. Downey follows:]
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Mr. Stupak. Thank you, Mr. Downey.
Mr. Villax, I understand you came from Europe to be with
us, and we appreciate that. Thanks for being here, and we look
forward to your testimony. If you would begin, please. Make
sure your mike is on.
TESTIMONY OF GUIDO VILLAX, IMMEDIATE PAST CHAIRMAN,
PHARMACEUTICALS BUSINESS COMMITTEE, MEMBER OF THE BOARD OF
DIRECTORS, EUROPEAN FINE CHEMICALS GROUP, BRUSSELS, BELGIUM
Mr. Villax. Thank you. Good afternoon, Chairman Stupak,
Ranking Member Whitfield, and members of the House Subcommittee
on Oversight and Investigations. Thank you for inviting the
European API industry to testify on the FDA's foreign
inspection program. I am here in representation of the European
Fine Chemicals Group. I am Guido Villax, chief executive of
Hovione, a producer of APIs based in Portugal, present in China
and in the U.S.A. Hovione was founded by my father 50 years
ago, so it has been about 40 years that I have had a front seat
watching changes in the pharmaceutical industry.
The European Union, like the U.S.A., has rules in place to
assure that the active pharmaceutical ingredients used to make
medicines meet cGMPs to assure that each medicine is identical
to the product approved by the health authorities. Last
century, medicines were either patented or branded and were
manufactured mostly in the West, in-house, and in compliance
with GMPs.
The world has changed. Today, driven by the demand globally
for lower healthcare costs, off-patent medicines make up the
majority of pharmaceuticals we consume. 80 percent of the API
volume used to make EU medicines comes from abroad, and not
everyone is playing by the rules. This is putting the safety of
our citizens at risk. Globalization has resulted in the
emergence of off-patent API production in the low-cost
economies where regulations and GMP requirements are very
limited compared to those in the EU. More complex and
fragmented supply chains increase the potential for
contamination, mislabeling, or substitution of one substance
for another, all of which increases the risk to patients.
Unprecedented pressure on prices and profit margins drive
generic and OTC companies to buy formulations and APIs at the
lowest cost, sometimes from API plants that have never been
inspected by any health authority from the EU or the U.S. This
pits quality and ethics against profits, in an uneven fight.
Without enforcement, the least scrupulous operator wins. In
this new world, the West no longer produces the antibiotics
that fight anthrax. The compliant industry has to meet ever
growing, tougher regulations that add 25 percent to the cost.
This makes cGMP-compliant plants uncompetitive versus non-
compliant ones.
The EU regulatory framework has not kept pace with these
dramatic changes. The lack of effective oversight, inspection,
and no enforcement by the authorities has encouraged non-
compliant, illegal trade, including the importation of APIs
into the EU, mainly from Asia, via certain brokers and traders.
This allows them to offer lower prices from a non-compliant
cost base and to import substandard, often counterfeit APIs
with a low chance of being caught. Oddly, the EU inspects API
plants based on proximity, not risk. In a year, European
authorities may inspect 30 to 50 API plants in Asia, when Italy
or France inspect a greater number in their own country alone.
The few foreign inspections by the European Directorate of
Quality of Medicines, EDQM, tell us something is broken. All
the suspended approvals resulting from inspections were related
to production in Asia. None were in the EU. All approvals that
were withdrawn by EDQM related to filings in the name of
middlemen. Some of the suspended approvals are of APIs for old
OTC drugs that could well be exported to the U.S.A. and those
facilities FDA would not have inspected. Some of the suspended
approvals and FDA warning letters seem to be related to API
producers that receive support from middlemen.
Last month, EFCG asked the European Commission to improve
the oversight and enforcement of the regulations for APIs by
increasing inspection resources and enforcement sanctions by
adopting some of the systems that the U.S. FDA has in place and
that here have been quite strongly criticized, but I would like
to emphasize that we don't even have those in Europe. And the
last thing we recommended to the European Commission is that
they should take the leadership to regular middlemen and to
seek international cooperation between agencies around the
world.
Several supranational bodies, the European Parliament, the
USP, and the WHO have recently recognized that more inspections
are key to stop non-compliant APIs from reaching the market.
Unscrupulous players cannot be allowed to take advantage of
uncoordinated jurisdictions that allow them to escape by
crossing the State line. The generics and the OTC medicines
that the world needs cannot continue to be regulated by 20th-
century structures and resources. The answer lies in more, but
especially smarter, enforcement and the global cooperation of
national medicines agencies. Thank you.
[The prepared statement of Mr. Villax follows:]
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Mr. Stupak. Thank you, Mr. Villax, for your testimony. I am
going to start with questions. We will start with the chairman
of the full committee, Mr. Dingell, for questions, please.
Mr. Dingell. Mr. Chairman, I thank you for your courtesy.
Mr. Villax, yes or no, isn't it true that in some places like
China and India basic clean water and sanitation are major
problems?
Mr. Villax. I think that, absolutely, yes. However----
Mr. Dingell. Doesn't this then mandate that a higher level
of care with regard to products of those countries, especially
with regard to inspection of plants there, should be one of the
guidelines of the United States' policy with regard to imported
foods and drugs?
Mr. Villax. China has made tremendous progress.
Mr. Dingell. But the progress isn't enough. They have still
got lots of dirty water, polluted air, major problems with
sanitation and health over there. And doesn't require us to
engage in much more careful inspection of products that are
manufactured there? Yes or no.
Mr. Villax. Yes.
Mr. Dingell. OK. And thank you for that. I don't mean to be
discourteous, but I have got 5 minutes, 1 minute of which is
now gone. Now, gentlemen, these questions. Dr. Dubeck, isn't it
true that nearly half of all drugs marketed in the United
States are produced or manufactured in foreign facilities and
that that number is increasing?
Mr. Dubeck. Those are statistics from FDA and GAO, correct?
Mr. Dingell. Isn't it a fact that cGMP inspections of
foreign firms result in significantly higher violation levels
than are seen in domestic firms?
Mr. Dubeck. That is what was reported at the Georgia GMP
conference, correct?
Mr. Dingell. Isn't it fair to say that foreign firms
generally pose a greater risk with regard to quality and safety
to consumers than do domestic firms?
Mr. Dubeck. I think that necessarily follows from the
above.
Mr. Dingell. Now, Mr. Downey, do you agree that the current
imbalance between foreign and domestic inspections places U.S.
domestic firms at a competitive disadvantage?
Mr. Downey. In some ways, yes. Other ways, no.
Mr. Dingell. In other words, we have got to meet high
standards, and they don't.
Mr. Downey. That is true, but it is also more difficult to
get a pre-approval inspection for a product as a foreign
manufacturer, so you are at a competitive disadvantage because
you are inspected less frequently.
Mr. Dingell. And they can slip bad stuff in here, and get
away with it and American firms can't?
Mr. Downey. I don't believe bad stuff is being slipped into
the country. I don't think that is so.
Mr. Dingell. Well, let us see about what the findings of
this committee might be on that particular point. Now, do you
think that it would be beneficial to have FDA open offices in
those parts of the world that are significant exporters of
production to the United States of prescription
pharmaceuticals?
Mr. Downey. I think there should be parity in inspections,
and that is one way to increase the inspections in Asia. Yes,
sir.
Mr. Dingell. Now, Mr. Downey, isn't it true that if a
facility is not inspected frequently, the safety of drugs
coming from that plant could be affected?
Mr. Downey. Could be, but not necessarily would be.
Mr. Dingell. But there is a better chance if they are not
inspected than if they are.
Mr. Downey. The inspection of the facility is one component
of a very comprehensive regulatory system, and----
Mr. Dingell. And it encourages good behavior and a right
conscience, does it not?
Mr. Downey. I think responsibility of what we are doing
encourages behavior, and that is the basis----
Mr. Dingell. Now, isn't it fair to say that as long as
FDA's foreign drug inspection program is so poorly funded and
its IT systems in disarray that our medicine supply is at risk?
Mr. Downey. I believe we need better foreign inspections,
more resources in that area, yes.
Mr. Dingell. Good. Mr. Villax, you had a comment.
Mr. Villax. Yes, I think that there has been a lot of
emphasis that we need more inspections, and I agree, but the
fundamental impact of inspections is deterrence, and this is
what is needed. You ought not to have areas of the industry
that get zero inspections. You ought to have them spread out
and probable. That is what causes the drive for compliance, and
this is where Europe is catastrophically weak.
Mr. Dingell. Gentlemen, you can have inspections at the
point of entry, you can inspect for efficacy and safety here,
but you also have to inspect or you have to have knowledge of
whether good manufacturing practices are carried forward in the
country of origin, and also whether or not the different
components that are exported here or the components that are
included in that country are in fact safe. Is that not true?
Mr. Villax. In fact, you must absolutely check the process.
Mr. Dingell. And not only the process but the components.
Mr. Villax. Well, I was talking from an API perspective.
When you make the active ingredient, you obviously have some
accepted sources or approved sources of raw materials, but you
need to make sure that it is GMP compliant, and you need to
make sure it is regulatory compliant. What I mean by this is
that you have to check two things. One, that you follow good
manufacturing practices.
Mr. Dingell. Yes.
Mr. Villax. The other thing is that you need to do what you
have put in your filing. In other words, the inspectors need to
make sure that what is in the filing in Washington is the same
thing that actually is taking place in the plant. Because that
is the only way you can actually guarantee traceability and
that what you did in your bioequivalence test remains the same
thing year after year.
Mr. Dingell. Gentlemen, I want to express my thanks to you.
I apologize for being so brusque, but that clock is a harsh
master. Thank you.
Mr. Stupak. Now Mr. Whitfield, for questions.
Mr. Whitfield. Thank you, Mr. Chairman. Mr. Villax?
Mr. Villax. Villax.
Mr. Whitfield. Villax, OK. Now, my understanding, you are
actually the chief executive officer of a company that makes
medicine, correct?
Mr. Villax. We manufacture APIs, both for the generic
industry and the innovator industry.
Mr. Whitfield. OK. And so you import into Portugal--is the
plant in Portugal?
Mr. Villax. We manufacture in Portugal, and we had our
first inspection by FDA in 1982 and export to the U.S. market.
We also manufacture in Macao. It is in south China, and that,
we had our first inspection there in 1987 and export into the
U.S.A.
Mr. Whitfield. Now, tell me again. You alluded to this a
little bit. How would you compare the European system with our
U.S. system as far as maximizing the safety for the consumer?
Mr. Villax. Well, Europe has been late in bringing in
systems that you have had for three, four, or five decades.
Europe does not yet have a foreign inspection system, although
the industry has been pushing them.
Mr. Whitfield. So Europe does not have any foreign
inspection system?
Mr. Villax. Well, we don't have a foreign inspection
system, but we have certain authorities around Europe that make
a special effort to go abroad and check. We have especially
something called the EDQM, the European Directorate for Quality
of Medicines, that is associated to the European Pharmacopoeia,
and they have been the agency that have tried hardest to go
abroad. But I think the numbers that I have is that in 7 years
they have done 80 inspections internationally, which is very
small.
Mr. Whitfield. In 7 years. Wow. So I know it is difficult
to summarize this, but as bad as our system is in the U.S., I
mean with our shortcomings, I am going to say----
Mr. Villax. You are way ahead.
Mr. Whitfield. We are way ahead.
Mr. Villax. And you are the gold standard.
Mr. Whitfield. All right.
Mr. Villax. In other words, if GMPs were developed, with
thanks to FDA, and Europe has been free riding on what FDA has
been doing.
Mr. Whitfield. Really?
Mr. Villax. Absolutely.
Mr. Whitfield. So despite our shortcomings, we are the gold
standard, and Europe has been free riding with us, then. That
is good. Now, let me ask you, you discussed in your testimony
some of the--no, actually it wasn't you. I guess it was Mr.
Dubeck. You discussed in your testimony some of the risks
presented by the fact that over-the-counter drugs are not
subject to any pre-approval barriers, especially with regard,
and I think you mentioned ibuprofen, and how would you propose
that FDA remedy that problem?
Mr. Dubeck. Well, ibuprofen is currently a new drug and is
under all of the inspection and reporting that Mr. Downey
summarized. The FDA proposal is to make it a not-new drug. Once
it does that, all of the additional precautions that Mr. Downey
mentioned disappear, and all you really have left is cGMP
monitoring. So there needs to be the same level of inspection
of OTC facilities because even though they may not have some of
the same inherent risk as some very new prescription drugs,
they are consumed by the public in much larger quantities.
Mr. Whitfield. Right.
Mr. Dubeck. And so impurities in those products wind up
causing much greater exposure to the American public, and there
is no inspection.
Mr. Whitfield. Which is hard to believe, really.
Mr. Dubeck. Our members that make these APIs and try to
compete also find that hard to believe.
Mr. Whitfield. Now, the foreign establishments that produce
these active pharmaceutical ingredients are not required by
Federal Law to register with the FDA if their products are not
directly imported into the U.S. Now, considering that more of
these manufacturers are being outsourced, you would recommend
that all the establishments be registered with the FDA?
Mr. Dubeck. If they are--I mean, under the Law, a drug
includes finished-dosage form and components of drugs. The
registration requirement includes APIs, so right now
registration is required for all the API manufacturers.
Mr. Whitfield. Even if they are not directly imported into
the U.S.?
Mr. Dubeck. No, only if they are imported into the United
States.
Mr. Whitfield. OK. All right. Now, Mr. Villax, would you
please describe the European Union Law that requires a
qualified person employed by a drug company to assure the
quality of APIs used in medicines?
Mr. Villax. Yes, this is a very recent legislation.
Mr. Whitfield. All right.
Mr. Villax. It came into force in October 2005, and what
that legislation says is, first, it is based on the fact that
we do have now as Law something that in the industry we refer
to as in other words, there is well-defined law that defines
what are GMPs, and the Law that came in, in 2005, states that
the QP, the qualified person, that is, the person that releases
batches of finished product in the marketplace, this person has
to make sure that they only use APIs that meet GMP. So this is
a bit of self-regulation. In other words, Europe doesn't really
believe in inspections, I think wrongly, and what they are
expecting is that the QP takes personal responsibility for
checking that the APIs meet GMP, and how this QP is expected to
meet these obligations is by developing a close relationship
with the producer of API. Like Mr. Downey said, he has a team
of six auditors that go round the world producing audits so
that the QP is expected to have audit reports that satisfy him
that the producer of the API meets the GMP.
Mr. Whitfield. And are there significant sanctions if a
company improperly assures the quality of the API?
Mr. Villax. I have written a couple of articles that
compare or that say that the liability of the QP is
substantially lower than that of a CPA that signs off a balance
sheet. In other words, shareholders are better protected than
patients, and one of the requests that we have made to the EU
Commission is that they have to somehow come up with personal
liability for the QPs, because otherwise we have the purchasing
department fighting with the quality unit.
Mr. Whitfield. Right.
Mr. Villax. And we all know who is going to win.
Mr. Whitfield. Thank you very much.
Mr. Stupak. Mr. Inslee, for questions.
Mr. Inslee. Thank you. To put it in the vernacular of the
peasantry, this is a fine kettle of fish that we have got. 80
percent of our active ingredients coming in from imports. It is
doubling the amount every 5 years, and we find out we just
don't have a meaningful inspection protocol. It is most
troublesome, and I just want to ask if my understanding is
correct that we are proposing that that actual situation is
going to get worse. As I understand it, I am told that the
full-time equivalents, the FTEs of the FDA's foreign inspection
program, was 149 in 2002. By fiscal year 2008, the FDA
estimates that number will actually drop to 102. Now, we have
tried to remedy that in our budget by increasing some of these
appropriations. The president has threatened to veto our
budgets, didn't have a veto pen for the first 6 years of his
presidency, and all of a sudden he wants to veto these budgets.
My understanding is that essentially, even though we already
have a pathetically indifferent system to these imports, they
are wildly less protective of the American public than our
domestic production. I am told we can't even find out who these
manufacturers are to have a really good compilation of them.
Even though we are already bad, we are going to get worse
unless we can override this president's veto on these
appropriations bills. Could you gentlemen help us in
understanding if that is correct or not?
Mr. Downey. I wouldn't agree with a good deal of your
comments. I will say this, that we have 12 full-time auditors
that audit our raw material suppliers, and we are a very small
part of our drug supply system, so I think having 100 or 150 is
definitely inadequate. But I don't agree----
Mr. Inslee. I am sorry. Did you say inadequate?
Mr. Downey. Absolutely, inadequate. I don't think you can
properly fulfill the role that inspection plays in the overall
regulatory process with that number of inspectors. I just don't
think it can be done. But, on the other hand, I think we have
in place a very large number of safeguards that I explained in
my testimony that I think protect and ensure that we have high-
quality, safe pharmaceuticals. I think the biggest risk are
counterfeiters who don't register, don't subject themselves to
inspection, and we really need to make sure that the first
priority is allocating the resources to discover the people who
are blatantly and in criminal violation of our statutes
bringing products into the United States and supplement that
with appropriate levels of inspection for those who are
regulated.
Mr. Inslee. Well, foreign field inspectors would help on
the counterfeit problem, would they not, as well?
Mr. Downey. I don't think they have a very large role in
that at all.
Mr. Inslee. OK. Well, let us talk about the first problem.
I thought I heard Mr. Downey say that there is no legitimate
reason to have a lesser standard of inspection for foreign
manufacturers than for domestic manufacturers?
Mr. Downey. I absolutely think that is true.
Mr. Inslee. You totally agree with that? Well, if you look
at the chart up here that I am holding, showing the FDA foreign
field funding, you see a constant decline that we are trying to
remedy in our appropriation that the president has threatened
to veto. Now, I want to make sure that I understand your
testimony. I thought you were telling us that you want, you
thought we should have the same level of inspections----
Mr. Downey. Absolutely.
Mr. Inslee. For foreign productions as domestic. We are not
doing that right now, and we have a decreasing number of people
that are going to do that, so I would assume you agree with me
that that is a bad state of affairs, and we should increase the
number of inspections and we should override the president's
veto if we have to, to get that done.
Mr. Downey. I think we should increase the number of
inspections. As I said, I think my recommendation would be
that, starting tomorrow, you reallocate inspectors to the
foreign inspections because relative to domestic inspections
they are too infrequent, and simultaneously work to increase
the resources to have enough inspectors to conduct the
appropriate number of inspections of both.
Mr. Inslee. Well, I think this hearing is instructive,
because I think it is important for the American public to know
that we have got a president who is threatening to veto a bill
that will increase protections of Americans against foreign
imports that do not meet accepted standards, and I am hoping
this hearing can help remedy that situation. Thank you.
Mr. Downey. I have very little power over the veto.
Mr. Inslee. We have some. We might need a few more votes.
If you have any friends, you might talk to them. Mr. Villax,
did you want to say something?
Mr. Villax. Yes. The plants located abroad that make APIs
find these inspections very important because it is tough to
meet the requirements of an inspection, and we need these
inspections to make sure we have a level playing field. And the
members of our association, we have gone on record to say we
are happy user fees for these inspections. These are important
inspections to have.
Mr. Inslee. Thank you. And when the EU gets a role in
Congress we know you are going to help us override this veto.
Mr. Villax. Well, I think you should approach the EU and
say that you want to set up some kind of, or FDA needs to agree
with them, to recognize each other's inspection reports. This
is what I meant by more smarter enforcement, because they do
between 20 and 50 inspections in Asia.
Mr. Inslee. I think that is an interesting proposal. Thank
you.
Mr. Stupak. Thank you, Mr. Inslee. Actually, that has been
a proposal the committee has made to the FDA, that why don't we
recognize the inspections that the EU may be making, provided
your regulatory scheme, which is same or similar to the FDA? It
doesn't make any sense for the EU to do one, and 6 months later
the FDA comes in. We could do that--Do you share information?
Does the EU share information with the FDA? Let us say you go
to a place, and you inspect, and you find a problem here. In
this country we call them 483s, a violation on inspection. Do
you share that information?
Mr. Villax. As I understand it, the Europeans approached
FDA many years ago to do these memorandums, or these mutual
recognitions, but since we didn't have a Law about what were
the standards of GMPs, it never moved forward. And I think
until such time as we have a foreign inspection program in
Europe it won't work, because you can't talk to 27 agencies.
You have to talk to a single one. Now, I understand that
informally there is quite a bit of information that goes
backwards and forwards.
Mr. Stupak. Well, good, but do you agree you don't know
what it would be on inspections of foreign plants?
Mr. Villax. This is very complicated, and it is very
political.
Mr. Stupak. I understand. The QP you talked about, this
quality person within the plant, the company that is
manufacturing the API, they are responsible for that
individual?
Mr. Villax. No, no. No, the pharmaceutical company that
makes the pills that go into the market----
Mr. Stupak. But not the API?
Mr. Villax. The API company----
Mr. Stupak. You don't have any QPs in your plant in
Portugal.
Mr. Villax. Not for the role that you are describing.
Mr. Stupak OK. So it is just the pharmaceutical that makes
the finished product?
Mr. Villax. Yes.
Mr. Stupak. And then that individual is responsible to make
sure the ingredients, the API ingredients, going into the final
product is----
Mr. Villax. Were made according to GMP, yes.
Mr. Stupak. OK.
Mr. Villax. So that is why they audit.
Mr. Stupak. And then that standard would be based upon the
country in which they are shipping it to?
Mr. Villax. The GMP standards that have to be met and that
the QP has to certify are the GMP standards of the market where
the pills are going to be sold, and----
Mr. Stupak. Correct.
Mr. Villax. In Europe we now have the same standards.
Mr. Stupak. OK.
Mr. Dubeck. Chairman Stupak?
Mr. Stupak. Yes, Mr. Dubeck.
Mr. Dubeck. I would like to comment that all the
inspections that the U.S. pharmaceutical companies do of
imported APIs do provide a high degree of quality assurance,
and so the mere fact that APIs made overseas don't get
inspected very much, that would include Mr. Villax's products,
does not mean we don't have high confidence in them. You will
see, however, that many more approval applications are now
being filed by foreign companies, which means that what is
coming in are finished-dosage forms, and you don't have the
U.S. manufacturer analyzing, reanalyzing the API and all the
quality steps that have been described when it comes in as a
finished-dosage form.
Mr. Stupak. Well, my question is going to be, and I don't
know if Mr. Downey or to you, Mr. Dubeck, if you have a quality
person, you have the same thing at Barr Pharmaceuticals, I take
it? Or not----
Mr. Downey. In our European facilities, for products made
for sale in Europe, they are released by the QP.
Mr. Stupak. What about here in the United States then?
Mr. Downey. Well, they are released by our quality
control----
Mr. Stupak. OK. Do you have any plants overseas and not in
Europe, not in the United States?
Mr. Downey. No, all of our plants are in--well, we have a
plant in Croatia, which is not part of the EU, but it is
European.
Mr. Stupak. Do you have a quality person there?
Mr. Downey. Yes, we have QPs. Actually, the QP for release
into the EU is in our polish facility, because not only does
the QP have to be there, but the actual release testing for the
European Union must be done in a European Union country, and so
our release testing for product made in Croatia is Poland.
Mr. Stupak. OK. Well, let me ask you this question. Our
committee staff was both in India and China during the August
break to check on the manufacturing practices at some of the
facilities over there. Our staff met with senior government and
industry officials in India, and both expressed strong support
to have the FDA locate a permanent office in India. China, we
got just the opposite. We got a push-back about having
permanent offices in China. Do you think it would be beneficial
for the FDA to open offices in those parts of the world where
significant drug production or APIs for the U.S. market is
taking place?
Mr. Downey. That is one way to address the need to have
parity in inspection, is to have people on the ground. That
would certainly reduce travel time, would probably be less
expensive, and I would say that that reaction, I am not
surprised, and I think the Indian pharmaceutical industry is
more advanced in terms of its quality systems, its exposure to
Western regulation, more modern regulation than our Chinese
suppliers. So I am not at all surprised by that. In fact, I
mentioned earlier, our Indian members of the GPhA complain that
they can't get inspected fast enough for their new product
approvals. As we mentioned earlier, there has to be an
inspection prior to a new approval, and they can't get people
on the ground there, and it is very frustrating to them.
Mr. Stupak. Right, and the Indian government officials felt
that if we had a permanent office there that those inspections
would take place much quicker.
Mr. Downey. It is certainly an idea that is worth
exploring. I can't comment as to whether it is the right way or
not.
Mr. Stupak. Mr. Dubeck, would you care to comment?
Mr. Dubeck. I think it would make a whole lot of sense. If
we have overseas U.S. personnel for Customs and Immigration and
for USDA, it makes sense it should be there for FDA.
Mr. Stupak. Well, let me ask you this, Mr. Dubeck. In your
testimony, it says that cooperative arrangements with foreign
governments to determine the safety of drugs for the U.S.
market are, and I quote now, ``a poor substitute for a visit by
the FDA''. The FDA is currently negotiating a memorandum of
agreement with China with regards to product safety. Are you
saying that this type of arrangement won't protect the safety
of the drugs as much as a FDA inspection of a plant in that
country?
Mr. Dubeck. Correct. I mean, these memorandum provide for
sharing of information, so that FDA would at least have access
to whatever inspection reports the Chinese may conduct, but, as
it has been commented, FDA is the gold standard. The FDA
inspectors, when they get there, they do the best inspections,
and so, I mean, that is part of the problem of relying upon
inspections by other government agencies. They are not the
same.
Mr. Stupak. GAO indicated and also our staff has reported
back that when you go to a foreign country, let us say like
India or China, you are under a time limit of how much time you
actually have, which is really counter-productive to-- in the
United States, if it takes a month, it takes a month. In
foreign countries, if you only have 3 days, you get in what you
can in 3 days.
Mr. Dubeck. Yes, and when it takes a month in the U.S., it
is usually not a month, every single day of the month.
Mr. Stupak. Right.
Mr. Dubeck. They come for a few days, they go back, they
get caught up on their paperwork, then they come back, they may
bring other people with them when they come back. And so it is
much more conducive to doing a thorough, competent job than
when you are on the road, going from hotel to hotel.
Mr. Stupak. I agree. Mr. Villax, in discussions with
committee staff, you expressed concern that the U.S. does not
sufficiently inspect foreign production of over-the-counter
medications or the ingredients that go into them. Why is this
important? What dangers come from the failure to inspect this
class of medicines?
Mr. Villax. I was referring very much to the issue that
John Dubeck raised, and this is related to the older drugs
that, as I understand it, are not in the realm of probability
to be inspected, and I think that the deterrence factor of FDA
inspections is the critical aspect and therefore every single
drug establishment ought to have a probability of being
inspected.
Mr. Stupak. OK.
Mr. Villax. And if I could add something on the
inspections.
Mr. Stupak. Sure.
Mr. Villax. Inspections abroad and inspections in the U.S.
are really very different. When FDA inspectors come to Hovione,
we invite them, and they are pre-announced, and they do not
last as long--it probably lasts 3 days or 5 days--but we have
had inspectors that have changed plans because they wanted to
stay longer. But they also start at 8 o'clock in the morning
and probably stay until 7 o'clock in the evening, and one of
the reasons why these inspections can go much faster is that in
the U.S. inspection, they have to collect data and have proof
in case they are taken to Court. In Europe, they have no need
to collect proof because if they don't like it they pick up the
telephone, they call Washington and say, tell Customs to hold
everything from Hovione. And we can't take them to Court, so it
is probably more effective and faster.
Mr. Stupak. The unadulterated drug angle of it. OK.
Mr. Downey. I would agree on that point that the problem is
the frequency of inspection, not the quality of the inspection,
at least as we experience it. I don't know about the language
barrier so much in Asia, but in European inspections, I would
say that they are quite comparable between the U.S. FDA
inspections conducted there and those conducted here in our
facilities.
Mr. Villax. One of the----
Mr. Stupak. Well, that is one of the things that we are
asking the GAO to follow up on, and then what happens to a 483
when it hits the FDA? What I understand, they are basically
deep sixed. Nothing ever happens to them on a foreign one, so--
well, those are things we are asking GAO to continue, and that
is why Dr. Crosse and her group did a great job given what they
had, but we are following up. Go ahead, Mr. Villax.
Mr. Villax. One of the benefits of having offices in India
or China is to bridge the culture. The culture distance between
the U.S. and Europe exists. But there is a much greater
distance, and I think having inspectors that gain an
understanding of these cultural differences is probably very
helpful in an inspection.
Mr. Stupak. Well, thank you, and thank you to this panel
for your insight and your assistance on this problem that has
been going on for some time. We are trying to address it. We
appreciate you coming. Mr. Villax, thank you for coming over
from Europe and sharing your insight on what you are doing in
Europe. Mr. Downey, Mr. Dubeck, thank you. We will excuse this
panel, and we will call up our third and final panel.
Our witness to come forward is the Honorable Dr. Andrew von
Eschenbach, Commissioner of the Food and Drug Administration.
Accompanying the Commissioner is Ms. Margaret Glavin, Associate
Commissioner for Regulatory Affairs at the FDA. It is the
policy of this subcommittee to take all testimony under oath.
Please be advised that witnesses have the right under the rules
of the House to be advised by counsel during their testimony.
Dr. von Eschenbach or Ms. Glavin, do you wish to be represented
by counsel today? Both witnesses indicate they did not.
Therefore we will take the oath, and we will begin.
Dr. von Eschenbach. Mr. Chairman, may I? Also at the table,
joining me is Deborah Autor, our Director of the Office of
Compliance, and would you swear her in as well, sir?
Mr. Stupak. OK.
Dr. von Eschenbach. Thank you.
Mr. Stupak. Would you spell that for the record, please,
just, Dr.----
Dr. von Eschenbach. A-u-t-o-r.
Mr. Stupak. A-u-t-o-r? OK. OK. Raise your hand, then.
[Witnesses sworn.]
Mr. Stupak. Let the record reflect that all three witnesses
have indicated the affirmative. That means they are under oath.
Dr. von Eschenbach, you are the only one going to be giving an
opening statement?
Dr. von Eschenbach. Yes, sir, I will give the sole opening
statement for this panel.
Mr. Stupak. Welcome, and please, whenever you are ready.
TESTIMONY OF ANDREW C. VON ESCHENBACH, M.D., COMMISSIONER, FOOD
AND DRUG ADMINISTRATION, U.S. DEPARTMENT OF HEALTH AND HUMAN
SERVICES; ACCOMPANIED BY MARGARET O'K. GLAVIN, ASSOCIATE
COMMISSIONER FOR REGULATORY AFFAIRS, FOOD AND DRUG
ADMINISTRATION, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES.
Dr. von Eschenbach. Thank you, Mr. Chairman and members of
the subcommittee, Mr. Whitfield. I very much appreciate the
endurance and the attention that the panel and the committee
has given to this very important issue. I very much appreciate
the opportunity to engage in a dialog about FDA inspections of
foreign pharmaceutical managers. But I think it is also
apparent from everything we have heard this morning and this
afternoon that we realize what the FDA has known for some time,
and that is, this problem is much bigger than the number of FDA
inspections that occur abroad. This is a problem that really
addresses a much more global issue, and I want to begin by
applauding the work of the committee and the committee's staff,
particularly the counsel, who is present with us today. I want
to appreciate the time that they have taken to update the FDA
on the observations that they made during their recent foreign
inspections, on which they accompanied FDA inspectors in China
and in India. I find this dialogue to be very helpful to me and
to the FDA staff.
We are well aware that, whether it is China or India, the
fact of the matter, Mr. Chairman, is the world is and has
radically and rapidly changed around us. We have heard about
the enormous challenges but also the great opportunities that
are now confronting us with regard to the issue of
globalization. Mr. Whitfield was very kind this morning in
commenting on his support of leadership at FDA to effect the
kind of changes that we must effect if we are going to be
responsive to these new challenges and these new opportunities.
And it is not only with regard to leadership as it relates to
identifying the need for and the application of resources
through a budget process, but even more importantly our
responsibility to present to you, to the administration, and
most important to the American people a strategy and a plan as
to how we would, in fact, begin to utilize these precious
resources in the most effective way. And so I would like this
afternoon to highlight just a few of the things that we are
doing at the FDA to not simply build our capacity to better
assure the safety of medical products or components that are
produced abroad or that Americans use at home but also what we
are doing to modernize the entire function and structure that
is needed at the FDA if we are going to continue to be what we
have just heard from our witness from Europe. We have been and
are the world's gold standard, and we intend to continue to
maintain that standard of excellence, but it will require
change.
Mr. Chairman, we all know that, given the scale and scope
of the problems that have been defined by you and other members
of the committee, the solution to assuring the quality of
imports does not reside only in increasing the number of
inspections we perform abroad or even at our border. In fact,
we agree, we must revamp our entire strategy, our entire game
plan, and we are doing this as it relates to the importation of
drugs and components of drugs from other countries in exactly
the same way that we are adapting our strategy and our approach
to all other FDA-regulated products. We are adopting an entire
life-cycle management and engagement process, from the very
production, all the way through to consumption. And so much of
our production now comes from outside our borders, we must be
global in our regulatory approach.
This total life-cycle engagement is consistent with the
first report of the President's Import Safety Working Group, on
which FDA, along with other members of the Cabinet, is an
integral part of the process. This import safety working group
report emphasizes the key components of FDA's new strategy. We
will be engaged in the total life cycle of these products
through implementation of initiatives that address prevention,
intervention, and our ability to respond. And we will do this
in a way that first and foremost assures quality is built in to
the products before they ever reach our borders, and we will
use greater resources and more modern sources of science and
technology to further enhance our efforts at both inspection
and verification, as well as leverage those resources through
collaboration and partnership with other government agencies,
other governments abroad, other regulatory agencies, and, most
importantly, the industry.
Let me give you one example of one of the tactics or
implementations that we have incorporated in this approach, and
that is our ability to use information technology, which is
critical across the entire spectrum of prevention,
intervention, and response. We recognize as the GAO pointed out
that information technology infrastructure was a problem at FDA
10 years ago, and it is a problem today. But unlike 10 years
ago, today we have technologies and capabilities that didn't
exist in 1997. None of us is using the same model of computer
or cell phone today that we did 10 years ago. We also have
recognized the development in other spheres of data mining
techniques and the ability to crosswalk through different data
systems, and our opportunity to adapt these new technologies
and these new strategies in IT is exactly how we will approach
and are approaching the modernization of IT.
I would like to point out on the panel's charts that will
be presented to you, if we could please put them up. The graphs
are on your screen, and if we could put the charts up, that
would be helpful.
[Slide]
Mr. Chairman, I would point out that this particular
schematic is a very complex display of the various components
of the information technology processes and components that are
operative in our ability to oversee the diverse portfolio that
FDA is responsible for regulating. As you can see on your left-
hand side, the current state is, and as has been pointed out,
there are multiple systems addressing multiple needs, but they
have been developed independently for specific missions, and
what has been absent is the ability to further integrate and
coordinate those systems. We have been engaged in a very
aggressive effort to migrate those systems into a unified,
coherent, single FDA approach to IT technology.
Once we have accomplished that, on the right-hand side, all
of those various applications will be able to have a degree of
interoperability of information sharing and information
analysis and outcome assessment that literally has not been
capable or able before, both because of technological
limitations as well as, as we indicated, structural changes
that needed to occur within FDA. In 2007, we brought in a Chief
Operating Officer and a Chief Information Officer, both of whom
had extraordinary experience in modernizing complex information
technology infrastructures. We created the Bioinformatics Board
at FDA to bring the operating components together to find
opportunities for synergy and interoperability, and we are
working with our external partners, particularly, for example,
as it relates to inspections, our colleagues in the Department
of Homeland Security-Customs and Border Protection, to further
enhance our opportunities for interoperability and
modernization of IT.
And we are allocating resources to this important issue.
Our 2008 budget request, currently before Congress, includes
$247 million for such efforts, and that actually accounts for
11 percent of the agency's budget, devoted and committed to
modernizing and implementing the kind of information technology
infrastructure that you and other members of the committee have
been calling for.
In addition to just simply looking at the infrastructure,
it is mostly and critically important to look at how we
interact with, collaborate, and cooperate with our partners.
This is a global problem, and it will require a global
solution. Inspections will verify quality, but they don't
create quality. Technology can exist, but it will never be able
to replace the ability of people interacting with other people
to create the kind of quality that Americans expect and will
continue to depend upon.
And so FDA is taking a very aggressive approach in our
effort to further enhance our own resources as it relates to
our ability to expand our workforce with the great, qualified,
talented people, as well as to collaborate more effectively
with our partners abroad so that we can collectively address a
problem that truly, as you heard from our colleague from
Europe, is something that everyone in the world is concerned
about.
Some of those opportunities are to expand FDA's
international presence beyond its borders. We are committed to
finding the kinds of options that you have discussed, namely,
placing FDA staff on long-term assignments in key locations
around the world, on a permanent basis. Our staff onsite in
those locations would have a number of important advantages
that weren't necessary in the past but are critical to the
future. They will be able to, number one, work very closely,
hand in hand, on an ongoing basis with our counterpart
agencies, who must be important partners in this global effort.
They will help build capacity in developing areas in which they
have not had the fruits and the benefits of the kind of support
that we have achieved or experienced here in the United States
with regard to your support of the FDA. We will be able to
provide technical assistance to foreign manufacturers to build
quality in and improve products long before they come to us,
and we will be able, as has also been indicated, on an ongoing
basis to create opportunities for partnership that transcend
cultural barriers, language barriers, and those things that
separate us rather than unite us. And we will have the
opportunity to leverage the impact of a global industry
expecting to produce and deliver global products around the
world.
We will be able to continue to expand our government-to-
government and agency-to-agency activities. Both Secretary
Leavitt, myself, and many, many FDA staff have been engaged in
substantial interactions with our counterparts, especially in
China. I personally visited China and interacted with my
counterparts, the Minister of Health, the head of the State
Food and Drug Administration in China, and leadership of its
export agency. We will continue these relationships to build
and assure the kind of quality that is necessary and to be able
to create the infrastructure that will assure that quality.
No one wants to live in the past, and neither you nor I,
nor any member of the committee, is satisfied with the status
quo of today. Together, I believe we can build for tomorrow the
FDA that will continue to be the gold standard of protecting
and promoting the health of not just Americans but everyone
else in the world as well. I look forward to the opportunity to
respond to any questions that you have.
[The prepared statement of Dr. von Eschenbach follows:]
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Mr. Stupak. Thank you, doctor, and thank you for being here
today and for listening to the first two panels, their
statements and their questions. The last time you were here at
the end of the meeting, it was on food safety. You indicated at
the meeting that it was important for you to hear the witnesses
and what they have to say on issues affecting the FDA, and I
appreciate that, and I appreciate your taking time to be here.
Dr. von Eschenbach. Thank you, sir.
Mr. Stupak. If I may, put up chart No. 3, the GAO chart.
This was GAO's chart earlier today--right there----
[Slide]
Mr. Stupak [continuing]. That they testified to and is part
of their testimony. If you would take a look, the first country
there listed is China, 714 plants with 13 inspections. How do
we close that gap? And you can go right up the line to any
country you want, but China and India are the biggest two
exporters to the United States. How are we going to close this
gap? I guess that is the whole question before this committee.
Dr. von Eschenbach. Mr. Chairman, I think we have a number
of strategies that must be and are being employed to close that
gap. Number one, as I indicated in my oral testimony, we are
engaged in government-to-government, minister-to-minister,
regulatory-agency-to-regulatory-agency interactions to build
capacity.
Mr. Stupak. Right. We are glad to hear you say that,
because when we met, committee staff met with Bill Steiger, he
is your Director of Office of Global Health Affairs and Special
Assistant to the Secretary of HHS, they told us basically they
weren't interested. They just pushed back on every suggestion
we have, like putting people in there, using other countries'
inspectors to help us, so we are very glad to hear that. In
fact, our staff on this committee, we are pleased to hear that.
We think that is a good start. We think India is a country in
particular that really wants the United States in there. The
only question I would have, then, as you do these agreements,
whether it is China, India, the UK, wherever, that country must
have some kind of regulatory scheme, then, for drug safety and
standards, much as ours, like----
Dr. von Eschenbach. Yes.
Mr. Stupak. Correct me if I am wrong, but China doesn't
have any standards like that.
Dr. von Eschenbach. Well, one of the important parts that
you are pointing out, and I think it is an important part of
this entire hearing's testimony, is that our presence in these
foreign countries gives us the opportunity to build capacity.
Build capacity, not just as it relates to our ability to
inspect more effectively this growing portfolio of producers,
but, even more importantly, to build capacity within those
regulatory agencies.
Mr. Stupak. Does that include putting people on the ground
there permanently?
Dr. von Eschenbach. Yes, sir. Yes, sir. As a matter of
fact, we look forward to that as being a very key element----
Mr. Stupak. We are glad to hear that, because we just think
that is one of the ways to go. We are going to do five votes,
and I don't want to keep you here with 45 minutes or waiting
for us for an hour to vote, so let us try to buzz through some
of these, if I may. Earmarks chart that you had up there, in
fact, the one that was up there before----
Dr. von Eschenbach. Yes, sir.
[Slide]
Mr. Stupak. The only caution I have on that is, we heard
all that before in 1998 and the 2000 hearing. Because everybody
was always worried about Y2K, and the FDA and all of them came
in with these same things. They said, we will guarantee all
these databases will talk to us. We are going to fix the Y2K
problem, and these will all talk to each other. They will be
integrated, and we won't have the problems. We still have the
same problems today, so excuse me if I am a little skeptical,
but why--my question, though, is, we heard from the previous
panel that this PREDICT which is a program going on right now,
you are using it for seafood, is doing all this, sort of
getting interoperable, grabbing the key words from different
databases, bringing it together. From what Mr. Nielsen said,
who used to be in your Office of Regulatory Affairs, it is
working, and it is working well. Why wouldn't you just expand
that instead of create a whole new computer regimen that I am a
little skeptical will work? If you have got one that is working
now, why would you disregard that and go to a different system?
Dr. von Eschenbach. We are not disregarding that, Mr.
Chairman. As a matter of fact, PREDICT is one of the important
models that we are beta testing, which I think has great
promise because of the kind of data that it acquires and puts
into our risk management system. In the interest of time, Mr.
Chairman, I would like to submit for the record a much more
detailed assessment of the specific steps that we are taking
that I think will demonstrate to you that this isn't just same-
old, same-old, or more planning, more ideas, but rather actual
implementation of many of the things that you have been
expecting and looking for. We heard this morning that there was
a plan that was developed by some of the members of the first
panel----
Mr. Stupak. ISP, correct.
Dr. von Eschenbach. And they seemed to indicate that
nothing had been done. I had not had the opportunity to hear
that before and respond to that, but I will be able to respond
to you with regard to the fact of the matter is, many things
have been done since that particular plan was put in place.
Mr. Stupak. Is the ISP plan being implemented?
Dr. von Eschenbach. Many parts and pieces of it are being
implemented, and in fact many parts and pieces of that have
been a core element of what is our more global import strategy
that is a part of the presidential import quality initiative.
Mr. Stupak. OK. You mentioned you are to spend----
Dr. von Eschenbach. I will submit that for the record.
Mr. Stupak. $247 million on this MARCS system to go to----
Dr. von Eschenbach. IT, and I want----
Mr. Stupak. Just in IT. Go to No. 4, if you would, chart
No. 4, from GAO.
[Slide]
Mr. Stupak. And here is what I want to know is, what
resources is it going to take to implement your full plan, your
IT plan, your increased inspections? If you look at this chart
right there, on the right-hand side of that chart as I am
looking at it, that is 2007, that is the lowest line. The next
one is 2008, where you predict a 40 percent increase in
inspections. Where are you going to get the resources? Have you
asked for additional resources for 2008? If so, how much is it
going to take to get back to where we are actually doing
inspections, which technically should be about 1,200 a year,
not 300?
Dr. von Eschenbach. We have asked and allocated in both the
2007 and have asked, and it is under consideration by Congress,
in the 2008 budget, increases in our resources to be able to
respond to this need, and we are continuing to build that
business plan as we are in the process of preparing our 2009--
--
Mr. Stupak. Will this be part of this presidential group
you have looking at food safety and drug safety?
Dr. von Eschenbach. Yes.
Mr. Stupak. And they will put in a specific request for
resources, then?
Dr. von Eschenbach. We are building and have presented, and
are in the process of building and presenting our 2009 budget
request, and as I indicated we already had increases in the
2008 which hopefully when we move beyond the continuing
resolution will have those resources to be able to be applied.
What I also want to continuously emphasize, Mr. Chairman, is
not only the absolute amount of resources, but, more
importantly, how we are allocating them strategically, because
I think we can leverage these resources to get more outcomes
and just measures.
Mr. Stupak. I agree. And I have to compliment the FDA today
that while we are talking about foreign drugs and import into
this country, you had a press release today saying the FDA
raided a place today because the place they were producing the
drug lacked FDA approval and remained under grossly unsanitary
conditions by General Therapeutics Corporation of St. Louis,
Missouri. So the problem isn't just other countries. It is even
right here in our own country. And with that, let me turn it to
Mr. Whitfield.
Mr. Whitfield. Thank you, and Dr. von Eschenbach, we are
delighted you are here with us today. The first panel today, we
had some distinguished panel with a lot of experience at FDA,
and they talked about this internal import strategic plan that
was developed at FDA, and that was about 3 years ago. From your
understanding, why has this plan not been implemented as of
today?
Dr. von Eschenbach. Mr. Whitfield, I am going to ask Ms.
Glavin to specifically comment on the number of initiatives
that we have underway, as we speak, and have been underway at
the FDA to do exactly that, to implement that plan. I regret
that the people on the earlier panel commented that we are not
aware of this, but I am pleased to present this to you.
Ms. Glavin. Well, we have already instituted a program to
evaluate the accuracy of import filer information so that we
can make sure that those filers are giving us accurate
information. We have just posted on our contracting site a
request for bids for verification of the registration data
worldwide. This is to have an independent organization go out
and actually see every one of these places so we have an
accurate registration database. We are testing the automated
system that has already been talked about, the PREDICT system.
We have developed a new----
Mr. Whitfield. Ma'am, what did you say about the PREDICT
system?
Ms. Glavin. We are testing that. That is a system to
automatically identify high-risk seafood imports for closer
examination.
Mr. Whitfield. And you all have been operating that as a
pilot program for, like, 3 years.
Ms. Glavin. No, no, no, sir. Just for a couple of months.
We started this back in the summer. We have been developing it
for about 3 years, but we have actually gotten it to the test
phase at this point.
Mr. Whitfield. You have been developing it for 3 years.
Dr. von Eschenbach. The software programs, and now they are
being beta tested in----
Mr. Whitfield. But the information I had is that it had
been operating as a pilot for 3 years, but you are saying it
is--OK.
Ms. Glavin. That is right. It has just recently been put
into a pilot phase. We have also developed a new screening test
for use at ports of entries. It is a very important part of
looking at imports. This gives more like rapid screening tests.
We have a very interesting one that has just gone online. We
are----
Mr. Whitfield. Well, let me just say that--I am sorry to
interrupt you, but we have votes on the floor, and we have a
very limited time, and--on this import strategic plan that was
developed internally, and you were kind enough to go through it
pretty precisely, are you saying that the majority of that plan
will be implemented? Is that what you are saying?
Ms. Glavin. We are working on almost all of the
recommendations in that plan and some of them have already come
to fruition, but there is still many more that are in earlier
stages. The ones I have mentioned are ones that are online.
Mr. Whitfield. And can you tell us as a part of the
forthcoming President's Working Group on import safety whether
you will be proposing a separate foreign inspection program?
Dr. von Eschenbach. It will not be part of the import
safety strategy per se----
Mr. Whitfield. Will not.
Dr. von Eschenbach. But it is a part of FDA's strategy.
Mr. Whitfield. All right. Of the FDA's. OK. Now, you had
also provided us with a graph of the IT program that you all
are working on right now, which appeared to be pretty
complicated----
Dr. von Eschenbach. Yes, sir.
Mr. Whitfield. Which I am sure it is. Do you have any time
table on that of when we----
Dr. von Eschenbach. Yes, sir.
Mr. Whitfield. Could you----
Dr. von Eschenbach. That is a 3- to 5-year implementation
plan. It is mapped with milestones and outcomes. It has got a
business plan underneath of it in terms of building our
resources to support it, and it does require a cultural change,
as was brought up earlier today, in terms of interoperability
of cross-functional units, whether we call them stove pipes or
silos, but that is all part of and integrated into the plan.
Mr. Whitfield. OK. But do you feel like when it is complete
it should at least have the information necessary to assess the
risk of foreign drug suppliers?
Dr. von Eschenbach. We will have a plan that, number one,
will get us better data in the first place, and that is
critical. We must have quality data to start with and
verification of the data. Two, better ability to acquire,
integrate, and assemble that data, better opportunities to
analyze and mine that data for information that we can then
take regulatory action on.
Mr. Whitfield. Thank you, Mr. Chairman.
Mr. Stupak. Well, thank you. I wish we had more time for
questions, but I am afraid if we went and voted, we have five
votes, that we would be there for an hour. So in lieu of
keeping you for another hour, we will go vote. We will submit
questions for the record and ask for your assurance that they
will be answered in a timely manner.
Dr. von Eschenbach. Yes, sir.
Mr. Stupak. We would appreciate it. And thank you again for
being , and thank you for sitting through this hearing.
Dr. von Eschenbach. Thank you, sir.
Mr. Stupak. That concludes all questioning. I want to thank
all of our witnesses for coming today and for your testimony. I
ask unanimous consent that the hearing record will remain open
for 30 days for additional questions for the record. With no
objection, the record will remain open.
I ask unanimous consent that the contents of our document
binder be entered in the record, except for No. 9 and No. 11.
We will scratch those two. So, without objection, those
documents will be entered in the record.
That concludes our hearing. Without objection, this meeting
of the subcommittee is adjourned. Thank you all.
[Whereupon, at 2:05 p.m., the subcommittee was adjourned.]
[Material submitted for inclusion in the record follows:]
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