[House Hearing, 110 Congress]
[From the U.S. Government Publishing Office]
THE ADEQUACY OF FDA
TO ASSURE THE SAFETY OF THE
NATION'S DRUG SUPPLY
=======================================================================
HEARINGS
BEFORE THE
SUBCOMMITTEE ON OVERSIGHT AND INVESTIGATIONS
OF THE
COMMITTEE ON ENERGY AND COMMERCE
HOUSE OF REPRESENTATIVES
ONE HUNDRED TENTH CONGRESS
FIRST SESSION
__________
FEBRUARY 13, MARCH 22, 2007
__________
Serial No. 110-5
Printed for the use of the Committee on Energy and Commerce
energycommerce.house.gov
U.S. GOVERNMENT PRINTING OFFICE
35-502 WASHINGTON : 2007
_____________________________________________________________________________
For Sale by the Superintendent of Documents, U.S. Government Printing Office
Internet: bookstore.gpo.gov Phone: toll free (866) 512-1800; (202) 512�091800
Fax: (202) 512�092250 Mail: Stop SSOP, Washington, DC 20402�090001
COMMITTEE ON ENERGY AND COMMERCE
JOHN D. DINGELL, Michigan, Chairman
HENRY A. WAXMAN, California JOE BARTON, Texas
EDWARD J. MARKEY, Massachusetts Ranking Minority 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 SHADEGG, Arizona
DIANA DeGETTE, Colorado CHARLES W. ``CHIP'' PICKERING,
Vice Chairman Mississippi
LOIS CAPPS, California VITO FOSSELLA, New York
MIKE 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 WILKENS 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
Bud Albright, Minority Staff Director
______
Subcommittee on Oversight and Investigations
BART STUPAK, Michigan, Chairman
DIANA DeETTE, Colorado ED WHITFIELD, Kentucky
CHARLIE MELANCON, Louisiana Ranking Minority Member
HENRY A. WAXMAN, California GREG WALDEN, Oregon
GENE GREEN, Texas MIKE FERGUSON, New Jersey
MIKE DOYLE, Pennsylvania TIM MURPHY, Pennsylvania
JAN SCHAKOWSKY, Illinois MICHAEL C. BURGESS, Texas
JAY INSLEE, Washington MARSHA BLACKBURN, Tennessee
(ii)
C O N T E N T S
----------
FEBRUARY 13, 2007
Page
Barton, Hon. Joe, a Representative in Congress from the State of
Texas, opening statement....................................... 8
Burgess, Hon. Michael C., a Representative in Congress from the
State of Texas, opening statement.............................. 13
DeGette, Hon. Diana, a Representative in Congress from the State
of Colorado, opening statement................................. 5
Dingell, Hon. John D., a Representative in Congress from the
State of Michigan, opening statement........................... 7
Ferguson, Hon. Mike, a Representative in Congress from the State
of New Jersey, opening statement............................... 5
Green, Hon. Gene, a Representative in Congress from the State of
Texas, opening statement....................................... 11
Markey, Hon. Edward J., a Representative in Congress from the
State of Massachusetts, prepared statement..................... 51
Murphy, Hon. Tim, a Representative in Congress from the
Commonwealth of Pennsylvania, opening statement................ 10
Schakowsky, Hon. Jan, a Representative in Congress from the State
of Illinois, opening statement................................. 9
Stupak, Hon. Bart, a Representative in Congress from the State of
Michigan, opening statement.................................... 1
Whitfield, Hon. Ed, a Representative in Congress from the
Commonwealth of Kentucky, opening statement.................... 3
Witnesses
Cisneros, Ann Marie, independent clinical research associate..... 27
Prepared statement........................................... 83
Answers to submitted questions............................... 84
Graham, David J., M.D............................................ 58
Prepared statement........................................... 129
Grassley, Hon. Chuck, a Senator from the State of Iowa........... 14
Prepared statement........................................... 90
Submitted material........................................... 94
Letter of August 24, 2005 to Dr. Lester Crawford........... 94
Memorandum of Understanding................................ 96
Letter of December 13, 2006 to Dr. von Eschenbach.......... 100
Senate Committee on Finance timeline....................... 120
Floor Statement of Senator Grassley, December 7, 2006...... 122
Nissen, Steven E., M.D........................................... 56
Prepared statement........................................... 85
Powers, John, M.D., Scientific Applications International
Corporation.................................................... 29
Prepared statement........................................... 78
Answers to submitted questions............................... 79
Ross, David, M.D., National Clinical Health Programs, U.S.
Department of Veterans Affairs................................. 25
Prepared statement........................................... 134
Answers to submitted questions............................... 152
Submitted Material
FDA timeline..................................................... 157
FDA News Release of February 12, 2007............................ 181
Sanofi-Aventis timeline.......................................... 168
Mathews, Anna Wilde, ``Fraud, Errors, Taint Key Study of Widely
Used Sanofi Drug'', the Wall Street Journal, May 1, 2006....... 185
Thornton, Mark, ``The Clinical Trial'', commentary from the Wall
Street Journal, February 12, 2007, submitted by Mr. Burgess.... 183
Whistleblower timeline........................................... 171
MARCH 22, 2007
Barton, Hon. Joe, a Representative in Congress from the State of
Texas, opening statement....................................... 197
Blackburn, Hon. Marsha, a Representative in Congress from the
State of Tennessee, opening statement.......................... 202
Burgess, Hon. Michael C., a Representative in Congress from the
State of Texas, opening statement.............................. 203
DeGette, Hon. Diana, a Representative in Congress from the State
of Colorado, opening statement................................. 201
Dingell, Hon. John D., a Representative in Congress from the
State of Michigan, opening statement........................... 195
Ferguson, Hon. Mike, a Representative in Congress from the State
of New Jersey, opening statement............................... 205
Murphy, Hon. Tim, a Representative in Congress from the
Commonwealth of Pennsylvania, opening statement................ 206
Schakowsky, Hon. Jan, a Representative in Congress from the State
of Illinois, opening statement................................. 202
Stupak, Hon. Bart, a Representative in Congress from the State of
Michigan, opening statement.................................... 191
Walden, Hon. Greg, a Representative in Congress from the State of
Oregon, opening statement...................................... 200
Waxman, Hon. Henry A., a Representative in Congress from the
State of California, opening statement......................... 199
Whitfield, Hon. Ed, a Representative in Congress from the
Commonwealth of Kentucky, opening statement.................... 194
Witnesses
Crosse, Marcia G., Director, Public Health and Military Health
Care Issues, U.S. Government Accountability Office............. 244
Prepared statement........................................... 267
Answers to submitted questions............................... 302
Furberg, Curt D., professor, public health sciences, Wake Forest
University School of Medicine.................................. 242
Prepared statement........................................... 282
Answers to submitted questions............................... 305
Psaty, Bruce M., M.D., professor, medicine and epidemiology,
University of Washington....................................... 241
Prepared statement........................................... 287
Answers to submitted questions............................... 307
von Eschenbach, Andrew C. M.D., Commissioner, U.S. Food and Drug
Administration................................................. 207
Prepared statement........................................... 261
Answers to submitted questions............................... 312
Woosley, Raymond L., M.D., president and chief executive officer,
the Critical Path Institute.................................... 245
Prepared statement........................................... 289
Answers to submitted questions............................... 314
Submitted Material
Angell, Marcia, M.D., et al, letter of March 14, 2007 to the
Committee on Energy and Commerce, et al........................ 297
Cohen, Robert, Newark Star Ledger, ``Ex-FDA Chief: Pharma Goal at
Odds With Safety'', February 22, 2007.......................... 295
Pediatric Exclusivity Labeling Changes........................... 301
THE ADEQUACY OF FDA TO ASSURE THE SAFETY OF THE NATION'S DRUG SUPPLY
----------
TUESDAY, FEBRUARY 13, 2007
House of Representatives,
Subcommittee on Oversight and Investigations,
Committee on Energy and Commerce,
Washington, DC.
The subcommittee met, pursuant to call, at 9:15 a.m., in
room 2123 of the Rayburn House Office Building, Hon. Bart
Stupak (chairman of the subcommittee) presiding.
Members present: Representatives DeGette, Waxman, Green,
Doyle, Schakowsky, Dingell [ex officio], Whitfield, Walden,
Ferguson,Murphy, Burgess, and Barton [ex officio].
OPENING STATEMENT OF HON. BART STUPAK, A REPRESENTATIVE IN
CONGRESS FROM THE STATE OF MICHIGAN
Mr. Stupak. I call this hearing to order. Today we will
have a hearing on the adequacy of the FDA to assure the safety
of the Nation's drug supply. We will begin with opening
statements. This is the first in a series of hearings this
committee will be holding to evaluate the Food and Drug
Administration's ability to safely approve new drugs and
provide post-marketing surveillance of our Nation's drug
supply.
This year Congress must reauthorize the Prescription Drug
User Fee Act or PDUFA, as we call it, and the Pediatric
Exclusivity law. PDUFA requires the FDA to quickly bring new
drugs to the market. In its rush to approve new drugs, the
FDA's ability to ensure a safe drug supply has been greatly
compromised. Prior to PDUFA, seldom was the FDA forced to
withdraw drugs from the market; within the first 3 years of
PDUFA, seven drugs, resulting in more than a thousand deaths,
had been removed. Those seven deadly drugs, rushed for approval
under PDUFA, were not needed to save lives.
In the 108th Congress, serious questions were raised about
the antidepressants SSRI's use in adolescents. SSRI's have not
been proven effective in treating adolescent depression. To the
contrary, their use may actually increase the suicide rate of
young patients. In response to these reports of increased
suicide rates with SSRI use, FDA officials suppressed their own
post-marketing surveillance, prohibited FDA employees from
discussing the report and launched an investigation to find the
person who leaked the information to the press. Today, SSRI's
remain on the market without a clear medical benefit to the
patient.
In the 108th and 109th Congress, the COX2 pain relievers,
Vioxx and Bextra, were the subject of hearings on the
regulatory failure by the FDA. These pain relievers were
supposed to be easier on the stomach and not cause ulcers for
the chronic users. Post-marketing surveillance revealed serious
cardiac side effects. Instead of focusing on these serious side
effects, the FDA became entwined in a 14-month battle on how
the cardiovascular risks should be labeled. FDA officials sided
with the drug manufacturer and down played the warnings and the
serious side effects of Vioxx. As a result, the FDA may have
allowed thousands of patients to die prematurely because of its
failure to believe its own scientist and his post-market
surveillance findings.
Today we will hear from a panel of whistleblowers who will
describe how Ketek was approved by the FDA, even though the FDA
knew the large safety study it required was fraught with data
irregularities. Ketek is prescribed for non-life threatening
illnesses, but the rush to approve has resulted in serious and
deadly consequences. There have been approximately 10 deaths
related to Ketek's use.
With each of these drugs, it appears the FDA is not
seriously questioning whether the risks outweigh the benefits
of the new drug. One must ask if the FDA is not protecting its
client, the American people, whose interest is being protected?
The problems with the FDA's drug approval and post-
marketing surveillance cannot be totally blamed on PDUFA. While
PDUFA may encourage a closer working relationship between
regulators and drug companies, it is the FDA's leadership which
has allowed the interaction to become incestuous. The FDA has
blocked, misled and ignored congressional inquiries into its
new drug and post-marketing surveillance programs.
Our first witness, Senator Charles Grassley, has been a
champion in questioning, challenging and over-seeing the FDA's
drug approval and post-marketing surveillance. As chairman of
the Senate Finance Committee, Senator Grassley has fought, on
behalf of the American people, to ensure our Nation's drug
supply is safe. Instead of working with Senator Grassley, the
FDA has obstructed, resisted and denied his congressional
efforts to oversee and hold the FDA to its core mission of
protecting Americans. The FDA has been so arrogant and
emboldened that it ignores the Senate Finance Committee's
subpoenas. If the FDA willfully ignores a U.S. Senate subpoena
issued by the committee of jurisdiction, whose interest and
mission is the FDA protecting?
Our second panel is made up of whistleblowers who will
testify how their efforts to disclose serious medical risks
with Ketek were ignored, covered up or dismissed by FDA
officials. In order for these brave individuals to appear
before this committee, each individual was subpoenaed.
Our final panel, Dr. Steven Nissen and Dr. David Graham,
who was also subpoenaed, will state that FDA officials ignored
their well-documented evidence, especially on Vioxx, and
compromised patient safety in the new drug approval and post-
marketing surveillance programs.
The FDA has lost sight of its mission. When the U.S.
Congress or FDA scientists or experts in the medical field try
to inject safety into the FDA drug approval process and post-
marketing surveillance, these individuals are ignored,
ridiculed or silenced.
As I stated earlier, this is the first of several hearings
this committee will be conducting on the FDA drug approval
process. Congress must confront the FDA and return it to its
core mission of protecting the American consumer, not the
pharmaceutical industry.
Members of this committee should keep in mind these
questions: Has the culture at the FDA lost sight of its core
mission? Has PDUFA made the FDA more beholden to the
pharmaceutical industry? Are the drug approval time limits
found in PDUFA contributing to drugs being rushed to market
without understanding the extent of the medical risks and
benefits? Does the FDA adequately provide post-marketing
surveillance?
While Ketek and its FDA approval is the focus of this
hearing, the American people and this Congress, must remain
vigilant in shaping public policy and re-writing PDUFA to
restore the FDA's core mission of ensuring America's drug
supply is safe for all Americans.
With that, I next turn to the ranking member of this
subcommittee, the gentleman from Kentucky, Mr. Whitfield, for
an opening statement, please.
OPENING STATEMENT OF HON. ED WHITFIELD, A REPRESENTATIVE IN
CONGRESS FROM THE COMMONWEALTH OF KENTUCKY
Mr. Whitfield. Thank you, Chairman Stupak, for convening
this important hearing on drug safety and the FDA's role in
assuring the safety of the drug supply. As Chairman Stupak
said, this will be the first in a series of hearings on this
important issue. The safety of our Nation's drug supply and how
it affects the health and well-being of our fellow citizens.
Questions have been raised for many years about the FDA's
management of safety issues with respect to the approval and
post-market surveillance of drugs, including questions raised
by this sub-committee with respect to the use of anti-
depressant drugs among children and studies showing that their
use was linked to increased risk of suicide.
While FDA's management of drug safety has received
increased scrutiny, this is certainly, as I have said, not a
new issue. In fact, in a 2006 report requested by then-
chairman, Joe Barton, and Senator Chuck Grassley, the
Government Accountability Office stated that problems have been
raised about the FDA's management of drug approval and post-
market surveillance for the last 30 years.
These are certainly complex issues and often involve
complicated scientific debate and judgment. Issues raised by
the FDA's approval of the drug Ketek, which we will learn more
about from today's witnesses, certainly demonstrate this. The
debate within FDA about the Ketek drug application was not
simply a matter of approving or disapproving the drug. Instead,
the Ketek application raised larger public health questions
that were debated by doctors and scientists within the FDA with
respect to the approval of antibiotics and about what types of
studies should be performed to demonstrate a drug safety
inefficacy.
At what point should data collected during drug trials be
included or disqualified from the study? How should data
regarding resistance to antibiotics be interpreted? And how
should this affect the availability of antibiotics? These are
questions about which scientists, physicians and experts
continue to debate. While it is critical that we examine drug
safety and whether FDA's decision making processes are suited
to ensure the safety of our drug supply, it is also critical
that we do so in a careful and deliberate way.
Today we will hear from two witnesses, Dr. David Ross and
Dr. John Powers, who were employed by the FDA when Ketek's
application was pending and who were involved, actually, in
reviewing the application. We will also hear from a third
witness, Ann Marie Cisneros, who was employed by a contractor
for a Ketek sponsor, Sanofi-Aventis. It is my understanding
that these witnesses disagree with the actions of the FDA,
Sanofi-Aventis or both with respect to how that application was
handled.
Today's witnesses have expertise and first-hand knowledge
of the events that took place, but it is also important to note
whom we are not hearing from today. Ketek's sponsor, Sanofi-
Aventis, is not present today to offer its side of the story,
nor are other FDA officials who took part in approving Ketek,
but who do not share the views of today's witnesses about the
approval decision or agency processes here to defend their
decisions. But they will be asked to testify at a later
hearing.
So we are at the beginning of our inquiry. We just sent a
document request to FDA and after obtaining additional records
by a hearing from all sides, we will be able to determine
whether mistakes were made during the FDA's examination of
Ketek and if so, what those mistakes were and whether those
mistakes were simply an aberration or a sign of a systemic
problem in the way FDA manages drug safety.
The GAO report, the Institute of Medicine report, FDA's
response to these reports and recent actions, today's
testimony, evidence collected by the subcommittee during
previous investigations and Senator Chuck Grassley and his
committee's investigation of Ketek all confirm that there is
certainly room for improvement in FDA's management of drug
safety.
So the subcommittee will be keeping an open mind looking at
the evidence, and I look forward to the hearing and certainly I
would be remiss if I did not thank Senator Grassley for joining
us this morning. He and his staff on the Senate Committee on
Finance have spent considerable time investigating the FDA's
oversight of drug safety and we look forward to his testimony.
Mr. Stupak. I thank the gentleman. He is right; we will
have the FDA and the manufacturer of this drug at a later
hearing. Exactly when that will be will probably depend upon
the cooperation we get from the FDA to open their files, so
that could be some time, but we expect them to testify. I next
recognize the gentleman from Pittsburgh, Mr. Doyle, for an
opening statement.
Mr. Doyle. Thank you, Mr. Chairman. I want to thank you for
convening this important hearing and I am going to waive my
opening statement.
Mr. Stupak. OK. The gentlewoman from Colorado.
OPENING STATEMENT OF HON. DIANA DEGETTE, A REPRESENTATIVE IN
CONGRESS FROM THE STATE OF COLORADO
Ms. DeGette. Thank you very much, Mr. Chairman. I want to
thank you for calling this hearing and thank you also for
committing to making this the first of many hearings that we
will have about drug safety and the FDA's handling of new drug
applications and also post-market review of adverse side
effects.
As the public's watchdog on prescription drugs, the FDA
plays a critical role in protecting us from drugs whose risks
outweigh their benefits. I also want to thank you for asking
Dr. Steven Nissen to testify today. I met Dr. Nissen last fall
when I was in Cleveland and his work, in 2004, on the FDA
advisory panel about the safety of Vioxx led us to a much
better understanding about the dangers of the drug.
Mr. Chairman, I remember hearings this committee convened
in 2004 to examine antidepressant use of pediatric populations
and at that time we talked about the need for the FDA to
fulfill its mission, to conduct objective studies with rigorous
scientific inquiries. When risks are identified, it is
essential that they be communicated to the public. And at that
hearing we talked about why there had been delays in
presentation of data on the link between suicides and
antidepressants. The system clearly had broken down.
I also remember when Vioxx was found to dramatically
increase the risk of heart attacks for those taking this
medication. We discovered that the FDA process was lacking as
the valid concerns of FDA scientists were overruled by high-
ranking officials. Again, the system had broken down. I hope,
Mr. Chairman, as we address concerns about FDA's apparent
mishandling of yet another drug review, that we can begin to
move towards systemic change and not more lip service.
I am confident that our witnesses today will provide us
with a comprehensive description of the inherent problems with
the FDA system, but beyond that, I think, Mr. Chairman, we need
to move far beyond talking about the problem and begin to
develop a real solution. Once all of us here have been on this
committee for a long time and these issues keep coming up again
and again, the FDA issue, the Los Alamos issues that we had
hearings on just a week or two ago. I think it is really time
for Congress to identify these issues but then move beyond that
and start to work in collaboration, of course, with the FDA and
others to begin the solve the problems and I look forward to
doing that and yield back my time.
Mr. Stupak. I thank the gentlewoman. Gentleman from New
Jersey, Mr. Ferguson, for an opening statement.
OPENING STATEMENT OF HON. MIKE FERGUSON, A REPRESENTATIVE IN
CONGRESS FROM THE STATE OF NEW JERSEY
Mr. Ferguson. Thank you, Mr. Chairman. I appreciate you
convening this hearing today. I thank Mr. Whitfield and our
panelists and our guest for being here this morning. I strongly
believe that one of the most vital functions played by any of
our Government agencies is that of the Food and Drug
Administration's responsibility to ensure the safety and
efficacy of pharmaceuticals for our citizens.
I would venture to say that at some point in almost every
American's life, when they are sick, they will turn to an FDA-
approved drug to make them better. Therefore, almost every
American will put their trust in the testing and the scientific
review done by the FDA. They must also trust that the drug was
approved with their best interests in mind, weighing the
relative risks and the benefits that that drug might bring.
I have long been interested in the issue of responsibility
for drug safety carried out by the FDA. This issue has been
brought my attention both by constituents in my district, but
also it has been my own very interests to ensure that our
Nation's drug supply is not only on the cutting edge of
medicine, but also is the safest in the world. I believe
information is vital for patients to make informed decisions
and I have urged, through letters and conversations with FDA
officials that they make available to patients necessary items
like medication guides when they are necessary.
Over the past few years news reports, some generated by
some of the panelists that we have here today, have chipped
away at the public's confidence in the ability of the FDA to
protect them. We need the FDA to be the worldwide gold
standard. Coupled with our leadership role in research and
development, the FDA must have the full and complete confidence
of the public to protect them. Cutting edge medicines can only
live up to their full potential when accompanied by public
confidence in the FDA. Therefore, I believe this conversation
that we are having today is a necessary one and I am very
pleased that we are looking into these issues.
But as I look at the list of panelists today, I note a
stark absence of other stakeholders that I view to be very
necessary to this conversation. For instance, we don't have
anybody today here who is speaking officially on behalf of the
FDA. We don't have anybody here who is speaking on behalf of
the patient community or the patient advocacy community. We
don't have anybody here today talking, representing the
Institute of Medicine, who have made some important
examinations and recommendations.
I doubt that the opportunity we will have today, that we
will have the necessary give and take to constructively talk
about what is wrong and what is going right and what we need to
do to fix the problems that we see. And I am hopeful that in
the future, Mr. Chairman, as you mentioned, that we will have
those opportunities.
Our conversation is particularly timely because we are
quickly approaching the end of the authorization of the
Prescription Drug User Fee Act or PDUFA, and looking through
the testimony offered today, some assail PDUFA, but let us not
forget why PDUFA was created in the first place. Before PDUFA
existed, there was the commonly held belief that life-saving
therapies were taking way too long to be approved by the FDA.
Advocates for patients with cancer, HIV-AIDS and many other
diseases cried out for a way to get drugs to market faster,
while safely weighing the relative risks and benefits that
those drugs might bring.
Let us not go back to the days when access to drugs was the
most important problem that we faced. Last year the Institute
of Medicine, at the behest of the FDA, completed a thorough
review of the state of drug safety at the agency. They issued a
number of recommendations and there are many ideas that we
ought to consider when we go through the reauthorization of
PDUFA this year. But again, the absence of a proper give and
take today will really preclude us from having the conversation
today, anyway, to help us to do the job that we need to do
properly.
Mr. Chairman, once again, this is a good conversation to be
having, although today it is incomplete, and I look forward to,
hopefully, in the future, that we will have an opportunity to
have a more complete, a more thorough and more comprehensive
examination of these issues so we will be able to move forward
and do the right thing for our constituents and for the
American people because at the end of the day, their confidence
and the safety of our drug supply is perhaps one of the most
important things we can be doing.
I appreciate, Mr. Chairman. I yield back.
Mr. Stupak. I thank the gentleman for his comments. Next we
turn to the chairman of the full committee, Mr. Dingell of
Michigan. It should also be noted, before Mr. Dingell begins,
Members will be moving back and forth as we have a climate
change hearing also going on under Mr. Dingell's leadership
where we have five hearings this week, so we are a busy
committee this week. With that, Mr. Dingell.
OPENING STATEMENT OF HON. JOHN D. DINGELL, A REPRESENTATIVE IN
CONGRESS FROM THE STATE OF MICHIGAN
The Chairman. Mr. Chairman, thank you, and thank you for
holding this oversight investigation and for holding the first
hearing of this Congress on drug safety and the Food and Drug
Administration. I commend you. This subcommittee has a long
history of FDA oversight and oversight of other agencies, too,
and by and large, FDA is a fine organization where many people
do good work for the American people.
Unfortunately, from time to time this committee has had to
address problems before that agency. It seems every so often
FDA loses its way, sometimes because of the work of scoundrels
and sometimes because of poor management or other unfortunate
events. But sometimes it is because of a more serious breakdown
in the policies and procedures that are critical to assure the
safety of food, drugs, blood and medical devices that are so
essential to the health of the American people.
Today's hearing will deal with just such a fundamental
breakdown in the policies and procedures for evaluating the
safety of drugs. It is clear from the work that Chairman Stupak
has already performed, which will be the subject of today's
hearings, that FDA is badly broken. I expect that before this
investigation is finished, and it is now just getting underway,
that we will discover whether the problems we have found are
due to the work of scoundrels, irrational penny-pinching or
because the doors to the FDA hen house have been thrown open to
foxes. It is possible that it will be a combination of all
three.
What we do know, from our dear friend, Senator Grassley,
who is going to be here this morning to testify and for whom we
have the greatest respect and extend a very warm welcome, is
that this administration appears to be engaged in hiding
wrongdoing at FDA. We see this in other Federal agencies, as
well. Today we will hear a warning from Senator Grassley that
during his investigation, that his committee was confronted by
obfuscation and delay and that this committee will face a
similar problem with an agency that seems to try to hide its
poor decision making behind the specious veil of Executive
Privilege, a matter with which this committee has some
familiarity over the years.
Those with the ear of the Secretary and the Commissioner of
the FDA may erroneously believe that the committees of
competent jurisdiction can be denied documents and interviews
to obtain information that Congress must have to fulfill its
constitutional obligations. They will find that that is an
error. There are those who may be counseling the Secretary and
the Commissioner that Congress may not interview or call to
testify Department of Health and Human Services and FDA
employees under any circumstances. There may even be those who
are tempted to think that it is possible to deliberately
mislead us. I warn them, these are dangerous thoughts.
I promise those in charge of HHS and any other department
that chooses to deny this committee the information and access
to proper personnel that is needed for oversight, as is our
responsibility, that they will not succeed. I promise them,
however, fair treatment if they will cooperate. I hope
enthusiastically, but at least they will cooperate. There is an
easy way to be investigated and there is a hard way, and I can
assure, all in authority, that the hard way is not the better
way.
Mr. Chairman, I thank you for your recognition.
Mr. Stupak. I thank the gentleman for his statement. We
next move to the ranking member of the full committee, the
gentleman from Texas, Mr. Barton, for an opening statement.
OPENING STATEMENT OF HON. JOE BARTON, A REPRESENTATIVE IN
CONGRESS FROM THE STATE OF TEXAS
Mr. Barton. Thank you, Mr. Chairman. We on the minority
side of this subcommittee support this particular
investigation. We must have an objective and balanced FDA. The
agency serves the American people and makes life and death
decisions every day that affect our public health. Any credible
concern that FDA's objectivity is in question must be examined.
We are at the very beginning of this particular
investigation; document requests have been made and are about
to be made; witnesses are being interviewed. We should have
additional hearings, including witnesses from the FDA and the
affected industry. Today we are at a very preliminary stage.
The subcommittee is going to be hearing serious allegations and
concerns about an antibiotic called Ketek, which is produced by
Sanofi-Aventis. Individuals, including some other former FDA
officials, who took part in this particular review, have
charged that the safety data presented by the company in
support of Ketek's approval was compromised or unreliable. They
contend that the company knew it, that the FDA knew it and that
although concerns were raised about the drug's safety, the FDA
went ahead and approved the drug anyway.
These allegations go to the heart of FDA's professionalism,
integrity, and the agency's mission. In fairness, I must note
that some representatives from the FDA and the company who
briefed the committee staff dispute some of the points that are
going to be made today. We have been assured by the majority
that additional witnesses from the FDA and the company will be
heard.
Given the life and death consequences that flow from the
FDA's decisions on drugs like this and from public information
about prescription drugs, this subcommittee needs to pursue
these issues very carefully, not attack the delicate and
complicated matters with a sledgehammer.
Having said that, it is important that we keep an open mind
today as we wait for the investigation to unfold. Until we
assemble the most complete and thorough record possible, we
should not draw premature conclusions about peoples' judgments,
motivations and integrity. Complicating our work is the fact
that debates over drug safety and the FDA decision making
process involve complex and sometimes abstract issues for
science and scientific judgment.
The FDA's decision with respect to Ketek's new drug
application took place against the backdrop of an ongoing
debate about antibiotic resistance, whether it is possible for
certain types of studies, such as non-inferiority trials, to
demonstrate a drug's effectiveness. Before we can determine
whether Ketek should serve as a case study of how the FDA's
management of drug safety is ineffective or worse, broken, we
must review the evidence in context and with perspective.
This is a very good investigation to be instigating. I want
to commend Mr. Dingell and Mr. Stupak and Mr. Whitfield for
their leadership on this. I look forward to working with him
and the other members of the subcommittee as we pursue this
important piece of work before our Oversight subcommittee.
With that, Mr. Chairman, I yield back.
Mr. Stupak. Thank you, Mr. Barton. Next, 5 minutes for
opening statements, Ms. Schakowsky of Illinois.
OPENING STATEMENT OF HON. JAN SCHAKOWSKY, A REPRESENTATIVE IN
CONGRESS FROM THE STATE OF ILLINOIS
Ms. Schakowsky. Thank you, Mr. Stupak, for holding this
hearing and for your efforts to improve drug safety. The
Oversight and Investigations Subcommittee has been a leader in
investigating problems and pushing for solutions at the FDA and
within the pharmaceutical industry. Ensuring the safety and
efficacy of prescription drugs remains a top priority and I am
glad that we are continuing our investigation on a bipartisan
basis.
I also want to thank Senator Grassley and his staff for
their efforts on the issue. It is clear we share a desire to
return to evidence-based decision making and to ensure that FDA
advisory groups, Congress and the public receive accurate and
science-based information about prescription drugs. It is also
clear that we have all faced enormous difficulty in getting the
information that we need from the Bush administration.
I hope that we will be able to work together to solve all
of these problems and protect the lives of our constituents.
The evidence that we are going to hear today about the Ketek
approval process and the failure to report potentially fatal
effects is extremely serious. What is more troubling is that,
as several witnesses will testify, Ketek is not an anomaly.
These same problems, the culture of secrecy and hiding of
significant health threats are mirrored in other drug
application experiences and they appear to be ongoing, despite
past investigations.
The testimony we will hear from Dr. Ross indicates that
last summer FDA scientists were still being told to be ``team
players'' and not report safety problems to those outside of
the FDA. This occurred after our subcommittee's hearings on
childhood antidepressants raised serious problems about the
lack of disclosure by drug companies and the FDA.
Last year the Union of Concerned Scientists and Public
Employees for Environmental Responsibility surveyed FDA
scientists. According to their survey, nearly one in five
scientists have been asked for nonscientific reasons to
inappropriately exclude or alter technical information in an
FDA scientific document. Sixty percent knew of cases where FDA
political appointees and commercial interests had
inappropriately influenced FDA actions. Only 49 percent agreed
that the FDA leadership was as committed to product safety as
to bringing products to the market. And only 47 percent
believed FDA routinely provides complete and accurate
information to the public.
What frightens me is that a survey taken today could show
the same results. One of my constituents whose mother committed
suicide after participating in an adult antidepressant trial
wrote me that ``there is a gaping hole between the data the FDA
is collecting and the information reaching the general
public.'' Today's hearing shows that the public is not alone.
FDA's own advisory committees have been kept in the dark. Data
has been falsified and manipulated and serious safety concerns
have been kept hidden from Congress, as well as physicians and
patients.
Mr. Chairman, it is time for full accountability and for
serious change. I look forward to hearing the recommendations
of our witnesses. I yield back.
Mr. Stupak. I thank the gentle lady. The gentleman from
Pennsylvania, Mr. Murphy.
OPENING STATEMENT OF HON. TIM MURPHY, A REPRESENTATIVE IN
CONGRESS FROM THE COMMONWEALTH OF PENNSYLVANIA
Mr. Murphy. Thank you, Mr. Chairman. Thank you for holding
this important hearing. We all want new drugs and new therapies
to cure diseases and save lives and we are thankful that so
many have come out of the research in this Nation. However, we
need to do so in a way that is scientifically reliable and
valid, and when errors are made in that reliability and
validity and errors are made in reporting problems with
research, so much comes into question of the organizations that
perform those studies and those that manufacture the
medications.
Today's hearing is an essential part of the ongoing
congressional role of oversight of the FDA. Well, there is a
continuing demand from the public, however, and our doctors,
for new drugs and we understand the prescription drugs, by
their nature, all have some risk associated with them. We must
ensure that the risks do not outweigh the benefits, thus
accurate research for new drugs is absolutely vital to continue
our efforts to discover the next generation of life saving
treatments or treatments for mental illness or treatments for
cancer or diabetes.
On the one hand, however, there is a constant pressure on
the FDA by many patients and families eager to realize the hope
these drugs may provide to review these medications quickly and
it is important that we do not succumb to that pressure just
for the sake of bringing out a medication if we do not yet have
the scientific data to tell us what those risks and benefits
are. This must be balanced. And this hearing is important to
review that balance because we must have accurate and reliable
research on medications so we can determine those risks and
benefits to restore confidence in the drug programs of the Food
and Drug Administration.
To do so, however, Congress must also approach these
hearings demanding the same scientific integrity and
comprehensive review of ourselves that we demand of the FDA.
Now, there are some concerns that perhaps this committee is not
receiving information yet from the administration. To my
knowledge, I don't think we have yet requested information from
the administration and the FDA and when we do so, my assumption
is we will get accurate and cooperative information. If we do
not, then we should act accordingly.
However, in the meantime, I believe that what the American
people expect of us is to keep the pressure on for scientific
integrity here; that all of us must review the studies,
ourselves; to bring out the truth, whatever that may tell us
about these medications, because at the very least, physicians
and patients and families want to know that that prescription
filled by their pharmacist and taken by themselves or a family
member, maintains a gold standard of quality that we can trust
and our Food and Drug Administration and all involved in that
process.
We are not here to stop research, we are not here to rush
drugs to market that are not ready, we are not here to stop
medication that is needed. We are here, however, to make sure
that integrity is what returns to the FDA and that all the
patients and physicians in America demand that and I look
forward to the results of this hearing to make sure we do look
at this information accurately. Thank you, Mr. Chairman.
Mr. Stupak. Next, for an opening statement, Mr. Green from
Texas.
OPENING STATEMENT OF HON. GENE GREEN, A REPRESENTATIVE IN
CONGRESS FROM THE STATE OF TEXAS
Mr. Green. Thank you, Mr. Chairman, for holding the hearing
today on the Food and Drug Administration drug safety
procedure. It is a pleasure to return to the Oversight and
Investigation Committee. I look forward to working with you and
our chairman, Chairman Dingell, on an aggressive oversight
investigation agenda to increase accountability among all
Federal agencies within our jurisdiction.
The first, though, in our subcommittee hearings of the
110th Congress, the continuation of good work this subcommittee
is performing on drug safety in the 108th and 109th Congresses
on a bipartisan basis. The investigation of the antibiotic,
Ketek, is particularly timely. In fact, it appears that the FDA
has been paying close attention to our hearing schedule, since
it made a significant announcement yesterday about label and
indication changes for Ketek.
Specifically, the FDA removed two of the three previously
approved indications from the drug's label leaving acquired
pneumonia as the only remaining indication for which Ketek is
appropriate. I think most of my colleagues on the committee
agree that it is too little too late. Three years after a
flawed advisory committee process paved the way for approval
for Ketek, the FDA has finally taken a step that represents its
commitment to serve the public's interest regarding Ketek.
The FDA's action yesterday is not the final word on the
matter and certainly does not rule out our need to analyze the
problems associated with the approval of Ketek. If anything, we
need to look at this case even closer to determine where the
problems lie in the approval process for new drugs and what
actions need to be taken to restore the public's confidence.
Certainly, a question arises whether non-inferiority studies
are appropriate, to begin with, as opposed to traditional
clinical trials where a drug is tested against a placebo, the
non-inferiority study simply tests whether a new drug is as
effective as a drug already approved for its specific
indication.
I look forward to a robust discussion on this issue, on the
use of these studies, in particular, and which cases are
appropriate and necessary. Despite that question of
methodology, I have significant concerns of the specific manner
in which this non-inferiority study was implemented. It doesn't
take a room full of scientists to know that it was completely
inappropriate for the full data to Study 3014 to be presented
to the FDA advisory committee, especially in the criminal
investigations being initiated on one physician investigator
and serious questions have been raised about data from other
sites with significant enrollment levels.
The Ketek investigation gives us tremendous insight in the
cultural failings of the FDA regarding drug safety. Although
this investigation may elicit more questions than answers, I
hope we can learn from Ketek case studies as we seek to address
the FDA's larger drug safety issues and implement policies to
ensure that the agency has the necessary tools to appropriately
weigh the risks and benefits of particular drugs for the
American people.
Mr. Chairman, I would like to thank the witnesses for
appearing today and offering us insight, and it is difficult in
a highly technical case, and I also look forward, as a member
of the Health Subcommittee, looking at FDA reform, Mr.
Chairman, so I know these studies for the last, this third
Congress, will hopefully significantly affect the FDA reform. I
yield back my time.
Mr. Stupak. I thank the gentleman from Texas. The other
member from Texas, Mr. Burgess, is recognized for 5 minutes.
OPENING STATEMENT OF HON. MICHAEL C. BURGESS, A REPRESENTATIVE
IN CONGRESS FROM THE STATE OF TEXAS
Mr. Burgess. Thank you, Mr. Chairman, and I thank the
chairman and the ranking member for opening this hearing. This
committee has a vital role in providing meaningful oversight
and investigations over important public health issues. As a
physician, I take this role extremely seriously and I thank the
leadership of this committee for their vigilant pursuit of
truth in regard to our Nation's healthcare issues.
Today we are here to discuss the FDA's process for the
approval of new and important life saving drugs. While I
appreciate the whistleblowers being here to discuss their
observations of the approval process of Ketek, I do find it
curious that the FDA isn't able to present their side of the
story today. The whistleblowers are making serious allegations,
allegations that need to be heard and deserve to be heard, but
I am disappointed that neither the FDA nor the manufacturers of
Ketek, Sanofi-Aventis, were invited to answer these serous
allegations and tell their side of the story.
Now, I do understand that there is another hearing
scheduled for later in March, but unfortunately, we all know,
with the shortened press cycle in this town, that the damage
will be done long before the weekend comes. We have heard some
discussion of fairness this morning. We really can't talk about
fairness. It is not reasonable to talk about an administration
stonewalling a document request that, frankly, has not yet been
made.
The question always comes down, in these hearings, what did
they know and when did they know it. That is important
information and this committee should dedicate itself toward
answering that question, but an independent review of internal
documents is going to be necessary before those questions could
be answered. I would also like to remind members of this
committee that we must be cautious not to come to conclusions
today.
It is merely the opening side of a preliminary
investigation. Today we will only hear one side of the story,
an important side, to be sure, but it is still only one side.
We must be cognizant of the fact that the power of oversight
is, in effect, the power to destroy, therefore it is crucial
this issue be fully vetted and that all sides are heard before
conclusions are drawn.
Mr. Chairman, as a physician, I have long had a love/hate
relationship with the FDA. I was concerned that they wouldn't
bring medications quickly enough to benefit my patients. It
seemed that other countries in the world could get newer
medications on a much faster timeline and yet, at the same
time, we look to the FDA to protect and ensure the certainty of
safety of drugs in this country. Most of us don't question when
a prescription is written, torn off the pad and put in our
hands. We don't question the validity or the safety of that
medication and that is a good thing, and we want that certainty
that surrounds the FDA to be assured.
The FDA has no small task. This is a Physician's Desk
Reference. I don't even know how many medications are listed in
this reference; the print is very small, the pages are very
thin and there is a lot of information in here. We charge the
FDA with staying up to date on all of those medicines and
assuring their safety. It is a big task. Do we fund it
properly? That is surely a question that is going to have to be
answered before these hearings are drawn to a conclusion.
Well, Mr. Chairman, as long as we are mindful of these
issues and truly diligent in the work to obtain real answers
and real conclusions, I am supportive of this investigation.
And I will yield back the balance of my time.
Mr. Stupak. I thank the gentleman. The gentleman from
Washington, State of Washington, Mr. Inslee, for an opening
statement.
Mr. Inslee. I will waive, Mr. Chair.
Mr. Stupak. OK, that concludes our opening statements. We
We now turn to our first witness, the Honorable Charles
Grassley, United States Senator from the State of Iowa.
Senator, it is a great pleasure to welcome you today, here
today as our lead witness in the first of what I predict will
be many hearings that this subcommittee will hold this
Congress, that will look into improving the way the FDA
protects the American people.
Before starting your prepared testimony, I would like to
note that it has been a long tradition of the Oversight and
Investigation Subcommittee to swear all witnesses, whether they
be private citizens, Cabinet members or Senators. I believe, if
my memory serves me correct, the last Senator to appear before
us was your colleague, Senator Hatch, in 1991, who was sworn in
and testified under oath before us on drug safety issues. So
accordingly, Senator, please rise and raise your right hand to
take the oath.
[Witness sworn.]
Mr. Stupak. Thank you, Senator. I believe that you have a
prepared statement for the record, as well as a shorter
statement to present this morning. Before starting, let me
advise my colleagues the Senator has a limited time and we will
take questions, 10 minutes on each side for questioning of the
Senator this morning. And Senator, again, thank you for being
here and thank you for your work on drug safety issues
throughout your career.
TESTIMONY OF HON. CHARLES GRASSLEY, A SENATOR FROM THE STATE OF
IOWA
Senator Grassley. Well, it is very much a privilege for me
to be invited here and I appreciate that invitation and I had a
chance to hear many members of this committee give opening
statements and I particularly want to thank Chairman Dingell,
Chairman Stupak, ranking members Barton and Whitfield for their
statements and most importantly, to all of you who are involved
in oversight because it is such an important constitutional
responsibility, one that I don't think we talk enough about or
do enough about, but it is important that you do the work you
are doing on this hearing and particularly, a hearing on drug
safety and particularly, the role of the Food and Drug
Administration.
During the last 3 years, I conducted extensive oversight of
the Food and Drug Administration while I was chairman of the
Senate Finance Committee and as you probably know, we have
jurisdiction over both Medicare and Medicaid. I view my role as
working to ensure the safety and well-being of the more than 80
million Americans who are beneficiaries of these programs. The
Medicare and Medicaid programs spend a lot of money on
prescription drugs and medical devices, and that money should
be spent on drugs and devices that are safe and effective.
In the course of my oversight of the Federal bureaucracy, I
have developed many good relationships with whistleblowers. And
it was FDA whistleblowers and concerned FDA scientists who
first drew my attention to the problems of the Food and Drug
Administration.
It started in early 2004 with an FDA psychiatrist named Dr.
Andrew Mosholder, who realized, through his work, that there
was a serious suicide risk for teenagers taking certain
antidepressants. He wanted to make a presentation about his
findings to an FDA advisory committee. But for some reason, FDA
supervisors didn't want this information out. They canceled Dr.
Mosholder's presentation and instructed him to write a script,
approved by his supervisors, that he would use if anybody asked
him why he was no longer presenting.
This fall, I held a hearing, or that fall, which was 2004,
I held a hearing on drug safety in the aftermath of Vioxx, the
blockbuster pain medication, being pulled off the market by its
manufacturer, rather than by the Food and Drug Administration.
The testimony at my hearing turned a bright spotlight on
problems with the FDA's post-marketing surveillance effort. The
Food and Drug Administration works tirelessly, as it should, to
approve new life saving and life enhancing drugs, but it could
do a lot better job of keeping track of developments with these
drugs after they get out onto the market. Reviewing what
happened inside the FDA with Vioxx and also working with a
number of whistleblowers who bravely stuck their necks out and
came to me after that landmark hearing, I have identified
problems at the FDA that consistently fit into a few themes.
First, scientific dissent is discouraged, quashed and
sometimes muzzled inside the FDA. Second, the FDA's
relationship with drug makers is too cozy. The FDA worries
about smoothing things over with the industry much more than it
should with its regulatory responsibilities. Third, inside the
FDA there is widespread fear of retaliation for speaking up
about problems. And fourth, the public safety would be better
served if the agency was more transparent and more forthcoming
with drug safety and drug risks. These problems involve, then,
the culture at the Food and Drug Administration. Those problems
are not isolated, but are systemic and they can be partly
attributed to the organizational structure at the FDA.
My concerns are not isolated, either. During the last year,
they have been validated by highly regarded Institute of
Medicine, as well as the independent Government Accountability
Office and more importantly, or as importantly, respected
medical journals. What is at stake is public safety and public
confidence in our Nation's world-renown Food and Drug
Administration.
My investigations of FDA issues have also revealed a deeply
troubling disregard for Congress' responsibility to conduct
oversight of the executive branch of Government, getting right
to the heart of whether or not the checks and balances of the
225-year history of our Government are functioning properly, to
see that the laws we passed are faithfully executed and to see
that the money that we appropriate is spent in accordance with
Congress intent. The FDA and the Department of Health and Human
Services have put up so much resistance to my efforts to find
out what happened inside the Food and Drug Administration with
a relatively new antibiotic called Ketek, that I can only
wonder what there is to cover up. Every excuse under the sun
has been used to create roadblocks, even in the face of
congressional subpoenas requesting information and access to
FDA employees.
In denying access to documents responsive to the subpoenas,
the Department and the Food and Drug Administration have
claimed the official words ``Prosecutorial deliberative
process,'' another one ``confidential communication,'' another
one, ``agency prerogative to determine who will be interviewed
or testify before jurisdictional committees.'' That strikes
right at the heart of the work you are doing here, Mr.
Chairman, today. Yet, during my years in the Senate, my
investigators have obtained access to every single one of these
categories of so-called confidential information, even from
HHS, as well as other executive branch agencies. So why now?
Further, I asked the Congressional Research Service to look
into the Department's policies regarding this matter and CRS
told me that there is, in their words, ``no legal basis'' for
the Department's executive branch assertions.
Nevertheless, the Department and FDA not only withheld
documents that do not appear to be privileged, but they also
won't say what has been withheld and why. The subpoenas compel
a privilege log, but the Department and the FDA will not
provide one.
The Department and the FDA say that they have been
responsive to the Finance Committee's Ketek investigation
because they made available millions of pages of documents. But
what they provided is quantity, not quality.
They delivered hundreds of pages simply marked, for
example, ``57 pages removed'' or ``43 pages removed,'' and that
is in attachments 1 through 5 that you will have. Other
documents have whole pages, paragraphs and sentences redacted
with no explanation for what has been held or redacted or why.
In fact, listen to this, the FDA redacted some of the same
documents differently and they even redacted one of my own
letters to them on a different matter, and that is attachment
6.
When I point out the absurdities in the Department's
response to my request for documents and interviews related to
Ketek, the Department argues it could not provide access to
information and individuals related to criminal investigations,
just like that was what I was trying to do. But I didn't ask
for access to open criminal investigations. I don't want to
jeopardize a criminal matter; you folks don't, either. The
Department and the FDA know that, yet they keep using that
excuse anyway.
Even so, what I have learned about what happened with Ketek
troubles me. I have learned that FDA gave its advisory
committee questionable data on Ketek and did not tell them
about problems with that data. I sent a letter to the FDA in
December regarding my findings on this matter and I am still
awaiting a response. The FDA approved Ketek without much safety
data from the U.S. The agency relied almost exclusively on
foreign post-marketing safety data. And lastly, Ketek's
sponsor, in all likelihood, was aware of the fact that it
submitted some questionable data to the FDA regarding its large
safety study. The sponsor was informed of problems with one of
the study sites prior to the date of submission to the FDA.
However, according to the FDA reviewers, the sponsor never
raised these problems with the FDA. FDA learned about them
after his own investigators inspected the site.
During the last 3 years, I have also tried to work in a
productive way with the Commissioners and Acting Commissioners
of the FDA. It will take bold leadership to get on top of the
FDA's problems and to turn the agency around. So far, lip
service has been fine; the reality has been a lot less.
Last month, Senator Chris Dodd and I introduced two reform
bills that we proposed in 2005 to get the safety, to fix the
safety shortcomings at FDA. Our first bill would elevate and
empower the office with the FDA that is responsible for
monitoring FDA-approved drugs after they are on the market. It
would make the post-market safety function within the FDA
independent, but within the FDA, instead of under the thumb of
the office and the center that puts the drugs on the market in
the first place and that is the way it is today.
I want to point your attention to the Wall Street Journal
in regard to Chairman Dingell. It is reported that he is
intrigued by the idea of drug safety center within the FDA. I
appreciate that view. It doesn't make any sense that the FDA
officials who are supposed to monitor the safety of a drug on
the market serve only as consultants to the FDA officials who
approve the drug in the first place. The officials who approve
the drug would obviously be conflicted in making a judgment
that approval is no longer appropriate or was a mistake in the
first place. Kind of like having egg on your face. A separate
center for drug safety within the FDA is a vital lynchpin when
it comes to meaningful reform and improvement of the agency's
post-marketing surveillance.
The second bill that Senator Dodd and I have introduced
would expand an existing public data base by mandating the
registry of all clinical trials and the results of those
trials. This reform is key to establishing greater transparency
regarding clinical trials, the good ones and the bad ones, and
to hold drug makers and drug regulators accountable and to give
doctors all the information they can to their patients. Both of
these legislative initiatives would make drug information used
by doctors and patients more complete and more accessible.
American consumers should not have to second guess the
safety of pills in their cabinet. I appreciate the attention
that all of you are giving to this important national issue
with this hearing. You will hear from some of the heroic
whistleblowers who have helped my work, without whom my work
would not have been possible. Two of the whistleblowers have
left FDA, outstanding scientists, outstanding investigators,
people that want to get to the bottom of something, something
that an agency like FDA can't afford to lose people like that.
It is a tremendous loss for our country when an agency like the
FDA gets so dysfunctional that specialists like these
whistleblowers are forced to leave the agency to avoid
retaliation.
Whistleblowers are like a skunk at a picnic. They ought to
be considered, though, by us, as patriotic Americans just
wanting to do what the law requires them to do and spend money
according to the way Congress wants it spent. I want to work
closely with you, Mr. Chairman, to make sure that FDA
whistleblowers can communicate with Congress without fear. We
got laws that protect them, but it doesn't protect them enough.
In addition, the existing agreement between the Inspector
General of HHS and FDA gives too much power to the FDA when it
comes to how allegations of criminal misconduct by FDA
employers are being investigated. And we have an attachment F
on that. That agreement should be revisited. I look forward to
reform opportunities in the year ahead. There is no doubt that
the FDA needs additional tools and resources in its work. The
FDA also needs an overhaul to make the agency more transparent,
more forthcoming and more independent minded.
I look forward to working with this committee and
particularly, with the leaders of the committee, both
Republican and Democrat, subcommittee as well as the full
committee. And I thank you and as you indicated, I will be glad
to stay and answer questions.
Mr. Stupak. Well, thank you, Senator. We appreciate your
time effort in appearing here today. We are going to take 10
minutes on each side. I will begin the questioning. I am going
to ask two questions. I will turn it over to Mr. Dingell and we
will move on.
Senator Grassley, you mentioned once again, in your
testimony about the agreement between the Office of Inspector
General for the Department of Health and Human Services and the
Food and Drug Administration. In that agreement, certain
responsibilities were given to the FDA when it comes to how
allegations of criminal misconduct by FDA employees are
investigated and you mentioned in your testimony,
whistleblowers, the retaliation. We still have some brave
scientists within the FDA who come forward and assist us in our
work and they are still there and I am concerned about the
retaliation. Could you explain that a little bit more what you
think should be done in this area on this agreement, how it
should be restructured?
Senator Grassley. Well, obviously it gets back to what is
very basic about Inspectors General; great deal of independence
over anything within the agency; only very remotely connected
with the administration of the agency; to do, basically, what
you and I do as individual Congressmen or as chairmen of
committees, to make sure that laws are faithfully executed and
an agency is doing what it is supposed to do; to basically get
down to being independent, to ferret out things that are wrong.
And so it seems to me that what we have here is the Office
of Internal Affairs in the FDA engaging what is abused of power
and an example of that, I referred to Dr. Mosholder. Two or 3
years ago he was threatened with being prosecuted, like Martha
Stewart, as an example. We saw the office used as a tool by
drug companies to investigate a safety review by the FDA's
Center for Veterinary Medicine and when the Office of Inspector
General was trying to do its work, it was reported to me that
they are concerned about the weaknesses that they uncovered in
that agency within FDA. So I can only say that, bottom line,
just get back to Inspectors General being able to do what they
are supposed to do and not see the FDA as an institution unto
itself.
Mr. Stupak. Thank you. On your testimony, you catalog your
personal experience with FDA's suppression of independent
researchers' opinions, harassment of whistleblowers, persistent
refusal to produce documents in response to your request in
your capacity as chairman of the Senate Finance Committee. So
with respect to Ketek, you say that you learned that the FDA
gave its advisory committee questionable data on Ketek and did
not tell them about the problems with the data. FDA approved
Ketek without much safety data from the U.S., that Ketek's
sponsor, in all likelihood was aware of the fact that it had
submitted some questionable data to the FDA regarding its large
safety study.
Senator, your experience with the FDA simply refusing to
respond to subpoenas, refusing to produce documents and other
information to aid your investigation is astonishing. I gather
this was not an isolated incident, but occurred on numerous
occasions and that the FDA is still refusing to give you
information that you requested on the Ketek investigation?
Senator Grassley. Without a doubt. And what is really
miraculous about that approach on their part, we asked for the
log that I have already referred to in my statement, so in a
sense, we don't even really know what is being held, withheld
from us, why it is being withheld, and we happen to be aware,
through information we get from inside, of some documents that
could be responsive and don't appear to be privileged, but
still being withheld from us. But see, there is no reason why
we can't at least have that log so we can separate where maybe
there is a legitimacy to their point of view or something.
Maybe it deals with proprietary information, as an example.
Although, if that doesn't get out to the public, that shouldn't
even be withheld.
Mr. Stupak. Senator, do you have any thoughts on the fact
that the FDA reported that it is changing the label on Ketek
and that changes include the removal of two of the three
previously approved indications, bacterial sinuses and acute
bacterial chronic bronchitis, from the drugs label? According
to news reports, the FDA determined that the balance of
benefits and risk no longer support approval of the drug for
these indications, being the sinus and the bronchitis. So now
Ketek will remain on the market for the treatment of community
acquired pneumonia of mild to moderate severity. In addition,
the FDA said it would work with the company to update the
product labeling with a boxed warning, FDA's strongest form of
warning. Any comments on that?
Senator Grassley. Well, I think it is quite evident, since
it just come out yesterday, you are having this hearing today,
that finally the heat in the kitchen got a little bit too hot
and they decided to move out of the kitchen. But also, it is
perfect evidence that eventually when you push the envelope
enough, they do show some respect for the scientific process,
but in all of this, whether it is Ketek or Vioxx or a lot of
others, it is a lack of respect for the scientific process that
I think is basic to what is wrong with some of these drugs
getting on the market and not getting there and when there is
dissidence, a dissident point of view, or let us say an
alternative point of view, not a dissident point of view,
alternative point of view among scientists.
All you got to do is let science operate. If Scientist
Grassley has a view and it has got to be reviewed by Scientist
Stupak and you don't quite agree with me, then it is out there
for peers to take action. Everything in science might not be
perfect, but it sure is a heck of a lot perfecter than the
subjective judgment of a few administrators stepping in, for
some reason or other, to short circuit the scientific process.
So if we get the FDA back to proper respect for the scientific
process, I don't know whether you and I would have to be here
today.
Mr. Stupak. Last month the FDA proposed an increase in
annual user fees paid to the agency by pharmaceutical companies
to improve drug safety oversight, the post-marketing
surveillance we speak of, to speed approval time for the new
drugs and monitor direct to consumer advertising. Do you think
user fees give companies too much influence over the FDA?
Senator Grassley. Well, from that standpoint, it is kind
of, since money is fungible, I suppose it shouldn't, but when
you have got an agency getting their money directly from the
industry that they are regulating, it is hard for the public
and maybe for us, and it causes us to be a little more
suspicious here in the Congress, but for the public that is
unsophisticated about how Government works, it is sure going to
appear to them of undue influence. But more importantly than
just the user fees, I can make reference to a lot of e-mails
that we have had access to from within the FDA that would say
things along this line, and I don't have a specific reference.
I could have my staff get you a specific reference, but things
that said well, if there is any question about this or that,
some specific drug they would mention, talk to us first or let
us have an opportunity to explain, et cetera. It is almost like
the pharmaceutical companies feel like they have a seat at the
table and maybe this fee business makes them feel that way. I
don't know for sure. But the point is, there should only be one
person across the table from the FDA and that is John Q.
Public, not members of the pharmaceutical industry.
Mr. Stupak. Senator, you went all the way to the Department
of Health and Human Services to talk to an agent regarding
Ketek. Has HHS finally given you access to that agent?
Senator Grassley. Absolutely not and there is not reason
to, but their excuse is that there is a criminal investigation
or there is an investigation generally, see, an investigation
generally. And I will tell you how absurd this gets. Now, they
referred to the fact that the Department of Justice is advising
them accordingly, see? So I am sitting in Judiciary Committee
in the United States Senate on an entirely different issue and
Senator Kennedy, with more seniority, goes ahead of me and he
says something to somebody from the Department of Justice, I
want to ask these line agents some questions. Well, you can
have access to these line agents.
Well, a light bulb goes off that Chuck Grassley can't have
access to a line agent because somebody in the Justice
Department told HHS that I couldn't talk to Agent West. So I
talked to the Justice Department about the situation right
after Senator Kennedy gets done and they said I could have
access the same way Kennedy had access, to other agents in some
other department. I still don't have access to Agent West. So
if the Justice Department is advising HHS that you can't have
access to Agent West but the Justice Department, in a similar
case of a line agent says Senator Kennedy has, well, what is
the policy of this administration on having access to line
agents? Is it one policy for Kennedy, a Democrat, and another
policy for Grassley, a Republican?
Mr. Stupak. I understand. I want to respect your time. I am
done with my 10 minutes. Any comments, Mr. Green? Ms. DeGette?
Thank you. Thank you. Mr. Whitfield, please, for 10 minutes.
Mr. Whitfield. Thank you, Mr. Stupak, and I have one
question and then we will let the other Members on our side
expend the 10 minutes.
Senator, we appreciate you being here. In your testimony,
you brought attention to one of the basic tenets of our
Government and that is the responsibility of oversight by the
legislative branch and I would just ask you a question because
I think you have touched on a significant issue, just the
difficulty that you had in obtaining information from a branch
of the Government on the executive side. Did you consider using
a subpoena at any time to, not only a subpoena, but holding
them in contempt?
Senator Grassley. In the Senate, you get to this place. We
considered that, yes. But you have to have a majority vote of
the committee. You have to have a majority vote of the Senate
for that to happen and so we did not decide to go that route
because we thought there were other routes we could go.
Obviously, the other routes have not been successful, either.
Mr. Whitfield. Well, we appreciate very much your bringing
attention to this issue and we look forward to working with you
as we try to address it and----
Senator Grassley. Well, let me suggest to you, Chairman, or
Ranking Member Whitfield, that you can be very helpful. This
double standard in this administration, that a Democratic
Senator, supposedly not as friendly with the administration as
I am, maybe they don't consider me friendly anymore, but the
point is if Senator Kennedy can get access to line agents why
can't Senator Grassley get access to a line agent, when I have
already had access to line agents over the years? So some sort
of new policy?
Mr. Whitfield. Yes, I understand. I get frustrated. I find
the appropriators sometimes have access to things I don't have
access to and it is very frustrating. Since I guess I am
controlling the time on our side, at this time I recognize Mr.
Ferguson, Mr. Burgess and then Mr. Walden.
Mr. Ferguson. Thank you, Mr. Whitfield. Senator, thank you
very much for being here today. I can fully identify with your
frustration in not always getting information that you are
looking for. I know you were commenting before on whether the
administration considers you a friend or not, we all certainly
here consider you a friend and we very much appreciate your
being here.
Senator Grassley. Well, sometimes I wonder why I spent 2
days in the car with President Bush riding around the cold of
Iowa to help him get nominated in the year 2000, as an example.
Mr. Ferguson. I wish I could shed more light on that for
you but maybe I ought to stick to my topic. Senator, you
mentioned before the Mosholder investigation on SSRI's with
children. That was a very, very important topic for this
subcommittee, something that I was very involved with
personally and really highlights the importance of this topic,
this issue of post-market analysis and I know, in your bill,
your approach in the bill that you have introduced would move
this issue of post-market review out of CDER, out of the Center
for Drug Education or Evaluation and Research.
Would you just comment on the differences between your
approach and the approach that was suggested by the
recommendations of the Institute of Medicine? I don't want to
bring up Senator Kennedy's name, because that seems to raise
your ire, but I know in the bill that Senator Kennedy has
introduced, his approach seems to be, anyway, more consistent
with the recommendation that the Institute of Medicine had
suggested. Would you just comment on those differences, please?
Senator Grassley. In a very general way, I think that the
main difference is that I want, within FDA--because some people
think we are setting up something outside FDA, so I want to
emphasize, we are doing it within FDA--report directly to the
Director so that there is no doubt that even though, on a chart
of organization, the Office of New Drugs is separate from the
post-marketing, the Office of Drug Safety, but as I indicated,
it is not really so. So I want to get this box over here,
wherever this box is located, I want it not to be under the
thumb of this agency, even though the chart doesn't show it
that way, reporting directly to it. And I think that Senator
Kennedy's approach, and it is probably a bipartisan bill, so it
is not a political, partisan issue, is that we are going to
still have a cloudy relationship, not the black and white
separation that I call for under the bill that came out of
committee last year. Now, I don't know whether Senator Kennedy,
in his new bill, is going the same direction this year or not,
but last year, that is the way it was and we just want
guaranteed independence in reporting directly so that we don't
have these people in the Office of New Drugs that says this
drug is safe, trying to quash out here when somebody says it
isn't safe. And I don't want what happened to some of your
witnesses who are patriotic Americans, wanted to make sure the
scientific process works, being blackballed and ruined
professionally because of that. It doesn't need to be. It
compromises too much and there is too much found out in post-
marketing surveillance that needs to have an independent
judgment of it. And I don't think that in the bill that Senator
Kennedy has that it goes far enough.
Mr. Whitfield. We have less than 4 minutes left. Dr.
Burgess, did you have a question?
Mr. Burgess. Yes, Mr. Whitfield. Senator, thank you for
being here. On perhaps just a side note. Yesterday in the Wall
Street Journal there was an op-ed article about clinical trials
and patients who have reached the end of their therapeutic
ropes, if you will, who are denied access to drugs that are in
phase 2 trials. It raises a separate issue with the FDA, but
physicians and clinical staffs who apply for exceptions to get
their patients into these clinical trials find the statistical
issues raised by the FDA staff aimed at the applying physician
can sometimes rival receipt from the IRS.
Clearly, that is an interference in getting new cutting
edge medications to patients, again, who have exhausted all
therapeutic activity, so I hope, Mr. Chairman, we can perhaps
spend some time looking at that, as well. I guess I am most
interested, Senator, and I do agree with you, the proper
respect for the scientific process needs to be paramount in our
minds. Line Agent West, whom you referenced, were you ever able
to establish contact with this individual and if not, Mr.
Chairman, are we planning on asking for similar access to Line
Agent West? Senator?
Senator Grassley. Well, I have not personally had access to
him in the way that makes any difference. I think maybe I
better not speak beyond that because I don't want to get
anybody in trouble, but we have some information, but we need
to get the information in an open, transparent way. And I don't
want to imply we got information, that we just want to be more
transparent. We don't have all the information we can get if we
can talk to him.
Mr. Burgess. But I judged from your tone and demeanor you
felt that this individual had some pretty important
information?
Senator Grassley. Oh, absolutely. Without a doubt.
Mr. Burgess. Thank you, Mr. Chairman. I will yield.
Mr. Whitfield. Mr. Walden.
Senator Grassley. Can I? On the first thing you brought up,
I don't think you meant to imply this, but just in case; I
don't want any misunderstanding. I hope, in all of my
testimony, that I don't want to interfere with the things that
you were bringing up that were in the Wall Street Journal in
the sense of special opportunities for people who are willing
to be guinea pigs because it is the end of the life, it might
save their life, it might not save their life. Where an
individual is totally aware of every gamble he is taking and he
is educated in that and he is will to take it and everything is
transparent, I don't want to stand in the way of that.
Mr. Whitfield. Mr. Walden.
Mr. Walden. Thank you. Thank you, Mr. Chairman. Senator,
welcome. We appreciate your work on this issue. I want to touch
on one topic and that is that Memorandum of Understanding that
I understand exists between the IG's office and HHS and the
FDA.
Senator Grassley. Yes.
Mr. Walden. To allow the FDA to investigate itself,
basically, on employee misconduct issues. And I am just
curious. I know that is an issue you have been concerned about,
Senator, and I wondered if you or your staff has learned
anything new regarding the status of that MOA?
Senator Grassley. Well, I think I better look at my staff,
but I don't think we have anything more than we are just
recommending that it should be reviewed and rewritten. I don't
know that we're in the process of thinking it is being reviewed
and rewritten. Yes. We have asked the IG to examine it. He has
come up with some recommendations. But your question to me is,
is it being rewritten and the answer is no. OK?
Mr. Walden. All right. It is just a concern I think we
share.
Senator Grassley. Well, yes, and it would be nice if--this
is an extremely powerful committee you have here and the extent
to which you can push that, it would be much appreciated by me,
but more importantly, the people's safety is at stake here and
independence from industry being regulated would be enhanced by
it, as well, I think.
Mr. Walden. I think we concur with that.
Senator Grassley. And maybe less pressure brought against
whistleblowers, too.
Mr. Stupak. Well, Senator, there is concern on that
memorandum that the FDA is using it under a criminal pretext to
suppress scientific opinion on drugs that are being approved.
It appears, from the SSRI, Vioxx and others, when a scientist
within the FDA or a whistleblower is going to speak out, they
suddenly find themselves under some kind of criminal
investigation from the FDA underneath this Memorandum of
Understanding. It seems like it is a form of retaliation and
harassment on scientists willing to speak up and speak out.
Senator Grassley. Yes. And let me tell you, you have stated
it better than I could and as a matter of emphasis, and more
importantly, because you are chairman of this subcommittee, I
hope people listen, from that point of view, and you pursue
that because you are absolutely right.
Mr. Stupak. Thank you. Mr. Dingell, anything for Senator
Grassley?
The Chairman. Mr. Chairman, only this. I want to thank our
old friend for coming over here. Thank you, Senator, very much
for being here. I would ask that perhaps if I send you a little
letter requesting some information on your statement today and
your comments on some questions before us related to this
matter. Perhaps maybe you would respond and I would ask
unanimous consent that that response be put in the record.
Senator Grassley. Yes, we will do that, Chairman Dingell,
and thank you for your leadership and I look forward to a
return to the days of your aggressive oversight work where
almost every agency knew that you were going to get to the
bottom of things and that they ought to cooperate.
The Chairman. Thank you. Well, you have set a good example
and I will certainly try to follow it, but we have an
outstanding chairman in this subcommittee, Senator, in the
person of Mr. Stupak and he will do a superb job of helping
folks understand that we all work for the taxpayers and the
people, as do you, sir. Thank you very much for being here.
Senator Grassley. That last statement he made, if I could
comment on it. We all work for the taxpayers and we have got
institutions, not just FDA. Maybe the example I always use is
the FBI more than the FDA in this manner, but we have got too
many agencies around here that talk about it as our agency or
our institution. In the case of the FBI, it was our
institution.
I got tired of the director saying that all the time at a
meeting we were in, our institution, and I said that is what is
wrong with the FBI and maybe that is what is wrong with the
FDA, although I haven't heard that from them, but the point is
that I said we all work for the American people. It is not your
agency, it is not my agency, it is the people's agency and we
are all working for the American people and the sooner we
understand we are working for the American people and not for
our institution, the better we are going to do our job.
Mr. Stupak. Well said. Any other comments? Senator, thank
you once again. Thank you for your time and thank you for your
work and we look forward to working with you.
Senator Grassley. Thank you.
Mr. Stupak. We will call our second panel up to testify.
Mr. Burgess. Mr. Chairman, while the second panel is
seating, can I ask for a unanimous consent request? I ask
unanimous consent that yesterday's op-ed from the Wall Street
Journal be submitted as part of the record?
Mr. Stupak. Hearing no objection, it will be made part of
the record.
Mr. Stupak. The second panel will consist of Dr. David
Ross, National Clinical Health Programs, U.S. Department of
Veterans Affairs; Ann Marie Cisneros, Independent Clinical
Research Associate; and Dr. John Powers, Scientific
Applications International Corporation. If they would come
forward, please. 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 testimony. Do any of the witnesses before us,
this panel, have counsel at this time? Do you want to introduce
your counsel, Dr. Ross?
Dr. Ross. My counsel is Mr. Mark Cohen of the Government
Accountability Project.
Mr. Stupak. OK. Ms. Cisneros?
Ms. Cisneros. My counsel is the same.
Mr. Stupak. Same. Dr. Powers?
Dr. Powers. Same.
Mr. Stupak. OK. Please rise and raise your right hand to
take the oath.
[Witnesses sworn.]
Mr. Stupak. OK, record shall reflect the witnesses have
been sworn and Dr. Ross, we will begin with your opening
statement, please.
TESTIMONY OF DAVID ROSS, M.D., NATIONAL CLINICAL HEALTH
PROGRAMS, U.S. DEPARTMENT OF VETERANS AFFAIRS
Dr. Ross Good morning, Mr. Chairman, Mr. Ranking Member and
members of the committee. Thank you for the opportunity to
speak before this committee. I am here today to speak about the
drug Ketek.
My name is David Ross. For purposes of identification only,
I am National Director of Clinical Public Health Programs for
the U.S. Department of Veterans Affairs. I am here today as a
private citizen. I was trained as a medical doctor at New York
University and Yale and am Board certified in internal medicine
and infectious diseases. I take care of patients at my local VA
hospital and teach medical students and residents.
I served for 10 years at the FDA in positions ranging from
primary reviewer of new drug applications to a member of the
senior leadership team of FDA's Office of New Drugs. I served
as both the primary safety reviewer and the safety team leader
for Ketek. FDA approved Ketek despite knowing that it could
kill people from liver damage and that tens of millions of
people would be exposed to it, despite FDA knowing that the
drug's maker submitted fabricated data, and despite knowing
that Ketek is no better than any other antibiotics and may not
even work.
Why does Ketek matter? Because FDA broke its own rules and
allowed Ketek on the market. Because dozens of patients have
died or suffered needlessly. Because FDA allowed Ketek's maker
to experiment with it on children over reviewers' protests.
Because FDA ignored warnings about fraud. And because FDA used
data it knew were false to reassure the public about Ketek's
safety. In March 2000, when Ketek was submitted to FDA,
reviewers were alarmed over a patient treated with Ketek who
had developed severe liver damage, an even that could mean
hundreds or thousands of deaths every year.
In April 2001, a Federal advisory committee was so
concerned about Ketek's potential to kill patients, that it
required a large safety study before the drug could be
approved. In October 2002, FDA reviewers, examining the safety
study found serious and pervasive misconduct point at fraud. In
December 2002, Ketek's manufacturer admitted that it had known
about issues at its largest enroller but hadn't told the FDA.
The company claimed that there were no other issues with the
study, even though every study site inspected by FDA turned out
to have major problems, an unprecedented situation in my
experience.
In January 2003, over reviewer's protests, FDA managers hid
the evidence of fraud and misconduct from the advisory
committee, which was fooled into voting for approval. Starting
the same month, FDA managers also pushed to use uncontrolled,
unreliable side effect reports from overseas supplied by the
drug's manufacturer. FDA's own division of scientific
investigations concluded that none of the safety study data
were reliable. One week later, FDA managers approved Ketek.
They repeatedly cited it was evidence of Ketek's safety.
In February 2005, 7 months after Ketek's launch, FDA
managers received the first reports of fatal Ketek-related
liver failure. They did nothing. In February 2006, I and other
reviewers warned senior FDA managers, in writing, about the
problems with Ketek, including reviewers being pressured to
change their opinions. The managers did nothing. In March 2006,
FDA managers received new warnings from criminal investigators.
They did nothing. In May 2006, FDA managers received warnings
from safety reviewers that Ketek was much more dangerous than
comparable antibiotics. They did nothing.
Only after congressional subpoenas, which FDA resisted, and
stories in the news media about Ketek and fraud, did FDA
managers finally do anything. They reworded the label. In late
June 2006, FDA reviewers, including myself, were summoned to a
meeting with Commissioner von Eschenbach in which he compared
the FDA to a football team and told reviewers that if they told
anyone outside the FDA about the problems with Ketek, they
would be traded from the team. Rather than be silenced, I chose
to move on to my current position.
How did this happen? The FDA reviewers did their job. This
is not their fault. Ketek can be laid directly at the door of
senior FDA managers who knew better because they were told
repeatedly by reviewers and criminal investigators, but chose
to look the other way. Their behavior was worse than being in a
state of denial. FDA managers were so bent on approving Ketek,
that they suppressed evidence of fraud and pressured reviewers,
including myself, to change their reviews.
What is the bottom line? An unsafe drug got past the system
despite warning after warning about fraud, liver damage and
death because FDA managers at the highest levels refused to
listen. Will this happen again? Yes. Without significant
changes in our drug safety system and in FDA, we are certain to
see more Keteks. Thank you. The views presented here are my
own. I will be happy to answer any questions from the
committee.
[The prepared testimony of Mr. Ross appears at the
conclusion of the record.]
Mr. Stupak. Thank you, Dr. Ross. Ms. Cisneros, for a 5
minute opening statement.
TESTIMONY OF ANN MARIE CISNEROS, INDEPENDENT CLINICAL RESEARCH
ASSOCIATE
Ms. Cisneros. Sure. Good morning, Mr. Chairman and members
of the committee. I am honored that you are giving me the
opportunity to tell my story.
My name is Ann Marie Cisneros. I am currently an
independent clinical research associate. I was trained in the
United States Air Force as a medical technologist, have a
Bachelors of Science Degree in Occupational Education from
Wayland Baptist University and a Masters of Business
Administration Degree from Pfieffer University.
I have worked as a clinical research associate for
approximately 8 years. My first 3 years in this industry I
spent at PPDI, a contract research organization, where I
monitored a number of protocols that included Study 3014. At
the time of Study 3014 I was a senior clinical research
associate and was asked to assist with the monitoring of Dr.
Anne Kirkman-Campbell's site.
Dr. Kirkman-Campbell is currently serving a 57-month prison
sentence for fraud associated with Study 3014. In addition, she
was ordered by the court to pay restitution to the drug
sponsor, Aventis, which had paid her $400 per patient enrolled.
Mr. Chairman, based upon what I observed and learned in
monitoring the Kirkman-Campbell site, Dr. Kirkman-Campbell
indeed had engaged in fraud. But what the court that sentenced
her did not know is that Aventis was not a victim of this
fraud. On the contrary. Let me explain.
Even before conducting the Kirkman-Campbell site visit, a
number of red flags were apparent. I knew that Dr. Campbell had
enrolled over 400 patients, or 1 percent of the adult
population of Gadsden, Alabama. By comparison, another site in
Gadsden had enrolled just 12 patients. In a recent quality
assurance audit by Aventis, several Informed Consent issues
were noted, as well as significant under-reporting of adverse
events and no reports of serious adverse events. No patients
had withdrawn from the study and no patients were lost to
follow up, an unusual occurrence given the number of subjects.
She enrolled patients within minutes of each other and upwards
of 30 patients per day. She enrolled patients at times and on
days when the office was closed.
Once we started reviewing patient charts, we discovered
that every informed consent had a discrepancy. Most of the
consents looked like they had been initialed by someone other
than the patient. A lot of the consents were dated by someone
other than the subjects. One consent was a blatant forgery.
There date discrepancies as to when patients were enrolled in
the study, had their blood drawn or signed their consent. Most
patients diagnosed with bronchitis either had no history of the
ailment or not have a chronic condition. She enrolled her
entire staff in the study.
Frankly, all Kirkman-Campbell seemed really interested in
was getting more business from Aventis as an investigator. At
one point during my site visit, she told Aventis project
manager Nadine Guenthe that I could only stay if Nadine got her
other studies at Aventis and Nadine agreed. It is my
understanding that when the FDA audited Kirkman-Campbell's
site, she was participating in another Aventis clinical trial.
While at the site, I was so concerned about patient safety,
I called Copernicus Independent Review Board to express my
concerns and seek guidance. An IRB, which is under contract to
the drug sponsor, has as its primary purpose as patient
advocacy. It is allowed to contact patients directly and is
duty-bound to report to the FDA any unanticipated problems
involving risks to subjects and serious noncompliance with
regulations. I spoke with the president of the company and was
told that while she shared my concerns, she preferred to wait
and see what actions Aventis took. I never heard from the IRB
again and to my knowledge, Copernicus never did audit,
blacklist the site or report any irregularities to the FDA.
I e-mailed a summary of my site findings to Robert
McCormick, head of quality assurance at PPD and copied Aventis
personnel. I also participated in a teleconference between PPD
and Aventis at which I discussed issues identified in my visit.
At some point after that, I understand that Aventis took site
management responsibilities away from PPD because Kirkman-
Campbell would not cooperate with anyone but the sponsor.
I subsequently left PPD but learned that the Kirkman-
Campbell site was being audited by the FDA. In preparation for
the audit, Aventis' Nadine Guenthe coached Dr. Campbell with
leading questions on how to explain away improper conduct.
Nadine would say, for example, is the reason you enrolled so
many patients in 1 day because that is when your supply of drug
came in? I was told about this by a trusted and distressed
former colleague of PPD who witnessed the prepping.
In my 8 years in clinical research work, this is the only
instance I have come across such bad behavior by a drug
sponsor. I feel I can speak for those who agonized over this
situation when I say we are pleased that Dr. Campbell is
serving prison time for her actions. But what brings me here
today is my disbelief at Aventis' statements that it did not
suspect that fraud was being committed. Mr. Chairman, I knew
it, PPD knew it and Aventis knew it. Thank you.
[The prepared testimony of Ms. Cisneros appears at the
conclusion of the hearing.]
Mr. Stupak. Thank you. Ms. Cisneros. Dr. Powers, opening
statement, please.
TESTIMONY OF JOHN POWERS, M.D., SCIENTIFIC APPLICATIONS
INTERNATIONAL CORPORATION
Dr. Powers. Thank you, Mr. Chairman, and members of the
committee. Good morning. My name is John Powers. I am a
physician-scientist who worked at the Food and Drug
Administration for 8 years, the last 5 of which I was the Lead
Medical Officer for Antimicrobial Drug Development and
Resistance Initiatives. I really do not consider myself as
having ``blown a whistle,'' but having done my job, since I
appropriately raised the issues that I will discuss with you
today to my supervisors at FDA. I chose to leave the agency to
pursue other research opportunities after over half a decade of
attempting to advance the science of clinical trials and
infectious diseases, feeling I could better serve the public
outside the agency. There are numerous individuals in both the
FDA and the drug industry who work hard appropriately
evaluating and I learned a tremendous amount while I was at
FDA. I would still be there today if I felt I could perform my
job in the way it should be done.
Many of the recent discussions regarding evaluation of new
drugs have focused on their safety, but there are also
important issues with the evaluation of drug effectiveness,
especially with antibiotics. In 1962, Congress amended the
Food, Drug and Cosmetic Act to state that there must be
substantial evidence of effectiveness from adequate and well-
controlled trials in order to justify the adverse events that
are inherent with all drugs. In the absence of substantial
evidence of effectiveness, any adverse effect, no matter how
rare, is not justifiable.
The approval of Ketek is a symptom of a larger problem.
Over the last 25 years FDA has approved approximately 68 new
drug applications for ear, sinus and bronchial infections,
which are mostly self-resolving. All of these drugs were
approved based on so-called non-inferiority trials. The word
itself, non-inferior, means not worse, but the purpose of these
trials is to rule out an amount by which the new drug's
effectiveness may, in fact, be worse compared to an older drug.
Showing a new drug is potentially worse than an old drug whose
effectiveness, itself, is unclear in the setting of a given
trial. It is like the Billy Preston song, ``nothing from
nothing leaves nothing.''
Previous placebo control trials show 12 of 17 studies in
sinus infections and 9 of 14 studies in bronchial infections
lack evidence of a benefit for antibiotics and the situation is
similar for ear infections, therefore showing that Ketek may be
less effective than older drugs is not evidence that Ketek is
effective at all in sinus and bronchial infections and this was
clear at the time the drug was approved in 2004.
While non-inferiority trials are justifiable in serious
infections where the benefits of antibiotics are clear, even
here the trial must be done properly in order to provide
meaningful results. The major problem is that many of the
safeguards and trials that protect against false conclusions
are less useful in the setting of non-inferiority trials. For
instance, trials in pneumonia may enroll patients who don't
have pneumonia, but instead have the common cold. This says
nothing about the new drug's effectiveness in pneumonia, but
the new drug may appear to be similar in effectiveness to the
old drug. This is like testing a new parachute against an older
proven parachute when all the people are jumping out of a plane
that is standing still and only two inches off the ground.
Everyone will do well, but it says nothing about how the new
parachute will work in a real life situation.
Lack of effectiveness is a more important problem in
antibiotics than it is for other types of drugs. If a non-
antibiotic doesn't work, it only affects the person who takes
it. If an antibiotic doesn't work, it affects the person who
takes it and other people, by spreading resistance to that drug
and to other related drugs, as well. Antibiotic resistance is a
safety issue and lack of effectiveness of antibiotics can
promote the problem of resistance we are actually trying to
combat. Why would FDA continue to allow approval of antibiotics
without substantial evidence of effectiveness?
Drug sponsors have exited the field of antibiotic
development over the last few decades and this was an attempt
to provide an economic incentive for sponsors to develop drugs
where we really need them, in serious and life threatening
diseases. We do need new antibiotics, but approval of
ineffective and therefore inherently unsafe drugs is not a
proper or effective incentive for drug development. Exposing
children who might not even have a bacterial infection to Ketek
in the setting of a non-inferiority trial is not the way to
develop new drugs, as children will be exposed to harm without
the ability to determine the drug's effectiveness. Despite the
approval over the last two decades of scores of antibiotics
whose effectiveness remains unclear, there has been no boom in
antibiotic development and developing economic incentives to
promote development is needed, but it is the province of
Congress, not the FDA.
In summary, FDA needs to require sponsors to perform
placebo control trials and self-resolving diseases. For serious
diseases, FDA needs to require appropriately designed,
conducted and analyzed trials to give clinicians the
information they need to make appropriate decisions for
patients. FDA needs to address the drugs that still carry
approvals for self-resolving diseases without substantial
evidence of effectiveness. FDA needs to promptly publish new
guidances based on appropriate scientific and regulatory
principles and remove the old guidances from its Web site now,
since they continue to mislead drug sponsors.
Mr. Chairman, the bottom line is we must preserve the
effectiveness of antibiotics, which are among the marvels of
modern medicine, and that means they must be studied in trials
that tell us whether they truly help people, not just have
activity in test tubes. Thank you.
[The prepared testimony of Dr. Powers appears at the
conclusion of the hearing.]
Mr. Stupak. Thank you. Before we begin questions, in order
to proceed in a more orderly and efficient manner, I would
propose that instead of minutes for each Member for
questioning, that each Member will have 10 minutes to use for
questioning during this hearing. If there is no objection, I
propose we do this this morning. Mr. Whitfield, do you have any
comments or thoughts on that, going to 10 minutes?
Mr. Whitfield. I don't have any objections.
Mr. Stupak. No objections? So ordered.
Dr. Ross, if I may start with you, please. In your
testimony, as powerful and as forceful as it was, you
indicated, in January 2003, over viewers protest, FDA managers
hid the evidence. You went on and talked about FDA managers
pushed to use uncontrolled, unreliable side effect reports from
overseas. You indicated throughout your testimony that they did
nothing, that FDA managers didn't review things; FDA managers
were aware of things but did not act. Who are these FDA
managers?
Dr. Ross. There are specifically six individuals I would--
--
Mr. Stupak. And we are just talking about Ketek right now?
Dr. Ross. We are just talking about Ketek, yes, sir. There
are six individuals I would point to: Dr. John Jenkins, the
director of the Office of New Drugs; his deputy, Dr. Sandra
Kweder; the director of the Office of Antimicrobial Products,
Dr. Mark Goldberger; his deputy, Dr. Edward Cox; his associate
director, Mr. David Roeder; and the division director for the
Division of Anti-infective and Ophthalmologic Drug Products,
Dr. Janice Soreth.
Mr. Stupak. OK. What rules did the FDA break in it approval
of Ketek? Now, you were there for 10 years, you were a senior
analyst on these drugs.
Dr. Ross. I was the safety team leader for Ketek and----
Mr. Stupak. Would that be like the medical review officer
assigned to Ketek?
Dr. Ross. It would be. I served at different points, two
roles.
Mr. Stupak. OK.
Dr. Ross. One was as the primary safety reviewer or the
person actually looking at the data, and during the second
review cycle, I directed a team of safety reviewers.
Mr. Stupak. OK.
Dr. Ross. And then later on in my career at FDA, I was a
member of what is called the senior leadership team for the
Office of New Drugs. So in terms of rules that FDA broke with
respect to Ketek, it approved Ketek based on a study that its
own investigators said was worthless, which breaks the rule
about needing adequate and well-controlled trials. When I say a
rule, that is a statutory requirement under the Food, Drug and
Cosmetic Act. It used uncontrolled foreign safety reports to
answer a critical safety question that should have been
answered by an adequate and well-controlled trial. It failed to
assess the overall integrity of the Ketek application, despite
warnings about potential systemic fraud.
Mr. Stupak. Warnings from whom?
Dr. Ross. Warnings from reviewers and warnings from
criminal investigators.
Mr. Stupak. Warnings from yourself?
Dr. Ross. Yes. And warnings, as well, from members of the
Office of Criminal Investigations.
Mr. Stupak. OK.
Dr. Ross. It failed to verify the integrity of foreign data
submitted to it before approving Ketek. It allowed managers to
violate Federal law by coercing reviewers into removing
disagreements from the administrative record. Title 21, part
10.70 of the Code of Federal Regulations provides that
disagreements on the provability of an application shall be
entered in the administrative record. Finally, the FDA failed
to carry out its responsibilities to enforce parts 50 and 56 of
title 21 of the Code of Federal Regulations by failing to hold
the Institutional Review Board for Dr. Kirkman-Campbell is
responsible for its actions. To this date, as far as I am
aware, there has been no action by FDA taken against that IRB.
Mr. Stupak. What evidence is there that the FDA used the
safety data from Study 3014 in its approval of Ketek? From what
I can gather, the FDA denies that it relied upon that study in
its approval process of Ketek. Can you shed any light on that?
Dr. Ross. Yes. Let me just refer first off to yesterday's
action by the FDA in changing the labeling for Ketek and at the
press conference for that, Dr. John Jenkins, the director of
the Office of New Drugs, stated unequivocally that they did not
rely on Study 3014 for the approval. Let me quote from an e-
mail that his own deputy sent on March 21, 2006 to myself and
another reviewer.
In speaking with the division about this, they did not
completely ignore the data from the 3014 study, but assessed
those AEs,
that is adverse events,
that were identified to qualitatively assess patterns of
toxicity.
Let me say the relevant clause again.
They did not completely ignore the data from the 3014
study.
Second, FDA cited the safety study when it first issued a
public health advisory about Ketek's potential to cause liver
damage. It is still citing it on that same public health
advisory as a large safety study. If they didn't use it for
approval, why are they citing it on their own Web site?
Finally, I have been told that in making the decision about
how and whether to prosecute Dr. Kirkman-Campbell, OCI asked
CEDR if it had used the study in making the approval decision
and the answer was yes.
Mr. Stupak. Dr. Ross, were you present at all three
advisory meetings for the approval of Ketek?
Dr. Ross. Yes.
Mr. Stupak. Why, at any one of these meetings, any one of
these three advisory meetings, did you not speak up about your
concerns about this study and how the approval process was
moving forward on Ketek?
Dr. Ross. Well, at the first advisory committee meeting, I
gave a presentation on the overall safety of Ketek and at that
point I did make my concerns very clear to the committee.
Mr. Stupak. And is that when the committee voted, then, to
do a larger study?
Dr. Ross. That is correct.
Mr. Stupak. OK.
Dr. Ross. At the second advisory committee, we had been
told by supervisors that the committee was not going to hear
about the fraud issues. If I had spoken about that, I would
have been fired immediately.
Mr. Stupak. So before the second one you were told by FDA
you were not allowed to bring up the fraud issue about, and
this would be Study 3014?
Dr. Ross. That is correct. We were told we are not going to
discuss it with the committee.
Mr. Stupak. OK. And you felt that if you would have brought
up that issue, the fraud in the study--obviously the FDA knew
about it then--you would have been fired?
Dr. Ross. There is no doubt in my mind and I think I likely
would have been subject to investigation by OCI that would have
been initiated.
Mr. Stupak. OK, then that is the approval of Ketek. Then
there was a third advisory meeting?
Dr. Ross. Yes. At that third committee meeting I appeared
as a private citizen and spoke at the open public hearing.
Mr. Stupak. Were you still an FDA----
Dr. Ross. No. At that point I was not. I took leave from my
current position for that day, so I was only appearing for
myself and I made facts known to the committee that they had
not been told by FDA.
Mr. Stupak. Thank you. Ms. Cisneros, in your testimony you
state that Aventis performed a quality assurance audit of the
Kirkman-Campbell site. Who, at Aventis, would have seen the
results of this audit?
Ms. Cisneros. Nadine Guenthe, who was the project manager
for Aventis and Ron Gincosly, who was the auditor.
Mr. Stupak. You also indicated, in your testimony, that
even before the visit to the Kirkman-Campbell site, a number of
red flags were apparent, you said. Would Aventis have known of
the these red flags?
Ms. Cisneros. Absolutely. I spoke with the in-house CRA
that managed Dr. Campbell's site and she had told me that she
was communicating with her superiors on almost a daily basis
about the oddities that were occurring at her site and it is my
understanding that the project manager at PPD would be having
discussions with Nadine Guenthe at Aventis about those issues.
Mr. Stupak. OK. There is a large binder right there. There
is exhibit No. 15, if you would look at that for me. In that
document, exhibit No. 15, it is sent to Nadine Guenthe of
Aventis attached to an e-mail dated February 27, 2002 by
Jessica Lasley of PPDI. A number of issues were raised with
regard to the Kirkman-Campbell site. For example, one item says
all subjects were 100 percent compliant with study medication.
Have you ever seen a study in which a hundred percent of the
subjects, in this case, some 400 people, were compliant with
the study medication?
Ms. Cisneros. No, I have not. And in this note that I gave
to Aventis, this referred to the 30 patients that I had
monitored at this site.
Mr. Stupak. OK. And you said you gave this to Aventis, so
this would have been February 27, 2002 or thereabout, so that
is some 2 years before Ketek was ever approved for the general
population?
Ms. Cisneros. Correct.
Mr. Stupak. In your last statement, I would like to shed a
little light on it, if you may. In your testimony you indicate
that you knew there were problems with the Ketek study with
this site; the FDA new and Aventis knew, and the PPD.
Ms. Cisneros. PPD knew.
Mr. Stupak. Right.
Ms. Cisneros. Right.
Mr. Stupak. How are you saying that Aventis knew of the
problems? You make a very emphatic statement at the end.
Ms. Cisneros. They could not have not known. The data, the
evidence was clear. They just had to prove a suspicion of
fraud. They didn't have to necessarily prove the fraud. They
just have to report a suspicion of fraud. And the evidence that
I brought back from my site visit, the evidence that was
discovered at the quality assurance audit, was pretty
extraordinary.
Mr. Stupak. So if I understand this correctly, if Aventis
knew there was suspicion of fraud in any of----
Ms. Cisneros. Right.
Mr. Stupak. Even a suspicion, you have to report that to
the FDA?
Ms. Cisneros. Correct.
Mr. Stupak. And that is required underneath your contract
to do this service?
Ms. Cisneros. I believe it is in the Code of Federal
Regulations, yes.
Mr. Stupak. Thank you. Mr. Whitfield for 10 minutes.
Mr. Whitfield. Thank you. Thank you, Mr. Stupak, and I
thank the three witnesses for being with us this morning, as
well. Dr. Ross, in your testimony, you went through a number of
pages here talking about how FDA managers had information, and
did nothing. They were warned by criminal investigators about
possible fraud, and did nothing. They received records from the
company that raised further concerns, and did not review them.
The FDA's own division of scientific investigation concluded
that none of the safety study data was reliable and then they
went on one week later and approved Ketek. Through a number of
very strong statements and as a citizen, a Member of Congress,
has oversight.
When these people are appointed in leadership positions, at
certainly FDA, they all are professionals; they are physicians,
they are scientists, they have great responsibility that has an
impact on all of our society in their decision. This seems to
be, from your testimony and the other testimony, so blatant.
Why would FDA managers do something like this? What would be
your best guess?
Dr. Ross. That is an outstanding question and it is
something I have been wracking my brains about. My best guess
is that there is two things. Overall, there is a culture of
approval that if you can get a product on the market, and this
was particularly egregious in this particular office, then you
find some way of doing it. The second thing that I have
concluded, and this is speculation on my part, but I do want to
bring it to the committee's attention, it is inconceivable to
me that after receiving a warning in July 2003 from an
experienced criminal investigator, that a decision to not have
an investigation was made at this level. I am also have been
told that Dr. Kweder was also briefed by OCI about the need for
a multi-jurisdictional task force. It is my belief that the
decision not to have an investigation was made at a higher
level and that would most likely be the Office of Chief
Counsel.
Mr. Whitfield. And how long were you at FDA? Ten years?
Dr. Ross. Yes, sir.
Mr. Whitfield. And you left simply because, as a physician,
you felt like you could not work at an agency with that kind of
culture, would that be safe to say?
Dr. Ross. One thing I have to say is FDA has wonderful
physicians and scientists who are public health heroes. They
really are dedicated to doing the best job possible. In the
office I was in, before I left, the Office of Oncology Drug
Products was one where I felt the managers were very committed
to doing the right thing, to getting life saving products out
quickly to the American public, but overall, seeing how the
senior managers, the individuals who I mentioned, were dealing
with what was clearly a horrible situation and not dealing with
it, I felt I couldn't, in good conscience, continue to work at
the agency and I gave them a chance to do this before I left. A
year ago, I met with Dr. Jenkins and Dr. Kweder in the presence
of a witness and followed this up with e-mails and told them
about what was going on and I said we have got a huge problem
here, but we can turn it around. We can solve this problem.
I gave them steps to follow, a corrective action plan
about Ketek and about the problems with scientific culture and
I said please do this. If we don't, we are going to get
crucified. They really didn't do anything. I told them survey
the reviewers, find out what the problem is. They didn't do
that. I said get everybody together in a room so we are not
sullying information about Ketek and let us see what the fraud
situation is. They said well, we will look into this. I found
out later that Dr. Kweder concealed my briefing that I had
given to her from the Office of Compliance within CEDR. So at
that point I felt I can't be in an agency that has a culture
like this even if I like the people and the work that I am
doing.
Mr. Whitfield. Now, you named one, two, three, four, five,
six people that were so-called senior management, that is Dr.
Jenkins and Dr. Kweder?
Dr. Ross. Yes, sir.
Mr. Whitfield. And then Mark Goldberger.
Dr. Ross. Dr. Goldberger.
Mr. Whitfield. And Dr. Cox.
Dr. Ross. Dr. Cox. Mr. Roeder and Dr. Soreth.
Mr. Whitfield. OK. And Dr. Powers, now, tell me again how
long were you at the agency?
Dr. Powers. I was there for 8 years.
Mr. Whitfield. Eight years. And you certainly heard the
testimony of Dr. Ross and the same question I asked him I would
ask you: why would they approve a drug like Ketek, assuming
that the facts that you have stated and that Dr. Ross has
stated are true, what would be your best guess? Now, he said
that there is a culture of approval.
Dr. Powers. Let me answer specifically about this drug,
first. I think, first of all, that there were economic issues
regarding antibiotic development that were pressuring FDA from
the outside.
Mr. Whitfield. Now, what do you mean by that?
Dr. Powers. So over the last 20 years several large
pharmaceutical companies had decided that they were no longer
going to participate in either discovering or developing new
antibiotics. And this was occurring at a time when we really do
need new antibiotics because of rising resistance and when I
say need, what I mean is in serious and life threatening
diseases where people could die if they don't get appropriate
therapy. In 2001 a member of the pharmaceutical industry and a
prominent academician wrote a letter in the journal Clinical
Infectious Diseases and that letter was titled ``The U.S. Food
and Drug Administration and the End of Antibiotics''. And in it
they outlined that if FDA made any moves to increase the rigor
of scientific studies in the area of antibiotics, that we would
be perceived as a scientific disincentive.
And I remember having a meeting about this and this is
clearly something we need to take account of and we do need to
make studies more efficient. In fact, placebo control trials
can be done with fewer numbers of patients. But that really
seemed to cause a lot of uproar within the agency, as well. I
think there is a second reason, though, and I think that there
is a bias about antibiotics, in general, and that is we tend to
focus on microorganisms instead of people. It is very clear
that antibiotics can kill microorganisms and they are very
effective in preventing death in serious diseases like
pneumonia. The question is what do they do for a disease like a
sinus infection where your own immune system gets you better,
even though they have a huge effect on bacteria, what do they
do for people? And I think a lot of scientists in this area
have this bias that if it affects the bug, that is all we need
to know.
And then there is the third issue and that is there were a
number of antibiotics approved in this method and it is just
human nature to sort of not want to go back and say whoa, wait
a minute. Maybe perhaps we need to readdress all of this. That
is a huge undertaking, actually. So I think that there is just
a human aspect to it, as well.
Mr. Whitfield. Now, in the article that was written about
the FDA being responsible for the ending of antibiotics,
research and development, what year was that article written?
Dr. Powers. It was published in early 2002, I believe.
Mr. Whitfield. And you say drug companies were letting it
be known that they were going to stop developing antibiotics?
Dr. Powers. Some already had and this is an issue that has
gone back to the 1980's, actually, where some companies had
decided to stop antibiotic discovery.
Mr. Whitfield. And the reason for that was just the rigors
of the approval process?
Dr. Powers. No. Actually, antibiotics have the highest
approval rate of any therapeutic class of drugs and in some
ways the studies are shorter and easier to do. You don't have
to study people for like arthritis for a year.
Mr. Whitfield. Yes.
Dr. Powers. The issue is that antibiotics are usually given
for a short period of time and therefore, the returns on
actually investing in an antibiotic are not as great as they
would be for a drug that you would take for your lifetime. And
there is also a lot of generic competition, as well.
Mr. Whitfield. Now, Ketek, of course is still on the market
and was originally approved for three conditions and now it is
being used or approved for only one and that is pneumonia, is
that correct?
Dr. Powers. Yes.
Mr. Whitfield. Now, somewhere I read or someone told me
that in some of the studies on Ketek that it said only 23 out
of 10 million would be expected to suffer any kind of liver
damage. Am I just imagining this figure or is there any basis
for that at all?
Dr. Powers. Let me go into that number. In May 2006, what
was then the Office of Drug Safety, presented an analysis of a
number of cases of acute liver failure that had been reported
and put that in the context of the number of prescriptions that
had been written. And let me just say in terms of the number of
prescriptions that have been written--I did a quick, back of
the envelope calculation last night. I would say at this point,
a Ketek prescription is written in this country every 22
seconds and this is after all of the publicity. Last year it
was every 4 or 5 seconds. There were, at the time, 12 cases of
acute liver failure that had been reported and without boring
members of the committee, acute liver failure is an extremely
serious condition that can lead to death or the need for liver
transplantation. Thirty percent of the patients dies.
So 12 cases probably doesn't sound like a lot, but the
problem is most serious liver events are never reported. If you
look at a study that was done in France, and this is the only
study of its type I am aware of, where researchers said how
many serious liver events actually get reported compared to how
many actually occur, they found that physicians only reported
one out of every 24,000 liver injuries and out of serious liver
injuries, things where people were dying from liver failure, it
was still one out of every 16. So for each one of those 12
cases, there are many patients who we don't know about.
So 23 out of 10 million, you could say well, that may not
sound like very much. If you compare that to other antibiotics,
for example a comparable antibiotic for the same indications,
the rate was only two per 10 million. Twenty-three per 10
million is a lot when you are talking about an antibiotic that
does not save lives.
Mr. Stupak. The gentlewoman from Colorado, Ms. DeGette.
Ms. DeGette. I thank you very much, Mr. Chairman. Actually,
Mr. Whitfield's question about how did this happen and why does
it happen was the first question I was going to ask, so I am
just going to follow up on that very excellent line of
questioning.
Dr. Powers, you gave three reasons why you thought maybe
this type of thing could happen and it is that there have been
disincentives to antibiotic development, that there is not a
focus on people and that people didn't want to have to go back
and revisit the whole thing. That might be a good explanation,
except for the fact that over the years in this committee, we
have seen similar problems at the FDA with respect to other
types of drugs that are not antibiotics. And so we begin to
wonder is the problem not just a drug specific problem, but
really a culture at the FDA that we have to figure out how to
fix for patient safety. Wouldn't you agree with that?
Dr. Powers. I think so and I have to say my experience with
this was actually quite confusing to me in terms of when this
became an issue, we had several public meetings before Ketek
was ever approved, in 2002 and 2003 where we addressed these
issues related to these kinds of studies. And the general
agreement was that really they didn't provide substantial
evidence of effectiveness and yet, we still got to the point
where, in 2004, we were approving drugs like Ketek.
When I went to people, my supervisors and then their
supervisors, I have to be honest and say there were people that
were very rightfully concerned. Why that never translated into
a change was really a mystery to me.
Ms. DeGette. And Dr. Ross, in your written testimony, you
said that Ketek was approved despite the FDA knowing that the
drug's maker submitted fabricated data, is that correct?
Dr. Ross. Yes.
Ms. DeGette. Now, how do you know that they knew that there
was fabricated data?
Dr. Ross. First off, the results of the initial inspections
from Study 3014 were available in the fall of 2002 and it was
clear at that point, it was clear as day that there were
serious, serious problems.
Ms. DeGette. And why do you think that they went forward
with this anyway?
Dr. Ross. I have never gotten a good explanation.
Ms. DeGette. Well, what is your opinion? What do you think?
Why would they do this knowing that data was fabricated and
knowing that the risks of the liver failure could be quite
high?
Dr. Ross. As I said, there is a culture of approval and let
me explain what I mean by that. Under the Prescription Drug
User Fee Act there are obviously goals, which everybody knows.
And FDA is fond of saying that that doesn't mean that we are
going to approve it, but the bottom line is the fastest way to
deal with a drug application, meet that deadline, is not to
raise too many questions and approve it. That is No. 1.
Number 2, FDA has limited resources and Dr. Jenkins is
very, been very vocal about how we have to stop having multiple
cycle reviews and I think the feeling was let us just get this
thing out of the way.
Ms. DeGette. Well, as Dr. Powers says, maybe you don't need
to have as large or many reviews, but you certainly have to
have thorough reviews that aren't fraudulent, right? You could
restructure the way you do the reviews.
Dr. Ross. I agree. One of the things that is missing right
now from the review process is any measure of quality. Once a
manager who has got sign off authority for a product writes a
review, nobody else looks at it and says what were you
thinking? So there is no measure of the quality of decision
making that goes on.
Ms. DeGette. Well, later this year we are going to be
reauthorizing PDUFA and I am wondering is, Dr. Powers, I would
also like to ask you this question, is do you think that tying
the user fees to the drug review is causing a bias in the
system and if so, what can we think about doing when we
reauthorize the Act to eliminate that bias?
Dr. Ross. Let me first say I do not believe we can go back
to the days in which we had 3 to 4 year reviews. We all know
that.
Ms. DeGette. Everybody knows that, that is right.
Dr. Ross. But I just want to put that on the record. But I
am mindful of a sign I saw in a repair shop once, ``fast, good,
cheap. Pick any two.'' And I think right now what we have got,
I hate to say it, is we are trying to do things on the cheap at
FDA. We need more resources and more reviewers and higher
standards there. And I think we are never going to get things
perfect, but we can have fast and good. It won't be cheap,
though.
Ms. DeGette. Dr. Powers.
Dr. Powers. I often think about when my medical license
comes up for renewal, I have to pay a fee to get that license
renewed. It seems clear to me that when a drug sponsor asks an
agency to review all of this information, it makes logical
sense to pay a fee. But I don't tell the medical licensing
board what they can do with my money. And I think the issue is
this negotiating of what the money gets used for, I think, is
an issue, in terms of PDUFA.
The second thing, I think, is that I don't know a single
reviewer at FDA who says gee, my paycheck is coming from a drug
company, I have to do what they say. That is not the way it
works and reviewers are really doing an excellent job, for the
most part. The question is his work done and some
accountability for when that work is not done properly. And if
that was built into the PDUFA system, it would be very helpful.
Ms. DeGette. Ms. Cisneros, I was struck in your testimony
about what you saw about the real fraud in the patients that
Dr. Kirkman-Campbell were seeing and I wanted to ask you a
couple of questions about that. Do you think that the fraud was
that she was enrolling all of these people and she wasn't
enrolling them? Or was she actually giving the drug to all of
these people who may be more sick? What was the problem?
Ms. Cisneros. Well, it came out in the FDA audit that they
never did find out what she did with the drug. She never
disclosed that and refused to do so. Now, I think they called
all 400 patients and she had actually enrolled maybe 50.
Ms. DeGette. OK.
Ms. Cisneros. And all of the other patients were
fabricated.
Ms. DeGette. So I guess the good news is she wasn't really
killing all of those people.
Ms. Cisneros. Yes.
Ms. DeGette. The bad news is she wasn't doing the job.
Ms. Cisneros. The concern that I had when I was at the site
is I didn't know what she was doing with the drug and she was
giving a potentially harmful investigative medication to
patients and not following them.
Ms. DeGette. Something else that piqued my interest,
because I have been working for a long time on the issue of
patient protection and patient notification, was when you
called the Copernicus IRB to talk to them and my question is--
and actually this is something both of the doctors could answer
too, is if we beefed up the IRB process in these drug reviews,
would that help maybe ensure the efficacy of some of these
independent studies?
Ms. Cisneros. Well, I am not quite sure who dropped the
ball here with the IRB issue. They did nothing. They did not
audit the site, they did not black list the site, even though
they should have received information about her data. That is
not usual for an IRB. I don't know what went wrong there.
Ms. DeGette. Was this a private IRB?
Ms. Cisneros. No, they are a central IRB.
Ms. DeGette. OK.
Ms. Cisneros. Yes.
Ms. DeGette. What about Dr. Ross? Do you think it would
help if we beefed up the IRB system in these cases?
Dr. Ross. Yes, I think there is two fundamental problems
here. One is the IRB system nationally is broken. IRBs don't
know what their responsibilities are. They don't know what they
are supposed to do when there is a problem. It is No. 1, so we
need to fix that. Number 2 is the enforcement side of things,
that FDA basically has cut its enforcement to the bone and
beyond. Just one example for the committee. We had a situation
in Texas, when I was a deputy office director, where an
investigator, a physician injected women with breast cancer
with a radioactive substance without getting proper informed
consent. When this came to our attention we jumped on it, but
it took FDA over a year to take any kind of action on this. So
you have an IRB system that is broken and then the enforcement
office at FDA with good people who basically are being not
supported by leadership.
Ms. DeGette. Dr. Powers, do you----
Dr. Powers. Yes, I am going to concentrate on the
scientific end of the IRB process. How does an IRB approve a
non-inferiority trial for Ketek in little children with ear
infections? So when you think about that, it says, well, what
are the people at the IRB thinking about? And when I was at
FDA, we actually got a letter back from an IRB, from a drug
sponsor who actually tried to do the right thing and tried to
do a placebo-controlled trial, saying we don't think you should
be doing these kinds of trials, and says there is a lack of
scientific understand at the IRB level, too.
Ms. DeGette. Mr. Chairman, I just asked those questions as
a commercial announcement for my legislation, the Patient
Protection Act, which I introduced the last two Congresses with
Mr. Greenwood when he was here, and we are working on this bill
and I have been talking to Mr. Dingell. I would hope that if
you folks had some ideas about ways we could work on this
legislation to make it effective. We do intend to move forward
with it. Thank you, Mr. Chairman.
Mr. Stupak. The gentleman from Texas, Mr. Burgess.
Mr. Burgess. Thank you, Mr. Chairman, and I too want to
thank the witnesses for being here this morning and
particularly thank you for the efforts you have done ensure
that we have safe and reliable medications in this country. Dr.
Powers, let me just pick up on something that you were
discussing with Ms. DeGette. In the PDUFA system, you mentioned
that the barriers, or what the requirement was, that we have
full transparency and accountability. What in your opinion are
the barriers to transparency and accountability in the PDUFA
system?
Dr. Powers. I think it is interesting for me now, as no
longer working for the FDA, what do I want to see as a
physician out there in the community? What I would like to see
is that when a drug gets approve, that all of the documents
which went into that approval, all of the data, including the
decision-making process, the meeting minutes, et cetera, go up
on the FDA's Web site within, say, 7 working days of when the
drug gets approved. Then everybody could look at this
information and be able to make those kinds of decisions. Right
now that kind of information gets up there and it is spotty at
best and when you see an advisory committee, you see enormous
amounts of information. That level of detail should be
available for every kind of drug as well. And then, if there is
scientific discussion within the review team and some people
have differences of opinion, those could also go into there.
Doctors could read those and be able to make their own
decisions about those things.
Mr. Burgess. Well, certainly if you made that a searchable
database, it would improve the information that is out there,
but I will also say, having been in a busy practice, you don't
always have time to avail yourself of those things and
unfortunately, like many people do, you rely on the other
information that is available to you, which may come through
post-marketing advertising. Dr. Ross, you talked about Dr.
Kweder, who concealed the briefing that you all had. Do you
know why this would've happened?
Dr. Ross. I assume she didn't want them to know about it.
Mr. Burgess. And what ultimately would have been the
benefit to either the FDA or Dr. Kweder about concealing that
briefing?
Dr. Ross. I think, in any bureaucracy, the one thing you
don't want are problems and the best way of making problems go
away is by controlling information and concealing them and that
is what I think was going on here.
Mr. Burgess. Well, I will just say, from my own experience,
I haven't been up here that long, but from my own experience,
it seems the function of bureaucracy is to consume dollars and
erode value, but that is from our hearings on Katrina,
Chairman. I just have to say, Dr. Ross, I am astounded by your
figures on the liver failure. Twenty-three cases of liver
failure attributable to Ketek in this country, is that correct?
Dr. Ross. No, I am sorry, sir. Right now what the most
current figures we have are 13 reported cases.
Mr. Burgess. Thirteen reported.
Dr. Ross. And that is what we know about. Of course, as I
said, most cases are never reported.
Mr. Burgess. Yes. And how does that happen? How do you not
report a case of acute liver failure requiring a transplant or
facing death? It is hard to miss the clinical symptoms.
Dr. Ross. When I say report, I mean report it to the
MedWatch Program at FDA and that is a structural hole, it is a
gaping hole that everyone, including FDA, says we have with our
current post-marketing system and what we need is much better
data. The reason that we have trouble making the right
decisions is that we don't have the right data systems in
place. And FDA just announced, after years of urging, that it
is going to have partnerships with the Veterans Health
Administration as well as other agencies that have large
databases that can be used for prospective collection of safety
data. But it is the sad fact that, except for devices where
there is mandatory reporting of problems, most drug events,
even very serious ones, never get reported.
Mr. Burgess. With how many cases of acute liver failure
requiring transplantation or resulting in patient death occur
with acetaminophen?
Dr. Ross. Acetaminophen is certainly the most common cause
of drug-induced liver injury. However, it is important to
remember that those events generally occur in the setting of
intentional overdose or in the setting of co-consumption of
alcohol, and if you correct that for the amount of
acetaminophen that is prescribed in this country or taken over
the counter, the rate is going to be lower, I believe, than
with Ketek and I believe that Dr. Graham may be able to address
this later. But I think this is not the only toxin on the
market. But if I could use a medical example, there is an
antibiotic that we as physicians are all familiar with,
chlorenphenocol, it is a lifesaving drug in the right
circumstances.
Mr. Burgess. Absolutely.
Dr. Ross. But it is rarely used right now because of the
risk of aplastic anemia, and I have only used it twice in my
career. That has a lower rate of aplastic anemia than Ketek
does of acute liver failure.
Mr. Burgess. I am embarrassed to tell you that I am old
enough to have taken chlorenphenocol as a child.
Dr. Ross. I am glad you are still with us, Dr. Burgess.
Mr. Burgess. Does the FDA hold periodic meetings,
regulatory briefings, that serve as an opportunity for
different views or questions to be heard on drug safety? Do you
guys all get together in a room and talk about this stuff?
Dr. Ross. They do but the problem is that it reminds me of
a cartoon I saw, where a bureaucrat is telling somebody on the
phone, I can assure you that your problem is being ignored at
the very highest level. The most recent example that I am aware
of occurred in April 2006, where a product called daptomycin
was discussed at a regulatory briefing and everybody
unanimously, with the exception of the division director, said
this product should not be approved for this indication.
Everyone had their say and then the division director, who
happened to have been Dr. Soreth, politely listened and ignored
them. Again, there is no accountability. You can simply ignore
good science and you won't be held to account for it.
Mr. Burgess. Let me ask you a question because you have
brought up the issue of post-marketing data and that is not all
bad, because also being old enough to have taken
chlorenphenocol, I am old enough to remember when Falitimide
was held up in this country because of, not post-marketing
data, but post-marketing data from other countries. Obviously
the experience in Europe tempered the judgment of the FDA at
that time, as to whether or not to release that medicine in
this country. So it is not all bad that the post-marketing data
comes from other countries.
Dr. Ross. No, I would never say that, but it is a question
of the quality of the data and on what do we want to be making
our decision. If I can go to a building analogy, which I am
fond of, in----
Mr. Burgess. Well, let me interrupt you before you make the
analogy. The inclusion of exacerbations of myosenic gravis and
the labeling of Ketek, did that not occur from an assessment of
post-marketing foreign experience with that medication?
Dr. Ross. I think the problem is that, while you can pick
up a signal, when you say, well, there is no signal here, there
is nothing going on, that is where we get into trouble.
Mr. Burgess. On the issue of foreign post-marketing
surveillance of adverse events, you referenced the study of the
adverse liver events and was that not a French study?
Dr. Ross. That is correct, but that used a prospective
database to determine what was going on.
Mr. Burgess. Thank you. Dr. Powers, let me just ask you
about the non-inferiority issue with the antibiotics. Like you
I am concerned about the emergence of multiply-resistant
strains of what previously were relatively easily disposed of
bacteria. Does Ketek play any of challenging these more
aggressive organisms?
Dr. Powers. I think the answer to that is we don't know. We
would like to know. We know that Ketek can kill some organisms
in a test tube that are not killed by other kinds of
antibiotics. The question is, has Ketek actually been shown to
be superior in people, in folks who are infected?
Mr. Burgess. Well, let me interrupt you on that point. Now,
say you did a side-by-side comparison of Ketek and Augmentin
and found that the Ketek was identical to Augmentin, would
there then be no reason to approve the Ketek because Augmentin
is going to do a good job?
Dr. Powers. If you were going to approve Ketek for
Augmentin-resistant organisms, that wouldn't make a whole lot
of sense.
Mr. Burgess. What about for people who are allergic to
penicillin?
Dr. Powers. Well, that is the issue, is you want to
actually then--but then you are saying that Ketek has a safety
benefit, not an effectiveness benefit. That is changing the
question.
Mr. Burgess. On the question of the institutional review
boards--I was involved with clinical studies back when I was a
resident, but it was a long time ago and they were generally a
pain in the neck because you had so much paperwork to fill out.
And the institutional review board was basically--for me it was
Parkland Hospital. Is it not the institution that is sponsoring
the study that is responsible for that institutional review
board, or is that just a misconception on my part?
Dr. Powers. No, I think that the name comes from an era in
which most research was conducted at academic institutions.
Mr. Burgess. So your example of the breast cancer
injections, was that just done in someone's clinic and not part
of an institution?
Dr. Powers. No, that was done at an institution.
Mr. Burgess. In Texas?
Dr. Powers. Yes, sir.
Mr. Burgess. All right. Well, off line you can tell me
which one and it will be funded. Thank you, Mr. Chairman. Ms.
Cisneros, just before we leave, in March 2002, when did you
become aware that the fraud that was being perpetrated by the
physician who was doing the investigation for Aventis?
Ms. Cisneros. Well, we always had suspicion and I think
that it was actually confirmed at the quality assurance audit
by Aventis.
Mr. Burgess. And was that the reason that you left the
company that you were working with at the time, PPD?
Ms. Cisneros. No, I left for a different reason.
Mr. Burgess. OK. Thank you, Mr. Chairman.
Mr. Stupak. Thank you. We have three or four Members who
would still like to question this panel, but we have four votes
on the floor pending right now. In fact, we have less than 10
minutes to vote on this first one, so let us recess this
hearing until 12:30 and let everyone stretch their legs, grab
something. Our witnesses, if you would come back at 12:30 and
we will finish up with the Members who have not yet asked
questions and then we will move to our last panel.
[Recess]
Mr. Stupak. We will resume our questioning with the panel
of Dr. Ross, Ms. Cisneros and Dr. Powers. Please come forward.
I would remind the witnesses that they remain under oath. I
appreciate your patience. They took care of one other matter on
the floor and it made us a few minutes late. But with that, I
would like to recognize the gentleman from Texas, Mr. Green for
10 minutes for questions.
Mr. Green. Thank you, Mr. Chairman, and I have a number of
questions, Mr. Chairman, and I don't know if we can get them
all in. Can we submit questions to the panel for later
response? Is that possible?
Mr. Stupak. Yes, there will be written questions and there
will be an appropriate time to do them later.
Mr. Green. OK. Thank you. Dr. Ross, how unusual is it to
see fraud in a clinical trial?
Dr. Ross. Well, it happens but it is unprecedented, in my
experience, to see it at this scope and scale.
Mr. Green. Why was the study considered unreliable?
Dr. Ross. Well, first off, out of 10 sites that were
inspected, all had serious problems that made their data
completely unreliable. FDA's investigators concluded that if
these sites which were high unrolling sites, which supposedly
the company had been keeping close tabs on the doctors, were
unreliable. The rest of the sites couldn't be relied on either.
Mr. Green. What do you mean that every site inspected by
FDA had problems?
Dr. Ross. Of the 10 sites inspected, every single one was
found to have significant violations of what are called good
clinical practices, the rule book for conducting clinical
trials. Four the 10, 40 percent, were referred for criminal
investigation. It is an outstanding percentage.
Mr. Green. Let me back up just a little bit, then. The
advisory committee, in 2001, was first concerned about liver
damage from Ketek, was that only concern, was the liver damage?
Dr. Ross. No, there were also concerns over effects of
Ketek on the heart and on vision, as well as Ketek's potential
for interaction with many other drugs.
Mr. Green. What exactly was the misconduct found in the
safety study?
Dr. Ross. Well, the largest enroller, as we have heard, was
convicted of fraud and this was not sophisticated or subtle
fraud. It was absolutely blatant. The second and third largest
enrollers had significant violations of procedure that called
into question the reliability of data from those sites. And I
think it is interesting to note that the third largest enroller
was arrested shortly after the study on cocaine and weapons
possession charges and this is not the type of investigator--
the study physician, rather, that FDA likes to see in clinical
trials.
Mr. Green. I can imagine. Coming from Texas, we don't mind
the weapons possession, but the cocaine bothers me. Ms.
Cisneros, what came out of your teleconference with Aventis and
regarding irregularities in the Kirkman-Campbell site. Did they
seem concerned about it?
Ms. Cisneros. No, they really just glossed over all the
issues. Nadine had an excuse for every irregularity that we
found. I walked away from it being astounded at the laisse-
faire attitude that they had about the issues that we found at
the site.
Mr. Green. To your knowledge, did anyone from RBPPD or
Aventis call the FDA to report the site?
Ms. Cisneros. To my knowledge, when I spoke with the FDA
auditor, she said that the reason for audit was because Dr.
Campbell was such a high enroller. There was not a for cause
audit.
Mr. Green. What made Dr. Campbell fraud so apparent to you
and not Aventis, as they are claiming?
Ms. Cisneros. Because the fraud wasn't sophisticated. And
Dr. Campbell was not a practicing research physician, so a lot
the mistakes she made were very obvious.
Mr. Green. In your experience, what would have been done
once fraud was suspected?
Ms. Cisneros. Normally, the site is closed immediately to
further enrollment of patients and the FDA and the IRB are
notified.
Mr. Green. Dr. Powers, some people argue that the placebo-
controlled trials in these self-resolving diseases would be
unethical. Is this really a problem?
Dr. Powers. Well, it is really not unethical to give people
a placebo in a situation where you are not really sure about
the effectiveness of the old drug in the first place. I think
the second issue is that these are diseases that people
commonly don't take antibiotics for. I had a sinus infection
myself last week. I didn't take anything for it and got better,
anyway. And third, people will sign a proper informed consent
in these studies. They know that they might be getting a
placebo. And fourth, there is actually some benefits to being
on the placebo group. You might get better anyway and yet not
be exposed to adverse effects. So the last thing is the real
issue of doing a placebo-controlled trial is, is there a
question to be answered, a thing called equipoise, and that
question still remains unanswered as to in whom and when are
antibiotics effect for these self-resolving diseases.
Mr. Green. Would there be any specific benefits evaluating
antibiotics in placebo-controlled trials?
Dr. Powers. I think, again, part of this is people would
not be exposed to adverse events. The other issue, we would
finally be able to figure out how beneficial these drugs
actually are. And in a placebo-controlled trial, you could also
weigh the adverse effects of those drugs as well. So say that
we do find out that antibiotics do decrease symptoms of ear
infections in kids by 2 percent compared to placebo. If they
cause diarrhea in 10 percent of kids, then we would be able to
actually make that assessment and make an overall risk benefit.
Mr. Green. Don't clinicians and patients want to know how
new drugs stack up against the old drugs in terms of safety and
effectiveness?
Dr. Powers. I think that is an important question and the
issue is, do we really just want to know that a drug is better
than a placebo? And that is why people do these kinds of trials
where they compare one drug to another. But the problem with
these trials is we miss the overall question of is it effective
at all? So if FDA had the authority to require three group
trials, that is, compare a new drug to old drug to placebo, we
could actually answer both of those questions, make sure that
both drugs are better than a placebo, and how one drug stacks
up against another one.
Mr. Green. The FDA doesn't have the authority to do that
right now?
Dr. Powers. Right now the only thing FDA has the authority
to say is, is the drug is effective compared to nothing. And
they are very fond of reminding us that there is no relative
efficacy standard. So all you have to do is be better than
nothing and that is actually the complaint some people have
about placebo-controlled trials, is some people say, well, this
just tells me it is better than nothing and that is not what I
really want to know.
Mr. Green. Thank you. Again, I would hope, out of this
oversight hearing, we will see FDA reform legislation and it
would be addressed in that through our committee process. Ms.
Cisneros, during the investigation of the three highest
enrollment sites, the Division of Scientific Investigation
determined that Dr. Salerno, the third highest enroller, had
been placed on probation by the State Medical Board and later
during the study had his medical license suspended. While I
understand your experience with this case was limited to Dr.
Kirkman-Campbell, can you speak to the typical measures taken
to ensure that the physicians participating in the usual care
settings are reputable? And do contract research organizations
check out the credentials of their enrolling physicians?
Ms. Cisneros. It is my understanding that the IRB is
supposed to do that and in my review of Copernicus, they are
actually given $600 per PI to investigate that physician. And
in my working with PPD, I believe we did review physician
licenses as well. It is a very simple process. It is on the
Internet. There is nothing to it.
Mr. Green. Dr. Ross, can you speak on this question from
the FDA's perspective?
Dr. Ross. Yes. There is a requirement that a drug that is
approved will be approved via adequate and well-controlled
investigations by investigators who are qualified by training
and experience. A physician who is on probation, medical
probation, which is a matter of public record, is not what I
would call a physician who is qualified by training or
experience.
Mr. Green. Dr. Ross, according to the FDA e-mail cited in
Senator Grassley's letter to FDA Commissioner von Eschenbach,
regarding irregularities associated with Ketek, and FDA
employee status states a total of 72 sites enrolled more than
50-patient maximum.
Dr. Ross. Yes, that is correct.
Mr. Green. The FDA goes on to ask in this e-mail, is it
common for companies to allow centers to enroll beyond the
allowable limit? Is this viewed as acceptable?
Dr. Ross. It is not. It is something that should
immediately trigger concerns and it is something that,
internally, I send e-mails to people in management about,
pointing out the high enrollers who are enrolling at rates that
were far greater than what would be expected in a normal trial.
Mr. Green. Does the FDA have any enforcement mechanism to
promote the compliance by these drug sponsors?
Dr. Ross. Yes, if they choose to use them.
Mr. Green. And in your experience, has there been recent
history of that, using them on the drug sponsors?
Dr. Ross. No. For example, Dr. Kirkman-Campbell the FDA did
not even more to disqualify her from conducting clinical
studies until after Ketek hit the news. As of this point,
although she is in prison, in a Federal correctional facility,
this physician is still eligible to conduct clinical trials.
Mr. Green. Ms. Cisneros, do you have any additional light
in the last 30 seconds I have?
Ms. Cisneros. There is definitely a fault in the system and
there was a breakdown on the Sierra level, on the IRB level and
there are people that were interested in coming here today but
felt, due to repercussions, they didn't feel comfortable doing
so.
Mr. Green. Mr. Chairman, I know your experience in upper
Michigan and our experience with depending on the FDA and drug
approval, compared to other countries, that it is really
shocking and I think it is shocking to our constituents to see
what is happening, because we depend Ms. Cisneros on FDA when
we deal with imported pharmaceuticals, but it is just not
there. So I guess the committee--again, being back on the
subcommittee after about three terms, I am just shocked and I
hope we can deal with it during the authorizing legislation.
Mr. Stupak. I thank the gentleman. Mr. Walden from Oregon
for 10 minutes.
Mr. Walden. Thank you very much, Mr. Chairman, and I want
to thank our witnesses, all of them, today for sharing your
stories with us. It is most helpful as we do our oversight
work. Dr. Ross, you indicated in your testimony that you were
pressured to change your view and I am just curious. Was that
pressure from the supervisor, uniformly in the direction of not
being as stringent on safety as the lower-level official?
Dr. Ross. That is correct. It might be helpful for the
committee if I outlined the sequence of events.
Mr. Walden. Yes, that would be good. Thanks.
Dr. Ross. In January 2003, the FDA issued an approval
letter to Aventis outlining requirements for Ketek to be
approved. I had been the safety team leader for that review
cycle. I finished my safety team leader memo, in September of
2003. which was about 8 months later and that was because I had
another priority review to work on. I gave that to my division
director. She called me into her office, I think, a couple
weeks later and said, could you soften this to give Mark, that
is Mark Golderberger, and Ed, that is Ed Cox, more wiggle room?
I knew from previous experience that if I refused, she would
get very angry. A number of colleagues advised me to comply
lest she retaliate.
I decided that I would comply, but I also sent an e-mail to
the office above hers, outlining what had happened. I put this
in writing. This was sent to Mr. David Roeder, who was Mark
Goldberger's associate director. I did not get any response in
writing, or otherwise, from Dr. Goldberger. When I didn't get
any response, I took my original review, without the changes
that Dr. Soreth had requested, put it in an electronic archive
and added a note about what would happen in case there was any
question down the line about the situation. I did that and
signed off on it on March 16, 2004. That was almost 3 years
before this committee hearing and it was almost 2 years before
Ketek hit the news.
Mr. Walden. Mr. Chairman, do we have any of the e-mail
traffic or any of that for the record?
Mr. Stupak. There is some e-mail traffic right in the big
binder there. You should have one right there.
Mr. Walden. OK. So we have a copy of the e-mail Dr. Ross
has referenced?
Mr. Stupak. The one that Dr. Ross has, yes, we do have that
e-mail.
Mr. Walden. OK. Because I was just provided with a story
out of the Wall Street Journal, I guess, where Dr. Soreth
denies ordering the change and says, ``If he felt strongly, he
was free to keep it,'' she says, adding that the review didn't
reflect Aventis' final submission to the agency. In both
versions, Dr. Ross' examination says Ketek could be approved
for a third condition, pneumonia. And I am just curious.
Obviously, it is a he said/she said from our vantage point. Why
would she say that?
Dr. Ross. Because she would get in trouble if she admitted
to it. That would be a serious infraction to pressure a
reviewer to change their reviews. I do not want to get
distracted on this, because while personally it was angering to
me, I think the real question is, why did FDA use this
fraudulent data? I will just say, however, that I documented,
at the time, what was happening. That was the only thing I knew
what to do.
Mr. Walden. No.
Dr. Ross. I went to upper management as well and said here
is what is going on.
Mr. Walden. And that seems like the responsible thing to do
and it is most helpful as we look at it. I am just trying to
figure out how all this works inside this particular box within
the agency.
Dr. Ross. Understood.
Mr. Walden. You state in your testimony that the FDA
reviewers, including yourself, were pressured to change reviews
by FDA managers. Were you pressured to change any reviews for
Ketek, and if so, which ones?
Dr. Ross. It was my team leader memorandum for the second
review cycle. The key change was that initially I had said that
it was doubtful that Ketek could be approved for the lesser
indications of acute bacterial sinusitis and acute exacerbation
of chronic bronchitis, the two indications that FDA just
removed, even if there was more safety data, given the fact
that these are self-resolving infections, with many other
antibiotics available, I changed that----
Mr. Walden. Was that for pneumonia?
Dr. Ross. I am sorry. Pneumonia. I said I thought, with
additional safety data, it could be approved, although I said I
did not think it could be approved for a particular type of
resistant bug, mainly because of the lack of data.
Mr. Walden. All right, all right. Good. And you have
indicated that you objected when you were asked to change your
data even though you changed it, you did notify her supervisor.
Dr. Ross. Yes.
Mr. Walden. All right. Why do you believe, as you put in
your testimony, that the FDA managers were so bent, I think was
the word you used, to approve Ketek? What was driving this?
Dr. Ross. I think there is a fear of being seen as holding
up new products.
Mr. Walden. Right.
Dr. Ross. And frequently there is a perception that just
because something is new, it must work, otherwise why would the
company be submitting it? And the sad fact is, for example, in
cancer therapies, 95 percent of therapies that start trials
never make it because they don't work. But I think, in this
instance and others, FDA managers were afraid of being
perceived as holding up an important drug and so they felt
really pressured to find some way to approve it.
Mr. Walden. And as you talk to other reviewers, I assume
you all run in circles where you are talking, I don't know that
for a fact----
Dr. Ross. No, it is----
Mr. Walden [continuing.] But I assume that. Is this an
isolated piece of FDA, the way this whole thing unfolded? Is
this what is happening in every division? Is it happening that
way in oncology?
Dr. Ross. No.
Mr. Walden. Is this an isolated incident?
Dr. Ross. Let me answer that. First off, it does not happen
in every division and I would certainly say, in oncology, when
I told my managers there about what had happened, they were
appalled. I cannot imagine this sort of thing happening in the
Office of Oncology. Having said that, however, there is a
number of instances that I saw in the Office of Antimicrobial
Products, in which reviewers were pressured, either directly or
more subtly, to kind of get with the program and find some way
of approving a product, even if they had reservations. Now, I
have to say that if a reviewer says don't approve this and a
manager disagrees, the manager is fully free to write their own
review and overrule that reviewer and put it on the record, and
everybody accepts that.
Mr. Walden. And that can go both ways, right?
Dr. Ross. That can go both ways.
Mr. Walden. Have you seen instances where it has gone the
other way?
Dr. Ross. I have not.
Mr. Walden. OK.
Dr. Ross. I will say, for example, for Gemzar, which was
approved for treatment of metastatical ovarian cancer and
oncology. The primary reviewer said, I don't think should be
approved, and the division director wrote a very carefully
reasoned memorandum saying I disagree. I am going to approve
it. And it was on the record for everyone to look at.
Mr. Walden. So your issue is that approach versus one where
the supervisor tells you to rewrite your report?
Dr. Ross. It is a way for the supervisor to avoid taking
responsibility.
Mr. Walden. Now, I note that you cite senior FDA medical
advisor Dr. Robert Temple in footnote 6 of your written
testimony. Do you consider Dr. Temple a reputable and credible
witness on clinical trial matters? And perhaps I think both Dr.
Powers and Dr. Ross, are any of you familiar with Dr. Temple?
Dr. Ross. Absolutely. I have enormous respect for Dr.
Temple. I have to say that he privately has condemned the use
of noninferiority trials, but publicly will not condemn the
agency's approach. That is No. 1. Number 2, I can tell you that
he has disparaged the idea that reviewers are pressured. He has
openly said--and this is in meetings of senior management--do
we ever know that this really happens? And I would go up to him
as a member of the senior leadership team and said, Bob, it
happened to me.
Mr. Walden. What would he say?
Dr. Ross. Just nothing. I think there is an air of
disbelief.
Mr. Walden. Do you think he would be a good witness for
this subcommittee to call?
Dr. Ross. I think it would be helpful to the committee to
get his perspective and raise these issues with him.
Mr. Walden. Dr. Powers, do you want to comment on Dr.
Temple?
Dr. Powers. I wanted to link the question about Dr. Temple
to a previous one you asked, about how systemic is this?
Mr. Walden. Right.
Dr. Powers. I consider that the agency wouldn't even be in
as good a position as they are now, in terms of the evaluation
of drug products, if it wasn't for people like Dr. Temple. And
in fact, Dr. Temple was one of the first people to write about
the issues with noninferiority trials back in the early 1980's.
I actually approached Dr. Temple several years ago about some
of these very issues with noninferiority trials and he was in
agreement. I think, then, the question becomes what is the
systematic issue when someone of his stature, who is a director
of the Office of Medical Products, is still unable to alter or
change the way things that were done in an office below him, in
the Office of Antimicrobial Products? And I think that is where
you get to the systemic issue and I know for a fact that if he
was capable of changing this, he would have.
Mr. Walden. So I guess the question is, he would probably
be a good person for us to ask under oath what is going on
below him, above him, around him?
Dr. Powers. Yes.
Mr. Walden. All right. Thank you, Mr. Chairman, and I want
to again thank our witnesses today. It is most helpful.
Mr. Stupak. We are joined now by Mr. Markey, a member of
the full committee who has asked to sit in on this hearing and
I know he has been bouncing around between the global climate
change hearing and this one. So I would like to enter his
opening statement for the record. Without objection, that will
be entered.
[The prepared statement of Mr. Markey follows:]
Prepared Statement of Hon. Edward J. Markey, a Representative in
Congress from the Commonwealth of Massachusetts
Chairman Stupak, thank you for allowing me to participate
in today's hearing.
The FDA is clearly in desperate need of oversight and
reform. Like Senator Grassley, I have been working on FDA
reform with whistleblowers for several years and asking the FDA
questions about Ketek since May, 2006. The FDA refused to
answer my requests for information.
It appears that the FDA has finally responded to
congressional oversight. It is not a coincidence that FDA
finally took action to protect the public from Ketek by making
changes to the label the day before this hearing.
But the FDA's long overdue actions on Ketek do not
eliminate the threat to the American people.
Although the FDA has acted to warn the public about Ketek,
we have no idea exactly how many dangerous products like Ketek
the FDA has allowed on the market and put our families at risk
every day. The FDA's problems are systemic and it is in dire
need of reform.
Today we will hear about the truly frightening problems at
the FDA including:
a culture of suppression and intimidation;
a lack of transparency into the review process;
the inaction of FDA management in response to
serious drug risks; and
a lack of scientific freedom and the inability of
FDA Reviewers to have their concerns heard by senior
management, FDA advisory committees and the public.
It is clear from the testimony that the FDA is a deeply
troubled agency that has failed to act in the best interest of
the public. We need the FDA to be a watchdog for public health,
not a lapdog for the industry.
We need to bring transparency, accountability and
scientific integrity back to the FDA through a combination of
increased oversight and legislative reform.
Today we begin the oversight and later this week I will
reintroduce my bill, the Swift Approval, Full Evaluation (SAFE)
Drug Act to address many of these problems.
We need to act now--not only to protect the public health
but also to restore the public's confidence in the FDA. A
Harris Poll conducted last year found that 80 percent of adults
say they are concerned about the FDA's ability to make
independent decisions that will ensure that patients have
access to safe and effective medicines.
We need to turn this agency around now and I look forward
to working with my colleagues on this committee to make the
changes necessary to ensure that the FDA can protect the public
health.
Mr. Stupak. The gentleman is recognized for 10 minutes.
Mr. Markey. Thank you, Mr. Chairman, and thank you for your
courtesy. I very much appreciate it. Dr. Ross, Dr. Powers, you
have been extremely courageous in the actions which you have
taken thus far and I just want to congratulate you for that. I
am going to go through some of the provisions in a piece of
legislation which I am introducing, the Swift Approval Full
Evaluation Drug Act, that I plan to reintroduce this week with
some changes and I want your opinions on whether these
provisions will improve things at the FDA and if so, how.
Number 1, you have talked about the culture of scientific
suppression and intimidation at FDA. The Safe Drug Act will
prohibit FDA employees from directing other FDA employees to
censor or suppress scientific research, analysis, opinions or
recommendations, directing employees to disseminate scientific
information that is known to be false or misleading. There will
be penalties for any employee who engages in this conduct. Will
that provision help minimize the culture of suppression and
intimidation at the FDA? Dr. Ross?
Dr. Ross. Representative Markey, yes, I believe it would.
Ketek happened because there were no penalties for FDA managers
who engaged in suppression of reviewers and ordered reviewers
to disseminate false information to an advisory committee. This
provision of the Safe Drug Act would deter, I believe, FDA
managers who might be tempted to suppress reviewers either
explicitly or by threatening retaliation through performance
reviews.
Mr. Markey. Great. Dr. Powers?
Dr. Powers. It is very hard to legislate culture, but
people do things for two reasons, either to avoid pain or to
gain pleasure. And if, in this case, as Dr. Ross is pointing
out, someone would try to force someone to alter their review
to refuse to take accountability for their own actions, and
this kind of a provision would help there be some transparency
and accountability.
Mr. Markey. Dr. Ross, in your response to Chairman Stupak,
you said that you believe that if you had told the second Ketek
advisory committee about the problems with Study 3014 and the
FDA's questions about fraud in the study, you would have been
fired. I am very concerned about the FDA's policy of censoring
information going to the advisory committees. We have not only
heard about this happening in your case, but we also have heard
that FDA is censoring science, when Dr. Marsholder wanted to
present information about the risk of suicide in children
taking SSRIs. The Safe Drug Act would ensure that any FDA
employee working on a matter related to an issue before an
advisory committee shall be allowed an opportunity to make a
presentation to the committee. This FDA employee presentation
shall be separate from the time allotted to the public to
comment on an issue before an advisory committee. Why is it
important for all FDA employees working on a matter to have an
opportunity to speak at advisory committee meetings? Would this
provision help ensure that advisory committees get complete
information from the FDA?
Dr. Ross. I think it is important that advisory committees
hear the full range of scientific opinions held by reviewers,
not just those that are approved by management. It is a sad
fact--and I am not saying it happens often, but I certainly
have seen it happen, that an FDA manager can manipulate the
information received by an advisory committee to get the
desired the conclusion. I think that the provision that you
outlined would help lessen the risk of advisory committees
being manipulated by FDA managers.
Mr. Markey. OK. Dr. Powers, do you have a view on that?
Dr. Powers. Yes, I think it is often said at FDA that they
need to speak with one voice. I think they need to make one
decision, obviously, but the scientific process isn't about
speaking with one voice. It is about hearing lots of voices and
then being able to make a cogent decision after that. Advisory
committees usually occur before the drug is approved and that
is the time to actually hear everybody's side of the story to
be able to give the advisory committee the information that
they need to give good advice.
Mr. Markey. OK. Thank you. My bill provides that, unless
publication or presentation of the data is subject to national
security laws or regulations or as proprietary information, FDA
and FDA-sponsored authors shall have the right to publish or
present their work. Have FDA employees had difficulty
publishing their work in the past, how would that provision
change things as they work today at the FDA?
Dr. Ross. I have definitely witnessed this when you submit
a manuscript. This did not happen at oncology. They are proud
of their work there and they publish it. But in the Office of
Antimicrobial Products, for example, you send a manuscript for
clearance and it vanishes into a black hole. I think that this
provision is important because it would allow removal of
arbitrary barriers for publication. It would be important, I
will say, to define proprietary information, that term, as
narrowly as possible so it couldn't be used as a pretext to
block a publication.
Mr. Markey. OK. Dr. Powers?
Dr. Powers. I can say that I myself was reprimanded for
writing a book chapter in the Premier Infectious Disease
textbook 2 years after I wrote it, actually.
Mr. Markey. Wow.
Dr. Powers. And even though this was not part of my work at
FDA, done on my own time, I cleared it with the ethics
department and I put a disclaimer at the bottom of it. So I
think it is very important that FDA reviewers should be allowed
to participate in the scientific discussion, not just within
FDA, but with their peers outside the FDA as well. And I would
actually say that the outside activity form that FDA requires
you to fill out now should be for informational purposes only,
that you allow the managers to know you are going to publish
something, but that should not be that there needs to be a
clearance process of what you are going to say.
Mr. Markey. OK. Thank you. You have talked about how it
seems that some people within the FDA act as if they were
working for the pharmaceutical industry rather than regulating
it. Part of this comes from the fact that the FDA must
negotiate with the industry over what they drug labels should
look like. My bill would give the FDA the authority to mandate
changes to drug labels instead of negotiating the label with
the sponsor company. Many other Members of Congress have also
proposed similar legislation. Do you think the FDA needs
greater authority to mandate label changes and require specific
information on the label? And do you think it will help empower
the FDA to act more like a full-fledged regulatory agency?
Dr. Ross. Yes. Under the current system, changes proposed
by the FDA are frequently watered down through extensive
negotiations with the sponsors and information on risks and
benefits that is accurate is not communicated to providers or
the public. And I think that that authority would be very
helpful. The comprised language that FDA accepted in June 2006,
on Ketek, with regard to myosenic gravis, is a perfect example.
That should have been a contrary indication to begin with, but
the company clearly didn't want it that way.
Mr. Markey. Dr. Powers?
Dr. Powers. I think it would be very helpful to spell this
out. One of the things I remember that I found very confusing
when I got to FDA was how people talked about it in terms of
labeling negotiations, and it went back and forth and back and
forth. I think the drug sponsor needs to obviously be a part of
that process and in fact, they are the ones who write the first
draft of the label. But it should come to FDA, go back one more
time, and then make a final decision. I think FDA already has
that authority, they don't use it, and it would actually be
very helpful to spell that out, that that is the way things
should work.
Mr. Markey. I would like to believe that we can reform the
FDA so that the FDA employees will no longer need to blow the
whistle on the FDA. We need to protect whistleblowers so that
they can come forward to warn the public, when necessary,
without fear of retaliation. My bill will require increased
protections for whistleblowers if they are retaliated against
for reporting violations of laws or regulations, or a
significant threat to public health and safety, to Congress,
GAO, Federal agencies or their bosses. How would whistleblower
protections improve the situation at the FDA?
Dr. Ross. I think they would allow greater freedom for
reviewers to inform the public about threats to public health,
they would discourage the suppression of reviewer reviews, and
they would help reform the culture at FDA with regard to
scientific dissent.
Dr. Powers. The hope is that if you had whistleblower
legislation, that that would mean you wouldn't need to use it,
actually, that that would form some transparency and openness
and that people would have that as an outlet valve if they
needed to, but that would form a culture at FDA where you
wouldn't have to have people going outside the agency to solve
the problems.
Mr. Markey. Thank you. Dr. Ross, Dr. Powers, Ms. Cisneros,
I thank all of you for your excellent testimony today. It is a
real tragedy that the FDA is losing good people with highly
specialized expertise, like Dr. Powers and Dr. Ross, because
they have dared to raise concerns about the safety of drugs.
According to the FDA mission statement, the FDA is responsible
for protecting the public health by assuring the safety, the
efficacy and security of human and veterinary drugs, biological
products and medical devices. If FDA's own medical reviewers
are prevented from raising questions about the safety and
effectiveness of drugs, the FDA cannot possibly fulfill its
stated mission. Instead of suppressing dissent and preventing
reviewers from asking questions about the safety of drugs, the
FDA should demand careful review of the risk of drugs that they
are putting on the market. You are latter day Paul Reveres
trying to warn the public about the dangers in the review
process at the FDA. You should be praised rather than punished.
We need to act now to reverse this dangerous trend at the FDA,
not only to protect public health, but also to restore the
public's confidence in the FDA. A recent Harris Poll found that
80 percent of adults now say they are concerned about the FDA's
ability to make independent decisions that will ensure that
patients have access to safe and effective drugs and medicines.
We need to turn the FDA around now, before further dangerous
decisions are made. I thank you, Mr. Chairman.
Mr. Stupak. I thank the gentleman. Just one or two
questions if I may. Ms. Cisneros, in response to Congressman
Green, the last question he put to you, you responded that, due
to repercussions, others would not come forward. Who are you
referencing, others at PPD, Aventis, Copernicus?
Ms. Cisneros. At PPD.
Mr. Stupak. OK. So these would be private individuals who
had a desire to come forward but were fearful of repercussions?
Ms. Cisneros. Yes. And what was told to me is that these
people were called by PPD attorneys and reminded of their
confidentiality agreement and that a PPD lawyer would have to
be present with them in order to talk to the agency.
Mr. Stupak. So they chose not to talk to the agency, then?
Ms. Cisneros. This one person did with a PPD lawyer
present. It is just an intimidation factor, in my mind. They
don't probably say as much as they would like to with that
person present.
Mr. Stupak. I thank you for your testimony. Dr. Powers, if
I may, we have talked quite a bit about noninferiority testing
in that example. But has FDA approached the problem of
resistance as a safety issue, as you suggested? Could you
explain that a little bit more? I just want to make sure I am
clear on that?
Dr. Powers. Unfortunately, no. I think the idea is that FDA
traditionally approaches it as if somebody a drug and they get
a skin rash, someone takes a drug and gets liver failure, that
is the way they traditionally think about safety. But with an
antibiotic, you are really not talking about just an adverse
effect in one person, you are talking about population effects,
which makes demonstrating effectiveness really even more
important. And I think we often talk about this, safety and
effectiveness, as if they are two different things. They are
really parts of a scale here and when people concentrate on the
side of, well, how many liver failures are there, there has got
to be something on the other side of the scale to balance that.
There has got to be effectiveness, otherwise even one case of
liver failure is too many. But the idea here is that most
antibiotics are actually used for these less serious diseases.
So for instance, there are about 34 million kids who get an
antibiotic a year for ear infections and there are about a
160,000 cases of hospital-acquired pneumonia. Which one is
driving resistance? It is the one where people use the
antibiotics the most. And some people have actually suggested
that perhaps antibiotics should be regulated in a different way
because of that. So for instance, in legislation that is coming
up now, the Kennedy-Enzi bill says perhaps we could look at
drugs for 3 years. Well, for antibiotics you are going to have
to look out longer than that, because that is exactly where
resistance is going to develop. The longer you use the drug,
the more resistance you are going to see.
Mr. Stupak. Thank you. Any other Members? Ms. DeGette?
Well, let me thank the witnesses, then, and thank you for
coming forward. It is an important issue and this committee
takes it very seriously. This is the first of a number of
hearings we will be having on drug safety. I think we all, on
both sides of this dais, would like to see changes in the FDA.
And with that, I dismiss this panel. Thank you again for your
testimony and your time.
Dr. Ross. Thank you, Mr. Chairman.
Mr. Stupak. We will call our last panel, Dr. David Graham
and Dr. Nissen. It is the policy of the subcommittee to take
testimony under oath. Please be advised that witnesses have the
right under rules of the House to be advised by counsel during
their testimony. Do either of you desire to be advised by
counsel at this time? If so, please introduce your counsel. Dr.
Nissen?
Dr. Nissen. No.
Mr. Stupak. Dr. Graham?
Dr. Graham. No.
Mr. Stupak. OK. And as you know, we require an oath. Would
you please rise and raise your right to take the oath?
[Witnesses sworn]
Mr. Stupak. The witnesses are now under oath. Dr. Nissen,
we will start with you, sir. And thank you for your time and
patience in being here.
TESTIMONY OF STEVEN E. NISSEN, M.D., FACC, CHAIRMAN, DEPARTMENT
OF CARDIOVASCULAR MEDICINE, CLEVELAND CLINIC FOUNDATION
Dr. Nissen. Thank you. My name is Steven E. Nissen, MD. I
am chairman of the Department of Cardiovascular Medicine at the
Cleveland Clinic, and the president of the American College of
Cardiology. My testimony does not reflect the views of either
the Cleveland Clinic or the ACC.
We face a crisis in public confidence in the FDA,
following an unprecedented series of revelations about drug and
device safety. The American people no longer trust the FDA to
protect their health. Unfortunately, patients are increasingly
suspicious of new therapies and sometimes are reluctant to
accept potentially lifesaving medications or devices. Decisive
legislative action is now essential to improve the safety of
drugs and medical devices and restore public confidence in this
critically important agency.
I have served on many FDA advisory panels and this
experience has undermined my confidence in the ability of the
agency to adequately protect the public health. In 2001, I
participated as a guest member of the arthritis advisory panel
that recommended a warning label for cardiovascular risk for
Vioxx. Under current law, the agency must negotiate with
industry to make even simple changes in drug labels and FDA
officials frequently make inappropriate concessions to
pharmaceutical companies. Following the 2001 advisory board
meeting, it took 14 months before the FDA could secure
agreement from the company to accept a weakly written warning.
During this period, patients and physicians were not
appropriately warned about the cardiovascular hazards of Vioxx.
When the label was eventually modified, the wording was so weak
that it did not adequately inform physicians and patients of
the potential for Vioxx to cause harm.
In 2005 another disturbing personal experience brought into
sharp focus the inadequacies of the FDA in assessing a new drug
application. On September 9, 2005, officials from the Endocrine
and Metabolism Division presented a new diabetes drug known as
muraglitazar to an advisory panel for consideration of
approval. Because of a previous lawsuit by an advocacy group,
Public Citizen, the FDA is required to publicly disclose the
briefing materials for advisory panels. Because of my interest
in this class of drugs, I reviewed the briefing documents
posted on the Internet by the agency on September 8, the day
before the public hearings. I observed that this
investigational drug seemed to lower blood sugar, but I also
noted that there was a striking excess of heart attacks,
strokes and deaths in patients treated with muraglitazar
compared with placebo or other diabetes drugs. Based upon this
observation, I assumed that the advisory board would recommend
that the agency not approve muraglitazar.
Yet, astonishingly, the following day agency reviewers
presented the drug in a favorable manner, understating any
concerns about cardiovascular risk. This advisory panel, that
did not include any cardiologists, voted to eight to one to
approve muraglitazar, ending the panel meeting at 2:00 p.m. In
Cleveland I watched the news reports, complete with predictions
from financial analysts that this drug would achieve annual
sales exceeding $1 billion.
I felt compelled to act. My statistician and I rapidly
downloaded the FDA material available from the Internet and
performed our own independent analysis of the risk and benefits
of this drug. We concluded that muraglitazar doubled the risk
of death, heart attack, stroke and congestive heart failure. I
phoned the editors of the Journal of the American Medical
Association, who treated our findings as a public health
emergency. Peer reviews were secured in a matter of days and
JAMA posted the manuscript on their Web site October 20, just 7
weeks following the FDA advisory panel meeting. Shortly prior
to our publication, the FDA issued an approvable letter to the
sponsor. Following this publication, the pharmaceutical company
developing muraglitazar abruptly ceased all further
development. Fortunately this drug will never threaten the
public health, but frankly, it was a close call.
We were able to independently analyze the risk of
muraglitazar because the drug was presented to an advisory
panel. For many new drugs, the agency approves them without
public disclosure of the key findings in pivotal clinical
trials. When drugs are presented to advisory panels, the agency
frequently provides an uncritical presentation that fails to
adequately inform the advisory panel members of any internal
FDA concerns.
This phenomenon was very evident during a meeting of the
drug safety and risk management advisory board of the FDA,
which met February 9, 2006 to review drugs used to treat
attention deficit hyperactivity disorder, or ADHD. I was asked
to serve on this advisory panel to help evaluate the
cardiovascular risks of these drugs, most of which are
amphetamines or amphetamine-like agents. These drugs are
closely related to methamphetamine, or speed, a major drug of
abuse.
At nearly all advisory panel meetings, the FDA provides a
list of questions to panel members, designed to assist in
discussions and to guide the formulation of an action plan.
When the advisory board briefing materials arrived, I was
rather surprised by the questions that agency intended to ask.
In this case, the FDA did not request the committee to consider
the risks of the ADHD drugs, nor did they ask us to comment on
the need to change labeling. Instead, they asked the committee
to discuss how the agency might study the class of drugs.
During the hearings, we learned that ADHD drugs substantially
increased blood pressure and we heard reports indicating that
approximately 25 children had suffered sudden cardiac death
after taking these drugs occasionally after the first dose.
ADHD drugs are closely related to Ephedra, a drug the FDA has
sought to ban from OTC products. We also learned that 4 million
Americans take ADHD drugs, including 1.5 million adults and up
to 10 percent of fifth grade boys.
By mid-afternoon, I had heard enough. I departed from the
FDA's carefully orchestrated agenda and introduced a motion
proposing that the committee recommend a black box warning for
the ADHD drugs. Surprisingly, the motion passed by an 8 to 7
vote. Agency officials looked horrified and quickly called a
news conference, where they defended the safety of the drugs
and sought to undermine the recommendations of the advisory
committee. Some months later, the FDA actually did write new
warnings, but it took a rogue advisory committee to motivate
the agency to act.
It is important for the Congress to recognize that there
are many fine and dedicated public servants working within the
FDA, however, their concerns often fail to reach advisory
committees because of the actions of their supervisors, who
adopt a less courageous approach. The Congress must now fully
evaluate the deficiencies within the FDA. Your engagement to
investigate the problem and take decisive action can improve
this agency. The 300 million Americans who rely upon drugs to
stay healthy are counting on you to take action. These measures
need not slow drug develop. If we improve drug safety
oversight, the increased vigilance will inspire confidence and
allow us to bring new medications to patients more quickly,
because we will have a better safety net.
In my more extensive written testimony, I outline 10
critical initiatives needed to put the FDA back on course. I
hope you will consider these ideas as you move forward, and
greatly appreciate the opportunity to appear before you. Thank
you very much.
[The prepared testimony of Dr. Nissen appears at the
conclusion of the hearing.]
Mr. Stupak. Thank you, doctor. Dr. Graham, your opening
statement, please.
TESTIMONY OF DAVID J. GRAHAM, M.D., MPH, ASSOCIATE DIRECTOR,
SCIENCE AND MEDICINE, FDA OFFICE OF SURVEILLANCE AND
EPIDEMIOLOGY.
Dr. Graham. Chairman Stupak and members of the
subcommittee, thank you for the opportunity to speak about a
subject of vital importance to all Americans. My name is David
Graham and I am the Associate Director for Science and Medicine
in FDA's Office of Surveillance and Epidemiology, or OSE. For
more than 20 years, I have worked as an FDA physician/
epidemiologist concerned with post-marketing drug safety. The
statements I make today are my own. I do not represent the
FDA's official view.
As we have heard from the previous panels, the Ketek story
is about FDA's betrayal of the public trust. FDA ignored safety
concerns raised by its own advisory committee and concealed
from the committee the evidence that a crucial clinical trial
was fraudulent. Subsequently, FDA issued a public health
advisory that referenced the same fraudulent study as proof of
Ketek's safety. FDA scientists were intimidated, suppressed and
ultimately compelled to the leave the agency. CDER used post-
marketing case reports from Europe and Latin America, where
reporting is far worse than it is in the United States, to
declare Ketek safe, rather than using clinical trials as it
should have. I cannot think of a single other example where FDA
used such data as the primary basis for the approval of a drug
safety. OSE, ostensibly responsible for post-marketing safety
issues, was relegated to the role of backseat consultant, with
no power or authority.
Unfortunately, Ketek is not an anomaly. In November 2004, I
testified before the Senate Finance Committee that FDA's
handling of Vioxx was a profound regulatory failure and that
FDA, as currently configured, was incapable of protecting
America against another Vioxx. I am here to tell you that
nothing has really changed. Our Nation is still at risk. Vioxx
was enormous national catastrophe. Up to 60,000 Americans, most
over the age of 50, died from Vioxx-related heart attacks,
about as many as the number of U.S. soldiers killed during the
Vietnam War. Another 80,000 suffered nonfatal, but nonetheless
life-threatening heart attacks. FDA had multiple opportunities
to prevent this but did nothing. To this day, FDA denies that
it made any mistakes and has yet be held accountable
Accompanying my testimony, I have included a table that would
show that every State in this country, every congressional
district in this country, had constituents who suffered heart
attacks and who died of heart attacks related to Vioxx.
Sadly, Vioxx was not anomaly either. Think SSRIs and
suididality in children. Think Accutane, pregnancy exposure,
and the need for restricted distribution. Think Propulsid and
sudden death; a drug that barely worked for nighttime heartburn
was left on the market for years while it killed hundreds,
including infants. The list goes on and on.
When it comes to drug safety, what is wrong with the FDA?
In my view, there are four broad areas of critical FDA
malfunction: (1) organizational structure; (2) organizational
culture; (3) the misuse and abuse of science; and (4)
suppression and intimidation of scientific staff. The most
important is organizational structure. CDER's primary mission
is to review and approve new drugs. Within CDER, the Office of
New Drugs, or OND, has this responsibility. Post-approval, OND
continues to have regulatory authority for all post-marketing
safety issues that arise. This represents an inherent conflict
of interest, because the same people who stamp their approval
on new drugs and certify that they are safe and effective, also
get to decide if a post-marketing safety issue is important and
if anything needs to be done about it. There is no internal
control; there is no safety net.
This organizational weakness is amplified by a massive
imbalance in staffing and resources within CDER between pre-
and post-market activities. Overall, roughly 90 percent of CDER
staff are focused on the review and approval of new drugs. As
the IOM report found, ``the imbalance in formal role and
authority between the review, that is OND, and surveillance/
epidemiology, that is OSE, staff denotes the subservience of
the safety function, and along with that, a management
devaluation of the latter discipline and approach.''
CDER's culture regards industry as the agency's primary
client rather than as an entity in need of regulation. The
agency's bias toward drug approval, noted by the IOM, is
enshrined in PDUFA, which requires the FDA to negotiate with
industry over how user fees shall be spent. Patients and
consumers, the public, get no seat at the table.
Finally, although this is not a legislative hearing, I am
compelled by conscience to make the following comments. Vioxx
is the main reason why legislation to reform FDA is being
considered. Hence, the litmus test by which potential
legislation should be judged is whether it would have prevented
the Vioxx disaster in the first place.
FDA's response to the IOM report, recently released, even
if fully implemented, would not have prevented a single Vioxx
death or heart attack. Vioxx was not a failure of surveillance
or resources. It was a failure of institutional decision
making. FDA's response to IOM would not have prevented Ketek or
the SSRI antidepressant issues from unfolding the way they did.
Unless post-marketing safety experts at FDA have regulatory
authority over the post-marketing portion of a drug's life
cycle that is separate and independent from OND and CDER, all
the money and databases in the world won't change the end
result.
Similarly, had the Kennedy-Enzi bill been in place when
Vioxx came to market, not a single life would have been saved.
This bill also would have had no effect on the way Ketek or the
SSRI antidepressant issues unfolded. Why? The bill does not
correct the root cause of FDA's failure to protect the public
health. FDA's failure with Vioxx and the other mentioned drugs
was a failure of institutional decision making, and the
organizational structure giving rise to this failure has been
left unchanged. Kennedy-Enzi leaves OND, the Office of New
Drugs, in charge of post-marketing drug safety. Unless this is
changed, we should expect more Vioxxes, more Keteks and more
SSRI disasters. Sadly, Kennedy-Enzi is not fundamental FDA
reform; it is fundamentally the status quo.
By contrast, the Dodd-Grassley bill in the Senate would
create line authority in a post-market center within FDA, with
explicit authority to protect the public from unsafe medicines.
This bill also frees post-marketing from the corrupting
influences of PDUFA. Had it been in place prior to Vioxx, most
of the 140,000 Vioxx-related heart attack deaths and injuries
would have been prevented. Likewise for Ketek and the
antidepressant issues.
Thank you for your consideration of this critical subject
and the opportunity to address you today.
[The testimony statement of Dr. Graham appears at the
conclusion of the hearing.]
Mr. Stupak. Thank you, Dr. Graham. Dr. Nissen, if I may. I
understand that you oppose Senator Grassley's proposal to
create a drug safety operation separate from the reporting line
through CDER. Both you and IOM seem to think that there is a
so-called culture at the FDA. Regulators are too close to those
they regulate. How do we get the FDA to take or to make the
best risk benefit decisions, if those with the safety expertise
are still subservient to the hierarchy that believes that the
industry is your primary client?
Dr. Nissen. Well, first of all, I think there are lots of
potential solutions and I don't, at least on the first pass,
the Grassley approach, which is to separate the safety and
efficacy assessment, has both benefits and there are risks. And
by the way, I greatly respect the Senator's passion and
commitment and his testimony today was compelling for all of us
that have been involved in this area. But here is the problem.
From my perspective, safety and efficacy are inextricably
linked. If you had a drug, a new drug for lung cancer that
rapidly killed 10 percent of the people that got it, but cured
the other 90 percent of lung cancer, it might be a very good
drug. It would save a lot of lives. It would have a huge safety
problem, but it would be a drug that I might want to approve.
And so I like the idea that an agency that is well run can
integrate safety and efficacy into a single decision. I think
the failure is a failure of leadership. I think we have had
horrible leadership at the top in the FDA and at the next
couple of levels down. The leadership is actually quite good at
the rank and file, although, frankly, there is a streaming of
talented people out of the agency now because of this culture
that exists. And so I think to fix the FDA, we need new laws,
but we also need new people at the top. And being very frank, I
think that goes all the way to the top.
Mr. Stupak. Could you discuss the negative publication bias
issue that you raised in your written testimony?
Dr. Nissen. This is one of the most profound problems in
medicine, I think, in general and here is the issue. When
companies do clinical trials, if the trials do not show a
favorable result, that is either efficacy or good safety, they
are simply never published. Only a small minority of clinical
trials that are actually conducted are published. And so as
physician/scientists, we only get to see a tiny fraction of the
actual data. One example I give in my written testimony is for
a class of drugs called PPARs, where there have been more than
50 drugs that are filed INDs, where the drugs have been
discontinued during development due to toxicity, and not one
single publication has appeared of why any of those more than
50 drugs were actually discontinued. How can we make good
decisions about successor drugs, about the next generation? How
can we protect people in clinical trials if we never get to see
the information?
And so negative publication bias, the practice of allowing
people to participate in clinical trials but we never see the
results of those studies, is not scientifically acceptable. It
is not acceptable in a public health sense for the citizens.
And here is the principle I would like you to consider. If one
of our citizens volunteers to participate in a clinical trial,
the results of that trail belong in the public domain; that
there is an ethical and a moral responsibility that that
individual's noble commitment will translate into advancement
of science. If that study is buried in a pharmaceutical
company, then their commitment results in no gain for the
public at all and it is just not an acceptable practice.
Mr. Stupak. In your PPARs example, where do those studies
end, phase I, phase II? Do you know?
Dr. Nissen. Some drugs were discontinued in animal studies,
but many were in phase I, many were in phase II. A few of them
got to phase III. The toxicities that had been reported were
extensive and bizarre; tumors in various organ systems, kidney
failure, cardiac injury. And by the way, muraglitazar, the drug
that I wrote about, is a member of that class.
Mr. Stupak. Thank you. Dr. Graham, you have been subpoenaed
to appear here today, correct?
Dr. Graham. Correct.
Mr. Stupak. The other witnesses--and there has been
discussion about retaliation for testimony and things like
that. If you have any experiences like that, please let this
committee know. We appreciate your willingness to come forward.
You are still an FDA employee?
Dr. Graham. I am still but only because Senator Grassley
prevented the retaliation from being completed that I was
subject to after my Senate Finance testimony in 2004. And I
must confess that I am extremely apprehensive that I will be
the victim of retaliation for appearing here today.
Mr. Stupak. Like I said, let us know. You stated in your
testimony--and this is your testimony, I take it. It wasn't
cleared through the FDA. This is your testimony?
Dr. Graham. That is correct.
Mr. Stupak. And this is your personal belief based upon how
many years in the FDA?
Dr. Graham. Twenty-three.
Mr. Stupak. Twenty-three years. You stated in your
testimony that the FDA doesn't believe it needs new regulatory
authority to ensure drug safety. Why do you say that and what
new regulatory authority or legal authority would you prescribe
for the FDA?
Dr. Graham. OK. Well, FDA has repeatedly said that it
doesn't need new regulatory authority and in this and many
other areas, FDA really cannot be trusted. During the hearings
that were held by the IOM to investigate FDA and drug safety,
senior managers were asked by the IOM committee, does the FDA
need new resources and more resources to do drug safety? And
categorically, all the managers who presented said no, we
don't. And the staff people complained to these managers after
the meeting, why are you guys lying to the IOM? What I was told
was and what my colleagues were told was that the word had come
from higher up that they were to state, if asked, that no
resources were needed.
Now, when it comes to labeling, FDA has repeatedly also
said, we don't need new authority. When all of this came out
about FDA, Vioxx, labeling delays, and does FDA have the
authority or don't they, FDA gave very evasive answers during
the Senate Finance testimony and then subsequently, where one
official was quoted as saying, no, we don't have the authority,
the official FDA spokesperson came out and said, oh, we have
the authority but we prefer to negotiate with companies. What
is really needed, in my opinion, is explicit authority. The
problem is going to be how does that authority get exercised?
We heard in the last panel that you really have a management
structure that is reluctant to use even the authority that it
has. Giving it new authority will not mean that that authority
gets used. And this, I think, it gets back to who is calling
the shots. Pre-approval, making a decision about whether a drug
comes on the market, and post-approval about what needs to
happen safety-wise, you need to have those handled by different
people and the regulatory authority needs to be separated out.
In the United Kingdom, which has, I believe--the world
would probably attest to this--they have a better pharma
vigilance system than we have in the United States. They are
the gold standard. In their system, the baton gets passed from
the pre-approval to the post-approval. The two sides talk to
each, but they have separate authority and regulatory
responsibility so that what happened with Vioxx, what happened
with Ketek--let us say that I am the FDA, I am the pre-approval
side and I want to approve cyanide. Well, cyanide is a
universal poison and it will kill everybody who takes it, but I
am the FDA, I am OND, and I say I am going to approve that
drug. Well, right now, cyanide would stay on the market because
there is no authority, if OND doesn't want it to happen, for
the drug to be removed from the market. You need to deal with
that.
You see, here is another thing that gets back to the
culture. There is so many things. This is like a carpet, with
so many different interwoven threads. The people who go in the
pre-approval side of the house, they focus on these clinical
trials. Basically a handful of patients, really. We are talking
a few thousand patients, which really, when you talk about a
drug that is going to be used by millions of people, it is a
handful. Think of it as an envelope and you got a little
postage stamp up in the corner. That postage stamp is the
diversity of the types of patients that get studied in a
clinical trial, in terms of age, gender; do you have an
underlying disease; what medicines are you taking? Once the
drug gets on the market in the real world, that is the rest of
the envelope and FDA doesn't pay any attention to that, because
that is the world I live in and that is the post-marketing
world. You need to have people who know what they are doing and
whose orientation is different. I come from a public health
background, internal medicine and public health. My orientation
is towards treating the population, treating the 300 million
people who are out there. They are my patients. And that
population perspective can take an adverse reaction and put it
into perspective, and that doesn't happen now. Sorry I went on
so long.
Mr. Stupak. That is all right. In your time in the FDA,
have you been on advisory panels?
Dr. Graham. I have presented to advisory committees, but I
am not a member of any of the advisory panels.
Mr. Stupak. Have you, in presenting to the advisory panels,
has your testimony been restricted or have you been forbidden
to make presentation to advisory panels?
Dr. Graham. Yes, I had that experience with Rezulin.
Rezulin was a diabetes drug from the same class of drugs,
actually, as muraglitazar. It was the original. OK. So this is
the Adam and Eve of all of this class of drugs and it caused
liver failure at a profoundly high rate and I thought that the
drug should come off the market. There was critical data from
clinical trials in which there were three different clinical
trials, they were small, but in each of the clinical trials, a
patient had died of acute liver failure and I wanted to present
that in an advisory committee meeting that was being held on
that topic. The company went ballistic when they learned that I
was going to do this. I was at the meeting and they went
ballistic and they actually raised their voices at the office
director from OND, who was there, who then subsequently after
the meeting asked me not to present that. And what I said to
him was, I said, I have to present it. If I don't present it,
that is scientific misconduct and it is a violation of my duty
as a public health scientist. I said, if you don't want me to
present, then you tell me not to present and I won't present,
period. But if I present, I am presenting this information.
Well, at the end, they allowed me to present.
Other people in drug safety--I could give you example after
example and I will give you just a couple. Acetaminophen, used
in Tylenol, the main ingredient in Tylenol, liver failure came
up earlier. In the UK and other places in the world, they have
done regulation of acetaminophen to reduce the possibility of
unintentional or intentional overdose and liver failure from
occurring. When our people wanted to present that at an
advisory committee several years ago that was convened
specifically to talk about this issue, they were ordered not to
talk about it before the committee. The same thing happened
with Lotronex, another drug. It has happened with Accutane. I
could go on and on, but that is routine. That happens routinely
and it is the Office of New Drugs telling the Office of
Surveillance and Epidemiology that it can't talk about safety
issues.
Mr. Stupak. Thank you. My time has expired. Mr. Walden?
Mr. Walden. Thank you, Mr. Chairman. I am going to yield to
Dr. Burgess here in just a moment because I know he has another
meeting to get to. But I just wanted to comment and follow up
on something you said and Dr. Graham, something you indicated
and that is the threat of retaliation. And filling in for the
ranking member here, I want you to understand and I want
anybody at FDA to understand that this committee does not
tolerate retaliation on witnesses who ask to come before this
committee, or servants of the public who in some way are trying
to make Government better for the American people. We don't
want their supervisors, those above them, or anywhere else
around them, to retaliate. We will not tolerate that. And so we
want you to have that assurance from this subcommittee and this
member that this is a bipartisan view, that retaliation is not
going to be tolerated.
Dr. Graham. I appreciate that.
Mr. Walden. Now Mr. Chairman.
Mr. Burgess. I thank the chairman and I thank Mr. Walden
for yielding. We have another hearing on global warming going
on and it was pretty warm in here earlier, but it seems to have
cooled off, so I am actually happy to stay.
Dr. Nissen. I will try to heat it up again.
Mr. Burgess. Dr. Graham, we heard testimony earlier, I
believe, from Dr. Ross that there were many more Keteks out
there that have yet to be either disclosed, elucidated or
discovered. Is that your opinion also?
Dr. Graham. Oh, yes, definitely.
Mr. Burgess. Can you----
Dr. Graham. Well, Dr. Ross is talking about--Ketek has some
common features with the experiences that I bring and some that
are more unique to the world that he lives on the pre-approval
side that deal with the actual clinical trials that give rise
to the approval of the drug and there being irregularities
there, in addition to there being this post-marketing safety
issue, where people try to sweep it under the rug. And it is on
that post-approval side that I have my most familiarity. What I
know on the pre-approval side, with clinical trials or
fraudulent conducting of them, or the way safety problems get
dealt with, is more by staff people who come and talk to me
because I am such an infamous individual. When they run into
difficulties in their workplace, I have become sort of a
central clearinghouse, if you will, for helping them navigate
through it. So the answer is yes.
Mr. Burgess. OK. I want to get back to the clearinghouse
function in just a moment, but let me ask you about the post-
marketing aspect. Before coming to Congress, I was a physician,
or still am a physician, and I would periodically get
communications from the FDA and it was for reporting for
adverse drug events. I can't honestly tell you that I ever
filled one out and sent it in, but I would get them all the
time and I would assume that they go somewhere within the
structure of the FDA. Are those things, in fact, looked at or
do most people just take the approach of I am too busy, let
someone else fill it out and send it in?
Dr. Graham. No. The Office of Surveillance and
Epidemiology, where I work, has a large number--well, maybe not
so large. It is like about 40 individuals whose full-time job
it is to evaluate those case reports when they come in. We call
them spontaneous or voluntary case reports, and sometimes it is
referred to as med watch reports. And they review those, sort
of a hands-on review of all reports that are classified as
serious and unlabeled, so it is things that FDA doesn't know
about. And then there is a long list of--I have lost count now
of how many--50 or 100 of what we call designated medical
events and these are particular serious things. I don't care if
aplastic anemia is in the label for this drug. If a report of
aplastic anemia for that drug comes along, an experienced human
eye is going to read that, because they have this depository in
their minds of what the experience with that drug and other
drugs in that class is like.
Mr. Burgess. Does that function now occur online? Again, I
remember getting the pieces of paper that we would then mail
out.
Dr. Graham. There is a way that it can be done on line, it
can be done by telephone and it can be done by paper. Most
physicians and health professionals, when they report, actually
end up telephoning the particular drug company if it is a name-
branded drug. That is how FDA ends up getting most of its
reports, is through the company.
Mr. Burgess. And then does FDA periodically disseminate
that information to clinicians?
Dr. Graham. I think that the answer to that is probably
not. I think there are plans, actually, for them to do some
kind of newsletter, but I don't think that there is any formal
mechanism in place up until this point.
Mr. Burgess. Well, actually going on the FDA's Web site, I
have found that, in fact, that sort of communication does
happen and it has been going on for some time. I just never
availed myself of the FDA Web site and went and looked at it.
Let us talk a little bit about your being the clearinghouse.
Can you tell the committee what other Keteks are out there?
What are some of the other red flags that we should be watching
for?
Dr. Graham. Well, I will tell you a couple. I would pay
careful attention to antipsychotic medications. Antipsychotic
medications--and you have got what are called the typical and
the atypical antipsychotic medications. The trend is the
atypicals because they reputedly have a better safety profile,
a lower side effect profile. The problem with these drugs: they
are enormously expensive. The problem with these drugs are that
we know that they are being used extensively off label in
nursing homes to sedate elderly patients with dementia and
other types of plot disorders. It is known that the drugs don't
work in those settings. And it is off label, they just do what
they want. But the fact is, is that it increases mortality
perhaps by 100 percents. It doubles mortality. So I did a back-
of-the-envelope calculation on this and you have probably got
15,000 elderly people in nursing homes dying each year from the
off-label use of antipsychotic medications for an indication
that FDA knows the drug doesn't work. This problem has been
known to FDA for years and years and years and----
Mr. Burgess. Well, let me just interrupt you. Is that the
FDA's issue or is that an issue of the policing of medical
practice?
Dr. Graham. No, I believe that it is a public health issue
and it is a public health issue because the companies are
laughing all the way to the bank. With every pill that gets
dispensed in a nursing home, the drug company is laughing all
the way to the bank. The FDA isn't there to step in where it
knows there is an--I am not talking about--there is off-label
use and there is off-label use.
Mr. Burgess. Sure.
Dr. Graham. This is off-label use where we have got so many
clinical trials that show you that these drugs don't work, that
it is like malpractice to be using it.
Mr. Burgess. Well, and that actually brings up another
issue, but do you have another one to put on watch list?
Dr. Graham. Well, I think it has been in the newspapers, in
the New York Times, Zyprexa and diabetes. What has FDA been
doing with this? All these clinical trials that we only learn
about in the New York Times, of the weight gain from Zyprexa
and the diabetes, and diabetes is a life-threatening disease.
Don't kid yourself. It is responsible for more lost years of
life than many, many disorders. It is a biggie and Dr. Nissen
could talk to you more about it. Zyprexa, it turns out, the
company knew for a long time, apparently, based on what I read
in the New York Times, that there was a big problem. My
question is--because I know FDA knew about too. And in talking
to reviewers at FDA about FDA's approach in dealing with this
safety issue, I am told it leaves much to be desired.
Mr. Burgess. Well, let me ask, then, both of you a question
because we have kind of got competing legislation with Kennedy-
Enzi that apparently appeals to Dr. Nissen, and Grassley-Dodd
that appears to Dr. Graham. Of both of these broad categories
that have been mentioned, which bill is going to do the better
job of protecting the American public? And I guess, let me ask
Dr. Nissen that question first.
Dr. Nissen. First of all, I must tell you that I don't
think either of them go far enough and there are a lot of
things that aren't in the bills and I tried to outline those in
my written testimony. And I think we need to understand and be
very clear about this, that we should not renew PDUFA. We
should repeal PDUFA. PDUFA is not the solution; it is at least
part of the problem. We started down the wrong pathway when we
said that the regulated industry was going to pay the FDA to
regulate itself. And I think that, ultimately, given the amount
of money that is involved, we spend about $2 per person in
America for drug regulation. That is the total expenditure. In
the Federal budget it is a drop in the bucket. It is nothing.
And yet we insist on industry paying that. Once you do that,
then they become the stakeholders for the FDA rather than the
American people. Why not come up with the money, find a way and
fund the FDA independently without user fees and I think you
will see improvements.
Mr. Burgess. And that may be something that we need to
explore, but it was done long before I got here.
Dr. Nissen. Yes.
Mr. Burgess. But it is my understanding, as a clinician at
the time, was that this was a way to open up the pipeline to
get things through in a more timely fashion. Because, as a
practicing physician, I used to view the FDA as kind of an
obstruction to getting new and timely treatments available to
my patients. So anything that would move that process along
more quickly, if it could be done in a safe manner, would be
something that would be beneficial.
Dr. Nissen. But we don't need PDUFA to do that. I think
what PDUFA did was it set up an arbitrary deadline that you
have to, by a certain date, make a decision and the problem is,
is in conditions of uncertainty, when you have an agency which,
at the top, is basically going to lean towards approval, what
you end up doing is what happened with muraglitazar, which was
you very nearly got a drug approved, because its PDUFA date was
coming up very shortly, that would have been a catastrophe and
I just don't think we can afford to do that.
Mr. Burgess. I see the point you are trying to make. Let me
just ask you, since you have brought it up. You say when you
knew people at the top in the FDA in my short tenure here, we
have had nothing but new people at the top.
Dr. Nissen. Yes.
Mr. Burgess. We just keep picking the wrong guy?
Dr. Nissen. Yes. Yes, in fact we do. I think we need to
move the FDA further away from the political arena and more
into the public service arena. We have had some very disturbing
events where it appears that, political decision making was
affecting what the FDA did. We are all aware of those and I
think we have to insulate the FDA from that kind of effect.
Mr. Burgess. And actually I agree. My time has expired, but
we always have to go through Senate confirmation process for
our FDA commissioner and administrator. Is that something that
is an anachronism and we should no longer be doing?
Dr. Nissen. No, but I think we have got to find people that
see their role as a public health official and not as a
political official.
Mr. Burgess. Forgive me, but if you go through a Senate
confirmation process, it is inherently political. You can't
help but be political. You saw a rather impassioned Senator.
There are 99 other of those men and women over there on the
side of the capitol.
Dr. Nissen. Yes. Let me just say I think----
Mr. Burgess. And anyone can put hold on the commissioner
for any reason.
Dr. Nissen. I understand. But we can do better. We can have
better leadership. We need better leadership at the FDA. It all
comes from the top.
Mr. Burgess. Well, and I agree, but it is just me wondering
if the process itself, whereby that person has to go through a
Senate conformation rather than a scientific assessment, leads
us to the types of decisions that we have been seeing. Mr.
Chairman, you have been indulgent. I will yield back.
Dr. Nissen. Interesting idea.
Mr. Stupak. Mr. Burgess, Senator Grassley did have a hold
on the current FDA commissioner at approval time and it was
released and he was approved.
Mr. Burgess. Mr. Chairman, that is exactly my point. We
have gone through a succession. Again, I have just been here a
short period of time.
Mr. Stupak. Sure--since you have been here.
Mr. Burgess. Dr. McClellan, Dr. Crawford and now Dr. von
Eschenbach. And it just seems to be a labor-intensive process
to get one of these individuals through the Senate and I can't
help but wonder if that doesn't harm the FDA to constantly have
its head changed or under the microscopic scrutiny of the
Senate.
Mr. Stupak. Well, I am not too sure the confirmation of the
commissioner results in what we are seeing within the FDA. We
need strong leadership there, there is no doubt it. If we
change every 2 years, you won't have that leadership. I would
agree with that point.
Mr. Burgess. But we have seen the same at Los Alamos with
the frequent change of leadership and we have gotten no
improvement with multiple hearings on that issue as well.
Mr. Stupak. That is my second favorite subject and----
Mr. Burgess. Again, I am going to go solve global warming.
I will see you later.
Mr. Stupak. OK. The gentlewoman from Colorado, Ms. DeGette.
Ms. DeGette. Thank you very much, Mr. Chairman. Dr. Nissen,
the fact that the FDA commissioner needs Senate approval, that
is not what you are talking about. You are talking about the
PDUFA approval process and the way the fees are conducted,
creating conflicts of interest within the FDA drug-approval
process, correct?
Dr. Nissen. Absolutely correct. And I just think it creates
an inherent conflict of interest that is not going to get
easily resolved until we repeal PDUFA.
Ms. DeGette. Dr. Graham, what do you think about Dr.
Nissen's view that we should just scrap PDUFA and find some
other way to do this?
Dr. Graham. Well, in my testimony, I talk about the
corrupting influence of PDUFA. PDUFA is a mistake. It was a
predictable mistake. It has had consequences. I would claim and
maintain that they are predictable consequences. I will give
Congress the benefit of the doubt and say that they are
unintended consequences, but they are consequences nonetheless.
Ms. DeGette. And in fact, what I was just sitting up here
thinking, the reason that we enacted PDUFA is so that we could
get important drugs approved more quickly, which is a good
goal. But actually, if you have problems later with those
drugs, then not only do you have a slow--it ends up being
slower because you have to go back and review them, but you
have a potential grave risk to human life.
Dr. Graham. Right. Well, it is even worse than that. If you
are on the pre-approval side of the house, your bonus, your
awards, your promotions, really have to do more with getting
the NDAs approved than anything else. And you are basically in
a factory and lots of reviewers, medical officers, talk about
it. You are in an NDA factory, a new drug application factory,
and you have got to meet these timelines to get these things
done. OK, I have got 6 months to review this application. Now
some drug that got approved 3 years ago has a safety problem
and I have this other review that I have got to do. Well, where
are my priorities? My priorities are here. They are not on that
safety issue. This is like the Office of New Drugs. It is the
same group that approved that drug that has to deal with post-
marketing and make all of the decisions. It is a backseat issue
because it is not a priority.
Ms. DeGette. Right, I understand. Dr. Nissen, do you think
there is some way that we could expedite approval of important
new drugs without building in the inherent conflicts that we
have built in through PDUFA?
Dr. Nissen. Yes, I do. And something that has been talked
about and I have talked about is the idea of conditional
approval and I actually think this could work. You have a drug
where you don't know enough about the drug, but you think it
may benefit patients. Maybe it is a cancer drug and it looks
like it is going to make a difference for people, but you would
like to know more. If you gave that drug a 3-year approval that
would automatically expire at the end of a period of time
unless sufficient studies were done and you outline what those
are, then you have got kind of club over the head of that
manufacturer. One of the problems we have is that most of the
post-approval studies that are promised are never performed.
Why are they never performed? Because once the drug is on the
market, the FDA rarely, if ever, puts the genie back in the
bottle.
I am suggesting that you might want to consider the
possibility of legislation allowing provisional approval that
would expire unless certain information were brought to bear
that could further describe the safety and efficacy of the
drug.
Ms. DeGette. And in fact, they do that in Europe, as I
understand.
Dr. Nissen. Yes, there are countries that do that. We don't
have to turn the FDA over to the pharmaceutical industry for
funding in order to get drugs more quickly approved. We need
better leadership. We need people that understand when you
should move quickly because something is a lifesaving drug. And
when it is an antibiotic used to treat trivial infections,
maybe you ought to slow down a little bit. Good leadership can
make these kinds of decisions if it is in place.
Ms. DeGette. And Dr. Graham, yes, go ahead.
Dr. Graham. I just wonder if I could follow on to Dr.
Nissen?
Ms. DeGette. Yes, please.
Dr. Graham. Part of the problem with PDUFA is that we talk
about--I have heard multiple different members talk about
bringing lifesaving drugs to the American people, as if every
drug was a breakthrough drug that was going to cure some cancer
or something else. The truth is most of the drugs approved
under PDUFA are not lifesaving drugs. They are what are called
me too drugs; another drug to lower your blood pressure,
another drug to treat diabetes, another drug to treat
cholesterol. So the innovation that you are looking for--I
guess what I am saying is----
Ms. DeGette. Well, but we did hear, for example, with
respect to antibiotics, on the previous panel, how there really
has been some difficulty in getting the development of some of
these drugs.
Dr. Graham. Well, that is true and part of the problem is
the pharmaceutical industry is really risk adverse because it
is so expensive to develop a drug. So most of the time they
will go after the sure thing, which is a me too. Maybe creating
incentives for industry, for example, to invest in the higher
risk of new drugs to treat diseases in new ways would be
something to explore. And make it more difficult, raise the
bar.
Ms. DeGette. I understand. So what you are saying is give
folks incentives to develop the drugs under stringent approval
guidelines and maybe conditional approval, rather than going
down the other path of approving drugs that haven't been
adequately tested or worse.
Dr. Graham. Right. And relating to PDUFA, I think that it
is basically a tax. I know Congress hates to hear the word tax,
but the companies are passing----
Ms. DeGette. I think all the Republicans left.
Dr. Graham. OK. The companies are----
Mr. Walden. Not quite.
Ms. DeGette. Oh, well. OK, I guess you are one.
Dr. Graham [continuing.] Companies pass that cost on to
consumers. If you were to charge a penny per prescription, a
penny prescription surcharge, put it in the Treasury and it is
not like Social Security, where you can transfer it, but it is
dedicated to safety, you could have complete funding of the
post-marketing aspects of drug regulation with no attachment to
industry, no ownership of industry, no control of industry over
it because it is coming from the people. Now it is called a tax
and that is a dangerous word, but you have got to launder that
money and you have got to cut the strings, because right now it
is a quid pro quo. We have given you the money; now approve our
drugs.
Ms. DeGette. I understand. Dr. Graham, you have spoken, and
also I think you spoke, Dr. Nissen, about the culture over at
the FDA. And one thing we have learned with this Los Alamos
issue is that, once you develop a culture--at Los Alamos, the
problem we have is that they keep accidentally losing top
secret data and very--the last one we learned about because
someone got searched for drugs in her home and lo, she had this
information. We have the same problem. We feel like it is
Groundhog Day up here because all of these key issues with
senior level Government officials, we keep seeing these
pharmaceuticals that are really threatening lives over and over
again. And at Los Alamos, as Mr. Burgess pointed out, we keep
changing the leadership and still these problems keep
happening. The thing at the FDA and I guess--I am wondering,
and we will start with you, Dr. Nissen, and then you, Dr.
Graham, what can we do, aside from repealing PDUFA or not
reauthorizing PDUFA, to change that culture at the senior
levels of the FDA, because I am not convinced that it is just
the head of the FDA. I think there is more of culture
throughout the agency.
Dr. Nissen. Well, there is clearly a cultural problem and I
think that it goes far beyond PDUFA, I agree, and it does go
beyond the director, but it does start at the top. And really,
if we had really passionate leadership at the FDA that was
strongly in favor of balancing safety and efficacy, rapidity of
drug approval with protecting the public, it would at least in
part trickle down. There are several cultural issues that I
wished I understood completely, but let me give you one of
them. There is the culture of secrecy, that everything seems to
happen in kind of closed black box. Now, why was I able to
publish a manuscript about muraglitazar? It is because they had
an advisory panel meeting and because of a lawsuit a number of
years ago, the FDA was forced to put on the Web the briefing
materials that they gave to the panel members. If a drug
doesn't go before a panel, you never get to see what actually
happened. You don't get to actually see that raw data and
science can't work effectively when you have blinders on. And
so you can, with legislation, take the blinders off. You can
say that clinical studies belong in the public domain. And then
it kind of doesn't matter, because there is always somebody out
there that will look at the data, reanalyze it, as I did for
muraglitazar, and say wait a minute. We have got a problem
here. So I think you can overcome some of that.
I wanted to say one more thing about this balance between
speedy approval and drug safety and that is this: if we knew we
had a robust post-marketing surveillance system that would pick
up problems quickly, then we could have more rapid drug
approval. This is an example where better safety monitoring
actually speeds bringing new drugs to market, because when I
sit on an advisory panel now, I have to be very cautious
because I know that if I let the genie out of the bottle, that
the chances are, if something bad happens, it won't get seen
for 5 years and then we have hurt a lot of people. But if we
had a very robust post-marketing surveillance system, and I
think there are ways to do that, then we could be more bold in
bringing medications to market more quickly.
Ms. DeGette. Thank you. Dr. Graham, briefly.
Dr. Graham. Right, briefly. Culture is a difficult thing to
address. What I would say is, is that the comments that Dr.
Nissen has made are good, but if you really want to change the
outcome, if you want Vioxx not to happen again and you want
Ketek not to happen again, you need to work on the structure.
You need to focus on how are decisions made. The orientation in
the pre-approval people are towards getting the drugs out the
door. The people in the post-marketing, who come from public
health backgrounds of population, it is towards what is going
on here? Is there a problem here? Is there something we need to
do protect the public? It is two different mindsets. One is
based on a population, the other is focused on these small,
little studies. And the culture of those two organizations is
remarkably different. What happens now is, is the dominant
culture, the OND culture, suppresses that post-marketing safety
culture and that is part of what we have. But if you want to
solve the problem, you separate the organizations in terms of
authority. How you do it, maybe you meld Kennedy-Enzi together
with Dodd-Grassley, but you have got to separate out who is
making decisions at which part of the life cycle of the drug.
And what you will see is, is there is going to be a feedback
loop now, because if we post-marketing people had pulled Ketek
when we said it needed to be pulled, or pulled Vioxx when we
said it needed to be pulled, or pulled Rezulin when we said it
needed to be pulled, the pre-approval people now, they are
getting feedback. Uh oh, we overlooked something, maybe. Uh oh,
if we make a mistake on this drug, we are going to get
embarrassed because those people are going to expose it. Right
now there are no internal controls, there are no checks and
balances.
Ms. DeGette. Thank you. Thank you very much.
Mr. Stupak. I thank the gentlewoman.
Mr. Walden. Mr. Chairman, a point of personal privilege?
Mr. Stupak. Absolutely.
Mr. Walden. I have the sad duty to notify you and the other
members of the committee and our audience that moments ago we
were notified that our friend and colleague who served on this
committee since 1995, Dr. Charlie Norwood, has passed away at
his home in Athens, Georgia. Our prayers are certainly with his
wife, Gloria, and his family and friends. He ably and
forcefully represented the people of Georgia in his district.
And Mr. Chairman, if we could have a moment of silence in honor
and memory of our friend and our colleague, a great American,
Dr. Charlie Norwood.
Mr. Stupak. Join us for a moment of silence.
[Moment of silence observed]
Mr. Stupak. Thank you. Mr. Walden, you are recognized for
10 minutes.
Mr. Walden. Thank you, Mr. Chairman. I know that obviously
throws a little curve in our hearing and our lives, but I
appreciate you in that. Back to our questions, because I know
Charlie would want us to pursue this issue, especially with his
passion for healthcare and improving the lives of Americans. So
Dr. Graham, let me start with you. In discussing Ketek, your
testimony states that the FDA scientists were threatened,
intimidated, suppressed, transferred and ultimately compelled
to leave the agency. Who are the FDA scientists that you are
referring to?
Dr. Graham. You have heard them. You have heard them speak
and I am sure they have colleagues. I know that there is at
least one other reviewer who was involved in the Ketek review
who was afraid of retaliation and who actually, no, is no
longer with that particular group. He was transferred to
another group to get out of that hell hole. But in any event,
that is who we are talking about.
Mr. Walden. And you know, because I asked Dr. Ross or
others about whether or not this is agency-wide or is it sort
of isolated in a couple of places. This type of practice.
Dr. Graham. This type of practice happens--I can tell you
now for post-marketing. A drug has been approved; it now gets
on the market. Now a safety issue comes up. I can tell you--and
I could assemble a list later of the multiple examples where we
in post-marketing bring a safety issue to the new drugs people
and they do nothing or worse. I will give you just one example,
because this was my introduction to FDA and the reality of what
it is to have the people who approve the drugs decide what
happens to them.
Mr. Walden. And how long ago?
Dr. Graham. I came to the agency in 1987, so this would
have been in 1988, 1989. OK, things have only gotten worse
since then, but listen to this example. The drug is Vericet. It
is a benzodiazepine. It is like Valium and it was used
intravenously for conscious sedation, to make you sleepy during
medical procedures such as colonoscopy. Well, the advantage of
this drug was it was water soluble. Valium is oily and it
doesn't--it causes the veins to get inflamed. So this is an
improvement for patient comfort. Soon after approval, we got 23
reports of patients who died of respiratory arrest. They
stopped breathing during their routine medical procedure. We
brought these 23 case reports to the Office of New Drugs, to
the division director and the office director. That office
director is still there. He is now higher up in CDER. His name
has already been mentioned once today at this meeting. Very
high up. And they threw out all 23 cases, saying there was
nothing here.
Mr. Walden. Why?
Dr. Graham. Two examples are, particularly, that stuck in
mind these years, one of them was a 63-year-old woman with
breast cancer, who they said she has got breast cancer for--she
has got to die sometime.
Mr. Walden. Did they actually say that?
Dr. Graham. Yes, they actually said that. The other was a
91 or 92-year-old, some guy in his nineties, OK. He is 91 years
old. He has got to die sometime. So he picked that very moment
to stop breathing. Fine. We go back to our office in dismay.
What are we going to do? Two years or so later, some academics
do some pharmacokinetic experiments where they determine that
FDA got the dose wrong. FDA had approved the dose of this drug
at about 10 times what it should have been. And so in point of
fact, these people were actually being killed by the drug and
FDA had approved that and FDA--our post-marketing system is
maligned, but it captures things like this. That is what it was
designed and intended to do.
Mr. Walden. And you say have a whole list of these?
Dr. Graham. Yes, I have got a list of other ones. Oh, yes.
Mr. Walden. Mr. Chairman, could I ask unanimous consent
that we ask the witness to supply that list to us?
Mr. Stupak. Sure.
Mr. Walden. That would be obviously helpful to the lives of
Americans.
Dr. Graham. Right.
Mr. Stupak. OK, with Dr. Graham's assurance, he will
provide that list to us. I know you have been to the Senate in
2004.
Dr. Graham. Yes.
Mr. Stupak. And there were about six of them then.
Dr. Graham. Right. And I will provide a list.
Mr. Walden. This goes back to 1987, so----
Dr. Graham. Right, but you see, we are talking culture
attitude what happens when you are OND, you are the people who
approve the drug and you are the lord and master and you
control everything that happens afterwards. Now the thing--in
the modern day, it has gotten even worse, because what happens
is, is that all of our supervisors, for example, in my office,
most of them come from the Office of New Drugs. We don't have
any promotion from within into the upper ranges of drug safety.
Mr. Walden. So are you saying by that that they sort of
protect their old turf, then?
Dr. Graham. Some of them do. They are not--our office
director is very good. He sees public health and that is really
wonderful. The problem is, is that not everybody who has come
over over the years--and we have had a lot of people come from
OND over to OSE--they don't have that public health background.
They are used to looking at the clinical trials and saying is
the P value less than .05? And if it is, it is truth, and if it
is not, we are going to forget about it, and that is not the
way population medicine is practiced and that is not the way
post-marketing is supposed to be done. Now the problem is--I
just have to get this little sound bite in--physicians bury
their mistakes one at a time. The FDA buries its mistakes in
unmarked mass graves. And what I have just described, this
dynamic of who is responsible for decision making pre- versus
post-marketing, that is the crux of that issue.
Mr. Walden. Do you think that these sort of internal
structural, cultural problems at FDA, do they predate the user
fee program?
Dr. Graham. They predate it, but PDUFA exacerbated it. What
happened with PDUFA was it is kind of--you have got--we talk
about logarithmic scales. PDUFA took what was a 10 and raised
it to 100 and it did it in several ways. What it did is--and
the IOM documents this. Basically it is like leash with a choke
collar on the neck of FDA and it is being jerked and they are
saying pay attention to getting these drugs out the door and
get them out fast, and safety is an afterthought. Pre-
approval--what happens now, pre-approval, is--yes, Dr. Gauson
has said 50 percent of CDER's resources are spent on safety. I
would like to see a real accounting of that, because the
medical officers I have talked to say the safety review is the
last thing that gets done and they don't spend nearly as much
time on it. And that is where we are just talking pre-approval.
I am most concerned about the post-approval. As I said before
if FDA wants to produce a poison or approve a poison, well, if
we have got a safety net out there to interdict it, then we
have got a check and balance.
Mr. Walden. That is kind of what Dr. Nissen is saying.
Dr. Graham. Well, yes and no.
Mr. Walden. Well, he is shaking yes, I think.
Dr. Graham. Well, maybe Dr. Nissen and I need to talk off-
line sometime so we can explore more, maybe, the similarities
in the way we about it, this benefit that Dr. Nissen has talked
about.
Mr. Walden. Right. Let me go on.
Dr. Graham. OK. I am sorry.
Mr. Walden. No, really, you are very passionate on this and
it is helpful. Did you perform a failure mode analysis in the
Vioxx case?
Dr. Graham. I did but FDA has not and this is one of the
critical issues. When an airliner goes down, the National
Transportation Safety Board is out there. Is the switched
colored the wrong way? Is there some reason, then we can fix
something, the engineer the solution. FDA did not look back at
Vioxx. The IOM was not asked to look at Vioxx. What IOM looked
at was FDA. IOM didn't put Vioxx up as an example and say, what
we are recommending, would actually have dealt with these
problems?
Mr. Walden. So explain to me how a failure mode analysis
works? What is it?
Dr. Graham. Well, it is used in engineering mostly, and in
systems analysis, where you basically have boxes on a process
chart or something like that and you can kind of see if this
breaks down and what happens if this breaks down. The failure
mode that I did was sort of looking at what is the evidence we
had on the drug and----
Mr. Walden. So what did you find on Vioxx?
Dr. Graham. OK, what I found is that pre-approval, we had
ample evidence that Vioxx would cause heart attacks. We knew
from the theoretical that it could cause heart attacks. That
was known by the company and it was known by FDA. The clinical
trials that were done showed a tendency, an increase in
cardiovascular events, but it didn't reach statistical
significance. And this is one of the problems at FDA. For
safety, it assumes the drug doesn't work and then a company has
to do a study and show statistically that it does work in order
for it to get approved. But for safety, FDA assumes, before it
gets on the market, that the drug is safe and now it is up to
the company to prove that it is not. Well, what company in
their right mind is going to do that? And the standard that FDA
places on safety is unreasonably high.
So with Vioxx, for example, there is ample evidence. The
medical officer says it right there: ``Cardiovascular events
are increased, but I don't have complete certainty.'' In other
words, the P value wasn't less than 0.05. So that was my
analogy in the Senate Finance. This was the analogy I was
trying to make about that I have 90 bullets in a 100-bullet
chamber and the gun is not loaded. Well, it is loaded, it is
just not loaded enough for you to agree it is loaded. And so
that is on the pre-approval. On the post-approval side, having
the suspicion that--would occur in April 2000, FDA had the
results of the bigger trial, which was a study that was started
before the drug got approved, finished after the drug got
approved, a large randomized clinical trial, and it showed that
Vioxx increased the risk of heart attack by a factor of five.
OK, a 500 percent increase. As a population medicine person,
what FDA should have done as soon as it had those results was
yank the high dose of Vioxx. There was no earthly reason for--
this was a high does study--no earthly reason for the high
dose. The high dose was approved for the short-term treatment
of acute pain. Well, 4 million women a year give childbirth and
have acute pain and there are a lot of safe pain relievers for
short-term use that don't increase your risk of heart attack
fivefold. FDA never did the benefit/risk analysis, because FDA
has never done a benefit/risk analysis in its entire history. I
have done several and each time I have done it, I have been
reprimanded for doing so.
In any event, the public health perspective would have been
to pull the high dose now, this thing called dose response.
Maybe the low dose does it as well. We see in the clinical
trials that as low a dose as 12\1/2\ milligrams increased the
risk, but it wasn't statistically significant. You would have
been faced with a dilemma there. Do I pull that dose or do I
say to the company, go out and do a really big study, really
fast, to answer the question on the low dose? And maybe we
could debate what happens. Hindsight shows that the low dose
did it as well and so--but you see, this is the difference of
who is calling the shots pre-approval and post-approval and
that is the core issue. The reviewers at the level--the
reviewer who said we don't have complete certainty, I know her.
We are friends. She is a very good reviewer. The reviewers at
FDA are very good, but the rules the operate under, they are
trained to think this way. So basically, in the pre-approval
world, they are all trained to say, if the P value isn't less
than 0.05, I can ignore it.
Dr. Nissen. If I could jump in a second, not only did they
not do that, but they let the company go ahead and put on
television ads with skaters skating around pain free. And so
what we saw here is here is a time, by 2000, by the time of the
bigger----
Mr. Walden. They knew there was a problem.
Dr. Nissen. And it was clear. It was clear in the
manuscript that was published, it was clear in the FDA's study
report, it was clear to us in February 2001 at the FDA panel,
and yet they allowed the company to continue to show us
people--a young skating around a ring without any pain.
Mr. Walden. Yes, Dorothy Hamill.
Dr. Nissen. Yes. I wasn't going to mention her name because
I am sure she was well remunerated for her time, but the point
is that that drove millions of people to use the drug. Now a
prudent agency would have said, OK.
Mr. Walden. Wait a minute.
Dr. Nissen. Maybe we can disagree about the data, but at
the very least, we ought to pull back here until we learn more.
We certainly ought not let the company go ahead and promote
this in this extravagant way.
Dr. Graham. And the drug was promoted heavily. In fact,
Vioxx was the most heavily promoted product on the Internet. It
exceeded promotion for pornography on the Internet. OK. Yes, it
was huge.
Mr. Walden. Having done a number of hearings on that issue,
that would be hard to believe.
Dr. Graham. Well, if I could just point out something here.
Kennedy-Enzi, as I understand it, would possibly have resulted
in--it was like almost this 2-year delay in FDA getting a label
change done. Kennedy-Enzi would probably shorten that or deal
with that, but you see, but that is not the problem. The
problem was this drug shouldn't have been there in the first
place. The high dose should have been gone immediately and the
low dose should have been feet to the fire, prove that it is
not dangerous. And Kennedy-Enzi--see, this is the mindset. So
just to give you insight into the way these things work.
Mr. Walden. I just have to probe one other issue that is
somewhat not related, but we had a hearing on this issue as
well, and that is supplements, dietary supplements. We had the
panel witnesses on Ephedra who, I think, the common
denominator--I don't think I will get in trouble for saying
this--is they had some sort of conviction for fraud and maybe a
high school education and the recipe was written on the back of
an envelope. This stuff is out there being marketed and people
are dying from that. Do you have any counsel? That is way off
our topic.
Dr. Graham. Dr. Nissen, you go first.
Dr. Nissen. In my written testimony, I actually speak to
this and I am going to tell you that if we don't do anything,
there will be a major catastrophe involving the dietary
supplement industry. What we are doing is absolutely insane. I
could go out in my backyard and I could cut up grass clippings
and put it in a capsule and put it in a bottle and say promotes
heart health and I could sell it at the local pharmacy for $300
a bottle and people just do that, that very thing. I recently
saw a patient. There is a drug we use called niacin. Niacin is
a drug that is used to raise HDL, the good cholesterol, and it
is an effective drug, although it has a problem, which is it
causes a lot of continuous flushing. People flush very badly
when they take the drug. And so health food stores, unregulated
by the FDA, have begun selling something called no-flush niacin
and there is only one problem with no flush niacin: it doesn't
have any effect on HDL. It is inert.
I had a patient recently that came in that had a very low
HDL. I had gotten his HDL up to a very high level and he was
counseled by his local health food store to go on no flush
niacin. His HDL dropped. He came in with a heart attack. The
patient came in with a heart attack, subsequently developed
severe congestive heart failure, needed a heart transplant and
died while waiting for a transplant. Now, anybody who tries to
tell you that dietary supplements are harmless is out of their
ever loving mind. Taking garlic rather than a real cholesterol-
lowering medication is harmful. And the greatest setback to
drug safety in the last 100 years was the Hatch-Richardson Act,
which took away the FDA's authority to regulate dietary
supplements. This has got to be dealt with if you are going to
deal with drug safety.
Mr. Walden. Mr. Chairman, thank you for your great
indulgence on the time. Thanks to our witnesses for your input.
It is most helpful.
Mr. Stupak. Thank you. Just one question, Dr. Nissen, if I
may. Dr. Graham mentioned a number of drugs. He was going to
provide a list to us of couple of drugs that he thought are out
and approved in the marketplace that we should take a closer
look at or someone should take a closer look at for safety. If
you have any suggestions or would like to provide a list to the
committee, we would be receptive to receiving that.
Dr. Nissen. I will certainly think about that and I will
inform you about some thoughts I have about that, but I do
think there are real issues in currently marketed drugs. I
don't think we have seen the end of the kind of drug safety
revelations that have occurred. Something that has come up
recently, if you watch the news that yesterday in the New
England Journal of Medicine there were five manuscripts about
the drug--which is a very hot controversy right now about
whether they, in fact, are as safe and effective for the
indication which the were developed. You are going to hear a
lot more about that in the next couple of years. We haven't
talked at all about the device side and one of the things that
is not in Enzi-Kennedy that really is missing, that I hope, on
the House side, something can be done about is the device
world. We have had problems with defibrillators that failed. We
have had a lot of safety issues on devices, heart valves, and
stints are a great example. And so if you want to look at
safety, it is not just pharmaceuticals, it is also devices. And
if anything, the regulatory environment on the device is more
like the wild west than it is on the drug side. It is actually,
if anything, worse.
Mr. Stupak. Well, it sounds like it is a great topic for
this committee. As we often say, we deal with crime, drugs and
sex all the time in this subcommittee and I am sure we will in
the future. As I said, this was the first of many hearings we
will be having on drug safety, and the three panels, the
excellent panels that we had today, have suggested other areas
that we will explore over the course of this Congress. Well,
that concludes our questioning and I want to thank all our
members, our panel members, and I think all of the Members for
coming down. A little bit of bookkeeping, or health keeping, I
should say. These documents found in the white pamphlet,
without objection, will be in for the record.
If any Members have additional questions for the record to
be answered by our relevant witnesses, we will give you 10 days
to submit them to the committee clerk within the next 10 days.
Please do so in electronic form. That will conclude this
hearing. Thank you again for all our witnesses. Thank you for
everyone for being here today.
[Whereupon, at 2:30 p.m., the subcommittee was adjourned.]
[Material submitted for inclusion in the record follows:]
Testimony of John H. Powers, M.D.
Good morning. My name is John Powers. I was a physician-
scientist at the U.S. Food and Drug Administration for the last
8 years, the last 5 of which I was the Lead Medical Officer for
Antimicrobial Development and Resistance Initiatives. I would
like to state that I do not consider myself as having ``blown a
whistle'', since I pointed out the very issues that I will
discuss today to FDA managers up the chain of command. I chose
to leave the agency to pursue other research opportunities
after over half a decade of attempting to advance the science
of clinical trials in infectious diseases, feeling that I could
better serve the public outside the agency. There are numerous
individuals in both FDA and the drug industry who work hard
appropriately evaluating new medicines for people. I learned a
tremendous amount at FDA and I would still be there today if I
felt I could perform my job in the way it should be done.
Many of the recent discussions regarding evaluation of new
drugs have focused on their safety. However, there are also
important issues with the evaluation of effectiveness,
especially regarding antibiotics. In 1962, the Food, Drug and
Cosmetic Act was amended to state there must be substantial
evidence of effectiveness from adequate and well-controlled
trials in order to justify the adverse events inherent with the
use of all drugs. In the absence of evidence of effectiveness,
any adverse effect, no matter how rare, is not justifiable.
The drug Ketek is a symptom of much larger problem. Over
the last 25 years, FDA has approved approximately 68 new drug
applications for ear infections in children, sinus infections
and bronchial infections in patients with underlying lung
disease. All of these drugs were approved based on so-called
``noninferiority'' trials. While the word ``noninferior''
strictly means ``not worse'', the purpose of these trials is in
fact to rule out an amount by which the new drug' effectiveness
may be worse than an old drug. Therefore, noninferiority trials
are really ``not too much worse'' trials. Showing a new drug is
potentially worse than an old drug when the effectiveness of
the old drug is unclear is like the Billy Preston song,
``nothing from nothing leaves nothing''. An evaluation of
previous placebo controlled trials shows that 12 of 17 studies
in sinusitis and 9 of 14 studies in bronchial infections lack
evidence of a benefit for antibiotics and the situation is
similar for ear infections. Based on these data, showing that
Ketek may be less effective than older drugs does not provide
evidence that Ketek is effective at all in sinus and bronchial
infections, and this was clear at the time the drug was
approved in 2004. Initiation of a noninferiority trial with
Ketek in ear infections in children is inappropriate and
unethical, as it exposes children to harm without the potential
to clearly provide evidence of benefits.
Noninferiority trials are justifiable in serious
infections where the benefits of antibiotics are large and
reproducible. However, even in serious diseases the trial must
be designed, performed and analyzed appropriately in order to
provide meaningful results. The major problem is that many of
the common safeguards in clinical trials that protect us from
drawing false conclusions are less useful in noninferiority
trials. For instance, if one performs a trial to evaluate a
drug in patients with pneumonia, but most of the patients
enrolled in the trial have the common cold, it is much easier
to make two drugs appear similar when in fact this says nothing
about the new drug' effectiveness in pneumonia. This is like
testing a new parachute against an older proven parachute, when
all the test subjects are jumping out a plane that is standing
still and only two inches off the ground. Everyone will do
well, but it says nothing about how the new parachute will
really work in a real life situation.
Lack of effectiveness is an even larger problem with
antibiotics than it is for other types of drugs. If a non-
antibiotic doesn't work, it only affects the person who takes
it. If an antibiotic doesn't work, it affects not only the
person who takes it, but can also affect other people who don't
take it by spreading resistance not only to that drug but to
other related drugs as well. Antimicrobial resistance is a
safety issue as lack of effectiveness can promote the very
problem of antibiotic resistance we are trying to combat.
We need new antibiotics to combat the inevitable increase
in antibiotic resistance, but approval of ineffective and
therefore inherently unsafe antibiotics is not an incentive for
drug development. After approval of numerous antibiotics whose
effectiveness is unclear, we have seen no boom in antibiotic
development, and in fact drug sponsors have exited this field.
Developing appropriate economic incentives to promote
development are the province of Congress, not the FDA.
We need to address these problems now. FDA needs to
require sponsors to perform superiority trials in self-
resolving diseases. Even in serious diseases, FDA needs to
require appropriately designed, conducted and analyzed
noninferiority trials to give clinicians the information they
need to make decisions for their patients. FDA needs to address
the issue of drugs that still carry approvals for self-
resolving diseases without evidence of effectiveness. FDA needs
to promptly publish new guidances based on appropriate
scientific and regulatory principles and remove the old
guidances from their Web site now, since they continue to
mislead drug sponsors.
The bottom line is this is about people, not about ``bad
bugs''. Most of us in this room have taken antibiotics or will
need to take them. We must preserve this precious resource that
has been one of the marvels of modern medicine by ensuring
these drugs are effective, safe, and used appropriately. Thank
you.
Answers to Submitted Questions
1. When did the issues with noninferiority trials first
become apparent to FDA managers?
These issues have been known for some time. At a recent
advisory committee on September 12, 2006, a senior FDA official
pointed out that drug sponsors knew about the issues with
noninferiority trials and that, in his words, this was ``not
hot news''. It was senior FDA officials who published some of
the first articles in the medical literature in the early 1980'
that address the problems with noninferiority trials. In 1985,
wording was added to the section in FDA regulations that
defines adequate and well-controlled trials to state, ``If the
intent of the trial is to show similarity of the test and
control drugs, the report of the study should assess the
ability of the study to have detected a difference between
treatments. Similarity of test drug and active control can mean
either that both drugs were effective or that neither was
effective. The analysis of the study should explain why the
drugs should be considered effective in the study, for example,
by reference to results in previous placebo-controlled studies
of the active control drug.''
2. Did FDA managers ever enforce these regulations with
antibiotics?
Over the last 8 years I can only remember one sponsor who
submitted a justification for doing a noninferiority trial, and
that was for an antifungal drug, not drugs like Ketek. At the
September 12 advisory committee another senior FDA official
pointed out that the drug sponsor had not, in his words, ``done
the mental exercise'' needed to scientifically justify this
kind of trial. Recently, after a letter from several members of
Congress raised issues about noninferiority trials, the
statistical team members began to send letters to drug sponsors
asking for a justification for noninferiority trials. One
division director expressed displeasure at them doing this. The
justifications sent in by many sponsors were not scientific
ones, but their reasoning was that FDA had allowed many of
these trials before, so that they should be allowed to continue
this practice.
3. You said that FDA managers knew that the evidence of
effectiveness for Ketek was lacking at the time it was approved
in 2004. Had there been prior discussions within and outside of
FDA about the issues with noninferiority trials?
Yes, there had been numerous discussions. In 2000, the
International Conference on Harmonization guidance E-10, titled
Choice of Control Groups and Related Issues in Clinical Trials
was first published. This guidance outlined many of the issues
with noninferiority trials. In addition, FDA held an advisory
committee in February of 2002 to specifically address the
issues of noninferiority trials, held advisory committees in
July of 2002 on ear infections, two workshops in November of
2002, an advisory committee on sinusitis in October of 2003,
and another workshop in April of 2004, and an internal
regulatory briefing in July of 2005. These issues again came up
at recent advisory committees in September and December 2006.
4. What were the results of these meeting?
At all these meetings there was scientific agreement that
noninferiority trials were not justifiable in self-resolving
diseases. FDA statisticians did lobby hard and got a change in
the FDA guidance on antibiotic development referred to as the
``Points to Consider'' document. However, sponsors continued to
submit applications based on noninferiority trials without an
accompanying scientific justification as specified in the
regulations. Regarding serious diseases, at the February 2002
advisory committee on developing drugs for diseases due to
resistant pathogens, the Office director at the time implied
that the only thing sponsors needed to obtain approval in
serious diseases due to resistant pathogens was ``a few well
characterized cases''. This seemed to contradict FDA' own
regulations about the need for adequate and well- controlled
trials. FDA regulations require some comparison with a control,
even if it is a comparison with a group of patients in the past
who did not receive treatment in what is called a
``historical'' control.
5. Did ignoring the regulations occur commonly?
I can only comment on the area in which I worked. It
seemed that there were other priorities other than following
the scientific principles spelled out in the regulations. It'
important to realize that the regulations are based in good
science, and they are not just rules for rules sake. But often
it was implied that the regulations were just a guide and they
FDA, in the managers words, ``had to be flexible''. Certainly
one can be flexible within what good science and the
regulations allow, but there is also a point where one can go
beyond what these principles allow as well. The major issue
seemed to be approving drugs for less serious diseases, which
are far more common, to provide an economic incentive for drug
sponsors to develop drugs for more serious diseases. Some FDA
managers also seemed to have the idea that FDA could not make
it ``too difficult'' for sponsors to do studies. Of course,
this depends on what you consider ``difficult'', which is
subject to opinion, not science. Sometimes it is challenging to
do an appropriate study that is meaningful, but this is far
better than exposing people to harm in a study that cannot
provide useful information.
6. Did you inform senior FDA officials of there problems?
Yes. I informed several levels of senior managers over the
span of 5 years that these issues were occurring.
7. Why did they not address the problem?
I was never certain as to why the issue was never
resolved. At several internal meetings, senior managers pointed
out that these noninferiority trials were not appropriate and
yet antibiotics continued to be approved on this basis.
9. Even after these meetings, were drugs for self-
resolving diseases still approved based on noninferiority
trials?
Yes. There were several drugs approved since 2000 for
these indications based upon noninferiority trials. At the
September 2006 advisory committee, the drug sponsor pointed out
that they felt ill used since other drugs were approved based
on noninferiority and they felt they should be approved also.
They specifically pointed to Ketek as an example of where a
drug had been approved based on noninferiority trials. One of
the issues is some FDA managers believe that once FDA has
agreed on a trial design, it cannot be changed. Section
505(b)(5)(C) of the Food Drug and Cosmetic Act states that FDA
can change the parameters of a study if ``a substantial
scientific issue essential to determining the safety or
effectiveness of the drug has been identified after the testing
has begun.
10. Do you think drug sponsors will do placebo controlled
trials in these diseases?
Yes. At the November 2002 workshop we held on
antimicrobial drug development, one drug company representative
stated that companies would be unwilling to do these trials,
but they would do them if FDA made it clear that they were a
regulatory requirement. That hasn't happened. And that same
person submitted an application a few years later for a drug
for ear infections in children based on noninferiority trials,
and few years after that submitted another application for a
different drug for sinusitis and bronchitis. You almost can't
blame companies if it' not made clear to them that
noninferiority trials are no longer acceptable. On the other
hand, however, companies clearly know these kind of trials are
not substantial evidence of effectiveness, yet they continue to
submit them.
11. Haven't some drug sponsors said that investigators will
not enroll patients in placebo controlled trials?
There have been 8 published placebo controlled trials in
sinusitis since the year 2000 and two published just last year
in ear infections so clearly people are doing these trials. If
an investigator does not wish to participate in these trials
they are free not to participate, but that does not mean FDA
should not insist on doing trials in a way that provides the
necessary information to evaluate drug effectiveness and
potential harms.
12. If investigators have been doing these trials, what
was FDA manager' response as to why they did not insist on drug
sponsors doing placebo controlled trials?
At meeting with drug sponsors, some sponsors insisted that
their investigators would not enroll patients in placebo
controlled trials. Of course, these investigators are free not
to participate in the trials if they wish, but the publication
of placebo controlled trials in medical journals shows these
trials can and are being done. The companies brought in experts
who insisted these trials cannot be done or would be difficult
to do. But allowing expert opinion to determine which trials
are done and how they are done sets us back to a time when
drugs were approved based on expert opinion alone. The hearings
at the time of the passage of the 1962 amendments and
subsequent court cases made it quite clear that clinician
opinion was not the standard upon which drug approval should be
based. FDA should taking a leadership role in advancing the
science and requiring trials that will answer important medical
questions, such as whether the drug is effective in the first
place. FDA has done so in the past in other therapeutic areas.
13. Don't we need drugs like Ketek for disease due to
resistant infections?
We do need new antibiotics, but we need them in serious
and life threatening diseases where resistance in a test tube
has the most impact on people. If it' not clear when and where
we need to use antibiotics in less serious disease, or whether
we need to use them at all, the impact of resistance is also
unclear. We have taken for granted that a measurement in test
tube must inherently mean something for patients, but that is
why we do trials, to see if what we find in the lab translates
into some meaningful benefit for patients. That is still
unclear in these less serious diseases. In addition, the
definition of resistance is not clear for many of these
diseases and it may overestimate the number of resistant
organisms, making drugs look ineffective when they are not.
14. How about people who are allergic to other drugs?
Wouldn't Ketek be an option for them?
For Ketek to be an option for any patient, even those who
are allergic to other drugs, it still have to be proven to be
effective first. It would not be useful to give an ineffective
drug to someone just because they have allergies. It is
important to realize that noninferiority trials do not show two
drugs are equal, and even in appropriately designed and
analyzed noninferiority trials, you might be giving up some
effectiveness for whatever other benefits the drug might have,
for instance improved safety. In the case of Ketek we just
don't know what those benefits are since we don't know if the
drug is effective in sinus and bronchial infections, and we
probably won't know if it is effective in ear infections if it
is studied in a noninferiority trial.
15. Who defines what organisms are called ``resistant''?
FDA defines resistance in the labeling for a drug when it
is approved. Over time, however, this definition may change as
the drug is used and more resistance may develop. There have
been many discussions over the last few years about how FDA
will interact with other non-governmental groups as to how
resistance will be defined. What is clear is that defining and
monitoring resistance is an important safety issue just like
other adverse events for other drugs. FDA need to approach
antibiotic resistance as a safety issue and change labeling
when necessary to make sure the definitions of resistance are
accurate. The changes should be based on adequate evidence and
not isolated case reports.
16. So when drugs organisms are called resistant when they
are not, does it cause doctors to use other antibiotics
instead?
Yes it does. And those antibiotics are usually newer,
which means that we have less experience with them in terms of
their safety, and they are usually more expensive. Taxpayers
may foot the bill for more expensive drugs that are really no
better than older drugs.
17. So for all these drugs approved without knowing that
they are any better than placebo, the American taxpayer is
still paying for these.
A. Yes, they are.
18. If noninferiority trials only rule out how much worse a
new drug might be compared to an old drug, why are we doing
these trials in situations where we are concerned the old drugs
don't even work any more because of resistance?
That is an important point. It is illogical even in
serious diseases to compare a new drug to an old drug when we
have concerns the old drug is no longer effective.
19 Yesterday the label for Ketek was changed to remove the
indications for sinusitis and bronchitis. What should be done
about the other drugs that carry labels for these indications?
FDA needs to clearly inform clinicians and patients that
the evidence of effectiveness for these drugs is insufficient.
That would not mean taking all those drugs off the market, as
most of those drugs are approved for other diseases like
pneumonia. FDA' own labeling regulations state, ``If there is a
common belief that the drug may be effective for a certain use
or if there is a common use of the drug for a condition, but
the preponderance of evidence related to the use or condition
shows that the drug is ineffective or that the therapeutic
benefits of the product do not generally outweigh its risks,
FDA may require that this section state that there is a lack of
evidence that the drug is effective or safe for that use or
condition.'' A statement such as this should be included in all
drugs that carry indications of sinus, ear and bronchial
infections as well as older drugs that include these
indications under the older name of lower respiratory tract
infections. This is not regulating the practice of medicine, as
some have asserted as clinicians can continue to use these
drugs where they see fit, but it does state a fact that there
has not been substantial evidence of effectiveness for these
drugs. It was concerning to hear a senior FDA official state at
the December 16 advisory committee that FDA will not address
these drugs unless there is a safety issue. Lack of substantial
evidence of effectiveness is a requirement according to the
FD&C Act, and these criteria are not meant to be applied
prospectively only, as court precedent has shown. Lack of
evidence of effectiveness is a safety issue, given the
inevitable spread of resistance and deaths from adverse events
without evidence of benefits. Since self-resolving diseases are
so common, a good proportion of the adverse events with
antibiotics occur in people who take them for self-resolving
diseases. Many of these people don't even have a bacterial
infection.
20. Why do clinicians believe these drugs to be effective
in treating human disease when so many placebo controlled
trials fail to show their benefits?
First, clinicians confuse mechanisms of action with
outcome. Because a drug kills bacteria in a test tube or even
in a person does not necessarily mean that the drug is helping
the person if they get better anyway without the drug, or if
the cure is worse than the disease in terms of adverse effects.
Secondly, the placebo controlled trials are not designed very
well, and people correctly point to those flaws, but
incorrectly state the drugs are effective until proven
otherwise. This goes against the basic medical premise of
``first do no harm''. Thirdly, some researchers have attempted
to combine these studies together in what is called a meta-
analysis. However, if you pool together flawed studies, you get
a flawed answer. A study in the New England Journal of Medicine
in 1997 shows that meta-analysis were contradicted by
subsequent large randomized trials almost half the time.
21. How would we avoid another Ketek?
FDA needs to operate with transparency and with
accountability. Managers need to make the final decisions on
drug approvals, but they need to make those decisions based
upon appropriate science and following FDA regulations. The
reviews for all approvals, including any non-approvals or
approvable actions for already approved drugs should be posted
on FDA' Web site and linked to clinicaltrials.gov where the
trials are registered within 7 working days of FDA taking an
action. FDA needs to take action on drug when there is a safety
or effectiveness issue even if sponsors do not initiate the
request. And there needs to be accountability for FDA staff who
do not follow the regulations or who attempt to intimidate of
bully other staff. Science is a process of discussion, and some
of the most momentous discoveries were made by people who did
not accept the status quo. FDA needs to have an environment
where those scientific discussions can take place without an
emotional overlay. It would help tremendously to have a
separate group evaluate drugs post-approval than the group who
evaluate drugs pre-approval. This would put checks and balances
into the system, and allow a fresh set up eyes, and might
stimulate more rigorous decision making if people knew their
decisions would be reviewed by both the public with the posted
reviews and by their peers. Finally, there needs to be no more
noninferiority trials in these self-resolving diseases and FDA
needs to take a leadership role in advancing the science of
clinical trials in infectious diseases.
----------
Testimony of Ann Marie Cisneros
Good morning Mr. Chairman and members of the Committee. I
am honored that you are giving me the opportunity to tell my
story.
My name is Ann Marie Cisneros, I am currently an
independent clinical research associate. I was trained in the
United States Air Force as a Medical Technologist, have a
Bachelors of Science Degree in Occupational Education from
Wayland Baptist University and a Masters of Business
Administration Degree from Pfieffer University.
I have worked as a clinical research associate for
approximately eight years. My first three years in this
industry I spent at PPDI, a Contract Research Organization,
where I monitored a number of protocols that included Study
3014. At the time of the 3014 study, I was a senior clinical
research associate and was tasked to assist with the monitoring
of Dr. Anne Kirkman-Campbell' site.
Dr. Kirkman-Campbell is currently serving a 57-month
prison sentence for fraud associated with Study 3014. In
addition she was ordered by the court to pay restitution to the
drug sponsor, Aventis, which had paid her $400 per patient
enrolled.
Mr. Chairman, based upon what I observed and learned in
monitoring the Kirkman-Campbell site, Dr. Kirkman-Campbell
indeed had engaged in fraud. But what the court that sentenced
her did not know is that Aventis was not a victim of this
fraud. On the contrary. Let me explain.
Even before conducting the Kirkman-Campbell site visit, a
number of ``red flags'' were apparent. I knew that Dr. Kirkman-
Campbell had enrolled over 400 patients or 1 percent of the
adult population of Gadsden, Alabama. (By comparison, another
site in Gadsden had enrolled just twelve patients.) In a recent
Quality Assurance audit by Aventis several Informed Consent
issues were noted as well as a significant under-reporting of
Adverse Events and no reports of Serious Adverse Events. No
patients had withdrawn from the study and no patients were lost
to follow up, an unusual occurrence given the number of
subjects. She enrolled patients within minutes of each other
and upwards of 30 patients per day. She enrolled patients at
times and on days when the office was closed..
Once we started reviewing patient charts, we discovered
that:
Every informed consent had a discrepancy.
Most of the consents looked like they had been
initialed by someone other than the patient.
A lot of the consents were dated by someone other
than the subject.
One consent was blatantly forged.
There were date discrepancies as to when patients
were enrolled in the study, had their blood drawn or signed
their consent.
Most patients diagnosed with bronchitis either
had no history of the ailment or did not have a ``chronic''
condition.
She enrolled her entire staff in the study.
Frankly, all Kirkman-Campbell seemed truly interested in
was getting more business from Aventis as an investigator. At
one point during my site visit, she told Aventis Project
Manager Nadine Guenthe that I could only stay if Nadine got her
other studies at Aventis. Nadine agreed. It is my understanding
that when the FDA audited the Kirkman-Campbell site, she was
participating in another Aventis clinical trial.
While at the site, I was so concerned about patient safety
I called Copernicus Independent Review Board to express my
concerns and seek guidance. An IRB, which is under contract to
the drug sponsor, has as its primary purpose patient advocacy.
It is allowed to contact patients directly and is duty-bound to
report to the FDA any unanticipated problems involving risks to
subjects and serious noncompliance with regulations. I spoke
with the president of the company and was told that, while she
shared my concerns, she preferred to wait and see what actions
Aventis took. I never heard from the IRB again. To my knowledge
Copernicus never did audit or blacklist the site, or report any
irregularities to the FDA.
I e-mailed a summary of my site visit findings to Robert
McCormick, head of quality assurance at PPD, and copied Aventis
personnel. I also participated in a teleconference between PPD
and Aventis at which I discussed issues identified in my site
visit. At some point after that I understand that Aventis took
site management responsibilities away from PPD because Dr.
Kirkman-Campbell would not cooperate with anyone but the
sponsor.
I subsequently left PPD but learned that the Kirkman-
Campbell site was being audited by the FDA. In preparation for
the audit, Aventis' Nadine Guenthe coached Dr. Kirkman-Campbell
with leading questions on how to explain away improper conduct.
Nadine would say, for example: ``Is the reason you enrolled so
many patients in one day because that is when your supply of
the drug came in?'' I was told about this by a trusted and
distressed former colleague at PPD who witnessed the prepping.
In my eight years in clinical research work, this is the
only instance I've come across of such bad behavior by a drug
sponsor.. I feel I can speak for those who agonized over this
situation when I say we are pleased that Dr. Kirkman-Campbell
is serving prison time for her actions. But what brings me here
today is my disbelief at Aventis' statements that it did not
know that fraud was being committed. Mr. Chairman, I knew it,
PPD knew it, and Aventis knew it.
Thank you for this opportunity to tell my story.
Answers to Submitted Questions
As of what date do you believe that Sanofi-Aventis
(Aventis) first knew that the problems at Dr. Kirkman-Campbell'
site constituted fraud?
I believe Aventis concretely knew of the fraud when their
own QA auditor, Rhanjan Khosla, audited the site. That was a
few weeks before my visit to the site in February 2002.
What is the basis for your belief that Aventis knew the
problems at Dr. Kirkman-Campbell' site constituted fraud?
The fraud was blatant, there was no attempt by the
Investigator to cover it up. Most research professionals and
especially employees of a Quality Assurance department receive
some level of fraud training. For Aventis to claim they didn't
recognize the sort of oddities described below constituted a
suspicion of fraud makes them either incompetent or not
completely honest.
Please remember that Aventis was never tasked with the
responsibility to prove fraud; the requirement is to report to
the FDA any site where fraud is merely suspected.
Please identify the particular circumstances, problems, or
events that you believe constituted fraud and of which Aventis
knew?
These events individually might have equaled GCP deviations
as is being claimed by Aventis. However, collectively, the
evidence is overwhelming the site was committing fraud.
The number of patients enrolled, 407 with no sub-
Investigator and only 3 study coordinators.
Forged consents.
Every informed consent was either initialed or
dated by someone other than the patient. (It is never
acceptable to forge anything on an Informed Consent)
Medical Charts consisting of one or two pages.
Every patient completing the study, adhering to
all study visits, being 100 percent compliant with study
medication.
Overwrites of dates and adding study diagnosis in
different color ink than what was used for the initial visit in
the medical chart.
The office staff would not speak with the
monitors.
Enrollment of patients within minutes of each
other, on times and days the office was closed and enrolling
patients when the site was completely out of study drug
(meaning sick patients would have to come back at a later date
to pick up the study drug)
Patients diagnosed with Acute Exacerbation of
Chronic Bronchitis that had never had bronchitis or a limited
history not meeting ``chronic'' definition.
The first several hundred patients were enrolled
with primarily Acute Sinusitis; when enrollment was closed for
that indication, the Investigator' remaining hundred or so
patients all had AECB. You would expect to see the enrollment
pattern intermingled, not all one group and then the other.
Significant under-reporting of Adverse Events and
Serious
Adverse Events given the number of subjects. This was an
indication that she was not following the patients after they
started taking the study medication.
c. Please identify the Aventis employees who were on notice
of the fraud you describe in response to question 1 (b).
Nadine Grethe
Rhanjan Khosla
Rhanjan' boss (head of QA department)
d. Please identify the employee of Pharmaceutical Product
Development, Inc. (PPD) who were on notice of the fraud you
describe in response to question 1 (b)
The following PPD employees diligently reported the fraud:
Beth Heding, CRA
Abby Wear, CRA
John Reynolds, MD
The following PPD employees were also aware of the fraud:
Stephanie Love, CRA
Robert McCormick, Head of QA
Roxann Evans, Project Manager
----------
Testimony of Steven E. Nissen, M.D.
My name is Steven E. Nissen, M.D. I am chairman of the
Department of Cardiovascular Medicine at Cleveland Clinic and
the President of the American College of Cardiology (ACC). My
testimony does not reflect the views of either Cleveland Clinic
or the ACC.
We face a crisis in public confidence in the Food and Drug
Administration (FDA) following an unprecedented series of
revelations about drug and device safety. The American people
no longer trust the FDA to protect their health. Unfortunately,
patients are increasingly suspicious of new therapies and
sometimes are reluctant to accept potentially life-saving
medications or devices. Decisive legislative action is now
essential to improve the safety of drugs and medical devices
and restore public confidence in this critically important
agency.
I have served on many FDA Advisory Panels and this
experience has undermined my confidence in the ability of the
agency to adequately protect the public health. In 2001, I
participated as a guest member of the Arthritis Advisory Panel
that recommended a warning label for cardiovascular risk for
Vioxx''. Under current law, the Agency must ``negotiate'' with
industry to make even simple changes in drug labels and FDA
officials frequently make inappropriate concessions to
pharmaceutical companies. Following the 2001 Advisory Board, it
took 14 months before the FDA could secure agreement from the
company to accept a weakly written warning. During this period,
patients and physicians were not appropriately warned about the
cardiovascular hazards of Vioxx''. When the label was
eventually modified, the wording was so weak that it did not
adequately inform physicians and patients of the potential for
Vioxx to cause harm.
In 2005, another disturbing personal experience brought
into sharp focus the inadequacies of the FDA in assessing new
drug applications. On September 9, 2005, officials from the
Endocrine and Metabolism Division presented a new diabetes drug
known as muraglitazar to an Advisory Panel for consideration of
approval. Because of a previous lawsuit by the advocacy group
Public Citizen, the FDA is required to publicly disclose the
``briefing materials'' for Advisory Panels.
Because of my interest in this class of drugs, I reviewed
the briefing documents posted on the Internet by the Agency on
September 8, the day before the public hearings. I observed
that this investigational drug seemed to lower blood sugar, but
I also noted that there was a striking excess of heart attacks,
strokes, and deaths in patients treated with muraglitazar
compared with placebo or other diabetes drugs. Based upon this
observation, I assumed that the Advisory Board would recommend
that the Agency not approve muraglitazar.
Yet astonishingly, the following day, Agency reviewers
presented the drug in a favorable manner, understating any
concerns about cardiovascular risk. This Advisory Panel, that
did not include any cardiologists, voted 8:1 to approve
muraglitazar, ending the panel meeting at 2 p.m. In Cleveland,
I watched the news reports, complete with predictions from
financial analysts that this drug would achieve annual sales
exceeding $1 billion.
I felt compelled to act. My statistician and I rapidly
downloaded the FDA material available from the Internet and
performed our own independent analysis of the risks and
benefits of this drug. We concluded that muraglitazar doubled
the risk of death, heart attack stroke and congestive heart
failure. I phoned the editors of the Journal of the American
Medical Association, who treated our findings as a public
health emergency. Peer reviews were secured in a matter of
days, and JAMA posted the manuscript on their Web site October
20, just 7 weeks following the FDA advisory panel meeting.
Shortly prior to our publication, the FDA issued an
``approvable'' letter to the sponsor. Following this
publication, the pharmaceutical company developing muraglitazar
abruptly ceased all further development. Fortunately, this drug
will never threaten the public health, but frankly, it was a
close call.
We were able to independently analyze the risks of
muraglitazar because the drug was presented to an advisory
panel. For many new drugs, the agency approves them without
public disclosure of the key findings in pivotal clinical
trials. When drugs are presented to Advisory Panels, the agency
frequently provides an uncritical presentation that fails to
adequate inform the advisory panel members of any internal FDA
concerns.
This phenomenon was very evident during a meeting of Drug
Safety and Risk Management Advisory Board of the FDA, which met
February 9, 2006, to review drugs used to treat Attention
Deficit Hyperactivity Disorder or ADHD. I was asked to serve on
this Advisory Panel to help evaluate the cardiovascular risks
of these drugs, most of which are amphetamines or amphetamine-
like agents. These drugs are closely related to methamphetamine
or ``peed'', a major drug of abuse.
At nearly all Advisory panel meetings, the FDA provides a
list of questions to the panel members designed to assist in
discussions and to guide the formulation of an action plan.
When the Advisory Board briefing materials arrived, I was
rather surprised by the questions that the Agency intended to
ask. In this case, the FDA did not request the committee to
consider the risks of the ADHD drugs, nor did they ask us to
comment on the need to change labeling. Instead, they asked the
committee to discuss how the Agency might study the class of
drugs.
During the hearings, we learned that the ADHD drugs
increase blood pressure and we heard reports indicating that
approximately 25 children has suffered sudden cardiac death
after taking these drugs, occasionally after he first dose.
ADHD drugs are closely related to ephedra, a drug that the FDA
has sought to ban from OTC products. We also learned that 4
million Americans take ADHD drugs, including 1.5 million
adults, and up to 10 percent of 5th grade boys.
By mid-afternoon, I had heard enough. I departed from the
FDA' carefully orchestrated agenda and introduced a motion
proposing that the committee recommend a black box warning for
the ADHD drugs. Surprisingly, the motion passed by an 8 to 7
vote. Agency officials looked horrified and quickly called a
news conference, where they defended the safety of the drugs
and sought to undermine the recommendations of the Advisory
Committee.
Some months later, the FDA actually did write new
warnings. But it took a rogue advisory committee to motivate
the Agency to act.
What the solutions to improving the performance of the
FDA?
The FDA operates in a ``culture of secrecy.'' When studies
reveal toxicity or lack of efficacy, the Agency does not
release the results and the findings are often not published,
thereby denying patients and physicians access to vitally
important safety information.\1\ This approach is antithetical
to the public health and undermines good scientific practice.
Free and open access to all relevant information is required to
enable physicians to thoughtfully select therapies for their
patients. The FDA withholds findings in deference to industry'
claims that such information constitutes ``trade secrets.'' In
my view, this is misguided. When a patient volunteers to
participate in a drug or device study, there is an implicit
moral obligation that the patient' participation will benefit
medical science and their fellow citizens.
Most relevant information on drug safety is readily
available to the FDA through ``study reports'' routinely
submitted by pharmaceutical and device companies. However,
these reports are usually not widely circulated within the
agency and invariably not released to the public or scientific
community. It remains theoretically possible to access
submitted study reports via a Freedom of Information Act (FOIA)
request, but we are usually unaware of the existence of
relevant studies. Accordingly, no one ever requests such
information.
There are innumerable examples of drug safety information
that took years to reach our attention despite reasonable
knowledge of the problem within the Agency. Examples include
Baycol, Ketek, Vioxx, and antidepressants risks in children.
During the months to years in which safety information was not
publicly available, many patients suffer complications
needlessly. Often, the FDA knew there was a problem. Those of
us who prescribe drugs did not.
This lack of transparency dramatically worsened after
passage of the Prescription Drug User Fee Act (PDUFA)
legislation. Although a well-intentioned effort to speed drug
development, PDUFA has seriously undermined the effectiveness
and transparency of the Agency. PDUFA makes industry, not the
American public, the FDA' primary stakeholder and creates a
conflict in loyalty for FDA employees. The time pressure
induced by PDUFA deadlines often forces the FDA to make hurried
decisions under conditions of considerable uncertainty,
resulting in poor outcomes. The premature Advisory Board
hearings on muraglitazar represent an excellent example of this
phenomenon.\2\ Good regulatory decisions are not performed in
an environment where a ``rush to judgment'' is forced by
artificial legally-mandated deadlines.
We should fund the FDA from public funds, not fees paid by
the regulated industry. Virtually, every American takes one or
more medications, so drug safety affects all of us. Yet the
annual expenditure for drug regulation approximates only about
$2 per person. We cannot expect outstanding performance for an
Agency operating on an inadequate budget. The Agency needs more
staff to adequate supervise a huge and complex industry. Salary
levels should be adequate to attract the most skilled
professional staff. The current flight of talented staff from
the Agency must be reversed. It takes many years of experience
to perform complex regulatory tasks in a skillful fashion. The
individuals currently leaving the FDA are simply irreplaceable.
The Agency has suffered from instability in leadership
extending to the highest levels. Regardless of which party
holds the White House, the FDA needs a passionate and committed
leader who will resist pressure to make regulatory decisions
based upon political expediency, rather than scientific
evidence. The successful efforts by political forces to prevent
or delay approval of over-the counter sales of ``Plan B'', an
emergency contraceptive for women, seriously undermined morale
at the Agency and must not be repeated. This Agency is too
important to allow political expediency to influence decisions.
We need new laws to strengthen the authority of the FDA.
Currently, the Agency must ``negotiate'' with industry to make
even simple changes in drug labels. Companies routinely make
commitments to perform Phase IV studies, but never actually
launch the promised clinical trials and the agency is powerless
to act. The requirement for the consent of the regulated
industry to change drug labels is simply bad regulatory
practice. Professional staff at the Agency should decide the
content of labels, not pharmaceutical and device companies.
Some industry practices have seriously undermined drug
safety. This problem of ``negative publication bias''--the
practice of suppressing and never publishing unfavorable
studies has a catastrophic effect on the drug development
system.\3\,\4\ When drugs show serious toxicity in patients,
the results are rarely published. Accordingly, other companies
expose patients to closely related drugs without knowing that
study of a similar agent showed significant harm. I am aware of
a class of drugs where more than a dozen compounds showed
serious toxicity, resulting in termination of development, but
without a single publication of results. When studies are not
published, we learn nothing from the experiment and make the
same mistakes over and over again. This practice also
significantly increases the costs of drug development (and
ultimately drug prices), because companies continue to follow
non-productive routes to drug development.
The post-marketing surveillance system for drugs and
devices functions poorly. Adverse event reporting is voluntary
and studies show that only 1 to 10 percent of serious adverse
events are ever reported to the Agency. Accordingly, the actual
incidence of serious or life-threatened complications cannot be
calculated accurately. There are many examples where the
failure of the FDA' Averse Event Reporting System (AERS)
resulted in serious harm to our citizens. Baycol'' caused
serious muscle toxicity at rate nearly 100 times greater than
other cholesterol lowering drugs in this class.\5\ Yet it was
marketed for years before this hazard became known and the drug
withdrawn.
I believe that Direct to Consumer (DTC) Advertising
requires decisive legislative action. The standard for
acceptable DTC advertising should require demonstration of a
compelling public health advantage for this type of
communication. Drugs with an addiction potential, such as
sleeping medications, should be specifically prohibited from
consumer advertising.
We must address another critical drug safety problem not
addressed in this bill--the nutraceutical industry, currently
not subject to regulatory scrutiny. This multi-billion dollar
industry sells so-called ``dietary supplements'' that are often
worthless and sometimes harmful.6 Patients take such drugs
instead of effective medications with catastrophic implications
for their health. I recently saw a patient who suffered a heart
attack after switching from prescription niacin, a drug that
raises HDL, the good cholesterol, to ``no flush'' niacin, a
fraudulent therapy with no favorable effects. His cholesterol
levels rapidly became abnormal after switching, resulting a
very bad outcome.
We need to amend or repeal the Dietary Supplement Health
and Education Act (DSHEA) of 1994. By moving dietary supplement
out of the regulatory scrutiny of the FDA, we are inviting a
public health catastrophe.
It is important for the Congress to recognize that there
are many fine and dedicated public servants working within the
FDA. However, their concerns fail to reach advisory committees
because of the actions of their supervisors, who adopt a less
courageous approach.
The Congress must now fully evaluate the deficiencies
within the FDA. Your engagement to investigate the problem and
take decisive action can improve this Agency. The 300 million
American who rely upon drugs to stay healthy are counting on
you to take action.
My recommendations for a 10-point program to fix this
vitally important agency:
(1) Insulate the FDA from political influence. Let
scientific data determine the outcome of regulatory decisions,
not politics.
(2) Install FDA leadership with a passion to properly
balance the vital need for speedy drug approval with
appropriate vigilance on safety.
(3) Create an ``open access'' system that allows the
public and the scientific community access to study reports to
enable full discussion of risks and benefits of therapies.
(4) Require all trials involving human subject to be
registered and either published or publicly disclosed.
(5) Repeal PDUFA and increase public FDA funding to enable
a more thorough, rapid and accurate review of new drug
applications and the safety of existing drugs.
(6) Strengthen the laws to allow the FDA to unilaterally
re-label drugs when issues of safety of efficacy arise.
(7) Consider stiff civil monetary penalties, and in
extreme cases, criminal penalties for withholding vital safety
findings from the Agency.
(8) Restructure the post-marketing surveillance system to
enable better identification of emerging safety issues.
(9) Restrict DTC advertising to messages that offer a
compelling public health benefit.
(10) Enable the FDA to regulate dietary supplements and
nutraceuticals.
These measures need not slow drug development. If we
improve drug safety oversight, the increased vigilance will
inspire confidence and allow us to bring new medicines to
patients more quickly, because we will have a better ``safety
net.''
References
(1) Avorn J. Dangerous deception--hiding the evidence of
adverse drug effects. N Engl J Med. 2006 Nov 23;355(21):2169-71
(2) Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar
on death and major adverse cardiovascular events in patients
with type 2 diabetes mellitus. JAMA. 2005 Nov 23;294(20):2581-
6. Epub 2005 Oct 20
(3) Smith ER.The importance of negative and neutral
clinical trials. Can J Cardiol. 2004 Oct;20(12):1267-8.
(4) Hensley S, Abboud L. Medical research has 'black
hole': negative results often fail to get published in
journals; some blame drug industry. Wall St J (East Ed). 2004
Jun 4;:B3
(5) Staffa JA, Chang J, Green L.Cerivastatin and reports
of fatal rhabdomyolysis. N Engl J Med. 2002 Feb 14;346(7):539-
40.
(6) Fontanarosa PB, Rennie D, DeAngelis CD.The need for
regulation of dietary supplements--lessons from ephedra.JAMA.
2003 Mar 26;289(12):1568-70. Epub 2003 Mar 10.
(7) DeAngelis CD, Drazen JM, Frizelle FA, Haug C, Hoey J,
Horton R, Kotzin S, Laine C, Marusic A, Overbeke AJ, Schroeder
TV, Sox HC, Van Der Weyden MB; International Committee of
Medical Journal Editors.Is this clinical trial fully
registered? A statement from the International Committee of
Medical Journal Editors. JAMA. 2005 Jun 15;293(23):2927-9.
----------
[GRAPHIC] [TIFF OMITTED] T5502.001
[GRAPHIC] [TIFF OMITTED] T5502.002
[GRAPHIC] [TIFF OMITTED] T5502.003
[GRAPHIC] [TIFF OMITTED] T5502.004
[GRAPHIC] [TIFF OMITTED] T5502.005
[GRAPHIC] [TIFF OMITTED] T5502.006
[GRAPHIC] [TIFF OMITTED] T5502.007
[GRAPHIC] [TIFF OMITTED] T5502.008
[GRAPHIC] [TIFF OMITTED] T5502.009
[GRAPHIC] [TIFF OMITTED] T5502.010
[GRAPHIC] [TIFF OMITTED] T5502.034
[GRAPHIC] [TIFF OMITTED] T5502.035
[GRAPHIC] [TIFF OMITTED] T5502.036
[GRAPHIC] [TIFF OMITTED] T5502.037
[GRAPHIC] [TIFF OMITTED] T5502.038
[GRAPHIC] [TIFF OMITTED] T5502.039
[GRAPHIC] [TIFF OMITTED] T5502.040
[GRAPHIC] [TIFF OMITTED] T5502.041
[GRAPHIC] [TIFF OMITTED] T5502.042
[GRAPHIC] [TIFF OMITTED] T5502.043
[GRAPHIC] [TIFF OMITTED] T5502.044
[GRAPHIC] [TIFF OMITTED] T5502.045
[GRAPHIC] [TIFF OMITTED] T5502.046
[GRAPHIC] [TIFF OMITTED] T5502.047
[GRAPHIC] [TIFF OMITTED] T5502.048
[GRAPHIC] [TIFF OMITTED] T5502.049
[GRAPHIC] [TIFF OMITTED] T5502.050
[GRAPHIC] [TIFF OMITTED] T5502.051
[GRAPHIC] [TIFF OMITTED] T5502.052
[GRAPHIC] [TIFF OMITTED] T5502.053
[GRAPHIC] [TIFF OMITTED] T5502.054
[GRAPHIC] [TIFF OMITTED] T5502.055
[GRAPHIC] [TIFF OMITTED] T5502.056
[GRAPHIC] [TIFF OMITTED] T5502.057
[GRAPHIC] [TIFF OMITTED] T5502.058
[GRAPHIC] [TIFF OMITTED] T5502.059
[GRAPHIC] [TIFF OMITTED] T5502.060
[GRAPHIC] [TIFF OMITTED] T5502.061
[GRAPHIC] [TIFF OMITTED] T5502.062
[GRAPHIC] [TIFF OMITTED] T5502.011
[GRAPHIC] [TIFF OMITTED] T5502.012
[GRAPHIC] [TIFF OMITTED] T5502.013
[GRAPHIC] [TIFF OMITTED] T5502.014
[GRAPHIC] [TIFF OMITTED] T5502.015
[GRAPHIC] [TIFF OMITTED] T5502.016
[GRAPHIC] [TIFF OMITTED] T5502.017
[GRAPHIC] [TIFF OMITTED] T5502.018
[GRAPHIC] [TIFF OMITTED] T5502.019
[GRAPHIC] [TIFF OMITTED] T5502.020
[GRAPHIC] [TIFF OMITTED] T5502.021
[GRAPHIC] [TIFF OMITTED] T5502.022
[GRAPHIC] [TIFF OMITTED] T5502.023
[GRAPHIC] [TIFF OMITTED] T5502.024
[GRAPHIC] [TIFF OMITTED] T5502.025
[GRAPHIC] [TIFF OMITTED] T5502.026
[GRAPHIC] [TIFF OMITTED] T5502.027
[GRAPHIC] [TIFF OMITTED] T5502.028
[GRAPHIC] [TIFF OMITTED] T5502.029
[GRAPHIC] [TIFF OMITTED] T5502.030
[GRAPHIC] [TIFF OMITTED] T5502.031
[GRAPHIC] [TIFF OMITTED] T5502.032
[GRAPHIC] [TIFF OMITTED] T5502.033
Answers to Submitted Questions for David B. Ross, M.D.
1. Why was liver damage in a single patient in the Ketek
clinical trials so alarming?
First, the damage in this patient appeared very similar to
that caused by another antibiotic called Trovan that was linked
to dozens of deaths due to liver failure in the 1990' (and
which was essentially withdrawn from the market). Reviewers
were very concerned that we might be looking at a reprise of
the Trovan situation with Ketek, in a setting where Ketek did
not appear to have dramatic life-saving effects.
Second, there' a statistical rule of thumb that if a side
effect occurs in 1 patient out of a thousand, you need 3000
patients to be sure of finding it. There were roughly 3000
patients in the original Ketek trials, and one developed severe
liver damage. So, the true rate might be as high as 1 case out
of every 1000 patients exposed. There are roughly 100 million
antibiotic prescriptions written every year in this country for
respiratory tract infections. If Ketek had 10 percent of the
share for that market, that side effect would translate into
10,000 cases a year of severe liver damage, and potentially
hundreds or thousands deaths a year.
2. What is the risk of liver failure with Ketek?
A. It is difficult to say with great certainty because of
the poor quality of the data available, but the FDA' Office of
Drug Safety estimated in May 2006 that the reporting rate (the
number of cases reported divided by the number of
prescriptions) is 23 reports/10 million prescriptions. By
comparison, Trovan was associated with 58 reports/10 million
prescriptions, while the next most riskiest drug compared to
Ketek in the ODS analysis, had a rate of 6.6 reports/10
million.
If we use the rule of thumb that only one out of ten cases
of severe liver injury is reported (an underreporting rate of
90 percent; the true underreporting rate is probably higher,
based on a French population-based study by Sgro et al.
published in 2002 in the journal Hepatology, as well as the
FDA' own estimates of how often adverse events are reported),
the incidence rate of acute liver failure with Ketek would be
about 1 case out of every 43,000 prescriptions. According to
Dr. Peter Honig, a former ODS director quoted in the May 2001
issue of FDA Consumer, a rate of about 1/50,000 is the usual
cut-off for withdrawing a drug from the market or severely
limiting its use.
3. Why the concern over liver failure with Ketek if other
drugs such as acetaminophen are more common causes of liver
failure?
Acetaminophen causes about half of all cases of drug-
induced liver failure in this country, but the vast majority of
these cases happen because of overdoses of acetaminophen or
taking it with alcohol. Avoiding this situation greatly lessens
the risk of liver failure with acetaminophen. Ketek can cause
severe liver injury just with a single dose even in patients
with no previous liver problems. There is no way to lessen the
risk with Ketek. Second, acetaminophen is used much more than
is Ketek, leading to many more opportunities for acetaminophen
poisoning. Thus, the risk of liver failure with Ketek (when
used as directed) is much higher than the risk with
acetaminophen (when used as directed)
4. What exactly was the misconduct found in the safety
study?
The largest enroller was convicted of fraud. The second
and third largest enrollers had significant violations of
procedure that called into question the reliability of data
from those sights. Of note, the third largest enroller was
arrested shortly after the study on cocaine and weapons
possession charges--not the type of study physician FDA likes
to see conducting trials.
5. What happened to the criminal investigations?
One doctor was convicted of fraud. From what I've been
told, a second doctor refused to turn over his records, and FDA
dropped the case. A third doctor was still under investigation
the last I was aware. A fourth doctor had very suspicious
findings (the doctor supposedly enrolled 90 patients in a town
of about 190 adults), but there was not enough evidence to
prosecute.
6. At the December 2006 Advisory Committee meeting,
Aventis said that the fraud by this doctor had been
``sophisticated.'' Was that true?
No. This was a blatant act of fraud that should have been
evident to Aventis' clinical trial team.
7. What reason is there to think the company might have
known of and been covering up fraud?
PPD warned Aventis about its lead enroller, both in terms
of suspicious behavior and a statistical analysis that showed
splitting of clinical samples. Aventis took over the
statistical analysis, and dismissed the problems; the project
manager who did this was the overall project manager for the
study. There was another study site in the same town as the
lead enroller that followed all the rules--this site only
enrolled 12 patients, compared to over 400 at the lead
enroller. It would have been impossible for Aventis to miss the
contrast between the two. Aventis failed to tell FDA about the
problems at the site until five months after they resubmitted
their NDA.
8. What kind of warnings did FDA managers get about
possible fraud on the part of the company?
In fall 2002, there were multiple warnings about fraud on
the part of individual doctors in the study. In December 2002,
the company admitted not telling the FDA about knowing of
``problems'' at the site of the physician who was convicted. In
April 2003, FDA managers were told that when FDA investigators
had demanded records from the company, the company had supplied
them with much of the text blacked out. Finally, in July 2003,
FDA managers received a briefing from FDA criminal
investigators about their suspicions about the company, and
recommending a task force to investigate the possibility of
systematic fraud.
9. Did the FDA start that investigation?
No. It did not start an investigation until Ketek hit the
news in 2006, at which it assigned an investigation to a ``task
force'' consisting of a single agent.
10. What is the current status of the FDA investigation
into Ketek?
Essentially dead. FDA had one agent, who was new to FDA
and had no experience in clinical trial fraud, working on the
case along with many others he was responsible for. He left the
FDA recently and to the best of my knowledge, no one has been
reassigned to it.
11. Do you know if the line agent whom Senator Grassley is
seeking to interview is willing to talk to Congress?
Yes, he is, but FDA won't let him.
12. Is it true that the FDA couldn't tell the advisory
committee about the problems because there was an open
investigation?
No. First, by their own admission, FDA managers did tell
the committee 8 weeks later in a closed session, when there was
still an open investigation; if FDA told the committee then,
FDA could have told them in January--before the committee
voted. Second, all the members of the committee were Special
Government Employees and were cleared to hear this information.
Third, people in OCI have told me that the investigation would
not have been compromised by telling members of the AC in
closed session.
13. Did FDA officials mislead the advisory committee that
just heard about Ketek in December?
Yes. First, they told the committee that they had stumbled
on the fraud as a result of routine inspections--only the first
one could be seen as routine (and even then there were
suspicions before the site was inspected). Second, they told
the 2006 committee that they couldn't have told the 2003
committee about the misconduct issues. That was untrue.
14. Were other reviewers pressured?
Yes. According to Sen. Grassley' report, the statistical
reviewer on the safety study was instructed to present the
results publicly even though he protested and thought the
committee needed to be told about the misconduct issues. The
primary medical reviewer who ended up recommending approval
told me that he had been instructed not to look at records from
the company that it was required to submit as part of the fraud
investigation, even though that was supposed to be part of his
review.
15. Did anyone else on the review team review those
records and prepare a written report?
To the best of my knowledge, no. I had the necessary
authorization to look at them myself, and did, but I was not
asked to be part of the review team and so couldn't prepare a
review.
16. What has happened to the FDA managers who were
involved with Ketek?
My division director is still in her position. Her
supervisor, who decided to allow the safety study to be
presented without mentioning concerns over fraud, and who
approved Ketek, was promoted last year to be director of
pandemic influenza planning for the FDA. His supervisors are
still in their positions.
17. Why was the liver failure death important in February
2005 if only one patient had died?
First, studies have shown that most adverse events are
never reported, so that a report of one fatal case probably
means there are many others that haven't been reported. Second,
the appearance of this case so soon after the drug launch is
very concerning-- it's completely consistent with a relatively
high risk of liver damage from Ketek. Third, the fact that the
case occurred in an otherwise healthy young man is not only
tragic, but suggests that Ketek is dangerous to people with
normal livers. Finally, appropriate follow-up would have
revealed that there were multiple cases of Ketek-induced liver
failure at the same medical center; the occurrence of a cluster
like that would be a tip-off that there may be many unreported
cases.
18. Why do you say that Ketek is much more dangerous than
other antibiotics?
A consult from FDA' Office of Drug Safety in May 2006
found that Ketek had a reported rate of acute liver failure 4-
11 times that of comparable antibiotics.
19. Aren't those from post-marketing reports that are
unreliable?
The magnitude of these differences is so huge that it
would be difficult to explain by differences in things other
than the drugs' relative risks. A randomized controlled trial
would be better--but that was supposed to be the point of doing
the original safety study.
20. Would you prescribe Ketek?
No. I do not believe it offers any advantages over other
antibiotics for the same infections, I don't believe that it
has acceptable risks, and given the unresolved fraud issues
with this application, I do not believe that its efficacy and
safety have been established.
21. A recent opinion piece by a former FDA reviewer in the
Wall Street Journal of February 12 claimed that physicians
attempting to obtain access to investigational drugs for
patients with life-threatening diseases such as cancer have to
go through hurdles with regard to manufacturing, statistical,
and clinical questions that are akin to an IRS audit. Is this
true?
A. No. This claim is flatly incorrect. Physicians seeking
approval of emergency or single-patient Investigational New
Drug Applications (IND) for individual patients typically
piggy-back their request onto an existing IND from a commercial
drug sponsor. The FDA' Oncology Office alone approves hundreds
of such requests every year; the typical request is granted in
24 hours. In fields such as infectious diseases where such
requests are made in the setting of acute disease, the approval
time typically takes an hour or less; I personally approved
dozens of such requests, and never turned one down. Situations
where such requests are turned down are unusual and generally
involve situations where a physician is requesting an
investigational therapy when standard therapies known to be
safe and effective are available and have not been tried.
22. How would you fix the problems with the FDA that Ketek
revealed?
A. (1) Mandate (and fully fund) the use of reliable post-
marketing safety data sources, such as observational data bases
by FDA, (2) Remove the line authority for post-marketing
regulation from the Office of New Drugs and give it to an
Office of Drug Safety, either formed as a new center, or based
on the current Office of Surveillance and Epidemiology. Just as
OND now regulates pre- marketing with consults from OSE, ODS
should regulate post-marketing with a consult from OND.,
(3) Make FDA managers criminally liable for coercion of
reviewers, and make senior managers liable for failure to
appropriately investigate and discipline managers who commit
coercion, and (4) Mandate (and fully fund) posting of all FDA
reviews immediately after a regulatory action is taken. Reviews
should not be redacted except for proprietary manufacturing
information. 11
Answers to Submitted Questions from Mr. Barton to David Ross, M.D.
1. Does the FDA hold periodic meetings called regulatory
briefings?
a. If yes, please describe these briefings.
These are internal meetings held to discuss a regulatory
question of current interest, with the goal of obtaining
guidance from FDA managers; usually the topic is a specific New
Drug Application (NDA) or Biologic Licensing Application (BLA)
that is under review (or a supplement to such an application).
In the Center for Drug Evaluation and Research (CDER,
regulatory) briefings are called at the discretion of the
division or Office of Drug Evaluation (ODE) in which the
submission is being reviewed. In CDER' Office of New Drugs
(OND), the audience typically consists of the review team and
upper management in the review division and ODE, along with
office and division directors from OND; occasionally,
management from other CDER Offices (e.g., Office of
Biostatistics) will attend. The meeting is generally chaired by
the director or deputy director of OND, although in some
instances the director or deputy director of CDER will chair
the meeting. Materials for the briefing will consist of a slide
presentation and a briefing document or documents, which are
distributed by e-mail in advance of the meeting. The format is
generally a presentation of the relevant regulatory and
scientific background, ending with key questions. The
regulatory issues are then discussed. A project manager will
prepare written minutes, summarizing any conclusions; these are
distributed to attendees.
b. Do you believe regulatory briefings serve as an
opportunity for different views or questions to be heard on
drug safety?
In my experience, upper management (division directors and
above) appears to feel free to offer their views at these
briefings. I do not believe the environment is one that
encourages primary reviewers or team leaders to speak freely,
although there is no formal bar to their doing so. The best
illustration I know of this is a regulatory briefing held in
April 2006 on an supplemental NDA for daptomycin (Cubicin), for
which the primary review team had recommended nonapproval, and
division and office management were exerting pressure to
approve the application. (Of note, the managers involved were
the same as on the Ketek NDA). In order to encourage free
discussion by the primary review team, the director of OND, Dr.
John Jenkins, had to make explicit statements that any attendee
who wished to speak could do so; Dr. Jenkins cited this event
in an e-mail to me sent in May 2006. The need for an explicit
statement that reviewers should feel free to speak up at an
internal meeting suggests strongly that there is a culture at
CDER that discourages free exchange of views by reviewers when
they are aware that management holds a different opinion.
2. Do you agree with the Food and Drug Administration (FDA)
Advisory Committee recommendation of December 15,2006, to limit
Ketek's approved indication to community acquired pneumonia?
I agree with that recommendation, and I feel the Committee
did an outstanding job of weighing the scientific evidence
presented to it by the Applicant and the FDA. However, I will
note that their recommendation was made without consideration
of the questions of data and application integrity that exist
for this NDA; a consideration of these issues might have led to
a recommendation that marketing of Ketek be suspended until the
validity of data presented to the Committee had been
determined. It should be noted that the FDA permitted the
Applicant to present data to the Committee that had not been
submitted to or reviewed by the FDA; the Committee' vote to
recommend continued marketing of Ketek for community-acquired
pneumonia may have been influenced by presentation of this
unvetted data.
3. Do you agree with FDA's announced labeling change of
February 12, 2007, for Ketek?
No. First, the Agency has not publicly provided any
scientific rationale for its label change, such as a posted
review. Second, the Agency disregarded the Committee' explicit
recommendation to add a Black Box warning regarding visual
adverse events. Third, and most importantly, the unresolved
fraud issues surrounding this application make any current
determination of risk and benefit for Ketek invalid; rather
than relabel the drug, the Agency should suspend its marketing
until such time as the application integrity issues for this
NDA have been resolved.
4. In your written testimony, you stated that FDA managers
ignored warnings that Ketek was more dangerous than comparable
antibiotics. In a May 1, 2006, Wall Street Journal article
(attached), Dr. John Jenkins of the FDA stated that Ketek's
liver-related problems look ``not all that different than we
would see for other antibiotics' for similar infections.'' Do
you agree with Dr. Jenkins' statement?
No. In the same month that he gave this interview, CDER'
Office of Office of Surveillance and Epidemiology (OSE) found
that the reporting rate for acute liver failure associated with
Ketek ranged from 3.5--11.5 times that of other antibiotics
used for similar infections; the rate for Ketek was 23 cases of
ALF/10 million exposures, while for Avelox' (moxifloxacin) it
was 6.6 cases/10 million, and for Levaquin (levofloxacin), it
was 2.1 cases/10 million; for the macrolide class that Ketek
was supposed to replace, the rates were 4.2 cases/10 million
(clarithromycin; Biaxin) and 3.7 cases/10 million
(azithromycin; Zithromax). While there are uncertainties
surrounding these estimates, differences in adverse event rates
adjusted for usage and severity of infection that are greater
than 3-fold generally are due to true differences in incidence
rate, rather than unknown factors that bias the estimates. By
way of comparison, the ALF reporting rate for trovafloxacin, an
antibiotic removed from the market in the 1990's for ALF, was
58 cases/10 million, only 2.5 times that of Ketek.
Dr. Jenkins has never provided a detailed scientific
explanation of the rationale for his statement. I am unclear as
to how a rate of 23 is ``not all that different'' from a rate
of 6.6.
5. To your knowledge, what is the best estimate of the
actual incidence rate of liver toxicity in the patient
population using Ketek and why do you consider it to be a
credible estimate?
It is important to remember that most liver adverse events
are never reported (please see attached paper by Sgro et al.
(Hepatology 2002; 36:451-5, which found that only one out of
every 16 liver adverse events was reported in a population-
based survey). The OSE consult mentioned above found a total of
35 serious adverse events reported in 5.3 million exposures, a
rate of 1 event/150,000 exposures. If one makes the
conservative assumption that serious events are twice as likely
to be reported as routine adverse events, so that for every one
reported event, there are eight actual events, the incidence
rate of serious liver toxicity with Ketek is approximately 1
event/20,000 exposures. This is in agreement with an estimate
by Dr. William Lee, one of the world' leading authorities of
drug-induced liver injury, a consultant to the FDA, and a
participant in the December 2006 Advisory Committee meeting on
Ketek. Dr. Lee gave as his estimate of the incidence rate of
Ketek-associated liver toxicity leading to hospitalization as
1/20,000-1/30,000 at the meeting (see www.fda.gov/ohrms/
dockets/ac/06/transcripts/2006-4266t1-part4.pdf, p. 400
(browser document p. 100 of 147)). Dr. Lee is Meredith Mosle
Distinguished Professor in Liver Disease at the University of
Texas Southwestern Medical Center; his address is UT
Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd,
Dallas, Texas 75390-8887; his telephone number is (214) 648-
3323; and his e-mail address is [email protected].
[GRAPHIC] [TIFF OMITTED] T5502.063
[GRAPHIC] [TIFF OMITTED] T5502.064
[GRAPHIC] [TIFF OMITTED] T5502.065
[GRAPHIC] [TIFF OMITTED] T5502.066
[GRAPHIC] [TIFF OMITTED] T5502.067
[GRAPHIC] [TIFF OMITTED] T5502.068
[GRAPHIC] [TIFF OMITTED] T5502.069
[GRAPHIC] [TIFF OMITTED] T5502.070
[GRAPHIC] [TIFF OMITTED] T5502.071
[GRAPHIC] [TIFF OMITTED] T5502.072
[GRAPHIC] [TIFF OMITTED] T5502.073
[GRAPHIC] [TIFF OMITTED] T5502.074
[GRAPHIC] [TIFF OMITTED] T5502.075
[GRAPHIC] [TIFF OMITTED] T5502.076
[GRAPHIC] [TIFF OMITTED] T5502.079
[GRAPHIC] [TIFF OMITTED] T5502.080
[GRAPHIC] [TIFF OMITTED] T5502.081
[GRAPHIC] [TIFF OMITTED] T5502.082
[GRAPHIC] [TIFF OMITTED] T5502.083
[GRAPHIC] [TIFF OMITTED] T5502.084
[GRAPHIC] [TIFF OMITTED] T5502.085
[GRAPHIC] [TIFF OMITTED] T5502.086
[GRAPHIC] [TIFF OMITTED] T5502.087
[GRAPHIC] [TIFF OMITTED] T5502.088
[GRAPHIC] [TIFF OMITTED] T5502.089
[GRAPHIC] [TIFF OMITTED] T5502.090
[GRAPHIC] [TIFF OMITTED] T5502.091
[GRAPHIC] [TIFF OMITTED] T5502.092
[GRAPHIC] [TIFF OMITTED] T5502.093
[GRAPHIC] [TIFF OMITTED] T5502.094
[GRAPHIC] [TIFF OMITTED] T5502.095
[GRAPHIC] [TIFF OMITTED] T5502.096
[GRAPHIC] [TIFF OMITTED] T5502.097
[GRAPHIC] [TIFF OMITTED] T5502.098
THE ADEQUACY OF THE FDA TO ASSURE THE SAFETY OF THE NATION'S DRUG
SUPPLY
----------
THURSDAY, MARCH 22, 2007
House of Representatives,
Subcommittee on Oversight and Investigations,
Committee on Energy and Commerce,
Washington, DC.
The subcommittee met, pursuant to call, at 9:35 a.m., in
room 2123 of the Rayburn House Office Building, Hon. Bart
Stupak (chairman of the subcommittee) presiding.
Members present: Representatives DeGette, Waxman, Green,
Schakowsky, Inslee, Dingell [ex officio], Markey, Whitfield,
Walden, Ferguson, Murphy, Burgess, Barton [ex officio], and
Blackburn.
Staff present: David Nelson, Joanne Royce, Kyle Chapman,
Scott Schloegel, John Sopko, Alan Slobodin, Karen Christian,
Krista Carpenter, John Halliwell, and Matt Johnson.
OPENING STATEMENT OF HON. BART STUPAK, A REPRESENTATIVE IN
CONGRESS FROM THE STATE OF MICHIGAN
Mr. Stupak. This hearing will come to order. Today, we have
a hearing on the adequacy of the FDA efforts to assure the
safety of the drug supply, part II. Each member will now be
recognized for 5 minutes.
Today, the subcommittee continues its inquiry into the
adequacy of the FDA's efforts to protect Americans from unsafe
prescription drugs. The FDA has a long history of not
adequately protecting the public from dangerous prescription
drugs. The FDA has placed the approval on marking of drugs
above its public safety mission. The Government Accounting
Office and the Institute of Medicine, and members of the FDA
old Drug Safety Advisory Committee have all released reports
detailing the inadequacies of the FDA's drug approval process,
post marketing surveillance, and inept leadership.
Representatives from these organizations will present their
testimony today, and we welcome their analyses.
This subcommittee has investigated three separate
instances, the anti-depressant SSRI's, the anti-inflammatory
medication Vioxx and Bextra, and the antibiotic Ketek, where
senior officials in the FDA's Center for Drug Evaluation and
Research, CDER, overruled competent, conscientious FDA medical
officer's warnings that the drugs were not safe. The senior FDA
officials who overruled the FDA medical officers performed no
independent analysis of the data, nor did they solicit the
opinion of unbiased, outside scientists. In fact, in the
antidepressant and Ketek cases, FDA officials took deliberate
steps to withhold critical information from the advisory
committee on the most important facts regarding the issues
under consideration.
In the Vioxx case, senior FDA officials refused to allow an
FDA official to share his critical study with the FDA advisory
committee. FDA officials responsible for protecting Americans
overruled their own scientists and chose instead to listen to
the self-interested pleadings of the drug companies.
In each case that this committee examined, the increased
suicide risk in adolescents from antidepressant drugs, the
unnecessary deaths from heart attack and stroke associated with
Vioxx, and the liver deaths from the Ketek, the FDA has
ultimately been forced to reverse its prior decisions regarding
the efficacy of the drug. Amazingly, the FDA senior officials
are still in a position of authority at the FDA and their
actions have forced many well-respected and conscientious
professionals within the FDA to leave their jobs. The American
people cannot afford to have senior FDA officials overruling
sound scientific analysis and approving dangerous drugs and
forcing out professionals who exposed the problems within the
FDA's approval and post marketing surveillance process.
On a positive note, our congressional investigations have
resulted in strengthened warnings and provided more information
to protect consumers. With the SSRI's, the FDA agreed to a
black box warning and changed the labeling regarding efficacy
in adolescents. With Bextra, the drug was pulled after our
committee staff began an investigation. With Ketek, just days
before our hearing the FDA announced a new black box warning
and limited Ketek's approved use.
Following inquiries by our committee, the Office of
Oncology Drug Products advocated for black box warning for the
EPO drugs and convened an advisory committee to discuss the
safety of EPO drugs. AmGen, Johnson and Johnson, and Roche
worldwide sales are above $10 billion for these EPO anemia-
fighting drugs, but in recent months, three off-label studies
have been stopped because of serious adverse events such as
blood clots, tumor growth, and death.
Another positive result of our bipartisan oversight
investigation work was that in November 2004, the FDA requested
the Institute of Medicine, IOM, to draft a detailed evaluation
of the FDA's drug safety system. We will hear testimony today
regarding the result of that IOM report and ways the FDA can
improve its drug safety.
Today, we will also have an opportunity to hear from Dr.
Andrew von Eschenbach, the Commissioner of the FDA. I look
forward to the Commissioner's account of all his drug safety
reforms to keep drugs like Ketek off the market. I also want to
know what he will do to retain dedicated, competent medical
officers who areleaving the FDA.
At our last FDA hearing, Doctors Ross and Powers were prime
examples of scientists who became so disillusioned with the
FDA's senior officials that they left the Agency. Our country
needs to keep doctors and scientists within the FDA where their
dedication is at the heart of drug safety.
As the full committee moves forward with the
reauthorization of PDUFA, the Prescription Drug User Fee Act,
and reviews the administration's draft, it is incumbent upon us
to protect the American public and not help the pharmaceutical
companies' profits. As this partnership between the FDA and the
drug companies produced an Agency which views its clients as
drug companies rather than the American public, I am curious to
learn how Commissioner von Eschenbach's drug safety plan
reverses the apparent partnership of automatic approval and
encourages retaliation against those FDA employees who question
the Agency.
I also want to hear what Dr. David Graham and other FDA
employees think when they disagree with the efficacy and safety
of the drugs. Will they be treated fairly? Will their voices be
heard?
I also hope to hear the Commissioner say that instead of
discouraging dissent, he will encourage dissenting views and
the FDA's advisory committee will hear from every FDA employee,
expert and consumer who may have concerns about the safety of a
drug.
I also hope to hear that both the pre-approval and post
marketing processes are going to become much, much more
transparent so that data can be evaluated inside and outside
the FDA. I hope to hear a commitment that advisory committees
will consist of members that are free of conflicts of interest.
The most trusted medical journals have no trouble finding
qualified peer reviewers who have no financial ties to the
medical issues they are reviewing. I cannot understand why the
FDA cannot field advisory committee experts who do not have an
interest in the drugs being approved.
I hope to see outside oversight of how the FDA treats its
whistleblowers. Specifically, I want to see the abolition of
the Office of Internal Affairs and termination of the
Memorandum of Understanding that has stripped the Inspector
General of the responsibility of ensuring integrity at the FDA.
The Memorandum of Understanding is improper and has been
systematically abused. FDA criminal investigators have been
sent to harass and intimidate FDA scientists who have refused
to compromise their scientific integrity. On the other hand,
there have been no publicly disclosed investigations of senior
FDA officials who violate whistleblower rights.
I want to hear that the FDA reviewers who uncover
discrepancies, question data from drug companies or scientific
misconduct at clinical sites will not be shunned. I hope that
the Commissioner's statement that he will not tolerate public
dissent from within the Agency has not discouraged
whistleblowers from coming forward.
I want to hear that FDA supervisors will not abuse their
authority by ordering safety reviews to be changed. Advisory
committees will not be misled, and drug companies will not
decide the content and placement of safety information on
labels and that crucial safety data will not be ignored. I
believe the FDA officials who abuse their authority by engaging
in such activities can endanger the public health and must be
removed from their supervisory capacity.
I wish to hear that the safety of the American public is
paramount concern for the FDA when it comes to food, drugs, and
medical devices.
More than just words, I wish the examples that the
Commissioner of the FDA can renew the FDA's mission to protect
the American people and not the pharmaceutical companies.
Without meaningful actions, how can Congress be expected to
hand the FDA another 5 years of unquestioned carte blanche
under PDUFA?
With that, I will next recognize the ranking member of the
subcommittee, my friend from Kentucky, Mr. Whitfield.
Mr. Whitfield, 5 minutes, please.
OPENING STATEMENT OF HON. ED WHITFIELD, A REPRESENTATIVE IN
CONGRESS FROM THE COMMONWEALTH OF KENTUCKY
Mr. Whitfield. Thank you, Chairman Stupak, for convening
this hearing. As you mentioned in your opening statement,
today's hearing is this subcommittee's second hearing examining
FDA's management of drug safety.
Recent reports by the Institute of Medicine and the
Government Accountability Office and testimony at our first
hearing make the case that the current system for monitoring
drug safety needs improvement. I am delighted also that today
Honorable von Eschenbach is with us. We appreciate your being
here, Commissioner, and look forward to your testimony very
much.
The FDA's responsibilities are great, and the American
people want new drugs to be introduced into the marketplace to
help fight deadly disease. Congress has asked FDA to promote
public health by approving, when appropriate, applications for
new drugs, drugs for which patients and physicians are often
anxiously awaiting.
FDA has approved more drugs than ever before over the last
10 years, and while the numerical percentage of drugs withdrawn
from the market has been stable over the years, the actual
number of drugs withdrawn has gone up because there are more
drugs on the market. Although this number is small compared to
the total number of drugs approved, that number is still too
great, as it represents patients whose health has suffered or
who have even died because the drugs they were prescribed were
not safe.
The Agency must balance promotion of public health with
protection of public health by monitoring safety before and
after a drug is approved. The FDA is asked to satisfy both
these missions, which are often intentioned with each other
under an ever-increasing workload.
We should also recognize that while we want FDA to act
quickly, once it has strong scientific evidence of a safety
problem there is also a risk of pulling a drug too early that
may actually not have anything wrong with it. for example,
several years ago it was mistakenly thought that Claritin
caused sudden death like Seldane, but on further analysis it
turned out not to be the case.
The Institute of Medicine and others have made a number of
recommendations for improving safety, but in order for FDA to
implement many of these proposals successfully, additional
resources are needed. You can't do your job without necessary
resources. With these resources, FDA would have the tools to
spot potential safety problems much sooner, perhaps in a matter
of months rather than years. According to Richard Platt of
Harvard Medical School, if data from large health plans were
pooled, more definitive evidence and potential safety risks,
such as the cardiovascular events linked to Vioxx, could have
been detected within just several months instead of nearly 3
years, enabling much faster action to address safety.
Today, as I said, we welcome Commissioner Andrew von
Eschenbach who has been invited to discuss the FDA's drug
safety initiatives, as well as issues related to the approval
of Ketek. I would like to point out that this subcommittee's
investigation of Ketek is at a preliminary stage. Dr. von
Eschenbach's testimony in this regard is somewhat out of
sequence. The standard practice is to have his testimony at the
end of the investigation, and this subcommittee issued document
requests to FDA 1 month ago, and FDA has produced some
documents but is working to complete its production. We have
not conducted interviews of the FDA staff involved with Ketek.
And with respect to Ketek and specific factual matters, we are
proceeding here today without the benefit of having a full
record before us.
However, that is not the only focus of this hearing. I
think it is also important to remember that many of the
problems described in the IOM and GAO reports are not new and
cannot be attributed only to certain individuals or personnel
issues. Instead, these reports suggest that these problems are
systemic and require comprehensive wide-ranging approach to
solving them. There does seem to be particularly a problem with
morale and some cultural problems within the FDA's Center for
Drug Evaluation and Research, and I know that the Commissioner
is focused on these morale problems, and it is something that
he places priority in dealing with.
While he has been acting Commissioner, I guess, since
September of 2005, he was confirmed by this Senate I guess
about 3 months ago, and so we need to give him a chance to work
with FDA employees, with experts, and with Congress to develop
the Agency's response to drug safety concerns.
In addition to discussing the IOM proposals with Dr. von
Eschenbach, I would also like to bring to his attention a
letter that Ranking Member Barton and I sent to the Inspector
General of the Department of Health and Human Services,
requesting an updated evaluation of FDA's oversight of clinical
investigators. Our request was spurred by FDA's delays in
disqualifying scientists who have been convicted or found to be
lying or cheating in studies used for FDA approval. For
example, minority staff found that Dr. Ann Kirkman Campbell, a
clinical investigator in the safety trials for Ketek who
pleaded guilty in 2003 to misconduct related to her
participation in the Ketek trial and has been in prison since
2004, has not yet been debarred by the FDA.
We look forward to the testimony of both panels of
witnesses, and we know that they will offer valuable insight on
this issue.
My time is expired, so thank you.
Mr. Stupak. But we work in such a cooperative atmosphere, I
was going to let you go a few more minutes.
With that, I recognize the gentleman from Michigan, the
chairman of the full Energy and Commerce Committee, Mr.
Dingell.
OPENING STATEMENT OF HON. JOHN D. DINGELL, A REPRESENTATIVE IN
CONGRESS FROM THE STATE OF MICHIGAN
The Chairman. Thank you for holding this hearing. It is
second in this committee's investigation of the handling of the
food, drug, and safety issues by the Food and Drug
Administration. I want to welcome Commissioner Dr. von
Eschenbach to the committee, and I want to commend you for the
vigor with which you are addressing the business of this
subcommittee.
The Commissioner should know that the FDA's response to the
committee's inquiries has been less than acceptable. Responses
have been slow to our document requests regarding food safety,
drug safety, and conflicts of interest. I would inform all,
including the Food and Drug Administration, that this committee
will see to it that our questions are answered properly and
speedily.
The Commission appears here today was preceded a month ago
by former FDA staff members who testified that they were forced
to flee the FDA because they feared retaliation from their
superiors. These are good doctors and good scientists that
exposed bad decisions, decisions that appear to have needlessly
cost American lives. This committee has a rather special
interest in whistleblowers and in their safety and comfort, and
we will take whatever steps are necessary to assure that that
intention by the committee is fully implemented by all who come
before us.
Both private statements and public quotes attributed to the
Commissioner indicate that he does not tolerate public dissent
from FDA employees. Private protests, I would note, within the
FDA do not appear to work either. For example, in the case of
the drug Ketek, only after the Congress was informed by FDA
former employees of the confused dictates of senior FDA
officials did the Agency finally rectify its mistakes. We have
heard testimony that the Commissioner told these same employees
that anyone not willing to be a team player would be traded.
That is unacceptable. Given that their protests went to
congressional offices, including this committee, I must remind
the commissioner and everybody else in the FDA, that
threatening FDA employees with retaliation for talking to
Congress is not only unacceptable, but it is illegal.
My concern is echoed in a letter dated March 9, 2007, by
our former colleague and my good friend, Senator Chuck
Grassley, to the Commissioner, and I believe that my committee
colleagues should review that matter and that letter. I
therefore ask that the letter be placed in the hearing record,
Mr. Chairman.
Mr. Stupak. Without objection.
The Chairman. Dr. von Eschenbach has been invited to tell
us today why the Agency's new drug safety initiative will
adequately express and address the cultural problems identified
by a number of experts on FDA drug safety policies. That
cultural problem comes down to what Senator Grassley calls
having grown too cozy with industry, and preferring drug
approvals over swift action when clear safety signals manifest
potential post market problems.
At our last hearing, Dr. David Graham framed a question for
today's hearing, and that is what in the FDA proposals would
prevent another Vioxx? For example, what in the new FDA
proposal would ensure that FDA reviewers would not negotiate
for more than 14 months on label changes, even after receiving
substantial evidence of serious cardiac side effects, as they
apparently did with Vioxx? Will the new proposed Office of New
Drugs act any differently upon the clear warnings regarding
Vioxx from epidemiological work performed in the Office of Drug
Safety? Under the new proposal, would the FDA medical officers
in the anti-ineffective division been allowed to present their
findings to the advisory committee? Under the new proposal, are
the advisory committees more likely to hear about potential
fraud or errors in political safety studies, or are they able
to make an honest judgment as to whether or not these studies
are sufficient to protect the public? Moreover, where in the
new FDA proposal is there any provision to fully inform the
public of the case risks and benefits prior to a drug's
approval?
I, for one, do not see anything in the new FDA proposal
that effectively responds to the many problems identified by
this committee over the past few years. None of these reforms
propose structural guarantees to stop the cultural bias that
has skewed the Agency's judgment.
One of the concerns that I have that is very specific is
how do these panels that would be set up or would continue to
serve at the FDA do the job that they are supposed to do and to
do so on the basis of an unbiased and independent group of
members of those agencies? In the end, what the administration
proposal really boils down to is a very simple word, ``trust
us''. My old daddy taught me to trust everybody, but he also
taught me to cut the cards.
We should then address this by understanding that it is
easier to accept that ``trust us'' if the FDA and the
Department of Health and Human Services were not resisting
congressional oversight and threatening whistleblowers.
Regardless of the drug safety questions, those questions
continue to be the central concern of this committee as
reauthorization of the Prescription Drug User Fee Act, PDUFA,
goes forward. I believe that all of us, including FDA, can
trust this committee that with the strong support of my
colleagues on both sides of the aisle, we will come up with
changes to ensure against another Vioxx.
I want to thank you, Chairman Stupak and Ranking Member
Whitfield, for holding this hearing. I believe that it is very
valuable, and I look forward to the testimony of today's
witnesses.
Mr. Stupak. Thank you, Mr. Chairman. Next turn to the
ranking member of the full committee, Mr. Barton from Texas.
Mr. Barton, sir.
OPENING STATEMENT OF HON. JOE BARTON, A REPRESENTATIVE IN
CONGRESS FROM THE STATE OF TEXAS
Mr. Barton. Thank you, Mr. Chairman and Ranking Member
Whitfield for holding this second hearing on drug safety. I
want to compliment all of the members that are here, especially
on the Republican side. I think we have 100 percent attendance,
so I want to compliment my minority members for all showing up
and being ready to investigate this important issue.
As I said in my opening statement at the first hearing
earlier this year, we on the Republican side support the
important investigation of FDA's oversight of drug safety. In
fact, as chairman of this committee in the last Congress, I
requested a Government Accountability Office review of the
FDA's organizational structure and decision-making processes
for drug safety. The GAO issues its report last spring and it
is going to present testimony on that report later today.
Recent drug safety incidents involving antidepressants and
Vioxx have raised the public awareness about the monitoring and
the safety of our drugs. In addition, there have been issues
raised about an antibiotic called Ketek, which was the focus of
the first hearing earlier this year. This subcommittee is
currently investigating this matter with the GAO report
followed by the Institute of Medicine's recommendations in 2006
to enhance post-market drug safety of the FDA, there is broad
agreement that our current system for monitoring the safety of
prescription drugs can definitely be improved.
This hearing can be, and I hope it will be, a constructive
step in achieving improvement in drug safety monitoring. It is
important to acknowledge and commend the FDA for making some
progress in response to the IOM report. Much remains to be
done, obviously, but the overwhelming need in responding to the
IOM report is additional resources for the FDA. With more
resources and more staff, more information and better quality
data, the FDA can make better decisions and gain more staff
consensus.
Of particular interest is what steps can be taken to
improve the ability to identify most adverse events in a
consistent and timely way. One possible solution would be to
develop a true systemic approach to identifying safety signals
in a broad part of the U.S. patient population by linking
individual databases together, combined with electronic
tracking of medication use and patient results. Recent analysis
by Richard Platt of the Harvard Medical School shows that data
from large health plans could be pooled to provide stronger
evidence of potential safety problems in months rather than in
years.
Finally, this subcommittee is examining the FDA's culture
and morale, the concern over what effect, indirect or direct,
this has on the FDA's ability to monitor drug safety. When the
IOM issued its report in September 2006, one of the most
important recommendations with regard to the FDA's culture and
morale was to stabilize the leadership of the FDA. In
particular, the report stated the absence of stable leadership
at the Commissioner level has been a continuous problem for the
FDA and its Center for Drugs. Thankfully, in December 2006, the
Senate confirmed Dr. Andrew von Eschenbach, who is with us
today, as the Commissioner of the FDA. FDA now has a newly
confirmed Commissioner with full authority to lead. He happens
to be somebody that I know personally, and I have full
confidence he is going to do the very best that he can to lead
the FDA.
I am glad that the subcommittee is giving Dr. von
Eschenbach an opportunity to be heard today. He should be given
an opportunity to actually lead, continue response to the IOM
report, and a chance to work with the FDA employees,
stakeholders, and the Congress to address drug safety concerns,
to improve his Agency's morale.
It is understandable and legitimate to question Dr. von
Eschenbach about the concerns raised by Senator Grassley and
other witnesses from the first hearing about Ketek. That is
what the oversight function of Congress is all about. I want to
remind our members, though, that we are in an open
investigation on Ketek. We are still gathering documents and we
are still interviewing witnesses. With these circumstances,
hopefully we will be careful not to make any premature
judgments or allegations at this hearing. I believe that the
members of this subcommittee on both sides of the aisle agree
that we must move forward now, and we have to do our part to
help the FDA address these problems. It is important, I think,
that we do it in a way that is constructive.
I welcome Dr. von Eschenbach. I look forward to hearing his
testimony. It is my hope that he is going to do everything
possible to ensure that the FDA's processes with respect to
drug safety are transparent, collaborative, and based on the
best science available.
I am also looking forward to hearing our second panel of
witnesses who are going to comment on improving the management
and oversight of drug safety.
Finally, Mr. Chairman, I think as you understand, we have a
telecommunication hearing that started about 30 minutes ago
upstairs, so I am going to be scuttling back and forth like a
little beetle, trying to listen down here and also participate
up there.
With that, Mr. Stupak, I yield back the balance of my time.
Mr. Stupak. I thank the ranking member and you are correct,
I will be joining you upstairs here in a second as I am going
to ask Ms. DeGette to take the Chair while I run up there and
ask my questions, and I will be right back down.
Also, so the ranking member knows, we were able to work
out, it looks like, our amendment for the 2:30 markup today.
That is what we have been doing this morning, so things are
progressing even though we look a little disorganized here this
morning.
With that, I would recognize for 5 minutes Mr. Waxman from
California for an opening, and then ask Ms. DeGette to take the
chair, please.
OPENING STATEMENT OF HON. HENRY A. WAXMAN, A REPRESENTATIVE IN
CONGRESS FROM THE STATE OF CALIFORNIA
Mr. Waxman. Thank you very much, Mr. Chairman. Dr. von
Eschenbach, welcome to the committee. I am pleased that you are
here.
I look at FDA, which was created a little over a century
ago, as the premiere public health agency. Millions of
Americans depend on it to protect us from unsafe foods,
medicines, and medical devices, and it is held up throughout
the whole world as the gold standard. It is an agency that
deserves our support in every way.
Recently, there have been some very serious and concerning
issues at FDA with respect to regulation of drug safety. A
series of post-market safety problems in the past few years
with Vioxx, Ketek has demonstrated beyond a shadow of a doubt
that FDA's drug safety oversight is in serious need of repair.
These examples make it abundantly clear that drug safety is at
least as important after the drug has been approved as it is
before, and the IOM has done an evaluation of this, and I am
pleased that they are going to be here with us as well. They
think it is seriously dysfunctional. Their report made one
thing quite clear. FDA cannot protect Americans from unsafe
drugs unless Congress provides more resources and more legal
authorities.
Post-market drug safety oversight is currently grossly
underfunded at FDA compared to drug approval side. This is in
spite of the fact that there is now an increased risk of
approving unsafe drugs, since PDUFA required that the timeline
for drug approvals be accelerated.
In addition, the pharmaceutical industry has always fought
giving FDA the modern enforcement powers it needs. I want to go
through some of these enforcement powers that I believe FDA
lacks and must have.
FDA lacks the authority to require post-market safety
studies, even when they are necessary to determine a drug's
risk. FDA lacks the authority to impose necessary restrictions
on the distribution of drugs shown to have risks. FDA lacks the
authority to place controls on the huge advertising campaigns
at the launch of new drugs which cause excessive use of drugs
before their safety profile is clear. FDA lacks the authority
to demand labeling changes after approval. Their authority
under the current system is so weak, it guarantees that drug
companies will be able to delay and water down needed warnings
on drugs. The case of Vioxx is a tragic illustration of this.
FDA was forced to endure 14 months of haggling with the company
before we finally saw a black box warning about the serious
cardiac risks associated with the drug.
I think we simply have to fix these problems. We need
strong leadership at the FDA to make the necessary changes, and
I am eager to hear from Dr. von Eschenbach today about the
steps he intends to take to address the very serious concerns
raised in the IOM report.
Congress has to do its part. I have my own ideas about some
steps we can take, and I introduced a bill this week to address
many of these problems. We here in Congress owe it to the FDA
to make certain that it has the basic tools and authorities it
needs to fulfill its core mission, to protect the public
health. We also need to do what it takes to get FDA adequate
funding to fulfill this mission. To do our job right, however,
we need full and complete information from the FDA.
For the last century, FDA has protected the health of the
American people. It is now clear that a course correction is
necessary to enable the Agency to continue its historic
mission.
I applaud the chairman for calling this hearing, and I am
looking forward to the testimony.
Thank you.
Ms. DeGette [presiding]. The Chair now recognizes the
gentleman from Oregon, Mr. Walden, for 5 minutes.
OPENING STATEMENT OF HON. GREG WALDEN, A REPRESENTATIVE IN
CONGRESS FROM THE STATE OF OREGON
Mr. Walden. Thank you, Madam Chairman. I will keep my
remarks very brief.
I think Mr. von Eschenbach has heard from the committee
already our concerns to make sure the American drug supply is
safe and that when people go to the drugstore and get something
that doctors prescribe, they know that they are going to get
better and not worse.
And so, we look forward to the continuing effort to make
sure this system works and works effectively, and we look
forward to your testimony. Obviously, we will have some
questions, so thank you for being here.
I yield back.
Ms. DeGette. The Chair recognizes herself for 5 minutes.
OPENING STATEMENT OF HON. DIANA DEGETTE, A REPRESENTATIVE IN
CONGRESS FROM THE STATE OF COLORADO
As the full committee prepares to reauthorize PDUFA, I am
confident that this series of hearings will be very informative
to that process. Given the importance of PDUFA to ensuring that
new drugs approved for the market are safe for patients, we
need to make sure that the FDA has the systems in place to do
the job effectively. As others have said today, we not want to
find ourselves with another Vioxx-type situation that we could
have prevented.
I would like to say that my questions for the panelists
today focus on how to improve our drug safety systems to
further improve protections for patients, but unfortunately I
have set my bar a lot lower. My goal today is to have a system
that avoids scenarios like Vioxx, Ketek, and SSRIs. At the very
least, I hope our witnesses can show us how we can prevent
those types of tragedies from occurring with some other kind of
drug.
To that end, I have several issues today regarding drug
safety at the FDA that I hope we can examine. First and
foremost, I am interested to know how the FDA has made systemic
changes to drug safety within the Agency to prevent large scale
drug safety problems. In my mind, any one of these events
should have spurred the FDA into corrective action, let alone,
all three of these events together. I would hope that the FDA
has not just tinkered around the margins this time, but has
made a careful examination about what went wrong and has a
large scale comprehensive plan for corrective action.
In light of our impending deliberations on PDUFA
reauthorization, I am also interested to hear from the
witnesses about how we might better address the issue of
conflicts of interest, both real and imagined. Clearly, the
current system makes it fairly easy for a collaborative, some
would say cozy, relationship between the FDA and drug
companies. While I certainly support the work done by
pharmaceutical companies to develop the treatments and cures we
have come to expect, we must maintain FDA's autonomy and its
true role as a regulator. The FDA should not have to negotiate
the black box warning label of a drug with the manufacturer.
Once the FDA makes the decision after consultation, the
decision should be in the hands of the FDA.
As I mentioned, there are a number of real problems with
the system by which the FDA manages drug safety. At the same
time, there is a feeling of mistrust by the public about the
work performed at FDA that further exacerbates the problem.
Instead of feeling that all drugs are safe and effective,
people are now questioning the drugs that they take. Frankly,
if we are going to maintain the health of the citizens of this
country, then they need to feel confident that the treatments
prescribed are safe. Furthermore, we need to prove to the
public that clinical trials are safe.
I know that we can make the changes to the FDA that will
improve drug safety. I can only hope that those changes will be
made with the full cooperation of all stakeholders to enable
true consensus on the approach. The American public deserves
nothing less.
And so I yield back the balance of my time, and now
recognize Mrs. Blackburn for 5 minutes.
OPENING STATEMENT OF HON. MARSHA BLACKBURN, A REPRESENTATIVE IN
CONGRESS FROM THE STATE OF TENNESSEE
Mrs. Blackburn. Thank you, Madame Chairman. I want to
welcome all of our witnesses today, and make note that Dr.
Woosley is someone that I had the opportunity to work with when
he was at our fine Vanderbilt University Medical Center as a
researcher in the mid-1980's and I was the chairman of the
board for the American Lung Association in Tennessee. We
welcome you and look forward to hearing from you. Commissioner,
we welcome you and look forward to hearing from you.
Very briefly, because I like to spend my time in questions,
and I just want to highlight with you all that we all recognize
that the public has an insatiable appetite for new therapies
and new drugs, and they are quite frustrated with what they
perceive to be a very slow process of commercialization and
moving these drugs and therapies to the marketplace once they
know that something is in to research or in to development.
We also realize, sir, that there is a responsibility that
rests with the FDA to make certain that these reach the
marketplace safely and in a timely manner. We will focus on
that through our questions and our comments to you, on behalf
of our constituents.
I look forward to both a conversation and a dialog, if you
will, as we move forward on this, on how we go about it with
fairness to everyone that is involved in this process: to you,
to your employees, to our constituents who are the consumers
and do have the desire for new things that will increase their
quality of life.
I do want to highlight with you that any time we have
constituents who hear about commissions or advisory committees,
I think that is a sensitive area with many now. They feel as if
that is a way that someone can toss aside a question or a
concern that you can say well, we are going to study it.
Studying never brings resolution to a problem. It is a form of
procrastination, and unfortunately in the Government arena,
many times when they hear ``we are going to delegate this to a
committee or a commission'' they know that an answer will never
be reached.
So we look forward to visiting with you, and we thank you
very much for your time. I yield back.
Ms. DeGette. Chair now recognizes the gentle lady from
Illinois, Ms. Schakowsky, for 5 minutes.
OPENING STATEMENT OF HON. JAN SCHAKOWSKY, A REPRESENTATIVE IN
CONGRESS FROM THE STATE OF ILLINOIS
Ms. Schakowsky. Thank you, Madame Chairman.
We have heard a great deal about problems at the FDA, and I
am glad that today we will hear from Dr. von Eschenbach about
his proposals for solutions.
The time for action is long overdue. Two years ago, the
National Center for Health Statistics told us ``The Nation's
medicine cabinets are more crowded than ever with almost half
of all people taking at least one prescription medicine, and
one in six taking three or more medications.'' Yet, in 2 years,
little has been done to reduce the risk Americans face when
they take their daily medications. You can't watch television
or pick up a newspaper or magazine without being bombarded by
direct to consumer advertising. Americans believe that when
they go to their medicine cabinet or pharmacy to purchase FDA-
approved drugs, they are getting medication that is safe and
efficacious.
Unfortunately, as this subcommittee has documented, too
often their trust is misplaced. We need to do better.
I was pleased that yesterday the FDA took steps to limit
conflicts of interest involving advisory committee members,
although I am interested in learning more specifics about the
rules. This is just one of many problems that past witnesses
and today's second panel have raised.
There are two issues that are of particular concerns to me.
First, I am deeply troubled by the atmosphere of secrecy
and the harsh treatment of whistleblowers that seems to pervade
the FDA, and in fact, most of the Bush administration. The
members of this committee, healthcare professionals, and the
public have a right to know about safety information. None of
us is well-served when FDA experts feel unable or even
threatened if they reveal serious and potentially deadly
concerns.
Second, I believe that we must act to ensure that the
policies and practices of the FDA reflect the needs of the
public and not the drug companies. The imposition of user fees
should not allow drug companies to dictate how those user fees
are used. I hope that when we reauthorize the Prescription Drug
User Fee Act, we make that clear. We should allocate funding
and set post-marketing drug safety surveillance standards in
order to protect consumers, not based on negotiations with the
industry being regulated. In the meantime, however, we need
assurances from the FDA that they are doing everything they can
to prevent the drug companies from dictating safety reviews at
the public's expense.
Thank you, Madame Chairman. I yield back.
Ms. DeGette. Chair now recognizes the gentleman from Texas,
Mr. Burgess, for 5 minutes.
OPENING STATEMENT OF HON. MICHAEL C. BURGESS, A REPRESENTATIVE
IN CONGRESS FROM THE STATE OF TEXAS
Mr. Burgess. Thank you, Madame Chairwoman and Ranking
Member Whitfield. I appreciate part two of this hearing. Part
one, which was held last month, was very disturbing on several
levels. The witnesses who testified told numerous troubling
stories about what they observed during the approval process of
the drug Ketek. While I was concerned about their personal
accounts in their testimony, I was also very concerned that
only one side of the story was told that day.
During the hearing, I called on the leadership of this
committee to swiftly invite the FDA, the manufacturer of Ketek,
Sanofi Aventis, to our committee so that they can address the
serious allegations against them and tell their side of the
story.
So thank you, Madame Chairwoman. I do wish the FDA had been
invited to last month's hearing, but I do thank you for calling
this hearing today and for inviting Commissioner Andrew von
Eschenbach.
Dr. von Eschenbach, welcome. As the newly confirmed top
administrator for the FDA, you have found yourself smack in the
middle of some significant controversies. Some will be within
your control, some are beyond your control. Last year when you
were still director of the National Cancer Institute, you were
kind enough to meet with me out at the NIH, and I thank you for
your time then, and thank you for your time today, as well.
As director, as I recall, you proved yourself to the entire
medical community to be, in fact a visionary leader. It was
through that vision and that leadership that you were able to
not only articulate, but to provide a roadmap of making cancer
a manageable chronic disease in 10 years time, by the year
2015. You brought together researchers, clinicians, and
politicians, and verbalized how we can accomplish that
worthwhile goal.
Commissioner, while you are immensely qualified to lead the
FDA, in my opinion, your leadership credentials are indeed
impeccable, that is not to say that there are not problems,
serious problems within the FDA. I feel that right now, this
Agency needs leadership and you are, indeed, a proven leader
for that job and indeed, I believe you to be the type of change
agent needed to strengthen the drug safety system.
One of the most crucial aspects of all organizations is
stable and steady leadership, but unfortunately that essential
component has been absent at the FDA for far too long. Not a
reflection of the FDA, but instead, a reflection on the Senate
confirmation process. The political battles that have brewed
over the years during this process have been a detriment to the
Agency that is charged with America's health and safety. For
the good of the American public, for the good of the FDA, the
Senate must act in a more expeditious manner with regard to
future confirmations. It is the only way we can assure a
continuous form of leadership.
Madame Chairwoman, I believe this committee must continue
our oversight regarding important public health issues. As a
physician, I take this role extremely seriously and you have my
commitment to work with you and Chairman Stupak and the entire
committee on the vigilant pursuit of truth to our Nation's
healthcare matters. As members of Congress, this is one of the
most important roles that we will ever have, and I look forward
to hearing from our witnesses today.
I yield back.
Ms. DeGette. The gentleman yields back.
The Chair now recognizes the gentleman from New Jersey, Mr.
Ferguson, for 5 minutes.
OPENING STATEMENT OF HON. MIKE FERGUSON, A REPRESENTATIVE IN
CONGRESS FROM THE STATE OF NEW JERSEY
Mr. Ferguson. I am kind of in no man's land here between
microphones.
Thank you, Madame Chair. Thank you for calling this
hearing. Dr. von Eschenbach, welcome. We are glad you are here.
We appreciate your service at the FDA and in your previous
positions.
I want to address an issue, first, that you and I have been
working on together with others since last summer, the
enforcement of regulations concerning the distribution of FDA
written medication guides, med guides to people who are
receiving prescriptions. I think we can all agree that
medication guides are an invaluable tool to inform people about
the drugs they are taking. They are written in plain English,
sometimes in a question and answer format, and they go a long
way toward educating patients and parents of patients of
potential concerns that can result when taking certain drugs,
particularly in the cases that we have seen in children taking
antidepressants.
I have been concerned that patients are not receiving the
medication guides in every instance that they ought to be, and
after examining medication guides and the supply chain for med
guides, I and our staff found that there are gaps in the
enforcement of med guide regulations. Drug manufacturers and
pharmacist organizations and the individual State Boards of
Pharmacy needs to be better informed and better instructed
about what their duties are to ensure the proper distribution
of medication guides.
After contacting a number of these different stakeholders,
the New Jersey State Board of Pharmacy agreed to include the
enforcement of medication guides as one of the protocols that
they would investigate as one of their routine pharmacy
inspections. Dr. von Eschenbach, I appreciate your willingness
to work with me on this issue, and I welcome your thoughts
today and in the future about what more the FDA could perhaps
to do to help ensure that medication guide regulations are
being enforced. You and your staff have been very, very helpful
and forthright and cooperative as we have conducted this
investigation in our office, and I am pleased. I do have your
most recent letter from your office indicating some of the
things that you are doing and will be doing in the future to
help, in particular, with this issue, and in particular, if you
could perhaps share with us today what the FDA may be able to
do in terms of contacting State Boards of Pharmacy to inform
them about medication guide protocols and what you might be
able to do to enforce those protocols.
I have a couple of other topics I would like to get into
during questions, but I just wanted to raise that during my
statement here. I certainly appreciate your service and the
work that you are trying to do. We have so many important
issues that we are dealing with and that you are dealing with
at FDA, and we look forward to continuing to work with you on
these many important issues.
Thank you, and I yield back.
Ms. DeGette. Chair now recognizes the gentleman from
Pennsylvania, Mr. Murphy, for 5 minutes.
OPENING STATEMENT OF HON. TIM MURPHY, A REPRESENTATIVE IN
CONGRESS FROM THE COMMONWEALTH OF PENNSYLVANIA
Mr. Murphy. Thank you, Madame Chair, and I want to thank
everyone who is going to testify today.
Many of the issues about why we are here have already been
raised from the standpoint of how we are concerned about drug
safety, but we are also concerned about getting drugs into the
hands of doctors and patients in a timely manner. I would like
to demonstrate the importance of this with two calls I received
just this week on Monday. One was a call from a friend of mine,
we will call him ``Joe'', who a couple of months ago had
approached me, saying that he had just come back from the
doctor and was informed that because of the kind of aggressive
cancer he had developed in several internal organs that he
really only had a couple of months left to live. He was told to
go home and put his affairs in order.
Joe doesn't operate that way. He has a business and he was
not about to let his employees, all those lose their
livelihood. He was going to do what he could to live for their
sake. We made a number of calls and eventually got him involved
in a trial program for a cancer drug. He began this medication,
and a couple of weeks later called me to say that he had some
blood tests, and there was no signs at all in his blood tests
that he had cancer. They increased the dosage then of this
experimental medication, and on Monday morning he called me and
said I just got back from a CT scan, and the doctor called and
said all my tumors are necrotizing. They are disappearing.
Pretty incredible news from a man who was told he was dying.
Sadly, a friend of mine named Jackie, who had similar sort
of aggressive cancer in the internal organs, I also had a call
on Monday that she had died. A woman who had given her life
helping so many causes, a young lady 41 years of age, gave much
of her life to programs such as Habitat for Humanity, a loss
for all of us to have someone like that gone.
Putting these two stories together tells me some of the
things that the FDA has got to help us with to make sure that
young women like Jackie do not go away too soon, and that
standard therapies for cancer are seen as something of the
past, and yes, indeed, we can treat this more as a chronic or
acute illness in the future, and we can give moms like her hope
that they will live to see their children grow up and help
others.
We are excited about the things that happened to Joe, but
still, all of this is experimental and we recognize part of the
burden the FDA has to have is how you can bring medications to
the market quick enough to save lives, but understand the
safety and the risks all along. It is not an enviable position.
I tell these stories to help us all understand, and the Nation
understand that we are dealing with lives here. That anytime we
have safety issues where someone has breached the scientific
ethics and has withheld information or put information that is
distorted, we are all deeply concerned about that, and we want
to make sure that doesn't happen.
We also want to make sure that medications that are out
there that show some promise, that show some possibilities,
that they get in the hands of physicians and patients as soon
as we can. We want to make sure that other lives are saved and
others are not lost, and that none of this gets caught up in a
bureaucracy and a whirlwind of paperwork that doesn't help
anybody.
I hope that what we can find out from these hearings today
and from future work with the FDA is that I believe the
employees of the FDA have to be committed--and I believe they
are. In their hearts, they want to make sure they are saving
lives and they are doing it the right way. And I am sure that
all of you that are testifying today will have that in your
hearts as well. You want to make sure that we don't have other
losses like Jackie out there.
Let us all make sure that what comes out of this hearing is
ways we can do this better, ways we can save more lives, and
ways that we can make more patients available to see their
children grow up tomorrow.
I yield back.
Mr. Stupak. That concludes all the opening statements.
Dr. von Eschenbach, we are ready for your testimony, but
before you do that, we have a policy of this subcommittee to
take all testimony under oath. Please be advised that you have
the right under the rules of the House to be advised by counsel
during your testimony. Do you wish to be represented by counsel
at this time? Will you please rise, then?
[Witness sworn]
Mr. Stupak. Thank you, Doctor. Consider yourself sworn in,
and we will now hear from you for your opening statement,
please.
TESTIMONY OF ANDREW C. VON ESCHENBACH, M.D., COMMISSIONER, U.S.
FOOD AND DRUG ADMINISTRATION
Dr. von Eschenbach. Thank you very much, Chairman Stupak,
Mr. Whitfield, and other members of the committee.
This is my first opportunity to appear before the
subcommittee as Commissioner of the FDA, and not only am I
looking forward to adequately responding to your questions, but
also to share my vision and commitment to ensure that the FDA
continues its record of excellence as a regulatory agency
dedicated to protecting and promoting the health of all
Americans.
My formal written testimony provides details about the
FDA's commitment to drug safety. My brief oral remarks this
morning I hope will describe the kind of well-managed,
efficient, and effective organization that I am committed to
leading.
Let me first say a word about the personal commitment to
that kind of effective leadership I hope to bring to the FDA.
Before I became director of the National Cancer Institute in
2002, I served in various leadership positions for almost 26
years, caring for patients at the M.D. Anderson Cancer Center
in Houston. While there, I strove to foster a multidisciplinary
and integrated approach to addressing the complex problem of
cancer, in order to bring the finest coordinated care to save
the lives of cancer patients. From the patient's perspective,
excellence depends not only on demanding the best from
individuals, surgeons, radiation therapists, or oncologists or
researchers, but also demanding effectiveness in combining and
integrating these skills.
I believe the same approach is required at the FDA. As we
manage the complexities of modern science and technology in an
effort to bring lifesaving products to patients, and assessing
the risk and benefit of drug, biologics, and medical devices,
we must have the analysis of various individual skills, but
they must also be integrated and coordinated.
At the FDA, we excel as individuals but patients and public
will benefit best and most when we work together. To adjust the
balance between understanding the benefits and risks of a new
drug, we are integrating the work of our Office of Surveillance
and Etiology, addressing drug safety with the work of the
Office of New Drugs. We are doing this for one reason: it
better serves patients and the public.
Throughout my career, Mr. Chairman, it has been my
commitment, my passion, if you will, to offer leadership that
fosters such an effective, efficient multidisciplinary and
integrated organization.
With regard to the culture of such organization, let me
assure you that I am committed to leading an FDA characterized
by a culture that has commitment to excellence, based on and
lead by science, and governed by a transparent and disciplined
regulatory framework. FDA must always remain an organization
dedicated to excellence, and that makes it a learning
organization. We learn from experiences and we will change.
For example, one of the lessons we have learned in the
pharmaceutical area of late is the need to address in detail
drug safety issues throughout the entire life cycle of
products, not just data coming in at the outset from clinical
trials, but also data derived when the drug is used in large
populations in a complex real world environment after approval.
This has led to a number of changes that will improve our post-
market surveillance and vigilance.
The FDA that I lead will be a science-based and a science-
led regulatory agency as it has been in the past and must be in
the future. New scientific discoveries are generating what
might be now termed an emerging science of safety. Today,
understanding of disease and its origin at the molecular level,
as well as the patient, provides us with new methods and
technologies for detecting molecular signals of both
effectiveness and adverse events. These and many other
scientific initiatives to be included in our effort are
articulated in our recent report, The Future of Drug Safety. We
are, as we speak, adopting 41 new measures to improve the
safety of medical products as a major step, but not the only
step, in an ongoing process of continuous improvement.
The FDA must also have a robust and disciplined regulatory
framework. Our analytical and decision-making processes must be
based on discipline and rigor. We must apply methods of
scientific analysis with consistency, uniformity, and
integrity. Our decision processes must be transparent and also
open to scrutiny.
During my career, I have learned that the best decisions
are those that are informed by diverse points of view and
vigorous academic debate. At the FDA, I will continue to foster
a climate of mutual respect that promotes dialog and informed
decisions, because I know these robust exchanges will produce
better public health decisions for American patients.
But even the best decisions, Mr. Chairman, can never
declare any drug perfectly effective or perfectly safe. These
decisions ensure the American people that in FDA's expert
judgment, the expected benefits of the drug outweigh its
potential risks for the intended use in a given population. The
FDA's effort in the past has made it the world's gold standard
as a regulatory agency, and I am determined that it remain so.
There will be no other priority or agenda for the FDA than
protecting and promoting the public health.
I look forward to working with you and the subcommittee as
we pursue our shared goal of a strong and effective FDA.
Thank you, Mr. Chairman.
[The prepared statement of Dr. von Eschenbach appears at
the conclusion of the hearing.]
Mr. Stupak. Thank you.
Before we begin with questions of Dr. von Eschenbach, I
want to take care of one housekeeping issue, and actually
compliment Department of Health and Human Services. I would
like to advise my colleagues as a result of our hearing last
week into the current healthcare situation in New Orleans,
Secretary Leavitt sent through Ranking Member Whitfield and me
a letter expressing his willingness to work with local
officials on a much smaller regional approach to address the
health concerns in New Orleans. In addition, Secretary Leavitt
also agreed to address the GME, Graduate Medical Education
payments. This is a significant accomplishment for our
oversight and investigations efforts, and I want to thank the
Secretary as well as Ranking Member Whitfield, members of our
subcommittee, and their staffs for their continued interest to
improve the healthcare situation in New Orleans. We are looking
for another hearing date in the near future to go down there
and continue to push healthcare to a state of acceptability
here in this country for the folks of New Orleans and the Gulf
region.
So I want to thank the Secretary for his help and
cooperation.
Mr. Waxman.
Mr. Waxman. Thank you, Mr. Chairman.
Dr. von Eschenbach, I want to ask you about this post-
market study commitment, also known as the phase 4 studies. I
think we all agree that when a drug first goes on the market,
we don't know all the information about that drug. It is not
tested on hundreds of thousands of people. There is a small
sample. We can't test drugs on tens of thousands. Very rare
side effects often cannot be detected in this small number of
subjects.
FDA often approves a drug on the explicit promise that the
manufacturer is going to conduct post-market studies after the
approval, and these studies are critical. They provide vitally
important information about a drug that can't be learned pre-
approval. In fact, these studies are so important, they are
imposed as a condition for approval of the drug in about half
of all new drugs, but by many accounts, a startling number of
pharmaceutical companies are failing to uphold their part of
the bargain that they need to do to make these studies and to
complete them.
FDA is required to submit to Congress an annual report on
how many of these post-marketing studies are completed, and
according to your most recent report in 2006, there were over
1,200 open or ongoing commitments to conduct post-marketing
studies, but manufacturers ended up completing or terminating
only 11 percent of these studies. That means 71 percent have
not even been started.
I would like to know your views on this. It seems to me
that it shouldn't be acceptable that 71 percent of the studies
are being delayed or pending. I want to hear what you think of
the situation. What is the problem there?
Dr. von Eschenbach. Thank you very much, Mr. Waxman.
I concur that this a process that definitely needs
improvement, and I believe that the approach that I want to
take is a process improvement approach from the perspective
that, first of all, we need to be able to engage in a much more
appropriate way in the kind of studies that should be conducted
in the post-market setting. One of the initiatives that we are
launching to provide the opportunity for much earlier
consultation discussion and decision-making process about the
assessment of the drug to define and determine both the need
for a post-market study, as well as what the content of that
post-market study should include.
By doing that in a much more strategic and much more
effective way earlier on in the process, I think we, first of
all, will have much better studies, studies that will be not
launched sort of after the fact, but will be integral to the
entire process of our entire life cycle management.
Mr. Waxman. That sounds good, but I am just concerned about
what your Inspector General said. He looked at these post-
market commitments last year and he found that in 1 year, about
one-third of the reports were missing or incomplete. So for
one-third of the studies that the companies promised to
conduct, FDA was left in the dark about whether or not they
were actually being done. So even if you consult with them
earlier, we are not guaranteed they are going to do the work.
They also found that even when these required reports were
provided to FDA, the information contained in them was so
lacking that it wasn't possible to even assess compliance.
Have you done anything to respond to the OIG's concern that
even when complete, the information contained in these reports
is inadequate?
Dr. von Eschenbach. Well, in addition to making sure that
we don't have inadequate responses, by virtue of the fact the
studies were not well developed and well designed and
therefore, did not get implemented, we also need to be much
more rigorous about that process itself. I believe we now have
tools that will enable us to have much better oversight because
of the ability to move to the post-market surveillance programs
that are going to be based on larger databases, much more
effective information technology tools, and we will be able to
provide much more rigorous oversight of these trials----
Mr. Waxman. But do you have tools to make sure the
companies do what they promise? Do you have the authority to
require a company to look at their own drug when important
safety things emerge after approval, or do you have to engage
in discussions with the companies and hope that they will agree
to be doing these studies that they promised they would do
before the approval?
Dr. von Eschenbach. Well, the development of the studies
can be a condition in the process as part of the approval
process. I think the important issue is to first make certain
that we are creating a pathway and a post-market study scenario
that is both effective, efficient, and rational to get better
outcomes and better results.
In addition to that, we are engaged in informing
legislation that is addressing the larger issue that you raised
with regard to authorities. But my purpose and focus in
addition to that and providing that technical assistance to
considered legislation is to look at the process itself and
make that better as well as oversight and authority.
Mr. Waxman. Well, your assumption is that the process is
the problem, and I am submitting to you that ultimately, you
don't have the tools. As I understand it, the only thing you
can do is to take a drug off the market for failure to submit
these studies. That is a pretty harsh sanction. Dr. Jenkins,
who you know from the Director of the Office of New Drugs, said
that pulling the drugs from the market for failing to complete
a post-approval study is just not an attractive option.
Has FDA ever taken a drug off the market for failure to
complete a post-approval study?
Dr. von Eschenbach. Not that I am aware of, sir, but I
would look at the record for that and provide further
information for the record for you.
Mr. Waxman. Sir, do you agree with the OIG that you lack
the ability to enforce compliance?
Dr. von Eschenbach. Well, I believe the opportunity to
enforce compliance is ultimately there. The effective way of
achieving compliance I believe is to get much better studies in
the first place, target them much more appropriately, monitor
them----
Mr. Waxman. In the first place meaning before approval?
Dr. von Eschenbach. As part of the process of approval,
yes, sir, and the development of the studies themselves.
Mr. Waxman. Well, you are under pressure because of PDUFA
and the user fees by the manufacturers to push for faster
approval of the drugs, not to slow down and require that more
studies be done that might give us signals for post-market
problems that otherwise wouldn't be anticipated.
Dr. von Eschenbach. Well, in PDUFA part of that process
will provide resources, FTEs, talented individuals who are
skilled in these areas to be engaged in the process earlier on
so that I think the resources will match the need, and we will
get the desired outcome that you are anticipating and wanting.
Mr. Waxman. I just want to leave this area by commenting
that I don't think you have sufficient authority, but I also
don't think you have sufficient resources, and I want to work
to make sure that you have the ability to do that, because if
you have to prioritize with inadequate resources, I am afraid
that very important functions get cut.
I want to ask you about drug advertising because I think it
plays a profound role in drug safety. When drug companies are
permitted to oversell new products whose risks are not yet well
established, the risks to the American public are substantially
increased. The Vioxx case was an example of that. And I want to
ask you about the pattern at FDA that is so troubling.
In 2002, I issued a report that found that enforcement
actions for false and misleading advertising dropped
dramatically during the Bush administration. GAO later largely
agreed with these findings. In 2004, I updated this report and
found that enforcement actions against false and misleading
drug acts continued to decline. The number of enforcement
letters sent by the Bush administration in 2003 was 75 percent
below the average for the last years of the Clinton
administration. When enforcement actions did occur, they were
mild mere slaps on the wrist and most of those were notice of
violations letters that required no corrective action from the
companies, rather than more severe warning letters. Even repeat
offenders faced no increased actions or sanctions.
FDA has the authority to issue injunctions and fines to
manufacturers, but none of these were issued in the timeframe
of the report. I am concerned about the ability of your Agency
to oversee these ads. At the time of my report, your Agency
received over 3,200 promotional pieces every month. That is
over 36,000 ads each year. How many staff are available to
review 3,200 advertisements each month, do you know?
Dr. von Eschenbach. As you point out, sir, the need to
increase our resources to be able to address this is, in fact,
part of our budget process for the current budget being
considered, as well as included in the reauthorization of
PDUFA, so that we will direct more resources to be able to more
effectively monitor and act upon direct to consumer
advertising, particularly from the point of view that is being
presented in visual media television ads.
Mr. Waxman. I know you need the resources, but I understand
the Bush administration decided it was essential, as they
claimed, to first review all the enforcement letters that went
to the companies, and then they said they want to just focus on
the worst violations and take strong action to follow up.
Can you tell us in the last 5 years how many court actions
the FDA brought against companies that have had repeated
violations?
Dr. von Eschenbach. No, sir, I will respond to the record
for you on that one when I get the exact data. I don't have
that.
Mr. Waxman. I would like to get it. I think it will show
very little action. This is all before you got there. We want
to work with you to change the situation. I think it has been
troubling.
Dr. von Eschenbach. Thank you, sir.
Mr. Waxman. Thank you very much, Mr. Chairman.
Mr. Stupak. Thank you.
Mr. Whitfield for 10 minutes for questions.
Mr. Whitfield. Thank you, Mr. Chairman.
Mr. von Eschenbach, to follow up on a comment by Mr. Waxman
of California, in regard to these post-marketing studies, he is
making the point that the Agency needs additional enforcement
authority, and the way to get that is through legislation. I am
really not familiar with these post-marketing studies, but
could you explain the process that companies go through in
conducting these post-marketing studies, just in a brief way?
Dr. von Eschenbach. Well, this is a very important area and
opportunity, I believe, Mr. Whitfield, where we now have tools
that were literally not available to us even 5, 10 years ago.
We are now able to look at large populations, be able to
acquire and analyze, if you will, data mine the actual
experience of that drug being used in that real world
environment. Often, diverse populations that were not included
in the original trials and clinical trials, often populations,
as has been pointed out by others, that are taking other
medication. So that opens up for us an entirely different
database with which we can learn about the drug both from the
point of view of unexpected, unpredicted adverse outcomes, but
also importantly, unpredicted and unexpected efficacy or
benefit that could give even further insight into the drug
development process.
So this is an extremely important part of a discovery,
development, delivery continuum, and it is essentially, in
short phrase, being able to gather data from large diverse
populations about the actual experience of the drug.
Mr. Whitfield. And what can you as an Agency do if a drug
company does not complete a post-market study? What options do
you have?
Dr. von Eschenbach. Well, as the ultimate option as part of
a commitment, our ultimate option is to withdraw, but----
Mr. Whitfield. Other than withdrawal.
Dr. von Eschenbach. Working directly with making that data
and that information known about lack of compliance and
publicizing that, so that there is a significant awareness in
the medical community of the fact that there is a lack of
compliance to that commitment.
Mr. Whitfield. I would think that publicizing would be an
important tool to have, and how often does the FDA really
publicize the fact that a post-marketing study has not been
completed or not----
Dr. von Eschenbach. Well, data is provided, obviously, to
Congress in the form of an ongoing report, but I think it is
true and important to point out that as we direct any kind of
action, there is both the goodwill of the sponsor, there is
also the publicity that is associated with lack of compliance,
and then ultimately, a regulatory authority.
Mr. Whitfield. Right. Mr. Stupak mentioned, I believe, in
his opening statement that Dr. David Ross, who is a former FDA
employee, testified before this committee about a meeting on
Ketek in late June 2006 with the Center Director, Dr. Stephen
Galson, and that you were invited to attend that meeting. I
think Mr. Ross talked about that you compared the FDA to a
football team, and having worked for a Fortune 500 company
myself before being in Congress, I do know the importance of
team building and people having that relationship. I think that
is very important, certainly, in a Federal Agency as well.
But Dr. Ross evidently came away with the impression that
an effort was being made to silence dissent on concerns of
particular drugs and a frugal process. You were at that
meeting, and I would just like you to respond to that. I am
assuming that you certainly would not discourage dissent at the
Agency.
Dr. von Eschenbach. Thank you, Mr. Whitfield.
First of all, let me emphatically express to you, to the
chairman, and to all members of the committee that I am
adamantly in support of and committed to the perfection of
legal rights for every single employee within the FDA or any
organization that I am associated with. That will be unwavering
on my part.
I deeply regret if there was a misunderstanding on the part
of Dr. Ross in terms of my comments. I would hope to have had
the opportunity for him to raise that, his misperception with
me directly so I could have corrected it. but in terms of the
question you posed, it reflects the perspective that I shared
earlier about my approach to the need for the FDA to be a
science-based and science-led academic-like organization that I
wish to provide an environment, if you will, a locker room, an
environment in which people with diverse points of view,
completely different perspectives on an issue or problem can
come together with mutual respect and vigorously, even
aggressively, debate and discuss those issues, and do that in
the comfort of that being respected and supported and even
encouraged--even, quite candidly, from my standpoint, expected.
That was the intent of my remarks was to create the awareness
among everyone that I really fully wanted to support diverse
opinion and vigorous discussion and debate.
I think the issue that is important to point out is that
that is where that kind of process can go on and be very
constructive to informed decision-making. When people don't
choose to participate in that and aren't willing to be a part
of that, and then simply express opinions independent of that,
I don't think that is helpful to the process.
Mr. Whitfield. I am not sure you were at the FDA at this
time, but officials in the Office of Drug Safety at FDA
evidently on the issue of serotonin reuptake inhibitors had
prevented a scientist from presenting to an advisory committee
his findings that the SSRIs posed a significant risk of
increased suicidal tendencies in a teenager.
Now, I am assuming that there would be--is there ever a
time when it is just not appropriate for a scientist to go
before an advisory committee to express his concerns? I am not
a scientist but I am assuming that it is non-scientific data
that it would not be suitable. Am I wrong or not?
Dr. von Eschenbach. Well, in general, Mr. Whitfield, as one
approaches an advisory committee, I think there is a very
significant commitment to presenting all the data that is
appropriate for that particular decision-making process. It may
be that if all of that data is not available at the time, it
would be perhaps not helpful to just present one part of it.
You would want to wait until you got the other parts of the
data from other sources, perhaps, or other studies, and then
present it all as a package so the advisory committee could see
it all. That may be one reason why you ask someone to withhold
presenting their data at a particular meeting, but not to
suppress data or not to prevent it from being presented or
surfaced, but to do it in the context of a full portfolio of
information.
Mr. Whitfield. Because you have to have transparency, that
is where you come up with your best product, when everyone has
an opportunity for input and to express their opinions, and
then the committee makes their decision based on that.
Dr. von Eschenbach. Absolutely, and I am adamantly
committed to creating a culture, if you will, an environment at
FDA that both encourages and expects everyone to have an
opportunity to express their perspective and their point of
view about a particular issue.
Mr. Whitfield. Weren't you the chief operations officer at
M.D. Anderson at one time?
Dr. von Eschenbach. Executive vice president and chief
academic officer.
Mr. Whitfield. Yes. So you always have these scientific
medical debates going on.
How do you deal with situations where maybe it is a
disgruntled employee, sometimes maybe it is an employee who has
a legitimate scientific dispute, when they go out to the news
media outside the spectrum of the organization, how do you as a
chief executive officer deal with that and balance that?
Dr. von Eschenbach. I think it is very important, in
addition to creating the environment and the opportunities and
the appropriate forums for the kind of discussion debate, to
also have pathways and mechanisms where people who have issues,
either about the process itself or have issues about the
conclusion that may have been drawn, that there are alternative
pathways for them to be able to bring their individual point of
view. That can be done through a grievance process, that can be
done through an appeal to a superior, it can be done in a
variety of different mechanisms.
One of the things that we need to always be sure of is that
we are providing multiple pathways where people feel that they
can have their perspective or point of view both heard and
appreciated and valued.
Mr. Whitfield. Thank you.
Mr. Stupak. Thank the gentleman.
I recognize the chairman of the full committee from
Michigan, Mr. Dingell, for 10 minutes for questioning, please.
The Chairman. Mr. Chairman, thank you for your courtesy,
and again, thank you for this hearing.
Commissioner, these questions will almost all be answerable
by yes or no. First of all, Senator Grassley sent you a letter
dated March 9, 2007, requesting that you clarify your position
on the rights of the FDA employees to talk to the Congress. Yes
or no?
Dr. von Eschenbach. I fully support their opportunity to--
--
The Chairman. No, but he sent you that letter? Is that
right, he sent that letter?
Dr. von Eschenbach. My recollection is that is correct,
sir, but I would----
The Chairman. Commissioner, the Lloyd LeFaud Act passed in
1912 protects Federal employees who blow the whistle to Members
of Congress. It states as follows,
The right of persons employed in the civil service of the
United States, either individually or collectively, to petition
the Congress or any member thereof, or to furnish information
to either House of Congress or any committee or Member thereof,
shall not be denied or interfered with.
Are you aware of this provision of law?
Dr. von Eschenbach. Yes, I am, sir.
The Chairman. Now, Commissioner, do you understand that FDA
employees then are free to share information with the Congress
without notifying their supervisors or the Office of
Legislative Affairs?
Dr. von Eschenbach. Yes, sir.
The Chairman. Now, Senator Grassley suggested that you
notify all FDA employees that they are free to talk to
Congress, and that you do not intend to interfere with their
rights to share information with this Congress. Have you done
that?
Dr. von Eschenbach. Yes, Mr. Chairman. November 30, I
issued to all FDA employees as Acting Commissioner a three-page
memorandum that specifically addresses, I think, the concern
and issue that you are raising. I didn't do it in response to
Senator Grassley's letter, I had done this as a matter of
policy back in November 2006.
The Chairman. Now, Commissioner, I assume then you
understand that neither you nor any other manager at FDA or any
other Government agency may interfere or retaliate against an
FDA employee or an employee of any other agency who shares
information with the Congress. Is that so?
Dr. von Eschenbach. Yes, sir.
The Chairman. Now, are you aware that the Office of
Internal Affairs has been used to attempt to identify and
threat whistleblowers?
Dr. von Eschenbach. No, sir.
The Chairman. Are you aware of any instance when the Office
of Internal Affairs has investigated allegations of unlawful
harassment of whistleblowers?
Dr. von Eschenbach. No, sir, not to that specific.
The Chairman. Now, Commissioner, this committee has made
document requests involving Ketek, the closing of FDA labs, and
conflicts of interest in FDA contracting. The responses to
these requests have either been late, incomplete, or redacted,
or all three. Do you recognize this committee has a right to
full, complete, timely answers to the questions regarding those
or any other subject?
Dr. von Eschenbach. Yes, sir, I am committed to providing
the information that is appropriate in response to those
inquiries, and doing it in a timely fashion.
The Chairman. Now, Commissioner, have any of the problems
with regard to the response to these requests come because of
intervention by lawyers or other HHS employees?
Dr. von Eschenbach. Only to the issue of the
appropriateness of the information being provided.
The Chairman. Only to the what?
Dr. von Eschenbach. Appropriateness of the information
being provided with regard to, for example, redacting
confidential proprietary information, or access to a line
investigator who was in the midst of an investigation. That
kind of guidance has been provided.
The Chairman. What steps will you then take to assure that
investigations by this committee are not delayed or slow-rolled
or misled by incomplete or redacted document production?
Dr. von Eschenbach. My commitment to fully cooperate with
the committee and any of those investigations and to continue
to live up to that assurance by providing appropriate
information upon request, and providing in the appropriate way.
The Chairman. Now, Commissioner, Senator Grassley has
introduced a bill to improve drug safety by establishing the
independence and the authority of a post-market safety office.
Do you agree with that proposal?
Dr. von Eschenbach. No, sir, I do not.
The Chairman. You do not. Why?
Dr. von Eschenbach. I believe that we have and are entering
into an entirely new era of science and technology in which
integration and coordination is far more an effective way of
being able to accomplish the goal of assuring effectiveness and
safety of the application of these drugs in the market, and
doing that in silos that tend to then be separate and apart and
do not then benefit from the opportunities to, first of all,
integrate the science of safety and effectiveness, and also to
be able to integrate the tools of our being able to understand
and analyze the real world experience of these drugs.
The Chairman. Thank you, Commissioner.
Mr. Chairman, this will surprise everybody. I yield back
the balance of my time.
Mr. Stupak. You are correct. We are stunned.
Mr. Barton for 10 minutes of questions, please.
Mr. Barton. Thank you, Mr. Chairman. I needed that extra
three minutes and 50 seconds to get ready. I am somewhat at a
loss here, but I will try to make up for it.
Dr. von Eschenbach, you were very active down in Houston at
the M.D. Anderson Cancer Center. I think that is where I first
met you. How many people were under your direct supervision,
ultimately, in your leadership position down there?
Dr. von Eschenbach. As far as faculty itself, independent
of fellows and residents and interns, but as far as faculty of
physicians, scientists, clinicians, over 1,000.
Mr. Barton. I don't want you to pat yourself on the back,
but my recollection is that your position down there, you were
universally recognized as one of the more outstanding cancer
center directors in the country. You had a positive reputation.
Dr. von Eschenbach. Thank you, sir.
Mr. Barton. You would agree to that.
Dr. von Eschenbach. My mother certainly does. Yes, sir.
Mr. Barton. You weren't unhappy in Houston; you were not
into self-promotion to come to Washington to--you would have
been happy to stay down there and do great things at M.D.
Anderson?
Dr. von Eschenbach. Yes, sir.
Mr. Barton. The President, basically, recruited you to come
to Washington and ultimately because of the prior
Commissioner's problems, to some extent you were the white
knight asked to go in and--I won't say save the FDA, but
reestablish morale and credibility to the FDA. I am not trying
to make you pat yourself on the back, but there was quite a bit
of hope when you were nominated to be Commissioner at the FDA,
that you could reestablish the credibility of the Agency. Is
that a fair statement?
Dr. von Eschenbach. I think the best way, perhaps, I can
express it is I did come to the FDA in response to a crisis not
by my own choosing or by my own intent or aspiration. That is
correct.
Mr. Barton. Now, we have an ongoing investigation that the
minority supports the majority looking into some of these
allegations of the whistleblower, Dr. Ross, with response to
the drug Ketek and whether it should be on the market or not on
the market and under what conditions, and we fully support. I
don't want there to be any misunderstanding. We fully support
the document requests, we fully support trying to get to the
bottom of it, but we want to do it in an open, transparent,
constructive way. We do have this investigation, we are
supportive, so I don't want to preclude any of that.
But I do want to ask a few questions, since Senator
Grassley testified, and I think it is fair that when we have
you here under oath that we can go into that a little bit.
This meeting where you made the comments about trying to be
a team player, whatever it was, that was not a meeting that you
called, is that correct?
Dr. von Eschenbach. That is correct, sir.
Mr. Barton. You were invited by the Senate Director?
Dr. von Eschenbach. Yes, sir.
Mr. Barton. OK. And Dr. Ross was at that meeting, is that
correct?
Dr. von Eschenbach. Apparently he was.
Mr. Barton. How many people were in the meeting?
Dr. von Eschenbach. The room was full and I would estimate
probably 30.
Mr. Barton. Thirty or 40 people.
Dr. von Eschenbach. Forty, something like that.
Mr. Barton. And at some point in time, the Senate Director
turned to you and asked if you wanted to make any remarks, and
you kind of felt compelled at that time, were you the
Commissioner or were you Acting?
Dr. von Eschenbach. Acting.
Mr. Barton. Acting. You felt compelled to participate. What
was your frame of mind when you made those remarks? Were you in
an intimidating frame of mind, were you in a healing frame of
mind, were you in a I would rather be anywhere but here frame
of mind? What was your frame of mind?
Dr. von Eschenbach. Well, as you point out, Mr. Barton, I
came to the FDA in the sense of in response to a crisis. I
became very acutely aware of the duress that the Agency had
found itself in for a variety of reasons. The stresses and the
strains of the enormous amount of responsibility that that
Agency bears, the increasing complexity of the products that it
is being asked to regulate, both in scale and scope, et cetera,
et cetera. And what I found my most important responsibility
was was to begin to talk to the people of FDA and bring them
together, create an enhanced environment of morale, and begin
to bring us together to look more positively at the future as
to how we were going to be able to together address the
challenges, to address the issues, and to continue to improve.
There was an agency that was beginning to celebrate its 100th
anniversary of being the world's gold standard, and I wanted us
to look forward to the next century, the 21st century, and be
the FDA of the 21st century.
Mr. Barton. So you were really there to listen, to
participate if asked, but you weren't there, in your mind, to
try to single out individuals and intimidate them to keep their
mouths shut?
Dr. von Eschenbach. Absolutely not, just the opposite. I
was there to reinforce the model that I learned at M.D.
Anderson where it was so important to not have people working
in isolation and silos, surgeons here and medical oncologists
there, but a woman with breast cancer needed all of us coming
together, working for her behalf. I believe that is the way
that the FDA can best become the FDA of the 21st century is
coming together as an organization, working together. And that
is what I was there to indicate to them was my vision of
leadership and what I was hoping to promote.
Mr. Barton. At the time of this meeting, had you met Dr.
Ross?
Dr. von Eschenbach. I can't recall ever meeting Dr. Ross.
Mr. Barton. To this day you have not met him?
Dr. von Eschenbach. No, sir, not that I can recall. He
might have introduced himself to me at some point, but not----
Mr. Barton. Based on what you know of Dr. Ross, do you have
a high opinion of him, a positive, professional opinion? I
understand he is no longer at the Agency and I think he has
moved to the VA, so----
Dr. von Eschenbach. My understanding of his credentials and
background, I have a high opinion of him, but I don't know him
personally.
Mr. Barton. And I would assume you support the
investigation to try to--if there are things that we can do to
make sure that the FDA is run in an up-front, transparent
fashion, you would be supportive of that?
Dr. von Eschenbach. Absolutely, absolutely. I welcome the
opportunities for oversight. That is the only way we
continuously improve is to be thoughtful and even self-critical
of that process. I never did an operation in my entire life, no
matter how well it turned out for that particular patient, my
response and duty to the patient was to follow, how could I do
it even better? So no matter how well we perform at FDA, I will
constantly be asking how can we do it even better, and I will
seek input and insights from a whole host of sources, both
inside and outside the Agency, to address that question, how
can we be even better.
Mr. Barton. Well, we have had ongoing issues with the FDA,
really, I would say for the last 20 years. We had issues with
Dr. Kessler when he was chairman of the FDA. Congresswoman
Eshoo and I introduced an FDA reform bill that is now law. It
is so important that we operate--and the FDA is one of the most
important Federal agencies, because we are the gold standard
for drug approval and safety issues for our drugs, medical
devices for our country and the world, and so this subcommittee
has a long bipartisan history of paying very close attention to
your Agency and very close attention to the way it reviews
these drugs and medical devices. And in order to have the best,
you have to have the ability within the Agency to dissent on
some of these literally life and death issues, and from all I
know, Dr. Ross was doing exactly what he felt he should do,
acting in a very positive, professional fashion. Some of these
are tough judgment calls. All I ask that you do in your
position of leadership at the FDA is insist that we have these
high standards and that we have a mechanism within the FDA.
There can be dissent, there can be debate, that people are not
punished for speaking out on policy grounds, and that we have a
method of reconciliation in the FDA to resolve these issues in
a fair fashion. Do you agree with that?
Dr. von Eschenbach. Yes, sir, I do.
Mr. Barton. Madame Chairwoman, I yield back.
Ms. DeGette. [Presiding] Thank you very much.
Commissioner, the first thing I want to ask you. You had
mentioned to the chairman, Mr. Dingell, that there was a memo
that you sent to the staff that Senator Grassley requested. I
am wondering if you could provide the committee with a copy of
that memo?
Dr. von Eschenbach. Madame Chair, just so I think I clarify
my response, I sent a memo to the staff on November 30, and I
will be happy to submit it for the record. I don't believe the
timing of this memo was in response to Senator Grassley's
letter. It was independent.
Ms. DeGette. OK. If you could provide us with a copy, that
would be great.
Dr. von Eschenbach. Yes.
Ms. DeGette. Commissioner, I know you will agree with me
that FDA credibility is its most important asset, and there is
a lot of concern that the pharmaceutical user fees that are
contained in PDUFA which support FDA operations have
contributed to a significant loss of public trust in the FDA.
So my first question is, how can restore the public faith in
the FDA when so much of the funding from PDUFA funds the speed
of drug approvable, and arguably, sometimes at the expense of
drug safety?
Dr. von Eschenbach. Well, Madame Chair, I think there are a
number of points I would like to make in response to the
question, because there is not one thing but many things that I
think we need to do to assure the confidence of the American
people that we are, in fact, serving them and no one else.
First of all, it is the issue of openness and transparency
in the decision-making process, regardless of where the sources
of resources or funds are coming from to provide that
infrastructure of the decision-making process is open and
transparent.
Ms. DeGette. And I agree with you on that. Are there ways
we can improve the transparency, because that is one of the
critiques of the approval process.
Dr. von Eschenbach. Yes, ma'am. I believe that there are a
number of ways we can improve process as it relates to our
decision-making and our communication of that decision-making.
I also believe that there are opportunities that, for example,
making certain that those fees are compartmentalized, used only
for the purposes for which they were applied. Investigators do
not have any direct knowledge of where their support is coming
from with regard to their own professional functions, which is
another important component. We want to separate this idea that
people are motivated by a source of their resources. They work
for the FDA.
Ms. DeGette. Right. What else?
Dr. von Eschenbach. In addition to processes that are
continuously improved, I think one of the important parts of
PDUFA IV negotiations is, in fact, that many of these funds
will now be used to specifically address the safety dimension
and component of drug approval, not just decisions about
efficacy or streamlining the approval process.
Ms. DeGette. Have you put these improvements in place or
are you working on that?
Dr. von Eschenbach. Some of the improvements as outlined in
our report following the IOM study that we commissioned, some
of them are in place. Some of them we are actively engaging in
as we speak, and some of them will be implemented as we get
further resources in the budgetary cycle.
But I want to just emphasize, Madame Chair, that even
those 41 initiatives that are currently as a part of that
report is a major step, but not the only step, and I am
committed to even further efforts to continue to improve this
process.
Ms. DeGette. Do you think that all of these efforts that
you have undertaken will take the inherent conflict of interest
out of PDUFA? We have had witnesses come in to talk to us, and
they just flatly said no matter what you try for transparency
and the compartmentalization of the fees and so on, you still
have an inherent conflict of interest.
Dr. von Eschenbach. Well, I view the issue of the user fees
to be a service to the American people, not a service to the
FDA or to the industry, even though there is a way of creating
this process so that it benefits all three. It is so that drugs
can be more efficiently approved and understood with regard to
their expected benefit and their expected risk. And the sooner
we bring them to the American people with the better
information to define their use and be able to continue to
monitor their use even after we approve them, I think really
then serves the American people best.
Ms. DeGette. Yes. How are you going to monitor all of those
things, because you know, we agree that it is important to
bring drugs quickly to market, but we also think that it needs
to be, obviously, safe and so how do you monitor that?
Dr. von Eschenbach. Well, that is the opportunity to take
advantage of what is emerging with regard to science and regard
to technology. Literally we now have information technology
tools and data mining tools that are being used in other
industries like banking, for example, or even your supermarket,
knowing about the purchases of the food that you are making.
Those kind of information technology tools can be applied now
to databases where we have large populations of patients, for
example, our agreement with the Veterans Administration, our
agreements that are emerging with the Center for Medicare and
Medicaid Services, and even large healthcare systems like
United Health, as they go to electronic medical records, we can
begin to really engage in a much more profound post-marketing
opportunity of pharmacal vigilance that I think will give us--
--
Ms. DeGette. And you think that data mining will be
sufficient post-market? I think it will be a tool, but will it
be enough of a tool?
Dr. von Eschenbach. Well, I think it is a major step. Other
steps that we can continue to define, as I said, I see this as
a process of continuous improvement. As other opportunities
present themselves, I look forward to engaging in those.
Ms. DeGette. The IOM report, and also four former FDA
commissioners, said last month that the Nation would be better
served if rather than funding PDUFA the way we do, Congress
just directly appropriated the money that the FDA needs to
review these drugs and get them to market. What do you think
about that?
Dr. von Eschenbach. Well, as I indicated, we are attempting
to build a resource base that presents both to the American
people and to the Congress options as to how we can fund that.
PDUFA happens to be one of the options that has been in place.
I think it is an option that has served us well. It needs to be
constantly continuously monitored, as you indicate, but it is
an important part of the resource base.
Ms. DeGette. But my question to you is, we are funding
PDUFA right now through these fees, and so the question I am
asking you--and I know that is the way we are doing it, but the
question is would it be better as the IOM and the FDA
Commissioners said, to just eliminate that portion which
creates a conflict of interest and go to direct congressional
appropriations?
Dr. von Eschenbach. Well, I think that the issue there is
it puts an even further burden on the American taxpayer, and
when there is an opportunity for others to contribute or
participate in the support of this process, I think it is
appropriate as long as it is done in an appropriate way.
Ms. DeGette. So you think that we can take the inherent
conflicts of interest out sufficiently through the ways that
you talked about to continue this funding?
Dr. von Eschenbach. I think we can be vigilant and vigorous
in that process, and at the same time, have the industry
contribute a share of the burden of being able to get these
drugs to patients in a much more efficient and effective way.
Ms. DeGette. What percentage of the CDER staff would you
estimate are focused on review and approval of new drugs? Do
you have a sense?
Dr. von Eschenbach. I cannot give you an exact percentage
of that. I would be happy to respond to that for the record of
an exact number.
Ms. DeGette. What about how much of their resources are
focused on the post-market safety of drugs?
Dr. von Eschenbach. Well, up to the present time, there has
not been a significant investment in post-market. It has been
evolving and I intend to accelerate it.
Ms. DeGette. In fact, we have had an estimate that Dr.
Graham estimated that 90 percent of the staff are focused on
review and approval of new drugs, and just a small 10 percent
or so are post-market safety review. Would you generally agree
with that?
Dr. von Eschenbach. I would generally accept a number. I
would have to look back to give you my own precise number, but
the fact of the matter is, I think we are changing that. I know
we are changing that. We are integrating the Office of
Surveillance and Epidemiology much more effectively and
efficiently into the new drug application process, and my idea
of----
Ms. DeGette. What is your timeframe for doing that?
Dr. von Eschenbach. We are doing it as we speak.
Ms. DeGette. So if we had you come back here in 3 months,
you could talk to us about the improvements that you have made?
Dr. von Eschenbach. Yes.
Ms. DeGette. Does the FDA have the funds to do the data
mining that you say you are going to do?
Dr. von Eschenbach. Well, we look forward to the
appropriations--that request is before Congress now to provide
these additional funds.
Ms. DeGette. So you don't have the funds right now, you are
going to need an additional appropriation?
Dr. von Eschenbach. We have requests for additional
appropriations, both in PDUFA IV, as well as in our
appropriations.
Ms. DeGette. And if that request does not come through, is
it your testimony that you won't have the funds to do it?
Dr. von Eschenbach. There will not be adequate funds to do
all the things that we have to do. We may make decisions with
regard to the use of our funds to apply them to this as a
priority, as opposed to something else within the Agency, but
we would have to find the funds somewhere else.
Ms. DeGette. Thank you.
Chair recognizes Mr. Burgess for 10 minutes.
Mr. Burgess. The last remaining member of the committee.
Thank you for the recognition. Again, thank you, Dr. von
Eschenbach, for being here. We appreciate you taking time out
of your schedule to be with us.
Let me just ask a question that is a little bit off the
point. I know when I was in clinical medicine, I resented the
fact that FDA took so darn long to approve anything. Europe
could have drugs decades before we could. And then we hear from
the committee this morning that maybe the FDA moves too fast on
approving some products. And then in a few weeks, we are going
to be talking either in this committee or the health
subcommittee about the concept of generics for biologics, big
large biologic molecules that some people believe that the
Federal Government can save billions of dollars if we move to a
generic process for that.
So do you see a problem with our consistency?
Dr. von Eschenbach. Well, I think, Dr. Burgess, we are
moving very much into an era where I don't believe that the
idea of moving the approval process through more efficiently
and more effectively necessarily means that it is therefore
allowing more dangers on drugs to be applied to patients. I
think the science is allowing us to both understand adverse
outcomes, as well as effectiveness, in a much more profound way
than we did before. As we move that process more efficiently
and more effectively, I think we are bringing both safe and
effective drugs to patients.
Mr. Burgess. Are we making unreasonable requests on the
FDA, asking you to approve the safety of generic biologics
since these are different from, say, a statin or an antibiotic?
These are much more complex molecules.
Dr. von Eschenbach. Well, that speaks exactly to the point
of science having to be the basis upon which those decisions
are made. As it relates to follow on proteins, as many have
appreciated, the complexity that is involved in complex
proteins is orders of magnitude different than what we
experience in small molecules that are drugs. And therefore,
the science that is required for us to be able to approve an
abbreviated application for a follow on protein is radically
different and much more complicated, much more sophisticated,
and some of it is not even developed. So we have to take an
appropriate approach to the particular issue.
Mr. Burgess. Let me ask you a couple of questions dealing
with the questions that Chairman Dingell was asking you about
Senator Grassley's letter. My understanding is a lot of that
came out of a newspaper article that was written after you
addressed a group called the Center for Public Medicine and
Interest, and the Newark Star Ledger reported that you would
not tolerate whistleblowers who go outside the Agency. Do you
think that article accurately reflected your remarks that day?
Dr. von Eschenbach. No, sir, it does not, and
interestingly, for purposes of recording my speech for the Web
site, that presentation and that question and answer period
afterwards actually was taped, which there is a transcript, and
my remarks were not in any way, shape, or form addressing the
issue of whistleblowers. I never used the word. They were
simply talking about a culture in which you have vigorous
academic debate and how constructive that can be when people
participate within that construct and within that opportunity,
rather than choose not to.
Mr. Burgess. Have you taken steps to address that?
Dr. von Eschenbach. Well, with all the other important
things to address, I didn't chose to respond. I think there has
been a second article written by that same newspaper, and there
is a letter to the editor that is now being prepared, since it
has occurred the second time in terms of a misquote of what my
comments were. So I hadn't before, but we are in the process of
doing it now.
Mr. Burgess. Then I guess just for the edification of the
committee, can you tell us your position on whistleblowers?
Dr. von Eschenbach. I fully support the legal rights of
every single individual at the FDA to exercise their response--
whistleblower, in that context, yes, sir.
Mr. Burgess. Going back to some stuff that Ranking Member
Barton was asking earlier, I believe Mr. Barton and Mr.
Whitfield have sent a letter to the HHS Inspector General
requesting an evaluation about the delays in FDA's disciplinary
actions against clinical investigators who have been convicted
or found to have engaged in misconduct during a clinical trial
regulated by the FDA. Do you have concerns over delays in the
FDA disqualifying individuals convicted or found to be
falsifying data submitted to the FDA?
Dr. von Eschenbach. Well, I respect the fact that there is
a legal process, and that legal process has its own inherent
pathway, if you will, that is beyond any control that we have.
Having said that, I believe that the FDA must be rigorous and
must be efficient and take rapid steps when those kind of
actions need to be employed.
So I can't control how long a legal process may take, but I
certainly expect the Agency to act promptly in initiating any
kind of process, once it has been recognized that there is an
issue.
Mr. Burgess. Currently, there is a Memorandum of
Understanding reached between the Inspector General of HHS and
the FDA, going back to 1994 and the HHS Inspector General
seated its authority to investigate the FDA matters--seated
that authority to the FDA. Assuming that the Inspector General
of HHS receives additional resources and wants to resume its
investigative authority over the FDA, would the FDA be open to
working with the Inspector General of HHS and letting the IG's
Office resume direct responsibility over FDA employee
misconduct cases and thus render unnecessary the FDA Office of
Internal Affairs?
Dr. von Eschenbach. Yes, sir, I would be open to any
discussions about how we can improve the process. I think that
we have always welcomed the Inspector General's participation
in any investigation, any process. There is value to having the
Office of Criminal Investigation within the FDA as at least a
part of that process because it provides the opportunity to
have individuals who are really extremely knowledgeable and
skilled about the unique particulars of the business of the FDA
in terms of the complexity of drug reviews and manufacturing,
et cetera, so that as we engage in investigations, they really
are both content experts and imbedded in the knowledge base by
being part of the FDA.
Now, they may not need to be the sole participant, but I
think to totally completely dismiss that element in favor of
something else might lose things that you want to retain while
you're trying to address another issue. So I am open to
discussions. I look forward to continuing to improve that
process, as I will any others, but I would just mention that I
think there is an important role for the internal process
within FDA.
Mr. Burgess. Thank you. You have a lot of written testimony
about the drug Ketek, which came to be available after I had
left the practice of clinical medicine, so I have had no
experience with that antibiotic. Do you think it is a
worthwhile addition to our antibiotic----
Dr. von Eschenbach. Yes, sir, I do, because as you know as
a physician, we have constantly struggled with continuing to
find and develop new antibiotics that would overcome resistance
that generally can occur with organisms that adapt and with
serious infection, the need for newer, more effective
antibiotics is a constant ongoing process, and any addition to
that can be a very valuable contribution to public health.
Mr. Burgess. The FDA has been criticized for going forward
with its advisory committee meeting even though the individuals
connected to the large-scale clinical trials were still under
criminal investigation and scientific misconduct
investigations. In a briefing with the staff, Dr. Jenkins, the
head of the Office of New Drugs, stated the same factual
pattern, if it presented itself to the FDA in the future, he
was of the view that the FDA would postpone the hearing and get
the results of the investigations first. Do you think that is
worthwhile position to take?
Dr. von Eschenbach. Yes, sir. This occurred prior to my
arrival at the FDA, but as I have looked at this process and
have been briefed on it, I believe that they made the best
decision they could at the time, given the information that
they had. But again, this concept and commitment to process
improvement and continuous improvement, as we look back upon
that in terms of lesson learned, I agree that it would--going
forward, not bringing that advisory committee together until
the issue of the data had been resolved would have been a more
preferable and ideal way to approach it, and the way we should
approach it in the future.
Mr. Burgess. And just for purposes of clarification for the
committee and the record, many of those events took place prior
to the time you were appointed Acting FDA Administrator, is
that correct?
Dr. von Eschenbach. That is correct, sir.
Mr. Burgess. In the very brief time I have left, let me
just ask you a quick question about post-marketing surveillance
process, post-marketing safety process. In a perfect world,
what would be your vision of the correct type of post-marketing
surveillance that the FDA should undertake?
Dr. von Eschenbach. I believe we have the opportunity with
electronic databases to be able to access the real world
experience of the drug in the context of not just the drug
itself, but the unique characteristics of the person taking
that drug, because that will vary widely as we all appreciate,
based on a whole host of factors, gender and on and on. And in
addition, the interaction of that drug with other substances
that that patient may be taking, because we are seeing an era
in medicine of patients taking multiple medications
simultaneously.
So with those kinds of opportunities to see that drug in
that context, I think that will provide enormous insight and
information to us in terms of not just how to manage that drug,
but how to continue to improve the process of discovery and
development on the front end with the next generation of drugs
in that class or of that variety.
Mr. Burgess. Or for that individual, given their individual
genetics?
Dr. von Eschenbach. And by being able to, for example,
identify populations, we will have tools in terms of genetic or
genomics to stratify. We are seeing that even now for an old
drug like lophine, a blood thinner, where we now can begin to
stratify and understand patients based on their genetic makeup
in terms of what the right dose could be.
Mr. Burgess. We are going to restrict your access to
genetic data this afternoon, so hurry up and gather that.
I yield back, Mr. Chairman.
Mr. Stupak. Well, you are well over, so nothing to yield.
For 10 minutes, Mr. Inslee. We are going to try to get Mr.
Inslee in before votes. We have 10 minutes and 30 seconds, so
Mr. Inslee for 10 minutes.
Mr. Inslee. Thank you.
Commissioner, in regard to Ketek, there has been some
discussion about use of non-inferiority trials as opposed to a
test with placebos, and as I understand it, there was a
recommendation to go to a placebo test rather than just a non-
inferiority test. That makes some sense to me, given the nature
of some of the problems we have encountered. Could you tell us
if you have any plans to review that?
Dr. von Eschenbach. Well, this is an important part of an
ongoing effort to look at the entire clinical trial's
construct, Mr. Inslee. We are evolving in science and we are
evolving in our utilization of clinical trials. New statistical
models like basian statistics that will enable us to use
adaptive trial designs are now emerging so the old traditional
models that we used in the past are evolving. The movement
within, particularly, the reference you are making to non-
inferiority studies is a part of that ongoing process of
learning as far as how we can apply the right kind of trial
design to the right question.
Mr. Inslee. So I am not sure what the answer is.
Dr. von Eschenbach. The answer is we are evolving based on
our learning and understanding of the utilization of trials as
new models become available to us, and recently, the Center has
issued and is in the process of issuing guidance to where and
when non-inferiority trials are appropriate and where other
trial designs are preferable.
Mr. Inslee. I want to ask you about disclosure, the summary
basis of approval documents. There has been a recommendation
that they essentially be available publicly except for genuine
trade secrets, and that, as I understand, that issue is still
stalled. Is there any progress in that front?
Dr. von Eschenbach. I will respond to the record with
regard to the specific details of the issue and the trajectory,
but overall, I am continuously committed to providing
information and data to be open and transparent in the
processes, while we, at the same time, respect and protect, for
example, confidential information, proprietary rights, the
other kind of issues that frame our ability to legally
disseminate information.
Mr. Inslee. So I will ask you just a little more pointed
question. Would you support amending the current FDA
regulations to require public disclosure of those except for
genuine trade secrets?
Dr. von Eschenbach. I have to be certain that there weren't
other issues besides genuine trade secrets that might impact
upon that, but I am committed to looking to provide as much
disclosure as is legally and appropriately possible.
Mr. Inslee. But legally is what you decide, so you decide
what is legal. And I hope you will consider that public
confidence in this system is very, very important.
Dr. von Eschenbach. I understand.
Mr. Inslee. We have had real concerns about that. I
understand the nature of propriety and information. I come from
a biotech community. We understand intellectual property. It is
very, very important. But I think that those two things should
be reconcilable to maintain and build public confidence and
still protect that property. I believe that can be done. I
would encourage you to look at a way to accomplish that.
Dr. von Eschenbach. And I am committed to continuing to
work through those kinds of processes to move us to a better
place. I give you that commitment to work with you and others
who have a vested interest in this.
Mr. Inslee. Thank you. I yield back.
Mr. Stupak. We have about 6 minutes left in this vote, so
we will take recess until 12:15 and we will be back.
Commissioner von Eschenbach, that three-page memo of
November 26, do you have copies made on whistleblowers that you
said you sent to all your employees?
Dr. von Eschenbach. I have to----
Mr. Stupak. We will have one of our staff people get it
from you and make it be available for everybody. I will ask
questions when we get back, and whoever else arrives, and we
will be finished.
Thank you. See you at about 12:15.
[Recess.]
Mr. Stupak. Mr. Commissioner, thank you again for appearing
here.
Go to tab three of your book there. Do you have a book
there with documents in from the committee? Go to tab No. 3 if
you would, please. In there is the March 9, 2007 letter from
Senator Grassley to you concerning treatment of individuals who
may not agree, and in particular talking about the
whistleblower issues.
In the first paragraph it says ``Careful congressional
oversight of the FDA is especially important to ensure the FDA
upholds its responsibilities to the public safety by properly
regulating the Nation's drug supply. Proper role of an agency
leader is to cooperate with legitimate congressional oversight
activities, not to impede congressional inquiries, or conceal
information from Congress.'' Do you agree with that statement?
Dr. von Eschenbach. I am sorry, sir. I was just trying to
find it.
Mr. Stupak. Paragraph one, middle of the page, starts
``Careful congressional oversight''.
Dr. von Eschenbach. As I indicated, Mr. Chairman,
previously----
Mr. Stupak. Do you agree with this statement?
Dr. von Eschenbach. I agree that individuals at FDA should
appropriately cooperate and participate with Congress.
Mr. Stupak. Very good.
Mr. Burgess and Mr. Whitfield both asked you about a 2006
conversation with Dr. Ross about an analogy to a football team
and having to be on part of that team, and you indicated that
you saw this as being constructive to have adversity on the
team and in no way did you indicate that you have to be on the
team--you can't be off the team. Is that right?
Dr. von Eschenbach. As I indicated, I was discussing my
perspective on being able to create an environment to have the
opportunity for vigorous, aggressive scientific discussion and
debate, and participating in that is constructive. Not
participating in that does not contribute to the well-being of
the institution.
Mr. Stupak. So they have got to be on the same page as the
rest of the team or they are not contributing to the
institution?
Dr. von Eschenbach. No, sir. What I am intending to say,
and hopefully continue to always express clearly, is it is not
a matter of being on the same page, it is a matter of bringing
your point of view, your opinion, your diverse perspective to
the process of deliberation and discussion.
Mr. Stupak. Are you going to allow scientists and doctors
within your Agency to bring their diverse view to advisory
committees and things like that if it is not with what the
supervisor at the FDA feel it should be?
Dr. von Eschenbach. Yes, sir. We need to provide
information to advisory committees and do that in a proper and
appropriate way.
Mr. Stupak. If that was November, then the second paragraph
of that letter says ``I was extremely troubled by the
statements that the Star Ledger reported you made on February
21 at a conference sponsored by the Center for Medicine and the
Public Interest. Star Ledger reported that you expressed your
unwillingness to tolerate whistleblowers who go outside the
Agency because they disagree with the final outcome.'' You are
further quoted as saying ``The people have to understand to go
outside that process is not constructive, it is actually
destructive.'' Did you make that statement?
Dr. von Eschenbach. That statement does not apply in any
way, shape, or form to whistleblowing----
Mr. Stupak. Did you make the statement, sir?
Dr. von Eschenbach. I did not make a statement about
whistleblowers, Mr. Chairman.
Mr. Stupak. I am not saying anything about whistleblowers.
The quote is ``The people have to understand to go outside the
process is not constructive, it is actually destructive.'' Did
you make that statement?
Dr. von Eschenbach. I made that statement with regard to
the process of deliberative discussion, scientific debate----
Mr. Stupak. Well, what is the difference of, let us say,
Dr. Ross who wishes--or Dr. Graham, who wishes to testify at an
advisory panel that may not be in keeping with the position of
the FDA. Are you going to allow them to do that?
Dr. von Eschenbach. As I indicated before, the appropriate
way and the appropriate fashion of bringing all the data and
all the points----
Mr. Stupak. No, what I asked is if Dr. Graham wants to go
before an advisory panel, let us say on Accutane, one he has
been really involved with and one he has been denied to present
testimony. Are you going to continue to deny Dr. Graham the
right to testify at advisory panels on, let us say, Accutane?
Dr. von Eschenbach. I would not deny to Dr. Ross, Dr.
Graham, or any other individual within the FDA the right to
express their professional opinion and point of view about an
issue.
Mr. Stupak. OK. You indicated that there was a tape of your
statements, and did that include the questions and answers at
this conference on February 21?
Dr. von Eschenbach. Yes, it did, sir.
Mr. Stupak. OK. Will you provide that tape to the
committee?
Dr. von Eschenbach. I would be happy to do that, sir.
Mr. Stupak. Great. Would you go to tab No. 4 please, in
that same big book? It is called ``Open Letter to Members of
Congress'' dated March 14, 2007. Sixth paragraph, right on the
bottom of the page. It says ``With expiration of PDUFA this
year, the FDA and PHARMA have negotiated terms for a 5-year
reauthorization. This negotiation completed behind doors had
only limited input from the public. Unfortunately, the proposal
crafted by the FDA and PHARMA does not come close to addressing
the problems identified by IOM.'' Has that agreement been
published at all?
Dr. von Eschenbach. The agreement was published in the
Federal Register and has been subject to open public discussion
and debate during----
Mr. Stupak. After it was published, not before, right?
Dr. von Eschenbach. The negotiation resulted in a
proposal----
Mr. Stupak. And that was open to public discussion, and now
is being presented to Congress.----
Mr. Stupak. And that was just FDA and PHARMA?
There has been no public discussion, not until after it
was published, right?
Dr. von Eschenbach. It was published in the Federal
Registry, it was----
Mr. Stupak. After the publication, it is now----
Dr. von Eschenbach. Further modification before the
proposal was----
Mr. Stupak. How does one discuss it publicly if it is
already published, it is already agreed upon? How do we have
input into the process?
Dr. von Eschenbach. The proposal was agreed upon. The
proposal was still subject to modifications and based on input
from a variety of sources through both public commentary to the
Agency prior to its coming to Congress as a final proposal.
Mr. Stupak. Will you provide us the documents of those who
have had input into this process, the closed door process, and
the rest will be provided to this committee when asked?
Dr. von Eschenbach. Provide the information regarding the
process that----
Mr. Stupak. No, no, the information that went into the
negotiations from the closed door meeting that you had with
PHARMA. Are you willing to submit those documents to us so we
can see them, see who had input in the FDA and PHARMA?
Dr. von Eschenbach. The discussions that went on between
FDA and PHARMA were done with negotiating teams that were made
up of content experts on the part of the FDA to work through
the package.
Mr. Stupak. Sure. And that was done behind closed doors,
and we want to see what input drug companies had in that
process, so will you make those documents available to us?
Dr. von Eschenbach. They were part of the discussion in the
process.
Mr. Stupak. I know they were.
Dr. von Eschenbach. The documents that are available, I
would be happy to look at that and provide the appropriate
documents to you in that regard.
Mr. Stupak. Not appropriate, all documents we asked for.
There is no proprietary interest in those negotiations.
Dr. von Eschenbach. Mr. Chairman, at this point in time, I
cannot certify or testify to all the content of whatever
materials are available. I would have to go back, look at that,
gather that together, and be responsive to you.
Mr. Stupak. Sure. Let me go to page 9 of your statement.
You didn't mention much about Ketek, but let me ask you. Page
nine of your statement you allege that ``Based on the
information available, the concerns [data, integrity issues]
study 3014 apply to only one site out of more than 1,800.'' In
fact, every site that the FDA investigators looked at had
serious problems. Look at tab 20 and you will find a series of
e-mails relating to the integrity--the data integrity at the
largest sites in study 3014, including an e-mail dated December
10, 2003, where the lead investigator says it looks like the
new drug application, NDA, will have to be put on hold.' Were
you shown the e-mail traffic between the review division and
the field inspection force relating to this study when you
prepared your testimony?
Dr. von Eschenbach. No, sir, I was not aware of e-mails as
I prepared for this testimony.
Mr. Stupak. Then who prepared your testimony, someone else
in your office, or did you prepare it?
Dr. von Eschenbach. I prepared it along with my staff, and
based on briefings and information that had been provided to me
over a series of meetings with the people who were involved and
engaged in this process.
Mr. Stupak. Were the individuals that presented the Ketek
case to you aware that you would be testifying under oath and
have written statement would be sworn testimony?
Dr. von Eschenbach. I would assume they were.
Mr. Stupak. OK. Then let me ask you this. Also on pages
nine and 10 of your testimony, you state ``After considering
the fact that the investigation results were preliminary and we
have not received formal recommendations about how to take the
results into account in review of the application, and the fact
that only in very rare cases do inspection results from
individual sites lead to the exclusion of an entire large
clinical trial, FDA decided to hold the advisory committee
meeting as planned. In fact, in an e-mail dated January 2,
2003, the office director writes David Ross stating that it
would not be 'productive' to present the data integrity
concerns to the advisory committee.'' So do you believe it is
appropriate to withhold from an advisory committee a study when
the integrity of that study is the principle study of the drug
in question?
Dr. von Eschenbach. When there is an issue about a
particular part or piece of the study that has been withheld in
previous circumstances and situations, when it is apparent----
Mr. Stupak. This is part parcel. I think that was very
clear, wasn't it, in that e-mail? Do you have the e-mail right
there? I think we provided it there in tab 20, there are number
of e-mails. It is really the second to last page of tab 20
there, all those e-mails, if you look at the second to last
page. It says ``E-mail of January 2 from Mark Goldberger to Mr.
Ross. In general, I don't believe spending time on these
issues, part parcel to these issues to the AC will be
productive. I do feel that having the company make the best
possible presentation of their PM data, focusing on information
from countries where we have confidence in the reporting would
be useful.'' So it sounds like you are not trying to discourage
Study 3014 from being presented.
Dr. von Eschenbach. First of all, Mr. Chairman, in
preparation of my testimony, I do not recall ever seeing this
particular e-mail or others that you may be alluding to. I
prepared my testimony based on the principles and fundamentals
of oversight of studies and their presentation to committees,
and it has been the policy, as I have come to understand at the
FDA, that certain parts of the study would be excluded----
Mr. Stupak. This is your testimony. You bring up all these
issues. Your statements and your testimony on Ketek do not
correspond to the e-mails that are right there in front of you.
That is why I asked you who prepared the testimony. Because
what you said in your testimony, which is under oath, is
contradicted by tab 20 and the e-mails contained therein.
So either you are not being forthright with us, when I
believe you are, but whoever is doing your work is trying to
lead this committee down the wrong path. We know these issues,
we are on top of these issues, so when you come and give us
testimony that isn't accurate, we are going to call you on it.
Dr. von Eschenbach. I fully appreciate and understand that,
Mr. Chairman. What I was hoping to communicate to you was the
fact that as I have viewed and understood this matter, the
decision to remove a part of the study or not present a
particular part or element of the study has been done prior to
this case----
Mr. Stupak. But you didn't remove it. 3014 was presented,
it was relied upon by FDA and by the advisory committee and the
FDA--even on your Web site you relied upon Study 3014. To
approve Ketek, that is contrary to what you say in your
testimony.
Dr. von Eschenbach. No, sir. May I clarify what I was
intending to say? 3014 was not used as part of the decision to
approve Ketek.
Mr. Stupak. That is not what your Web site says.
Dr. von Eschenbach. The Web site was incorrect, sir, and it
should not have been presenting that information. The decision
to approve Ketek was made after 3014 had been removed entirely
from the analysis. The decision when 3014 was presented to the
advisory committee was not to approve Ketek, even though the
advisory committee recommended doing so. That decision to
approve Ketek came after 3014 had been removed.
Mr. Stupak. Well, that is what you continue to claim. In
fact, on page 11 you say ``Study 3014 was dropped for
consideration, making the decision whether to approve Ketek.''
Dr. von Eschenbach. To approve Ketek, yes.
Mr. Stupak. That is false. See the March 21, 2006 e-mail
from Queter. ``In addition, the FDA cites 3014 as part of
evidence it had before Ketek's approval of the drug safety.''
Again, look at your Web site. Also ``Prior to approval, FDA
looked extensively at the potential for hepatitic toxicity in
patients treated with Ketek. The data examined included a
25,000 patient study.'' If it wasn't used for approval, why was
it cited on your Web site and why it in the 2006 e-mail, March
26, saying we used it as the evidence to approve Ketek?
Dr. von Eschenbach. Mr. Chairman, it should not have been
presented on the Web site. That was an error.
Mr. Stupak. Nor in your testimony.
Dr. von Eschenbach. My testimony, sir, it was never
intended to indicate Ketek was used to approve--3014 was used
to approve Ketek. My testimony was to indicate the approval
decision was made after 3014 had been removed from the
analysis.
Mr. Stupak. Well, we hope to hear from the manufacturer of
Ketek, once they ever get the information, so we can go through
it, and we will have you come back up and explain it then with
them in the room. Maybe we can sort this thing out. I would
strongly advise you to correct your Web site, if it is wrong.
And your testimony be reviewed before you come so it is
accurate.
Mrs. Blackburn for questions, 10 minutes.
Mrs. Blackburn. Thank you, sir, I appreciate that, and
thank you for your endurance and your patience this morning. We
appreciate that.
First, I have got two or three different questions, and
then hopefully I can yield back, Mr. Chairman, so that we can
move on with the other witnesses and the rest of the hearing.
I want to go to page four of your testimony, and you talk a
little bit about the IOM and their recommendations, and as I
mentioned in my opening statement, they do recommend the
establishment of an advisory committee. So many times now, our
constituents, they know that these are not going to get us
where we want to go. They have grown weary of seeing advisory
committees and commissions and things of that nature, and view
it as a procrastination mechanism. I know that you have
mentioned that you can do this administratively and work with
an advisory committee administratively.
So I would like for you to do a couple of things very
quickly, so that we can move forward. Lay out how you feel like
you can go about administratively instituting some reform on
these IOM recommendations, and then also what we repeatedly
hear from individuals that deal with the FDA process is their
frustration with the bureaucracy and the desire to see some
efficiency there. So if you can do this administratively, how
can you do this and not increase the bureaucracy over there?
Not increase the number of people, not increase the paperwork
load on individuals who are trying to go through your process.
Dr. von Eschenbach. I am going to be happy to provide much
detail in that regard for the record, but let me just quickly
address the issue from what I believe I can do administratively
from the Office of the Commissioner leading this Agency.
I address this from the point of view of talent, tools, and
structure. We can continue to increase and provide expertise
that will look at the safety issues specifically and integrate
them and coordinate them much better into the approval process.
We will have better tools, both scientific tools to our
critical path initiative with which to make those decisions, as
well as information technology tools, as I have indicated
before, in post-market surveillance. Even structural changes
that we are making by much greater integration between the
Office of Surveillance and Epidemiology and the Office of New
Drugs, simple facts of how they are now engaging in meetings on
a much more regular and frequent basis, how they are dialoging
and communicating by virtue of the fact that we have co-located
them in our facilities at White Elk as they have been
constructed.
So very briefly and quickly, I see this as a multi-step,
multi-phase way of bringing this organization into a much, much
better integrated coordinated and efficient in functioning
organization that will make these decisions, enhance our
decision-making about safety and effectiveness, and do that
without creating more bureaucracy.
Mrs. Blackburn. You mentioned the critical path initiative
as a structural tool, and I would like to hear from you a
little bit about the value of the public private partnerships
that are over there, if you think there is a value, and what
that is bringing to the table as far as the critical path
initiative goes, and also the value of having some outside
consultants with a different set of eyes that are looking to
the problems and the workload, the paper load, the
documentation load that is a part of that process, a
frustrating part of the process.
Dr. von Eschenbach. I think one of the important areas of
public private partnership and collaboration is the fact that
industry and academia both have an enormous amount of data and
information and insight into molecular mechanisms associated
with these drugs and to their unique impact on various organs,
both beneficial and perhaps adverse, and having FDA be able to
access and participate and acquire and analyze that data
further informs our regulatory decision-making.
Mrs. Blackburn. Does the same thing apply to international
data? Do you use it in the same way in your communications?
Dr. von Eschenbach. Well, all of the data that is available
for an application is required to be presented to the FDA, and
that includes international data, which is always looked at,
and then weighed and valued in terms of the impact that it can
have on our approval process.
Mrs. Blackburn. One other question on your guidance on
communication of drug safety. As you laid out that guidance,
quickly, what did you use to formulate those guidelines and
then on the workload, how much of that was done internally and
how much did you outsource?
Dr. von Eschenbach. I would respond to the details of that
with regard to the record in giving you accurate information
about outsourcing and how that was developed and defined, and I
will be happy to provide that for you.
Mrs. Blackburn. That would be wonderful.
I yield back, Mr. Chairman.
Mr. Stupak. Thank the gentle lady for yielding back.
Mr. Green from Texas for 10 minutes.
Mr. Green. Thank you, Mr. Chairman.
Mr. Chairman, I apologize and Dr. von Eschenbach, this has
been one of those mornings where I have three committee
meetings and the problem is I am on the Ethics Committee, and
that is like serving on the jury that they don't do it unless
you are there, too. I am glad to be through with that for at
least a little while.
Mr. Chairman, I would like to have my full statement placed
into the record.
Mr. Stupak. Without objection.
Mr. Green. One, I want to welcome Dr. von Eschenbach,
because having known you for many years before and your career
at M.D. Anderson and University of Texas there both as a
physician and researcher and a cancer survivor, and I sometimes
wonder why you left the National Cancer Institute and came to
the FDA, and sometimes under questioning from my colleagues,
you might wish you were back there.
Some of the questions I have, and because I am also on the
health subcommittee, and so this fits right in with some of my
concerns is that the culture of the FDA, and I know you
rejected the IOM recommendation to appoint an external advisory
board to develop a strategy to change the organizational
culture, and you set off to hiring an external management
consultant. Was the external management consultant something
that you personally felt, or is that something that came from
somewhere else?
Dr. von Eschenbach. The consultant was engaged by the
Center itself. They had been actively involved in internal
assessment and brought in the opportunity of an external
consultant to help them address issues of culture. I in
particular feel that this is my responsibility to be actively
engaged in that process and to provide leadership and direction
for that process as well. I am continuing to do that.
Mr. Green. How was the consultant selected?
Dr. von Eschenbach. I cannot tell you the specific criteria
that the Center used in selecting the consultant----
Mr. Green. When you say Center, I apologize----
Dr. von Eschenbach. Center for Drug Evaluation; CDAR.
Mr. Green. Do you have any idea on how long this review
will take?
Dr. von Eschenbach. I believe they have a preliminary
report thus far. I have seen some of that information regarding
some of the principles of enhancing interaction, communication
within the organization, within the Center. I don't know if
they have the final report at this point, but I have seen some
preliminary findings.
Mr. Green. Will that final report be made public?
Dr. von Eschenbach. I would be happy to provide that to any
appropriate source that would be interested in it.
Mr. Green. Mr. Chairman, I would hope our Oversight and
Investigation Subcommittee, and frankly, the Health
Subcommittee, because since we have direct oversight on FDA,
but I would like to see--because it is structural reforms that
may need statutory consideration. Our committee needs to look
at that.
Will you post commitment to the zero tolerance retaliation
for FDA employees, you speak candidly with these consultants?
Dr. von Eschenbach. Well, I am certainly, as I stated
before, completely dedicated and committed to preserving and
protecting the legal rights of every member of the FDA.
Mr. Green. And I know that without a permanent advisory
board as recommended by the IOM is the director--will you
assure that the recommendations from the consultant will be
enforced?
Dr. von Eschenbach. Well, I look forward to it in a couple
of ways, Mr. Green.
One is to directly address issues that may be particular to
that Center, as well as really addressing this issue more
broadly across the entire Agency. I have engaged within the
Office of the Commissioner changes that will specifically
address our ability as an Agency to continue to enhance the
environment that I have spoken to earlier in my testimony.
Changes I made with regard to deputy commissioners, bringing in
a deputy commissioner and chief operating officer to
specifically address our management functions and make them
much more efficient and effective, including our communication
tools. But also, particularly creating the deputy commissioner
and chief medical officer position that Dr. Woodcock will now
occupy that will specifically focus on our issues of us being a
science-based and science-led regulatory agency.
Mr. Green. That brings up my next question. The FDA
response to the Institute of Medicine report puts a great deal
of weight on the science of safety to address the problems of
FDA drug safety programs. But a recurrent criticism is that
politics is put ahead of science, and why will the science of
safety fair any better with new initiatives than it did with
the science of Vioxx or Ketek or some of the other things that
we have heard about? Do you feel comfortable that we are
actually going to see that culture change?
Dr. von Eschenbach. I am very confident that the FDA will
continue to be a science-based Agency, and I want it very much
to also be science-led. The nuance there is that we are
integrating these tools that are enhancing our opportunity to
make better informed decisions, both about safety and efficacy
of these drugs, and the processes by which we do that will be
both disciplined and rigorous and precise, and I believe that
will enhance our performance, rather than slow it down.
Mr. Green. Thank you.
Mr. Chairman, I know that in substantive work it is other
subcommittee, but I will just say this in addition to my
statement that will go in the record.
Some of us who voted for PDUFA never intended for that to
be the ultimate decision-making on someone paying a fee ahead
of time, and that is what worries me and that is what some of
the interest is, and so both from our report from this
committee and hopefully our Subcommittee on Health will be able
to deal with the issue.
Thank you.
Mr. Stupak. Thank you, Mr. Green. We are going to hold just
a minute for Mr. Markey, who is on his way down. He is chairing
a hearing upstairs, the one I have been bouncing back and forth
on.
While we wait a minute, any questions from Mr. Whitfield?
Mr. Whitfield. No, sir.
Mr. Stupak. Let me ask a question, if I may. I don't want
to waste this valuable time, since we have got the Commissioner
here.
Mr. Waxman indicated that there are about 1,200 studies
pending, or about 1,200 post-market studies that should be done
that have been promised to be done that are not being done, and
71 percent have not even started. Who determines of these 1,200
which ones are going to have priority to get done to urge the
drug companies to do them? Do you have some kind of priority
list, or do you just sit back and wait until drug companies
submit them?
Dr. von Eschenbach. Well, it is one of the important issues
that needs to be addressed and will be addressed, Mr. Chairman,
in terms of our prioritization of our resources and using these
post-market studies in a way that they are designed extremely
well----
Mr. Stupak. Well, wouldn't the drug companies do the
studies, not you?
Dr. von Eschenbach. The drug companies carry out the
studies, but they carry them out at our direction.
Mr. Stupak. So it depends on the severity of the issue, or
how do you prioritize them?
Dr. von Eschenbach. They should be designed and developed
in ways that answer questions----
Mr. Stupak. Correct. How do you prioritize those, those are
life-saving drugs, or how do you do it?
Dr. von Eschenbach. Some of those may have questions having
to do with adverse outcomes that might be expected. Some of
them may have to do with our ability to learn and how to better
utilize that drug, dosages, for example, or a particular
population.
Mr. Stupak. Let us take Accutane, a controversial drug.
They have been talking about dosage studies for a long time,
and Roche has been asked to do it. As far as I know, it has
never been done. Why don't you do that one? It is sort of a
controversial drug. We have birth defects, we have suicides
related to it. Why hasn't a dosage study ever been done? There
is a question that the dosage is maybe 200 percent greater than
what it should be.
So why hasn't a study been done on that? I think we have
been waiting for if one has been done, correct me, but I don't
think one has been done, and I think it has been about 8 years
now, 9 years maybe?
Dr. von Eschenbach. Accutane has been available as a very
important part of the armamentarium to treat nodular acne, and
there is a very rigid and very stringent process called I
Pledge to manage the utilization----
Mr. Stupak. No, I am talking about dosage.
Dr. von Eschenbach. I am not aware of a need for a specific
dosage study.
Mr. Stupak. I sent you a report back on, I think it was
like November 2006, very lengthy, about 23 pages, laid it all
out for you, the things that had to be done, and I got this
letter back saying yes, we continue to monitor it. But I asked
specifically about the dosage study, why wasn't anything done
on that?
Dr. von Eschenbach. I would be happy to look into that
again, Mr. Stupak, and give you that specific response with
regard to dosage itself.
Mr. Stupak. Yes, just when are you going to do this dosage
study?
Dr. von Eschenbach. I am not sure that a dosage study is
necessarily required, but I would be happy to----
Mr. Stupak. It was recommended about 8 years ago or 9 years
ago. Take a look at it.
Mr. Markey is here. Mr. Markey for 10 minutes, please.
Mr. Markey. I thank you very much, Mr. Chairman, for your
graciousness.
Dr. von Eschenbach, on the first day of this series of
hearings on FDA issues, several former and current FDA
employees testified about the truly frightening problems at
FDA, including a culture of scientific censorship and
intimidation, a lack of transparency in the review process, the
inaction of FDA management in response to serious drug risks,
and a lack of scientific freedom and the inability of FDA
reviewers to have their concerns heard by senior management FDA
advisory committees and the public.
It was clear from the whistleblower's testimony that the
FDA is an Agency that needs to be changed, in the best interest
of the public. I would say that I was disturbed by your
responses to Chairman Stupak regarding your testimony and the
apparent contradictions between your testimony on Study 3014
and the internal FDA e-mails. It is clear that we are not
getting an accurate and complete picture of what went on at the
FDA during the lead up to the Ketek approval.
It is this kind of lack of transparency and openness about
serious issues at the FDA that has made this Congress and the
public very concerned about the FDA's ability to communicate
effectively to the public and to be a true watchdog for public
health.
My first question, Dr. von Eschenbach, is I would like to
ask you about the FDA's policy of providing complete
information to advisory committees. In response to Mr. Stupak's
excellent questions about allowing FDA employees to present to
advisory committees, you testified that you believe that
employees should be able to present to advisory committees even
if their managers do not want them to. Just to clarify, do you
believe that any FDA employee working on a matter related to an
issue before an advisory committee should be allowed an
opportunity to make a presentation to the committee?
Dr. von Eschenbach. Mr. Markey, if I can clarify. I believe
that employees of the FDA that have material contributions to
make should have opportunities to present that. Presenting to
an advisory committee is something that would include, if and
when it was appropriate. There may be reasons why it might not
be appropriate to present, for example, only one portion of the
data, when other portions or other perspectives were not
available. That may need to be withheld from that particular
meeting until those other parts and pieces are assembled.
So there may be reasons to not be allowed to present at
that specific meeting, but that is not to say that that is
equivalent to suppressing important, valid information that has
to bear on the decision. I will not tolerate that.
Mr. Markey. Would you support the provision in my bill H.R.
1165, the Safe Drug Act, which would clarify that any FDA
employee working on a matter related to an issue before an
advisory committee should be allowed an opportunity to make a
presentation to the committee?
Dr. von Eschenbach. I think they should be allowed
opportunities to have their position and point of view made and
included in the process, the deliberative process. How that
comes about, whether it is by direct presentation to the
advisory committee, whether it is a submission of a report, or
whether it is including their particular point of view in an
overall analysis is something that I think needs to be
determined on a case-by-case basis.
Mr. Markey. I believe that the provision in my legislation
to ensure that advisory committees have access to complete
information is necessary because of not only what we saw with
Ketek, but also because in 2004, this committee conducted an
investigation that found that the FDA had prevented a scientist
from presenting data to an advisory committee that SSRIs
increased the risk of suicidality in adolescents. I am worried
that the FDA has a pattern of restricting information presented
to advisory committees, and believe that Congress needs to act
to clarify the scientific censorship because I don't think that
that is acceptable.
So in my opinion, the purpose of an advisory committee is
to examine all the available scientific data, to make a
recommendation to the FDA. If the FDA puts its thumb on the
scale and only presents part of the story, then the public will
not get the benefit of having the best scientific minds examine
all of the information and give unbiased recommendations
regarding the best course of action at the FDA.
I have a second question for you.
At our last hearing, former FDA employee Dr. David Ross
testified that Ketek happened because there were no penalties
for FDA managers who engaged in suppression of reviewers and
dissemination of false information. Do you believe that it is
acceptable for managers to ask their subordinates to exclude or
alter scientific information for non-scientific reasons?
Dr. von Eschenbach. I believe it is never permissible for
anyone to ask or influence someone else to change their
scientific data or their scientific opinion.
Mr. Markey. Well, according to a 2006 survey conducted by
the Union of Concerned Scientists, of the 997 FDA scientists
who responded to the survey, nearly one-fifth, 18.4 percent
said that they have been asked for non-scientific reasons to
inappropriately exclude or alter technical information or their
conclusions in an FDA scientific document. Do you agree with
that conclusion reached by the Union of Concerned Scientists in
their survey? Are you aware of a culture of suppression at the
FDA?
Dr. von Eschenbach. I am aware of the fact that there are
times in the development of any particular body of information
that there is an opportunity for drafts of that information to
be changed, modified, or altered, depending upon input that
comes from a variety of sources. That is a different issue than
asking someone to change or alter scientific data or alter
their particular conclusions. They have the opportunity to
present that, to stand behind that. Others who disagree with
that can provide alternative rebuttal if they have a different
point of view. That is different than preparing a report that
requires distillation of information from a variety of sources.
Mr. Markey. Well, would you agree that it is important to
have penalties in place for FDA employees who do seek to censor
or suppress scientific information for non-scientific reasons?
Dr. von Eschenbach. When someone acts inappropriately and
illegally to suppress that type of information as you are
describing it, that is clearly in violation of what would be
considered law, then that should have penalties associated with
it, and those penalties can include disciplinary action of that
individual, including severance of their relationship with the
FDA.
Mr. Markey. Would you also agree that if an FDA employee
reports through the appropriate channels that censorship or
suppression of scientific information has occurred at FDA, then
that person should be protected under the whistleblower laws?
Dr. von Eschenbach. I believe all legal rights having to do
with whistleblowers should be protected. I believe that when
someone issues a complaint or a concern or registers an issue,
that needs to be investigated, evaluated, the certainty of that
needs to be determined, and then actions need to be taken. I
believe that is an important part of managing and meeting this
kind of a complex scientific-based organization.
Mr. Markey. So do you believe that we should ensure that
reporting of scientific censorship is covered under the
Whistleblower Protection Law?
Dr. von Eschenbach. I believe that the legal rights of
people need to be protected.
Mr. Markey. So if we made that more clear, that those
whistleblowers----
Dr. von Eschenbach. If Congress passed a particular law
with particular language, I would always be committed to
enforcing that law. That is correct.
Mr. Markey. So I thank you, Doctor, very much, and I do
believe it is important for Congress to act in order to give
the FDA employees a scientific bill of rights so that there is
no misunderstanding that the fact is that full scientific
discussions must be at the center of all FDA decisions. The
Safe Drug Act that I have introduced is designed to do just
that, and I look forward to continuing to work with you,
Doctor, and members of the committee towards the goal of giving
these protections to the workers at your Agency.
I thank you for your testimony here today.
Thank you, Mr. Chairman, again, for your more than generous
tolerance of my tardy arrival. Thank you.
Mr. Stupak. And you put up with me all morning running back
and forth, so that is the least I can do. Thank you.
Thank you, Mr. Commissioner, and we look forward to working
with you on this reauthorization of PDUFA, pediatric
exclusivity, and some other pieces of legislation.
There will probably be written questions and follow-ups to
you, and we look forward to documents we requested from you.
Thank you for being here today.
Dr. von Eschenbach. Thank you, Mr. Chairman and Mr.
Whitfield, and other members of the committee for your
consideration this morning.
Mr. Stupak. We will immediately go into our second panel.
They have us under a timeframe again today, and at 2:30 we have
a full committee markup, so they want the full committee room.
So we will try to move along with panel 2 here. I would ask
panel two members to come up. Bruce Psaty, a doctor, professor
of medicine, Epidemiology and Health Services at the University
of Washington, School of Public Health and Community Medicine.
Next we have Marsha Crosse, Director of Public Health and
Military Healthcare Issues, U.S. Government Accountability
Office.
We have Dr. Curt Furberg, professor of Public Health
Services, Division of Public Health Services, Wake Forest
University School of Medicine. And we have Dr. Raymond Woosley,
president and CEO of Critical Path Institute.
As you know, it is the practice of this committee to take
all testimony under oath. I would ask each witness to stand and
raise their right hand, please.
[Witnesses sworn]
Mr. Stupak. Let the record reflect all witnesses answered
affirmatively as to the oath.
We will start with Dr. Psaty.
TESTIMONY OF BRUCE M. PSATY, M.D. PROFESSOR, MEDICINE AND
EPIDEMIOLOGY, UNIVERSITY OF WASHINGTON
Dr. Psaty. Mr. Chairman and members of the committee, my
name is Bruce Psaty, a professor of medicine and epidemiology
at the University of Washington. I served on the IOM Drug
Safety Committee.
The IOM safety review was undertaken at the request of the
FDA after the withdrawal of Vioxx had raised questions about
the integrity of the U.S. drug safety system, and this
testimony reflects my views as a public health scientist.
According to one former FDA Commissioner, the only novel
IOM recommendation was the proposed 6-year term for future
Commissioners. All the other recommendations had been made in
one form or another in a dozen previous reports, yet in the FDA
response to the IOM report, all actions are listed as recently
initiated, new, or planned in PDUFA IV. What happened to the
scores of previous recommendations? Whether this time the FDA
responses will eventually improve drug safety remains to be
seen.
The FDA, which has many outstanding scientists, has a
difficult job. The interests of the pharmaceutical industry and
risks and benefits are not symmetrical. There is little short-
term economic interest in safety, and some sponsors lack
imagination when it comes to the design of safety studies,
hence the need for a strong, science-based regulation to
protect the health of the public.
The current business model pre-market evaluation drug
approval and marketing, which is mirrored at the FDA, is the
primary structural flaw that allowed the Vioxx drug disaster.
The current drug safety system, in which approval largely
signals the end of evaluation, could hardly be weaker. The FDA
centerpiece, the Adverse Event Reporting System, creates a case
series, the weakest form of epidemiologic evidence.
Other major drug safety efforts are the post-marketing
study commitments, and as some of the questions have pointed
out today, 71 percent, 899 remain still pending. The completion
rate has dropped from 62 percent in the 1970's down to 24
percent in recent years.
To improve the system, the IOM Committee recommended a life
cycle approach to drug evaluation, an ongoing, systematic
effort to identify safety signals, translate them into high
quality studies, evaluate both health benefits and health
risks, and integrate the information into risk-benefit analyses
and communicate that information to patients and physicians.
FDA needs additional resources. While some FDA responses to
the IOM report were excellent, or were limited by inadequate
resources, others seemed to embrace the culture, vision, and
values of the status quo at the Agency. For all new molecular
entities, the IOM recommended a reevaluation of post-approval
data by the FDA, an idea that will merely be pilot tested.
Leaving the review of new safety data in the hands of industry
may, on occasion, be a hazard to the health of the public. The
IOM recommended public release of the FDA's risk-benefit
analysis after the completion of post-marketing studies. FDA
plans to do so only on a case-by-case basis.
Transparency is, however, essential. Although the Agency
usually needs to make one decision, physicians and patients
deserve to hear not one constrained voice, but the range and
the quality of the evidence that underlie a regulatory
decision, and scientific disagreements should be incorporated
into that information that is released. It should not be a
matter of legality and whistleblowers. We need to know what the
scientific disagreements are. They will be good predictors of
drug safety problems. Otherwise, the FDA fails in its mission
to serve as a trusted intermediary of complex information.
The IOM recommended joint authority for the Office of New
Drugs and the Office of Surveillance and Epidemiology. The FDA
plans a few pilot projects. This response, which fails to
acknowledge even a future commitment to the spirit of joint
authority does not signal a major cultural change at the FDA.
The IOM recommendations to involve advisory committees in the
review of all new molecular entities was largely ignored. The
failure to recognize the importance of independent review
provided by advisory committees is not in the spirit of broad
cultural change.
These responses, taken together, do not represent
``fundamental changes that will entail a cultural shift within
the FDA.'' A fundamental change would involve actively
embracing an ongoing lifestyle evaluation that includes both
transparency and independent review. Cultural changes need to
come first. They need to come from the top, and include
leadership that relies on science in its decision-making
process, leadership that values and harnesses scientific
disagreement to improve the drug approval process, and
leadership that is at once courageous under outside pressure
and passionate about the health of the public.
Thank you.
[The prepared statement of Dr. Psaty follows appears at the
conclusion of the hearing.]
Mr. Stupak. Thank you. Dr. Furberg, please, for 5 minutes.
Thank you, sir.
TESTIMONY OF CURT D. FURBERG, M.D., PROFESSOR, PUBLIC HEALTH
SCIENCES, WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE
Dr. Furberg. Mr. Chairman and members of the committee, I
am Curt Furberg. I am professor of Public Health Sciences at
Wake Forest University School of Medicine, with expertise in
drug evaluation and safety. I also serve as a member of the FDA
Drug Safety and Risk Management Advisory Committee. This
testimony reflects my personal views.
I am a firm believer in law and order. Congress has a very
critical role in developing and passing laws to protect what is
right and fair. Laws and regulation are effective, because
violations have consequences. Our citizens cherish the notion
that no one is above the law. Therefore, it troubles me that
drug makers can violate FDA regulations, commitments, and
public trust without apparent consequences.
Here are some examples. One company, testing its depressant
in adolescents, reported and made public only three of its 13
trials. The other 10 did not support the company's claim for
efficacy and safety. Despite this suppression, the FDA has
taken no action against the sponsor. Another company delayed
for several years submitting unfavorable safety data from a
trial of its COX-2 inhibitor in Alzheimer's disease. The FDA
has taken no action. The third company submitted falsified data
for an FDA hearing of its antibiotic, as discussed in the
previous hearing on drug safety. Again, the FDA has taken no
action against the company.
Thus, it appears to me that regulatory violations have no
consequences in the United States.
The fourth company stalled negotiations for 14 months over
label changes that would add an important black box warning to
its COX-2 inhibitor. Decisions about label warnings should take
only 1 to 2 weeks. This irresponsible delay had no consequences
for the drug maker.
These cases illustrate the industry's malfeasance. They are
alarming and have serious implications for public health.
Tragically, they represent only a small fraction of the total
problem.
These examples pale in comparison to the potential public
health harm caused by industry's unmet commitments to conduct
post-market safety trials. The approval of many new drugs is
based on these commitments. As of last fall, there were 1,259
unmet commitments, with more than two-thirds not even
initiated. What has the FDA done? Nothing.
In my view, it is critical for Congress to provide FDA with
enforcement tools, give the FDA legal authority to change drug
labels, and to withdraw unsafe drugs without negotiation,
ensure, through Congressional oversight that the FDA utilizes
this new authority appropriately and in a timely manner.
I was asked to comment on the FDA's responses to the IOM
recommendations. Overall, I find them disappointing. Although
many of the responses have merit, there are several
shortcomings.
First, the Agency's apparent unwillingness to ask Congress
for more authority to enforce drug safety regulations is
troubling.
Second, FDA's plan lacks concrete and constructive steps to
bring drug safety to parity with drug benefit in the evaluation
process. After all, decisions about drug approval and later,
use of a drug, are based on the balance between benefit and
harm.
The Office of Surveillance and Epidemiology needs more
experts in drug safety, public health, and surveillance. The
Director of this Office should report directly to the
Commissioner, and the Office should have its own external
advisory committee.
Third, another concern not addressed is FDA's lack of
transparency. Prescribers and the public are not given safety
information known to FDA officials in a timely manner. The
reasons for disapproving a drug, and the reasons for requesting
post-marketing safety studies are kept secret.
Fourth, also missing in FDA's response is an evaluation
plan. Progress towards improvement of the drug safety problems
needs to be closely monitored and reported, and corrective
actions being taken if goals are not met.
Finally, the measure of FDA's performance needs to be
changed. It should not be based only on the number of drugs
approved within a certain time period. Full credit should be
given for disapproval of drugs for safety reasons. These were
the problems highlighted in the recent article entitled ``The
FDA and Drug Safety: A Proposal for Sweeping Changes,'' which I
would like to add to my testimony. This article was written by
me and four other current and past members of the FDA Drug
Safety and Risk Management Advisory Committee.
Thank you so much.
[The prepared statement of Dr. Furberg appears at the
conclusion of the hearing.]
Mr. Stupak. Thank you, Doctor. And that article, I think we
all have it, and it will be made part of your opening
statement. Thank you.
Dr. Marcia Crosse.
TESTIMONY OF MARCIA G. CROSSE, Ph.D, DIRECTOR, PUBLIC HEALTH
AND MILITARY HEALTH CARE ISSUES, U.S. GOVERNMENT ACCOUNTABILITY
OFFICE, ACCOMPANIED BY MARTIN T. GAHART, PH.D., ASSISTANT
DIRECTOR
Dr. Crosse. Mr. Chairman and members of the subcommittee, I
am pleased to be here today as you examine FDA's process for
decision-making regarding post-market drug safety.
My remarks today are based on GAO's March 2006 report on
this topic, and on steps FDA has taken that respond to the
recommendations we made in that report. Our work focused on two
FDA Offices that are involved in post-market drug safety, the
Office of New Drugs, OND, and the Office of Drug Safety, ODS,
which has since been renamed the Office of Surveillance and
Epidemiology. Consistent with our report, I am referring to
this Office as ODS.
As we reported in March 2006, we found a failure to
appropriately manage the post-market drug safety process. We
found a lack of clarity about how decisions were made, and
about organizational roles. There was insufficient oversight by
management, and there were significant data constraints.
Importantly, there was a lack of criteria for determining
what safety actions to take and when to take them, which
contributed to disagreements over decisions about post-market
safety.
Specifically, certain parts of ODS' role in the process
were unclear, including ODS' participation in scientific
advisory committee meetings that were organized by OND to
discuss specific drugs. We found examples of the exclusion of
ODS staff from making presentations at certain meetings.
For example, in the case of Arava, an arthritis drug with
concerns about liver toxicity, ODS staff were not allowed to
present their analysis of post-market safety at a meeting held
to review Arava's safety risks and benefits. We also found that
insufficient communication between ODS and OND was an ongoing
concern, and hindered the decision-making process.
For example, ODS did not always know how or whether OND had
responded to ODS' safety analyses and recommendations for
safety actions. ODS management did not systematically track
information about the recommendations its staff made, and OND's
response. This limited the ability of management to ensure that
safety concerns were resolved in a timely manner.
Moreover, FDA faced data constraints that contributed to
the difficulty in making post-market safety decisions. In the
absence of specific authority to require drug sponsors to
conduct post-market studies, FDA has relied on drug sponsors
voluntarily agreeing to conduct these studies, but studies have
not consistently been completed.
FDA was also limited in the resources it had available to
obtain data from outside sources. Annual funding for this
program was less than $1 million a year for 2002 through 2005,
and was $1.6 million in 2006, which allowed for four data
contracts.
The problems we identified were not new. For example, FDA
conducted a lessons learned review in 2000, of the withdrawal
from the market of the nighttime heartburn drug Propulsid
following safety concerns about serious heart arrhythmias. In
its internal review, FDA identified the need for better
communication between the organizational groups, and called for
the development of a standard approach to post-market safety,
including what types of evidence to use, when labeling changes
or other safety actions are warranted, who should be involved
in the process, and how to present the issues to advisory
committees. Yet when we conducted our review more than 5 years
later, FDA had not acted on its own recommendations.
Today, almost a year after our report was issued, FDA has
begun to take steps that could address the goals of three of
our four recommendations. First, we recommended that FDA
systematically track post-market drug safety issues, and the
Agency is in the process of implementing a tracking system.
Second, we recommended that FDA revise and implement its
draft policy on the decision-making process for major post-
market safety actions, and FDA has made revisions to, but not
finalized, its draft policy. Third, we recommended that FDA
clarify the safety staff's role in scientific advisory
committees, and the Agency is developing, but has not
finalized, guidance to clarify their role. And fourth, we
recommended that FDA improve its process to resolve
disagreements, but FDA has not taken actions in response to
this recommendation.
In conclusion, while FDA has taken positive steps, its
actions are not yet fully implemented, and it is too soon to
evaluate their effectiveness in addressing these longstanding
concerns.
Mr. Chairman, this concludes my prepared remarks. I would
be happy to respond to questions you or other members of the
subcommittee may have.
[The prepared statement of Dr. Crosse appears at the
conclusion of the hearing.]
Mr. Stupak. Thank you, Dr. Crosse. Dr. Woosley, please, for
5 minutes. Your opening statement, sir.
RAYMOND L. WOOSLEY, M.D., PRESIDENT AND CHIEF EXECUTIVE
OFFICER, THE CRITICAL PATH INSTITUTE
Dr. Woosley. Mr. Chairman, members, thank you for the
opportunity to provide testimony to the subcommittee on this
very important topic. As mentioned, I am Raymond Woosley. I am
President of the Critical Path Institute, a publicly-funded
nonprofit that is based in Tucson, Arizona and Rockville,
Maryland.
I am a pharmacologist and a physician for the last 40
years. I have had a lot of experience with the study of
medications, and often working very closely with the FDA and
its scientists. I was at Georgetown for 13 years. I appear here
today because I am very concerned about the future of the
pharmaceutical industry, not an easy stand to take. But even
more, I am concerned about the patients who need their
medicines, and the new medicines.
This industry that everyone thinks is so successful and
profitable is, in fact, threatened by the inefficiency,
threatened by the resulting unacceptably high prices for its
new products, and threatened by the unacceptably high rate of
product failure during development and after development.
After millions are spent in the laboratory, 90 to 95
percent of drugs that enter clinical testing today fail to make
it to the market. We can't survive with those statistics. The
rare success that gets to the market requires an estimated
investment of 15 years and $1.3 billion. Therefore, as you
consider how to improve drug safety, which we must do, you must
do, we must also maintain and create incentives for innovation.
I can't resist quoting a colleague and friend, Hugh Tilson,
who said: ``Without innovation, all we have are the products of
yesterday.'' So innovation is important, and safety is even
more important.
In the remaining few minutes, I would like to share with
you some of the lessons I have learned about drug safety over
the last 40 years. I am sure others have testified that the
complete profile of a drug's risk or benefit can never be fully
defined before a drug reaches the market.
Also, though, patterns of use can change on the market, in
the marketplace, meaning that drugs must be carefully evaluated
throughout their lifecycle, even decades after they have been
on the market. That must be paid for, and it is not even
covered in user fees today.
I have learned that surveillance signals that suggest harm
are just that, signals. Before alarming patients with public,
early disclosure of premature data, these signals need to be
confirmed, and many will turn out to be false alarms, and I
could cite you many of those. Also, I have learned that when a
drug has to be removed from the market due to toxicity, it is
not necessarily the result of mistakes made by anyone,
including the developer or the FDA. Some new drugs will have
adverse effects that could never have been anticipated. We must
find those problems early, though.
Yet today, there are some important opportunities to do
better. Some of those have been discussed. Prior to
administering drugs in humans today, we rely on the same
laboratory tests that we developed over 50 years ago. As part
of the Critical Path initiative, the FDA has helped create pre-
competitive collaborations with groups of companies that now
share and validate their testing methods. This work will result
in safer drugs entering human testing, and eventually reaching
the market.
It will also identify biomarkers. These are the clinical
tests that can predict which patients are at risk for harm
before they receive the drugs. This is the essential first step
before we get what we all have asked for, personalized
medicine.
The FDA, though, needs more resources to fully participate
in these collaborations, and to incorporate the results of that
work into new standards for testing. Post-marketing safety
assessment can also be greatly improved with a modest
investment, in fact, by using the modern information technology
that is already available. The U.S. does not have a system
capable of rapid and accurate detection of adverse drug events.
The AERS system is effective, but it is too slow.
For the last 19 drugs that were removed from the market,
their average time on the market was 6.6 years. That is too
long. We must do better. We have got the tools to detect those
adverse events much more quickly.
For example, the ARC funded centers for education and
research on therapeutics that was mentioned twice this morning,
Rich Platt. Those centers have access to medical records from
health plans that can readily be expanded to form a network of
health plans that serve approximately 100 million people. A
network such as this could readily serve as an early detection
system.
Lastly, does the FDA need extensive reform? I don't think
so. I think they need the resources, the permanent leadership,
to do the job we are asking of them.
In closing, I remind all of us. For some time now, we scan
the barcodes of everything in our grocery basket. We know how
many suitcases were lost by every airline in the Nation each
month. We can tell which cell tower picked up our friend's
call, yet we don't have a safety system in place today.
Clearly, we have the technology available today to establish a
world-class safety surveillance system, and at the same time,
maintain the path for safer, innovative new therapies to each
patients.
Thank you, Mr. Chairman.
[The prepared statement of Dr. Woosley appears at the
conclusion of the hearing.]
Mr. Stupak. Thank you, Dr. Woosley.
Tab four in that big binder has the open letter to Chairman
Kennedy, Chairman Dingell, and members of this committee.
You were talking about, and I quoted it earlier, at the
bottom of the page, where it said the FDA and pharma have
negotiated terms for a 5-year reauthorization. This
negotiation, completed behind closed doors, had only limited
input from the public. The proposal crafted by FDA and pharma
does not come close to addressing the problems identified by
the IOM.
Care to expand on that just a little bit more? You signed
it, I believe.
Dr. Psaty. Yes, I did. I would be happy to comment.
Under PDUFA, the U.S. has become increasingly the country
of first launch, the kind of testing ground for new drugs. For
the first 10 years of PDUFA, the FDA was prohibited from using
any of those fees for safety.
This occurred during Kessler's time, when he was
Commissioner. He indicated that they wanted to use some of
these fees for safety, but industry said no. So Congress
enacted PDUFA legislation that really entrusted safety to the
pharmaceutical industry, and did not adequately fund the FDA.
So, this has been a problem that has existed for some time, and
will take some time to fix.
In the implementation, and this is part of the issue that
you are getting to, the appearance is that FDA has industry as
its primary client.
There are negotiations that take place between the
regulator and the regulated that exclude the Academy and
patient groups, and just about everyone else, until things are
published in the Federal Register. So, there have been problems
with the implementation as well.
The IOM report expressed a preference for general
appropriations and we did this largely because we think drug
safety is a public good.
Mr. Stupak. Dr. Furberg, would you care to comment on that
at all?
Dr. Furberg. I would like to add the safety aspect, the
rush to meet deadlines and be paid. That is a price, and the
price, according to new scientific evidence, is there is an
increase in adverse effects, when those drugs are rushed
through. And overall, since 1997, there is a two and a half
fold increase in serious adverse events in the United States.
Mr. Stupak. Should PDUFA and the scope of PDUFA be limited,
then, to those drugs that we need for life-threatening
illnesses like AIDS and cancers, that are almost incurable?
Should we use that kind of a timeline in approving those types
of drugs? That is how PDUFA sort of got, politically got its
legs, because they were saying it was taking too long for AIDS
drugs, if I remember correctly 15 years ago.
Dr. Furberg. Yes, but there is another solution that is
used in Europe, conditioned approval, which wouldn't slowed
down introducing a drug on the market. You just put
restrictions on the approval, so during the period of
probation, basically, companies wouldn't have to provide the
safety information that you don't have at the time of giving
approval.
Mr. Stupak. One of your testimonies had to do with, when
you approve a drug, it is like a 2-year conditional approval,
and then after 5 years, go back and look at all the adverse
events that have been reported, and things like that. So, it is
like a 2-year approval, which is on the package, to show that
it is still in its, sort of like trial stage, and then go back
after 5 years, and look at it. Is that what you are----
Dr. Furberg. Yes. And that is done in several countries in
Europe.
Mr. Stupak. Doctor?
Dr. Psaty. Part of the problem is that the approval process
almost ends the evaluation. Companies commit to these post-
marketing studies and then don't do them, and the FDA doesn't
have resources to do studies, and the AERS system is not
adequate. What we need is a kind of lifecycle approach, where
there is an ongoing evaluation, integration of that
information, assessment of risk and benefit, so that the
approval process doesn't signal the end of an evaluation.
Right now, companies put together teams to get these drugs
approved. Once they are approved, they disband those teams, put
them to other drugs, and create marketing teams. We need a
system that evaluates drugs throughout their entire lifecycle.
Mr. Stupak. What about off-label use? Do you believe the
FDA currently, is currently structured--Dr. Crosse, you may
want to hit this--off-label use, do they have a right to
restrict off-label use?
Dr. Crosse. Mr. Chairman, no. The FDA has the
responsibility to approve the marketing of the drug for the
labeled indications. The usage of the drug is then in the hands
of the medical community, and oversight is by state medical
boards, if there are, if there is a belief that a particular
use has been inappropriate.
Mr. Stupak. But do the state medical boards actually try
them--for off-label use----
Dr. Crosse. In instances where there are malpractice
charges brought.
Mr. Stupak. I see.
Dr. Crosse. Or where there is a concern about a
particularly unusual prescribing pattern. But in general, FDA
has no responsibility or ability to contain----
Mr. Stupak. Do you believe they should be given the ability
to limit off-label use?
Dr. Crosse. I don't think I am qualified to comment on
that. I think the concern is whether FDA is monitoring the
promotion of the off-label use of drugs.
Mr. Stupak. OK.
Dr. Crosse. And FDA does have the ability and the
responsibility to oversee whether inappropriate marketing is
being done by the pharmaceutical companies, but the practice of
medicine, I think, particularly in the area of cancer, has
often extended the use beyond the labeled indication, but there
are certainly accounts out in the public about more unusual
uses of a drug, and that is something, I think, that is part of
policing within the medical community.
Mr. Stupak. OK. Dr. Woosley, if I may. The article you co-
authored, entitled ``A New System for Moving Drugs to Market,''
contains your recommendation that newly approved drugs should
be given a defined population under observed conditions only.
Wouldn't this require an initial ban on most of the direct to
consumer advertising, since a newly approved drug would be
approved for a carefully defined population?
Dr. Woosley. Well, I think the problem is that the direct
to consumer advertising, as originally conceived, would not
require that, but the way it is executed today, it should. The
direct to consumer advertising was created so that patients who
had an illness knew they could go to the doctor, but instead,
the direct to consumer advertising has become hyping one drug
against the other, and selling the drug, and trying in a 30
minutes sound bite to convey risk and benefit. That is a very
dangerous situation, but I think the patients could be told,
under the system I suggest, that if they have an illness and
certain characteristics, they should see their doctor, but not
try to sell the drug to them on the TV.
Mr. Stupak. I asked the Commissioner this question. Let me
ask this panel, and maybe you have some suggestions. As we have
heard, there is over 1,200 studies or commitments to do
studies, on post-marketing issues.
Is there a way, should they be prioritized on which ones
the FDA should put pressure on these manufacturers to develop
them, or do we just sit back and let the FDA, let the
manufacturers bring forth their studies whenever they feel like
getting them?
Dr. Psaty. I can comment briefly. There have been about 800
studies in this pending category for a long time. Some of them
are old, and many of them were developed rapidly within a
couple of weeks before the approval time. Many of them aren't
well designed, and probably 20 percent don't deserve to even be
done. I think the FDA needs to go through all of these studies,
take a look at them, decide which ones need to be done, drop
the rest, assign a start date to all of them. Many of them
don't have a start date. They are going to remain pending in
perpetuity here. And you will see them on this list year after
year, so some need to be dropped, some need to be redesigned.
They all need a start date, and the medical officers in the OIG
report in March 2003, many of them were uncertain about what
sort of post-marketing commitments to ask of companies.
And we need epidemiologists to help the medical officers
think about the proper design, independent review would help.
In the current system, in which there is a rush to create these
studies right at the last minute, under the PDUFA guidelines,
really contributes to the weakness of the U.S. drug safety
system.
Mr. Stupak. Doctor.
Dr. Furberg. Yes, I would like to add that we also need a
completion date, and hold the sponsors responsible for those,
and if they don't produce the studies on time, there should be
consequences. Staggered consequences, eventually with drug
withdrawal, if these studies are not done.
Mr. Stupak. Well, Doctor, you also brought up in your
testimony, the average time to make label changes, and I
mentioned pediatric exclusivity, I lost a battle 5 years ago,
but I am ready to fight it again. Here is a chart here, this is
based on 2001, pediatric exclusivity, where you get the patent
for doing the study, but then if there is a label change that
is required, on this one here, it could be as high as 18
months. The average was 14 months back then in 2001. I am sure
it has only grown, so we do the study, we see for the
adolescent community, you have to prescribe it, dosage, or it
may be contraindicated use, but we don't know about that until
months, on average, 14 months after you get your patent
extension.
That is insane. There is no incentive, then, to do the
study or to change the labeling. The extension should be given
after the label change, after the study is completed, not
before.
Dr. Furberg. That is correct. Then you can add to that the
delay in getting the new package inserts out to the customers.
Mr. Stupak. Sure.
Dr. Furberg. It could be up to a year before all packages
have the new insert.
Mr. Stupak. Let me ask you one more. Subpoena power. I have
gone around and around with the FDA on subpoena power. I know
in Accutane they are looking for an eye exam, the raw data,
they have been waiting over 14 years for that. They still can't
seem to get it. Every time I ask the FDA about it, they say oh,
we don't need subpoena power. Without subpoena power, how do
you compel, or how do you get the information you need,
especially raw data? If they submit a study, you see maybe a
flag goes up, you want to see the raw data, how do you obtain
it if you don't have kind of subpoena power? I think the FDA is
about the last regulatory body we have in the Federal
Government that doesn't have subpoena power.
Dr. Furberg. I agree with you. I think it is essential. If
you are going to see any change in the problem with drug
safety, we have to have consequences for the drug makers. And
what is interesting in the meeting with the former
Commissioners, they all admitted we have no enforcement power.
The best we can do is to go public and embarrass a company.
What kind of a system is that?
Mr. Stupak. Well, I asked them the last time they tried
that, and they said they have never done it. So, even your so-
called bully pulpit, they are even afraid to use that.
Dr. Furberg. Yes.
Mr. Stupak. I could go on forever, but my time is up, so I
am going to turn to my friend from Kentucky, Mr. Whitfield, for
10 minutes, please.
Mr. Whitfield. Thank you, Chairman Stupak, and thank you
all for being so patient today. We welcome you, and appreciate
your interest in this important issue.
Dr. Psaty, you are a member of the IOM, and I was curious,
how, as a person selected to be a member of the IOM, are you
appointed, or----
Dr. Psaty. I am actually not a member of the IOM. I was a
member of the IOM Drug Safety Committee, and I can't really
speak to the selection process, since I was on the other end.
The members included a diverse group, who had expertise in
epidemiology, pharmacology, law, regulation, organization, but
I don't, I can't speak to how we were selected.
Mr. Whitfield. And how were you appointed to the committee
that you are a part of?
Dr. Psaty. I was asked by the IOM if I would be interested.
I was screened for conflicts of interest. Personally, I have
worked on drug safety issues for many years. So, I suspect that
is why I was asked.
Mr. Whitfield. And Dr. Furberg, now, you are a member of
the FDA Advisory Committee on Drug Safety. How were you
selected for that?
Dr. Furberg. Again, it was an invitation that came from the
FDA.
Mr. Whitfield. From the FDA.
Dr. Furberg. I went through the same screening, and like
Dr. Psaty, I have been in the field for many, many years.
Mr. Whitfield. Yes. I am assuming that all four of you
would agree that when you are having an Agency like FDA, as
complex as it is, and I don't know how many employees they
have, 9,000 or 10,000, I guess, over 9,000 or 10,000, but it is
my understanding they have only had a Commissioner, full-time
confirmed Commissioner two out of the last 6 years, at the top
spot. Does that concern any of you, or does that bother you?
Dr. Furberg. It bothers me, and I think what bothers me is
this is a little bit too much a political process.
Mr. Whitfield. Yes.
Dr. Furberg. And that is what the Commissioner has pointed
out, the four former Commissioners. It is too much politics
going in, and we are getting away from science.
I wish we would appoint Commissioners based on credentials,
scientific credentials, management skills, and so on, the way
academic institutions do it.
Mr. Whitfield. Yes. Well, Dr. Woosley.
Dr. Woosley. I would just add I agree completely, and it is
not just at the Commissioner's level. They have had acting
Directors for Center, all the way down the line, it is acting
everybody, and the inability to make decisions, the inability
to plan, the inability to make change, is crucial to that
organization, and without the resources, and without somebody
in power, it is not going to happen.
Mr. Whitfield. Yes. Dr. Psaty.
Dr. Psaty. The IOM Committee did recommend a 6-year term
for the Commissioner. It is an effort to get someone in there
to stabilize the process, and 6 years crosses a Presidential
term.
Mr. Whitfield. Right.
Dr. Psaty. And the idea is to create stability at the top.
Mr. Whitfield. Some continuity.
Dr. Psaty. Yes.
Mr. Whitfield. Dr. Crosse.
Dr. Crosse. Yes. We also found that there was significant
turnover in the leadership of the Office of Drug Safety, and we
believe that was a major contributor to some of the problems
and some of the lack of followup on issues that were uncovered.
Mr. Whitfield. Yes.
Dr. Crosse. Because there was frequent turnover of
leadership in that Office.
Mr. Whitfield. And is that a political appointment?
Dr. Crosse. That is not a political appointment.
Mr. Whitfield. It is not a political appointment. Yes.
Dr. Woosley. Just to follow up on that. A lot of the
criticisms have been because the Agency hasn't done this or
hasn't done that. A lot of this comes down to just lack of
simple infrastructure. They don't have, and they are starting
to gather, a database of what the previous commitments are.
They don't even know. How can they enforce it?
Mr. Whitfield. They don't know what the post-market
commitments are?
Dr. Woosley. They have no database of that. Two years ago,
they had a three ring binder on the desk inside the
Commissioner's office, where people handwrote when they
received an NDA. Now, it is getting better, but it is
unbelievable the restraints in resources that those people have
to live through.
Mr. Whitfield. Yes. Well, to appoint for 6 years, is that
something we would need to do legislation on?
Dr. Psaty. I believe that is true.
Mr. Whitfield. OK. Listening to your testimony, and talking
about the integrity of the drug approval process, and the post-
marketing process, it sounds so bad that it would almost lead
one to believe that our drug approval system, as it currently
exists, is presenting a major concern for safety of the
American people. Would you agree with that statement, or is
that not true?
Dr. Psaty. It is possible we actually in some cases don't
know, because the questions don't get asked and answered. I
have to say that the FDA does many good things, and the medical
officers who review these drugs, who think about them, who work
with the companies, and the pre-approval process is a good
process, and it generally works well. I think they need to work
on how they handle scientific disagreement. That needs to be
incorporated into the information that is provided to the
public. But in general, the FDA does a good job in the pre-
approval process. Once a drug is approved, in the old days, we
let the drugs come on the market in Europe, and let Europe
detect the problems, and then, we didn't have to worry about
them.
Mr. Whitfield. Right.
Dr. Psaty. And with the speedup of the drug approval
system----
Mr. Whitfield. Is there anything wrong with that?
Dr. Psaty. Well, the issue is, that then Americans don't
get drugs that we would benefit from.
Mr. Whitfield. Right.
Dr. Psaty. And that is the problem with that. But we need a
correlative, strong drug safety system if we are going to move
them in the U.S., if we are going to move them to market
quickly.
Mr. Whitfield. Right. Dr. Furberg.
Dr. Furberg. Well, thank you for asking that question. I am
supportive of a strong pharmaceutical industry. They have
changed the whole face of medicine over the past decades,
improved survival, reduced complications, alleviated symptoms.
That is wonderful, but it has come at a price, and I am not
prepared to pay that price. I like the benefit side. Let us
support that. But on the safety, the situation could be much
improved, and that is why I am here, to argue for better ways
of reducing the safety issues.
Mr. Whitfield. Dr. Crosse, do you have any comment?
Dr. Crosse. I would agree that I believe the pre-approval
process is very rigorous. I think that they work really hard to
try to be sure that those decisions are correctly made. I think
there are some fundamental problems in the kind of information
that the Agency has had available, and in the support for
pursuing that sort of information and figuring out how to best
use it in assessing the problems that occur once a drug is on
the market.
Mr. Whitfield. And Dr. Woosley.
Dr. Woosley. I think we need to look at the full spectrum.
Our Nation invests $90 billion in research and development
every year, and we spend only $300 million to see if it was
worth giving to the public, and I think that is the problem. We
haven't invested in that final tip of the filter.
Mr. Whitfield. Are talking about the post-marketing aspect?
Dr. Woosley. No, I am talking about the process of
reviewing all that science. And because we have not invested
well in that, because we only spend that much money at the FDA,
what I am getting at is the incentives for new product
development are drying up. The number of new products submitted
to the FDA has fallen by 50 percent, even though we have
increased our R&D by 250 percent.
Mr. Whitfield. Fallen by 50 percent?
Dr. Woosley. Right. The number of new, innovative chemicals
submitted to the FDA, not sitting there being reviewed, coming
in the door, and that is in spite of more than doubling our
investment.
Mr. Whitfield. Well, everyone has to be concerned about
that, because we hear as laymen that more and more people are
becoming, certain antibiotics are not having any impact on
them, and so we need more R&D and more drugs coming to market,
and then your comment that the average cost to take a drug to
market is like $1.3 billion, and it takes 15 years. Is that a
concern to you all, or does that bother you, or does that not
bother you? Dr. Furberg.
Dr. Furberg. Yes, it bothers me, and I think the solutions
are on the industry side. They need to be more efficient, and
really focus on innovations. Right now, much of what they are
doing is driven by profit motives. They are developing me-too
drugs, rather than focusing on the new ones. They should really
be, they should be encouraged and rewarded if they bring new
products to the----
Mr. Whitfield. How do you do that? How do you encourage and
reward them for doing that?
Dr. Furberg. Well, there are different suggestions. One is
to extend the patent period for certain drugs.
Mr. Whitfield. Extend the patent period.
Dr. Furberg. Yes.
Dr. Woosley. And you could have the market exclusivity that
they get today to be dependent upon innovation.
Mr. Whitfield. Yes.
Dr. Woosley. I think there are many ways that we could
create carrots. Honestly, I think we have got far too many
hammers that are hitting our own thumb in many cases.
Mr. Whitfield. Yes. One other question, Dr. Psaty. You have
made the comment that there is little economic, little short-
term economic interest in safety.
Dr. Psaty. Yes, sir.
Mr. Whitfield. Now, are you referring to the drug
companies?
Dr. Psaty. Yes, sir.
Mr. Whitfield. What about this issue of the lawsuits, the
class action lawsuits, and things like that? I have never
worked for a drug company, but I know some of these are pretty
expensive, and I would think that that would be a motivating
factor to be concerned about safety, but----
Dr. Psaty. There are large numbers of safety studied that
are designed by companies, that can't answer useful questions,
that will not answer useful questions, and if you don't have
the answer to the question, then you don't have the
information.
And industry does not pursue questions about safety with
the same vigor, interest, and aggressiveness that they do
questions about efficacy, and I think it is in their, as you
point out really, in their long-term disinterest. Merck now
faces billions of dollars in lawsuits but I think that that
could have been prevented had patients known about the risk
associated with Vioxx in a timely fashion, and had the company
studied it and informed people. But instead, it was on the
market for 6 years.
Mr. Whitfield. Thank you.
Mr. Stupak. I understand Ms. Blackburn's coming, or
Burgess, one of them. While we are waiting here, just a general
question. Has PDUFA helped our drug safety issue, or has that
hurt it? In hindsight now, it has been over 10 years since we
have had it here. Has PDUFA been a good bill for drug safety in
this country, and the drug approval process?
Dr. Furberg. Well, for the first two version of PDUFA,
nothing could be spent on safety, so they had no impact
whatsoever, and now, they are slowly moving up and allowing
some of the funding to go towards safety, but even in the new,
behind closed door development agreement between FDA and
industry, the ratio is 13 to 1, so $13 slated for approval
reviews and general expenses per $1 going to safety. So it is a
total imbalance.
Mr. Stupak. Do you have a comment?
Dr. Woosley. I would say that PDUFA wiped out the backlog.
Back when it was taking 40 months to review new drugs, it got,
it is down now for important new drugs to be 6 or 8 months. So
it worked in that sense. I agree there should have been money
there for safety from day one. That needs to be made clear.
The other part of it is, and one of the advantages of
almost being, and there are few advantages of almost being 65,
is looking back, and I was very opposed to PDUFA entirely. I
would say in a perfect world, we would have only money coming
from the Government. But I thought about it and realized that
the FDA approval process gives the company a better product, so
yes, they should pay for that better product, and it is a gold
stamp of approval that helps them market their drugs, and they
should pay for that. But the public needs to maintain control,
so if we have to have user fees, I think there is a rationale
for it, but I think it has to be kept in balance. To have more
than half of the money coming from user fees right now at the
FDA is not a good balance.
Mr. Stupak. Mr. Burgess for 10 minutes.
Mr. Burgess. Thank you, Mr. Chairman. Dr. Woosley, I guess
let us stay with you, if we could. When a drug is taken off the
market, does that mean that someone at the FDA messed up, did
something wrong?
Dr. Woosley. No. I think one of the things that the public
expects, that when a drug is approved, it is absolutely pure as
the driven snow, and when something goes wrong, somebody should
be blamed, but in fact, drugs are very, very potentially toxic
agents. We are all very, very different people, and there will
be examples where we could not have anticipated, no matter what
we had done, the toxicity. Drugs being taken off the market is
not a bad thing. Taken off the market too late is a bad thing.
So, I think that is a very important thing. It is very
difficult for people to understand, the public.
Mr. Burgess. Pfizer Corporation just had a very famous, a
few months ago, the drug that they had thought was going to be
the next generation of LDL lowering medication, I don't
remember the name of it now, but had to be withdrawn. In all
likelihood, the scientists at Pfizer learned something along
the way in that process. Would that not be a fair statement?
Dr. Woosley. Yes, they did. They learned it too late,
though. I think after $1 billion of investment, that is not a
success.
Mr. Burgess. But is there a likelihood that by changing the
molecule, by changing something about the character of the
medication, that they could come up with one that would
ultimately be beneficial and not toxic?
Dr. Woosley. Absolutely, and I think that is one of the
things that we miss in post-market surveillance. We don't do a
postmortem, as you will understand, to find out what could we
have done differently next time. We continue to make the same
mistakes with drugs, unfortunately, so an investment into what
went wrong, and I am sure Pfizer will do it for their product,
but what about the other companies that won't learn from that
process? I think we need an open, and when I wrote the paper
that was cited earlier, we talked about the need for an NTSB.
When planes go down, we need to look at the system. When drugs
go down, we need to look at the whole process openly, and see
are our standards right? Was there something wrong with the
science, which has been the case, or is there something wrong
with the regulation?
And that kind of independent overlook, I think is missing
in all this. I would quickly say I am not calling for
separating the decision-making on risk and benefit. I am saying
something that is looking at not within the Agency, but from a
societal point of view. In many cases, 60 percent of the drugs
taken off the market were safe when used as directed, so as a
former medical educator, am I to blame? Did I not teach doctors
how to use those drugs?
So, again, I think when the problem occurs, we need to----
Mr. Burgess. You are under oath. Let me instruct you to
answer the question. Just kidding, Mr. Chairman. And you are
quite right. I can think of Bendectin, some 15 years ago,
removed from the market, and withdrawn voluntarily by the
manufacturer, never actually withdrawn by the FDA. The Copper-7
IUD, famously went away because of liability, potential
liability costs, not because of anything wrong with the product
itself, and Vioxx, that we are all familiar with most recently.
Is there a risk of the FDA mistakenly concluding that a
drug does have a safety problem when in fact none exists?
Dr. Woosley. I think it is a great risk. There have been
examples where they have spent an enormous amount of money and
time to investigate signals, and then find out at the end that
it didn't occur, and you and I are probably--we will remember
the days when we used Reserpine for treating high blood
pressure.
Mr. Burgess. I am not that old.
Dr. Woosley. Sorry. But there was a signal that it may
cause breast cancer, and a lot of extra studies were done, and
finally concluded that it didn't. There are many examples like
that, that have to be looked at carefully.
Mr. Burgess. Well, I do recall synthetic progestins were,
at one time, thought to cause endocardial cushion defects in
newborns, and now they are used for the early days, or perhaps
to prevent a pregnancy, if clearly that would be a risk, if
that had really been true.
What was the rate of withdrawal of drugs from the U.S.
market before the user fee that you have been talking about,
before PDUFA?
Dr. Woosley. It was about 3.1 percent, as I recall. It was
slightly higher after PDUFA, but not significantly different.
Mr. Burgess. Has PDUFA, though, made an impact? Again, I
reference my earlier question to Dr. von Eschenbach. When I was
a clinician, we used to gripe about how long the FDA took to
approve anything, and that the great doctors over in Europe
could have drugs available to them 10 or 15 years before we got
our hands on them. Has PDUFA been useful in speeding up that
timeline?
Dr. Woosley. It has. Now, significant new drugs are
reviewed in 6 to 8 months. For AIDS drugs, it was only 3 to 4
months. In one case, it was 1\1/2\ months of review. So we can
do better. AIDS drugs were developed in 3 to 4 years, not 12
years.
So, we can, and there were no shortcuts. No AIDS drug has
ever been taken off the market. There has been no surprises
with AIDS drugs. So, we can do it faster and safer when
somebody puts a gun to us.
Mr. Burgess. We don't need that mental age, but the avian
flu might be a similar situation, should that come to be the
problem that some people feel it might, where it will be
necessary to develop a vaccine under a very, very short
timeline.
Well, since I brought up Europe, in our first hearing, some
witnesses raised concerns about the reliance on foreign post-
marketing data. Do you think that there is a place for us to
change here? Is there some other system that we should adopt?
Dr. Woosley. I think we need our own system. We buy data
now from the UK on how drug experiences occur post-market
there, but we have different drugs on the market in this
country. We have different uses and patterns in this country,
so we need our own active surveillance system that responds
very quickly. We should look at the data from the rest of the
world, absolutely, but we should compare it to ours, not rely
on it entirely.
Mr. Burgess. But if there is a glaring example, such as
Thalidomide, yes, sir, I am sorry. Someone was raising a finger
there?
Dr. Furberg. Yes. No, I being the European on the panel.
Mr. Burgess. Please. We have got some other European
questions here, too.
Dr. Furberg. Thank you. No, I think we can, we should
collaborate and work with Europe. Europe has made major
strides. They introduced conditional approval for new drugs.
They have a risk management program that is mandatory, and they
have a very successful pharmacovigilance system in many
countries. They pick up side effects long before we do, in a
shorter time period.
So, we can learn a lot from collaborating with those. Thank
you.
Mr. Burgess. Thank you. Director Woosley, just one, and I
think you, in fact, tried to answer this, and I got you off-
track, but the observation that over half the drugs removed
from the market in the last 15 years were safe when used as
directed, which brings up the issue of using a drug off-label.
Could you address that?
Dr. Woosley. Yes. I wasn't really thinking so much of off-
label, because again, this is one of the things I have learned
over the years. The label is a very artificial piece of paper.
It is something that is dependent upon what data were submitted
to the FDA for review, and if someone doesn't submit data for a
new use, it is not going to be in the label. And if we waited
for all their uses to be submitted to the FDA, we would rarely
use drugs very effectively. Most of the pediatric use is off-
label. Most cancer drug therapy is off-label, so we shouldn't
look at that as good as bad. We should be looking at the use of
the medications and the clinical outcome. The label is, as I
said, a very artificial part of that analysis.
Mr. Burgess. Well, just to finish up, the Ketek case study,
is that a good example of the FDA disregarding safety?
Dr. Woosley. I haven't followed that carefully enough. I
think the hearings here and others are going to help really
inform that. I would say, though, that everybody talks about
Vioxx. I followed that one carefully, and I would say the only
mistake made in Vioxx was when it was taken off the market by
the company. Because the system really worked with Vioxx. It
was a drug developed to prevent bleeding. It was a drug that we
knew very early could cause heart disease, but we didn't know
the risk-benefit. Only when it was put into a large enough
trial to see if it prevented cancer did this come up. So again,
I think it is another one of those drugs that if it could have
been used when appropriate, it could have stayed on the market,
and been a very important drug for many patients with arthritis
at risk for GI bleeding, and keep it away from those people who
could be harmed.
Mr. Burgess. Yes.
Dr. Psaty. I just wanted to comment on Vioxx. I reviewed
Vioxx in detail for the Finance Committee. The company was
concerned about the possibility of adverse cardiovascular
events back in 1996. They sought to design a large trial that
would minimize the chance of finding any cardiovascular harm,
and maximize the chance of finding benefit.
The FDA needs to make sure sponsors ask and answer the
right questions. There were signals in the NDA for Vioxx, and
they were not followed up with the appropriate well-designed
studies.
Mr. Burgess. So, did Merck Corporation deliberately set out
to cause harm and cover it up?
Dr. Psaty. They didn't ask the question that a public
health scientist would ask: ``What is the risk and benefit of
this drug? Who am I going to help, and who might I harm?''
Mr. Burgess. But Dr. Woosley pointed out it wasn't until
they began to use this in a widespread trial, looking for the
prevention of colon polyps, that it actually, that the
difficulties came to light.
Dr. Psaty. Well, the difficulties came to light in the
bigger trial, and those results were available within about a
year after the drug was on the market, and those signals were
not, they were not pursued and not taken seriously.
Mr. Burgess. Do you have a comment about that, Dr. Woosley?
Dr. Furberg. Yes. I think the initial trials were not very
informative. Focus was on low risk people, they did short-term
studies, and follow them for a very short period of time, so it
was fairly uninformative. So, that is how they got around
detecting the problem. They should focus on the future users,
but they are excluded from the pre-approval trials.
If you are on another drug, or if you have a concomitant
condition----
Mr. Burgess. Wait a minute. They have got to focus on the
future users. There is no way of telling when you bring a drug
to market what some clinician or some patient is going to do.
Dr. Furberg. No, future users are those that are most
likely to use the drug after it is marketed, and you know that
if you have a painkiller, it is older people who have multiple
conditions, taking multiple drugs, and they excluded those from
the studies.
Dr. Psaty. Six week trials, many of the trials were 6 weeks
long, and arthritis doesn't go away in 6 weeks. And Vioxx
doesn't cure arthritis. So, people are going to use these drugs
for a long time, until they had a joint replacement or
something.
Dr. Woosley. I would add, though, I think it is all human
nature. It always comes back to that in making decisions, and
if you are in a company, and you are looking at your options,
would I invest money into seeing if a drug prevented colon
cancer, or see if it is causing heart attacks, or go after the
colon cancer, and hope that it doesn't cause heart attacks,
expect the public to find out what is wrong with those things?
The NIH is doing trials, and has done trials to find out
the unknowns out there, and yes, there is a responsibility of
the company to find out all they need to know about the drugs,
but to go after every signal, and ignore potential benefits
like preventing cancer, I think you have got to recognize that
those are decisions along the way in drug development that are
not easy, and we, as a society, have to do something to provide
the balance. This is a free enterprise Nation. We want
companies to succeed. If every company does every study to find
out what is wrong with their products, we are not going to last
as a free enterprise society very long.
Mr. Stupak. I am going to call time. You are way over.
Mr. Burgess. Sure. Thank you, Mr. Chairman.
Mr. Stupak. And we have another member who wants to go, and
we are getting pressured to leave the room here for the markup.
We don't want to have them do every study. We just want the
1,200 done.
Mrs. Blackburn for 10 minutes.
Mrs. Blackburn. Yes. Kind of huffing and puffing, running
between meetings.
Dr. Crosse, I want to come to you. And this goes along the
same line of questioning that I had with the Commissioner, as
we started looking at efficiencies, and the way the FDA works,
and the frustration that we hear from individuals who are going
through the FDA process, and then, also from constituents when
they know something is in the pipeline over there, they are
hearing this.
But making the FDA workable for everyone, and one of the
things that we like to focus on is being certain that we do
this, and just not throw money at it. I think all too often,
when we look at dealing with the bureaucracy, reforming the
bureaucracy and making it workable, what Congress has a
tendency to do is just go throw some money at something.
So, do you have, for lack of a better word, a checklist of
things that you feel like we could do legislatively or
statutorily, or through rulemaking authority, or that would
improve the system over there, and not be just throwing money
at it?
Dr. Crosse. Well, we did recommend in our report that FDA
be given additional authority to require post-market drug
studies, and we believe that is something that would not be a
burden, in terms of the finances of the Agency. It would,
however, cost drug companies to pay for studies that FDA has
evidence are needed, if there are strong indications of some
sort of problem once a drug is on the market.
There are clear problems with the resources that have been
available for post-market drug safety, the kinds of data that
the Agency has been able to acquire, and the resources needed
to develop a better system of accessing some of the data.
Now, some of that effort is underway, and some of it is
being proposed by the department in its PDUFA IV proposals,
that would call for additional funding, that would allow for
development of some databases. We certainly would be supportive
of that, but we have not developed any sort of comprehensive
checklist of all of the needs of the organization.
Mrs. Blackburn. OK. Sometimes, I think that if we were to
have from you all those specific recommendations, that that
would be helpful. And you just started touching on something,
and I want to go back.
In your testimony, you had mentioned that most of the time,
that the Office of New Drugs and the Office of Surveillance and
Epidemiology agree on what actions to take with respect to drug
safety, and I wanted to see if you could give us an estimate on
the percentage of the number of times, or is it 20 percent, 50
percent, 80 percent?
Dr. Crosse. Oh, I think it is more in the range of 80
percent or 90 percent of the time when there is agreement
between those offices. It is only in a limited number of cases
that have come to light where there has been extremely strong
disagreement. I think that in the day to day course of
reviewing information, there are likely more minor kinds of
disagreements that may be worked out, as additional information
comes in, but certainly, the vast majority of cases, there is
agreement among those staff.
Mrs. Blackburn. OK. All right. Thank you.
Dr. Woosley, I want to come to you with one thing. Staying
on the same topic, looking at the FDA, their structure, how we
achieve efficiencies and make the system workable. In your
testimony, you had talked a little bit about the cultural and
the organizational problems that are currently facing the FDA,
and you made a statement I think is worthy of note. Stable
leadership and adequate resources, and that that positive
change would follow if the FDA had that.
So, what do you think, how do you view this? Stable
leadership, define that for me, as far as people goes, as far
as a mission goes, as far as a direction, and do you think that
the Commissioner fills that role, and then, what about adequate
resources, and the availability for that, as far as that stable
leadership? Go ahead.
Dr. Woosley. I think that I fully support the IOM
recommendation of a 6-year appointment for the Commissioner. I
think that is the kind of endorsement that a leader of this
kind of an organization really must have. I think the acting
leadership positions below the Commissioner have to be given
more stability.
They need to be given the resources. These are mostly
scientists, or at least people trained in science and medicine
and pharmacy, that come into this Agency, and they want, they
are some of the most dedicated people that I have ever met.
They want to do the right thing, they want to serve the public
health, and they are crying for more data, more interaction
with science. They are put in, it used to be the Parklawn
Building, and isolated, and not able, they don't have a travel
budget to go to scientific meetings.
If anybody wants to meet with the Agency, they have to have
the meeting in Washington and bring everybody here. So, they
are really isolated. They are given the science in a bolus, a
big dump of data, and asked to act on it. They are not given
any warning. They may see a new kind of test in the NDA that
they have never heard of, because they have been reviewing NDAs
for the last 5 years, not keeping up with the science.
And I don't mean that as criticism. I also don't mean that
they should be doing research to be good scientists. I think
you need a good science background, you need an opportunity to
keep up to date by interacting with good people who do science.
Mrs. Blackburn. So, basically, you are saying continuing
education or professional development.
Dr. Woosley. That, but also interaction. I don't think you
can learn these things in courses, and this group that we now
have working, 160 scientists from industry and 20 regulators
that get together, are talking science. They are not talking
products, and they are learning about new methods of drug
testing. That is the kind of interaction I think is the most
effective.
Mrs. Blackburn. Thank you. Mr. Chairman, I will yield back.
Mr. Stupak. I thank the gentle lady for yielding back. That
concludes the questions for this panel. I want to thank this
panel.
Mr. Whitfield and I were saying we enjoyed the interaction.
I wish we didn't have these time constraints, because I think
we could get a lot more done, but it is very important to have
the record, and you helped build this record, so as we do PDUFA
and pediatric exclusivity reauthorizations, when we look back
at the record and your good suggestions, and the documents you
provided us, so I want to thank this panel for their work in
furthering the cause of drug safety in this country.
Thank you for your testimony, you can be dismissed now. I
ask for unanimous consent that the hearing record remain open
for 30 days. I also ask for unanimous consent to have items in
our evidence binder, the binders before us here, be made part
of the record. Without objection, so ordered.
I thank the panel again. The hearing is now adjourned.
[Whereupon, at 2:10 p.m., the subcommittee was adjourned.]
[Material submitted for inclusion in the record follows:]
Statement of Andrew C. von Eschenbach, M.D.
Mr. Chairman and members of the Committee, I am Andrew von
Eschenbach, M.D., Commissioner at the United States Food and
Drug Administration (FDA or the Agency). I am pleased to be
here today to share my vision for the future of FDA's drug
safety program and to present a few of the initiatives and
opportunities that we have embraced. I also will discuss the
Agency's approval of Ketek.
FDA'S DRUG SAFETY INITIATIVE
New drugs, devices, and diagnostics present a significant
opportunity to improve health care. For many patients, the
improvement in the quality of their life directly attributed to
new therapies vastly outweighs the risks that such treatments
pose. Ensuring the safety of drugs and other medical products
regulated by FDA has always been a key focus of our commitment
to protect and promote the public health. In the past few
years, FDA has reassessed its drug safety programs because of
rapid advances in science and technology that have resulted in
increasingly complex medical products. We are aware of
increased attention and take very seriously our response to
safety-related issues raised by consumer advocates, health
professionals, academic researchers, and Members of Congress.
FDA has a proud, 100-year record of being the world's gold
standard and we have maintained this record by our willingness
to look internally to see what transformations are necessary to
sustain this standard. For this reason, the Agency asked the
Institute of Medicine (IOM) to assess the U.S. drug safety
system, with an emphasis on the post-marketing phase, and to
assess what additional steps FDA could take to learn more about
the side effects of drugs as they are actually used. We asked
the IOM to examine FDA's role within the health care delivery
system and to recommend measures to enhance the confidence of
Americans in the safety and effectiveness of their drugs.
On September 22, 2006, the IOM released its report
entitled, The Future of Drug Safety--Promoting and Protecting
the Health of the Public. The report recognized the progress
and reform already initiated by the Agency. We have implemented
an aggressive effort, including developing new tools for
communicating drug safety information to patients. Through our
Critical Path initiative, we are working with our health care
partners to improve the tools we use and to more effectively
evaluate products and processes.
The IOM report makes substantive recommendations about
additional steps FDA can take to improve our drug safety
program. The recommendations are consistent with the Agency's
commitment to drug safety, including: (1) strengthening the
science that supports our medical product safety system, (2)
improving communication and information flow among key
stakeholders, and (3) improving operations and management. Our
Prescription Drug User Fee Act (PDUFA) proposal will, in part,
support some of these initiatives.
Strengthening the Science. First, I am committed to
strengthening the science that supports our medical product
safety system at every stage of the product life cycle, from
pre-market testing and development through post-market
surveillance and risk management. We will focus our resources
on three areas of scientific activity: (1) those relating to
improving benefit and risk analysis and risk management, (2)
surveillance methods and tools, and (3) incorporating new
scientific approaches into FDA's understanding of adverse
events.
Specifically, new scientific discoveries are generating an
emerging science of safety that will help prevent adverse
events by improving the methods used in the clinic to target a
specific drug for use in patients for whom benefits relative to
risks are maximized. This new science combines an understanding
of disease and its origins at the molecular level (including
adverse events resulting from treatment) with new methods of
signal detection, data mining, and analysis. This approach
enables researchers to generate hypotheses about and to confirm
the existence and cause of safety problems, as well as explore
the unique genetic and biologic features of individuals that
will determine how he or she responds to treatment. This
science of safety encompasses the entire life cycle of a
product, from pre-market animal and human safety testing to
widespread clinical use beyond original indications and should
be used for all medical products so that safety signals
generated at any point in the process will robustly inform
regulatory decision-making.
Improving Communications. Second, I am committed to
improving communication and information flow among all
stakeholders to further strengthen the drug safety system. This
will require a comprehensive review and evaluation of our risk
communication tools with the benefit of Advisory Committee
expertise, improving communication and coordination of safety
issues within FDA.
One example of our efforts to improve communication is
establishing a new advisory committee to obtain input on how to
improve the Agency's communication policies and practices and
to advise FDA on implementing communication strategies
consistent with the best available and evolving evidence. We
will include patients and consumers on the committee as well as
experts in risk and crisis communication and social and
cognitive sciences. Although IOM's report recommends
legislation to establish this Advisory Committee, we intend to
implement this recommendation more expeditiously through
administrative procedures.
Improving Operations and Management. Finally, I am
committed to improving operations and management to ensure
implementation of the review, analysis, consultation, and
communication processes needed to strengthen the U.S. drug
safety system. We are and will continue to be committed to drug
safety. Consistent with the IOM recommendations, we will be
implementing several reforms that, together, will improve the
culture of safety at FDA, and in the Center for Drug Evaluation
and Research (CDER). Under my direction, CDER has initiated a
series of changes designed to effect a true culture change that
will strengthen the drug safety system. CDER has moved to
reinvigorate its senior management team and charged its members
with the responsibility to lead the Center in an integrated
manner that crosses organizational lines.
CDER has employed process improvement teams comprising
staff in various organizations including the Office of
Surveillance and Epidemiology (OSE) and Office of New Drugs
(OND) to recommend improvements in the drug safety program.
Their recommendations to (1) establish an Associate Director
for Safety and a Safety Regulatory Project Manager in each OND
review division within CDER and (2) conduct regular safety
meetings between OSE and all of the OND review divisions are
now being implemented. We are committed to providing the
necessary management attention and support to effect sustained
culture change in our drug safety program.
We have recently engaged external management consultants to
help CDER develop a comprehensive strategy for improving CDER/
FDA's organizational culture. In addition to the ongoing FDA
activities to improve how our organization supports the
individuals who work on safety issues in FDA, we are enlisting
the help of external experts in organizational improvement to
help us identify additional opportunities for change and assist
us with carrying out those needed changes.
Ketek
This is the second part of a two part hearing on the
adequacy of the safety of the U.S. drug supply. FDA's approval
of the drug Ketek was discussed at your first hearing. I am
glad to have the opportunity to elaborate today on the Ketek
approval process. FDA maintains the highest worldwide standards
for drug approval and a review of the approval package for
Ketek substantiates this. See: http://www.fda.gov/cder/foi/nda/
2004/21-144--Ketek.htm. In these materials, we acknowledged the
problems with a large safety study, Study 3014, and confronted
challenges which arose as a result, in a way which, at the
time, seemed appropriate. Notwithstanding the fact that Study
3014 had to be disregarded, as explained below, the Agency
proceeded to approve Ketek because the product was otherwise
shown to be safe and effective.
Due to the emergence of antimicrobial resistance, it is
essential that we have access to a number of antibiotics to
treat microbial infections. If we were to rely on just a few
drugs, the development of resistance to those drugs could have
serious public health consequences. Antibiotic resistance has
been called one of the world's most pressing public health
problems.
Ketek is the first member of a new class of antibiotics
known as the ketolides, antibiotics which are closely related
to the macrolide class (e.g. azithromycin, clarithromycin and
erythromycin). Ketek has activity against bacteria that cause
upper and lower respiratory tract infections, including multi-
drug resistant Streptococcus pneumoniae. The company that
markets Ketek submitted its application for marketing approval
to FDA in the year 2000. FDA's counterpart in Europe, the
European Medicines Evaluation Agency, approved Ketek in July
2001 for use in the fifteen member countries. The drug was
first launched in October 2001 in Germany and in 2002 in other
European markets. By June 2003, Ketek was marketed in 36
countries around the world, including Canada and Japan. In the
United States, FDA approved Ketek on April 1, 2004, after
rigorous scientific evaluation but did not approve the product
for the full range of indications approved elsewhere.
Notwithstanding the great need for new antibiotics, and
contrary to some of the misimpressions that have circulated
publicly, FDA did not rush to approve Ketek. The Agency
approved Ketek after three cycles of rigorous scientific
review.
First Cycle. The sponsor submitted its Ketek new drug
application (NDA) on February 28, 2000, seeking approval for
four indications (community-acquired pneumonia, acute bacterial
sinusitis, acute bacterial exacerbation of chronic bronchitis,
and pharyngitis), including a claim for drug-resistant
Streptococcus pneumoniae. The Agency discussed the Ketek NDA at
an April 2001 Anti-infective Drugs Advisory Committee meeting,
and, except for the pharyngitis claim where substantial
evidence of efficacy was not demonstrated, the Committee
recommended that the clinical trials demonstrated similar
efficacy for Ketek and comparator antibiotics for the other
three claims. The April 2001 Advisory Committee recommended
approval for the indication of community acquired pneumonia. At
that time, safety concerns led Advisory Committee members and
the Agency to ask the sponsor for additional safety and
efficacy data for the claims for acute bacterial sinusitis and
acute bacterial exacerbation of chronic bronchitis. The safety
concerns included liver, heart, and visual side effects. The
Committee also recommended more studies to demonstrate efficacy
in patients with resistant Streptococcus pneumoniae, as well as
more safety data to characterize more fully the benefit/risk of
Ketek in the broad population. Nevertheless, rather than issue
an approval letter for this indication, the Agency issued an
approvable letter in June 2001, requesting more information.
Second Cycle. In late July 2002, the sponsor submitted
additional safety and efficacy studies. The submission included
multiple Phase I studies to address safety and pharmacokinetics
in various populations; three Phase III studies in patients
with community-acquired pneumonia and acute exacerbation of
chronic bronchitis; and the results from Study 3014, a large
controlled usual care trial in approximately 24,000 patients
with outpatient respiratory tract infections at approximately
1,800 sites. Study 3014 was designed to address the need for
additional safety information by examining potential toxicities
of Ketek with regard to liver, heart, and visual adverse
events. FDA scheduled a meeting of the Anti-Infective Drugs
Advisory Committee for January 8, 2003, to discuss these new
data, including Study 3014.
Shortly before this planned meeting, CDER's Division of
Anti-Infectives and Ophthalmology Products (the Division)
started to see preliminary results of inspections of clinical
investigation sites from Study 3014. This began with
information about the site with the highest enrollment that
raised substantial concerns about data coming from that site.
Shortly thereafter, results from investigations at other sites
also showed deficiencies, though not nearly as concerning as
those that had arisen in the first inspection. As this
information began to come to light, in accordance with normal
practice, the Division met with the sponsor. The sponsor
informed the Division that it was aware of some data
irregularities and concerns about processes at the first site
and assured FDA that there were no similar problems at any
other sites.
Please note that at the time of the January 8, 2003,
Advisory Committee, inspections had occurred at only three of
approximately 1800 sites, and the findings at that time were
quite preliminary. To avoid compromising any ongoing
investigation, it is Agency policy not to publicly disclose
even the existence of a pending investigation. Therefore, we
could not discuss the data integrity issues of Study 3014 at
the public Advisory Committee meeting. However, we also
believed, based on the best information available to us, that
the concerns applied to only one site out of more than 1800. It
is not unusual for data from some sites to be eliminated from a
study but to accept data from the other sites. At the time,
there was less information about the other sites under
investigation.
After considering the fact that the investigation results
were preliminary and we had not received formal recommendations
about how to take the results into account in review of the
application, and the fact that only in very rare cases do
inspection results from individual sites lead to the exclusion
of an entire large clinical trial, FDA decided to hold the
Advisory Committee meeting as planned. The Agency made this
decision, knowing that any advice from the Committee would have
to be later taken into account in the context of additional
information about the integrity of data from Study 3014. It is
not unusual for more information to come to FDA for review
after an Advisory Committee meeting is held about an
application. The Advisory Committee voted that the safety and
efficacy of the requested indications had been demonstrated,
based on the information it was provided, including Study 3014,
and limited international post-marketing data provided at the
meeting.
Although the Advisory Committee recommended approval, on
January 23, 2003, (two weeks after the Advisory Committee
meeting) FDA issued another approvable letter to the sponsor
because of the remaining questions about the safety of Ketek.
The letter specifically noted the unresolved data integrity
issues associated with Study 3014 (issues confirmed in the
final clinical inspection summary of the Agency's audits of the
first three clinical trial sites) and the incomplete post-
marketing safety data from foreign countries. FDA noted that
the final decision regarding approval of each indication would
be made after a review of the information and analyses
requested in this letter.
On March 3, 2003, during a closed session of the Advisory
Committee convened to discuss other matters, FDA briefly
explained that an approvable letter was issued because the
Agency wanted to see more information about data from Europe
and Latin America. With regard to Study 3014, FDA explained
that there were unresolved inspectional issues.
Third Cycle. The sponsor submitted a complete response to
the approvable letter in October 2003. The October 2003
submission addressed issues of Study 3014 and included post-
marketing reports for spontaneous adverse events for
approximately four million prescriptions for patients in other
countries where Ketek had already been approved. Upon
completing the review of the sponsor's October submission,
including the findings from the additional audits of clinical
trial sites summarized in a March 2004 memorandum from the
Division of Scientific Investigations, the Agency decided that
it could not rely on Study 3014 to support approval of Ketek
because of the systemic failure of the sponsor's monitoring of
the clinical trial to detect clearly existing data integrity
problems. Accordingly, Study 3014 was dropped for consideration
in making the decision whether to approve Ketek. The Agency
considered data from other clinical trials and the
international post-marketing experience to conclude there was
adequate evidence of safety.
FDA approved Ketek for three indications on April 1, 2004,
following a very thorough analysis of pre-clinical and clinical
safety data.
FDA's Medical Officer Safety Review dated March 31, 2004,
specifically reviews the post-marketing data from countries
where Ketek had already been approved, and data from a Phase
III visual adverse event re-analysis submitted on October 17,
2003. In addition, the reviewer evaluated data from Study 5001
(an intensive monitoring study conducted in Germany) and a
five-month safety update that provided post-marketing data from
August 2003-December 2003. The reviewer also referred to the
second cycle safety review which included data from eight
additional Phase I studies, three new Phase III studies, and
post-marketing data from approximately 1 million prescriptions
for telithromycin (the generic name for Ketek) in countries
where the drug had been approved.
The safety information evaluated in the March 31, 2004,
review included post-marketing safety reports generated from an
estimated 3.7 million uses in countries where the drug was
already approved. This post-marketing data was collected in 36
countries. The majority of prescriptions were dispensed in
France and Germany (2.2 out of 3.7 million). Other countries
with more than 100,000 prescriptions dispensed included Italy,
Spain and Mexico.
In addition to review of cumulative adverse events by organ
system, the safety reviewer conducted focused reviews of
deaths, serious adverse events, hepatic toxicity, cardiac
toxicity, visual toxicity, and use in Myasthenia Gravis,
including review of individual reports.
Even with its limitations, post-marketing adverse event
reporting has proven valuable in detecting rare adverse events
that are not seen in a clinical trial database. Limitations,
such as under-reporting, were taken into account in assessing
the data derived from these reports. Experience has shown that
the full magnitude of some potential risks do not always emerge
during the mandatory clinical trials conducted before approval
to evaluate these products for safety and effectiveness. An
example in this very case was the finding of exacerbations of
Myasthenia Gravis in the post-marketing reports from countries
outside the U.S. for Ketek. These reports led to the inclusion
of a statement in the warnings section of the Ketek product
label about exacerbations of Myasthenia Gravis at the time of
approval in the U.S.
FDA's belief that valuable information can be gained from
the marketing of a drug in countries outside the U.S. is
expressed in our drug regulations, which require an NDA
applicant to provide information of foreign marketing history
at the time of an NDA submission. We can provide the Committee
with numerous examples where post-marketing adverse event
reporting data has been used to inform FDA's approval and
labeling decisions (e.g. Tindamax (tinidazole), Zonegran
(zonisamide)). In most cases, post-marketing reports from other
countries have provided evidence of toxicities that have led to
either the non-approval of the drug by FDA (e.g. Thalomid
(thalidomide), Angex (lidoflazine) or to re-labeling to include
serious adverse events (e.g. Tasmar (tolcapone), Tamiflu
(oseltamivir).
Ongoing Postmarket Surveillance. As noted previously, the
full magnitude of some potential risks does not always emerge
during the mandatory clinical trials conducted before approval.
That is why Congress has supported, and FDA has created, a
strong post-market drug safety program designed to assess
adverse events identified after approval for all of the medical
products it regulates. This life-cycle approach is a complement
to the pre-market safety reviews required for approval of
prescription drugs. Monitoring the safety of marketed products
requires close collaboration between our clinical reviewers and
drug safety staff to evaluate and respond to adverse events
identified in ongoing clinical trials or in voluntary reports
submitted to us by health care providers and their patients, or
in mandatory reports submitted to us by manufacturers.
The evaluation of the safety of Ketek, as well as all FDA-
approved drugs, is an ongoing process. FDA continues to
evaluate spontaneous reports and consult with outside experts.
In March 2005, FDA began a comprehensive safety review of Ketek
to coincide with the completion of its first year of marketing.
Although one case of liver failure that resulted in death was
found, it was not clear that this represented a signal beyond
what had been seen in the data available at the time of
approval. A second annual review was planned for March 2006. In
January 2006, FDA was informed that a collection of three cases
of serious liver toxicity, including one death, were to be
reported in the Annals of Internal Medicine. Those cases had
previously been reported to FDA, although in less detail,
making conclusions about them difficult to reach until the
published information was available. With that information now
available, on January 20, 2006, FDA issued a Public Health
Advisory to advise the public about the cases and that the
Agency was conducting a comprehensive review of all cases of
liver toxicity reported for the drug.
That review was complex and included a review of additional
data requested from the sponsor about Ketek, liver toxicity of
similar drugs, assessments of drug utilization and more in-
depth review of the three cases reported in the Annals of
Internal Medicine, all of which had occurred in one region, an
unusual phenomenon. On June 29, 2006, FDA issued a press
release regarding completion of the safety review and to inform
the public that a new warning about liver toxicity was being
added to Ketek's label.
Most recently, in a December 14 and 15, 2006, joint meeting
of the Anti-Infective Drugs Advisory Committee and the Drug
Safety and Risk Management Advisory Committee, the joint panel
advised that the available data, including data acquired since
the initial approval of Ketek, support a conclusion that the
benefits of Ketek outweigh the risks in patients with community
acquired pneumonia, but not for patients with acute bacterial
sinusitis or acute bacterial exacerbation of chronic
bronchitis. They also recommended a boxed warning for the drug.
On February 12, 2007, FDA acted on the recommendations of
the joint panel and announced revisions to the labeling and
indications for Ketek designed to improve the safe use of Ketek
by patients. The changes include the removal of two of the
three previously approved indications--acute bacterial
sinusitis and acute bacterial exacerbations of chronic
bronchitis--from the drug's label. Based on the new evidence,
the Agency has determined that the balance of benefits and
risks no longer support approval of the drug for these
indications. At present, Ketek remains on the market for the
treatment of community acquired pneumonia of mild to moderate
severity (acquired outside of hospitals or long-term care
facilities).
In addition, the Agency has worked with Ketek's sponsor,
Sanofi Aventis, to update the product labeling with a "boxed
warning," FDA's strongest form of warning. The warning states
that Ketek is contraindicated (should not be used) in patients
with Myasthenia Gravis, a disease that causes muscle weakness.
FDA also worked with the manufacturer to develop a Patient
Medication Guide that informs patients about the risk of the
drug and how to use it safely. The Medication Guide (an FDA-
approved patient information sheet) will be provided to
patients with each prescription.
Other labeling changes included a strengthened warning
section regarding specific drug-related adverse events
including visual disturbances and loss of consciousness. As
noted previously, warnings for hepatic toxicity (rare but
severe symptoms of liver disease) were strengthened in June
2006.
This most recent action is the result of comprehensive
scientific analysis and thoughtful public discussion of the
data available for Ketek, and includes important changes in the
labeling designed to improve the safe use of Ketek by patients
and give health care providers the most up-to-date prescribing
information.The Ketek approval and post-approval process
conformed to the high standard the American public has come to
expect from FDA. Furthermore, we believe that the data
integrity issues in connection with Study 3014 uncovered by FDA
staff are a testament to our staff's unrelenting dedication and
commitment to the processes we have in place to help ensure the
safety of our drug supply. We always welcome suggestions on how
to improve these processes.
Conclusion
At FDA, providing the American public with safe and
effective medical products is our core mission. We base
decisions to approve a drug, or to keep it on the market if new
safety findings surface, on a careful balancing of risk and
benefit to patients. This is a multifaceted and complex
decision process, involving scientific and public health
issues. The recent initiatives we have announced will improve
our current system to assess drug safety. Moreover, we will
continue to evaluate new approaches to advance drug safety. As
always, we value input from Congress, patients and the medical
community as we develop and refine these drug safety
initiatives.
Let me assure you, Mr. Chairman, that I am deeply committed
to ensuring the safety of drugs and other medical products
regulated by FDA. Once again, thank you for the opportunity to
testify before the Committee today. I am happy to respond to
questions.
----------
[GRAPHIC] [TIFF OMITTED] T5502.099
[GRAPHIC] [TIFF OMITTED] T5502.100
[GRAPHIC] [TIFF OMITTED] T5502.101
[GRAPHIC] [TIFF OMITTED] T5502.102
[GRAPHIC] [TIFF OMITTED] T5502.103
[GRAPHIC] [TIFF OMITTED] T5502.104
[GRAPHIC] [TIFF OMITTED] T5502.105
[GRAPHIC] [TIFF OMITTED] T5502.106
[GRAPHIC] [TIFF OMITTED] T5502.107
[GRAPHIC] [TIFF OMITTED] T5502.108
[GRAPHIC] [TIFF OMITTED] T5502.109
[GRAPHIC] [TIFF OMITTED] T5502.110
[GRAPHIC] [TIFF OMITTED] T5502.111
[GRAPHIC] [TIFF OMITTED] T5502.112
[GRAPHIC] [TIFF OMITTED] T5502.113
[GRAPHIC] [TIFF OMITTED] T5502.114
[GRAPHIC] [TIFF OMITTED] T5502.115
[GRAPHIC] [TIFF OMITTED] T5502.116
[GRAPHIC] [TIFF OMITTED] T5502.117
[GRAPHIC] [TIFF OMITTED] T5502.118
[GRAPHIC] [TIFF OMITTED] T5502.119
[GRAPHIC] [TIFF OMITTED] T5502.120
[GRAPHIC] [TIFF OMITTED] T5502.121
[GRAPHIC] [TIFF OMITTED] T5502.122
[GRAPHIC] [TIFF OMITTED] T5502.123
[GRAPHIC] [TIFF OMITTED] T5502.124
[GRAPHIC] [TIFF OMITTED] T5502.125
[GRAPHIC] [TIFF OMITTED] T5502.126
[GRAPHIC] [TIFF OMITTED] T5502.127
[GRAPHIC] [TIFF OMITTED] T5502.128
[GRAPHIC] [TIFF OMITTED] T5502.129
[GRAPHIC] [TIFF OMITTED] T5502.130
[GRAPHIC] [TIFF OMITTED] T5502.131
[GRAPHIC] [TIFF OMITTED] T5502.132
[GRAPHIC] [TIFF OMITTED] T5502.133
[GRAPHIC] [TIFF OMITTED] T5502.134
[GRAPHIC] [TIFF OMITTED] T5502.135
[GRAPHIC] [TIFF OMITTED] T5502.136
[GRAPHIC] [TIFF OMITTED] T5502.137
[GRAPHIC] [TIFF OMITTED] T5502.138
[GRAPHIC] [TIFF OMITTED] T5502.139
[GRAPHIC] [TIFF OMITTED] T5502.140
[GRAPHIC] [TIFF OMITTED] T5502.141
[GRAPHIC] [TIFF OMITTED] T5502.142
[GRAPHIC] [TIFF OMITTED] T5502.143
[GRAPHIC] [TIFF OMITTED] T5502.144
[GRAPHIC] [TIFF OMITTED] T5502.145
[GRAPHIC] [TIFF OMITTED] T5502.146
[GRAPHIC] [TIFF OMITTED] T5502.147
[GRAPHIC] [TIFF OMITTED] T5502.148
[GRAPHIC] [TIFF OMITTED] T5502.149