[House Hearing, 110 Congress]
[From the U.S. Government Printing Office]

                          THE ADEQUACY OF FDA
                       TO ASSURE THE SAFETY OF THE
                          NATION'S DRUG SUPPLY



                               BEFORE THE


                                 OF THE

                        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


35-502                      WASHINGTON : 2007
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                  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
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


                             C O N T E N T S


                           FEBRUARY 13, 2007

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


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


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



                       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].


    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 
    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 
    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 
    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.


    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 
    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 
    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 
    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 
    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.


    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 
    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.


    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 
    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.


    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 
    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 
    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.


    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 
     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.


    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 
    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 
    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.


    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 
    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 
    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 


    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 
    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.


    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 
    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 
    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 
    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.


    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
     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.


    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 
    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 
    [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.


    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.


    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 
    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 
    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 

     Let me say the relevant clause again.

    They did not completely ignore the data from the 3014 

    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 
    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 
    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 
    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 
    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 
     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 
    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 
    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, 
    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 
    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 
    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 
    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 
    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 
    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 
    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.
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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. 
    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 

    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 
    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. 
    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.


    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 
    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.


    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 
    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 
     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 
    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 
    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 
    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 
    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 
    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 
     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 
    Ms. DeGette. And in fact, they do that in Europe, as I 
    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. 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 

                     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 

     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 

     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 

     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 

     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 
     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 
     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 
      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'' 
      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 
     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 

    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 
      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 
      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 
    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 
     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 
     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 
     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 
     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 
     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 
     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 
     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 
     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 


     (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-
     (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.































































         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 
    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 

     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 

     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 

     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 

     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 

     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 

     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 

     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 

     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 
    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 
    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 
    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 william.lee@utsouthwestern.edu.





































                        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 
    Staff present: David Nelson, Joanne Royce, Kyle Chapman, 
Scott Schloegel, John Sopko, Alan Slobodin, Karen Christian, 
Krista Carpenter, John Halliwell, and Matt Johnson.


    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 
    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 
    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.


    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 
    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. 


    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 
    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 
    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 
    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 
    Mr. Stupak. Thank you, Mr. Chairman. Next turn to the 
ranking member of the full committee, Mr. Barton from Texas.
    Mr. Barton, sir.


    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 
    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 
    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 
    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.


    Mr. Waxman. Thank you very much, Mr. Chairman. Dr. von 
Eschenbach, welcome to the committee. I am pleased that you are 
    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 
    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 
    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.


    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.


    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 
    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.


    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.


    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 
    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 
    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.


    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 
    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 
    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.


    Mr. Ferguson. I am kind of in no man's land here between 
    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 
    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 
     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.


    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 
    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 
    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, 


    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 
    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 
    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 
    So I want to thank the Secretary for his help and 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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. 
    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 
    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 
    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. 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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.
    Mr. Stupak. Mr. Commissioner, thank you again for appearing 
    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, 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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.


    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 
    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.


    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 
    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 
    First, the Agency's apparent unwillingness to ask Congress 
for more authority to enforce drug safety regulations is 
    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 
    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.


    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 
    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 
    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 
    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.


    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, 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    Mr. Whitfield. Right.
    Dr. Psaty. And with the speedup of the drug approval 
    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 
    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 
    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 
    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 
     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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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.


    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 
    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 
    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 
    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 
    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 
    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 
    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 
    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.


    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 
    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